>>WELCOME TO THE
8th ANNUAL BRAIN INITIATIVE
MEETING SCIENCE AND TOOLS.
WE FIND OURSELVES IN THIS
VIRTUAL ENVIRONMENT.
SORRY, WE COULD NOT MANAGE THE
IN-PERSON COMPONENT OF WHAT WAS
SUPPOSED TO BE THE MEETING.
WHILE THERE'S DISAPPOINTMENT TO
NOT HANG OUT TOGETHER THERE'S
OPPORTUNITIES FOR DIGITAL
CONNECTIONS AND ENGAGEMENTS AND
LOTS OF GREAT DISCUSSION.
AT THE NATIONAL INSTITUTES OF
HEALTH BRAIN INSTITUTE HAS
SUPPORTED RESEARCH TO BUILD AND
LEVERAGE NEW TECHNOLOGIES
REVOLUTIONIZING THE DEVELOPMENT
OF THE BRAIN AND BY THEATION
THE INNOVATION OF THE
TECHNOLOGIES THEY FOR THE FIRST
TIME SHOWS HOW INDIVIDUAL CELLS
AND COMPLEX CIRCUITS INTERACT IN
SPACE AND TIME.
THE BRAIN INITIATIVE WAS
LAUNCHED IN 2014 WITH THE FIRST
AWARD SINCE THEN THE NIH HAS
INVESTED OVER $2.4 BILLION WITH
A "B", DOLLARS IN THE BRAIN
INITIATIVE SUPPORTING OVER 1200
AWARDS TO DATE.
THE ANNUAL BRAIN INITIATIVE
MEETING CONVENES STAFF AND
LEADERSHIP AND AWARDEES IN THE
CONTRIBUTING AGENCIES AND NSF,
DARPA AND THE NIA AND MEMBERS OF
THE MEDIA, PUBLIC AND MEMBERS OF
CONGRESS.
THE PURPOSE OF THIS OPEN MEETING
IS TO CONTINUE TO BUILD THE
BRAIN COMMUNITY SUCH AS IT IS IN
THE VIRTUAL ENVIRONMENT BUT WE
PROVIDE A FORUM FOR DISCUSSING
EXCITING NEW SCIENTIFIC
DEVELOPMENTS AND POTENTIAL NEW
DIRECTIONS AND TO IDENTIFY AREAS
OF COLLABORATION AND RESEARCH
COORDINATION.
SO WE'RE LOOKING FORWARD TO THE
NEXT FEW DAYS TOGETHER.
PLEASE ENJOY IT.
THERE'S TONS OF CONTENT HERE AND
LOTS OF GREAT TALKS.
TO KICK IT OFF A TERRIFIC TALK
BY OUR FIRST PLENARY SPEAKER
DR. BAUTISTA THE MEMORIAL CHAIR
AND CLASS OF DEVELOPMENTAL
BIOLOGY AND NEUROBIOLOGY IN THE
SCIENCE INSTITUTE AT THE
UNIVERSITY OF CALIFORNIA
BERKELEY.
SHE RECEIVED HER BACHELOR'S
DEGREE IN CHEMISTRY FROM THE
UNIVERSITY OF OREGON AND LOOKED
AT MEMBRANE CALCIUM.
SHE THEN PURSUED A POST-DOCTORAL
FELLOWSHIP IN CALIFORNIA STATE
SAN FRANCISCO AND CONDUCTED
SEMINOLE INVESTIGATIONS OF THE
INTERACTION OF VARIOUS CHEMICAL
QUEUES WHERE THE NERVOUS SYSTEM
LOOKING AT CHEMICAL IRRITANTS
WITH A TRIP A1 CHANNEL AND FOUND
MENTHOL GIVES US THE SENSE OF
COOL ACTIVATED THE TRIP M8
CHANNEL AND LITERALLY COOL
RESULT SHE FOUND THE ACTIVE
INGREDIENT IN CITRON PEPPER CORN
WHICH GIVES A NUMBING IN CERTAIN
CHINESE DISHES INHIBITS SPECIFIC
POTASSIUM CHANNELS.
SO WHEN I GO TO A CHINESE
RESTAURANT OR IRRITATED BY
SOMETHING CHEMICAL I ALWAYS
THINK OF DIANA.
HER CURRENT RESEARCH HAS BEEN
RECOGNIZED BY NUMEROUS AWARDS
BASED ON HER CURRENT AND RECENT
RESEARCH ON THE CELLULAR
MECHANISMS OF ITCH, TOUCH AND
PAIN UNDER NORMAL AND DISEASE
CONDITIONS AMONG HER MANY AWARDS
ARE THE SOCIETY FOR YOUNG
INVESTIGATORS AWARD AND THE 2019
NIH DIRECTOR'S TRANSFORMATIVE
AWARD AND IN 2021 SELECTED AS A
HOWARD HUGHES MEDICAL
INVESTIGATOR.
HER CURRENT RESEARCH IS FOCUSSED
ON MECHANISMS OF ITCH, TOUCH AND
PAIN AND IS CURRENTLY FOCUSSING
ON THE NEURO IMMUNE INTERACTIONS
OF ITCH AND AIRWAY INFLAMMATION.
IN HER TALK ENTITLED PERIPHERAL
NEUROIMMUNE ACTIONS DRIVE ITCH
AND INFLAMMATION SHE'LL EXPLORE
A TOPIC DERMATITIS AN ITCH
DISORDER THAT AFFECTS 15% OF
CHILDREN WORLDWIDE HALF OF WHOM
GO ON TO DEVELOP ALLERGIES AND
ASTHMA AND NEURONS AND IMMUNE
CELLS IS A HALLMARK OF THIS AND
THE TALK WILL HIGHLIGHT HER
EFFORTS TO DECIPHER THE IMMUNE
INTERACTIONS DRIVING THE IMMUNAL
HYPEREXCITABILITY IN ITCH AND A
TOPIC DISEASE.
AS A HOUSEKEEPING NOTES YOU CAN
SUBMIT QUESTIONS IN THE Q&A BOX
TO DR. BAUTISTA AND WE LOOK
FORWARD TO A GREAT DISCUSSION
AND JOIN ME IN WELCOMING
DR. DIANA BAUTISTA.
ALL YOURS.
>> TODAY I'LL TELL YOU ABOUT OUR
RECENT EFFORTS TO START TO
DECIPHER THE NEURO IMMUNE
INTERACTIONS UNDERLYING CHRONIC
ITCH AND INFLAMMATION AND WALK
YOU THROUGH THE BIG QUESTIONS IN
THE FIELD AND GIVE AN
INTRODUCTION TO HOW WE APPROACH
THESE PROBLEMS AND END WITH SOME
UNPUBLISHED DATA LOOKING AT THE
PERIPHERAL AND CENTRAL NERVOUS
SYSTEM TO UNDERSTAND HOW CHANGES
ARE OCCURRING ACROSS THE NERVOUS
SYSTEM IN THE INFLAMMATORY
DISORDERS.
ALL OF YOU HAVE PROBABLY
EXPERIENCED AN ALLERGIC RASH OR
BRUSH WITH POISON OAK OR PERHAPS
THAT ITCHY MOSQUITO BITE THAT
MADE YOU ITCH AND TOOK PLEASURE
IN WAYSO SCRATCH THAT ITCH.
ALL THESE EXAMPLES I MENTIONED
ARE EXAMPLES OF ACUTE ITCH WHICH
IS DEFINED AS AN IRRITATING
SENSATION THAT CAUSES A DESIRE
TO SCRATCH.
OUR SENSE OF ITCH IS HIGHLY
CONSERVED AND LIKE ACUTE PAIN
IT'S THOUGHT TO BE PROTECTIVE.
THE ACT OF SCRATCHING NOT ONLY
REMOVES THAT MOSQUITO OR WORM
THAT BURROWED INTO YOUR SKIN OR
OTHER PATHOGENS BUT ACTIVATED
NEURONS THAT RELEASE MEDIATORS
THE PROMOTE THE DIRECTED INFLUX
OF IMMUNE CELLS INTO THE SKIN TO
INCLUDE PROTECTIVE CELLS AND
PROMOTE HYPERSENSITIVITY THAT
TRIGGERS BEHAVIORS.
THAT ITCHY SENSATION HELPS YOU
REMEMBER NEXT TIME TO PUT ON
DEET, PUT ON A JACKET TO MAKE
SURE YOU DON'T GET THOSE BITES.
NOW, IT'S NOT JUST HUMANS AND
HAIRY ANIMALS THAT SCRATCH.
IT'S HIGHLY CONSERVED AMONG THE
ANIMAL KINGDOM AND THOUGH FISH
CAN'T SCRATCH THEMSELVES THEY
CAN RUB UP AGAINST CORAL TO
REMOVE PATHOGENS IN THECATION OF
THIS EEL YOU SEE THEY VISIT
CLEANING STATION WHERE'S OTHER
SMALL FISHES COME IN AND SURVIVE
BY REMOVING POTENTIALLY HARMFUL
PATHOGENS AND EAT THEM AND THEN
THERE'S A REALLY ROBUST SYSTEM
SO THAT CERTAIN MARINE ORGANISMS
INCLUDING EELS KNOW WHEN TO
VISIT THE CLEANING STATION AND
WHEN TO LEAVE THAT CLEANING
STATION SO THERE'S NOT FURTHER
TISSUE DAMAGE.
EVEN DROSOPHILA YOU CAN SEE YOU
CAN SEE IT KICK THE MITE OUT TO
PREVENT INFECTION.
SO FAR I'M TALKING ABOUT ACUTE
ITCH BUT THERE'S OTHER
DEBILITATING CONDITIONS WITH NO
CURE OR EFFECTIVE TREATMENTS.
SO 1 IN 10 PEOPLE WILL SUFFER
FROM CHRONIC ITCH IN THEIR LIFE
AND THERE'S A TOPIC DERMATITIS
WHICH I'LL FOCUS THE REST OF MY
TALK ON TODAY BUT CHRONIC ITCH
IS ASSOCIATED WITH A VARIETY OF
SYSTEMIC CONDITIONS INCLUDING
KIDNEY FAILURE AND SOME FORMS OF
DIABETES ARE ASSOCIATED WITH
CHRONIC ITCH AND CANCERS LIKE
LYMPHOMA HAVE CHRONIC ITCH AS A
SIDE EFFECT AND OFTEN IN THE
CASE OF LYMPHOMA IT'S THE ITCHY
SENSATION THAT PEOPLE GET THAT
FIRST CAUSES THEM TO GO TO THE
DOCTOR.
IT'S AN ALERT SYSTEM TELLING
THEM SOMETHING'S WRONG.
A VARIETY OF INFECTIOUS DISEASES
CAUSE CHRONIC ITCH AND THERE'S A
GROWING LIST OF DRUGS WITH
CHRONIC ITCH AS A SIDE EFFECT.
THERE'S PSYCHOLOGICAL FACTORS
THAT CAN CONTRIBUTE TO ITCH LIKE
YAWNING, SEEING SOMEONE ITCH IS
A TRIGGER TO FEEL ITCHY AND
START SCRATCHING AND PSYCHO
PHYSIO STUDIES HAVE SHOWN 70% OF
PEOPLE WHO SEE SOMEONE ELSE ITCH
OR THE PHOTO OF SOMEONE
SCRATCHING THEMSELVES WILL ALSO
FEEL ITCHY AND SCRATCH WITHIN A
FEW MINUTES.
AND I THINK THE DEBILITATING
URGE TO SCRATCH THE ITCH IS FROM
AN ARTICLE MORE THAN A DECADE
AGO FOR A PATIENT WHO HAD
SHINGLES AND ANTIHISTAMINES,
NOTHING WOULD RELIEVE THE ITCH
AND THOUGH SHE TRIED TO PROTECT
HERSELF BY WEARING MITTENS,
SLEEPING WITH A HAT ON, EVEN
TYING HER HANDS SHE COULDN'T
RESIST THE URGE TO SCRATCH AND
ACTUALLY SCRATCHED AND EXPOSED
HER FRAME.
THOUGH IS AN EXTREME CASE, IT
ILLUSTRATES THE DEBILITATINING
NATURE OF CHRONIC ITCH AND WHY
PEOPLE WHO SUFFER FROM CHRONIC
ITCH HAVE A DECREASED QUALITY OF
LIFE ON PAR WITH WORSE CHRONIC
PAIN CONDITIONS AND THERE'S FEW
EFFECTIVE TREATMENTS.
ANTIHISTAMINES ARE COMPLETELY
INEFFECTIVE IN TREATING CHRONIC
ITCH AND CORTICOSTEROIDS WHILE
THEY MAY HELP AT FIRST ACTUALLY
MAKE CHRONIC ITCH WORSE WITH
PROLONGED USE SO THERE'S
INTEREST IN UNDERSTANDING THE
MECHANISMS THAT DRIVE CHRONIC
ITCH DISORDERS.
SO MY LAB STUDIES THE SOMATO
SENSORY SYSTEM THAT CONSISTS OF
OVER 30 DIFFERENT SUBTYPES OF
SENSORY NEURONS, PRIMARY AFERONS
LABELLED IN GREEN IN THIS
BEAUTIFUL IN SITU OF THE MIGHT
AND THE GREEN HUMAN SCHEMATIC
AND THESE SHOW TOUCH,
TEMPERATURE, PRESSURE, CHEMICALS
IN THE ENVIRONMENT THAT CAN
CAUSE HARM AS WELL AS CHEMICALS
IN THE BODY.
MY LAB USES MOUSE AS A MODEL
SYSTEM AND WHEN AVAILABLE FROM
DONORS WE ALSO LOOK AT PRIMARY
HUMAN CELLS INCLUDING IMMUNE
CELLS, SKIN CELLS AND ALSO
PRIMARY SENSORY NEURONS FOR OUR
STUDIES.
ABOUT 10% OF SOMATO SENSORY
NEURONS ARE THOUGHT TO BE
DEDICATED TO TRANSMISSION OF H
SIGNALS.
THESE H NEURONS AFFECT THE
EPIDERMIS SHOWN IN THE CROSS
SECTION OF HUMAN SKIN AND THE
PRIMARY AFFERENTS HAVE LARGE
RESPECTIVE FEEL AND THIS IS
WHERE THE DETECTION OF ITCHY
STIMULI ARE FIRST DETECTED AND
TRANSDUCED.
THE SIGNALS ARE TRANSMITTED TO
THE SPINAL CORD ARE WHERE
THERE'S MODULATION AND THEY'RE
TRANSMITTED TO HIGHER LEVELS IN
THE BRAIN GOING THROUGH THE
THALAMUS, THE NUCLEI AND CAUSE
THE SENSATION OF ITCH WHY CAN BE
ALL CONSUMING.
SO THE BIG PUSH WE'VE BEEN
TRYING TO TACKLE INCLUDE TRYING
TO UNDERSTAND HOW PERITOGENS
AFFECT THE SIGNALS AND WE WANT
TO TEST.
TEST.
THAT IMMEDIATE THE RESPONSES TO
INFLAMMATORY PROTEASES AND
CHRONIC ITCH IN THE SKIN AND
WE'RE SEEING THE PHOSPHATE AND
CYTOKINES LINKED TO CHRONIC ITCH
AND CHRONIC PAIN INCLUDING PSLP
AND THE INFLAMMATORY CYTOKINE
RELATED TO ECZEMA AS WELL AS
ASTHMA.
WE WANT TO TAKE AN UNBIASSED
APPROACH AND DECIPHER IING AND
LOOK AT HOW THEY CAN DRIVE
CHRONIC ITCH DISORDERS AND WE
DECIDED TO TACKLE OUR
UNDERSTANDING OF A TOPIC
DERMATITIS BECAUSE THE MOST
COMMON TIME.
PEOPLE WITH ECZEMA SUFFER FROM
RED, ITCHY SCALY REGIONS ON
THEIR HEAD AND NECK AND LEGS AND
ARMS AND 10% OF ADULTS WORLDWIDE
AND 15% OF CHILDREN SUFFER FROM
ECZEMA.
AND TO THE IT DECREASES IN AGE,
TOPIC DISEASES INCLUDING FOOD
ALLERGIES, ALLERGIC RHINITIS AND
A SEVERE FORM OF ASTHMA HAVE
THAT'S VERY DIFFICULT TO TREAT.
THIS PROCESS IS CALLED THE A
TOPIC MARCH BECAUSE THERE'S A
WAVE OF INFLAMMATION THAT GOES
FROM THE SKIN TO THE AIRWAYS AND
IN SOME PEOPLE EVEN THE GUT.
BECAUSE ACUTE HALLMARK IS
DERMATITIS IT WAS THOUGHT TO BE
A DISEASE OF THE SKIN AND WE
DIDN'T HAVE A SOLID
UNDERSTANDING HOW THE NERVOUS
SYSTEM FIT INTO A TOPIC
DISEASES.
THAT'S SOMETHING WE WANTED TO
ADDRESS.
WE KNOW A VARIETY OF IMMUNE
CELLS ARE PRESENT IN ITCHY
LEGIONS INCLUDING TYPE 2 CELLS
AND T CELLS AND BASOPHILS AND WE
KNOW SENSORY NEURONS CAN
CONTRIBUTE ACTIVELY TO
INFLAMMATION IN THE CONTEXT OF
CHRONIC PAIN AND WANTED TO ASK
IF THE NEURON NOT SIMPLY PASSIVE
PLAYERS IN A TOPIC DISEASES
TRIGGERING ITCH REFLEXES BUT
WHETHER THEY MAY BE PLAYING AN
ACTIVE ROLE IN PROMOTING CHANGES
IN THE SKIN AND DRIVING
INFLAMMATION AND REPRESENTING A
NEW TARGET FOR THESE A TOPIC
DISEASES.
NOTHING UNUSUAL INDICATIVE THEY
DON'T REALLY MIND THIS VEHICLE
TREATMENT IN CONTRAST IF YOU
INJECT AN ITCH COMPOUND OR TREAT
TOPICALLY WITH S3NO3 IN THIS
CASE WE FIND THE MICE WILL
DISPLAY A DIFFERENT BEHAVIOR
WHICH IS SCRATCHING WITH A HIND
PAW AND THIS IS QUITE DISTINCT
FROM PAIN WHERE IF YOU TREAT
WITH CAPSAICIN THE MOUSE WILL
HAVE A VERY LOCALIZED RUBBING
BEHAVIOR WITH ONE LIMB AND USING
THE CHEEM.
HERE YOU CAN SEE QUANTIFICATION
OF MUCHING OVER SCRATCHING OVER
SEVEN DAYS OF TREATMENT YOU GET
AN INCREASE IN SCRATCHING
BEHAVIORS THAT PERSIST UP TO
THREE WEEKS POST TREATMENT AND
IT SHOWS IT'S A GREAT MODEL FOR
STUDYING DISEASE MECHANISMS WE
CAN STUDY WHICH TRYINGERS THE
DEVELOPMENT OF ITCH AND LOOK AT
ACUTE TO CHRONIC PERSISTENT ITCH
POST TREATMENT AND WE'VE
IDENTIFIED A SLEW OF MECHANISMS
THAT DRIVE THIS DISORDER.
AND LOOKING AT THE A TOPIC
MARCH, WHAT WE DECIDED TO DO WAS
TO TAKE A SYSTEM'S PHYSIOLOGY
APPROACH BY LOOKING ACROSS TIME
AND LOOKING ACROSS TISSUES THAT
ARE IMPACTED IN A TOPIC
DERMATITIS IN THE A TOPIC MARCH
AND TWO STAFF LOOKED AT THE
MODEL IN QUANTIFYING THE ITCH
BEHAVIORS AND DISSECTED THE SKIN
AND BASAL GANGLIA AND LUNG AND
BRAIN AND LOOKED FOR
INFLAMMATORY MEDIATORS,
HISTOLOGY AS WELL AS SORTING
IMMUNE CELLS.
I'LL TELL YOU FIRST ABOUT WHAT
WE FOUND IN THE SKIN BECAUSE WE
CHARACTERIZED THE MOST AND IT'S
A PROJECT STILL ONGOING.
THE FIRST THING WE DID WAS TO
LOOK AT GREEN EXPRESSION IN THE
MODEL ACROSS ECZEMA DEVELOPMENT
OVER EIGHT DAYS.
WHAT WE FOUND REMARKABLY WAS IN
LOOKING AT HUMAN DISEASE GENES
LINKED TO A TOPIC DERMATITIS THE
MODEL SHOWED ABOUT 70% OF THE
GENES LINKED TO HUMAN A TOPIC
DERMATITIS WERE DISREGULATED
ACROSS THE FIRST EIGHT DAYS OF
THE MODEL AND WE WERE ABLE TO
LOOK AT THE TEMPO KINETICS OF
ALL THE DISEASE GENES WHICH GAVE
US SOME HINT ABOUT HOW THEY MAY
BE CONTRIBUTING TO HUMAN ECZEMA.
LOOKING ACROSS THE LITERATURE
ACROSS ALL HUMAN CHRONIC ITCH
DISORDERS WE FOUND IN THE MODEL
ABOUT 60% OF HUMAN DISEASE GENES
WERE FOUND TO BE DISREGULATED AS
WELL.
WHEN WE DID GENE ONTOLOGY
ANALYSIS WE FOUND THAT THESE
CATEGORIES INCLUDED EXCITABILITY
AND A VARIETY OF OTHER GENES
INCLUDING GENES LINKED TO
INFLAMMATION AND GUIDANCE AND
IMMUNE CELLS AND SKIN BARRIER
FUNCTION.
WHAT I'LL DO IS GO THROUGH SOME
OF THESE KEY FINDINGS.
SURPRISINGLY WE SAW A VARIETY
OF PROTEASES THAT AGAIN ARE
CORRELATED WITH DISEASE
SEVERITY.
WHAT WE WANTED TO DO WAS TO TEST
FUNCTION
FUNCTIONALLY WHAT THEY MAY BE
DOING IN TERMS OF DISEASE
GENESIS.
WE TURNED TO FUNCTIONAL STUDIES
USING PRIMARY AND MOUSE AND
THERE WAS CALCIUM SIGNALLING AND
OSCILLATIONS BY ACTING ON THE
PROTEASE ACTIVE RECEPTOR 2
HIGHLY UP REGULATED IN HUMAN
DERMATITIS LESIONS AND LOOKED AT
THE PATHWAY AND THIS TRIGGERS
NFAT DEPENDENT GENE
TRANSCRIPTION OF A VARIETY OF
CYTOKINES INCLUDING TSLP.
WHILE THAT WAS WELL KNOWN TO
ACTIVATE IMMUNE CELLS AND
TRIGGER INFLAMMATION IT TRIGGERS
TSLP RELEASE TO ACTIVATE NOT
ONLY
AND HAD POTENTIAL FIRING TO
DRIVE PERSISTENT ITCH IN THE
ABSENCE OF FURTHER STIMULATION.
BY DAY TWO OF THE MODEL WE FOUND
THE SKIN EXPRESSED A VARIETY.
SUGGESTING THAT WHILE THE CELLS
AND CHEMO KINES ARE PLAYING A
KEY ROLE.
THEY WEREN'T REQUIRED DURING THE
INITIAL DEVELOPMENT OF
INFLAMMATION AND ITCH IN THIS
MODEL.
BY DAY 8 OF THE MODEL IN
ADDITION TO THE IMMUNE CELL
CHANGES WE SAW A NUMBER OF
CHANGES IN GENE EXPRESSION OF
RECEPTORS THAT ARE THOUGHT TO BE
NEURONALAL INCLUDING TO THE
RECEPTOR IL31 AND DRIVE NEURON
DEPENDENT INCHING AND SCRATCHING
BEHAVIORS.
SO WITH WE WANTED TO TEST THE
REQUIREMENT OF SENSORY NEURONS
AND THE DEVELOPMENT OF ITCH AND
TO TEST THIS WE USED A VARIETY
OF APPROACHES INCLUDING LKING
AT MOUSE MUTANT AND WHILE WILD
TYPE LITTER MATES EXPRESSED
ITCHING WHEN WE LOOKED AT THE
DEFICIENT ANIMALS WE DID NOT SEE
THE SCRATCHING SUGGESTING TRIP
A1 SENSORY NEURON REQUIRED FOR
THE DEVELOPMENT OF ITCH
BEHAVIORS.
WE ALSO FOUND TRIP A1 WAS
REQUIRED MUCH TO OUR SURPRISE
FOR THE DEVELOPMENT OF THESE
EARLY LESIONS THAT PROCEED ITCH
ABOVE SCRATCHING SUGGESTING THE
SENSORY NEURONS AND TRIP A1
CHANNELS ARE NOT JUST PASSIVE
PLAYERS IN PROMOTING SCRATCH
REFLEXES BUT RATHER PLAY AN
ACTIVE ROLE IN EARLY CHANGES AND
INFLAMMATION IN THE SKIN.
NOW, WE ALSO WANTED TO TAKE A
LOOK AT THE ROLE OF THE SENSORY
NEURONS AND WHAT ROLE THE
NEUTROPHILS MAY BE PLAYING IN
DRIVING A TOPIC DERMATITIS
DISEASE AND DRIVING SIGNA TO
THE INFORMATION SYSTEM.
WHAT WE DID WAS USE AN ANTI-GR1
ANTIBODY TO ALLOW TO US DEPLETE
CIRCULATING AND INTRUDING
NEUTROPHILS AND THE TREATMENT
SIGNIFICANTLY ATTENUATES THE
NUMBER OF INFILTRATING
NEUTROPHILS CAPABLE OF ENTERING
INFLAMED TREATED SKIN.
AND WHEN WE LOOKED ABOVE SCRATCH
MODEL WE FOUND DEPLETION OF
NEUTROPHILS SIGNIFICANTLY
ATTENUATED ITCH ABOVE SCRATCHING
ACROSS ALL DAYS OF THE MODEL
TELLING US THE NEUTROPHILS AND
THE SENSORY NEURONS ARE KEY
DRIVERS OF A TOPIC ITCH.
WE WANTED TO NEXT ASK WHAT THE
SIGNALLING PATHWAYS BETWEEN
NEUTROPHILS AND NEURON AND THE
RECEPTORS AND SIGNALLING
PATHWAYS AND CYTOKINES THAT
ALLOW THE COMMUNICATION BETWEEN
THE TWO DIFFERENT CELL TYPES.
SO TO TEST THIS WE FIRST USED
RNA SEQ TO LOOK AT WHAT CHANGES
ARE OCCURRING IN GENE IN THE
DORSAL ROOT GANGLIA ITSELF AND
I'LL SHOW YOU SOME DATA.
BEF BEF
WE FOUND THE TREATMENT TRIGGERED
GENE EXPRESSION CHANGES IN ABOUT
70 GENES AND SENSORY GANGLIA AND
THEY FELL INTO FOUR CATEGORIES.
EXCITABILITY, IMMUNE, NEURAL
INFLAMMATION AND INTERESTINGLY
WE SAW AN INTERESTING SUB
POPULATION OF IMMEDIATE EARLY
GENES PREVIOUSLY LINKED TO
NEUROPATHIC PAIN AND WE'RE
INTERESTED IN CHARACTERIZING THE
ROLES OF THESE GENES.
WE SAW MPPB THOUGHT TO BE AN
ITCH TRANSMITTER AND THE TRIP A1
CHANNEL AND CYSLTR2.
ON THE DAY TWO WE SAW IMMUNE
SPECIFIC GENES AND SAW A
SIGNIFICANT INCREASE IN CD45
POSITIVE IMMUNE CELLS IN THE
SENSORY GANGLIA ITSELF
SUGGESTING THAT INFLAMMATION IS
IN THE GANGLIA AND THAT'S SHOWN
IN THE QUANTIFICATION.
YOU CAN SEE THE CD45 POSITIVE
CELLS LABELLED AND THE THOSE
LABELLED HERE.
FURTHER ANALYSIS SHOWED THERE
WAS A SIGNIFICANT INCREASE IN
CD8 POSITIVE T CELLS AS WELL AS
B CELLS INFILTRATING THE SENSORY
GANGLIA AND SAW DECREASE IN
DENDRITIC CELLS SUGGESTING SOME
RESIDENT CELLS MAY BE
TRAFFICKING TOWARDS LYMPH NODE
TO TRY TO PRIME AN INFLAMMATORY
RESPONSE.
AND INTERESTINGLY WHEN WE LOOKED
AT THE SAME CHANGES IN THE
NEUTROPHIL DEPLETED ANIMALS WE
FOUND THE PERIPHERAL NEUTROPHIL
INTERACTIONS REALLY DRIVE ITCH
AND INFLAMMATION ACROSS THE SKIN
AND NERVOUS SYSTEM.
SO WE SAW SIGNIFICANT DECREASES
IN THESE UPREGULATED GENES
INCLUDING THE IMMEDIATE EARLY
GENES ALL THE RECEPTORS AND
EXCITABILITY GENES.
WE JUST DIDN'T SEE BROAD GENE
EXPRESSION CHANGES IN THE
SENSORY NEURONS.
WE ALSO FOUND THAT NEUTROPHIL
DEPLETION PREVENTED THAT EARLY
HYPER INNERVATION OF THE SKIN.
AND WHEN WE LOOKED AT THE SKIN
TO TRY TO GET A HANDLE ON WHAT
THESE NEUTROPHILS MAY BE DOING
AND HOW THEY'RE CONTRIBUTING TO
THIS WAVE OF INFLAMMATION, WHAT
WE FOUND IS NEUTROPHIL DEPLETION
REALLY SELECTIVELY ATTENUATED
EXPRESSION OF THREE CHEMO KINES.
CXC1910 AND 11 AND THIS DEPICTS
THE QUANTIFICATION OF GENE
EXPRESSION IN OUR RNA SEQ DATA
SHOWING THE UPREGULATION OF
CXCL10.
WE VALIDATE THE RESULTS LOOKING
AT THE PROTEIN LEVEL AND
SECRETION AND NEUTROPHIL
DEPLETION ATTENUATED THIS ROBUST
CXCL10 DEPLETION IN THE
INFLAMMATORY ITCH MODEL.
WHEN WE LOOKED AT THIS WE WERE
EXCITED BECAUSE A LAB PREVIOUSLY
SHOWED THAT THE RECEPTOR FOR
CXCL10, CXCL3 IS REQUIRED FOR
ACUTE ITCH IN A MOUSE MODEL OF
DERMATITIS AND THOUGHT THIS MAY
BE THE LINK BETWEEN THE
NEUTROPHILS AND THE NEURONS.
TO TEST THIS DIRECTLY WE USED A
COMMERCIALLY AVAILABLE AN
ANTAGONIST OF THE RECEPTOR AND
WE FOUND THE ANTAGONIST BLOCKED
ITCH ABOVE SCRATCHING ACROSS ALL
DAYS OF THE MODEL AND THIS WAS
AN ACUTE INJECTION INTO THE SKIN
SUGGESTING THAT CXCL10
SIGNALLING IS PERSISTENT AND
CHRONIC ACROSS ALL DAYS OF THE
MODEL BOTH DURING THE ONSET OF
ITCH DURING THE FIRST EIGHT DAYS
AS WELL AS AFTER THAT ACUTE TO
CHRONIC ITCH TRANSITION IN THE
ABSENCE OF ANY TREATMENT.
SO WE'VE IDENTIFIED THIS
PROTEASE MEDIATED SIGNALLING
EVENT THAT TRIGGERED THE RELEASE
OF CXCL1 WE KNOW CAN ACT
DIRECTLY ON SENSORY NEURONS TO
TRIGGER THE RELEASE OF
INFLAMMATORY MEDIATORS.
AND WE KNOW THAT THE CXCL1
PROMOTES SECRETION OF CXCL10 TO
TRIGGER ITCH ABOVE SCRATCHING
BEHAVIOR THROUGH TRIP A1 ION
CHANNELS.
NOW, WE WANTED TO LOOK BEYOND
THE DORSAL ROOT GANGLIA TO ASK
IF THERE ARE CHANGES IN OTHER
PARTS OFF THE NERVOUS SYSTEM.
WE KNOW THAT FOR PERSISTENT
INFLAMMATORY PAIN THERE'S A LOT
OF MODULATORY EVENTS.
WE STARTED TO LOOK AT CHANGES IN
THE SPINAL CORD AND LOOK FOR
MECHANISM DRIVE PERSISTENT ITCH.
LOOKING AT THE SPINAL CORD WE
FOUND DRAMATIC CHANGES IN GENE
EXPRESSION INDICATIVE OF
DEMYELINATION AND MARKERS OF
DIFFERENTIATION.
WE SAW EVIDENCE FOR AXON PATH
INDICATIVE PROGRAMS OF SYNAPTIC
CONNECTIONS AND INNERVATION AT
THE DORSAL HORN AS WELL.
AS WELL MARKERS FOR REACTIVE
ASTRO GLIOSIS.
AND WE ALSO SAW SIGNIFICANT
UPREGULATION OF LCN2 WHICH HAS
BEEN PREVIOUSLY SHOWN TO AGAIN
BE RESTRICTED TO ASTROCYTES AND
INDICATIVE OF A CHRONIC
PERSISTENT PAIN AND ITCH
PHENOTYPE.
I SHOULD ALSO MENTION THAT WE
DID SEE SIGNIFICANT CHANGES IN
EXCITABILITY AND WE DON'T YET
KNOW WHETHER THAT'S AN
EXCITATORY OR INHIBITORY
NEURONS.
IT'S SOMETHING WE'RE INTERESTED
IN LOOKING AT.
AND FINALLY, WE JUST STARTED TO
DO SOME ANALYSIS LOOKING AT GENE
EXPRESSION CHANGES AND IMMUNE
CELL INFILTRATION IN THE BRAIN
AND REMARKABLY TO OUR SURPRISE
AS WELL AS DAY EIGHT OF THIS
MODEL WE SAW A SIGNIFICANT
INCREASE IN THE NUMBER OF B B
CELLS AS WELL AS BASOPHILS AND
WE KNOW THEY PLAY KEY ROLES IN
INFLAMMATION IN A NUMBER OF
INFLAMMATORY DISORDERS.
IN STROKE THEY CAN RELEASE
INFLAMMATORY MEDIATOR TO RECRUIT
DIFFERENT IMMUNE CELLS AND
ACTIVATE RESIDENT IMMUNE CELLS
AND GLIAL CELLS AND THAT UNDER
CONDITIONS OF INFLAMMATION THEY
CAN BE BOTH PRO AND
ANTI-INFLAMMATORY AND B CELLS
MAY PLAY A ROLE IN INFLAMMATION
IN THE BRAIN IN PERIPHERAL
INJURY OR DISEASE AND THIS IS AN
ACTIVE AREA OF INVESTIGATION FOR
OUR LAB AS WELL AS OTHER LABS
WHO ARE INTERESTED IN LOOKING AT
PERIPHERAL NERVE INJURY AND HOW
THAT AFFECTS SYSTEMIC
INFLAMMATION ACROSS THE
PERIPHERAL AND CENTRAL NERVOUS
SYSTEM.
SO I'VE TOLD YOU SO FAR THAT WE
SEE THAT THERE ARE THESE
DRAMATIC CHANGES IN THE SKIN
THAT INVOLVE NEURO IMMUNE
INTERACTION THAT DRIVE
INTERACTION FROM THE SKIN TO THE
SENSORY GANGLIA TO THE SPINAL
CORD AND BRAIN AND WE'RE ALSO
ACTIVELY PURSUING THE MECHANISMS
BY WHICH THEY CAN DRIVE AIRWAY
INFLAMMATION.
WE THINK THIS IS GOING TO BE A
VERY IMPORTANT COMPONENT OF THIS
A TOPIC MARCH BECAUSE WE KNOW
THAT LOOKING AT THE TRIGEMINAL
GANGLIA, FOR EXAMPLE, THE SAME
NEURONS THAT DENSELY INNERVATE
THE SKIN ARE INTERMIXED WITH THE
SENSORY NEURONS THAT INNERVATE
THE AIRWAYS.
THIS IS TRUE FOR THE TRIGEMINAL
GANGLIA AND WORK FROM A LAB SHOW
THAT THE SENSORY NEURONS ARE
FUNCTIONING GAP JUNCTIONS AND
THROUGH DENSELY SURROUNDED BY
SATELLITE GLIA AND THAT
COMMUNICATE AND WE THINK THE
HYPERACTIVATION OF THE AFFERENTS
IN THE SKIN CAN CONTRIBUTE TO
THE WAVE OF INFLAMMATION WE SEE
AND THIS IS AN ACTIVE AREA OF
INVESTIGATION.
AND SOME PRELIMINARY RESULTS
SHOW THAT AS EARLY AS DAY EIGHT
OF THIS MODEL WE SEE DRAMATIC
CHANGES IN THE IMMUNE PROFILE IN
THE LUNG INCLUDING ROBUST
INFILTRATION BY ALVIAL
MACROPHAGES THAT PLAY INTO
AIRWAY INFLAMMATION DISORDERS.
AND SEE INFLAMMATORY BASOPHILS
AND THEY EXPRESS IGE RECEPTOR
SUGGESTING THE LUNGS AND AIRWAYS
ARE PRIMED FOR ACTIVATION BY
ALLERGEN OR OTHER IRRITANTS AND
WILL RESPOND TO FUTURE STIMULI
IN A HYPER RESPONSIVE WAY
INDICATIVE OF ASTHMA.
WE THINK THIS IS CLINICALLY
RELEVANT.
THERE'S A RECENT STUDY BY BRIAN
KIM'S LAB AT WASH U WHERE THEY
SHOWED PATIENT SAMPLES SHOWING
THAT THE SAME UPREGULATION OF
THE RECEPTOR IN THE SERUM OF
PATIENTS WE THINK THIS PROVIDE
AS A NICE CONNECTION OF
CIRCULATING BASOPHILS THEN
INFILTRATING THE AIRWAY TO
TRIGGER AIRWAY INFLAMMATION.
WE'RE BOTH VERY INTERESTED IN
UNDERSTANDING THESE MECHANISMS
OF WHAT TRIGGERS THE ACTIVATION
OF THESE CELLS AND WHAT TRIGGERS
THEIR MIGRATION TO THE AIRWAYS
UNDER THESE DISEASE CONDITIONS.
SO OVER ALL WE'VE SHOWN THE
EARLY SIGNALLING PATHWAYS IN
EPITHELIAL CELLS IN THE SKIN
TRIGGER MEDIATORS IN THE AIRWAYS
AND THERE'S A CLOSE FUNCTIONAL
COUPLING BETWEEN IN THE SKIN AND
IN THE LUNG AND UPPER AIRWAYS
BETWEEN THESE HYPERACTIVE
EPITHELIAL CELLS AND SENSORY
NEURONS THAT EXPRESS TRIP A1 AS
WELL AS IMMUNITY CELLS SHOWN BY
A NUMBER OF GROUPS TO CLOSELY
INTERACT WITH BOTH EPITHELIAL
CELLS AND FREE NERVE ENDING TO
PROMOTE AIRWAY INFLAMMATION IN
THE CONTEXT OF ASTHMA AND WE'RE
ALSO ACTIVELY PURSUING THE ROLES
OF THE SAME CELLS AND MOLECULES
IN THE CASE OF AIRWAY
INFLAMMATION TRIGGERED BY
VIRUSES LIKE COVID-19.
WE'RE STARTING TO SEE A LOT OF
THE SAME MOLECULAR PLAYERS,
CELLULAR PLAYERS AND SIGNALLING
PATHWAYS THAT ARE COMMON TO A
VARIETY OF VIRAL AND BACTERIAL
INFECTIONS AS WELL.
AND WITH THAT I'D LIKE TO THANK
ALL THE MEMBERS OF MY LAB WHO
DID THE HARD WORK IN DRIVING THE
PROJECTS.
I'D LIKE TO THANK MY FUNDING
AGENCIES AND THANK YOU FOR YOUR
TIME.
I'D BE HAPPY TO ANSWER ANY
QUESTIONS.
>> THANKS, DIANA.
THAT WAS WONDERFUL AS ALWAYS.
THE WORK FROM YOUR LAB IS
INCREDIBLY TIMELY DEMONSTRATION
AND NEW DEMONSTRATION OF HOW THE
NERVOUS SYSTEM DOES INTERACT
WITH THE PERIPHERY AND HOW THEY
CAN BE BI-DIRECTIONAL.
THAT'S TERRIFIC.
THERE'S A BUNCH OF QUESTIONS IN
THE AT.
LET'S SEE.
I'LL START FROM THE TOP AND WORK
MY WAY DOWN.
THE FIRST ONE IS QUITE
INTERESTING.
THE QUESTION IS CAN YOU
ELABORATE ON HOW THE B CELLS
INFILTRATES INTO THE BASAL
GANGLIA IS THE CCXL TYPE WHAT DO
WE KNOW ABOUT THAT?
>> GREAT QUESTION.
SO THIS IS A LARGE STUDY SO I
SHOWED YOU OUR EARLY STUDIES.
THIS IS A VERY ACTIVE PART OF
OUR LAB SO WE DON'T HAVE ALL THE
ANSWERS BUT THOSE ARE EXACTLY
THE QUESTIONS WE'RE TRYING TO
UNDERSTAND.
IN THE SKIN WHERE WE'VE DONE THE
MOST WORK WE'VE DONE EARLY
RELEASE OF CXCL1 IS VERY
IMPORTANT IN DRIVING THE INFLUX
OF NEUTROPHILS AND IT'S THE
OTHER CYTOKINES THAT THEN DRIVE
A SECOND WAVE OF INFLAMMATION WE
AND OTHERS BELIEVE ARE REALLY
IMPORTANT FOR THAT CHRONIC
PHASE.
I THINK WE HAVE A HANDLE ON THE
NEW EARLY PATHWAY BUT WE'RE
TRYING TO UNDERSTAND HOW THE
WAVE OF INFLAMMATION STARTS TO
MOVE AND WHAT THE MECHANISMS
THAT DRIVE THAT.
SO WE KNOW SOME OF THE MOLECULES
AND CYTOKINES BUT NOT ALL OF
THEM.
WE KNOW THE NEURONS PLAY AN
IMPORTANT ROLE IN DRIVING THAT
INFLAMMATION BY PROMOTING
VASCULAR LEAKAGE AND ACTIVATION
OF DIFFERENT NEURONS AND WHAT
PRIMES THE SYSTEM TO
HYPERACTIVITY.
IN THE MODEL THE HYPERACTIVATION
OF THE SENSORY NEURONS AND
COMBINED WITH ACTIVATION OF
OTHER CELL TYPES IN THE SENSORY
GANGLIA PERHAPS SATELLITE GLEEIA
AND SENSORY IMMUNE CELLS START A
SECOND CASCADE WE START TO SEE
ON DAY EIGHT OF THE MODEL MAY BE
DRIVING THE CHANGE IN
INFLAMMATION.
>> SO I GUESS THIS IS A QUESTION
WITHOUT AN ANSWER BUT FOR ME IT
BEGS THE QUESTION I CAN SEE HOW
THE INTERACTIONS IN THE
PERIPHERY CAN SERVE A PROTECTIVE
EFFECT BUT WHAT DO YOU THINK THE
ROLE IS FOR THE IMMUNE
INFILTRATION ROLE IS IN THE GANG
LE
-- GANGLIA?
FOR CHRONIC ITCH WE DON'T KNOW
OF ANY PROTECTIVE FUNCTION.
ACUTE ITCH PLAYS A ROLE IN
CLEARING INFECTION RESOLVING
INFLAMMATION BUT WHAT IS CHRONIC
ITCH DOING?
I THINK THAT AT LEAST FOR ACUTE
ITCH IT'S IMPORTANT IN LEARNED
BEHAVIOR AND IN THE CASE LIKE
PAIN THE HYPERSENSITIVITY IS
TRANSIENT.
YOU STOP GOING OUT WITHOUT DEET,
YOU REMOVE YOUR HAND FROM THE
FIRE AND SCRATCH FOR PATHOGEN
AND HAVE HYPERSENSITIVITY AND
HAVE INFECTED CELLS AND RECOVER.
WHY YOU SEE THIS ACROSS PAIN AND
THE PERSISTENT HYPERSENSITIVITY
AT DOESN'T RECOVER OR RETURN
OR RESET TO NORMAL IS A MYSTERY
AND HOW CAN WE TARGET THAT TO
REVERSE IT OR PREVENT IT IN THE
FIRST PLACE IS REALLY THE GOAL.
>> I THINK YOUR WORK HAS
IDENTIFIED A HOST OF CELLULAR,
MOLECULAR DRUGGABLE TARGETS.
THE NEXT QUESTION IS DO YOU
THINK CHRONIC ITCH MAY LEAD TO
PERSISTENT MODIFICATIONS IN THE
BRAIN I THINK THE PERSON IS
ASKING NEURAL CIRCUITS THAT
OUTLAST THE SOURCE OF THE ITCH
MUCH LIKE PHANTOM PAIN?
>> THAT'S A GREAT QUESTION.
I THINK SO FAR WE SPEND A LONG
TIME STUDYING INFLAMMATORY PAIN
AS WELL.
EVERYTHING THAT WE LOOKED AT
FOLLOWS THE SAME RULES.
YOU GET -- IT STARTS IN THE
PERIPHERY, IT SPREAD TO THE
CENTRAL NERVOUS SYSTEM AND THEN
YOU HAVE CHANGES IN MODULATION
OF THE CENTRAL INFORMATION
SYSTEM SO YOU NO LONGER NEED
THESE PERIPHERAL SIGNALS.
WE'RE STARTING TO SEE THE SAME
RULES -- DIFFERENT MOLECULES,
DIFFERENT CELLS BUT SAME
OUTCOMES.
WE'RE EXCITED ABOUT REALLY
UNDERSTANDING THOSE MECHANISMS,
HOW LONG DO THEY TAKE TO SET IN?
IT'S REALLY JUST THE TIP OF THE
ICEBERG WE'VE STARTED TO DEFINE
THE EARLY EVENTS BUT WHAT TYPES
OF PLASTICITY IS THERE AND HOW
MIGHT WE CHANGE THAT?
I SHOULD SAY WE ALSO FOR ACUTE
ITCH ARE STILL AS A FIELD TRYING
TO UNDERSTAND THE CIRCUITRY AND
MODULATIONS IN THE SPINAL DORSAL
CORD THAT MEDIATE PAIN.
THERE'S A LONG WAY TO GO AND
LOTS OF INTERESTING QUESTIONS
EVEN FOR ACUTE ITCH YET ALONE
HOW CHRONIC ITCH CHANGES OCCUR.
>> SO I'LL ASK YOU THE QUESTION
I ALWAYS ASK THE RELATIONSHIP
BETWEEN PAIN NOCICEPTION AND
ITCH AND ATEAST AN ACUTE ITCH,
PAIN SEEMS TO MODULATE THE
ITCHINESS.
SO DO YOU THINK THAT A, WHAT DO
WE KNOW ABOUT THAT?
THERE'S BEEN CONTROVERSY HOW
THAT HAPPENS AND, B, COULD THAT
TELL US ANYTHING ABOUT HOW TO
DEAL WITH CHRONIC ITCH FROM THE
ACUTE ITCH MODELS?
>> I THINK WE'VE ALL EXPERIENCED
THE PLEASURE OF SCRATCHING THE
IT
ITCH.
WHAT PEOPLE DO IS SCRATCH THE
MOSQUITO BITE UNTIL IT BLEEDS OR
PUT ON ICE TO RELIEVE THE ITCH.
THERE'S SEVERAL KNOWN MECHANISMS
BY WHICH THAT OCCURS.
IT'S KNOWN THERE'S INTERNEURONS
AND THERE'S BEAUTIFUL WORK TO
FIND INTERNEURONS THAT MEDIATE
THE PAIN PATHWAY AND ITCH
PATHWAY SO WHEN YOU ACTIVATE
BOTH SIMULTANEOUSLY YOU DECREASE
THE ITCH SIGNALS THAT GET
TRANSMITTED TO HIGHER LEVELS.
WE ALSO KNOW THAT THERE ARE
REWARDS THAT WE GET FROM
SCRATCHING AND TOP-DOWN
MODULATIONS IN THE SPINAL CORD
GIVE THE REWARD AND CAN DRIVE
THAT ITCH-SCRATCH CYCLE.
WE KNOW IN ACUTE ITCH THERE'S
RELIEF BUT IN CHRONIC ITCH IT
MAKES THINGS MUCH WORSE.
SO ONE POSSIBILITY CAN BE CAN WE
TARGET CENTRAL PATHWAYS SO THAT
WE BLOCK ITCH TRANSMISSION AND
THERS DEFINITELY A LOT OF
INTEREST IN THAT.
>> RIGHT, THANKS.
I'LL KEEP ASKING QUESTIONS OVER
AND OVER AGAIN.
NEXT QUESTION IS ARE THE
RECORDING FROM SPINAL SENSORY
NEURONS TO LOOK AT THEIR FIRING
PROPERTIES CHANGE DUE TO CHRONIC
ITCH.
>> THERE'S BEEN LOTS OF WORK
LOOKING AT HYPER EXCITABILITY
DEFINING PROPERTIES OF NEURONS.
WHILE WE HAVE A LOT OF
INFORMATION ABOUT THE DIFFERENT
SUP SETS OF PRIMARY AFFERENTS IN
THE PERIPHERY AND PEOPLE HAVE
USED ELEGANT OPTOGENETIC TOOLS
TO DECIPHER HOW AFFERENTS MAY
DRIVE ITCH VERSUS PAIN WE HAVE A
LONG WAY TO GO IN LOOKING AT THE
SPINAL CORD AND DEFINING THE SUB
POPULATIONS AND HOW ITCH VERSUS
PAIN IS ENCODED IN FIRING
SUBSETS IN THE SPINAL CORD.
STILL THE BIG DEBATE ABOUT
INTENSITY CODING AND POPULATION
CODING AND COMBINATIONS HAVE
BEEN SEEN.
WE DON'T HAVE A GOOD HANDLE ON
HOW THESE SIGNALS ARE BEING
PROCESSED.
>> SO I GUESS THE RELATED
QUESTION DO YOU THINK SPINAL
CORD INFLAMMATION PER SE, DRIVES
CHANGES IN EXCITABILITY.
PERHAPS IT'S A TWO-WAY STREET?
>> IT'S HARD TO DECIPHER THOSE
TWO AND THEY TEND TO GO HAND IN
HAND.
WE THINK THE HYPER EXCITABILITY
-- EXCITABILITY IN THE GANGLIA
AND CAUSES INCREASES IN THE
FIRING IN THE SPINAL CORD AND WE
SEE ASTROGLIOSIS AND ACTIVATED
MICROGLIA AND THE PRELIMINARY
DATA SHOWS IT EVEN REACHES THE
BRAIN.
WHAT THE WAVES OF INFLAMMATION
DO AND HOW LONG THE CHANGES TAKE
TO OCCUR AND WHAT THE
CONSEQUENCES ARE ON SIGNAL
TRANSMISSION AND PROCESSING WE
DON'T REALLY KNOW YET.
>> SO IN TERMS OF THE EARLY
CHANGES YOU MENTIONED IN THE
PERIPHERY WHERE YOU GET
HYPERINNERVATION AND
EXCITABILITY DOES ONE SEE
HYPERALGESIA OR ALLODYNIA
BECAUSE OF THAT AND HOW
TRANSIENT IS THAT?
>> YEAH, SO THE HYPERINNERVATION
OCCURS ON DAY TWO AND IT'S BY
DAY TWO AND A HALF AND IT'S
TRANSIENT AND FOLLOWED BY ITCH
BEHAVIORS.
WE THINK THAT'S SOMEHOW PRIMING
THE NERVOUS SYSTEM TO START
DISPLAYING THE PERSISTENT ITCH
PHENOTYPE.
AS WELL AS THE OTHER PART OF
YOUR QUESTION.
>> I FORGET.
>> CAN YOU EXPLAIN THE ROLE OF
ASTRO GLIA AS A NEURO
INFLAMMATORY MARKER?
>> IT'S BEEN KNOWN IN A VARIETY
OF CHRONIC ITCH MODELS THERE'S
EVIDENCE OF ASTROGLIOSIS AND
ACTIVATED MICROGLIA AND A RECENT
STUDY SHOWED IT'S A KEY SWITCH
IN THE TRANSITION FROM ACUTE
ITCH TO A CHRONIC PERSISTENT
ITCH STATE.
WE KNOW IT'S THE SAME FOR
LOOKING AT NEUROPATHIC OR
INFLAMMATORY PAIN THAT
ASTROCYTES AND GLIA PLAY A KEY
ROLE IN THE CHRONIC PAIN
CONDITION AND NOT JUST LOOKING
AT NEURONS BUT CHANGES IN GLIA
CAN GAIN INSIGHT TO THE SYSTE
AND WE'RE USING SINGLE CELL
SEQUENCING TO GET A HANDLE ON
THE CELL SPECIFIC CHANGES ACROSS
THE NERVOUS SYSTEM.
>> RIGHT.
SO I GUESS ONE QUESTION AND THIS
GETS TO THE NEXT QUESTION IN THE
CHAT ARE ALL THESE ARE SHARING
CHRONIC MECHANISMS.
THE QUESTION IS HOW'S THE
MECHANISM OF CHRONIC ITCH FROM
HIVE REACTIONS ARE SYMPTOMS GO
AWAY AFTER DIFFERENT TIMES.
A MOSQUITO BITE WILL GIVE AN
INITIAL ITCH OR SOMETHING ON
YOUR ARM WILL GIVE A SHORT
DURATION EFFECT WHEREAS A TOPIC
DERMATITIS YOU'RE TALKING ABOUT
WEEKS, MONTHS, YEARS, VERSUS
HIVES WHICH MAY BE ON THE ORDER
OF DAYS OR WEEKS.
TO WHAT DEGREE ARE WE LOOKING
AT?
SIMILAR MECHANISMS?
ARE WE LOOKING AT DIFFERENT
PHASES OF THE REACTION BEFORE
THE IRRITATION GOES AWAY?
WHAT DO WE KNOW ABOUT THE
COMMONALITIES OR NOT?
WE KNOW A LOT ABOUT WHAT HAPPENS
IN THE SKIN AND WHAT TYPES OF
IMMUNE CELLS INFILTRATE.
WE KNOW FOR EXAMPLE FOR THE
ITCHY MOSQUITO BITE AND SOME
FORMS OF ALLERGY THAT HISTAMINE
PLAYS AN IMPORTANT ROLE.
WORK FROM A LAB A DECADE AGO
SHOWED A SUBSET OF SENSORY
NEURONS THAT EXPRESS THE H1
HISTAMINE RECEPTOR AND THE
CAPSAICIN RECEPTOR TRIP B1 AND
IN THOSE CELLS WHERE THE
RECEPTORS ARE FUNCTIONALLY
COUPLED, THAT THOSE CELLS
MEDIATE HISTAMINE-DEPENDENT
ITCH.
BUT THAT PATHWAY DOES NOT SEEM
TO BE ENGAGED UNDER CONDITIONS
OF CHRONIC ITCH AND THERE ARE A
WHOLE SLEW OF NON-HISTAMINERGIC
NEURONS SHOWN THAT THERE ARE
COMPLETELY DIFFERENT PATHWAYS IN
DIFFERENT CHRONIC ITCH
DISORDERS.
UNFORTUNATELY AND IT'S TRUE FOR
PAIN AS WELL, THERE'S NOT JUST
ONE PAIN PATHWAY OR ITCH PATHWAY
THAT ITCH ENGAGE.
THERE SEEMS TO BE DIFFERENT
MOLECULES, CELLS, IMMUNE CELLS
AND NEURONS THAT DRIVE THESE
DIFFERENT DISEASE STATES FOR
INFLAMMATORY PAIN VERSUS
NEUROPATHIC PAIN OR SPINAL CORD
INJURY OR CHEMO THERAPY OR
NEURONEUR
NEUROON NEUROPATHY AND MAYBE
THERE'S NOT ONE THING THAT WILL
GET RID OF ALL CHRONIC ITCH
MAYBE MULTIPLE OR MAYBE WE'LL
FIND A COMMON PATHWAY IN THE
NERVOUS SYSTEM AT HIGHER LEVELS
THAT MAY BE THE WAY TO GO.
>> AND PRESUMABLY --
SIMPLISTICALLY THERE MAY BE
FORMS OF CONVERSION THAT MAY NOT
BE HAPPENING OUT IN THE
PERIPHERY.
>> YEAH, THAT'S RIGHT.
THERE'S INTERACTION BETWEEN ITCH
AND PAIN AND GIVING PAIN
PATIENTS MORPHINE THAT UNMASKED
ITCH EVOKED RESPONSES THE
PERSISTENT ITCH.
AND SOMETIMES THE ITCH IS WORSE
THAN THE PAIN AND THE PATIENTS
ASK TO STOP TAKING THE MORPHINE.
THEY'D RATHER HAVE THE PAIN
VERSUS THE ITCH.
THE INTERACTION BETWEEN THE TWO
SYSTEMS MAKES IT QUITE
COMPLICATED AS WELL.
CAN WE FIND SOMETHING SPECIFIC
THAT MIGHT WORK.
>> ONE QUESTION IS HAVE YOU
LOOKED AT THE POSSIBLE USE OF
VARIOUS DRUGS KNOWN TO DECREASE
THE ACTIVATION OF BASOPHILS?
THERE'S A BIG AREA OF INTEREST
AND A NUMBER OF GROUPS ARE
WORKING ON THIS.
WE'RE ALSO VERY INTERESTED IN IF
WE CAN BLOCK THE PATHWAYS BY
GETTING RID OF THE NEUTROPHILS
WHILE MOST HUMAN STUDIES
FOCUSSED ON MATURE LESIONS,
THERE'S A COUPLE CLINICAL
STUDIES DONE WHERE THEY CAN
INDUCE LESIONS OR CAUGHT THEM BY
DEVELOPING LESIONS IN ECZEMA
PATIENTS AND THEY FOUND THE
NEUTROPHILS WERE INDEED THERE
AND THERE'S A NUMBER OF DRUGS
THAT ARE CURRENTLY ON THE MARKET
FOR OTHER INDICATIONS TO BLOCK
NEUTROPHIL INFILTRATION.
WEHINK THAT'S AN INTERESTING
AVENUE TO PURSUE ESPECIALLY
SINCE WE SEE BLOCKING THE
NEUTROPHILS CAN AFFECT THE
NERVOUS SYSTEM CHANGES.
>> COOL, A COUPLE QUESTIONS
LEFT.
I THINK WE HAVE A LITTLE BIT OF
TIME.
IS THERE A PERCENTAGE OF PEOPLE
OR WHAT IS THE PERCENTAGE OF
PEOPLE WITH ECZEMA THAT DEVELOP
ASTHMA IN THE A TOPIC MARCH?
>> IT'S QUITE HIGH.
SO IT'S THOUGHT TO BE SOMEWHERE
BETWEEN 50% TO 70
FOR CHILDREN IT'S HALF OF KIDS
WHO HAD SEVERE ASTHMA AS A KID
EVEN IF IT GOES AWAY AND THEY
DEVELOP ASTHMA MUCH LATER.
THE WORK SHOWED CIRCULATING
PRIMED BASOPHILS IN SERUM AS
WELL AS WORK IN OUR ANIMAL MODEL
AND OTHERS SHOWING THAT THESE
BASOPHILS ARE PRIMED TO MAKE
THEM A KEY TARGET AND BRIAN
KIN'S GROUP SHOWED THEY PLAYED A
KEY ROLE IN INFLAMMATION DURING
THE CHRONIC PHASE AND IN
RESPONSE TO FURTHER ALLERGEN
CHANNEL TO THE SKIN.
>> IS THERE ANY INTEREST OR WHAT
DO WE KNOW HOW CHRONIC ITCH MAY
AFFECT PREGNANT MICE AND THEIR
OFFSPRING?
IS THERE AN IMMEDIATE EFFECT ON
THE SKIN AND TRANS GENERATIONAL
INHERITANTS ARE HOT RIGHT NOW
AND THERE CHANGES CENTRALLY AND
PERIPHERALLY?
>> YOU DEFINITELY THESE CHRONIC
ITCH CONDITIONS RUN IN FAMILIES
AS DOES ASTHMA AND OTHER A TOPIC
DISEASES.
GENERALLY THEY'RE INCREASING IN
PREVALENCE ESPECIALLY IN THE
UNITED STATES, SWEDEN AND JAPAN
AND DRAMATIC INCREASES IN FOOD
ALLERGIES AND CASES OF ASTHMA
AND HOW MUCH OF THAT IS GENETIC
VERSUS EXPOSURE I THINK IS A
DEBATE.
THERE'S ALSO DRAMATIC
DIFFERENCES BETWEEN MEN AND
WOMEN RAISING THE POSSIBILITY OF
DIFFERENT REACTIONS DURING
PREGNANCY AS WELL AND WE ALSO
KNOW THAT PREGNANCY AND HORMONES
CAN TRIGGER CHRONIC ITCH AS
WELL.
WHAT THAT CYTOKINE EXPOSURE AND
ITCH-SCRATCH EXPOSURE IS NOT
REALLY KNOWN.
>> GREAT.
OKAY.
WELL, I THINK WE'RE COMING ON
TIME HERE.
I WANT TO THANK YOU FOR A
TERRIFIC TALK.
YOU UNCOVERED THE IMPORTANT
INTERACTIONS BETWEEN NOT JUST
THE BRAIN AND CENTRAL
INFORMATION SYSTEM AND THE
PERIPHERY BUT REALLY IN THE SKIN
AND HOW THESE INTERACTIONS
BETWEEN THE NEURONS AND THE SKIN
AND THE IMMUNE CELLS IN THE SKIN
ARE HAVING SUCH A PROFOUND
EFFECT ON BEHAVIORS.
I REALLY APPRECIATE THIS AGAIN.
LOOKING FORWARD TO HEARING THE
NEXT SET OF AMAZING EXPERIENCE
OF EXPERIMENTS TO COME FROM YOUR
LAB AND LOOKING FORWARD TO
SEEING YOU I HE IN PERSON ONE
DAY SOON.
>> YEAH, THANKS SO MUCH, JOHN.
IT WAS GREAT TO HAVE THIS
OPPORTUNITY AND TO HEAR ALL THE
GREAT QUESTIONS EVERYONE HAD AND
DISCUSS THEM.
>> GREAT.
THANKS AGAIN.
I WANT TO GO THROUGH THE WORK
DONE OVER THE LAST FIVE YEARS TO
AMASS TRULY SPECIAL AND BREATHE
TAKING DATA RESOURCES ON BEHALF
OF THE BICCN.
THE DATA SETS INVOLVE CUTTING
EDGE TECHNOLOGIES AND WE'VE GOT
SEVERAL SPEAKERS WHO HAVE BEEN
BUILDING THE DATA ARCHIVES OF
THE BRAIN CENTER AND THE BCDC
AND THOSE DRIVING RE-USE OF THE
DATA.
YOU'LL HEAR FROM QUITE A BREADTH
OF SPEAKERS ABOUT THE RESOURCES
AVAILABLE TO YOU.
HERE'S SOME OF THE PRESENTATIONS
YOU'LL BE HEARING THE ORDER MAY
CHANGE A LITTLE BIT BUT YOU'LL
HEAR ABOUT THE BRAIN CELL DATA
CENTER AND CATALOGING THE DATA
FROM CAROL THOMPSON AND DATA
RESOURCES FROM THE LIBRARY FROM
ALEXANDER OVALESSI AND
REPLICABILITY IN SINGLE-CEL
DATA.
NOW OVER TO CAROL.
>> GOOD MORNING, HAPPY TO BE
HERE TO TELL YOU MORE ABOUT THE
BRAIN CELL DATA CENTER AND THE
CATALOGING OF THE BICCN.
SO THE BRAIN INITIATIVE CENSUS
NETWORK IS ONE OF THE SERIES OF
DIFFERENT CONSORTIA EFFORTS AND
THERE WAS A CONSORTIUM WHICH
WORKED WITH STRATEGIES AND
TECHNIQUES.
AFTER THAT IT WAS FOUND THE
METHODS AND STRATEGIES LAUNCHED
THE BRAIN INITIATIVE CELL CENSUS
NETWORK TO INTEGRATE MOLECULAR
AND ANATOMICAL AND FUNCTIONAL
DATA.
IT'S BEEN LARGELY THE WORK OF
THE LAST FIVE YEARS FROM 2017 TO
2022.
LATER IN 2022, THE NEXT
CONSORTIUM IS DUE TO START THE
BRAIN INITIATIVE CELL ATLAS
NETWORK.
DATA BEING GENERATED FROM BICCN
INCLUDES A LOT OF TRANSCRIPTOMIC
TRANSCRIPTOMICS DATA AND SPATIAL
DATA AS WELL AND ANATOMY AND
PHYSIOLOGY TECHNIQUES AND
LOOKING AT MARKERS AND
TECHNIQUES LOOKING AT AREAS OF
THE BRAIN, CONNECTIVITY AND
BRAIN IMAGING TECHNIQUES AND
MULTI-MODAL TECHNIQUES SUCH AS
PAC SEQ INCLUDING OMICS.
WITH ALL THE TYPES OF DATA IT'S
BEEN AMAZING THE BREADTH OF DATA
BEING GENERATED.
I WANTED TO MAKE SURE PEOPLE
COULD FIND THE DATA EASILY.
THE BICCN OPERATES WITH A
DISTRIBUTED ECO SYSTEM.
PARTICIPATING LABORATORIES
GENERATING DATA AND THE BRAIN
CELL DATA CENTER POSTED BY THE
ALLEN INSTITUTE COORDINATES DATA
FOR MISSION AND STANDARDS WITH
OUR PARTNERS THERE THE BROAD
INSTITUTE.
THE DATA ATLAS YOU'LL HEAR FROM
SOME TODAY INCLUDING
TRANSCRIPTOMICS AND EPIGENOMICS
DATA AND THE IMAGE LIBRARY FOR
BRAIN MICROSCOPY DATA AND DANDI
WHICH IS NEUROPHYSIOLOGY AND
CALCIUM IMAGES AND SOME MRI.
AND THE ANIEST ARCHIVE BOSS DB
SPOERTSZ ELECTED
ELECTROSCOPY.
WE HAVE MEMBERS ON THE ROSTER
COMING FROM 57 GRANTS.
EACH NOT JUST ONE MANY HAVE
MULTIPLE PARTNERS.
COLLECTIVELY THEY'VE LOGGED IN
86 DIFFERENT PROJECT AND 162
DATA COLLECTIONS.
WE HAVE WE KNOW THEY'RE USING AT
LEAST 42 DIFFERENT MAJOR
DISTINGUISHABLE TECHNIQUES TO
ANALYZE CELL TYPES.
WE HAVE 97 PROTOCOLS AND WE HAVE
TONS OF DATA ARCHIVES.
DATA ENCOMPASSES MANY MODALITIES
FROM 23 SPECIES WHICH INCLUDES
PROFILING 4300 MOUSE AND 150
HUMAN AND 30 OTHER DIFFERENT
SPECIES.
SO THE BRAIN CELL DATA CENTER IS
TRYING TO MAKE IT AVAILABLE THE
PORTAL AT WWW.BICCN.org AND YOU
CAN GET TO THE CATALOG SHOWN
HERE AND YOU CAN USE A FACETED
SEARCH TO FIND DATA COLLECTIONS
OF INTEREST TO YOU.
YOU CAN LOOK AT A PROJECT
SUMMARY PAGE TELLING YOU WHAT
THE DATA COLLECTIONS ARE, IF YOU
LINK SOME DOWNLOAD THEM AND GIVE
YOU IMPORTANT INFORMATION ON HOW
TO GET THROUGH DATA AND WHAT
LICENSE IT'S UNDER AND WHAT
PROTOCOLS WERE USED AND AUTHORS
AND FUNDING SOURCES.
FROM THE DATA YOU CAN SEE A
LISTING OF WAYS TO ACCESS DATA.
THE TOP BUTTON IS TO SEARCH THE
INVENTORY.
THIS TAKES YOU TO THE CHURCH AND
YOU CAN GO DIRECTLY TO THE
ARCHIVES TO BROWSE THROUGH THE
DATA AVAILABLE AT EACH ARCHIVE.
YOU CAN SEE EXAMPLE IMAGES OF
SOME OF THE BROWSER VIEWS ON
SOME OF THE PORTS.
FOR DATA SEARCH AND ACCESS I
DON'T HAVE A LIVE DEMO HERE FOR
YOU TODAY BUT IF YOU WERE TO
CLICK ON THE FILTER ICON IN THE
UPPER LEFT ON THE DATA CATALOG
YOU WOULD BE ABLE TO GO IN AND
CHOOSE WHICH GRANT YOU WERE
INTERESTED IN LOOKING AT DATA
FROM OR WHAT SPECIES, WHAT
TECHNIQUES WERE USED TO GENERATE
THE DATA TO NARROW DOWN YOUR
SEARCH FOR WHICH DATA SETS YOU'D
LIKE TO LOOK AT.
AS I'VE DESCRIBED YOU CAN LOOK
AT THE PROJECT SUMMARY PAGE AND
GET LINKS DIRECTLY DOWN TO THE
DATA.
WE ALSO HAVE FOR A SELECT SET OF
THE PROJECTS AND ARE WORKING TO
BACK TOP -- POPULATE THE REST
YOU CAN GET THE LINKS TO THE
INDIVIDUAL DATA FILES AVAILABLE
AT EACH OF THE ARCHIVES.
SO ANOTHER BIG THING THAT
HAPPENED IN THE BRAIN INITIATIVE
IS THIS IS A GREAT OPPORTUNITY
TO HAVE ALL THESE SCIENTISTS
COLLABORATE.
ONE OF THE THINGS WE CHOSE TO
COLLABORATE ON INITIALLY WAS A
CELL CENSUS OF THE PRIMARY MOTOR
CORTEX AND THIS CAME ABOUT A
TRANCHE OF DATA AND WANTED TO
MAKE SURE THE DATA WAS AVAILABLE
TO EVERYONE AND THERE'S A
ONE-STOP SHOP TO FIND THE DATA
GENERATED SO WE ALSO HAVE THIS
PAGE THAT HAS A LISTING OF THE
PAPERS PART OF THE STUDY WHERE
DIFFERENT LABS USED DIFFERENT
TECHNIQUES BUT COLLABORATED ON
ANALYSES TO UNDERSTAND THE
SUBTYPES IN THE CORTEX OF
MULTIPLE SPECIES.
ALONG SIDE THE LINK TO THE
PAPERS THERE'S TOOLS FOR HOSTING
DATA ASSOCIATED WITH THIS.
INCLUDING NEMO ANALYTICS AND THE
TRANSCRIPTOMICS EXPLORER AND
METHYLATION VIEWER AND SINGLE
CELL PORTAL AND THERE'S A LOT OF
PARTNERS IN THE EFFORT WHO HAVE
COME TOGETHER TO TRY TO MAKE THE
DATA ACCESSIBLE TO PEOPLE.
ONE TOOL WE MADE AVAILABLE AT
THE ALLEN INSTITUTE IS FROM THE
DATA CATALOG TOGGLE BETWEEN THE
DATA CATALOG TO THE CELL
TECHNOLOGY EXPLORER.
WE HAVE HOSTED TAXONOMIES OF THE
PRIMARY MOTOR CORTEX FROM THREE
SPECIES.
THIS WAS DONE PART OF THE LARGE
COLLABORATIVE EFFORT BY THE
BICCN SO YOU CAN GO AND EXPLORE
THE HUMAN AND MOUSE TAXONOMIES
AS WELL AS GO TO EACH PAGE AND
UNDERSTAND AND LOOK AT THE DATA
SUPPORTING THE DIFFERENT CELL
TYPES THAT WERE IDENTIFIED IN
THE STUDIES.
THIS INCLUDES LINK OUTS TO
TYPOLOGY DEVELOPED AS PART OF
THIS WORK.
WITH THEY WANTED TO CONCLUDE BY
SAYING THERE WERE AS I SAID, 57
NIH GRANTS CONTRIBUTING TO THIS
PROJECT AND SO IT'S HARD TO GIVE
THANKS TO EVERYBODY THAT WAS
INVOLVED IN THE EFFORT BUT WE
HAVE A LISTING OF TWO PAGES OF
GRANTS.
WE HAVE SO MANY GRANTS DEDICATED
TOOLS AND EXCELLENT DATA THAT
CONTRIBUTED TO OUR UNDERSTANDING
OF CELL TYPES AS WELL AS A
NUMBER OF INFRASTRUCTURE GRANTS
AND THE WORK FOR THE BRAIN CELL
DATA CENTER IS FUNDED BY THE
U-24 GRANT AWARDED TO P.I.s.
THANK YOU.
>> I'M TIMONEY TICKLE FROM THE
DATA SCIENCES PLATFORM AT THE
BROAD INSTITUTE.
I'M HERE IN THE EFFORT OF DOING
BIG SCIENCE WITH THE MOUSE-BRAIN
WORKING GROUP.
FROM THE HUMAN GENOME WE'VE
GROWN OUR DATA RESOURCES AND
WE'RE IN A SPACE WHICH IS
AMAZING TO ME WE CAN HAVE
PROJECTS WORK WITH A MILLION
HUMAN GENOMES ASKING QUESTIONS
SPANNING AROUND THEM AND THAT'S
TRUE NOT ONLY WITH GENOMICS BUT
SINGLE-CELL OMICS AND STARTED
MAKING ATLASES FROM ONE LAB THAT
WERE POWERFUL AND DESCRIPTIVE
AND MOVING IT A SPACE WHERE MANY
PEOPLE WORK TOGETHER TO COMBINE
DATA SETS AND MODALITIES TO
CREATE INTEGRATED ATLASES.
IT'S AN AMAZING SPACE.
WE WEREN'T ABLE TO SUPPORT THIS
EFFORT IN THE BICCN.
WHEN THINKING ABOUT THAT WE'RE
ASKING BIG QUESTIONS.
SOMETIMES THE AND PEOPLE MAY
BRING THE DATA TO THE RESEARCHER
AND TOPPY THE DATA AND TAKE IT
AND WORK ON IT INDEPENDENTLY OR
IN SMALL GROUPS AND PEOPLE AND
ANALYSES MAY BE DIFFERENT AND
INDEPENDENTLY WORKING TOGETHER
AS A GROUP THAT COULD BE
DIFFICULT.
WE WANTED TO BE ABLE TO SUPPORT
MORE OF A COMMON SPACE TO ASK A
QUESTION TOGETHER AND ONE OF THE
APPROACHES INVOLVED AND THIS IS
ONE WE DECIDED ON OF THE MANY
AND FOR THIS YEAR OPPOSED TO
BRINGING THE DATA TO THE
RESEARCHER, BRINGING THE
RESEARCH TO DATA RESOURCES AND
COMPETING RESOURCES.
THAT ALLOWS EVERYONE TO HAVE THE
SAME DATA AND PIPELINE TO RUN
AND HAVE EVERYTHING UNIFORM AND
SHARE INSTANTANEOUSLY TOGETHER.
WE THOUGHT THAT WOULD BE
IMPORTANT TO TRY AND WE'RE
LEVERAGING TARA.
IT'S A CLOUD-BASED
INFRASTRUCTURE SPA THAT SPANS
MULTIPLE INSTITUTES AND ASK BIG
QUESTIONS -- TERRA.
PEOPLE CAN WORK IN WORK SPACE
ARE SECURE.
AND IT BE ABLE TO SHARE AMONGST
PEOPLE THEY WOULD WANT TO TO
WORK WITH PROCESSING PIPELINES
OR USE DATA IN LOCAL RESOURCES
AND THERE'S NO REASON TO NOT
LEVERAGE THOSE AND MAKE THEM
MAKE SENSE.
SO TERRA IS A COMMON SPACE THAT
BRINGS PEOPLE TOGETHER.
NOT ONLY THAT IT'S PART OF A
LARGER ECO SYSTEM THAT HAS
STANDARDS TO BRING TOGETHER
PROJECTS AND DIFFERENT COMMUNITY
EFFORTS AND IN THIS CASE I'LL
DOUBLE CLICK A LITTLE BIT ON THE
INTERACTION BETWEEN NEMO AND
TERRA IN THE ECO SYSTEM
INDEPENDENT INFRASTRUCTURES THAT
WORK TOGETHER AND IN A LARGER
ECO SYSTEM.
WITH THE VISION OF SUPPORTING
LARGE SCIENCE ONE OF THE GROUPS
IS THE WHOLE MOUSE WORKING
GROUP.
THIS IS ONE WE HAD A LINE VISION
TO CREATE LARGE ADD LASS AND SO
WITH THAT WE WORKED WITH TO
THINK ABOUT WHAT WOULD THEY NEED
TO DO TO BE ABLE TO CREATE THIS
LARGE WHOLE BRAIN MOUSE
INTERACTIVE ATLAS.
TAKING DATA AND BEING ABLE TO
PERFORM ANALYSIS TOGETHER IN ONE
SPACE.
WE REALIZED WE COULD DO THAT AND
LEVERAGING THE NEMO ARCHIVE AND
MOVING IT TO THE ENVIRONMENT AND
LEVERAGING DIFFERENT PIPELINES
FOR PROCESSING AND A SPACE TO DO
ANALYSIS SPANS MULTIPLE
INSTITUTES.
THE FIRST WAS TO HAVE THE DATA
BROUGHT TO A SCALABLE COMPUTING
ENVIRONMENT.
WE WERE WORKING WITH THE NEMO
ARCHIVE.
WE WERE ABLE TO CREATE A HANDOFF
FROM THE NEMO ARCHIVE WHICH HAS
THE BICCN MOLECULAR DATA.
IT HANDS OFF LINKS TO FILES SO
IT'S FAST AND EFFICIENT AND
OPEN, AVAILABLE FUNCTIONALITY
ANYONE CAN LEVERAGE IF YOU'RE
INTERESTED.
WITH THAT IN HAND, WE WERE ABLE
TO DATA FROM THE NEMO ARCHIVE TO
TERRA BLINKS AND PROFESSION THEM
AS IF THEY WERE NORMAL
PROCESSING AND NEXT WAS TO HAVE
A UNIFORM PROCESSING.
WE WORKED IN A CONSORTIA
PARTNERING APPROACH.
WE PARTNERED WITH DIFFERENT LABS
AND GROUPS TO BRING PIPELINES
THEY HAVE AND HAVE CONFIDENCE IN
AND MAKE THEM AVAILABLE TO A
LARGER COMMUNITY AND LEVERAGE IT
IN OUR OWN PROCESSING.
THIS ENABLED US TO MAKE PIPELINE
FOR THE PROCESSING AND THE
PIPELINES ARE AVAILABLE AT THE
BICCN PORTAL AND THERE WE HAVE
I.D.s TO MAKE SURE THEY'RE
IDENTIFIABLE AND HAVE THE FULL
CODE AVAILABLE IN GITHUB NET
BOOKS AND HAVE THEM INSTALLS IN
TERRA WORK SPACES WHICH BRINGS
THE PIPELINE TO A CLOUD
ENVIRONMENT IF YOU'D LIKE TO USE
IT AND PUBLICATIONS ASSOCIATED
WITH THE ORIGINAL PARTNERS THERE
AS IF THEY WERE AVAILABLE.
WE WOSHGSD WITH THE WORKING
GROUP TO MAKE SURE THIRD PART
YEAR EVALUATED AND AUDITED TO
MAKE SURE IT WAS UNDERSTANDABLE
AND READABLE AND USABLE IN
MULTIPLE PLACES.
WE ALSO WORKED IN CREATE
WORKSHOP TO MAKE SURE THE
RESOURCE NOT ONLY ACCESSIBLE BUT
REUSABLE AND MADE SEVERAL WORK
SHOPS.
WE'VE RECORDED THEM ON YOUTUBE
AND GO FROM NEMO TO ANALYSIS.
I'LL THE DOCUMENTATION IS
AVAILABLE ONLINE AS WELL.
OUR FRIENDS WERE ABLE TO PROCESS
ALL THE DATA AND ALMOST FINISHED
DOING THAT.
IT'S BEEN AMAZING HOW QUICKLY
THEY'VE BEEN ABLE TO DO THAT.
WE'RE MOVING INTO A SPACE TO DO
ANALYSIS TOGETHER.
WE HAVE THE DATA AND COMPUTING
IN ONE SPACE TO SHARE AND THE SO
YOU'LL BE ABLE TO IN A WORK
SPACE FOR INSTANCE USE THE RAW
DATA LINKED USED FOR PROCESSING
TO DESCRIBE WHAT YOU'RE SEEING
AND THAT'S SOMETHING YOU CAN
CONTROL AND ADD TO AS A GROUP.
DOCUMENTATION HOW TO RESOURCE
THIS IS AVAILABLE AND YOU CAN BE
AWARE OF HOW TO SHARE OR
WHATEVER IT MIGHT BE AND A SPACE
TO DOCUMENT THAT.
CENTRALIZED WORK FLOWS USED FOR
PROCESSING CAN BE MADE AVAILABLE
TO LEVERAGE AND YOU CAN USE A
JUPITER NOTEBOOK AND YOU CAN DO
IT THAT WAY AND ONE AGAIN IT'S
SECURE AND SHARED SO THE
CONSORTI HAVE THE POWER TO SHARE
AS THEY NEED TO.
AS WE'VE GONE THROUGH THIS
APPROACH WE'VE LEVERAGED OPEN
SYSTEMS ANYONE CAN LOG INTO.
WE CREATED PIPELINES AND MADE
THEM AVAILABLE IN MANY WAYS.
ALSO THEY'RE IN DOC STORE SO
LOTS OF PLACES THE PIPELINES ARE
AVAILABLE AND HAS COMPUTATIONAL
NEEDS TO BIG SCIENTIFIC
QUESTIONS WHICH I'M PERSONALLY
PROUD OF.
THIS WAS A LARGE EFFORT WITH
MANY PEOPLE INVOLVED.
I WOULD LIKE TO HIGHLIGHT THE
BROAD TEAM AND NEMO TEAM AND
COLLABORATORS AND THE BRAIN
WORKING GROUP AND STANDARDS
WORKING GROUP AND INFRASTRUCTURE
WORKING GROUP.
THANK YOU FOR YOUR TIME.
>> HI, EVERYONE.
>> I'M HERE TO TELL YOU ABOUT
THE MULTI-OMIC ARCHIVE.
THE NEMO ARCHIVE.
SO NEMO IS THE GENOMIC ARCHIVE
FOR THE BRAIN INITIATIVE AND OUR
GOALS ARE AS FOLLOWS.
WE'RE TRYING TO PROVIDE ACCESS
TO THE RAW AND GENOMIC DATA
BEING GENERATED BY ALL THE
PROJECTS BEING FUNDED BY BICCN
AND OTHER EFFORTS OUR GOAL IS TO
MAKE THE DATA FAIR, FINDABLE,
INTEROPERABLE AND REUSEFUL AND
MAKE IT POSSIBLE FOR ANYONE IN
THE WORLD TO USE THESE DATA FOR
WHATEVER PURPOSES THEY HAVE I'LL
TELL YOU ABOUT THE WAYS.
THERE'S NEMO ARCHIVE.org.
NOT TOO MUCH TO SAY ABOUT THE
LANDING PAGE ITSELF OTHER THAN
THIS IS WHERE YOU GO FIND THE
DATA.
THE RESOURCES HAVE INCREASED
DRAMATICALLY SINCE THE ARCHIVE
WAS FOUNDED IN 2017.
YOU CAN SEE WE HAVE HUNDREDS OF
DATA PROVIDED TO US WITHIN OUR
COLLABORATIVE.
THE DISTRIBUTION BY DATA TYPES
IS SHOWN ON THE LEFT.
THE BULK ARE SINGLE CELL AND
SINGLE NUCLEUS RNA SEQUENCING
DATA AND A LARGE COLLECTION OF
SINGLE CELL EPIGENOMIC DATA.
INCREASINGLY GROUPS ARE
DEVELOPING OTHER DATA SUCH AS
FACIAL TRANSCRIPTOMICS.
THIS IS INCREASINGLY A RICH
RESOURCE.
THE SO THE FIRST WAY TO FIND
DATA WITHIN THE NEMO ARCHIVE IS
THE NEMO PORTAL.
WE DEVELOPED A FACETED SEARCH TO
ENABLE USERS TO IDENTIFY FILES
THEY'RE INTERESTED IN BAIFT ON
THE -- BASED ON THE INVESTIGATOR
AND PHILE TYPE.
YOU CAN SEE THE PIE CHARTS THAT
DYNAMICALLY UPDATE HOW MUCH DATA
CORRESPOND TO EACH OF THOSE
TYPES AND AS YOU SEARCH IN
YOU'LL BE ABLE TO IDENTIFY THE
SPECIFIC FILES THAT CORRESPOND
TO THAT.
WHEN YOU DO THAT, YOU CAN ADD A
PARTICULAR DATA SET TO WHAT WE
CALL A SHOPPING CART AND ALLOWS
YOU TO INTERACT IN SEVERAL WAYS.
THE ONE CASE JUST DISCUSSED IN
NICE DETAIL IS TO MOVE DATA SETS
FROM THE ARCHIVE INTO THE
PIPELINES FROM TERRA.
THIS ENABLES PEOPLE TO PROCESS
DATA USING THE CONSENSUS
APPROACHES AND DOWNLOAD YOUR
DATA TO USE OTHER PIPELINE.
I'LL TELL YOU THE SETS FURTHER
ALONG BECAUSE THEY'RE PART OF
THE PUBLICATIONS FROM LAST FALL.
IN ADDITION TO THE DATA AND THE
PROCESSED COUNTS AVAILABLE SOON
WE CREATED ADDITIONAL RESOURCE
TO MAKE IT EASY TO IDENTIFY THE
DATA AND BEGIN TO ANALYZE THEM.
FOR EACH DATA SET THERE'S A
LANDING PAGE THAT PROVIDES THE
CRITICAL METADATA FOR UNDER
THING WHICH THINGS WERE USED
SORRY, THE SLIDES ARE ADVANCING
NOT THE WAY I INTENDED.
THERE'S ALSO AN HTTP SITE WHERE
YOU CAN IDENTIFY ALL THE
INDIVIDUAL FILES AND DOWNLOAD
THEM AS YOU WISH.
IN ADDITION WE BUILT A WEB
BROWSER CALLED NEMO ANALYTICS
THAT ALLOWS ANALYSIS OF THE DATA
AND VISUALIZATIONS INCLUDING
DYNAMIC VIEW MAPS AND A SINGLE
CELL WORK BENCH THAT ALLOWS TO
YOU DO PARTS OF THE ANALYSIS.
IT ALLOWS USERS TO UPLOAD THEIR
OWN DATA SETS AND CREATE
PROFILES OF THEIR OWN.
THESE PROFILES ARE CURRENTLY
AVAILABLE FOR SEVERAL OF THE
FLAGSHIP DATA SETS FROM THE
PRIMARY MOTOR CORTEX AND FROM A
GROWING COLLECTION OF BRAIN
DEVELOPMENT DATA SETS.
SO OUR TEAM, THE PRINCIPLE
INVESTIGATOR OF THE NEMO ARCHIVE
IS OWEN WHITE.
THIS HAS BEEN A PARTNERSHIP WITH
A NUMBER OF OTHER GROUPS.
WE WORKED CLOSELY WITH BCDC WITH
THE ANALYSIS WORKING GROUPS AND
THE TEAM AT THE BROAD AND
ANALYTICS IS HEADED BY A LARGE
TEAM OF ENGINEERS AND ANALYSTS
THAT MAKE IT ALL POSSIBLE.
THANK YOU VERY MUCH.
>> I'M ALEX ROPELEWSKI.
THE BRAIN IMAGE LIBRARY IS A
PUBLIC RESOURCE SERVING NOOURS
COMMUNITY BY PROVIDINING -- THE
LIBRARY RELIES ON CONTRIBUTIONS
FROM DATA PRODUCERS SUCH AS THE
INVESTIGATORS PART OF THE BICCN
CONSORTIUM.
I DO WANT TO NOTE THE LIBRARY IS
ONE OF SEVERAL DATA ARCHIVES
ESTABLISHED TO RECEIVE DATA FROM
NIH BRAIN INITIATIVE PROJECT
WITH EACH ARCHIVE FOCUSSING ON A
PARTICULAR DATA TYPE, IN OUR
CASE MICROSCOPY.
WHILE THE LIBRARY IS NIH FUNDED,
NIH FUNDING IS NOT REQUIRED TO
CONTRIBUTE DATA BUT THE DATA
NEEDS TO BE RELEVANT TO THE
BRAIN INITIATIVE.
TO MANY DATA SETS WE HOUSE AT
BILL ARE QUITE LARGE.
WE PROVIDE AN EXTENSIVE
COMPUTATIONAL ACCESS WHERE USERS
CAN EXPLORE DATA IN PLACE
WITHOUT DOWNLOADING IT.
THERE'S NO CHARGES FOR DEPOS ING
DATA OR USING COMPUTATIONAL OR
OTHER SERVICES BILL PROVIDES.
THE DATA SCOPE FOR BIL INCLUDES
WHOLE AND PARTIAL BRAIN DATA
SETS FROM MICE, PRIMATES
INCLUDING HUMANS AND MODEL
ORGANISMS.
TARGET MICROSCOPE ENABLED
EXPERIMENTS INCLUDING
CONNECTIVITY BETWEEN CELLS AND
TRANSCRIPTOMICS AND HISTORICAL
COLLECTIONS OF VALUE TO THE
COMMUNITY.
TO GIVE A PREVIEW OF THE HIGH
QUALITY BICCN DATA IN BIL, THE
VIDEO SHOWS CELL COUNTING DATA
SET CONTRIBUTED BY DR. AUSTIN
NOW AT CERTIGO THERAPEUTICS.
THE DATA SET IS AAA -- A FEW
HUNDRED SPLICES LONG.
SOME OF THE LARGEST COMES FROM
BICCN AND THEY'RE GENERATED
USING THE FMOSS TECHNOLOGY.
THESE FMOSS DATA SETS RANGE FROM
8 TO 13 TERABYTES EACH AND
CONTAIN 15,000 SLICES AND UP AND
THE INDIVIDUAL SLICE IN FMOS
DATA SETS IS A Z SPACING OF
ABOUT SAY A MICRON.
IN TERMS OF EXISTING COVERAGE
THE OVERWHELMING AMOUNT OF DATA
SETS CONTRIBUTED ARE FROM MICE
WITH A HANDFUL FROM MARMOSETS
AND HUMANS.
IN TERMS OF DATA MODALITIES MOST
PRIMELY DATA SETS ARE IMAGE
STACKS FROM WHOLE BRAIN IMAGING
EXPERIMENTS.
IN ADDITION TO THOSE DATA SETS
WE HAVE THOUSANDS OF TRACING
FROM PRIMARY DATA IN THE
ARCHIVE.
IN TERMS OF TECHNOLOGY WE HAVE
DATA FROM MOST MICROSCOPE TYPES
AS WELL AS MICROSCOPY RELATED
DATA FROM SPATIAL
TRANSCRIPTOMICS AND MULTIMODAL
EXPERIMENTS AND WE HAVE ABOUT 10
MILLION PUBLIC FILES.
YOU CAN FOLLOW THE LINK FROM THE
MAIN BICCN SITE OR USE THE BIL
SEARCH PAGE WHICH SHOWS BASIC
METADATA FOR THE DATA SET, A
DOWNLOAD LINK TO THE DATA AND
THE LOCATION OF DATA ON OUR
ANALYSIS ECO SYSTEM.
OUR COMPLETES DATA INVENTORY IS
ALSO DOWNLOADABLE FROM THE
SEARCH PAGE.
WE'RE IN THE PROCESS OF
TRANSITIONING ALL DATA IN BILL
INCLUDING THE BICCN DATA TO A
MORE EXTENSIVE DATA MODEL
DEVELOPED BY CAROL HAMILTON'S
BRAIN INITIATIVES STANDARDS
PROJECT.
AS PART OF THAT TRANSITION
PROCESS WE HAVE BEGUN TO ISSUE
DIGITAL OBJECT IDENTIFIERS FOR
ALL COMPLIANT DATA SETS IN BILL.
WE EXPECT THIS PROCESS TO BE
COMPLETE FOR ALL BICCN DATA
WITHIN THE NEXT FEW MONTHS.
THIS WILL BY TRANSITIONING TO
D.O.I.s WILL ALLOW EASE OF USE
OF CITATION AND EASE OF USE FOR
PEOPLE LOCATING THE DATA LISTED
IN THE PUBLICATION.
IN TERMS OF COMING ATTRACTIONS
WE'LL HAVE ONE-CLICK
VISUALIZATION FROM THE LANDING
PAGES IN THE NEAR FUTURE.
ILLUSTRATED HERE IS ANOTHER
BICCN COUNTING DATA SET MAKING
USE OF THE SOFTWARE.
I'D LIKE TO MENTION THE NUMEROUS
RESOURCES WE HAVE THROUGH OUR
ANALYSIS ECO SYSTEM.
THIS INCLUDES SMALL AND LARGE
MEMORY NODES, NODES WITH GPU'S
AND OUR CS2 SYSTEMS.
BIL ALSO PROVIDES A DESK TOP
ENVIRONMENT AS WELL AS THE
CAPABILITY TO HOST UNIQUE WEB
INTERFACES TO THE DATA AS WELL
AS SUPPORTING NUMEROUS SOFTWARE
PACKAGES.
OTHER SERVICES OFFERED INCLUDE
HELP DESK SERVICES AS WELL AS
NETWORK PATH ANALYSIS AND
TROUBLE SHOOTING WHICH IS
IMPORTANT TO TRANSFER LARGE DATA
SETS.
I WANTED TO MENTION THERE ARE NO
CHARGES FOR USING ANY OF THESE
RESOURCES AND SERVICES AND THE
INSTRUCTIONS FOR HOW TO GET
ACCESS TO THE ANALYSIS ECO
SYSTEM ARE AVAILABLE ON OUR
WEBSITE.
TO GET STARTED EITHER AS A DATA
CONTRIBUTOR OR DATA USER WE ARE
OFFERING WORKSHOPS JULY 27 AND
28.
THE WORKSHOP ON THE 27th WILL
FOCUS ON HOW TO CONTRIBUTE DATA
TO BILL AND THE WORKSHOP ON THE
28th WILL FOCUS ON HOW TO USE
DATA THROUGH THE ANALYSIS ECO
SYSTEM.
PLEASE VISIT OUR WEBSITE AT
WWW.BRAINIMAGELIBRARY.org OR
SEND E-MAIL TO BILL-SUPPORT AT
PSC.EDU FOR MORE INFORMATION
ABOUT THESE WORK SHOPS OR ANY
QUESTIONS YOU MAY HAVE.
FINALLY, I'D LIKE TO ACKNOWLEDGE
OUR BICCN AND OTHER DATA
CONTRIBUTORS AND COLLABORATORS
AND THE BIL TEAM AND OUR PRIMARY
FUNDER, THE NATIONAL INSTITUTES
OF HEALTH.
I'M JESSE GILLIS.
I'M HERE TO TALK ABOUT
REPLICABILITY IN SINGLE CELL
DATA AND WE'VE ANALYZE THE
NETWORK DATA AND SHOW RESULTS
AND METHODS AND HOPE YOU MAKE
YOU CONFIDENT THE DATA IS HIGH
QUALITY AND CAN BE USED FOR LOTS
OF PURPOSES DOWN STREAM.
SO THE FIRST THING I'D LIKE TO
HIGHLIGHT IS THAT A LOT OF THE
METHODS AND THINKING AROUND CELL
TYPE CLUSTERING CAN BE SEEN IN
EARLIER RESEARCH AND
PARTICULARLY CANCER RESEARCH
WHERE THE WORK CLUSTERS PEOPLE
ARE TRYING TO IDENTIFY ARE
CHARACTERIZED AS REPLICABLE.
YOU DO HAVE THE PROBLEM YOU
CAN'T STEP IN THE SAME RIVER
TWICE AND IT'S HARD TO TAKE
DATA, COLLECT IT AND RE-COLLECT
THE SAME DATA AND SAY WHETHER IT
REPLICATIONS.
THERE'S VARIATION ACROSS
POPULATION AND SAMPLING CANCER
AND SINGLE-CELL DATA WE CAN HAVE
DIFFERENCES AND HAVE TO HAVE A
WAY TO DETERMINE WHETHER THE
CLUSTERS CAN BE MEANINGFULLY
REPLICATED AN THERE'S A
STATISTICAL APPROACH NOT TO
COMPLICATED AND ONE TRIES TO SAY
WHETHER THE SETS OF GENES THAT
DEFINE THE CLUSTERING ARE
MEANINGFULLY CORRELATED BETWEEN
DATA SETS AND THAT MEANS THE
SAME SETS OF CELLS IN THE SAME
WAYS.
THIS IS AN APPROACH AS I'M
HIGHLIGHTING ON THE SLIDE FOR
DATA AND REDISCOVERING IT IS
SOMETHING WE WORKED ON FOR THE
LAST FEW YEARS.
THE ESSENCE OF THE APPROACH IS
IF YOU HAVE THREE DATA SETS AND
CELL TYPES THAT CHARACTERIZE
CLUSTERS OF THE DATA SETS YOU
CAN BUILD A NETWORK ACROSS THE
DATA SETS AND CHARACTERIZE THE
CELLS.
ONE MAY USE A CORRELATION OF
SOME GENES TO A GENOMICS PROFILE
TO DETERMINE IF THE CELLS ARE
CORRELATED WITH RESPECT TO THE
GENES AND ASK WHETHER THE
CLUSTER IN ONE DATA SET IS
CORRELATED WITH A CLUSTER IN
ANOTHER DATA SET WHETHER IT
DEFINES THE SET OF CELLS IN THE
OTHER SET AND IF THE DATA IS
CLUSTERING AND THAT'S WHAT WE
MEAN BY CALLING A CELL TYPE
REPLICABLE AND IDENTIFYING A
CELL TYPE CORRECTLY.
IT DOESN'T REQUIRE SUPERVISE
DATA BUT CAN LOOK AT THE TWO
DATA SETS.
WE APPLIED THIS IN THE CELL
CENSUS NETWORK DATA AND IT
CLEANS UP THE DATA AND
REPLICATES ACROSS LABORATORIES
ACROSS TECHNOLOGIES AND
MODALITIES AND SPECIES AND WE
CAN MAKE COMPARATIVE ASSESSMENTS
AND LOOK AT STRUCTURE ACROSS
STRONG FORCES AND POTENTIAL
ARTIFACT.
AND YOU CAN LOOK AT THE CELL
TYPES WHERE THEY'RE IDENTICAL
ACROSS THE TECHNOLOGIES AND
LABORATORIES.
THIS THERE IS NO CORRECTION OR
MERGING OF THE DATA OR MODEL
THAT MERGES THE DATA.
THERE'S IF IT REPLICATES WELL IT
CHARACTERIZES THE DATA THEN YOU
SAVE THE DATA.
THERE'S A RELATIVELY SCALABLE
APPROACH.
AND ONE NICE THING IS IT DOESN'T
ASSUME THERE'S NOT REQUIREMENT
FOR DATA BE MERGED.
ONE CAN LOOK AT REPLICABILITY
AND HERE IN COLLABORATION WITH
SCIENTISTS YOU CAN SEE THERE'S
DATA SETS THAT HAVE
NON-SIGNIFICANT PARTS OF THE
HEAT MAP SCALED TO WHITE AND
THERE'S REPLICABLE CELL TYPES
AND THEN YOU CAN STUDY
TRANSCRIPTOMICS BETWEEN THE TWO
SPECIES AND THOSE DO SHOW
VARIATIONS SOMETIMES AND THEY
DON'T ALIGN PERFECTLY BUT MOST
DO.
AND SOME GENES WON'T ALIGN
PERFECTLY.
IF THE CELL TYPE IS REPLICABLE
YOU CAN SEE AS WE MAKE THE TASK
MORE AND MORE DIFFICULT IT'S
MORE AND MORE IMPORTANT TO TAKE
AN INFORMATIVE GENE SET.
AND AS THE TASK BECOMES ALMOST
IMPOSSIBLE MEANING TWO CLUSTERS
TRYING TO DISTINGUISH FROM ONE
ANOTHER ARE VIRTUALLY IDENTICAL
AND LOO LOOKING AT THE
TRANSCRIPTOME YOU STOP BEINGIBLE
TO DISTINGUISH AND THE ORIGINAL
ARE DEFINED FROM THE UN
UNSUPERVISED AND WE CAN GO BACK
AND LOOK AT THE GENES AND
LOOKING AT COMPARISONS WHICH ARE
THE SETS OF GENES WHICH
CONTRIBUTE MOST TO THE BRAIN
INITIATIVE CELL CENSUS DATA AND
WE CAN DO THE SAME ANALYSIS AND
DO MORE GENERAL REPLICABILITY
ANALYSIS AND THE MIDDLE IS
METHODOLOGICAL DATA AND LOOK AT
INDIVIDUAL DATA SETS AND LOOK
ACROSS MODALITIES SO THERE'S
WITHIN THIS TAXATION AND
METHYLATION AND RNA SEQ DATA
SOME WHICH MAY NOT LINE UP
PERFECTLY BUT DOES AT A BROAD
RANGE AND THERE'S CELL LINES
THAT LINE UP WHICH MAY BE
HELPFUL TO SOME DEGREE BUT
REQUIRES YOU IF YOU WANT TO USE
THE INFORMATION TO REDOWNLOAD
THE DATA SET IN SOME WAY.
SOME OF THE MORE SHARABLE PIECES
OF DATA ARE THE TRANSCRIPTOMICS
FEATURES THAT DEFINE THE CELL
TYPES IN SOME MEANINGFUL WAY.
NOW WE HAVE LINED UP DATA SETS
AND LOOK AT WHETHER SOME
REPLICATE ACROSS THE DATA SETS.
BECAUSE WE HAD NO MERGING OF THE
DATA YOU CAN ASSESS WHETHER IT'S
IN ONE DATA OR A LARGER SET OR
SOME SUBSET OF DATA.
WE FIND THERE'S A TRADE-OFF
BETWEEN MARKERS THAT ARE THERE'S
NEURONS THAT DON'T IDENTIFY
NEURONS AND THEY'RE RECALLED AND
OTHER MARKERS USEFUL BECAUSE
THEY'RE BROADLY EXPRESSED SO
THEY'RE NOT VERY PRECISE AND DO
IDENTIFY IN A WEAK SENSE A LOT
OF THE NEURONS.
THAT'S THE TRADE-OFF YOU'RE
SEEING IN THE BOTTOM LEFT
CORNER.
AND WE MADE ALL THESE AVAILABLE
AND YOU CAN LOOK AT ONES THAT
TRANSLATE BETWEEN SPECIES OR
MODALITIES OR ANYTHING ELSE.
IT'S A SHAREABLE WAY OF THE DATA
WITHOUT USING ALL THE DATA.
I'M ENTHUSIASTIC IT'S SHAREABLE
AND DELIVERABLE FOR THIS.
WE LOOKED AT THE INITIAL
CONSORTIUM AND YOU CAN SEE THE
BRIGHT SQUARES SHOW GOOD
ALIGNMENT FOR ALMOST ALL THE
CELL TYPES EXCEPT THE ONES WHERE
THEY WEREN'T PRESENT
PARTICULARLY.
THAT'S BECAUSE WE PICKED MARKER
SETS THAT REPLICATED AND IT'S NO
SURPRISE THEY REPLICATED OR
CONTINUE TO REPLICATE FURTHER.
SEEING THEY REPLICATED IN
MULTIPLE DATA SETS IS STRONG
EVIDENCE THEY'RE USEFUL.
OUR MISSION STATEMENT IS TO MAKE
THIS ACCESSIBLE IN A WAY
SCIENTISTS CAN DIRECTLY USE AND
HAPPY TO DISCUSS REPLICABILITY
AND WITH THAT I'LL THANK MY LABS
AND ALL THE DATA GENERATORS YOU
HEARD FROM AND COLLABORATORS AT
THE CONSORTIUM AND FUNDING
AGENCIES.
THANK YOU VERY MUCH.
>> HELLO.
I'M GOING TO WRAP UP TODAY'S
REPRESENTATION BY TALKING ABOUT
STANDARDS IN THE BICCN FOR STAR
DARDS TOWARDS FAIR NEUROSCIENCE.
WHY STANDARDS AND WHY FAIR?
WHY ARE WE DEVOTING A TALK TO
THIS?
AS YOU CAN IMAGINE AND HEARD IN
THE PREVIOUS PRESENTATIONS THAT
BICCN IS SET UP AS A DISTRIBUTED
INFRASTRUCTURE HANDLING MANY
DIFFERENT TYPES OF DATA ACROSS
MANY SCALES THAT ARE GENERATED
BY DOZENS OF LABS AND HOSTED BY
MULTIPLE ARCHIVES.
SO MAKING SURE THE DATA ARE
FINDABLE, ACCESSIBLE AND
INTEROPERABLE AND REUSABLE IS
CRUCIAL TO FUNCTION AND
STANDARDS ARE THE THINGS THAT
ALLOW US TO BOTH INTEGRATE DATA
ACROSS DIFFERENT TYPES AND HOW
TO MORPHOLOGICAL TOOL BASE TO
UPLOAD IN THE ARCHIVES AND REUSE
OF THE DATA BY MULTIPLE PEOPLE.
WE HAVE A SECTION IF YOU'RE
INTERESTED IN MORE DETAILS ABOUT
THE STANDARDS USED AND HOW TO
THEY'RE DEVELOPED.
THERE'S A SECTION OF THE WEB
PORTAL DEVOTED TO THAT.
YOU CAN ACCESS IT UNDER THE
STANDARDS MENU UP THERE AND IT
BASICALLY SHOWS THREE SECTIONS.
ONE IS THE BICCN WORKING GROUP.
THESE ARE BICCN INVESTIGATORS
WHO COME TOGETHER AROUND SOME OF
THE NEW TECHNIQUES AND
TECHNOLOGIES AND TYPES GENERATED
AND DETERMINE WHAT THE BEST
PRACTICES AND STANDARDS CAN BE
TO MAKE THE DATA MORE FAIR.
WE ALSO HAVE A SET OF STANDARDS
ALEX MENTIONED ONE DEVELOPED BY
THE BRAIN INITIATIVE AND ALSO
IMPLEMENTED ACROSS HERE AND
THERE'S COMMUNITY STANDARDS SUCH
AS THOSE LISTED BY THE
INTERNATIONAL COORDINATING
COMMITTEE THE BICCN ADOPTED.
VERY IMPORTANT INSIDE ALL THIS
DATA IS SPATIAL ALIGNMENT AND
FOR THAT WE'RE USING THE BRAIN
COMMON FRAMEWORK AND ALL THE
RESEARCHERS AGREED TO ALIGN THE
DATA USING THE COORDINATE
SYSTEM.
JUST A LITTLE BIT MORE
INFORMATION ABOUT FAIR ITSELF.
THE FAIR DATA PRINCIPLES WERE
ISSUED BACK IN 2016 AND WHEN THE
BICCN STARTED THERE WAS VERY
LITTLE AWARENESS OF FAIR SINCE
FAIR HAS BEEN PROMOTED IN A LOT
OF THE DATA SHARING POLICIES THE
BRAIN AND NOW NIH IN GENERAL.
I HOPE MOST OF THE AUDIENCE ARE
IN FACT FAMILIAR WITH WHAT THE
ACRONYM MEANS.
THEY'RE HIGH-LEVEL PRINCIPLES TO
MAKE DATA FINDABLE, ACCESSIBLE,
INTEROPERABLE AND REUSABLE AND
THERE'S RECOMMENDATIONS PUT IN
PLACE FOR DATA TO BE USED BY
COMPUTERS AND PEOPLE AND THERE'S
REQUIREMENTS OF FAIR.
A GOOD DATA MANAGEMENT PRACTICE
IN LABORATORY AND ROUTINE USE OF
STANDARDS BOTH INSIDE THE
ARCHIVES AND AMONGST THE
INVESTIGATORS DEPOSITING DATA
THEMSELVES.
THE IDEA OF FAIR IS THAT IT'S
ASPIRATIONAL AND AT THE
BEGINNING OF THE BICCN THE
ARCHIVES WERE COMING ONLINE AND
THE STANDARDS WERE NOT YET
DEVELOPED AND THE DATA TYPES AND
TECHNIQUES BEING USED DIDN'T
HAVE STANDARDS OR BEST PRACTICES
AVAILABLE.
BUT THE CORE OF FAIR IS TO USE
THINGS LIKE PERSISTENT
IDENTIFIERS.
YOU HEARD ALEX TALK ABOUT
D.O.I.s.
PERSISTENT IDENTIFIESERS LI ERER ERERS --
IDENTIFIERS SO ONE CAN FIND IT
ON THE WEB AND ACCESS IT.
THE USE OF LANDING PAGES IS VERY
IMPORTANT BECAUSE THE DATA SET
LANDING PAGE PROVIDES A LOT OF
THE CONTEXTUAL INFORMATION ONE
NEEDS TO BE ABLE TO UNDERSTAND
THE DATA SET AND MAKE IT
REUSABLE AND INTEROPERABLE AND
PROVIDES ACCESS AND ADDITIONAL
SUPPORTING INFORMATION THAT
MAKES IT EASIER TO USE THE DATA.
SO FOR EXAMPLE, LINK TO
PROTOCOLS, LINK TO TOOL SETS
THAT CAN BE USED WITH THE DATA.
PROVENANCE FROM THE LAB AND
UNIVERSITY THAT ORIGINATED THE
DATA AND THE EXPERIMENTAL
PROTOCOL THAT GAVE RISE TO THE
DATA AND METHODOLOGICAL DATA AND
IF IT'S A DERIVED DATA SET WHAT
IS THE PARENT DATA SET IN WHICH
IT WAS DERIVED FROM AND A LOT OF
TIMES DATA SETS HAVE MULTIPLE
VERSIONS AND THEY NEED TO BE
HANDLED IN A FAIR MANNER AND USE
OF THE COORDINATE SYSTEMS AND
COMMUNITY ONTOLOGY AND
CONTROLLED VOCABULARIES TO
DESCRIBE THE DATA IN A
CONSISTENT WAY THAT IS
CONSISTENT ACROSS THE DATA HEEKO
SYSTEM THAT HAS BEEN BUILT FOR
THE BRAIN INITIATIVE.
AS I MENTIONED AIDS FOR
UNDERSTANDING AND REUSING THE
DATA AND ALSO THE USE OF CLEAR
LICENSES AND DATA USE AGREEMENTS
SO THAT EVERYONE WHO NEEDS TO
REUSE THE DATA UNDERSTAND THEIR
RIGHTS AND RESPONSIBILITIES FOR
REUSE.
AND HERE'S NEURO PHYSIOLOGY DATA
AND THIS IS A LANDING PAGE
THAT'S BEEN SET UP TO FACILITATE
FAIR.
THIS WORK AS YOU SAW IS UNDERWAY
ACROSS ALL THE DIFFERENT
ARCHIVES TO TRY AND MAKE THE
DATA AND METADATA THAT ARE
AVAILABLE ON THE LANDING PAGES
CONSISTENT SO THAT USERS HAVE A
CONSISTENT EXPERIENCE WHEN THEY
GO ACROSS THE ARCHIVES.
BUT HERE YOU CAN SEE A TITLE OF
THE DATA SET.
YOU SEE THE DOI THE IDENTIFIER
AND OTHER USEFUL INFORMATION,
METADATA, FILE ACCESS THAT CAN
BE USED IF YOU'RE INTERESTED IN
BEING ABLE TO FIND THE DATA AND
ALSO REUSE THE DATA.
AND KEY WORDS AND OTHER THINGS
SEARCH ENGINES CAN LOOK AT AND
ARTICLES PROVIDED AND A CONTACT
PERSON HAS BEEN PROVIDED AND THE
THINGS THAT MAKE IT MOST LIKELY
FOR PEOPLE TO REUSE THE DATA AND
THERE'S A CONTACT PERSON TO
ANSWER YOUR QUESTIONS IF YOU
NEED ABOUT A PARTICULAR DATA
SET.
ONE THING THAT WE FIND WITH
RESEARCHERS WHEN THEY'RE
DESCRIBING THEIR DATA IS THEY
TEND TO USE VERY MECHANISTIC
TERMS AND WE GET A LOT OF
DESCRIPTIONS THAT JUST SAY
MICROSCOPY IMAGES.
WE'RE ENCOURAGING RESEARCHERS TO
PUT IN A RICH DESCRIPTION THAT
HELPS SOMEBODY UNDERSTAND THE
CONTEXT OF THE DATA SET AND WHAT
IT'S USEFUL FOR AND STANDARDS
AVAILABLE AND USING STANDARDIZED
VOCABULARIES BEING IMPLEMENTED
BY BICCN AND THE ARCHIVES.
I ALSO WANTED TO POINT OUT THE
IMPORTANCE OF EXPERIMENTAL
PROTOCOLS.
CAROL MENTIONED THESE ALREADY.
THERE'S BEEN A BICCN GROUP
CREATED IN PROTOCOLS.IO THE
ONLINE PERFORM AND MOST HAVE
BEEN STUDIED AND THEY'VE BEEN
ACCESSED OVER AND OVER AGAIN
OVER 43,000 TIMES AS OF APRIL OF
2022.
AND MAKE SURE THOSE WHO DEPOSIT
THEIR DATA AND MAKE IT AVAILABLE
SO WE CAN TRACK AND REUSE.
WE'RE BASICALLY IMPLEMENTING THE
RECOMMENDATIONS ON FORMAL DATA
CITATION AND THE ARCHIVES ARE
TRYING TO MAKE THAT EASY AND YOU
CAN USE THIS IN YOUR DATA
AVAILABILITY STATEMENT OR ALSO
IN THE REFERENCE LIST ACCORDING
TO RECOMMENDATIONS FOR BEST
PRACTICES.
SO JUST TO WRAP UP HELPING
CREATE UNIFORM STANDARDS ACROSS
BICCN.
IT'S A WORK IN PROGRESS BUT
WE'RE TRYING TO WORK TOWARDS A
COMMON AND STANDARDIZED
EXPERIENCE FOR USERS TO MAKE IT
EASIER TO NAVIGATE, FIND DATA
AND BE ABLE TO REUSE IT.
IT DOES REQUIRE COOPERATION
BETWEEN INVESTIGATORS AND THE
ARCHIVES.
THOSE WHO SUBMIT DATA REALLY THE
BURDEN IS ON TO YOU MAKE SURE
YOU PROVIDE THE TITLES AND
DESCRIPTIONS AND AS MUCH AS
CONTEXTUAL METADATA YOU CAN
PROVIDE.
BUILDING FAIR AND DATA SHARING
IN YOUR DATA MANAGEMENT
PRACTICES SO IT'S NOT A MATTER
OF PRODUCING AND ALIGNING AT THE
END BUT YOU BASICALLY ALIGN
DURING THE ENTIRE LIFE CYCLE AND
WE'RE IN THE PROCESS OF CREATING
A FAIR DATA STARTER KIT THAT
SHOULD MAKE THAT EASIER FOR
INVESTIGATORS TRYING TO SUBMIT
DATA USING THE BICCN AND
SUBSEQUENT VERSIONS OF THAT.
FOR DATA USERS WE HOPE THIS
SYMPOSIUM HAS GIVEN YOU AN IDEA
OF THE RICHNESS OF THE DATA
AVAILABLE AND HELP DRIVE THE
RE-USE OF THE DATA BUT IF YOU
RUN INTO A PROBLEM LET US KNOW.
THE RE-USE CASES MAKE THE
INFRASTRUCTURE BETTER AND I WANT
TO URGE TO YOU GIVE CREDIT TO
THE DATA PRODUCER AND BICCN WHEN
DO YOU RE-USE DATA BY USING FAIR
DATA CITATION PRACTICES.
JUST TO END I WANT TO THANK THE
METADATA WORKING GROUP AND
INFRASTRUCTURE MEETING OVER THE
LAST FIVE YEARS.
ON THE ISSUES HAMMER THIS OUT
A QUESTION SAYS IS THERE
POSSIBILITIES OF USERS ADDING
CONTEXT OR INFORMATION TO DATA
FROM OTHERS THEY USE, E.G., THE
DATA IS USEFUL FOR X.
DOING THIS IN THE FORM OF
CURATED COMMENTS COULD BE
HELPFUL.
IT'S A GOOD POINT AND QUESTION
AND THESE IN THE FORM OF A READ
ME FILE OR CURATED NOTES THAT
HELP PEOPLE UNDERSTAND WHAT THEY
CAN USE THE DATA FOR ARE HELPING
TO DRIVE REUSE.
I THINK MOST THE ARCHIVES WOULD
ALLOW THAT TYPE OF INFORMATION
TO BE ADDED.
THE QUESTION IS WHETHER OUTSIDE
REUSERS CAN CONTRIBUTE THEIR
CONTENT AND SOMEHOW HAVE THE
LINK TO THE DATA SETS.
ONE OF THE REASONS FOR USING
DATA CITATION IS IT WILL MAKE IT
POSSIBLE, FORMAL DATA CITATION
TO UNDERSTAND WHEN RESEARCH HAS
BEEN PUBLISHED USING ONE OF
THESE DATA SETS AND I THINK IT
WOULD BE GOOD TO EXTRACT THAT
AND MAKE THAT AVAILABLE.
ANYBODY ELSE FROM THE ARCHIVES.
>> I'LL CHIME IN A LITTLE BIT.
SO WE DO HAVE PLANS FOR -- WE
HAVE A LOT OF PRIMARY DATA SETS
IN BILL THAT ONLY A FEW NEURONS
HAVE BEEN TRACED.
SO WE DO HAVE PLANS TO ALLOW
THIRD-PARTY CONTRIBUTIONS.
IN THAT CASE IF SOMEONE WANTS TO
HOLD THE HACKATHON, FOR EXAMPLE,
AND GO THROUGH A BRAIN AND SEE
HOW MANY NEURONS FOLKS CAN TRACE
AND HAVE SOME QUALITY MEASURE
WITH THEM, WE WILL ACCEPT THOSE
INTO BIL.
THERE IS SOME OPPORTUNITY FOR
THAT.
AS FAR AS ADDING COMMENTS TO
DATA SETS, WE'D NEED TO THINK
ABOUT THAT BUT CAROL WANTS TO
CHIME IN.
>> ADDING COMMENTS IS KEY AND
CURATED IS KEY BECAUSE IT WOULD
BE DIFFICULT TO GO THROUGH THIS
AND IT WOULD INTERESTING TO HAVE
COMMENTS SAYING DID YOU FIND
SOMETHING USEFUL AND WERE YOU
ABLE TO DO SOMETHING WITH IT.
WE HAVE LINK OUTS FROM THE
PRIMARY MOTOR CORTEX OUT TO A
TOOL WHERE YOU CAN GO MAP YOUR
DATA GNLS THE TAXONOMY.
THERE ARE -- AGAINST THE
TAXONOMY AND YOU CAN SAY I'M
TRYING TO FIGURE OUT IF DATA I
HAVE THAT WAS SOMEWHAT
DIFFERENTLY CAN RELATE.
BEING ABLE TO LINK IN IS ONE
THING AND MAP YOUR DATA AND
IDEALLY WHAT USERS CAN DO AT
SOME POINT IS BE ABLE TO SAY,
HEY, THIS IS WHAT HAPPENED WHEN
I TRIED TO PUT THAT DATA IN THE
CONTEXT OF MY DATA OR MY DATA IN
THE CONTEXT OF THAT DATA.
AND START TO PUBLISH THOSE
LINKAGES AND BUILDING THE LARGER
KNOWLEDGE BASE WHICH IS MORE
USEFUL MORE BROADLY TO EVERYONE.
THERE'S A COUPLE THINGS.
ANNOTATING DATA.
IT MAY BE USEFUL.
I HAVE A BATCH PROBLEM AND THIS
YOU HAVE TO NORMALIZE.
THAT WOULD BE GREAT.
SOMETHING LIKE THAT MAY BE
USEFUL IN TERMS OF BEING ABLE TO
DO THAT SOMEWHERE WHERE YOU HAVE
A SHARED WORK SPACE.
IT'S NOT SOMETHING WE HAVE
FORMALLY RIGHT NOW BUT SOMETHING
THAT COULD BE DONE WHERE YOU
HAVE A SHARED COLLABORATION WORK
SPACE AND PEOPLE START ADDING
NOTES ON TO DATA.
>> SETH.
>> I'LL BE BRIEF BUT I THINK THE
CONCEPT OF MULTIPLE ANNOTATIONS
OF CELLS IS KEY.
THERE'S A SET OF ANNOTATIONS
FROM THE BICCN MINI AT LLAS AND
THEY'LL BE RE-ANNOTATE AND I
DON'T THINK BICCN HAS GROUND
TRUTH ON WHAT THE CELL TYPES
ARE.
IT'S IMPORTANT TO NOTE AND THE
INFRASTRUCTURE WILL SUPPORT THIS
TO ENABLE USERS TO ARE WORKING
WITH THE DATA POTENTIALLY IN
MUCH LARGER DATA SETS TO HELP US
RE-ANNOTATE CELLS AS WE MOVE
FORWARD AND HAVE PROVENANCE ON
THAT AND I THINK THE WORK THAT'S
BEEN DONE AND ESTABLISHING
D.O.I.s OR IDENTIFYING SPECIFIC
CELLS IN THE DATA SETS IS GOING
TO MAKE THAT POSSIBLE WHICH IS
REALLY EXCITING.
>> THANK YOU.
>> JESSE, GREAT TALK.
HOW DO YOU BALANCE SPECIFICITY
AND COVERAGE IN MARKER
DETECTION?
>> SO I THINK THAT WAS THE
INTERESTING FEATURE THAT PEOPLE
TALK ABOUT MARKERS BUT THERE IS
A TRADE-OFF.
SO THERE'S THE IDEA OF A
PARIETAL FRONT WHERE YOU SAY AM
I BETTER AT SPECIFICITY OR
COVERAGE EVEN IF I'M NOT BETTER
IN SPECIFICITY OR AM I SLIGHTLY
GOOD AT BOTH IN A WAY NO ONE
ELSE IS?
REALLY THE STATEMENT IS WE
BALANCE IT BY AGGREGATING ACROSS
MARKERS AND IT'S IMPORTANT TO
HAVE A METAMARKER AND A
METAMARKER SIGNATURE WHERE YOU
AGGREGATE MARKERS AND SOME ARE
SPECIFIC AND SOME HAVE BROAD
COVERAGE.
>> THIS ONE IS FOR TIM.
THESE WORK FLOW RESOURCE
EXCITING BUT IS ONE RETIRED TO
USE THE SYSTEM AND LEVERAGE
THEM?
>> THANK YOU.
>> YOU DON'T NEED TO.
SO THE WORK FLOWS ARE AVAILABLE
IN GITHUB AND AVAILABLE IN DOC
STORE AND IN TERRA FORCE BECAUSE
WE'RE LEVERAGING THEM THERE.
YOU CAN LEVERAGE THEM AND
THEY'RE OPEN SOURCE AND LICENSE
AND LEVERAGE THE RAW SOURCE AND
IF YOU WANT TO RUN IN CROMWELL
OR BOTH THE PIPELINES ARE
CATEGORIZED AS WELL.
ALL THE STEPS ARE CHARACTERIZED
TO LEVERAGE IN THE ENVIRONMENT.
HOPEFULLY THERE'S A LOT OF PIECE
THERE'S IF YOU WANT TO RUN IT
AND SOMEBODY ESTABLISHED THAT
YOU HAVE.
>> THIS HAS BEEN THE BANE OF OUR
EXISTENCE HOW ARE THE
LABORATORIES ALIGNED USING THE
SAME SCHEMA OR MODELS AND WHAT'S
THE OVERLAP BETWEEN THE METADATA
ELEMENTS AT THE RESOURCE?
WHO'S LIKE TO TAKE THAT ONE?
HOW ARE THE METADATA ALIGNED.
DO WE AGREE TO A COMMON SCHEMA
IS THERE?
>> THERE'S DIFFERENT NEEDS FOR
THEIR INFRASTRUCTURE THEY HAVE
SET UP THERE.
DIFFERENT TECHNIQUES HAVE NEEDS
FOR DIFFERENT FIELDS.
TRANSCRIPTOMICS DATA WILL HAVE
DIFFERENT NEEDS FOR TRACKING THE
STATE OF THEIR DATA VERSUS WHAT
THE IMAGING HAS.
IMAGING HAS A 3-D MICROSCOPY
STANDARD WITHOUT REFERENCE THAT
IS SUPPORTED BY CAROL HAMILTON'S
GRANT.
THERE'S THINGS THAT PAY AT THE
BIG SPACE AND LOTS OF STANDARDS
THAT WERE LOOKED AT AND WE'VE
BEEN TRYING TO FIGURE OUT OUR
WAY THROUGH.
WHAT WE HAVE ALIGNED TO IS BASE
INFORMATION ABOUT THE DATA
COLLECTION.
A LOT OF THE STUFF ABOUT THE
DATA COLLECTIONS HAS MIGRATED
TOWARDS THE DATA SIGHT STANDARDS
BECAUSE OF THE DESIRE TO CREATE
D.O.I.s OR THE DATA SETS.
THERE'S ALIGNMENT THERE AND
THERE'S A CONTINUING STUDY AND
WILL ALWAYS BE A CONTINUING
EFFORT TO DEVELOP THE NECESSARY
METADATA.
WE HAVE A BASE SET METADATA WE
COLLECT FOR SPECIMENS.
THERE'S A LITTLE BIT FOR THE
DONORS AND THEN THERE'S SO MUCH
MORE TO CONTINUE TO COLLECT AND
HOPE TO ENRICH THAT SPACE AS WE
GO UP.
WE HAVE LANGUAGE OF BASIC
METADATA ACROSS THE
INFRASTRUCTURE BUT EVERY ARCHIVE
BECAUSE IT'S GOT DIFFERENT TYPES
OF DATA AND EVERY ARCHIVE HAS
ITS OWN UNIQUE NEEDS AS WELL.
>> YEAH.
I WOULD SAY OVER THE LAST FIVE
YEARS THIS HAS BEEN SOMETHING
THAT HAS STEADILY BEEN GOING ON.
AS ANYBODY WHO DEALS WITH
METADATA OR RUNS A RESOURCE
KNOWS IT'S ALWAYS AN ISSUE
BECAUSE THE BRAIN INITIATIVE
INFRASTRUCTURE WAS SET UPS A
DISTRIBUTED INFRASTRUCTURE AND
SOME THINGS ALREADY EXISTED AND
SOME HAD TO BE DEVELOPED.
THEY STILL HAD TO DEVELOP THEM
EVEN IF THE STANDARDS WEREN'T IN
PLACE UNTIL WHAT YOU SEE IS
CHAOS IN THE BEGINNING BECAUSE
EVERYTHING NEEDS TO BE UP AND
RUNNING AND PEOPLE NEED TO
UNDERSTAND WHAT THEY'RE DOING
AND YOU START TO GRADUALLY ALIGN
OVER TIME AS THINGS BECOME
AVAILABLE AND NEW BEST PRACTICES
COME OUT.
ANYBODY ELSE HAVE ANYTHING ELSE
TO OFFER ON THAT ONE?
>> I CAN SAY THAT ONE OF THE
THINGS I THINK WAS VERY HELPFUL
WAS THE INVOLVEMENT OF BICCN
WHEN THE ARCHIVES WERE GETTING
STARTED.
I THINK AT LEAST FOR THIS
PROJECT IT HELPED TO ALIGN THE
METADATA BETWEEN MY ARCHIVE AND
THE NEMO ARCHIVE AT SOME BASIC
LEVEL AND WE'RE ALL TALKING AND
KNOW WE CAN DO A BETTER JOB BUT
EACH OF OUR ARCHIVES HAS A
BROADER AUDIENCE AND HAVE TO
BALANCE THOSE NEEDS AS WELL.
BICCN HAS HELPED QUITE A BIT IN
DRIVING THAT STANDARDIZATION
ACROSS ARCHIVES.
WE HAVE SPECIFIC QUESTIONS.
SHOULD WE UPLOAD OUR RAW DATA TO
THE BICCN OR NEMO?
BASICALLY HOW DOES THE ECO
SYSTEM WORK?
WE PRODUCE MASS SPEC TROM ETRY
AND WHAT DOES ONE DO WITH A DATA
TYPE THAT IS PERHAPS A LITTLE
BIT DIFFERENT AND WHAT DO WE DO
WITH RAW VERSUS THE DERIVED
DATA.
>> WHEN YOU DO THAT WE ASK YOU
PROVIDE A MANIFEST THAT INCLUDES
BASIC METADATA IN ADDITION WE
WORK TO PROVIDE ADDITIONAL
METADATA.
I APOLOGIZE.
WE APOLOGIZE THAT'S A MULTI STEP
PROCESS BUT IT ENABLES THE
COORDINATION.
FOR DETAILS E-MAIL US AND WE'LL
WORK WITH YOU.
WE HAVE A TEAM OF DATA REGULARS
THAT CAN HELP WITH THAT.
>> IT CAN BE MASS SPEC ABOUT THE
BEST DESTINATION FOR THAT TYPE
OF DATA.
IT MAY BE YOU HAVE SOME VERY
SPECIAL MULTI-MODAL DATA WHERE
YOU HAVE THINGS SO INTERLINKED
YOU DON'T WANT TO SPLIT THEM
ACROSS ARCHIVES.
THERE ARE SPECIAL WAYS WE CAN
ACCOMMODATE THE DATA FOR
INSTANCE AT DANDI SOME
NEUROPHYSIOLOGY DATA AND IT'S A
DISCUSSION ABOUT WHERE'S THE
BEST HOME WORD AND SOMETIMES IT
WILL BE ABOUT WHAT TOOLS YOU'LL
WANT ALONG WITH THE DATA.
THE FIRST SPACE IS TO TALK TO US
AND IT'S A DISCUSSION ABOUT THE
BEST DATA.
>> AND IN GENERAL -- GO AHEAD.
>> I WAS GOING TO MAKE THIS MORE
BROADER AND IF IT IS A DATA
MODALITY AND NOT PART OF BICCN
REACH OUT TO YOUR PROGRAM
OFFICER.
MY PROGRAM OFFICER THERE'S A
NUMBER OF DIFFERENT DATA
ARCHIVES THAT HAVE BEEN
ESTABLISHED AND SEVERAL
ESTABLISHED NOT PART OF THE
BICCN NETWORK.
YOUR PROGRAM OFFICER WILL
CONTACT MY PROGRAM OFFICER AND
THEY'LL DISEASE WHERE YOUR DATA
NEEDS TO GO.
THAT'S THE WAY I WOULD ANSWER
THAT A LITTLE BIT MORE
GENERICALLY.
>> ALSO I WANTED TO TALK WHEN
THE BROAD DATA QUESTION AND THE
CONCEPT OF DATA LEVELS IS
INTEGRAL TO THE WAY THE DATA ARE
ORGANIZED AND SETS OF RAW DATA
ALWAYS GOES TO THE ARCHIVE BUT
THERE'S DIFFERENT LEVELS OF
PROCESSING, ALIGNMENT, LINKAGE
THAT HAPPENS TO AN INDIVIDUAL
DATA SET AND THIS IS ONE OF THE
FEATURES OF THE WAY THE BICCN
DATA ARCHIVES ARE ORGANIZED AND
WE'RE CURRENTLY WORKING ON HOW
TO PRESENT THOSE STEPS AND
LEVELS TO THE COMMUNITY.
I'LL ANSWER QUICKLY A QUESTION
IN THE CHAT ABOUT HOW USERS
FINDS THE DATA SETS OF
RELEVANCE.
IS THERE A CENTRALIZED SEARCH
AND YOU CAN GO TO THE PORTAL AND
USE THE DATA CATALOG WHY SEARCHS
ACROSS ALL OF THEM.
I WANTED TO WRAP THIS UP WITH A
QUESTION DIRECTED TOWARDS JESSE
AND I THINK THE BICCN IN
GENERAL.
DO YOU THINK THE EXISTING DATA
IS SUFFICIENT TO GENERATE MARKER
GENES AND CELL ANNOTATION AND
HOW MUCH DO WE NEED AND HOW DO
WE KNOW WHEN WE'RE DONE?
>> I LIKE THAT QUESTION A LOT.
RELIABLE UNDER WHAT
CIRCUMSTANCE?
SO IT'S IMPORTANT TO THINK WITH
THE CLASSES AND THE BICCN
SAMPLED ACROSS A LOT OF
TECHNOLOGICAL VARIABILITY BUT
DIDN'T SAMPLE ACROSS GENETIC
BACKGROUND VARIABILITY AND IF
YOU DO EXPERIMENTS YOU CAN HAVE
A STRAIN LARGE YOU'D LIKE AND
ROBUST AS LONG AS YOU'RE WITHIN
THE SYSTEM.
IF YOU'RE INTERESTED IN APPLYING
THIS TOWARDS DISEASE WE MAY NOT
BE QUITE THERE YET IN MATERIALS
OF GENERALIZABLE SIGNIFICANCE.
I THINK WE'RE VERY RELIABLE ON
CELL TYPES AND MARKER SETS FOR
TRANSCRIPTOMICS SIGNATURES AND
MOVING ON TO PRIMATE SOON WE'LL
BE THERE AS WELL.
>> THANK YOU.
SO I THINK WE ARE ALMOST AT THE
END OF OUR SESSION.
I WANT TO THANK THE SPEAKERS FOR
THEIR EXCELLENT PRESENTATIONS.
I HOPE YOU LEARNED A LOT ABOUT
ALL THE DATA RESOURCES THAT HAVE
BEEN AMASSED ON BEHALF OF THE
BICCN AND ARE MAINTAINED ACROSS
THE BRAIN INITIATIVE ECO SYSTEM.
I ALSO WANT TO GIVE
ACKNOWLEDGEMENT TO MY CORRELATES
WHO HELPED PUT THE SESSION
TOGETHER AND IF WE HAD BEEN LIVE
AND WOULD HAVE BEEN MODERATING
WITH ME AND I WOULD LIKE TO TURN
THIS OVER AND THANK THE AUDIENCE
FOR LISTENING AND TURN IT OVER
TO THE ORGANIZERS.
I UNDERSTAND THERE'S LUNCH AND
AWARDS COMING UP.
THANK YOU, EVERYBODY.
THANK YOU FOR YOUR ATTENTION AND
FEEL FREE TO REACH OUT TO ANY OF
US IF YOU HAVE ADDITIONAL
QUESTIONS.
>> ALL RIGHT WELCOME EVERYONE.
TO THE WINNER ANNOUNCEMENT OF
THE SECOND YEAR OF THE BRAIN
INITIATIVE CHALLENGE FOR HIGH
SCHOOL STUDENTS AT THE NATIONAL
INSTITUTES OF HEALTH.
WE'LL ANNOUNCE THE THIRD, FINAL
AND FIRST-TIER PRIZE WINNERS.
THE UNIQUE COMPETITION FOR HIGH
SCHOOL STUDENTS.
IN ADDITION TO THE AMAZING
SUBMISSIONS WE'LL GET TO HEAR
TAKEAWAYS.
>> WE HAVE DR. JOHN NGAI AND THE
DIRECTOR OF THE NEUROLOGICAL
DISORDERS AND STROKE AND THE
DIRECTOR OF THE INSTITUTE ON
DEAFNESS AND OTHER COMMUNICATION
DISORDERS AND DR. RICHARD HODES
THE DIRECTOR OF THE NATIONAL
INSTITUTE ON AGING.
YOU'LL THOSE INTERESTED IN THE
THE -- AND ENHANCE STUDENTS IN
NEUROETHICS.
ELIGIBLE STUDENTS SUBMITTED
THEIR IDEAS AND PERSPECTIVES IN
THE FORM OF A ESSAY OR SHORT
VIDEO.
>> IT WAS A PLEASURE AND THERE'S
FIVE SUBMISSIONS THAT RECEIVED
HONORABLE RECOGNITION DISPLAYED
HERE.
FIRST LET'S HEAR FROM THE TOP
WINNERS.
>> AND MINIMIZE THE SYMPTOMS OF
CHRONIC DISEASE SUCH AS
PARKINSON'S TODAY.
THERE'S A DILEMMA FOR TREATMENT
THAT CAN INCREASE OR DECREASE
THEIR QUALITY OF LIFE BY
CHANGING THEIR PERSONALITY.
PATIENTS AND THEIR FAMILIES
OFTEN HAVE DIFFERENT VIEWS AS
THE PATIENTS ARE OFTEN HAPPY THE
SYMPTOMS LISTEN.
THE FAMILY HOWEVER, VIEWS IT A
DIFFERENT LIGHT AS THE LOVED ONE
HAS UNDER GONE PERSONALITY
CHANGES THAT AFFECT THEM IN
THEIR DAILY LIVES.
SOME FAMILIES DESCRIBE THEM AS
NOT THE SAME PERSON.
THERE'S MANY EXAMPLES SUCH AS A
PATIENT WHO AFTER UNDERGOING DBS
HAS A NEW STATE OF CONSTANT
EUPHORIA.
WHILE THE PATIENT IS CONTENT
WITH THE NEW STATE IN
PERSONALITY, THE FAMILY BARELY
RECOGNIZES HIM AND CAUSES THEM
TO FEEL HAPPIER BUT THEY HAVE TO
MAKE A DECISION TO BE PLACED IN
AN MENTAL INSTITUTE OR NOT AND
NO ONE KNEW WHETHER TO ALLOW THE
VERSION OF THEMSELVES TO MAKE
THE DECISION OR THE NORMAL
PERSONALITY MAKE THE DECISION.
ADDITIONALLY, THIS BEGS THE
QUESTION OF WHAT STATE PRE OR
POST PBS IS A PERSON CONSIDERED
RESPONSIBLE AND IN CHARGE OF
THEMSELVES.
AND I WOULD SAY SOME OF THE
MAJOR TAKEAWAYS I HAD WAS THAT
ALTHOUGH THE PATIENTS SHOULD BE
THE ONES WHO FINALLY HAVE THE
DECISION TO DECIDE WHAT
TREATMENT IS RIGHT FOR THEM AND
WHETHER DBS IS THE RIGHT FORM OF
TREATMENT FOR THEM DUE TO THE
FACT THEY COULD HAVE
LIFE-ALTERING AFFECTS THE
PERSONALITY CHANGES, THEY SHOULD
BE FULLY INFORMED BY THEIR
DOCTOR AND CAREGIVERS SO THE
BENEFICIAL AND HARMFUL AFFECTS
OF THE TREATMENT COULD HAVE ON
THEIR LIVES BECAUSE IN MANY
CASES THE PATIENT MAY NOT BE
FULLY INFORMED ABOUT WHETHER THE
DBS COULD IMPACT THEM NEGATIVELY
OR HAD A CHANCE TO IMPACT THEM
NEGATIVELY AND SO THEY UNDER GO
THE AND THOUGH THEY MAY BE
CONTENT IT'S IMPORTANT THEY
WOULD HAVE KNOWN WHETHER OR NOT
THIS WOULD CHANGE THEIR
PERSONALITY BECAUSE THOUGH THEY
MAY LIKE THE NEW PERSONALITY
LATER, WE MAY NOT KNOW IF THAT'S
SOMETHING THEY WANTED IN THE
FIRST PLACE WHEN UNDERGOING THE
TREATMENT.
ADDITIONALLY, IT'S IMPORTANT TO
HAVE MORE RESEARCH ON DBS IN
GENERAL TO UNDERSTAND HOW THESE
SIDE EFFECTS ARE EVEN ABLE TO
TAKE PLACE SO THEY CAN SEE IF
THEY CAN MITIGATE AND LISTEN
SIDE EFFECTS.
>> THANK YOU.
WELL DONE AND WELL COMMUNICATED.
NEXT THE THIRD TIER WINNING
ESSAY ON INVASIVE BMIs AND THEIR
ETHICAL CHALLENGES.
CAN YOU READ AN EXCERPT FROM
YOURS AND SHARE TAKEAWAYS WITH
US.
>> THANK YOU FOR HAVING ME.
I'M HONORED TO BE HERE RIGHT NOW
AND SO I'VE WROTE ABOUT INVASIVE
MACHINE INTERFACES AND THEIR
ETHICAL CHALLENGES.
THIS RAISES SEVERAL SIGNIFICANT
CONCERNS.
HOW MUCH DO COMPANIES HAVE TO A
PATIENT'S DATA AND HOW MUCH DO
THE DATA POINTS BECOME
DISTINGUISHABLE FROM MEMORY AND
IS PRIVACY POSSIBLE WITH ACCESS
TO OUR BRAINS?
AND PERHAPS MOST SERIOUS AT WHAT
POINT IS HACKING BECOME THE MOST
SERIOUS CRIME OF ALL?
HACKING INTO A HUMAN BRAIN COULD
RESULT IN DEATH AND ALSO RESULT
IN MEMORY LOSS, PARALYSIS OR THE
INDIGNITY OF HAVING ONE'S BRAIN
INVADED BY ANOTHER AND-IN-LAWF --
AND THIS COULD BE A MORE SERIOUS
AFFRONT AND AS WE IMPLANT AND
THERE'S MORE CAPABLE THAN EVER
BUT WE ALSO BECOME MORE
VULNERABLE.
THIS PARADOX WILL DEFINE
HUMANITY AND ONE OF THE MOST
IMPORTANT QUESTIONS WE HAVE TO
ASK OURSELVES DURING THE COURSE
OF THE NEXT MILLENNIUM IS WHAT'S
IT MEAN TO BE HUMAN?
MY TAKEAWAY FROM THIS IS
LEARNING HOW COMPLEX THE BRAIN
IS AND LIES WITHIN THE PARADOX I
TALKED ABOUT AND WHAT IT MEANS
TO BE HUMAN.
WHEN IT COMES TO BRAIN MACHINE
INTERFACES THERE'S A LOT TO SAY.
THE BRAIN IS A VERY COMPLEX
ORGAN.
THE MOST COMPLEX IN THE UNIFORM
SO FAR BUT AS THE BRAIN IS
THINGS ONLY GET MORE COMPLICATED
WHEN YOU RAISE THE QUESTION OF
INTERFACING AND IF MY BRAIN
INTERFACES WITH A PIECE OF
TECHNOLOGY CAN IT BE SAID I'M
STILL FULLY ME?
WOULDN'T IT BE FAIR TO SAY I'M A
CYBORG PART THE AND PART
TECHNOLOGY AND AT SOME POINT THE
BRAIN BECOMES PROPERTY AT THE
SAME TIME THE BRAIN BECOMES
SUSCEPTIBLE TO COMPUTER HACKING
LIKE CARS AND DOOR LOCKS AND
ANYTHING CONNECTED TO THE WEB.
WHO BEARS RESPONSIBILITY FROM
DEFENDING OUR BRAINS FROM
HACKERS?
US?
THE COMPANIES THAT MAKE THE
INTERFACE?
SOME THIRD PARTY?
MORE IMPORTANTLY WE CAN HAVE
ACCESS TO THE WORLD'S KNOWLEDGE
INSTANTANEOUSLY.
WHEN EVERY FACT AND FIGURE AND
PIECE OF KNOWLEDGE IS BUILT INTO
OUR BRAINS FROM AN INTERFACE HOW
DO WE DISENTANGLE WHAT THE
INDIVIDUAL KNOWS VERSUS
COLLECTIVE.
THIS SOUNDS LIKE SCIENCE FICTION
BUT BEFORE IT COMES WE BETTER
GET SOME ANSWERS READY.
>> THANK YOU FOR A GLIMPSE AT
THE PRESENT AND FUTURE AND NOW
BACK TO DEB.
>> THANK YOU.
THOSE WERE INSIGHTFUL ESSAYS.
I'D LIKE TO CONGRATULATION LUKE
ALSO FROM WINSTON CHURCHILL HIGH
SCHOOL IN MARYLAND WHOSE ESSAYS
IS ETHICAL ISSUES IN RESEARCH
WITH GENE EDITING TECHNOLOGIES
AND SHARE ONE THING FROM YOUR
ESSAY AND WHAT READ URZ SHOULD
REMEMBER.
>> MANY NEW TECHNOLOGIES ARE
BEING DEVELOPED.
WHAT HAPPENS WEN IT DOES NOT
FUNCTION CORRECTLY AND HOW CAN
WE FIX IT?
DR. ALLISON MOTERY DIRECTOR OF
THE UNIVERSITY OF CALIFORNIA AT
SAN DIEGO STEM CELL PROGRAM
WORKS WITH WHAT HE CALLS MANY
BRAIN ORGANOIDS GROWN FROM HUMAN
STEM CELLS IN THE LAB.
HE FOUND HIS BRAIN ORGANOIDS CAN
PRODUCE COORDINATED WAVES OF
ACTIVITY PRE RESEMBLING THOSE IN
BABIES AND THIS MAY SEEM LIKE AN
A FAR-OFF DREAM BUT IT'S
HAPPENING NOW AND BOSE -- POSED
AND IS THIS A CHARACTERIST IC OF
CONSCIOUSNESS?
AS BEING CONSCIOUS MEAN TO BE
ALIVE?
IF THESE HUMAN MINI BRAIN
ORGANOIDS HAVE CONSCIOUSNESS AND
ALIVE, IS IT OKAY TO DO TESTING
ON THEM?
ONE CAN THEN ASK CAN THE
ORGANOIDS RESPOND TO OUTSIDE
STIMULUS.
IT SEEMS THEY RESPOND TO
ELECTRICAL STIMULUS BUT WHAT
ABOUT SITE, PAIN AND OTHER
RESPONSES AND ARE THEY CAPABLE
OR MARK BY THOUGHT, WILL, DESIGN
AND PERCEPTION?
CAN THE ORGANOIDS THINK?
WHAT COULD IT MEAN IN THE
ORGANOIDS?
CAN THE CREATE MEMORIES AND
REMEMBER?
THESE ARE ASKED BY SCIENTISTS
DUE TO THE ARGUMENT THEY CAN BE
USED AS ACCURATE MODELS TO STUDY
BRAIN.
DO THE MEANS JUSTIFY THE END IF
THE ORGANOID CONSIDERED
CONSCIOUS AND ALIVE.
MY TAKEAWAY FROM MY ESSAY IS HOW
FAR ARE WE WILLING TO GO FOR
SCIENTIFIC ADVANCEMENT?
IF THESE BRAIN ORGANOIDS TRULY
WERE CONSCIOUS, WOULD THAT MAKE
IT OKAY TO DO TESTING ON THEM IN
ORDER TO FIND NEW CURES FOR
DISEASES?
WELL, IT COULD BLUR THE LINES
BECAUSE WHAT IS ETHICAL AND NOT
AND COULD LEAD TO TESTING ON
OTHER THINGS THAT COULD BE
DEEMED CONSCIOUS.
TESTING ON SOMETHING LIKE A
BRAIN ORGANOID COULD BE A
SLIPPERY SLOPE SO IT'S IMPORTANT
TO HAVE DISCUSSIONS SURROUNDING
WHAT CONSCIOUSNESS IS NOW TO
ESTABLISH ETHICAL BOUNDARIES
ALREADY QUESTIONING THE
DEFINITION OF BEING HUMAN.
THANK YOU.
>> THANK YOU.
YOU ALSO RAISED INTERESTING
QUESTION POSSIBLE INEQUITIES IN
HEALTH DISPARITIES.
MAYBE WE CAN TOUCH ON THAT IN
THE DISCUSSION LATER.
SO THOSE WERE ALL GREAT ESSAYS.
NOW I'LL INTRODUCE THE THIRD
TIER VIDEO TEAM WINNERS FROM
STAPLES HIGH SCHOOL IN
CONNECTICUT WHO PRODUCED THE
VIDEO CALLED NEURAL DATA USAGE
AND THE LEAP OF FAITH IN NEURAL
ETHICS.
LET'S WATCH THE TEAM'S VIDEO AND
SEE WHAT THEY'D LIKE VIEWERS TO
REMEMBER.
>> MENTAL DATA PRIVACY ISSUES
AND AS WE START TO SEE WITH
EMERGING TECHNOLOGY.
MANY PROPOSED ETHICS FRAME WORKS
FOR MANAGING IMAGING DATA RELY
ON EXISTING ONES.
THE BRAIN 2.0 NEUROETHICS REPORT
PROPOSED THE FOLLOWING EXAMPLES
WHICH IS FROM THE BELMONT REPORT
IN THE PRESIDENTIAL COMMISSION
FOR THE STUDY OF BIO ETHICAL
ISSUES AND OTHER NEUROETHICS
REPORT.
>> OUTSIDE ANALYSIS CLAIMS IT
ALSO FOCUSSED ON MORE
THEORETICAL TOPICS SUCH AS
HUMANIST AND MORAL
RESPONSIBILITY AND
CONSCIOUSNESS.
WHILE IN THE SHORT TERM IT MAY
BE TEMPTING TO BUILD OFF DATA
BUT WE HAVE ETHICAL STANDARDS OF
PATIENT-DOCTOR CONFIDENTIALITY
CONCERNING OURSELVES WITH
NORMATIVE AND COMPLIANCE ISSUES
WE AGREE WITH THE REPORT AND
REDEFINING THE RULES OF THE
GAME.
THE INNOVATIONS IN NEUROSCIENCE
REPRESENT A BROADER SHIFT IN
ETHICS.
>> WHILE STANDARDS SUCH AS
PRIVATE HAVE BECOME NORMATIVE,
MORE HAS TO BE CONSIDERED WHEN
UNPACKING THE HISTORIES OF THE
HUMAN BRAIN AND DOCUMENTING
THEM.
THE MIND REPRESENTED REALITY
THROUGH ONE'S OWN CONCRETE
EXPERIENCE BEING THE CORE OF
HUMAN EXISTENCE.
WITH THESE TECHNOLOGICAL
ADVANCES WE HAVE TO THINK HOW IT
STILL HOLDS TRUE IN OUR
MORALITIES AND LOOK AT NATURAL
POSITION IN NEUROETHICS
GUIDELINES GOING FORWARD.
>> GREAT WORK, GUYS.
YOU TOUCHED ON SOME ISSUES WE
STRUGGLE WITH A LOT WHEN WE
ADDRESS THESE ISSUES.
NEXT I'M EXCITED TO INTRODUCE
THE SECOND TIER WINNERS.
SUSAN ATTENDS MOUNTAIN VIEW HIGH
SCHOOL IN WASHINGTON STATE AND
WROTE ABOUT A BRIDGE BETWEEN
PAST AND PRESENT.
SHE IS UNABLE TO JOIN US TODAY.
SHE JUST STARTED A NEW
INTERNSHIP THIS WEEK WHICH IS
AWESOME.
SO COULD YOU PLEASE READ A
PORTION OF HER ESSAY SO EVERYONE
CAN HEAR HER IMPRESSIVE IDEAS.
>> BEFORE WE GET TO THAT I THINK
WE MAYBE SKIPPED OVER AND DIDN'T
GIVE A CHANCE FOR THE TEAM TO
GIVE THEIR TWO-MINUTE
HIGHLIGHTS.
>> SORRY ABOUT THAT.
>> NO PROBLEM.
>> YOU GUYS GO.
>> THANK YOU FOR HOSTING
THE CHALLENGE.
IT'S TRULY AN HONOR BEING ABLE
TO SHARE THOUGHTS ON SUCH AN
INFLUENTIAL PLATFORM.
A BIG TAKEAWAY FROM OUR WORK IS
HOW DIFFERENT FIELD INTERSECT
WITH EACH OTHER AND ALLOW US TO
UNDERSTAND TOUGH ISSUES IN A
MORE HOLISTIC MANNER.
WE TOOK PERSPECTIVES FROM THE
PHILOSOPHIES FROM THE 19th
CENTURY AND OUR OWN EXPERIENCES
WITH OUR CREATIONS AN REFLECTING
ON NIH-DEVELOPED INTERFACING
WITH HUMAN BRAIN.
IN THE TIME THERE WEREN'T THE
EXACT SAME TECHNOLOGICAL
CONSIDERATIONS IN PLAY THE
SUBJECT OF THE HUMAN BODY ITSELF
WAS IN ITS INFANCY RELATIVELY
SPEAKING AND THE WINDS OF CHANGE
WERE BLOWING.
IN HIS CENTURY SCIENTISTS
DISCOVERED MORE ABOUT NATURAL
PROCESSES PREVIOUSLY ONLY
EXPLAINABLE THROUGH RELIGION
INCLUDING WHERE WE CAME FROM IN
THE FIRST PLACE.
AND A TIME WHERE OBJECTIVE PROOF
AGAINST CHRISTIAN DOGMA SEEMS TO
GROW DAILY.
WHILE THE INSTINCT OF THE
CONTEMN PORE ARS WAS -- CONTEMN
PORARIES AND IN OUR VIDEO WE
DISCUSSED HOW OUR RAPIDLY
EVOLVING INFORMATION OF HOW THE
HUMAN BRAIN MAKES DECISIONS CAN
POTENTIALLY SHAPE THE POSITION
OF THE BRAIN, FREE WILL AND
HUMAN DECISION MAKING.
THROUGH A LENS OF PHILOSOPHY
WE'RE ABLE TO BETTER REFLECT ON
HOW EXPIRATIONS ARE ON THEIR OWN
BASIS GOING FORWARD.
THAT'S ONE MAJOR TAKEAWAY.
>> GREAT, THANKS.
YOU'VE GIVEN US A LOT TO THINK
ABOUT FOR SURE.
OKAY, WHERE WERE WE?
SORRY ABOUT THAT.
IF CARLO CAN READ SUSAN'S ESSAY.
>> THIS IS AN EXCERPT.
PARKINSON'S DISEASE IS A
NEUROGEE GENERATIVE DISORDER DUE
TO THE LOSS OF DOPAMINERGIC
NEURONS IN THE BRAIN AND
PATIENTS CAN EXPERIENCE
DIFFERENCES IN MOOD AND DEMENTIA
AND SOME TREATMENTS EXIST.
TECHNOLOGY HAS PROVIDED AN
ALTERNATIVE TREATMENT FOR
PATIENTS WHO STRUGGLE TO RESPOND
TO MEDICATION.
DEEP BRAIN STIMULATION OR DBS.
IT INVOLVES IMPLANTATION OF
MOVEMENT OF CENTERS OF THE BRAIN
AND COUNTER NEURAL SIGNALS THAT
CAUSE THE MOTOR SYMPTOMS OF
PARKINSON'S DISEASE ALLOWING
PATIENTS A CERTAIN DEGREE OF
RELIEF.
THE POTENTIAL IS HUGE EXPANDING
BEYOND PARKINSON'S DISEASE WITH
ACTIVE RESEARCH ON THE VIABILITY
OF DBS TO TREAT ALZHEIMER'S,
DEPRESSION, ANXIETY AND
TOURETTE'S BUT IT'S SIMILAR TO
THE OUTDATED PROCEDURE OF
PREFRONTAL LOBOTOMY CURING THE
DISEASE AT THE RISK OF A PERSON
LOSING A PORTION OF THEMSELVES.
A WOMAN RECOUNTED HOW THEIR
FAMILY WOULD GRIEVE FOR THE OLD
HER AND FOUND HERSELF STRUGGLING
TO CONTROL HER ANGER.
THIS LEADS TO A DILEMMA.
DBS CAN IMPROVE THE QUALITY OF
LIFE BUT THE PATIENT MAY THEN BE
AT RISK OF LOSING THEIR OWN
IDENTITY.
THOUGH PATIENTS OF PARKINSON'S
ARE AFFORD THE RIGHT OF INFORMED
CONSENT IT'S BEEN SHOWN TO
IMPAIR FUNCTION SUCH AS PLANNING
AND CONFLICT RESOLUTION.
AND IN ORDER TO ALLOW PATIENTS
TO MAKE DECISIONS THEY MUST BE
EDUCATED EVEN BEFORE THE DISEASE
MANIFESTS.
THE ONLY WAY TO ENSURE THE
ABILITY TO MAKE DECISIONS AND TO
INTRODUCE KNOWLEDGE EARLY AND
ALLOW THEIR OPINION OF THE
KNOWLEDGE TO EVOLVE ALONG WITH
THEIR PERSONALITY AND IN THIS
MANNER THOUGH SOME INDIVIDUALS
DIAGNOSED WITH NEUROLOGICAL
DISEASES MAY STRUGGLE WITH
DECISION MAKING AND MAY HAVE
EXPERIENCE WITH TREATMENT OPTION
TO GUIDE TOWARDS THE BEST OPTION
FOR BOTH WHO THEY WERE THEN AND
WHO THEY ARE NOW.
REALLY AWESOME ESSAY AND FOR
THOSE LISTENING IN THAT WAS AN
EXCERPT FROM SUSAN HONG ON DBS.
>> THAT WAS TERRIFIC.
I KNOW FROM HEARING FIRST-HAND
PATIENTS ARE RELUCTANT TO SEEK
OUT DBS TREATMENT FOR THE ISSUES
YOU RAISED.
HOPEFULLY WE CAN CONTINUE TO
NAVIGATE THAT SPACE FROM A
NEUROETHICS POINT OF VIEW AS WE
DEVELOP TECHNOLOGIES THAT WILL
NOT HAVE THESE SIDE EFFECTS.
OKAY.
I THINK WE'RE ON TO THE OUR NEXT
SECOND TIER ESSAY WINNER IN
MISSOURI WHO'S WINNING ESSAY IS
EXPLORING THE ETHICAL IMPLY
IMPLICATIONS IN CERTAIN
SETTINGS.
>> THE MAIN FOCUS OF MY ESSAY
WAS NEUROCOGNITIVE ENHANCEMENTS
IN THE MILITARY.
ONE OF MY MAIN SUBJECT AREAS WAS
EQUALITY.
THE IDEA OF NEUROACCOUNTING
NEUROCOGNITIVE ENHANCEMENTS.
WILL THEY ONLY BE AVAILABLE TO
THE WEALTHY OR WHO THEY HAVE
ACCESS TO?
UNLESS THE GOVERNMENT STEPS IN
THE SITUATION THEY MAY BE
PROMOTING INEQUALITY WITHIN THE
UNIT THE CLASSES OF STRONGER
MORE ADVANCED GROUPS CAN
DOMINATE THE OTHER GROUPS AND
WILL HAVE TO PASS A LAW
REGARDLESS OF BACKGROUND CAN
HAVE ENHANCEMENT.
ENHANCED SOLDIERS TALKS ABOUT
HOW WE INTEGRATE WITH SEPARATE
TROOPS DO WE HAVE TROOPS OF EN
ENHANCED FIGHTERS AND HOW WILL
TRAINING WORK?
WILL ENHANCED FIGHTERS GET
PREFERENTIAL TREATMENT WITH
ENHANCED AND UNENHANCED SOLDIERS
HAS THE POTENTIAL TO LOWER
MORALE AND FIGHT.
PREFERENTIAL TREATMENT LEADS TO
SENDING IN THE NORMAL TROOPS AS
RECONNAISSANCE BEFORE SENDING IN
THE SOLDIERS WHEN IT'S DEEMED
SAFE TO DO SO.
WITHOUT PROTECTIVE MEASURES THIS
PUTS THE LIVES OF UNENHANCED
TROOPS AT RISK.
THE ISSUE CONTINUES AFTER THE
PERIOD OF SERVICE.
HOW DOES THE SOLDIER FIT BACK
INTO NORMAL CIVILIAN LIFE?
HOW DO WE DEAL WITH THE
POTENTIAL OF SUPERIOR ENHANCE
ENHANCEMENTS MAY DOMINATE
OTHERS?
REMOVING COGNITIVE ENHANCEMENTS
REQUIRED SURGICAL INTERVENTION.
THIS IS UNNECESSARILY PUTTING
THE SOLDIER'S LIFE IN DANGER AND
THERE'S NO PROOF THEY'LL REVERT
TO THEIR STATE OF MIND AND
GOVERNMENTS MAY NEED TO PASS
LEGISLATURE PROMOTING EQUALITY
AND PROVIDING ACCESS TO QUALITY
HEALTH CARE AND THERAPEUTIC
SERVICES.
THE OUTCOME IS VETERANS CAN
ASSIMILATE BACK TO LIVE TO
ENSURE EQUALITY.
AND MY MAIN TAKEAWAY WAS WITH SO
MUCH ADVANCE RESEARCH IN THE
BRAIN THE POSSIBILITIES ARE
ENDLESS.
NEW THINGS ARE BEING DISCOVERED
EVERY DAY.
MANY WITH A CHANCE TO BENEFIT
SOCIETY BUT WITH THE COGNITIVE
ENHANCEMENTS THERE'S POTENTIAL
CONSEQUENCES OF WHICH I'LL
HIGHLIGHT.
WHILE WE SHOULD BE ENCOURAGING
THE RESEARCH IT'S IMPORTANT TO
TAKE A STEP BACK AND PUT AS MUCH
AS EFFORT INTO CONSIDERING THE
IMPLEMENTATION AND EQUALITY OF
THE TECHNOLOGIES.
SO MILITARY AND SOCIETY
SETTINGS.
THE TECHNOLOGIES ARE OF NO USE
IF WE CANNOT EFFECTIVELY AND
SAFELY USE THEM.
>> WE GOT GREAT INSIGHTS AND I'M
EXCITED TO ANNOUNCE THE WINNERS.
THE FIRST WINNER IS EVAN AND
SOPHIA FROM EAST SIDE PREP
SCHOOL WASHINGTON STATE PRODUCED
A VIDEO ENTITLED HALFWAY HAPPY.
AT LEAST HALFWAY HAPPY.
LET'S WATCH THE PORTION OF THE
VIDEO AND HEAR THEIR MESSAGE AND
THEIR TAKEAWAY FROM THE VIDEO
AFTERWARDS.
>> IN 2012 A 33-YEAR-OLD GERMAN
PATIENT WENT TO THE EMERGENCY
ROOM BECAUSE HIS DEEP BRAIN STIM
BASE OR DBS IMPLANT RAN OUT OF
BATTERY AND THEY EXPERIMENTED
WITH SETTINGS OF 1 TO 5 VOLTS
AND ASKED THE PATIENT TO
SELF-RATE HIS HAPPINESS ON A
SCALE OF 1 TO 10.
THE PATIENT REPORTED AN INCREASE
IN FEELING OF PLEASANTNESS THAT
CORRELATED WITH AN INCREASE IN
VOLTAGE.
>> HE DID NOT INITIALLY KNOW THE
VOLTAGE AND IT HAS AN EFFECT ON
THE EMOTIONAL STATE CAN
HAPPINESS BE INDUCED BY AN
ELECTRICAL SHOCK AND THEY
REQUESTED THE ACTIVITY DESPITE
HARMFUL CONSEQUENCES TO ONE'S
WELL BEING.
>> HOWEVER, UNLIKE SOMATIC
AFFECT OF ADDICTION TO DRUG,
PSYCHIATRIC EFFECTS DBS IS
HARDER TO ASSESS BECAUSE
EVALUATION DEPENDS ON SUBJECTIVE
FINDINGS.
WHILE THERE'S NO SUGGESTION DBS
IS BIOLOGICALLY HARMFUL BUT
PLEASURE-SEEKING CAN BE
IRREVERSIBLE.
>> IT CAN TEACH US ABOUT
LONG-TERM HAPPINESS.
A DEONTOL OGIST WOULD SAY IT'S
THE SUM OF PLEASURES AND PANELS
WHICH IS WHAT DBS IS EXCEPTIONAL
AT INDUCING.
WHILE DBS MAY NOT BE AN
INSTANTANEOUSLY SOLUTION IF WE
UNDERSTAND THE RISKS, BENEFITS
AND LIMITATIONS IT HAS THE POWER
TO SOLVE HALF THE EQUATION FOR
HAPPINESS.
>> WE WANT TO SAY THANK YOU TO
TEAMS.
IT WAS FUN TO TAKE ON THE
PROJECT AND IT WAS FUN TO LOOK
AT THE FIELD AT THE INTERSECTION
OF BIOLOGY AND IT'S POWERFUL AND
VERSATILE S THAT CAN RESULT FROM
A SIMPLE ELECTRICAL SHOCK TO THE
BRAIN.
WHILE ELECTRICALLY STIMULATING
THE BRAIN MAY SEEM LIKE A
STRAIGHTFORWARD WAY TO IMPROVE
QUALITY OF LIFE AS WE LOOKED AT
THE LONG-TERM IMPACTS IT CAN
HAVE ON ONE'S EMOTIONS AND
PERSONALITY THEY'RE NOT AS
STRAIGHTFORWARD AS IT APPEARED.
>> TECHNOLOGY CAN BE EFFECTIVE
FOR TREATING MOVEMENT DISORDERS
LIKE TREMORS IN PARKINSON'S
DISEASE BUT CAN HAVE
UNCONTROLLED
>> SO IT SHOULD BE CONTAINED.
WHAT IF ON THE OTHER HAND DBS
WERE APPLIED TO IMPROVE QUALITY
OF LIFE IN ORDINARY PEOPLE?
WHILE STIMULATION CAN CAUSE
HEDONIC HAPPINESS AND NOT THE
MORE MEANINGFUL PNEUMONIC
HAPPINESS.
WE CAN'T IMPROVE LIVES BY
ELECTRICALLY STIMULATING THE
BRAIN.
ATTEMPTING THIS WHILE PERFORMING
EXTENSIVE AND INACCESSIBLE
SURGERY ONLY TO BRING ABOUT
SENSATION OF PLEASURE AND MAYBE
ADDICTION.
SO IT IS IMPORTANT NOT TO PUSH
THE LIMITS OF TECHNOLOGY BEYOND
THE ETHICAL BARRIER.
INVESTIGATING NEUROTECHNOLOGIES
FROM A COMBINED ETHICAL
SCIENTIFIC PERSPECTIVE ALLOWS
INFORMED DECISIONS ABOUT PATIENT
TREATMENTS AND PRESENT DAY
TECHNOLOGY.
THANK YOU SO MUCH.
>> THANK YOU, GUYS.
YOU HIT ON A REAL PROBLEM WE ARE
GRAPPLING WITH, WE ARE WORKING
TO HELP PEOPLE WHO HAVE BRAIN
CONDITIONS TO TRY TO GET THEM TO
BE MORE FUNCTIONAL AND HAVE A
MORE FULFILLED LIFE.
THESE TECHNOLOGIES COULD ALSO BE
USED FOR OTHER PURPOSES AND
THOSE ETHICAL GUIDELINES WHICH
WE HAVE IN MEDICINE DON'T REALLY
EXIST, THEY ARE THE KIND OF
THINGS YOU KIND OF TALKED ABOUT.
SO VERY INSIGHTFUL.
THANKS VERY MUCH.
NOW PLEASED TO INTRODUCE A
SECOND WINNER TEAM, ARAVAN AND
AVIT, THE HIGH TECHNOLOGY HIGH
SCHOOL IN NEW JERSEY.
THEIR VIDEO IS ENTITLED
NEUROETHICS THE PROBLEMS THAT
ARISE FROM EMERGING
NEUROTECHNOLOGIES.
LET'S WATCH THEIR VIDEO AND HEAR
THEIR TAKE AWAY MESSAGE.
>> YOU SEE HERE DESIGNED TO BE
INPUTTED DIRECTLY INTO THE BRAIN
AND SIMULATE VIRTUAL --
(INAUDIBLE) IT IS BECOMING
INTERESTINGLY COMMON NOW DAYS,
BIG TECH COMPANIES PLEDGING TO
BE THE NEXT BEST THING IN FIELD
OF NEUROSCIENCE BUT WHAT FAILS
TO NOSIS THE NEUROETHICS THE
ETHICAL DILEMMAS THAT COME WITH
INCREASING PERVASIVENESS OF
NEUROTECHNOLOGY IN SOCIETY.
DATA EVERYWHERE, LARGE COMPANIES
UTILIZE DATA TO ENHANCE FURTHER
DEVELOP PRODUCTS TO REACH LARGER
AUDIENCE.
FOR EXAMPLE, SOCIAL MEDIA
COMPANIES USE DATA TO PROVIDE
CONSUMERS WITH PERSONALIZED ADS
BASED ON THEIR BROWSER HISTORY.
WHILE SOCIAL MEDIA COMPANIES
FOCUS ON INNOVATION AND REVENUE
ONLY CONSIDERETHICS AFTER
NUMEROUS DATA SCANDALS THAT
FORCE THEM TO ACT.
THESE SOCIAL MEDIA COMPANIES
MAKE ALMOST AUTISM REVENUE FROM
SELLING ACCESS TO USER DATA TO
ADVERTISERS AND A MORAL GRAY
AREA.
IN ADDITION, PEOPLE ARE SHARING
THEIR OF AND HAVE LIMITED
AWARENESS ABOUT THE INFERENCES
THAT CAN BE MADE BASED ON THEIR
DATA.
PROFESSOR OF BIOETHICS STATED WE
HAVE CONSENT BUT NOT INFORMED
CONSENT AND FOR SOME REASON WE
HAVE ACCEPTED THAT CONSENT
WITHOUT INFORMING CONTENT IS
OKAY.
SOCIALLY ACCEPTABLE AND
JUSTIFIABLE.
HE CALLS THIS IMPLICIT COERCION.
RECENTLY MANY COMPANIES HAVE
COMMITTED TO INCORPORATING
MORALS AND ETHICS INTO THEIR
BUSINESS MODEL AND IS QUITE RARE
THAT ETHICAL CONSIDERATIONS ARE
INCORPORATED EARLY ON IN DESIGN
PHASE.
>> ON THE CONSUMER SIDE WE NEED
TO IMPROVE MODELS OF CONSENT.
MAKE AFFIRMATIVE CONSENT
MANDATORY FOR CONSUMER
TECHNOLOGY APPLICATIONS.
(INAUDIBLE) MAYBE IMPLEMENTED
GET CONSUMERS MAXIMUM CONTROL OF
DATA AND PRIVACY.
RESEARCHERS HAVE THE (INAUDIBLE)
>> OVERALL THE TECHNOLOGY HAS
POSSIBILITIES AND FUTURE AND IT
IS OUR RESPONSIBILITY TOP
ACCURATELY ENFORCE IT.
(INAUDIBLE) *
>> SO FIRST OF ALL THANK YOU FOR
HOSTING THIS CHALLENGE AND
GIVING US THE OPPORTUNITY TO
COMPETE.
GOING TO THIS CHALLENGE WE
DIDN'T HAVE MUCH EXPERIENCE WITH
NEUROETHICS OR EVEN NEUROSCIENCE
IN GENERAL.
SO WHILE CREATING VIDEO PART WE
HAD THE OPPORTUNITY TO DELVE
DEEP INTO RESEARCH DATA
MANAGEMENT AND LEARNING HOW
NEUROSCIENCE IMPACTS ON MODERN
COAT.
FOR EXAMPLE SOCIAL MEDIA
COMPANIES COLLECT DATA LIKE
PHOTOS, ACTIVE HOURS ON SOCIAL
MEDIA, AGAIN EDGEMENT RATES WITH
CERTAIN TYPES OF CONTENT.
THE VIDEO THIS DATA IS USED FOR
MARKETING OR SOLD TO OTHER THIRD
PARTY COMPANIES, GENERATE SO
MUCH REVENUE SO WHAT CAN THEY DO
WITH THIS BRAIN DATA AS WELL?
WE CAN LEX FOR TECHNOLOGIES SUCH
AS NEUROLINK, COMPANIES
DEDICATING PAID TO DEVELOP A
DEVICE THAT ONCE IMPLANTED HUMAN
BRAIN ALLOW COMPUTER TO
TRANSLATE PERSONAL THOUGHTS INTO
ACTIONS AND THEN THIS DATA WOULD
HAVE BEEN USED -- WOULD HAVE TO
BE USED ALONG STRINGENT
GUIDELINES AND BY LAWS IN ORDER
TO BE ETHICALLY USED BUT WE ALSO
GOT THE OPPORTUNITY TO LEARN
MORE ABOUT WESTERN RESEARCH
FREEZING METHODS TO REVEAL TRUE
STRUCTURE OF THE BRAIN
CONNECTIONS.
SO OVERALL THE BRAIN INITIATIVE
CHALLENGE GOT US EXCITED ABOUT
NEUROSCIENCE AND WE WOULD LOVE
TO DIVE INTO SPECIFICS RESEARCH
AND OTHER OPPORTUNITIES.
>> GREAT.
THANKS VERY MUCH.
SO LET'S SEE, YOU GUYS FROM NEW
JERSEY, IS THAT RIGHT?
ACROSS FROM NEW YORK CITY?
THANKS VERY MUCH.
OFF TO JOHN.
>> THANKS VERY MUCH.
BOTH WE AND YOU LEARNED A LOT
FROM THIS WHICH IS I GUESS THE
GOAL OF ALL THAT WE DO.
GREAT WORK.
SO WITHOUT FURTHER DELAY, THINK
IT IS TIME TO GET TO OUR FIRST
ESSAY WINNER.
ASHLEY FROM GREENWITCH HIGH
SCHOOL CONNECTICUT.
EQUITY IN THE COMING WORLD OF
NEURAL ENHANCEMENTS.
CONGRATULATIONS ASHLEY, CAN YOU
TURN ON YOUR VIDEO UNMUTE AND
READ US AN EXEMPT? EXCERPT?
>> I'M ASHLEY MALKIN.
FIRST THANKS TO THE NATIONAL
INSTITUTE OF HEALTH FOR THIS
NORTHERN AND THE OPPORTUNITY TO
DISCUSS NEUROETHICS.
HERE IS AN EXCERPT FROM MY ESSAY
EQUITY IN THE COMING WORLD OF
NEUROENHANCEMENTS.
NEUROTECHNOLOGY HAS POTENTIAL TO
ELEVATE OUR ACT DELLIC ATHLETIC
AND SOCIAL ABILITIES TO NEW
PEAKS.
THESE ARE OPTIMISTIC PROMISES
BUT WITH NEW ADVANCES IN
NEUROSCIENCE AN ENGINEERING,
THEY ARE WITHIN REACH.
HOWEVER, THE COMING WORLD OF
NEUROENHANCEMENT ISN'T ALL
UTOPIAN IDEALS.
THERE ARE SERIOUS PRESSING
CONCERNS ABOUT HOW
NEUROENHANCEMENTS DEVISE,
INSCRIBING THE HAVES AND HAVE
NOTES INTO OUR BIOLOGY.
EQUITY IS A MAJOR ISSUE
SURROUNDING NEUROENHANCEMENTS.
BOTH IN EQUITABLE ACCESS TO THIS
TECHNOLOGY AND EQUITABLE USE.
EQUITABLE NEUROENHANCEMENT
ISSUES MUST BE ADDRESSED TO
ENSURE NEUROTECHNOLOGY AND THE
POTENTIAL BENEFITS THEY MAY
BRING CAN BE ENJOYED BY ALL.
ONCE NEUROENHANCEMENT BECOMES
AVAILABLE TO THE GENERAL PUBLIC,
SERIOUS EQUITABLE ISSUES ARISE.
STUDENTS CAN USE
NEUROSTIMULATION WHILE STUDYING
FOR EXAMS IMPROVING COGNITIVE
ABILITIES AND LIKELY TEST
PERFORMANCE WITHOUT STUDYING
HARDER.
THIS WOULD PUT THEIR UNNESS
HANSED PEERS A DISADVANTAGE AS
IT WOULD BE DIFFICULT TO COMPETE
WITH THOSE WHO OWNED EXPENSIVE
NEUROENHANCEMENT EQUIPMENT.
THE PROBLEM EXTENDS TO WORKPLACE
AS WELL.
WHY WOULD EMPLOYER HIRE
UNENHANCED PERSON WHEN THEY CAN
HIRE ENHANCED PERSON WHO WOULD
WORK FAR MORE EFFICIENTLY?
THE WEALTH GAP IS A MAJOR CRISIS
AROUND THE WORLD AND IF EQUITY
CONCERNS ARE NOT ADDRESSED,
NEUROENHANCEMENT WILL COMPOUND
THIS PROBLEM TO AN UNIMAGINABLE
DEGREE.
THUS, THE GOVERNMENT NEEDS TO
CREATE CLEAR REGULATIONS
DEFINING BOUNDARIES FOR
NEUROENHANCEMENTS.
ALTHOUGH DRAWING THESE LINES CAN
BE COMPLICATED IT IS NECESSARY
TO ARE CREATE PROTECTION FROM
DANGEROUS OUTCOMES AN ENSURE
EQUITY.
A REGULATORY FRAMEWORK SHOULD BE
ESTABLISHED DETAILING WHEN
NEUROENHANCEMENTS SHOULD BE
ALLOWEDND UNDER WHAT CONDITIONS.
THIS SHOULD BE GLOBALLY
COORDINATED TO PREVENT FROM
OBTAINING UNREGULATED
IMPLANTABLE NEUROENHANCEMENTS.
MAINTENANCE OF IMPLANTABLE
DEVICES MAY NEED REGULATION AS
PEOPLE WITH NEUROENHANCEMENTS
SHOULD ALWAYS HAVE ACCESS TO
SAFETY UPDATES.
DISCLOSURE OF NEUROENHANCEMENTS
MAY ALSO REQUIRE REGULATION.
AND ANTI-DISCRIMINATION
REGULATION SHOULD BE AN
IMPORTANT PART OF THIS
FRAMEWORK.
AT A MINIMUM THE GOVERNMENT
SHOULD BAN COMPANIES FROM
REQUIRING NEUROENHANCEMENTS FOR
THEIR EMPLOYEES.
THE PROBLEM OF EQUITABLE
NEUROENHANCEMENTS IS NOT AN EASY
ONE.
IT WILL IMPACT NEARLY EVERY
FACET OF LIFE INCLUDING ECONOMIC
OPPORTUNITIES SOCIAL ACCEPTANCE
AND OTHER AREAS.
NEUROENHANCEMENTS HAVE POTENTIAL
TO HEIGHTEN HUMANITY YET ISSUES
OF EQUITY GO UNADDRESSED SOCIETY
WILL SPLIT TO TWO SECTIONS.
THOSE WITH NEUROENHANCEMENTS AND
THOSE WITHOUT.
IT IS UNJUST TO SUB JEW GATE
THOSE BECAUSE OF THEIR ECONOMIC
STATUS.
NEUROSCIENTISTS LAWYERS AND
ETHICISTS NEED TO COME TO
SOLUTIONS WITH THIS ISSUE.
THE PROGRESS OF TEENINGNOLOGY
WILL CONTINUE UNABATED.
THE PROGRESS OF OUR LAWS
SURROUNDING NEUROENHANCEMENTS
MUST MATCH IT.
THANK YOU AGAIN FOR THIS HONOR
TO GIVE YOU A LITTLE BIT ABOUT
MY BACKGROUND I HAVE BEEN
FASCINATED WITH NEUROSCIENCE AS
LONG AS I CAN REMEMBER.
I SPENT THE LAST YEAR DEVELOPING
A MACHINE LEARNING DIAGNOSTIC
FOR EARLY STAGE TBI USING I
TRACKING METHODS.
FOR MY MAIN TAKE AWAY I BELIEVE
NEUROETHICS IS A CRUCIAL
COMPANION TO NEUROSCIENCE.
SCIENCE AND TECHNOLOGY ARE
INHERENTLY NEUTRAL, THUS THE JOB
OF NEUROETHICS TO ENSURE THE
BUDDING TECHNOLOGY OF
NEUROENHANCEMENTS IS USED TO
BENEFIT HUMANITY.
IT IS VITAL TO INRATE EQUITABLE
CONCERNS TO PREVENT
INSURMOUNTABLE BIOLOGICAL DIVIDE
BETWEEN THE HAVE AND HAVE NOTES.
WE MUST CREATE A REGULATORY
FRAMEWORK THAT INCORPORATES LAWS
SUCH AS SAFETY, MAINTENANCE
DISCLOSURE AND
ANTI-DISCRIMINATION.
NEUROENHANCEMENTS HAVE MANY
EXCITING APPLICATIONS WHICH WILL
IMPROVE OUR LIVES.
AS LONG AS WE ARE MINDFUL TO
APPROACH THEIR DEVELOPMENT
THROUGH THE LENS OF NEUROETHICS.
THANK YOU.
>> THANK YOU VERY MUCH.
NOW PLEASED TO MOVE TO THE FIRST
TIER VIDEO WINNER, AFTER THAT
FANTASTIC ESSAY, THANKS SO MUCH,
ASHLEY.
OUR WINNER IS JAKE FROM
UNIVERSITY OF MICHIGAN,
NORTHEAST OF DETROIT.
PRODUCED A VOID CALLED WHAT DOES
FUTURE LOOK LIKE.
LET'S WATCH A VIDEO CLIP AND
HEAR THE TAKE AWAY MESSAGE FROM
JAKE.
HI, JAKE.
>> HEY.
HI.
NICE TO MEET YOU.
MY NAME IS JAKE.
WHEN I WAS YOUNGER I WAS A
PRETTY ORDINARY KID.
I LOVED TO RUN AROUND FLYING
QUIETS, RIDING MY BIKE, DO
GYMNASTICS AND FLIP INTO THE
POOL.
AT NIGHT THAT ALL CHANGED WHEN I
WAS DIAGNOSED WITH A
DEGENERATIVE NEUROMUSCULAR
DISEASE CALLED ATAXIA.
NOT ONLY DID I START GOING TO
SCIENTIFIC CONFERENCES WITH
SUPER SMART SCIENTISTS, BUT I
HAVE NOW LOST THE ABILITY TO
WALK OR EVEN STAND WITHOUT
SUPPORT.
SPUE AS YOU MIGHT IMAGINE I'M
VERY PASSIONATE ABOUT ADVANCING
RESEARCH WITH OUR BRAINS.
I ENCOURAGE SCIENTISTS TO PURSUE
ANY AVENUE AND OPEN ANY BOX THAT
MIGHT LEAD TO A BREAK THROUGH
FOR ME AND FOR OTHERS LIKE ME.
I DO HAVE THE BASIC FRAMEWORK TO
THE BRAIN INFORMATION THAT I
CONTRIBUTE TO RESEARCH.
MY PARTICIPATION IS VOLUNTARY
AND SHOULD ALWAYS STAY THAT WAY.
WHAT IS MINE IS MINE UNTIL I
DECIDE TO SHARE IT.
AND WHEN I DECIDE TO SHARE MY
BIOLOGICAL INFORMATION WITH
SCIENTIST, IT IS VERY IMPORTANT
THAT IT IS DEIDENTIFIED.
I'M HAPPY TO CONTRIBUTE MY
INDIVIDUAL INFORMATION TO BE
PART OF THE GREATER HOPE.
BUT THAT CONTRIBUTION SHOULD
NEVER BE ABLE TO BE REWORKED AND
TRACED BACK TO ME AS
TECHNOLOGIES ADVANCE.
MOST IMPORTANTLY WE SHOULDN'T
HESITATE TO CONTINUE TO PUSH OUR
UNDERSTANDING OF THE HUMAN BRAIN
IF WE MOVE FORWARD WITH THE
FOCUS ON CURING DISEASES.
AS SOMEONE WHO HAS SO MUCH TO
CONTRIBUTE, AND WHOSE BRAIN HAS
SO MUCH MORE CAPACITY THAN MY
CEREBELLUM WILL ALLOW MY BODY TO
UTILIZE, WHAT DOES THE FUTURE
LOOK LIKE?
THANK YOU FOR WATCHING.
>> THANKS, JAKE.
DO YOU WANT TO GIVE US A TAKE
HOME MESSAGE FROM THAT ONE?
>> ABSOLUTELY.
SO HELLO, EVERYONE, AT THE BRAIN
INITIATIVE.
THANK YOU, VERY MUCH FOR THIS
OPPORTUNITY TO SPEAK MY MIND
ABOUT THE ETHICS OF BRAIN
RESEARCH.
AS A 16-YEAR-OLD KID WHO
FREQUENTLY PARTICIPATE IN
MEDICAL RESEARCH, I APPRECIATE
THE CONCERN FROM ETHICAL
REQUIREMENT.
WHILE IT IS IMPORTANT TO
CONSIDER THESE ETHICS IT IS ALSO
IMPORTANT TO REMEMBER THAT
DISEASES ARE MOVING FAST.
SO THE RESEARCH NEEDS TO MOVE
EVEN FASTER.
TIME IS REALLY IMPORTANT TO ME.
EVEN JUST TWO YEARS AGO I WAS
ABLE TO WALK NORMALLY AND SINCE
THEN MY RIGOROUS ATAXIA HAS
STOLEN MY ABLE TO WALK AND EVEN
TO STAND.
IN FACT RIGHT AFTER THIS I'M
GOING TO PICK UP MY FIRST POWER
WHEELCHAIR AND ALTHOUGH IT IS
REALLY NEAT AND REALLY COOL
CHAIR IT WILL BE EVEN COOLER IF
I DIDN'T NEED A CHAIR AT ALL.
SO I HOPE THAT RESEARCHERS ALL
AROUND THE WORLD RECOGNIZE MY
PLEA FOR HELP AND HELP ME AND
OTHERS WITH BRAIN RELATED
DISEASES.
WE NEED YOUR HELP AND WE NEED
YOU BACK BOLDLY AND SWIFTLY, THE
PANDEMIC HAS TAUGHT US THAT WE
CAN DO JUST THAT.
AS I QUOTED IN MY MOVIE, ANY
ADVANCED TECHNOLOGY IS
INDISTINGUISHABLE FROM MAGIC.
IF WE AS PATIENTS AND YOU AS
RESEARCHERS WORK TOGETHER WITH
URGENCY, TRANSPARENCY AND MUTUAL
RESPECT, THEN I AM CONFIDENT WE
WILL FIND A CURE FOR MY DISEASE
AND OTHERS LIKE IT.
TO ME, THAT WILL FEEL LIKE
MAGIC.
THANK YOU.
>> THANKS, JAKE.
YOUR STORY IS INSPIRING AND
CERTAINLY INSPIRES US TO WORK
EVEN HARDER TO ADDRESS THESE
ISSUES.
YOUR INSIGHTS ARE ALSO INSPIRING
AND THE ONE THING THAT THAT
RESONATE WITH ME AND UNDERSCORE
YOU DO HAVE A LOT TO CONTRIBUTE
AND PLEASE CONTINUE TO DO SO, IT
WILL MAKE US ALL BETTER AND MAKE
US ALL WORK THAT MUCH HARDER FOR
YOU AND EVERYBODY WHO NEEDS IT.
>> OKAY.
SO JUST TO WRAP UP, WE ARE
THRILLED WE RECEIVED SO MANY
FANTASTIC SUBMISSIONS, FROM ALL
ACROSS THE COUNTRY.
LET'S BRING ALL OF OUR PRIZE
WINNERS BACK IN IF WE CAN ON
CAMERA SO WE CAN ACKNOWLEDGE
THEIR CONTRIBUTIONS AND THEIR
CREATIVITY.
SEE THEM POPPING UP HERE.
ALSO LIKE TO TAKE A MOMENT TO
HIGHLIGHT THE FIVE HONORABLE
MENTIONS.
THAT SLIDE WILL POP UP IN A
MOMENT.
DO WE HAVE A FEW MINUTES TO DO A
LITTLE GROUP DISCUSSION HERE,
PANEL DISCUSSION?
>> WE HAVE THE TIME, JOHN.
>> THAT'S GREAT.
LET'S SEE.
WALTER AND RICHARD STILL HERE
YOU CAN TURN ON YOUR CAMERAS.
AND DEB AS WELL. RICHARD HAS
RUN OFF TO ANOTHER APPOINTMENT.
BUT AGAIN CONGRATULATIONS TO ALL
OF YOU, IT IS GREAT TO PUT THESE
CHALLENGES OUT THERE AND TO SEE
WHAT COMES BACK IN AND THIS YEAR
DID NOT DISAPPOINT, QUITE THE
OPPOSITE.
AND AGAIN WHAT IS VIKING TO ME
IS YOU GUYS HAVE WENT O THE
HEART OF SOME ISSUES WE TALK
ABOUT EVERY DAY.
WE DON'T YET HAVE FULL ANSWERS
TO BUT WITH A LOT OF SMART MINDS
AND HOPEFULLY NEW BRIGHT MINDS
COMING INTO FOLD WE WILL MAKE
SOME PROGRESS OVER THE YEARS.
THIS IS ALSO AN OPPORTUNITY FOR
YOU GUYS TO ASK US QUESTIONS.
WE PRESUMABLY MADE IT TO SOME
LEVEL WHERE WE ARE DEEPLY
INVOLVED IN THE RESEARCH AND WE
WOULD LOVE TO HEAR YOUR
QUESTIONS AND YOUR THOUGHTS AND
ANSWER ANY QUESTIONS YOU MIGHT
HAVE ABOUT SEEING YOURSELF COME
INTO THE FIELD AS YOU GET
THROUGH COLLEGE AND PERHAPS
GRADUATE AND MEDICAL SCHOOL OR
OTHER PROFESSIONAL SCHOOL.
>> CAN I ASK A QUESTION?
>> PLEASE.
>> SO LIKE TO ANY OF THE
PANELISTS IN YOUR WORK IN
NEUROSCIENCE WHAT ARE SOME OF
THE ETHICAL ISSUES THAT YOU SEE
MOST PROMINENTLY IN YOUR DAILY
WORK?
>> WELL I WOULD SAY JUST TO
STATE THAT WHEN THE BRAIN
INITIATIVES STARTED RIGHT AT THE
BEGINNING THE U.S. BIOETHICS
COMMITTEE TO KIND OF PUT
TOGETHER ISSUES THAT WE HAVE TO
CONSIDER GOING FORWARD.
WE HAVE A WORKING GROUP,
NEUROETHICS WORKING GROUP TO
GIVE US GUIDANCE.
THEY DEAL WITH A NUMBER OF ISSUE
US THAT COME UP THAT ARE
CONCRETE.
ONE OF THE BIGGEST ONES WE HAVE
BEEN STRUGGLING WITH IS THE
ETHICS OF PLACING DEVICES IN THE
BRAIN OF PEOPLE TO IMPROVE
FUNCTION AS PART OF RESEARCH AND
HOW TO TAKE CARE OF THEM ONCE
RESEARCH IS OVER.
REAL STICKY PROBLEM.
THE RESEARCH PROJECTS GENERALLY
RUN FIVE YEARS, THEY END IF
THERE IS A DEVICE THAT IS
IMPLANTED, SOMEONE TALKED ABOUT
A BATTERY GOING -- EMERGENCY
ROOM, THOSE ARE THE KINDS OF
ISSUES WE GRAPPLE WITH IN TERMS
OF WHO IS GOING TO TAKE CARE OF
THOSE FOLKS IN THE LONG RUN.
VERY CONCRETE, VERY SPECIFIC BUT
IMPORTANT ONE.
>> WE JUST HAD AN INTENSE AND
SENSITIVE TWO DAY WORKSHOP ON
THIS ISSUE.
AND WE ARE TRYING TO SORT
THROUGH SOME SOLUTIONS WHICH FOR
A BUNCH OF REASONS IS PROBABLY
GOING TO REQUIRE WORK AROUNDS
BECAUSE OF EXISTING BARRIERS THE
WAY PAYMENTS ARE SET UP AND
LEGALITIES HOW WE GIVE OUT
MONEY, BUT THIS IS CERTAINLY ONE
THING THAT DOES -- I THINK SOME
OF US LOSE A LITTLE SLEEP AT
NIGHT FOR SURE.
THERE WAS A QUESTION FROM THE
AUDIENCE, METERED OUT, ONE OF
THE THREE OF US CAN ADDRESS IT,
MANY STUDENTS TALKED EQUITY AND
KNOWLEDGE OF ACCESS TO NEUROTECH
HOW CAN WE GET MORE STUDENTS
INVOLVED IN THESE DISCUSSIONS?
WHAT ARE YOUR THOUGHTS ABOUT
HOUSE STUDENTS CAN NOW FRAME
THESE DISCUSSIONS WITH THEIR
PEERS AS A FOUNDATION?
WALTER, DEB, YOU WANT TO TACKLE
THIS ONE?
>> TALK ABOUT HOW COCHLEAR
IMPLANTS HOW DID THAT WORK?
THAT WAS PROBABLY THE FIRST ONE
TO COME ON THE SCENE.
>> YEAH.
NO, EXACTLY RIGHT.
THAT RESEARCH I THINK PROCEEDED
PRETTY SEAMLESSLY BECAUSE THERE
WERE COMPANIES THAT STARTED 20
OR SO YEARS AGO AND THOSE
COMPANIES ARE STILL WORKING
TODAY.
SO THERE IS NOT A SITUATION
WHERE A COMPANY STARTED A
TECHNOLOGY BUT THEN BENT OUT OF
BUSINESS.
THERE IS THE OPPOSITE SITUATION
WITH THE VISUAL IMPLANT, I
REMEMBER READING ABOUT THAT NOT
TOO LONG AGO THAT A VISUAL
IMPLANT WAS CREATED THE COMPANY
ULTIMATELY WENT OUT OF BUSINESS
AND NOW THERE ARE PEOPLE WHO
REALLY DO DEPEND ON BENEFIT THEY
GET FROM THOSE RETINOL IMPLANTS
AND NO LONGER HAVE ANY SUPPORT
AT ALL.
SO I THINK THAT THE COMPANIES
ARE VERY WELL INTENTIONED WHEN
THEY START, THEY BEGIN ALL OF
THIS, THEY TRY TO BE EQUITABLE
IN THEIR IN BRINGING IN
PATIENTS.
ONE ETHICAL ISSUE THAT CAN ARISE
WITH THESE YOUNG COMPANIES IS
OFTENTIMES PEOPLE ARE ENTICED TO
PARTICIPATE, THEY MAY BE
SUFFERING FROM DISPARITIES AND
ACCESS TO HEALTHCARE, AND THEY
PARTICIPATE BECAUSE THAT GIVES
THEM THE ABILITY TO ACCESS TECH
NOTHING THAT MAY NOT BE ABLE TO
ACCESS OTHERWISE.
SO THERE IS DISCUSSION ABOUT IF
PEOPLE ARE ENTICED ERRONEOUSLY
IN SOME WAY BECAUSE THEY ARE
INCENTIVIZED TO TAKE ADVANTAGE
OF TECHNOLOGY BUT REALLY ARE
VULNERABLE IN THOSE
VULNERABILITIES HAVE TO BE TAKEN
INTO CONSIDERATION AS WELL.
>> MAYBE JUST FOR THE GROUP HERE
COULD YOU JUST EXPLAIN IN A
QUICK WAY WHAT THE COCHLEAR
IMPLANTS WOULD DO FOR PEOPLE
LIKE THAT
>> COCHLEAR IMPLANT IS A
SURGICALLY IMPLANTED DEVICE THAT
IS UNSEATERRED INTO THE COCHLEA
OR INNER EAR OF SOMEONE WHOSE
HEARING LOSS IS SO VEER THEY
CAN'T BENEFIT FROM A HEARING AID
SO THEY HAVE INNER EAR NOT
FUNCTIONING WELL ENOUGH TO
EITHER BE ABLE TO AMPLIFY SOUND
SO THEY CAN HEAR IT SO COCHLEAR
IMPLANT PROVIDES ELECTRICAL
STIMULATION TO THE HEARING
NERVE.
THIS IS A MIRACULOUS TECHNOLOGY
THAT HAS TRANSFORMED LIFE FOR
MANY, MANY PEOPLE WITH
SIGNIFICANT HEARING LOSS.
>> THIS IS YOUR -- ONE OF YOUR
SPECIALTIES.
IF I UNDERSTAND CORRECTLY.
WOULD YOU SPEAK A LITTLE BIT
ABOUT THE PATIENTS THE FAMILIES
ACCEPTANCE OF THIS TECHNOLOGY
AND MY UNDERSTANDING IS NOT
EVERYBODY SEES THIS AS A GREAT
THING FOR THEM, OR THEIR CHILD.
>> THERE HAVE BEEN SOME ETHICAL
CONSIDERATIONS WITH THE COCHLEAR
IMPLANT YOU ARE RIGHT, JOHN.
SO I THINK THE BIGGEST ISSUE HAS
BEEN WITH THE DEAF COMMUNITY.
SO WE REFER TO THE DEAF
COMMUNITY AS A CAPITAL D DEAF SO
THESE ARE MOSTLY INDIVIDUALS WHO
ARE DEAF FROM BIRTH AND
OFTENTIMES BORN INTO FAMILIES
WITH DEAF PARENTS.
AND THERE IS A LOT OF CULTURE IN
THE DEAF COMMUNITY.
THERE IS A SPECIAL LANGUAGE SIGN
LANGUAGE UTILIZED, AND A
CULTURAL ELEMENT TO THIS THAT
DEAF PEOPLE WANT TO PRESERVE.
SO MANY OF THEM SEE COCHLEAR
IMPLANTATION AS A THREAT TO HAIR
WAY OF LIFE.
SO THAT HAS BEEN THE MAIN
BARRIER FOR THE MOST PART
COCHLEAR IMPLANTS ARE WELL
ACCEPTED IN THE HEARING WORLD.
SO WHEN A CHILD IS BORN
ROUTINELY THEY SHOULD BE
SCREENED FOR HEARING LOSS AND
PROVIDED WITH COCHLEAR
IMPLANTATION AS OPTION IF THEY
ARE CANDIDATE BUT IF A CHILD IS
BORN TO DEAF PARENTS THERE IS
THE DISCUSSION AND OFTENTIMES
THE PARENTS ARE VERY RELUCTANT
TO ALLOW FOR THAT IMPLANT TO
TAKE PLACE IN A TIMELY FASHION.
>> GREAT.
THANKS.
SO MUCH TO THINK ABOUT WITH
THESE NEW TECHNOLOGIES.
SO MANY DIFFERENT PERSPECTIVES.
TO CONSIDER.
I THINK WHAT DEB IS UNDERSCORING
HERE IS THE MOST IMPORTANT
PERSPECTIVE IS THE ONE OF THE
PATIENT AND THEIR FAMILIES.
SO WE HAVE GOT THE FIVE MINUTE
WARNING GOING ON HERE.
IF ANYBODY HAS A QUESTION FROM
ONE OF THE STUDENTS SHOUT OUT OR
PUT UP YOUR HAND I GUESS.
DON'T LET US DO ALL TALKING
HERE.
LOOKS LIKE SOFIA HAS HER HAND
RAISED.
>> WHAT DOES PATIENT RESEARCHER
COMMUNICATION LOOK LIKE TODAY?
>> SORRY REPEAT THE QUESTION.
>> WHAT DOES PATIENT AND
RESEARCHER COMMUNICATION LOOK
LIKE TODAY SPECIFICALLY WITH
NEUROTECHNOLOGIES PARTICULARLY
INVASIVE NEUROTECHNOLOGIES?
>> GREAT QUESTION.
I WOULD SAY IT IS A WORK IN
PROGRESS.
I WOULD LIKE TO THINK THAT AS
WALTER MENTIONED, THE KINDS OF
THINGS WE DO DOES INVOLVE
OFTENTIMES IMPLANTED DEVICES
THAT FIT PEOPLE'S HEADS.
IT KIND OF -- IT RAISES A LEVEL
OF SCRUTINY THAT WE NEED TO GET
TRULY INFORMED CONSENT.
I THINK THE BASIS OF TRULY
INFORMED CONSENT IS
COMMUNICATION, TO MAKE SURE THE
PATIENTS UNDERSTAND WHAT THEY
ARE GETTING INTO, LIMITATION,
WHAT ARE THE RISKS AND AS
MENTIONED ONE OF THE LONG TERM
RISKS, STUDIES TYPICALLY DON'T
LAST MORE THAN FIVE YEARS AND
THE HUGE CHALLENGE IS HOW DO WE
COMMUNICATE TO PEOPLE FAIRLY
WHAT THEY ARE GETTING INTO
KNOWING THERE IS A POSSIBILITY
NOT ONLY NOT A MATTER OF NOT
HAVING ACCESS TO -- THEY MAYBE
STUCK WITH SOMETHING THAT IS
IMPLANTED THAT IS NOT DOING ANY
GOOD IF PARTS DON'T BECOME
AVAILABLE IF PEOPLE ARE AROUND
TO UPGRADE OR UPDATE OR TREAT
THEM AND EVEN EXPLANT DEVICES IF
NECESSARY OR IF THEY ARE RUNNING
TO OTHER ISSUES.
SO I THINK THIS REALLY DOES
UNDERSCORE THE NEED FOR EVERY
GREATER COMMUNICATION, I THINK
OUR GROUPS ARE DOING A GOOD JOB
AT THIS AND THIS IS SOMETHING WE
DO LOOK FOR WHEN WE FUNDS THESE
GRANTS WE LOOK TO SEE NOT JUST
AS IRB APPROVAL BUT EXTRA LEVEL
SCRUTINY TO MAKE SURE THERE IS
GOOD COMMUNICATION OF RICKSES
BECAUSE THERE ISN'T UNDUE
INFLUENCE AND SO FORTH BECAUSE
PEOPLE ARE FRANKLY AT THEIR
WIT'S END, THIS IS THE LAST
STEP.
I SEE, WHO IS NEXT?
>> QUICK QUESTION, I DO DBS IN
MY ESSAY AND ANY -- IN MY TALK,
SOME OF THE ARTICLES TALKED
ABOUT ETHICAL CONSIDERATIONS
ABOUT WHICH VERSION THE PATIENT
HAS THE CONSENT TO GIVE, BECAUSE
THERE'S THE VERSION WITH DBS
ACTIVATED WITH SOMETIMES GIVING
A NEW PERSONALITY VERSUS
DEACTIVATED WITH ORIGINAL
PERSONALITY SO WONDERING WHAT
VERSION OF THE PATIENT WOULD
HAVE CONSENT?
TO GIVE -- NEW MEDICAL
PROCEDURES AND THAT -- WHERE
THEY HAVE TWO PERSONALITIES,
WHICH WOULD YOU CHOOSE?
>> THAT IS A REAL ETHICAL ISSUE.
GENERALLY WHAT YOU TRY TO DO IS
IS TO ANTICIPATE THESE THINGS IN
ADVANCE SO CONSENT IS REALLY FOR
THE PURPOSE OF IN PARKINSON'S
FOR APPROVING MOTOR FUNCTION OF
THE INDIVIDUAL BUT THEN YOU
DISCUSS THESE KIND OF OTHER
EFFECTS THAT MIGHT OCCUR YOU
LIKE TO DO THIS TO HAVE FAMILY
THERE.
SO THAT IF THESE THINGS COME UP
THEY CAN BE A DISCUSSION WITH
THE FAMILY AND THE INDIVIDUAL GO
INTO HOW DEVICE WILL BE TUNED
USUALLY LIKE TO STAY AWAY FROM
THESE NON-MOTOR EFFECTS WHICH
ARE NOT THE MAIN GOAL OF DBS AND
PARKINSON'S BUT THEY DO CROP UP
SO YOU NEED TO HAVE A PLAN TO
HAVE A DEAL WITH THEM IN ALL
KINDS OF REPROGRAMMING THE
DEVICE TO GET RID OF THEM BUT
SOMEBODY LIKES THEM THEN YOU
HAVE A PROBLEM IN TERMS OF
SITTING DOWN, THE PROBLEM IS
THAT IN PARKINSON'S THE ISSUES
THAT SURROUND THE SENSE OF WELL
BEING LEAD TO SOME VERY
DESTRUCTIVE BEHAVIORS INCREASE
GAMBLING, ALL SORTS OF
INTERPERSONAL RELATIONSHIPS THEY
WOULDN'T OTHERWISE HAVE DONE.
SO IN GENERAL THEY END UP
CAUSING TROUBLE SO YOU LIKE TO
TRY TO REPROGRAM SO THEY DON'T
OCCUR AND YOU STILL GET THE
MOTOR BENEFIT.
>> ALL RIGHT.
LOOKS LIKE WE ARE AT TIME.
THIS WAS ABSOLUTELY WONDERFUL.
THANK YOU ALL AGAIN FOR
SUBMITTING THESE WONDERFUL
ESSAYS AND VIDEOS, VERY
THOUGHTFUL, HOPE YOU CAN
CONTINUE THESE DISCUSSIONS WITH
THE OTHER CLASS MATES AN
STUDENTS AND HAVE GREAT CAREERS
AHEAD OF YOU.
>> THANKS, EVERYBODY.
>> THANK YOU.
>> TAKE CARE.
GOOD LUCK WITH EVERYTHING.
HI, EVERYBODY.
WELCOME TO ONE OF THE AFTERNOON
SYMPOSIUMS HERE FOR THE BRAIN
INITIATIVE MEETING.
TITLE OF THIS SYMPOSIUM IS
NEUROMECHANISMS THAT GENERATE
INTERNAL STATES ACROSS
ORGANISMS.
AND THE IDEA OF THE SYMPOSIUM
WAS TO BRING TOGETHER SPEAKERS
STUDYING THE MECHANISMS THAT
GENERATE INTERNAL STATES USING
LOTS OF DIFFERENT TOOLS AND IN
DIFFERENT ANIMAL MODELS.
SO YOU CAN HEAR FROM SPEAKERS
STUDYING THE BASIS OF INTERNAL
STATES IN ANIMALS AS DIVERSE AS
WORMS, FLIES, FISH AND MICE.
AND USING TOOLS AS DIVERSE AS
BRAIN WIDE CALCIUM IMAGING,
TARGETED IMAGING OF SPECIFIC
CIRCUITS AND THEORETICAL
APPROACHES AS WELL.
THE IDEA IN GENERAL IS THIS IS
AN AREA THAT'S SEEN GROWTH IN
RECENT YEARS AND WE THOUGHT IT
MIGHT BE INTERESTING TO COMPARE
NOTES ACROSS DIFFERENT AREAS OF
THE FIELD AND SEE IF THAT
ILLUMINATES EMERGING THEMES OR
PRINCIPLES.
SO WE HAVE FIVE SPEAKERS, WE ARE
GOING TO RUN THROUGH THEM IN
ORDER AND SAVE A LOT OF
QUESTIONS FOR THE END HOPEFULLY
AT THE END THERE WILL BE TEN
MINUTES OR MORE FOR QUESTIONS.
SO PLEASE SAVE YOUR QUESTIONS
THEN AND DO CHIME IN WITH THEM
AT THE END.
EITHER SPECIFIC QUESTIONS FOR
SPEAKERS OR GENERAL QUESTIONS
FOR THE WHOLE PANEL.
THEN TO PRESERVE AS MUCH TIME AS
POSSIBLE FOR EVERYBODY WE WILL
JUST GET STARTED AND SO OUR
FIRST SPEAKER OF THE SYMPOSIUM
IS JENNIFERL JENNIFER LI AT THE MAX PLANK
INSTITUTE FOR BIOLOGICAL CYBER
NETTICS.
TAKE IT AWAY, JENNIFER.
>> HI, EVERYONE.
SO I JUST WANT TO THANKS TO
STEVE FOR PUTTING TOGETHER THIS
REALLY NICE SYMPOSIUM.
EVERYTHING I'M GOING TO BE
TALKING ABOUT TODAY IS DONE WITH
MY CO-PI AND OUR GOAL IN LIFE IS
TO FIGURE OUT HOW NATURAL
BEHAVIORS ARE ORGANIZED BY
INTERNAL BRAIN STATES.
WHAT I REALLY LOVE RIGHT NOW
LIKE WHAT STEVE SAID, IS THAT WE
SEEM TO BE AT A MOMENT WHERE
THERE IS THIS RENEWED
APPRECIATION FOR NATURAL
BEHAVIORS IN NEUROSCIENCE AND
THAT'S REALLY INTERESTING TO
THINK ABOUT BECAUSE THERE IS
ALSO WHAT I ALSO FIND
INTERESTING, THERE IS THIS GAP
BETWEEN THE THEY DAY OF CLASSIC
MYTHOLOGY, 1950s AND REVIVAL
AS COMPUTATIONAL THE LAST FEW
YEARS.
THIS GAP REFLECTS A LOT OF
CHALLENGES, IN ACTUALLY LOOKING
AT NATURAL BEHAVIORS, AT
INTERNAL STATES, I WOULD SAY
THAT THERE IS TWO REALLY
DIFFICULTIES. ONE IS THAT THE
LEGIT ANYTIME COMPLAINT IS THERE
IS A LACK OF CLEAR CONCEPTUAL
FRAMEWORK SOMETIMES, IT IS A
LITTLE VAGUE.
YOU THINK ABOUT IT, THERE IS
INFINITE VARIETY OF ANIMAL
BEHAVIOR, WE CAN'T CATEGORIZE
ALL.
SO WE SAY WE WANT TO UNDERSTAND
NATURAL BEHAVIOR IT IS A
QUESTION OF WHAT EXACTLY ARE WE
TALKING ABOUT.
SO MY LAB OR MY LAB WHAT WE ARE
INTERESTED IN IS TWO VERY
SPECIFIC ET LOGICAL QUESTIONS,
STATEMENT OF THE -- AND
MULTI-OBJECTIVE PROGRAM.
SO STATE DEPENDENT COMPUTATION
IS A SIMPLE PROBLEM.
THE IDEA IS THAT THE BRAIN IS
NOT A STATELESS SYSTEM SO IF YOU
HAVE A STATELESS SYSTEM
SOMETHING THAT PERFORMS THIS
INVARIANT TRANSFORMATION,
BEHAVIORAL -- IF YOU ARE A CAT
YOU SEE A MOUSE THEN YOU WOULD
TRY TO KILL IT EVERY TIME BUT OF
COURSE THAT IS NOT THE CASE FOR
ANYONE WHO IS EVERY OWNED A CAT.
THIS IS BECAUSE THE BRAIN IS
THIS COMPLICATED DYNAMICAL
SYSTEM THAT CAN HOLD ON TO
INFORMATION ACROSS TIME AND
THOSE INTERNAL STATES PERSISTENT
INTERNAL STATES ADJUSTS RESPONSE
TO EXTERNAL ENVIRONMENTAL QUEUES
AND WHAT BEHAVIOR IT PRODUCES.
DO MEAN ALL BEHAVIOR IS STATE
DEPENDENT THE LOGICAL NEXT
QUESTION IS THEN HOW ARE THESE
INTERNAL BRAIN STATES ORGANIZED,
BECAUSE GIVEN ANY MOMENT IN TIME
IS A LOT OF DIFFERENT COMPETING
OBJECTIVES AND SO YOU NEED SOME
WAY, SOME HEURISTIC TO ORGANIZE
AND PRIORITIZE ALL THESE
DIFFERENT OBJECTIVES.
THAT IS A QUESTION THAT GOES
BACK TO THE EARLY DAYS OF MYTH
THOLING AND IT IS ONE EVERYBODY
IN THIS SYMPOSIUM IS TRYING TO
FIGURE OUT.
SO THE OTHER PROBLEM THOUGH IS A
NICE QUESTION, THE OTHER PROBLEM
IS THAT TECHNOLOGY FOR DOING
THIS IS NOT TRIVIAL.
IF YOU WANT TO UNDERSTAND
INTERNAL STATES NATURAL
BEHAVIORS WHILE LOOKING AT
NEUROAT THIS TIME AT THE SAME
TIME REQUIRES A LOT OF
TECHNOLOGICAL PROBLEM.
SO JUST TO GIVE AN EXAMPLE, OUR
LAB WORKS ON THE -- ZEBRAFISH
THE REASON WE CHOSE IN THE FIRST
PLACE IS IT SEEMED LIKE THIS
IDEAL MODEL ORGANISM FOR SYSTEMS
NEUROSCIENCE BECAUSE THE ENTIRE
BRAIN IS TRANSPARENT YOU CAN
RECORD CALCIUM ACTIVITY
THROUGHOUT EVERY SINGLE CELL IN
ITS BRAIN AT THE SAME TIME BUT
IT TOOK US MANY YEARS BEFORE WE
WENT FROM JUST DOING CALCIUM
IMAGING AND WHOLE BRAIN CALCIUM
IMAGE TO BEING ABLE TO DO THIS
FLEELY SWIMMING -- FREELY
SWIMMING ANIMAL THAT WE CAN
ACCESS THE NATURAL BEHAVIORS OF
THIS ANIMAL AND START TO ASK
QUESTIONS ABOUT HOW INTERNAL
BRAIN STATES OF THIS ANIMAL ARE
ORGANIZED.
SO JUST -- SO WE HAVE TO HAVE
THIS TECHNOLOGY WORKING, WE DID
JUST THE SIMPLEST EXPERIMENT YOU
CAN IMAGINE, WE PUT THIS
ZEBRAFISH INTO ARENA AND FILLED
WITH PARE PLEASEIA.
THE ZEBRAFISH LIKES TO EAT.
BY OBSERVING BEHAVIOR FOR ONE TO
TWO HOURS WITHOUT ANY CHANGE TO
THE ENVIRONMENT, IS THAT THIS
ANIMAL, THIS IS WORK BY TWO
FORMER POST DOCS, WE FOUND THIS
ANIMAL SPONTANEOUSLY OSCILLATES
BETWEEN TWO STATES, ONE WHERE
YOU ARE SPATIALLY RESTRICTED AND
BIASED TOWARDS HUNTING BEHAVIOR,
AND WE CALL EXPLOITATION STATES
LASTS FOR SEVERAL MINUTES AT A
TIME AND ANOTHER STATE WHERE
THEY ARE ROAMING THE ENTIRE
BEHAVIOR ARENA AT HIGH SPEED,
AND COMPLETING DIFFERENT -- SO
THEY CAN SWIM THROUGH A POOL
PARAPLEASEIA AND THEN AS IF THEY
DON'T EVEN SEE IT.
SO THESE EXPLOITATION AND
EXPLORATION STATES ARE OUR FIRST
POINT OF ENTRY TO WHAT THE
ORGANIZATIONAL STATES IN THIS
ANIMAL.
BECAUSE WE CAN IMAGE THE BRAIN
AT THE SAME TIME, WE LOST THE
BEHAVIOR WE CAN PULL OUT
NEUROPOPULATIONS THAT ARE
CORRELATED WITH THESE TWO
STATES.
ON THE LEFT YOU SEE THE ANIMAL
HUNTING FOR PREY AND ON THE
RIGHT YOU SEE ALL THE CELLS IN
THE BRAIN THAT LIGHT UP IN
RESPONSE TO SPECIFIC BEHAVIORS,
AND BEHAVIORAL STATES.
WHAT WE FOUND ARE NEURONS OR
NEURAL POPULATIONS CORRELATED
WITH EACH ONE OF THESE
EXPLOITATION AND EXPLORATION
STATE.
ONE OUR FAVORITE POPULATIONS
THAT WE FOUND IS THIS
SUBPOPULATION DORSAL AND THE
DORSAL RAFI THESE POPULATIONS
ARE INTERESTING FOR SEVERAL
REASONS, ONE WHEN WE DID
PRINCIPLE COMPONENT ANALYSIS
ACROSS THE ENTIRE BRAIN, ALL
CELLS AT ONCE, THE GLOBAL BRAIN
ACTIVITY OSCILLATES ALONG A
PRINCIPLE ASSETS AND THE DORSAL
ACTIVITY MAPS BASICALLY
PERFECTLY ON TO THIS PRINCIPLE
COMPONENT ACCESS.
WHAT WE -- THE SECOND THING IS
THAT I REALLY LOVE THE SHAPE OR
TEMPORAL DYNAMICS OF THESE
STATUS.
WHAT IT HAS IS THAT IF YOU LOOK
AT THE STATE TRANSITION FROM THE
EXPLORATION TO EXPLOITATION,
THESE DORSAL RAFI CELLS HAVE
RAPID RISE FOLLOWED BY THIS LONG
LINEAR DECAY ACROSS THE DURATION
OF THE STATE.
WHEN THIS CASE BACK TO BASELINE
THE ANIMAL EXITS EXPLOITATION
STATE AND ENTERS THE EXPLORATION
STATE AGAIN.
I LOVE THE SHAPE OF THE SIGNAL
IS THAT OVER THE LAST SEVERAL
YEARS VERY RECENTLY THERE'S BEEN
MANY SERIES OF INTERESTING
PAPERS THAT ESSENTIALLY SEES THE
SAME TEMPORAL DYNAMICS ACROSS
MULTIPLE ORGANISMS AND ACROSS
PARADIGMS SO THE HYPOTHESIS THAT
OUR LAB LIKES BUT ONE THAT I
WILL LOVE TO SEE TESTED ACROSS
ALL THESE MODEL ORGANISMS AND
BEHAVIORS IS THAT THIS IS A KIND
OF TIME KEEPING MECHANISM, THIS
IS A WAY FOR THE ANIMAL TO CLOCK
OUT GIVEN INTERNAL STATE.
IN ADDITION TO THESE CELLS, WE
ALSO SEE IN THE BRAIN ARE CELLS
THAT ARE ACTIVE RIGHT AT THE
TRANSITION CALLED THE TRIGGER
CELLS SO WITH THE TRIGGER CELLS
AND THESE STAIN CODING CELLS YOU
CAN FORM VERY SIMPLE DYNAMICAL
SYSTEMS MODEL HOW YOU GET
DIFFERENT STATE DURATIONS.
SO THAT IS WHERE WE WERE AT IN
-- IN THE LAST TWO YEARS TRY TO
ANSWER A LOT OF THE OPEN
QUESTIONS THAT WE RAISED BY JUST
IDENTIFYING TWO STATES.
NOW WE HAVE A I WOULD SAY MUCH
RICHER UNDERSTANDING OF INTERNAL
STATES FACE WITH THIS ANIMAL,
THIS IS NOT SOMETHING I HAVE
TIME THE TALK ABOUT TODAY, THESE
ARE SORRYIOUS WILL HEAR THE NEXT
YEAR OR TWO.
BUT I'M GOING TO CONTINUE THIS
THEME TODAY.
OF THIS CO-EVOLUTION OF
TECHNOLOGY AND TALK HOW VERY
SIMPLE PIECE OF TECH WE
IMPLEMENTED CAN HELP ANSWER
REALLY INTERESTING QUESTIONS IN
STATE ORGANIZATION.
WHICH IS VARIABILITY IN STATE
STRUCTURE.
THIS IS AN EXPERIMENT WE DID
WHERE WE PUT FISH IN EMPTY
CHAMBER, NO PREY, SLIGHTLY
DIFFERENCE EXPERIMENT BUT ALSO
SEE STATE TRANSITIONS FUNDS FROM
EXPLORATION AND QUIA YES, SIR
SENSE, SOME FISH SPEND EQUAL
AMOUNTS OF TIME EXPLORATION AND
QUIA YES, SIR SENSE AND THEN
THERE WERE SOME QUIA YES, SIR
SENSE.
SO LONG EXPLORATORY STATES AND
THE VERY SHORT QUIESCENT STATES.
YOU HAVE SOME OPPOSITE, MOSTLY
QUIESCENT WITH BURSTS OF
EXPLORATION SO SOME WONDERED FOR
YEARS IS IS THIS PERSONALITY IS
THIS MOOD?
IS THIS SOMETHING THAT'S
SPECIFIC TO FISH AND STABLE
ACROSS TIME?
OR THESE DIFFERENT MODES OR META
STRUCTURES OF INTERNAL STATE
EACH FISH CAN ACCESS.
BUT IN ORDER TO ANSWER THIS
QUESTION WE NEEDED TO EXTEND OUR
IMAGING DURATION TO HOURS AND
DAYS, WE WANTED TO PRESERVE THE
IMAGING SPEED AND THE FIELD OF
VIEW OF OUR BEHAVIORAL ARENA AND
SPATIAL RESOLUTION.
SO THIS IS A CLASSIC
LONGITUDINAL MULTI-SCALE IMAGING
PROBLEM.
AND YOU CAN GO TRADITIONAL ROUTE
TO GUIDE BY DIFFERENT KINDS OF
CAMERAS YOU CAN BUY A CHEAP
CAMERA, THIS AFFORDABLE CAMERA
UNDER 1,000 AND IT HAS LOW PRAY
FRAMEWORK OR BUY A HIGH SPEED
CAMERA BUT WITH A MUCH HIGHER
COST, ORDER OF MAGNITUDE MORE
COST.
SO WE DEVELOPED A VERY SIMPLE
SIMPLE HACK TO APPLY LIKE A WIDE
RATE OF CAMERAS YOU CAN HAVE
BEST OF BOTH WORLDS YOU CAN I
APPLY TO A LITTLE FEAR AND TURN
IT INTO A HIGH SPEED RAM CABBY
DYNAMICALLY ADDRESSING MORE
ROIs.
IN THE CENTER OF THIS CAMERA SO
DASHER IS THE WAY THAT IT WORKS
IS WITH CONVENTIONAL IMAGING YOU
CAN HAVE THE ENTIRE FIELD OF
VIEW LOSING SPATIAL RESOLUTION
OR YOU CAN HAVE A SMALL FIELD OF
VIEW AND YOU CAN HAVE HIGH
SPATIAL RESOLUTION AND -- WITH
THAT YOU CAN HAVE ALL THESE, YOU
CAN HAVE LARGE FIELD OF VIEW,
HIGH FRAMEWORK AND HIGH SPATIAL
RESOLUTION.
SO IF YOU LOOK AT WHAT FISH THAT
IS MOVING AROUND ARENA YOU CAN
SEE THE FIELD OF VIEW OF ARENA
IS STILL VERY LARGE RELATIVE TO
ANIMAL BUT IF YOU LOOK AT THE
INDIVIDUAL ANIMAL YOU CAN SEE
ACTUALLY A LOT OF STRUCTURE IN
ITS IN THIS IMAGE YOU CAN SEE
INDIVIDUAL PIGMENT CELLS, EYES
AND EAR AND COMPARED TO
CONVENTIONAL IMAGING TECHNIQUES
IF YOU USE -- TO INCREASE ALL
THAT INFORMATION BE GONE SO YOU
CAN USE THIS STRATEGY TO LOOK AT
THESE INDIVIDUAL BODY FEATURES
YOU CAN PRESERVE THE 250 IMAGING
RATE TO LOOK AT INDIVIDUAL
MOVEMENTS, AND YOU CAN APPLY
THIS VERSION OF THIS TO MULTIPLE
ANIMALS ACROSS A LARGE FIELD OF
VIEW.
AND IT IS VERY EASY TO USE, OUR
FORMER POST-DOC TOOK THIS HOME
AND IMAGED HER PET SHRIMP WITH
IT.
SO JUST TO FINISH UP, WITH THIS
HACK FOR LONGITUDINAL
MULTI-SCALE IMAGING WE CAN
ANSWER THIS QUESTION OF IS THIS
PERSONALITY POOR MOOD AND WHAT
IS VERY CLEAR JUST FROM SINGLE
FISH IS INDEED THERE IS ACTUALLY
META STRUCTURE IN THE
ORGANIZATION OF INTERNAL STATE
SO THERE ARE TRANSITIONS
EXPLORATION AND QUIESCENT BUT
THERE IS ANOTHER LEVEL
ORGANIZATION ON TOP OF THIS.
SO THAT IF YOU ARE META STATE
ONE VERSUS TWO, IF YOU WERE TO
FIT A HIDDEN MODEL YOU HAVE A
DIFFERENT TRANSITION MATRIX.
SO THIS IS JUST TO SAY EACH TIME
POINT YOU HAVE THIS MULTI-SCALE
INFORMATION AND THEN LASTLY THIS
IS JUST A SHOUT OUT TO OUR
COLLABORATORS WHO ARE TRYING TO
COMPLIMENT THE WHOLE BRAIN
IMAGING AND BEHAVIOR TRYING TO
DO WITH TRANS-SYNAPTIC GENETIC
TRACING FOR -- (INAUDIBLE).
I WANT TO THANK MY LAB AND THEN
I AM DONE.
A
>> I'M GOING TO START FOR SAKE
OF TIME, THANK YOU STEVE FOR
INVITING ME TO GIVE THIS
PRESENTATION AND I WILL TRY TO
TELL YOU OUR LAB WORK TO TRY TO
UNDERSTAND STATE DEPENDENT IN
DROSOPHILA.
THEIR INTERESTING UNDERSTANDING
HOW BRAIN REGULATES STATE
DEPENDENT SENSORY PROCESSING AND
ACTION SELECTION, AND WE CHOOSE
TO STUDY THIS IN MODEL OF FOOD
INTAKE BEHAVIOR BECAUSE FOOD
INTAKE IS UNIVERSAL, BASICALLY
ANIMALS HEDDLED TO OVERLAY
METABOLIC FIZZ Q2 LOGICAL LEVELS
AND -- PHYSIOLOGICAL LEVELS AND
CHANGE ORIGIN BEHAVIORS TO FIND
SPECIFIC NUTRIENTS. THIS IS A
CONSERVED BEHAVIOR, ALL NEEDS TO
DO THAT SINGLE CELL ORGANISMS
LIKE PARAMESIUM.
THIS IS AN INTERESTING PROBLEM
AND THE QUESTION HERE YOU ARE
TRYING TO UNDERSTAND IS HOW DOES
THE BRAIN INTEGRATE THE SMELL,
THE SIGHT TASTE OF FOOD
METABOLIC SIGNALS TO MAKE FOOD
INTAKE DECISIONS.
SOMETIMES YOU MIGHT WANT SWEET,
SOMETIMES YOU WANT SAVORY AND
HOW DOES THE BRAIN REGULATE
THESE PROCESSES AND WHAT ARE THE
SURFACE UNDERLYING -- CIRCUITS
UNDERLYING THAT.
THERE HAS BEEN KNOWLEDGE THAT
THERE IS A LOT OF RESEARCH DONE
ON THIS TOPIC.
WE KNOW IN THE RODENT BRAIN VERY
CLEAR AREAS LIKE THE -- EGR
REGULATE HOMEOSTATIC HEIGHT
BEHAVIORS IN MICE AND RODENTS
AND POTENTIALLY HUMANS.
WE ALSO KNOW ABOUT THE
DOPAMINERGIC NEURONS IN BTA
WHICH ARE INVOLVED IN HEADNISTIC
EATING LIKE PLEASURE OF
CONSUMING INPUT BUT ONE THING
LACKING IN THIS PICTURE IS THE
ENTIRE SURFACE THAT SAMPLE IT IS
FOODS AND INTEGRATES THIS
INFORMATION, WITH METABOLIC
STATE OF THE ANIMAL, IN
ACCORDINGLY RELATES THIS
INFORMATION ABOUT THE MOTOR
SURFACE CONSUME REGULATE.
THIS BASICALLY HOLD NEURAL
CIRCUITS IS STILL MISSING IN
ALMOST ANY MODEL ORGANISM MAYBE
EXCEPT C ELEGANS.
THAT IS BASICALLY OUR GOAL IS TO
FIND THESE THINGS.
SO WE ARE USING THE FLY AS A
MODEL BECAUSE FLIES HAVE
BEHAVIORS THEY GET -- FOR
SPECIFIC NUTRIENTS IN DIFFERENT
METABOLIC STATES.
WE HAVE BASICALLY OVER THE YEARS
DEVELOP BEHAVIORAL ASSAYS TO
MEASURE BEHAVIORS AND RECENTLY
HAVE -- FLY BRAIN SO LIKE THIS
IS BASICALLY A VERY EXCITING
TIME NEUROSCIENCE BASICALLY
POTENTIALLY ONCE WE HAVE NEURON
IN HAND THAT REGULATES BEHAVIOR
YOU CAN TRACE TO THE ENTIRE
CIRCUIT.
AND WE ALSO HAVE GENETIC ACCESS
TO MANY OF THE NEURONS.
BASICALLY ACTIVATE NEURONS THEIR
ACTIVITY ON GENES IMAGED THEIR
ACTIVITY AND SO ON.
TO STUDY DECISIONS IN FLIES THAT
WE HAVE DEVELOP THIS ASSAY WHICH
ALLOWS US TO MEASURE EACH
FEEDING PART OF AN INDIVIDUAL
FLY WHILE CORRECTING THEIR
ACTIVITY.
HERE IS AN EXAMPLE, HERE IS A
MALE FLY, FOUND SUPER RESOLUTION
INGESTING AND ON THE RIGHT SIDE
YOU CAN SEE THAT THE SENSOR IS
DETECTING THIS (INAUDIBLE)
SPECIFICALLY.
YOU CAN BASICALLY MEASURE THE
BOT VOLUME THE TIME AND EPIJUST
SHUN RATE SO THIS IS IN WHICH
DATA SETS QUANTIFY MERGING
BEHAVIOR FROM SINGLE FLY, WE
ALSO HAVE TRACKING DATA SO WE
CAN LOOK AT HOW DOES THE ANIMAL
MOVE BEFORE AND AFTER EATING.
SO SYSTEM WE HAVE DONE NORMAL
INHIBITION SCREEN LIKE
DEACTIVATED THE ACTIVITY OR
SYNAPTIC RELEASE FROM THE
DIFFERENT POPULATIONS OF NEURONS
AND WE FOUND THESE NEURONS WE
CALL THEM IM 1.
THESE NEURONS ARE LOCATED IN THE
(INAUDIBLE) CALLED (INAUDIBLE)
SCENE.
THESE ARE INTERNEURONS BASICALLY
EXCITATORY SO THEY BASICALLY
DON'T PROJECT INTO A SENSORY,
PROCESSING AREA OR MOTOR AREA,
THEY ARE BASICALLY LOCAL NEURONS
IN THIS TASTE SENOR.
IF YOU INHIBIT THE (INAUDIBLE)
IN HUNGRY FLIES, THEY FOOD
INTAKE IS SHOWN IN THIS SO THE
BRAIN WANTS BASICALLY ARE
SHOWING YOU GENETIC CONTROLS AND
THE BLUE PLOT IS SHOWING YOU THE
FLIES THAT ARE INACTIVE IM
NEURONS.
WE HAVE DEVELOPED AN IMAGING
TECHNIQUE TO IMAGE THE ACTIVITY
OF NEURONS IN FLIES AND AS YOU
CAN SEE ON THE RIGHT ANIMALS EAT
FOOD THE IM NEURONS GET EXCITED
SIGNIFICANTLY.
MOREOVER WE HAVE RECORDED THE
ACTIVITY OF (INAUDIBLE)
DIFFERENT STATES, SO ON THE LEFT
YOU SEE THE GREEN PLOTS SHOWING
YOU HUNGRY MALE FLY INGESTING
ONE MOLAR SUGAR SOLUTION AN
BASICALLY THE SMALL TICK IN THE
BOTTOM OF THE PLOT SHOWS YOU THE
ANIMAL ATE.
SO (INAUDIBLE) SPECIFIC SUGAR
INGESTION AND THEY HAVE THIS
PERSISTENT ACTIVITY LASTS FOR
ALMOST MINUTES.
IN HUNGRY FLIES.
SAME EXPERIMENT IN PET FLIES
WHICH IS MIDDLE PLOT YOU CAN SEE
THE -- NEURONS STILL RESPOND AND
ANIMAL EAT BUT THIS PERSISTENT
ACTIVITY IS TEMPERED LASTLY ON
THE RIGHT SIDE YOU SEE THAT IM
NEURONS ARE BASICALLY THIS IS
LIKE EXPERIMENT FLIES LOW
CONCENTRATION OF SUGAR.
YOU CAN SEE THE ACTIVITY,
BASICALLY SEE THIS VERY ACUTE
ACTIVATION OF NEURONS WHICH WILL
NOT HAVE AS MUCH AS THE ONES
THAT BASICALLY EAT (INAUDIBLE)
SO THESE BASICALLY SUGGEST IMR
NEURONS ARE IN THE VERY EARLY
STAGES OF THE TASTE PERCEPTION
HAS A STATE DEPENDENT -- SO
DECIDED TO BASICALLY FIGURE OUT
HOW THIS WORKS.
SO IM NEURONS REGULATE IMAGES?
IN ORDER TO DO THAT, WE HAVE
TAKEN OPTOGENETICS APPROACH.
WE DECIDED TO FIGURE OUT WHAT
INPUTS THE IM NEURONS ARE
GETTING FROM SENSORY -- SO WE
DID THIS AGAIN IN VIVO FLIES
USING COUPLING OF GENETIC
ACTIVATION WITH TWO PHOTON
CALCIUM IMAGING THE FLIES ARE
BASICALLY -- IN A BOWL AND WE
DECIDED THE FIRST -- TO FIST
LOOK AT THE THREE CLASSES OF
SENSORY NEURONS IN FLY, SO THE
FIRST CLASS IS SUGAR SENSITIVE
NEURONS, THE SECOND CLASS IS
BITTER NEURONS AND THE THIRD
CLASS IS MOTOR SENSITIVE
NEURONS.
INTERESTINGLY WE FOUND THAT IMR
NEURONSEN ONLY GET ACTIVATED
WHEN SUGAR SENSITIVE TASTE
NEURONS WERE ACTIVATED WITH
OPTOGENETIC STIMULATION BUT
DIDN'T RESPOND TO BITTER.
SO LOOKS LIKE IMR NEURONS ARE
GETSING ACTIVATED BY SUGAR
SENSING SWEETENERS.
WE KNOW THERE'S DIFFERENT
CLASSES OF SUGAR SENSITIVE
NEURONS SO WE WANTED TO FIGURE
OUT EXACTLY WHICH POPULATION IM
NEURONS ARE GETTING INPUT FROM,
REGULATE INGESTION SO WE DID
ANOTHER OPTOGENETIC MANIPULATION
SCREEN LABELING DIFFERENT
POPULATIONS OF SUGAR SENSITIVE
NEURONS IN THE FLY IN THE
SYSTEM.
INTERESTINGLY WE FOUND TWO
CLASSES OF NEURONS GR 64,
BASICALLY THE REACCEPT TO IS
SHOWN TO RESPOND TO SUCROSE
SPECIFICALLY AND GR 43 NEURONS
WHICH ARE KNOWN TO BE
(INAUDIBLE) GLUCOSE.
INTERESTINGLY WHEN WE LOOK AT
THE EXPRESSION PATTERNS OF THESE
NEURONS ONE THING BASICALLY
POPPED UP FUNDAMENTAL DIFFERENCE
IN TERMS OF LABELING GR 64
NEURONS WERE NOT LABELING ANY
NEURONS IN THE NUCLEUS OF THE
FLY WHICH IS BASICALLY THIS
NUCLEUS SITTING RIGHT BETWEEN
THE BRAIN AND THE GUT.
GR 43 NEURONS STRONGLY ACTIVATED
IMR NEURONS HAD THESE POPULATION
ABOUT TEN CELLS IN THIS NUCLEUS.
WHEN WE LOOK AT MORE ANATOMICAL
STRUCTURE OF THE NEURONS WE
FOUND THESE GR 43 NEURONS THAT
ARE PRESENT IN THE NUCLEUS
INNERVATED THE GUT IN DIFFERENT
REGIONS AND THEIR PROCESS IS
ANSWERED, SO WE THOUGHT THESE
NEURONS MIGHT BE SENSING THE
SUGAR WHILE ANIMAL IS EATING AND
SENDING FEEDBACK INFORMATION IN
TO THE BRAIN TO SUSTAIN OR
TERMINATE SUGAR INGESTION.
WE DEVELOP A TECHNIQUE TO
MEASURE ACTIVITY OF THESE
NEURONS WHILE THE ANIMALS ARE
INGESTING SUGAR, IT IS SHOWN
HERE SO WE CAN OPEN UP IMAGING
WINDOW OVER TOP OF THE GUT AND
VENTRAL NERVE PARTS AND WE CAN
IMAGE ACTIVITY OF THESE NEURONS.
LONG STORY SHORT WE DID
EXPERIMENTS AND FOUND THAT ABOUT
HALF OF THESE NEURONS RESPOND
SPECIFICALLY TO INGESTION OF
SUGAR AND HALF -- THE OTHER HALF
WAS TONICALLY ACTIVATED, TRYING
TO UNDERSTAND WHAT THAT MIGHT
BE.
THERE IS THE VIDEO, THAT SHOWING
THAT ACTIVATION.
SO CURRENTLY OUR MODEL IS THAT
WE THINK THAT THE IMR NEURONS
ARE RECEIVING SPECIFIC INPUT
FROM THE GUT IONOMER
INVESTIGATING AROUND PARTICULAR
NEURONS THAT EXPRESS GR 48
RECEPTOR.
THIS IS BASICALLY A -- IN A VERY
FAST TEMPORAL SCALE TO ADJUST
WHAT THE ANIMAL IS EATING AND
MEET THAT ENERGY DEMAND
BASICALLY GENERATED BY THE
INTERNAL STATE OF THE ANIMAL.
SO IT IS BASICALLY VERY FAST
CONTROL OF INGESTION AND QUALITY
CONTROL IN FLY (INAUDIBLE).
RECENTLY THERE'S A LOT OF WORK
DONE IN MICE SHOWING THAT IN
MICE THERE IS ACTUALLY A DEEP
FAST FEEDBACK CONTROL FROM THE
NEURONS THAT INNER INVESTIGATE
DIGESTIVE TRACK THAT HAVE CELLS
IN THE VAGUS.
THE TIP OF THIS VAGAL NEURONS
REPLY CAD IN GAI GANGLIA, STUDY GUT
BRAIN IN THE FUTURE OF THE MODEL
ORGANISMS SO THIS IS MY LAB.
THIS WORK WAS DONE BY MY GRAD
STUDENTS, WITH HELP FROM POST
DOCS.
THANK YOU SO MUCH AND I HOPE
THAT YOU HAVE ENJOYED MY TALK.
>> EXCELLENT.
MY NAME IS STEVE FLAVELL, I'M
EXCITED TO SHARE THE WORK WE
HAVE BEEN DOING IN MY LAB TRYING
TO UNDERSTAND THE NEURAL
MECHANISMS THAT GENERATE LONG
LASTING BEHAVIORAL STATES IN C
ELEGANS.
THE MOTIVATION BEHIND THE
PROJECT REALLY COMES FROM SET OF
STUDIES THAT CAME OUT OVER THE
LAST FEW YEARS, USING LARGE
SCALE RECORDING TECHNOLOGIES IN
PARTICULAR IN THE MOUSE.
THESE STUDIES HAVE SHOWN WHEN
ANIMALS SWITCH BETWEEN DIFFERENT
INTERNAL STATES LIKE HERE IS AN
EXAMPLE OF THIRSTY VERSUS
NON-THURSDAYTY MOUSE, IF THERE'S
WIDESPREAD CHANGES IN NEURAL
ACTIVITIES SPANNING MANY BRAIN
REGION AS ANIMAL SWITCHES
INTERNAL STATES.
IN ADDITION NUMBER OF STUDIES
CAME FROM ANN HOE HARRIS LAB AND
MANY OTHERS SHOWING EVEN
GRANULAR MOMENT BY MOMENT
BEHAVIORAL VARIABLES ARE ALSO
SURPRISINGLY BROADLY REPRESENTED
IN THE BRAIN SPANNING MULTIPLE
BRAIN REGIONS AS WELL.
SO REALLY THIS REALLY GIVES RISE
TO A VIEW THAT IN MOST BRAIN
REGIONS THERE ARE ONGOING
REPRESENTATIONS OF AN ANIMAL
MOMENT BY MOMENT BEHAVIOR AND
ONGOING INTERNAL STATE.
HOW THESE TWO THINGS INTERACT TO
GIVE RISE TO STATE DEPENDENT
BEHAVIORS IS MORE MURKY.
SO WE DECIDED TO LOOK AT THIS IN
C ELEGANS AND WE HERE IS TWO
FABULOUS GRADUATE STUDENTS, WHO
TEAMED UP ON THIS PROJECT AND
WERE JOINED BY A FABULOUS
TECHNICIAN.
SO WE DECIDED TO RECORD BRAIN
WIDE ACTIVITY IN C ELEGANS WHILE
ALSO MEASURING COMPREHENSIVE
BEHAVIORAL INFORMATION OF THE
ANIMAL.
THEN THEY WANTED TO BUILD MODELS
TO RELATE NEURAL ACTIVITY TO
BEHAVIOR AND LOOK AND SEE WHAT
HAPPENS WHEN THE ANIMAL STATES.
SO TO DO THIS THEY HAD TO BUILT
HARDWARE AND WRITE ENORMOUS
SOFTWARE TO MAKE THOSE TYPES OF
RECORDINGS, ADAM HAS POSTER HERE
AT THE CONFERENCE WITH ALL THOSE
TECHNICAL DETAILS, I
UNFORTUNATELY HAVE TO JUMP OVER.
SO I WILL SHOW YOU THE RESULT OF
ALL THAT HARD HARD WORK WHICH IS
THE DATA SET LIKE THIS.
HERE IS AN EXAMPLE OF ONE O
THEIR DATA SETS, ON THE LEFT
THIS IS ABOUT 150 RECORDED
NEURONS FROM A WORM, OVER 16
MINUTES.
THE ROWS OF DIFFERENT NEURONS
YOU CAN SEE LOT OF G CAMP
DYNAMICS IN THE DIFFERENT
NEURONS AND IN SOME CASES SOME
EVIDENT CORRELATIONS AMONG
NEURONS.
ON THE RIGHT ARE ALL THESE OTHER
BEHAVIORAL VARIABLES RECORDED
FROM THE SAME ANIMAL, THINGS
LIKE LOCOMOTION OF THE ANIMAL,
EATING RATES, SWEEPING
OSCILLATORY MOVEMENTS OF NOSE AN
HEAD AND POSTURAL CHANGES AS
WELL.
SO WE WANTED TO RELATE NEURAL
ACTIVITY TO BEHAVIOR AND WE WERE
WORRIED THERE MIGHT BE MOTION
ARTIFACTS IN OUR DATA BECAUSE
THE JOB EXTRACTING CALCIUM
TRACES FROM THE MOVING WORM IS
VERY TRICKY.
SO DIRECTLY TEST THAT WE
RECORDED A STREAM GFP IN PLACE
OF G CAMP AND THEN PERFORMED OUR
IMAGE ANALYSIS PIPELINE IN THOSE
ANIMALS.
THIS IS ALL ADAM'S POSTER BUT WE
DELIGHTED TO SEE NEGLIGIBLE
ARTIFACTS IN THE DATA.
THE TINY AMOUNT WE CORRECTED FOR
IN THE ANALYSES I WILL DESCRIBE
TO YOU.
WE WANTED TO MEASURE
QUANTITATIVELY.
WE HAD ABYSMAL TIME DOING IT.
TURNS OUT THIS BRIEF FEATURES OF
HOW NEURONS ENCOPPED BEHAVIOR IN
THE WORM WE HADN'T PROPERLY
APPRECIATED SO I'LL UNPACK ON
THIS SLIDE.
FIRST IS MANY NEURONS IN THE
WORM BRAIN ARE MULTIPLEXING OR
CON JUDGE TVLY REPRESENTING
MULTIPLE MOTOR PROGRAMS.
TO I WILL INVESTIGATE THIS HERE
IN BLUE SAN EXAMPLE OF NEURON WE
RECORDED.
AND BELOW THAT IS IN THIS ANIMAL
THAT OSCILLATORY MOVEMENTS OF
THE HEAD AND THEN BELOW IS
VELOCITY.
YOU CAN SEE THIS BLUE NEURON
LIKE SOMETIMES IS DOING A REALLY
GOOD JOB TRACKING THE HEAD ANGLE
OF ANIMAL AND OTHER TIMES IT
CLEARLY ISN'T.
THIS STARTS TO MAKE SENSE IF WE
CONSIDER VELOCITY BELOW, AND IN
PARTICULAR LOOKING AT EVERY TIME
VELOCITY DIPS BELOW ZERO, WHEN
THAT HAPPENS THE BLUE NEURON
SHUT OFFICE, PROVIDED THE ANIMAL
IS MOVING FORWARD THE NEURON
RELIABLY TRACKS ANGLE OF ANIMAL
HEAD SO THIS NEURON IS
REPRESENTING THE ANIMAL MOVEMENT
DIRECTION AND THE STEERING OF
THE ANIMAL HEAD.
WE FIND IN OUR DATA CONJUNCTIVE
REPRESENTATIONS OF BEHAVIOR IN
DIFFERENT C ELEGANS NEURONS LIKE
THIS.
WHICH WE THIS IS IMPORTANT FOR
ANIMAL ABILITY TO COORDINATE
DIFFERENT MOTOR NEURONS.
SECOND COMPLEXITY THAT WE
HAVEN'T APPRECIATED IS NEURONS
ARE TUNED IN VERY COMPLEX WAYS
TO INDIVIDUAL MOTOR PARAMETERS.
SO TO ILLUSTRATE THIS HERE IN
BLUE IS THE DIFFERENT NEURON
RECORDEDDED IN A DIFFERENT
ANIMAL, THIS NEURON IS OBVIOUSLY
MORE ACTIVE DURING REVERSE
MOVEMENT THAT PINK COLOR IN THE
BACKGROUND AND FOR NEURON THAT
ENCODES VELOCITY, PEAKING
NEGATIVE REVERSE VELOCITIES YOU
CAN IMAGINE NEURON ENCODES
VELOCITY WITH TUNING CURVE LIKE
THIS ON THE LEFT, MAYBE ENCODES
VELOCITY IN DIGITAL MANNER MORE
LIKE THIS.
THIS NEURON HERE ENCODES
VELOCITY IN THIS WAY SHOWN HERE
WHICH IS THAT DURING FORWARD
MOVEMENT THE NEURON CARRIES NO
INFORMATION ABOUT FORWARD SPEED,
BUT DURING REVERSE MOVEMENT
CARRIES INFORMATION ABOUT
REVERSE SPEED.
WE SEE FUNKY TUNINGS OF NEURONS
TO DIFFERENT BEHAVIORAL
VARIABLES LIKE VELOCITY WITH
TUNING CURVES LIKE THIS.
THEN THE FINAL THING WHICH WAS
THE HARDEST TO FIGURE OUT IS
THAT THE NEURONS ALSO APPEAR TO
ENCODE MOTOR VARIABLES OVER
VASTLY DIFFERENT TIME SCALES IN
SOME CASES.
SO TO ILLUSTRATE THIS TOP RIGHT
I'M SHOWING THE VELOCITY OF A
WORM THAT WE RECORDED AND BELOW
THAT VELOCITY OF SAME ANIMAL,
THAT NOW THAT VELOCITY IS
INVOLVED WITH A FILTER SO YOU
SEE TIME POINT EXPONENTIAL
ANIMAL VELOCITY OVER THE LAST 14
SECONDS.
THE REASON I SHOW VELOCITY OVER
TWO TIME SCALES IS WE CAN SEE
DIFFERENT NEURONS HERE
OVERLAYING TWO IN BLUE THAT
REALLY BEAUTIFULLY REPRESENT
VELOCITY THESE TWO DIFFERENT
TIME SCALES.
THERE IS NOTHING SPECIAL ABOUT
THESE TIME SCALES, WE CAN FIND
NEURONS SPAN BACK 30 SECONDS AND
MORE AND MANY POINTS IN BETWEEN.
SO WE THINK THIS COULD BE REALLY
IMPORTANT FOR THE COMPUTATIONAL
COMPLEXITY OF THE WORM, MIGHT
MEAN IT HAS REPRESENTATION NOT
JUST OF ITS ACUTE MOTOR ACTION
BUT ALSO RECENT MOTOR ACTION IN
THE NERVOUS SYSTEM.
ONCE WE UNTANGLED THOSE
FEATURES, THEY WERE ABLE TO DO A
NICE JOB BUILDING QUANTITATIVE
MODELS AND ENCODE BEHAVIOR.
THE TASK IS TO PREDICT THE
ACTIVITY AS FUNCTION OF
BEHAVIORAL VARIABLE AND THEN
SIMPLIFIED VERSION OF MODEL THEY
USING IS SHOWN BELOW BUT
BASICALLY WHAT I SHOWED YOU.
EACH NEURONS ACTIVITY CAN BE A
MODEL COMBINATION OF THE
DIFFERENT MOTOR PROGRAMS
INCLUDING DIGITAL VERSION OF
THOSE MOTOR PROGRAMS AND EACH
GETS ITS OWN TIME SCALE SO TAKE
THIS MODEL AND APPLY UNIFORMLY
TO ALL NEURONS IN RECORDINGS AND
WE WERE DELIGHTED TO SEE WITH
THIS MODEL WE CAN GET EXTREMELY
GOOD FITS WITH LOTS OF NEURONS
WITH DIFFERENT REPRESENTATIONS
OF BEHAVIOR.
THERE IS A DOZEN NEURONS, OVER
ABOUT 15 ANIMALS RECORDED WE CAN
FIT OVER 100 NEURONS PER ANIMAL.
THIS MODEL CAPTURES MAJORITY OF
NEURAL VARIANTS RELATED TO
ANIMALS OVERT BEHAVIOR AND THAT
IS BECAUSE WE HAVE DONE THINGS
LIKE TAKEN RESIDUALS OFF MODELS
AND PERFORMED PRINCIPLE
COMPONENT ANALYSIS ON RESIDUALS
TO TRY TO FIND MODES OF DYNAMICS
IN THE NERVOUS SYSTEM NOT
EXPLAINED BY OR MODEL.
AND WE DO FIND THOSE WE SEE
PRINCIPLE COMPONENTS WITH REAL
DYNAMICS, NOT RELATED TO ANY
OVERT BEHAVIOR WE CAN FIGURE OUT
SO RESIDUAL DYNAMICS ARE
INTERNAL VARIABLES OR SENSORY
VARIABLES OR SOMETHING LIKE
THAT.
SO WE HAVE NEURONS WE HAVE THESE
MODELS BEFORE WE CAN START
LOOKING ACROSS STATES WE HAVE TO
SOLVE ONE MORE PROBLEM.
WHICH IS THAT IT WAS TEMPTING TO
DO THE FOLLOWING.
TEMPTING TO TAKE A NEURON WE
RECORDED, APPLY ONE OF THESE
ENCODING MODELS TO THE NEURON,
THEN GO LOOK AT PARAMETERS OF
THE RESULTING MODEL HIGHLY
INTERPRETABLE AND CONCLUDE BASED
ON PARAMETERS MAYBE THE NEURON
IS VELOCITY HEAD ANGLE.
THE WORRY P WE DID THAT MAIN
THERE IS ANOTHER MODEL THAT FITS
THE NEURON NEARLY AS WELL AND
MAYBE THAT MODEL IS DIFFERENT
PARAMETERS AND THEN WHICH IS THE
CORRECT ASSERTION ABOUT THE
NEURONS.
IN OTHER WORDS UNCERTAINTY IN
THESE MODELS BECAUSE THEY
TRAINED ON FINITE DATA.
SO WE NEEDED TO DO IS REALLY TO
ESTIMATE THE DISTRIBUTION OF
POSSIBLE PARAMETERS GIVEN OUR
EMPIRICAL NEURON BEHAVIORAL
DATA.
SO TO DO THIS WE COLLABORATE
WITH THE GROUP AT MIT WHO
DEVELOPED A PROBABILISTIC
COMPUTING PLATFORM THAT
BASICALLY SOLVES THIS EXACT
PROBLEM, POSTERIOR DISTRIBUTION
OF MODEL PARAMETERS GIVING
EMPIRICAL DATA SETS LIKE THIS.
THIS NOW ALLOWS US TO ASK
QUESTIONS AND STATISTICALLY
MEANINGFUL WAYS WITH THESE
CLOUDS OF DATA LIKE THIS, YOU
CAN IMAGINE IF WE HAVE TWO
DIFFERENT NEURONS WE CAN
STATISTICALLY ASK WHETHER ABLE
TO ASSERT THE NEURONS ENCODE
BEHAVIOR DIFFERENTLY AND THINGS
LIKE THAT.
SO NOW WE HAVE NEURONS, WE HAVE
THESE MODELS, MODELS SUGGEST
TUNINGS BASED ON PARAMETERS AND
IMPORTANTLY WE HAVE CONFIDENCE
ON THOSE TWO, BASED ON
ESTIMATION OF UNCERTAINTY.
THERE WERE LOTS OF NEURONS WE
RECORDED ONE THING WE
IMMEDIATELY WANTED TO KNOW WAS
WHETHER THE NEURONS DIFFERENT
NEURONS ACROSS THE WORM BRAIN
ENCODE BEHAVIOR DIFFERENTLY OR
IF WILL IS JUST A FEW CANONICAL
FORMS OF ENCODING BEHAVIOR IN
WORM BRAIN.
TO TEST THAT WE DEVISED A
DISTANCE METRIC ANY PAIR OF
NEURONS QUANTIFIES HOW SIMILAR
IS ENCODING OF BEHAVIOR BY TWO
NEURONS.
YOU CAN IMAGINE MANY AXES TO
THAT ME RICK LIKE ENCODING
VELOCITY, OF FEEDING, HEAD
ANGLE, SO ON.
AND ONCE WE HAVE GOT THAT
DISTANCE METRIC WE CAN EMBED THE
NEURONS IN TWO DIMENSIONAL
SPACE, A PIECE MEAL PLOT LIKE
THIS.
EACH DOT IS A DIFFERENT NEURON
AND IF DOTS ARE CLOSE TOGETHER
THAT THAT MEANS THE TWO HEN
CODED BEHAVIOR EXTREMELY
SIMILARLY AND IF THEY FAR APART
INDEED CODING OF BEHAVIOR WAS
DIFFERENCE.
THE NEURONS ARE LIKE TILED
SPEISES FAIRLY EVENLY INDICATING
TO US HETEROGENOUS
REPRESENTATION OF WORM BEHAVIOR
ACROSS THE BRAIN OF THE ANIMAL
WITH MORE COMPUTATIONAL
COMPLEXITY AND WE THINK WE CAN
APPRECIATE IT.
THAT DOESN'T MEAN NO STRUCTURE
AS YOU CAN SEE ON THE RIGHT,
THEY ARE ORGANIZED BY ENCODING
BUT THERE IS NOT TIGHTNESS TO
IT.
SO NOW WE WANTED TO TAKE THIS
KIND OF STRUCTURE, THIS SYSTEM
THAT ENCODES BEHAVIOR IN THIS
WAY, HAVE A LOOK AND SEE WHAT
HAPPENS WHEN THE ANIMAL SWITCHES
STATES.
WE LOOKED A IN THE BECAUSE
IMMEDIATELY WE NOTICED MANY
NEURONS CHANGE HOW THEY ENCODE
BEHAVIOR THROUGHOUT THE VIDEO.
SO HERE ON THE LEFT IS
ILLUSTRATION OF THIS NOT
HAPPENING SO NEURON IN GRAY.
WE ARE TRAINING ONE OF THESE
ENCODING MODELS ON BLUE PART OF
THE DATA AND PREDICTING NEURAL
ACTIVITY OVER TIME SERIES.
FOR THIS NEURON HERE WHEN WE
TRAIN ON THE LEFT PART OF THE
DATA, PREDICT RIGHT PART IT DOES
OKAY AND RECIPROCAL IS TRUE DOWN
BELOW.
ON THE RIGHT IS DIFFERENT NEURON
FROM SAME RECORDING YOU CAN SEE
IF WE TRAIN A MODEL ON THE LEFT
PART OF THE DATA PREDICT NEURAL
ACTIVITY ON THE RIGHT, DOES
AWFUL JOB RECIPROCAL IS TRUE.
SO SOMEHOW THIS NEURON ENCODES
BEHAVIOR IS CHANGED
DRAMATICALLY.
WE SEE THIS EVEN IN SPONTANEOUS
RECORDINGS AND ON THE ORDER OF
15 TO 25% NEURONS IN A GIVEN 20
MINUTE RECORDING.
WE THOUGHT THIS MIGHT BE RELATED
TO INTERNAL STATE OF THE ANIMAL
CHANGING OVER TIME SO THE MORE
DIRECTLY TESTING THAT WE EVOKED
ETERNAL STATE CHANGE IN ANIMALS.
WE BASICALLY JUST USED INFRARED
LASER TO LOCALLY HEAT UP THE
AREA AROUND THE WORM HEAD FOR A
FEW HUNDRED MILLISECONDS.
WE DID THIS VERY ABRUPTLY SO THE
WORM HATES IT AND THE ANIMAL
IMMEDIATELY DOES REVERSAL
AVOIDANCE BEHAVIOR AND STOPS
EATING AND AFTER A -- FOR A FEW
MINUTES AFTER SIGNAL THE ANIMALS
HAVE REDUCED AN BASICALLY
AGITATED LOCOMOTION.
THIS ALLOWS US TO LOOK AT
SENSORY INDUCED BEHAVIOR STATE
CHANGE SEE HOW BEHAVIOR ENCODED
DURING THAT AVERSIVE BEHAVIORAL
STATE.
WE SAW BASICALLY WHAT I SHOWED
YOU WHICH IS THAT A LOFT NEURONS
ABRUPTLY CHANGE HOW THEY INDEED
BEHAVIOR UPON ENTRY INTO THAT
STATE.
HERE AGAIN IS ONE NEURON, IN
GRAY, TRAINING ONE OF THESE
ENCODING MODELS ON THE LEFT PART
OF THE DATA AND PREDICTING
NEURAL ACTIVITY ACROSS THE TIME
SERIES.
AS YOU CAN SEE THE MODEL STARTS
DOING A TERRIBLE JOB PREDICTING
THE NEURON ACTIVITY RIGHT AFTER
THAT HEAT STIMULUS AND TRY ENTRY
INTO AVERSIVE STATE THOUGH
NEURONS STILL IS DYNAMIC SO THIS
NEURON CHANGED HOW IT ENCODES
BEHAVIOR DURING THAT STATE.
WE SAW MANY EXAMPLES OF THIS,
DIFFERENT TYPES OF EXAMPLES OVER
HERE ON THE TOP RIGHT NEURON
INACTIVE, UPON HEAT STIMULATION
WAS RECRUITED INTO BEHAVIORAL
CIRCUIT DURING THE AVERSIVE
STATE.
THIS IS JUST A SUMMARY PLOT SHOW
YOU THESE CHANGES IN HOW NEURONS
ENCODE BEHAVIOR AGAIN ON THE
ORDER OF 15 TO 25% NEURONS
DEPENDING ON RECORDING, CHANGE
REALLY IS TIME LOCKED TO THAT
HEAT STIMULUS AND NOT OBSERVED
ABRUPTLY IN ANIMALS WITHOUT HEAT
STIMULUS CONTROL ON THE RIGHT.
SO TO SUMMARIZE WHAT I SHOWED
YOU, WE CONSTRUCTED THIS VERY
GENERAL USE ENCODING MODEL WE
CAN USE TO DESCRIBE HOW EACH
NEURON ACROSS THE WORM BRAIN
ENCODES FEATURES OF MOMENT BY
MOMENT BEHAVIORS IN DOING THIS
WE LEARN SOME NEW THINGS ABOUT
THE WAY THE C ELEGANS NERVOUS
SYSTEM ENCODES BEHAVIOR, NAMELY
MANY NEURONS ARE MULTIPLEXING
ENCODING MOTOR PROGRAMS WITH
DIVERSE TUNING CURVES AND
REPRESENTING BEHAVIOR IN SOME
CASES VERY DIFFERENT TIME
SCALES.
AND FINALLY WE ARE GETTING A
SENSE THIS NETWORK THAT ENCODES
BEHAVIOR IN THIS FASHION IS
FLEXIBLY CHANGING IN PARTICULAR
IF WE ABRUPTLY EVOKE A STATE FOR
THE ANIMAL.
THEN MOST IMPORTANT SLIDE I WANT
TO ACKNOWLEDGE THE BIG DRIVERS
OF THIS PROJECT AND JOINED BY
FABULOUS TECHNICIAN, AND ALSO
OUR COLLABORATORS AND ALSO WANT
TO THANK THESE FOLKS FOR COMING.
>> THANK YOU FOR THE OPPORTUNITY
TO LET ME PRESENT OUR WORK
LOOKING AT PREFRONTAL CORTICAL
ENDOGENOUS OPIOIDS AND THREAT
ASSOCIATED BEHAVIORAL STATES.
IT IS REALLY APPRECIATED THE
VENTRAL MEDIAL PREFRONTAL CORTEX
EXERTS CONTROL OVER THREAT
RELATED BEHAVIOR THROUGH THE
COMPLEX INTERACTIONS WITH OTHER
REGIONS, THOUGH WE HAVE MADE
LONG SIGNIFICANT ADVANCES IN
UNDERSTANDING HOW THESE CIRCUITS
OPERATE WE HAVE NO IDEA HOW
NEURAL PEPTIDES REGULATE THESE
CIRCUITS.
OUR LAB HAS BEEN PARTICULARLY
INTERESTED IN ENDOGENOUS OPIOID
SYSTEMS, MOST TIMES WHEN WE
THINK ABOUT ENDOGENOUS OPIOIDS
WE THINK ABOUT THE POSITIVE
EFFECT ON MOOD AND MOTIVATION
THAT OPIOIDS EXERT.
MOST PEOPLE THINK ABOUT ENDOOR
FINS THAT BIND MU AND DELTA
RECEPTORS THAT DRIVE EUPHORIA,
MOTIVATION, ADDICTIVE BEHAVIOR,
SOCIAL BEHAVIOR AS WELL AS HE
HEDONIC FEEDING.
THE DINORFIN WHICH BINDS TO CAP
RA RECEPTORS.
ACTVATION DRIVES DYSPHORIA,
MOTIVATIONAL LOSS, AS WELL AS
ANXIETY.
IT IS THIS SYSTEM THAT INTRIGUES
ME AND IT IS NOT SURPRISING THAT
THIS SYSTEM EXERTS THESE
BEHAVIORS IS HIGHLY ENRICHED IN
LIMB BIC REGIONS INCLUDING THE
PREFRONTAL CORTEX.
DESPITE THE FACT WE MOW THE
SYSTEM IS THERE WE DON'T HAVE
MUCH UNDERSTANDING HOW IT MIGHT
REGULATE BEHAVIORAL STATES
CONTROLLED BY THREATS AND THE
FUNCTION OF THE CIRCUITS.
SO OUR LAB HAS MONITORED THE
ACTIVITY OF DIMORFIN PRODUCING
CELLS IN THE VENTRAL MEDIAL
PREFRONTAL CORTEX USING
MINIATURIZED SCOPES.
HERE WE RECORD ACTIVITY OF CELLS
DURING PEER CONDITIONING
PROCEDURES.
WE OBSERVED DINORFIN CELLS GAVE
ROBUSTLY ACTIVATED BY SHOT AND
SHOT PREDICTED QUEUES AT
INDIVIDUAL CELL LEVEL.
MOREOVER OUR LAB DEMONSTRATED
DINORFIN CELLS COME IN DIFFERENT
SUBTYPES. INHIBITORY CELLS THAT
PRODUCE SOMATOSTATIN AND WHEN WE
MONITOR THE ACTIVITY OF THIS
CELL POPULATION SELECTIVELY
USING INTERSECTIONAL APPROACHES
WE FIND THAT THIS CELL
POPULATION RESPONDS TO SHOCKS,
INITIALLY BUT NOT TO QUEUES
UNTIL THOSE QUEUES ARE
REPEATEDLY PAIRED WITH SHOTS.
THEN YOU START TO GET ASSOCIATED
RESPONSES TO THE SHOT PREDICTIVE
QUEUES.
MOREOVER WHEN WE MONITOR
ACTIVITY OF EXCITATORY CELLS
WITHIN THE VENTRAL PRE-FRONT IT
WILL KARATEKAS LIKE THE COUNTER
PARTS THEY RESPOND TO SHOCKS BUT
UPON ASSOCIATIVE LEARNING START
TO DEVELOP CONDITION RESPONSES
QUEUES THAT PREDICT THE SHOTS AS
WELL.
THIS DOESN'T TELL US THE CELLS
ARE ACTUALLY RELEASING NEURAL
PEPTIDE, BUT IT DOES TELL US
THESE CELLS ARE ACTIVATED BY
THREATS SUCH AS SHOCKS AND
QUEUES THAT PREDICT THEM.
SO TO MONITOR NEURAL PEPTIDE
RELEASE IN RESPONSE TO FEAR
CONDITIONING PROCEDURES WE
TEAMED WITH DR. -- UC DAVIS WHO
HAS DEVELOPED A FLUORESCENT
KAPPA RECEPTOR SENSOR, NOW THIS
K LIKE SENSOR SHE DEVELOPED
DOESN'T FLUORESCE AT BASELINE
BUT UPON LIGAND ACTIVATION OF
SENSOR, BY DINORFIN AND OTHER
MOLECULES YOU GET ROBUST
FLUORESCENCE.
WE HAVE BEEN ABLE TO USE THIS
SENSOR IN AWAKE BEHAVING ANIMALS
AND MONITOR ACTIVITY OF THE
SENSOR USING -- DURING FEAR
CONDITIONING PROCEDURES WE FIND
THAT THIS SENSOR HAS NICE
ACTIVATION IN RESPONSE TO SHOT
PREDICTIVE QUEUES AS WELL AS
SMALL RESPONSE TO THE SHOCKS
THEMSELVES.
THESE ARE EFFECTS WE DON'T
OBSERVE WITH OUR CONTROL SENSOR
WHICH DOES NOT FLUORESCE IN
RESPONSE TO LIGAND ACTIVATION.
MOREOVER WE HAVE BEEN ABLE TO
DEMONSTRATE THIS SENSOR SHOWS
TRANSIENT RESPONSES DURING
RESTRAINT STRESS, AN EFFECT WE
DON'T SEE IN CONTROL SENSOR SO
TAKEN TOGETHER WE HAVE BEEN ABLE
TO DEMONSTRATE DIFFERENT TYPES
OF DINORFIN CELLS IN PREFRONTAL
CORTEX THAT ACTIVATE DURING
RESPONSE TO THREATS AND RELEASE
PEPTIDE LOCALLY.
THE QUESTION IS IS THAT PEPTIDE
DOING SOMETHING TO REGULATE
BEHAVIORAL STATES ASSOCIATE WITH
THAT THREAT.
TO DETERMINE THIS WE UTILIZE AV
EXPRESSING DINORFIN SH RNA WE
GENERATED IN OUR LAB, INFUSED TO
THE VENTRAL MEDIAL PRE-FOR TALL
CORTEX OF MICE AND LOOK AT
FREEZING BEHAVIOR DURING THE
PEER CONDITIONING OF BEHAVIORS.
KNOBBING DOWN GENE EXPRESSION
WITHIN THE VENTRAL MEDIAL
PREFRONTAL CORTEX OF MICE
ENHANCE FREEZING BEHAVIOR.
THIS IS INTERESTING IN LIGHT OF
THE FACT THAT IN RESPONSE TO
THREAT IN ANIMAL CAN MOUNT ONE
OF TWO DEFENSIVE BEHAVIORS THAT
CAN BE FREEZING, OR ACTIVE
DEFENSIVE BEHAVIOR SUCH AS
AVOIDANCE OR ESCAPE BEHAVIOR TO
GET OUT OF DODGE.
NOW, THIS DATA SUGGESTS THAT
DINORFIN RELEASE IN RESPONSE TO
THREATS MOBILIZE ACTIVE
DEFENSIVE BEHAVIORS AND WHEN WE
KNOCK DOWN GENE EXPRESSION
WITHIN THE VENTRAL MEDIAL
PREFRONTAL CORTEX WE GET RID OF
THIS DEFENSIVE BEHAVIOR AND
PROMOTE FREEZING BEHAVIOR.
TO TEST THIS OUR LAB PERFORMED
PLATFORM MEDIATED AVOIDANCE
PROCEDURES WHERE WE EXPOSED
ANIMALS TO QUEUE PREDICTIVE
SHOCK.
BUT WHAT WE DID HERE THAT WAS
DIFFERENT THAN EXPERIMENTS
BEFORE WAS PLACE A LITTLE PLEXI
GLASS PLATFORM IN THE CORNER
THAT THE ANIMAL CAN MOUNT TO
AVOID THE SHOCK.
CONSISTENT WITH THE HYPOTHESIS
THAT DINORFIN DRIVES ACTIVE
DEFENSIVE BEHAVIORS IN RESPONSE
TO THREATS, WE OBSERVED THAT
LOSS OF DINORFIN WITHIN THE
VENTRAL MEDIAL PREFRONTAL CORTEX
RESULTED IN AVOIDANCE DEFICITS
AND MORE SHOCKS APPROVED.
IN THE REAL WORLD WHENEVER WE
WANT TO PURSUE REWARDS WE ARE
ALWAYS PUTTING OURSELVES AT RISK
OF THREATS.
WE HAVE TO BE ABLE TO MOBILIZE
RAPID CHANGES IN BEHAVIOR STATES
FROM PASSIVE TO ACTIVE DEFENSIVE
BEHAVIORS AS THOSE THREATS
CHANGE.
SO TO FURTHER DETERMINE WHETHER
DINORFIN SYSTEM MIGHT BE
TOGGLING THIS ACTIVE AND PASSIVE
DEFENSIVE BEHAVIORS, OUR LAB
EMPLOYED MODIFIED VERSION OF THE
PLATFORM MEDIATED AVOIDANCE TASK
WHERE WE ASK THE ANIMALS TO
PURSUE REWARD WHEN IT BECOMES
AVAILABLE.
IN THIS CASE WHEN THE LIGHT
TURNS ON REWARD.
DURING THESE MOMENTS ANIMALS GET
SUCROSE AT THIS REWARD PORT BUT
AT THE SAME TIME WHAT WE ARE
DOING IS PRESENTING THEM
OCCASIONALLY A QUEUE THAT
PREDICT AS SHOCK.
WHICH POINT THE ANIMALS AVOID
THE SHOCK BY JUMPING ON THE
PLEXI GLASS.
THE PLATFORM IS ON THE
OPPOSITENT OF THE CHAMBER SO
THEY HAVE TO MOUNT ACTIVE
APPROACH IN RESPONSE TO THESE
THREATS WHERE THEY CAN MAXIMIZE
AMOUNT OF REWARDS THEY CAN GET
BUT DO SO IN TIME TO AVOID
GETTING SHOCKED.
WHAT WE OBSERVED HERE IS ANIMALS
LACKING DINORFIN WITHIN THE
VENTRAL MEDIAL PREFRONTAL CORTEX
HAD DEFICITS IN THIS BEHAVIOR,
THEY ACCRUED LESS REWARDS
RELATIVE TO CONTROL COUNTER
PARTS AND THAT'S BECAUSE THEY
SPEND MOST TIME FREEZING ON THE
PLATFORM.
TAKEN TOGETHER THIS COMES
TOGETHER TO TELL US THAT
DINORFIN CELLS WITHIN THE
PREFRONTAL CORTEX RESPOND WITH
INCREASE ACTIVITY IN RESPONSE TO
THREATS, THAT RELEASE DENORFIN
LOCALLY AN SUBSEQUENTLY CHANGE
CIRCUIT TO DRIVE ACTIVE
DEFENSIVE BEHAVIORS, WE GET RID
OF DINORFIN SIGNALING AND THE
EFFECTS WE CAN TOGGLE TOWARD
PASSIVE TO TRANSITIVE STATE.
WHAT IS THIS BLACK BOX WHAT IS
IT DOING TO VENTRAL MEDIAL
PREFRONTAL CORTICAL CIRCUIT?
OUR LABORATORY HAS BEEN ABLE TO
DEVELOP A MODEL BY WHICH
DINORFIN REGULATES VENTRAL
MEDIAL PREFRONTAL CORTICAL
CIRCUITS.
THERE IS PRE-SYNAPTIC KAPPA
RECEPTORS THAT INHINT INPUTS
FROM BASAL LATERAL AMYGDALA, THE
PARAVENTRAL NUCLEUS AS WELL AS
CONTRALATERAL CORTEX BUT INPUTS
FROM VENTRAL HIPPOCAMPUS ARE
COMPLETELY ENSENSITIVE TO
DINORFIN KAPPA RECEPTORS BECAUSE
THEY DON'T MAKE THIS SYSTEM.
MOREOVER WE HAVE BEEN ABLE TO
SHOW IT CAN INHIBIT THE RELEASE
OF GLUTAMATE FROM INPUTS THAT
MAKE PRE-SYNAPTIC KAPPA
RECEPTORS AND ULTIMATELY
DINORFIN FILTERS ANY INPUTS
COMING THAT HAVE PRE-SYNAPTIC
KAPPA RESOP TORRS INCLUDING
AMYGDALA LA, SUPPRESS THE
ACTIVITY THIS IS INPUTS ARE ABLE
TO DRIVE.
SO MUCH LIKE GETTING RID OF THE
GAS ON THE CAR.
WE HAVE ALSO BEEN ABLE TO SHOW
THAT DINORFIN REGULATES
EXCITATION INHIBITION BY ACTING
ON GABAERGIC INTERNEURONS, KAPPA
EXPRESSING CELLS ARE THAT DRIVE
INHIBITOR INTERNEURONS WITHIN
THE PREFRONTAL CORTEX ARE SHUT
DOWN BY DINORFIN.
SUB SETS OF GABBA INTERNEURONS
EXPRESS KAPPA RECEPTORS ON
TERMINALS AND IT SHUTS DOWN
GABBA RELEASE ON TO PRINCIPLE
NEURONS AND IT IS REALLY THESE
TWO CONCERTED EFFORTS OF THE
KAPPA SYSTEM TO ACT ON
INHIBITION THAT DRIVES
DISINHIBITION OF PREFRONTAL
CORTEX.
NOW THIS DISINHIBITION ACTS TO
AMPLIFY KAPPA LACKING INPUTS
COMING TO PREFRONTAL CORTEX LIKE
THOSE FROM VENTRAL HIPPOCAMPUS.
WHAT IT IS DOING IS RELIEVING A
BREAK ON THE SYSTEM AND TOGETHER
WHAT IT IS ABLE TO DO IS CHANGE
THE WAY THAT DIFFERENT INPUTS
COMING INTO THE PREFRONTAL
CORTEX EXERTS ON PREFRONTAL
CORTICAL NETWORKS.
TO SUMMARIZE EVERYTHING WE HAVE
BEEN ABLE TO DEMON INVESTIGATE
THAT DINORFIN CELLS ACTIVATE IN
RESPONSE TO THREATS, THEY
RELEASE PEPTIDE LOCALLY WITHIN
THE PREFRONTAL CORTEX AND THIS
ULTIMATELY REORGANIZES WHO IS
CONTROLLING THE VENTRAL MEDIAL
PREFRONTAL CORTEX.
AND DOING SO THE KAPPA SYSTEM IS
ABLE TO DRIVE ACTIVE DEFENSIVE
BEHAVIORS IN RESPONSE TO
THREATS.
IF WE GET RID OF ACTIVITY OF THE
SYSTEM WE CAN TOGGLE BEHAVIOR
TOWARDS PASSIVE DEFENSE
BEHAVIORAL STATE.
WITH THAT I WOULD LIKE TO THANK
THE MEMBERS OF THE LAB, AND OUR
FUNDING SOURCES.
AS WELL AS YOU FOR YOUR TIME AND
ATTENTION.
I WILL TAKE ANY QUESTIONS AT
THIS TIME.
THANK YOU.
>> MY NAME IS ANN KENNEDY,
ASSISTANT PROFESSOR NORTHWESTERN
UNIVERSITY, I WILL BE WRAPPING
UP THE TALKS PART OF THIS
SESSION WITH DISCUSSION OF THE
CONTROL SOCIAL BEHAVIOR AND
SETTING UP MOTIVATIONAL STATES
BY HYPOTHALAMUS.
I WILL START BY THANKING THE
FOLKS WHO DID THE WORK, I WILL
TALK ABOUT EXPERIMENTAL DATA
COLLECTED BY (INDISCERNIBLE) IN
THE LABORATORY OF DAVID ANDERSON
AT CAL TECH WHERE I DID MY POST
DOC.
THE COMPUTATIONAL ANALYSIS
SHOWING TODAY IS MORE RECENT
PROJECT BY (INDISCERNIBLE) A
GRADUATE STUDENT IN MY LAB AT
NORTHWESTERN.
SO IN GENERAL I'M INTERESTED IN
UNDERSTANDING WHAT IS HAPPENING
IN THE BRAINS OF ANIMALS
INTERACTING WITH THE WORLD
AROUND THEM.
YOU CAN THINK OF THIS AS SERIES
OF STEPS THE ANIMALS RECEIVE
SENSORY QUEUES FROM THE
ENVIRONMENT, THEY PERFORM MOMENT
TO MOMENT ACTION SELECTION IN
RESPONSE TO THOSE QUEUES.
BASED ON THAT ACTION SELECTION
THEY GENERATE BEHAVIOR.
BUT WHAT MAKES ANIMALS DIFFERENT
FROM INP OUT OUTPUT ROBUST IS
THEY HAVE INTERNAL STATES THAT
MODIFY THEIR ACTION SELECTION
PAST EXPERIENCES, LEVELS OF
STRESS OR HUNGER OR FEAR, ALL
MODIFY THIS ACTION SELECTION
PROCESS TO CHANGE THE WAY
ANIMALS RESPOND TO SENSORY
QUEUES IN THEIR ENVIRONMENT.
RELATED COMPONENT OF THIS
PROCESSING OF SENSORY QUEUES IN
GENERATION BEHAVIOR IS THE -- IS
THERE IS A CHALLENGE IN HOW WE
MAP QUEUES TO BEHAVIORAL
OUTPUTS.
THINK AN EXAMPLE OF THIRST TYING
BACK TO EARLIER TALKS, ANIMALS
CAN EXPERIENCE VARIETY OF
SENSORY QUEUES LIKE WATER
DEPRIVATION OR HEAT DEPRIVATION
AND SENSORY QUEUES CAN PRODUCE A
VARIETY OF RESULTING BEHAVIORS
THAT INCREASE AMOUNT OF WATER
ANIMALS DRINK, INCREASE
TOLERANCE FOR BITTERNESS IN
WATER AND AS INCREASE THE NUMBER
OF ACTIONS AND NUMBERS SENSORY
QUEUES THAT CAN SHAPE ANIMAL
BEHAVIOR, THIS MAPPING BECOMES
VERY HIGH DIMENSIONAL VERY
QUICKLY, YOU HAVE WATER N TIMES
N POSSIBLE FROM SENSORY STATES
TO MOTOR OUTPUTS.
A SOLUTION THAT GETS -- IN
ADDITION, IF YOU WANT TO
MODULATE THIS MAPPING BY ANOTHER
SENSORY QUEUE FROM A DIFFERENT
BEHAVIORAL REGIME LIKE FOND
RESPONDING TO PREDATOR THERE IS
NOT AN EASY WAY TO SCALE THESE
MAPPINGS IN RESPONSE TO THAT
SIGNAL.
SO IF YOU INTRODUCE THE CON SET
OF INTERVENING VARIABLES SUCH AS
THIRST THEN THIS BECOMES A MUCH
MORE TRACKABLE COMPUTATIONAL
PROBLEM.
YOU MAP DOWN VARIOUS
COMPUTATIONAL SENSORY INPUTS TO
THIS DIMENSIONAL REPRESENTATION
OF THIRST THAT CAN BE USED TO
DRIVE VARIOUS INNATE AND LEARNED
BEHAVIORS AND CAN BE MODULATED
BY OTHER FORMS OF INTERVENING
VARIABLES TORR FLICK ADAPT
ANIMALS BEHAVIOR TO THEIR
ENVIRONMENT.
SO WITHIN THE LAB WE ARE
INTERESTED IN UNDERSTANDING
THESE INTERVENING VARIABLES AND
WAY THEY CAN MODIFY ANIMAL
BEHAVIOR, HOW THEY INTERACT WITH
EACH OTHER, SO TO QUICKLY GIVE
AN EXAMPLE IN DEFENSIVE AND
SOCIAL INTERACTIONS, THESE
INTERVENING VARIABLES MOTIVATION
HAVE SCALABLE PROPERTY THAT
SHAPE THE KINDS OF BEHAVIORS
ANIMALS PRODUCE.
THE ABSENCE OF A THREAT OR
SPECIFIC BASELINE BEHAVIOR BUT
AS YOU ENCOUNTER ESCALATING
LEVELS OF SENSORY INPUT FROM A
THREAT OR SPECIFIC YOU WILL
CHANGE YOUR BEHAVIOR IN RESPONSE
TO THAT SENSORY INPUT IN ORDER
TO ADAPT TO THE LEVEL OF THREAT
OR LEVEL OF ESCALATION OF SOCIAL
ENCOUNTER AND THAT CHANGE IN
BEHAVIOR WILL MOVE YOU UP OR
DOWN THAT'S ESCALATING LEVEL OF
INTENSITY OF BEHAVIOR.
LEVELS OF MOTIVATIONAL STATES
ARE SCALABLE THING IN THE BRAIN
THAT CAN MODIFY HOW ANIMAL
RESPONDS TO UNRELATED SENSE ARE
I QUEUE AND THEY CAN DRIVE
TRANSITION BETWEEN DIFFERENT
STAGE OF BEHAVIORS SUCH AS
DEFENSIVE OR SOCIAL
INTERACTIONS.
IN MY LAB WE ARE INTERESTED IN
STUDYING THE STRUCTURE OF ANIMAL
BEHAVIOR AND WHAT IT TELLS US
ABOUT CONTROL POLICIES WHICH
INTERNAL STATES SHAPE ANIMALS
MOMENT TO MOMENT ACTIONS AND
ALSO WE WANT TO UNDERSTAND HOW
THE BRAIN GIVES RISE TO THESE
CONTROL POLICIES.
SO FOR THE -- GOING TO TELL YOU
A BRIEF STORY ABOUT A RECENT
EFFORT TO UNDERSTAND THIS WITH
RESPECT TO IMAGING DATA IN THE
HYPOTHALAMUS.
THIS IS AREA OF DEEP INSIDE
BRAIN EXTENSIVE INPUT FROM
SENSOR REGION AND PROJECTS OUT
TO MOTOR AREAS, OPPOSED TO SET
OF DENSELY CONNECTED NUCLEI.
FROM OPTOGENETIC STUDIES YOU CAN
INHIBIT NUCLEI AND PRODUCE
STRIKING BEHAVIORAL EFFECTS LIKE
AAGGRESSIVE BEHAVIOR BETWEEN
INTERACTING MICE.
A Z YOU ACTIVATE CELL
POPULATIONS YOU CAN SEE
DIFFERENT STRIKING SURVIVAL
BEHAVIOR PROGRAMS EXECUTED BY
ANIMALS.
SO RAISES THE QUESTION HOW THESE
NUCLEI ARE INTERACTING WITH ETCH
OOH OTHER TO SHAPE ANIMALS
MOMENT TO MOMENT BEHAVIOR.
TO ADDRESS THIS QUESTION, MY
COLLABORATORS ANDERSON LAB
IMAGED HYPOTHALAMUS OF
INTERACTING ANIMALS AS THEY WERE
ENGAGED IN SOCIAL INTERACTIONS
WITH INTRUDER MOUSE ADDED TO
ANIMAL HOME CAGE.
WE EXAMINED THE RESPONSES OF
NEURONS IN TWO OF THOSE SENSORY
QUEUES FROM SPECIFICS.
SO I WILL TALK ABOUT TWO DATA
SETS, ONE COLLECTED IN MEDIAL
PRE-OPTIC AREA BY -- AND ONE
FROM VENTRAL LATERAL PORTION OF
HYPOTHALAMUS, (INAUDIBLE) SO WE
IMAGE THE B ACTIVITY WITH BUNCH
OF NEURONS IN THESE REGIONS AND
HOW THEY RESPOND TO BEHAVIORS.
AND PREOPTIC AREA WE SEE A SMALL
NUMBER OF CELLS THAT RESPOND TO
THIS SEX OF THE INTRUDER WHETHER
MALE OR FEMALE IS PRESENT.
WE SEE LARGE NUMBER OF CELLS
THAT RESPOND TO DIFFERENT
SPECIFIC SOCIAL BEHAVIORS THAT
THE ANIMALS ARE PERFORMING LIKE
INVESTIGATION OR ATTACK
BEHAVIOR.
WHEN WE TRIED TO DO THE SAME
ANALYSIS IN VENTRAL LATERAL
PORTION OF VENTRAL MEDIAL
HYPOTHALAMUS WE SAW SOMETHING
DIFFERENCE WHICH IS MANY CELLS
RESPONDED TO JUST THE SEX OF THE
INTRUDER REGARDLESS OF WHAT
BEHAVIORS THE ANIMALS WERE
PERFORMING, AND THERE WERE VERY
SMALL NUMBER OF CELLS THAT
RESPONDED TO SPECIFIC MOTOR
ACTION OF THE ANIMALS.
SO THESE REGIONS DIFFERED NOT SO
MUCH IN REPRESENTING SAME MATING
VERSUS FIGHT BUT DIFFERED EXTENT
WHICH THEY ENCODED MOMENT TO
MOMENT ACTION OF THE ANIMAL
VERSUS JUST CELLS THAT WERE
ACTIVE OVER THE ENTIRE COURSE OF
PERIOD OF SOCIAL ENTERACTION A.
SO TO MAKE SENSE OF THIS
ACTIVITY, GRADUATE STUDENTS THAT
I WORKED WITH IN LAB FIT THE
POPULATION DYNAMICS OF THE --
WITH RECURRENT SWITCHING LINEAR
DYNAMICAL SYSTEMS MODEL SO IN
THESE MODELS YOU FIT A
TRANSITION MATRIX BETWEEN SET OF
STATES THAT ARE INFERRED BASED
ON NEURAL ACTIVITY, EACH OF
THESE STATES IS A LINEAR
DYNAMICAL SYSTEM FIT TO BE
OBSERVED POPULATION ACTIVITY.
SO WE ARE ABLE TO PRODUCE A LOW
DIMENSIONAL SUMMARY POPULATION
OF LORDED NEURONS IN THE BRAIN
IS DOING.
WHEN WE FIT THESE SYSTEMS TO
ACTIVITY IN VENTRAL LATERAL
PORTION OF VENTRAL MEDIAL
HYPOTHALAMUS WE SAW LONG LASTING
STATES.
THESE ARE LASTING FOR TENS OF
SECONDS TO MINUTES.
WE SAW GRADUAL TRANSITION FROM
ONE STATE THAT WAS PRESENT
DURING INVESTIGATION BEHAVIOR TO
ANOTHER PRESENT DURING LOW
INTENSITY REGRESSION BEHAVIOR TO
ANOTHER PRESENT DURING A TECH.
IT WAS STRIKING THESE STATES
DON'T COINCIDE WITH THE
INITIATION OF INDIVIDUAL BOUTS
OF BEHAVIOR, RATHER GRADUAL
ESCALATION OF GRADUAL TRANSITION
FROM STATE TO STATE TO STATE
THAT IS ACCOMPANYING AND
CORRELATE WITH THE ESCALATION OF
AGGRESSIVE BEHAVIOR BETWEEN
ANIMALS.
AND ANOTHER THING THAT WAS --
THIS IS ONE WITHOUT ANY
VISUALIZATION OR ANY INFORMATION
ABOUT THE ANIMALS MOMENT TO
MOMENT ACTION.
THIS IS JUST DISCOVERED BASED ON
THE STRUCTURE OF NEURAL
ACTIVITY.
IF WE GO IN AND LOOK ACROSS THE
ANIMALS AT ONE OF THE DIMENSIONS
THIS FIT DYNAMICAL SYSTEM
ANOTHER STRIKING THING WE SAW IS
THAT THIS ONE DIMENSION WHICH
HAS A LONG TIME CONSTANT
INTEGRATION MUCH LONGER THAN
REST OF THE SYSTEM, SHOWS
DYNAMICS AND TIME CONSTANT OF
THIS RAMPING THE CORRELATED WITH
LEVEL OF AGGRESSION WITH
DIFFERENT INDIVIDUAL ANIMALS.
MICE THAT WERE VERY AGGRESSIVE
SHOWED RAMPING UP OF ACTIVITY OF
THIS DIMENSION AN PERSISTED A
LONG PERIOD OF TIME REGARDLESS
OF ANY ACTION VERSUS MICE NOT
AGGRESSIVE, WE SAW INPUT ALONG
THIS DIMENSION BUT DECAYED BACK
TO BASELINE.
WE FOUND THIS INTEGRATOR WHICH
IS PRODUCING A SCALABLE LEVEL OF
AGGRESSIVE MOTIVATION MANY THE
ANIMALS AND AS ACTIVITY MOVES
ALONG THIS INTEGRATION DIMENSION
YOU SEE A TRANSITION FROM LOW
INTENSITY TO HIGH INTENSITY
AGGRESSIVE BEHAVIOR.
SO THIS GRADUAL RACHING OF
AGGRESSIVE MOTIVATION REFLECTED
IN THE DYNAMICS OF VMHTL
POPULATIONS.
WE DID THE SAME THING LOOKING
AGENT THE DYNAMICS OF NEURONS IN
MEDIAL PRE-OPTIC AREA AND HERE
WE SAW SOMETHING VERY DIFFERENT.
WE DIDN'T SEE THAT'S IS A RATION
OF MOTIVATIONAL STATE INSTEAD WE
SAW STATES THAT WERE TIGHTLY
CORRELATED WITH THE MOMENT TO
MOMENT ACTIONS OF THE ANIMALS
SUCH THAT IF YOU VISUALIZE THE
STATES ALONGSIDE ANIMALS ACTION,
YOU CAN SEE STATES TIGHTLY
CORRELATE WITH INITIATION OF
DIFFERENT STAGE OF IN THIS CASE
REPRODUCTIVE BEHAVIOR, STATESES
PRESENT DURING INVESTIGATION
BEHAVIOR DURING INITIATION OF
MOUNTING AND LAPPETTER STAGES
MOUNTING AND ENTIRE MISSION.
SO IT SEEMS THAT IN MEDIAL
PREOPTIC AREA WE DON'T SEE SLOW
RAMPING, WE SEE MOMENT TO MOMENT
TRANSITION BETWEEN DIFFERENT
BEHAVIORS REFLECTED IN THE
POPULATION ACTIVITY OF THESE
NEURONS.
SEEMS LIKE WE HAVE TWO REGIONS
THAT HAVE VERY DIFFERENT
ENCODING OF MOTIVATIONAL STATES
AN ACTIONS WE HAVE A REGION
MEDIAL PRE-OPTIC AREA, BEHAVIOR
SPECIAL NEURAL POPULATIONS AND
WE HAVE VENTRAL LATERAL PORTION
OF VENTRAL MEDIAL HYPOTHALAMUS
THAT DOESN'T ENCODE MOMENT TO
MOMENT ACTION OF ANIMAL BUT
SHOWS STRIKING RAMPING DYNAMICS
THAT ARE CORRELATED WITH
ESCALATION OF AGGRESSIVE
BEHAVIOR.
THIS SEEMS TO BE A GENERAL
FEATURE OF VENTRAL -- VENTRAL
MEDIAL HYPOTHALAMUS, AND
NEIGHBOR, YOU SEE SLOW DYNAMICS
IN A RELATED STIR STORY I WON'T
TELL YOU TODAY WE SEE A SLOW
DYNAMICS GENERATE PERSISTENT
ACTIVITY IN THIS REGION THAT
MAINTAIN A MOTIVATIONAL STATE OF
THE ANIMAL.
PERSISTENT ACTIVITY IN VHTL
RELATED TO AGGRESSIVE MOLTVATION
INVOLVED IN DEFENSIVE BEHAVIOR
PERSISTENT ACTIVITY RELATED TO
MAINTENANCE OF PERSISTENT
DEFENSIVE BEHAVIORS.
SO TO WRAP UP SEEMS LIKE WE HAVE
REGIONS LIKE VMHTL GLUTAMATERGIC
THAT SEEM PRODUCE A CONSIST SENT
REPRESENTATION OF MOTIVATIONAL
STATE AND OTHER GABAERGIC AREAS
THAT PERFORM MOMENT TO MOMENT
ACTION SELECTION OF ANIMAL
BEHAVIOR OR REFLECT ACTION
SELECTION BEING PERFORMED IN
OTHER PARTS OF THE BRAIN.
GOING MORE BROADLY SEEMS LIKE
THESE PERSISTENT REPRESENTATIONS
ARE REFLECTING THE CHANGE IN THE
ANIMAL MOTIVATIONAL STATE AND
ESCALATION OF AGGRESSIVE
MOTIVATION AND UNDERLYING CHANGE
IN THE CONTROL POLICY THAT IS
SHAPING THE ANIMAL MOMENT TO
MOMENT ACTIONS.
WITH THAT, I WILL WRAP UP AND
THANK AGAIN EXPERIMENTALISTS WHO
DID THE DATA COLLECTION AND --
WHO DID AMAZING JOB ON THE
ANALYSIS.
THANK YOU FOR YOUR TIME.
>> ALL RIGHT.
THANKS AGAIN TO ALL THE SPEAKERS
FROM THE SESSION.
WE HAVE A LITTLE BIT OVER TEN
MINUTES, JUST ABOUT TEN MINUTES
FOR QUESTIONS.
THERE ARE A BUNCH VIEWERS HAVE
ASKED SO I WILL READ OUT FOR
DIFFERENT PEOPLE, GREAT PLACE TO
START.
IF YOU HAVE MORE QUESTIONS
PLEASE FEEL FREE TO ENTER THEM I
CAN SEE THEM LIVE AS THEY INPUT
HERE.
SO JUST GO IN ORDER OF THE
TALKS, SO JEN, THERE WERE BUNCH
OF QUESTIONS ABOUT THAT CAMERA,
SO QUESTION IS CAN YOU HACKK
TECHNIQUE USED ON HIGH SPEED
CAMERA TO MAKE IT SUPER HIGH
SPEED.
FIND MORE ABOUT HACK WHEN YOU
ARE READY TO SHARE THE DETAILS.
THANKS.
>> THAT IS THE MULTI-FISH SLIDE
THAT I SHOWED IS ACTUALLY
HACKING A HIGH SPEED CAMERA.
HUGE SENSOR HIGH SPEED CAMERA SO
YOU CAN DO EXACTLY THAT.
SO YOU CAN MAKE A CAMERA 100
HERTZ GO MUCH LIER FRAME RATES
SO WE WILL PUT A PRE-PRINT UP IN
A FEW WEEKS.
>> EXCELLENT.
GOING IN ORDER FOR NILAY,
QUESTION IS STATE DEPENDENT
CHANGES IN THE I AND 1 NEURONS,
YOU THINK THOSE ARE INHERITED
UPSTREAM OR DO THEY ARISE IN
THAT CIRCUIT.
HOW DO THEY ARISE?
>> I THIS THEY IS A MILLION
DOLLAR QUESTION YOU ARE TRYING
TO ANSWER.
RIGHT NOW IT LOOKS LIKE
(INAUDIBLE) ON NEURONS SO OPTO
GENETIC BASICALLY -- EXPRESS
FROM SOME SAME NEURON AND JUST
LIKE PULSATE IN DIFFERENT SAMPLE
SCALES, WE CAN'T GET THEM SWITCH
THE -- SO THAT IS TELLING ME IT
IS POSSIBLE, NOT THE INNATE
SIGNALING SYSTEM THAT IS
GENERATING THAT FOR SYSTEM
STATE, WE DO THINK IT IS RELATED
TO THE GUT INPUT.
WE DO NOT KNOW YET IF THE GUT
NEURONS THEMSELVES ACTUALLY HAVE
PERSISTENT STATE.
THE PRELIMINARY RESULTS SUGGEST
THEY DO NOT.
SO IT IS A BIT OF PUZZLE NOW FOR
US PERSISTENCE OF IN 1 IS COMING
FROM STATE DEOPINION DEN SHY ON
THAT MATTER.
WE ARE ONGOING CIRCUIT PROJECT
WE WOULD LIKE TO RESOLVE AT SOME
POINT.
>> IT REMINDS ME OF A NEURON IN
C ELEGANS CALLED NSM THAT IS
MORE A GUT RESPONDER, IT HAS
INHIBITORY FEEDBACK, SO THAT
MEANS WHINNYINGTORY FEEDBACK
GOES AWAY IT GETS STRONGER AND
LONGER RESPONSES, SO SEZ, DOES
THAT RECEIVE A LOT OF -- FROM
OTHER BRAIN CIRCUITS IN THE FLY?
>> IT DEFINITELY -- WE HAVE
IDENTIFIED SOME OTHER
INTERNEURONS IN THE BRAIN THAT
CAN ACTUALLY INHIBIT NEURONS SO
WE DON'T KNOW ALL THE
CONNECTIONS UNFORTUNATELY THE
HELP BRAIN, COMPLETELY
RECONSTRUCTED IN --
>> I THINK WE LOST HER.
>>
>> WE GOT MOST QUESTIONS
ANSWERED THOUGH.
SO NEXT ONE, I GUESS I WILL TAKE
ONE SINCE I WAS THE NEXT
SPEAKER.
ARE WE BACK NILAY, WE LOST THE
LAST 20 SECONDS.
>> I WAS GOING TO SAY THAT AREA
IS NOT REALLY RECONSTRUCTED SO
WE DON'T KNOW ALL THE INPUTS OR
OUTPUTS.
LEARNING IN PROGRESS.
>> EXCELLENT.
>> QUESTION FOR ME DID YOU
IDENTIFY NEURONS ENCODING
EXTERNAL CONTEXT LIKE LOCATION
AS IN THIS WILL BE IN C ELEGANS,
GRID CELLS OR PLATE CELLS OR
CHEMICAL ENVIRONMENTS?
THAT IS A GREAT QUESTION.
WE DID NOT IDENTIFY NEURONS LIKE
THAT, THOUGH WE HAVE NOT -- WE
HAVE NOT LOOKED EXHAUSTIVELY AT
THE LIST OF ALL POSSIBLE WAYS OF
REPRESENTING EXTERNAL SPACE, WE
DID -- WHEN WE EARLY ON WHEN
ANALYZING THE DATA WE DID CREATE
VARIABLES OF LIKE THE ANIMAL
HEADING DIRECTION OTHER SPATIAL
VARIABLES ABOUT ENVIRONMENT.
THERE WAS SOME GENERAL HINTS THE
NEURAL MIGHT BE REPRESENTING
WHICH WAY IT WAS MOVING, IT WAS
NOT A VERY SIMPLE REPRESENTATION
AT LEAST.
SO WE STILL HAVE NOT PURSUED
THAT I WILL SAY SOME OF THE
NEURONS WE FIND LIKE ENCODE
CONJUNCTIVELY MULTIPLE BEHAVIORS
AND IT IS POSSIBLE ALREADY
SIMPLER WAYS DESCRIBING WHAT
THOSE NEURONS ENCODE THAT
REQUIRE US TO GRAPPLE WITH THE
STRUCTURE OF THE ANIMAL MOVEMENT
AND HOW IT ENGAGES IN THE
ENVIRONMENT.
THAT IS AN EXCELLENT QUESTION,
ONE THAT WE HAVEN'T FULLY
GRAPPLED WITH, THAT SAID BE
SURPRISED IF THERE WAS
REPRESENTATION OF SPACE IN THE
WORM BRAIN SIMILAR TO HOW THEY
ARE REPRESENTED IN A MOUSE.
FOR HUGO.
IT SAYS FOR DR. TEJEDA, DINORFIM
IS AFFECTING TYPE OF BEHAVIOR
DISPLAYED.
DO YOU THINK MANIPULATING THE
DINORFIN SYSTEM SOLELY DURING
CONDITIONS AFFECT THE BEHAVIOR
GENERATED BY THE QUEUE?
>> GREAT QUESTION.
SO WE HAVEN'T ADDRESSED THAT, TO
SEE IF THE SYSTEM IS AS ANIMALS
ACQUIRING LEARNED BEHAVIORS
ABOUT THREATS AND MIGHT TRANSFER
INTO RECALL.
WE HAVEN'T LOOKED AT THAT
SPECIFICALLY.
SO UNFORTUNATELY MOST
MANIPULATION, KNOCK DOWN GENE
EXPRESSION OR GENETICALLY
OBLIQUE RECEPTOR, BUT THAT IS A
GREAT QUESTION I THIS I THAT
SOMETHING WE SHOULD LOOK AT OR
LOOK AT IN FUTURE.
>> FOR ANN, THERE IS A QUESTION
HERE WHERE IN THE BRAIN ENCODES
THE MOTIVATION IN QUOTE FOR
SEXUAL BEHAVIOR?
DOES THIS BRAIN REGION ALSO SHOW
INTEGRATIVE FEATURES LIKE THE
VMHL DOES FOR AGGRESSION ORIENT
GRATED MODEL WORKS OHIO OR THE
INTEGRATED MODEL, CAN'T JUSTIFY
-- I THINK THAT ARE LOOK FOR A
SEXUAL BEHAVIOR RATHER THAN
AGGRESSIVE BEHAVIOR, WHETHER
THERE'S SIMS TYPES --
>> I DISCONNECTED WHEN YOU
STARTED ASKING THE QUESTION.
>> LET ME ASK IT ONE MORE --
BASICALLY THEY ARE ASKING IF FOR
WHERE IN THE BRAIN IS MOTIVATION
FOR SEXUAL BEHAVIOR WOULD YOU
EXPECT TO SEE SIMILAR INTEGRATOR
MODELS LIKE YOU SEE FOR
AGGRESSIVE BEHAVIOR IN THE VMHVL
FOR SHALL BEHAVIOR?
>> RIGHT.
MEDIAL PREOPTIC AREA HAS BEEN
ASSOCIATED WITH MOTIVATION FOR
SEXUAL BEHAVIOR IF YOU
STIMULATED OPTOGENETICLY YOU CAN
INVOKE MOUNTING BEHAVIOR IN
MALES AND LOUR DOESIS IN
FEMALES.
WE DON'T SEE ANY RAMPING
DYNAMICS SO IT IS UNCLEAR TO ME
WHETHER YOU WOULD SEE A RAMPING
REPRESENTATION OF MOTIVATION FOR
EVERY BEHAVIOR OR NOT.
WE DO SEE SOME RAMPING OF
ACTIVITY IN VMHVL DURING FEMALE
MALE INTERACTIONS WHEN
(INAUDIBLE) IS OCCURRING SO IT
COULD BE THIS IS ALSO A
MOTIVATIONAL REPRESENTATION THAT
IS INVOLVED IN REPRODUCTIVE
BEHAVIOR.
BUT IT COULD ALSO BE THERE ARE
OTHER REGIONS WE SHOULD BE
LOOKING FOR REPRODUCTIVE
MOTIVATION.
>> IF I CAN FOLLOW-UP WITH ONE
QUESTION, LIKE I WAS STRUCK BY
DIFFERENCE BETWEEN MPO, I ALWAYS
THINK IMPLEMENTATION SO I
PRESUME, I DON'T KNOW HOW MUCH
ABOUT MOUSE ANATOMY, IT WASN'T
THAT SIMPLE BUT IS THERE ANY
OBVIOUS STRUCTURAL OR INPUT
DIFFERENCE BETWEEN MPO AND VMHVL
THAT MIGHT MAKE IT SO THE H,V
WILL HAS MORE SIGNIFICANCE OR
RECURRENCE OR MODULATORY OR
SOMETHING LIKE THAT?
>> THE VAST MAJORITY OF SUB
CORTICAL AND HIPPOTHALAMIC
STRUCTURES ARE GABAERGIC, VHML
IS ONE EXCEPTION THAT THE
NEURONS ARE GLUTAMATERGIC WITH
THIS GABAERGIC SHELL AROUND THEM
AND THERE'S RECURRENT
CONNECTIVITY, IT IS SPARSE BUT
ENOUGH TO WORK BETWEEN CELLS IN
VMH SO SEEMS LIKE WELL SUITED TO
MAINTAIN PERSISTENT ACTIVITY IN
JUST BY THIS RECURRENT
CONNECTIVITY.
FOR OUR PAPER ON DEFENSIVE
BEHAVIOR THAT I DIDN'T GET INTO
WE DID MODELING TO SEE WHETHER
RECURRENT NETWORK FIT WITH
DYNAMICS.
WE FOUND THAT IT WAS OKAY BUT TO
GET A PROPER FIT WE ALSO HAD TO
ADD IN SOME SLOW PEPTIDE JUDGE
NEURON DYNAMICS.
THE PERSISTENCE IS REALLY
COMBINATION OF HAVING RECURRENT
EXCITATION BUT ALSO HAVING SLOW
NEUROMODULATORY TRANSMISSION
BETWEEN CELLS TO SUSTAIN
MOTIVATIONAL STATES ON TIME
SCALES OF BEHAVIOR.
>> I LOVE THAT MODEL BY THE WAY.
>> QUESTION FOR HUGO.
SO THESE DINORFIN NEURONS DO
THEY MODULATE OTHER TYPES OF
BEHAVIOR LIKE AGGRESSIVE
BEHAVIOR OR OTHER FORMS OF
ACTIVE BEHAVIOR?
>> GOOD QUESTION.
WE ARE LOOKING AT OTHER
BEHAVIORS THAT ARE ACTIVE IN
NATURE AND LESS PASSIVE.
WE DON'T HAVE THE ANSWER QUITE
YET BUT THEY DON'T SEEM TO
REGULATE LIKE REWARD SEENING
BEHAVIOR ONE PREDICT HAS ACTIVE
COMPONENT.
AT LEAST SO FAR SEEMS LIKE
PARTICULARLY TUNED TO AVERSIVE
EXPERIENCES
>> WONDERING BECAUSE OF STEVE'S
NICE TALK ABOUT MULTIPLEX, IT IS
UNCLEAR HOW MUCH IS HAPPENING IN
OTHER SYSTEMS.
I THINK STEVE HAS LIKE PROBABLY
THE MOST COMPREHENSIVE VIEW BUT
IT IS NOT A NEUROMISDEMEANOR LAY
TORR MOUSE ON CERTAIN BEHAVIOR,
PROBABLY A SET OF BEHAVIORS SO I
DON'T KNOW HOW YOU THINK ABOUT
THAT.
>> MAYBE STEVE HAS THE ANSWER.
>> C ELEGANS DEFINITELY
MODULATED LIKE THE SAME
MODULATOR CAN BE DEPLOYED IN
DIFFERENT CIRCUITS LIKE THE
MODULATOR WE STUDY BETH BEST IS
SEROTONIN WHICH DRIVE REPETITIVE
ROAMING DWELLING BEHAVIOR.
IT IS THE SEROTONIN DEPLOYD BY
NEURONS NOT INVOLVED IN THOSE
BEHAVE YEARS BEHAVES DIFFERENTLY
AND SOME CIRCUMSTANCES SEEMS TO
ACT MORE THROUGH SYNAPTIC THAN
VOLUME TRANSMISSION.
SO WE THINK THAT ASCRIBING ONE
TO ONE MODULATOR TO BEHAVIOR IS
THIS THE COUNTER EXAMPLE IS JUST
ABOUT TO PRESENT ITSELF.
IN A GIVEN CIRCUIT THEY ARE
REPRESENTING SOMETHING THAT IT
IS POSSIBLE TO DESCRIBE WITH
WORDS AND IS INTUITIVE.
TO CHIME IN ON THAT AS WELL.
I AGREE THAT I THINK IT IS MORE
AWARE NEUROMISDEMEANOR LAY TORR
BEING EXPRESSED WHICH
NEUROMODULATOR IT IS.
(INDISCERNIBLE) COLLABORATOR OF
MINE WHEN POST-DOC IN ANDERSON
LAB WAS STUDYING TACKY QUININE 2
AND ROLE OF STRESS AND EFFECT OF
SOCIAL ISOLATION ON AGGRESSIVE
AND ANXIETY LIKE BEHAVIORS.
WHERE SHE INDUCED OR KNOCKED
DOWN TAC 2 EXPERIENCE YOU SHE
SEE THE AGGRESSION PHENOTYPE OR
THE STRESS LIKE PHENOTYPE SO I
THINK WHERE THAT PEPTIDE OR
NEUROMODULATOR IS ACTING IS
DETERMINANT OF FUNCTION RATHER
THAN IDENTITY.
BOTH ARE IMPORTANT BUT IN THE
SAME WAY THAT GLUTAMATE DOES
DIFFERENT THINGS IN DIFFERENT
BRAIN AREAS THESE PEPTIDES
NEUROMODULATORS PROBABLY DO AS
WELL.
>> AGREE.
I THINK TO ADD TO THAT, IN SOME
WAYS WE CAN THINK ABOUT THESE
NEUROMODULATORS LIKE RADIO
SIGNALS THAT FLOODING ANY OF US
AT A GIVEN POINT BOMBARDED BY
RAID YES SIGNAL BUT WE DON'T
HAVE RADIOS THAT ARE
PARTICULARLY ATTUNED TO THAT
STATION SO WE CAN'T HEAR THOSE
SIGNALS.
NEURAL PEPTIDES MAY ACT LIKE
THAT, ONLY THOSE CELLS OR
SYNAPSES THAT HAVE THE RECEPTOR
FOR THE NEUROMODULATOR THAT ARE
GOING TO BE ACTIVATED OR INHIBIT
INHIBITED AND SINCE THEY HAVE
THEY OPERATE VIA VOLUME
TRANSMISSION, IT GIVES ANOTHER
MODE OF OPERATION RELATIVE TO
THAT TRANSMISSION.
>> DO YOU THINK --
>> GO AHEAD.
>> I WAS GOING TO ASK TO WHAT
EXTENT YOU THINK THESE SIGNALS
ARE VOLUME TRANSMISSION VERSUS
FAST TRANSMISSION AT LOCALIZE
SYNAPSE.
DO WE KNOW?
>> IN OUR HANDS WE HAVE EVIDENCE
THAT FOR INSTANCE DINORFIN CAN
BE RELEASED WITH SENSOR ON THE
ORDER OF SECONDS.
L SO THAT IS TO ADDRESS THAT.
BUT WE ALSO HAVE EVIDENCE USING
SLICE PHYSIOLOGY WHERE WE CAN
INDUCE RELEASE OF DINORFIN FROM
THOSE PRODUCING CELLS ACT IN
RETRO GRADE MANNER AND AMYGDALA
INPUT.
AS WELL TO NON-DINORFIN PRODUCE
CELLS, SO THEY INFLUENCE
ACTIVITY OF THE NEIGHBORING
CELLS THAT DON'T PRODUCE THE
SAME PEPTIDE.
>> MAYBE ONE LAST QUESTION, THIS
IS TOO BIG A QUESTION FOR ONE
MINUTE 40 SECONDS BUT WE DISCUSS
LIKE WHAT REALLY IS AN INTERNAL
STATE AND IT IS LIKE AN
OPERATIVE DEFINITION WE ALL USE
BUT WE USE IT SLIGHT SLIGHTLY
DIFFERENTLY.
SO WONDER IF ANY PANELISTS JUMP
IN AND PUT THEIR BEST FOOT
FORWARD USEFUL DEFINITION OF
INTERNAL STATE, MAYBE DEFINITION
LOOSE SYSTEM NEEDS TO MOST WORK.
>> MAYBE I CAN ANSWER YOUR
QUESTION WITH ANOTHER QUESTION.
WHETHER WHEN WE SAY INTERNAL
STATE, WHAT TEMPORAL SCALE WE
ARE TALKING ABOUT.
THERE IS LIKE -- IS IT -- IS THE
BRAIN TEMPO INTERNAL STATE OR IS
IT JUST LIKE MULTIPLE AT THE
SAME TIME.
ONE THING THAT I WONDER A LOT.
WHAT LEVEL WE WILL DETERMINE
INTERNAL STATE.
BASICALLY TERMINAL FREQUENCY
LIKE SPARKING LEVEL OR IS IT
PEPTIDE LEVEL OR MORE IN IN THE
OTHER SIGNALING PATHWAYS THAT
WHAT IS HAPPENING IN THE BRAIN.
WILL IS DIFFERENT TIME SCALES
THAT WE DO NEED TO CONSIDER WHEN
WE ARE DISCUSSING INTERNAL STATE
AS WELL, I THINK A VERY
CHALLENGING OPTICS TO ADDRESS --
TOPICS TO ADDRESS.
>> I LIKE THAT INTRODUCTION
ABOUT THE CHALLENGE REDUCTION.
THAT IS THE LEAST CONCEPTUALLY I
FEEL LIKE THAT IS ONE OF THE
REASONS WE HAVE IDEA OF INTERNAL
STATE.
I TOTALLY AGREE THERE'S
DIFFERENT TIME SCALES BUT WHAT
IS INTERESTING IS THOSE TIME
SCALES WILL NEED DIFFERENT
IMPLEMENTATIONS.
WHICH REALLY FUN TO FIGURE OUT.
>> LOOKS LIKE OUR SESSION TIMER
IS UP.
>> I DON'T KNOW WHAT HAPPENS
NOW.
>> YOU CAN KEEP GOING FOR A
MINUTE UNTIL THEY CUT US OFF.
IN RESPONSE TO WHAT YOU SAID,
THE IDEA OF MAYBE THAT THERE'S
PARALLEL DIFFERENT TIME SCALES
OF BEHAVIOR GOING ON LIKE
SYNCHRONOUSLY FROM THE NESTED
VERSION WHERE HIERARCHICAL
VERSION WHERE THERE IS STATES
AND WITHIN THEM YOU ORGANIZE
FINER TIME SCALES, AND YET EVEN
IN C ELEGANS I DON'T HAVE A
CLEAR ANSWER WHETHER THERE'S
ARBITRARY TIME SCALES OF
BEHAVIORS IN PARALLEL VERSUS
TRUER HIERARCHICAL ORGANIZATION.
THAT MIGHT BE AT LEAST LIKE A
FRAMEWORK THAT FEELS LIKE WE
COULD SEPARATE OUT THOSE
DIFFERENT HYPOTHESES.
>> GOOD AFTERNOON, I'M WALTER
KOROSHETZ, DIRECTOR OF THE
NEUROLOGICAL INSTITUTE.
MY PLEASURE TO INTRODUCE DR.
ELIZABETH BUFFALO WHETHER OR NOT
WILL TALK ABOUT THE
NEURODYNAMICS MEMORY FORMATION
AND THE PRIMATE HIPPOCAMPUS.
SHE WILL TELL US HOW STUDYING
MONKEYS TO EXPLORE COMPLEX
VISUAL IMAGES AS LED TO NEW
INCITES ABILITY HOW NEURAL
FIRING PATTERNS AND OSCILLATORY
ACTIVITY DRIVE THE STRENGTH OF
MEMORIES.
I THINK WE WILL ALL PROFIT BY
HEARING HER THOUGHTS ON HOW
TEMPORAL ORDER OF EXPERIENCE
FEEDS INTO THE ANTIVIRAL CORTEX
NETWORK HIPPOCAMPUS TO CREATE A
TOPOLOGY THAT LINKS A VARIETY OF
MODALITIES OF EXPERIENCE WITHIN
A RELATIONAL NETWORK.
BOTH SPATIAL AND NON-SPATIAL
SALIENT EVENTS, MAYBE EVEN ALL
SALIENT EVENTS.
BEFORE CONTINUING WITH THE
INTRODUCTION IF YOU CAN SHOW THE
FIRST SLIDE, I WANT TO
ACKNOWLEDGE A TREMENDOUS
CONTRIBUTIONS OF WOMEN
SCIENTISTS TO THE BEGINNING,
PRESENT AND FUTURE OF THE BRAIN
INITIATIVE.
HERE IS A PHOTO OF ELIZABETH
BUFFALO MURPHY ADRIENNE ANN
CHURCHLIN ADRIENNE FAIRHALL AND
ELIZABETH SHAVER AT THE EARLY
DAYS OF BRAIN INITIATIVE AND NO
THIS IS NOT A BREAK IN TO SENATE
CHAMBER, THIS WAS AD BRIEFING
THE GREAT SCIENTISTS GAVE TO
CONGRESSIONAL FOLKS.
SO IF WE COULD TAKE DOWN THE
SLIDE NOW, ELIZABETH IS THE
CHAIR AND THE PROFESSOR OF
DEPARTMENT OF PHYSIOLOGY AND
BIOPHYSICS, THE WAYNE ENDOWED
CHAIR, CHAIR OF PHYSIOLOGY
BIOPHYSICS UNIVERSITY OF
WASHINGTON, SHE ATTENDED WELLSLY
COLLEGE AND WITH A STINT AT
OXFORD STUDYING PHILOSOPHY.
THEN WENT ON TO STUDY BOTH
PHILOSOPHY AND PHYSIOLOGY AT THE
UNIVERSITY OF CALIFORNIA SAN
DIEGO.
GOT HER Ph.D. AND LARRY SQUIRE
AND WENT TO NIMH INTRAMURAL NIH
PROGRAM WITH BOB DESIMONE OUT OF
HERSELF ACADEMIC JOB AT EMORY,
RISING TO ASSOCIATE PROFESSOR
AND THEN TO UNIVERSITY OF
WASHINGTON IN 2012.
LABORATORY IS IDENTIFIED NOVEL
SIGNAL IN THE MONKEY HIPPOCAMPUS
AS THE SINGLE NEURON AND NETWORK
LEVEL THAT UNDERLIE MEMORY
FORMATION.
SO IT IS A GREAT PLEASURE
LOOKING FORWARD TO THE TALK
ELIZABETH.
OVER TO YOU.
>> THANK YOU, WALTER.
FOR THAT GREAT INTRODUCTION.
ALSO FOR THAT WONDERFUL MEMORY
AND THAT PHOTO.
I DEFINITELY REMEMBER THAT DAY.
AND THAT WAS SUCH A GREAT EVENT.
REALLY FUN TO BE PART OF THE
EARLY DAYS OF THE BRAIN
INITIATIVE.
I'M EXCITED TO BE ABLE TO TELL
YOU ABOUT SOME RECENT WORK
TODAY.
AND REALLY JUST TO SAY FROM THE
BEGINNING THAT MOST OF THIS WORK
WOULDN'T HAVE BEEN POSSIBLE
WITHOUT THE GENEROUS SUPPORT
FROM THE BRAIN INITIATIVE.
WHEN YOU KNOW YOU WILL HEAR A
TALK ABOUT THE HYMN CAP PUS MOST
OF YOU ARE HOLDING TWO IDEAS
SIMULTANEOUSLY IN YOUR MINDS.
MEMORY AND SPATIAL NAVIGATION.
SO STEMMING FROM THE PIONEERING
WORK OF BRENDA MILNER IN THE
1950s, PATIENTS LIKE PATIENT
HM WHO SUFFERED FROM DAMAGE TO
THE HIPPOCAMPUS AND MEDIAL
TEMPORAL LOBE CORTEX HAVE
SEVERELY IMPAIRED MEMORY.
FROM A PARALLEL LINE OF RESEARCH
BEGINNING WITH JOHN O'KEEFFE IN
THE 1970s INCLUDING THE
BEAUTIFUL WORK OF ED HART AND
MARGARET MORRIS FROM 2000s,
CELLS IN THE RODENT HIPPOCAMPUS
AND INTRONNAL CORTEX SHOW
EXQUISITE SPATIAL
REPRESENTATIONS.
SO MY LAB FOCUSES ON
UNDERSTANDING NEUROPHYSIOLOGICAL
SIGNALS IN THE MONKEY RELATED TO
MEMORY AND AS I WILL DESCRIBE IN
A MOMENT UTILIZING A
NATURALISTIC VIEWING TEST WE
UNWHITTINGLY DISCOVERED FOR RUMS
OF SPATIAL REPRESENTATION AND
SPENT SEVERAL YEARS TRYING TO
LEARN FROM THE MONKEY MODEL HOW
WE MIGHT RESOLVE APPARENT
CONTROVERSY BETWEEN SPATIAL AND
PNEUMONIC VIEWS IN THE
HIPPOCAMPUS.
A MONKEY PROVIDED GREAT
OPPORTUNITY FOR BRIDGING THE GAP
BETWEEN THESE TWO SPECIES OF
HUMANS AND RODENTS.
WE CAN TRAIN OUR MONKEYS TO
PERFORM BEHAVIORAL TASKS THAT
PARALLEL TASK USED IN HUMAN
PATIENTS AND WE CAN ADAPT TOOLS
AND TECHNIQUES FROM RODENT
NEUROPHYSIOLOGICAL STUDIES TO
RECORD ACTIVITY OF POPULATIONS
FROM SINGLE NEURONS DEEP IN THE
MACAQUE BRAIN.
SO TODAY I WANT TO TELL YOU
THREE LINES OF RESEARCH IN MY
LAB, IN THE FIRST I WILL
DESCRIBE OUR DISCOVERIES AROUND
SPATIAL REPRESENTATIONS MANY THE
MONKEY MEDIAL TEMPORAL LOBE.
THESE WERE DISCOVERED DURING
TASKS MONKEYS WERE PERFORMING
TASKS THAT UTILIZE NATURALISTIC
VIEW AND BEHAVIOR, THESE
REPRESENTATIONS ARE ASSOCIATED
WITH VISUAL EXPLORATION.
THEN ALSO I WILL PRESENT NEWEST
DATA USING VIRTUAL REALITY
IMMERSIVE VIDEO GAMES FOR
MONKEYS TO PROBE THE MECHANISMS
OF REFORMATION UNDERSTANDING THE
NATURE OF THE COGNITIVE MAP.
AT THE END I WILL DISCUSS OUR
WORK LOOKING AT RHYTHMIC
NEURONAL ACTIVITY IN THE
HIPPOCAMPUS AND RELATIONSHIPS
BETWEEN HIPPOCAMPAL ACTIVITY AND
EYE MOVEMENTS.
TOGETHER I THINK THESE STUDIES
HAVE LED TO EMERGING IDEA ABOUT
HOW WE MIGHT RECONCILE THIS
SPATIAL PNEUMONIC VIEWS OF THE
FUNCTION OF THE HIPPOCAMPUS.
SO ONE THING THAT IS CLEARLY
DIFFERENT ABOUT PRIMATES AND
RODENTS IS VISION IS A PRIMARY
SENSORY MODALITY FOR PRIMATES.
WE USE EYE MOVEMENT TO EXPLORE
THE WORLD AROUND US.
WITHOUT NECESSARILY NEEDING TO
PHYSICALLY MOVE AROUND IN OUR
ENVIRONMENT.
IN THE LATE 1960s ALFRED
JARVIS MADE THE DISCOVERY THAT
EYE MOVEMENTS PROVIDE
INTERESTING INDEX INTO SUBJECTS
COGNITION.
SO AS WE MOVE OUR EYES
DIFFERENTLY DEPENDING ON IN THIS
EXPERIMENT THE INSTRUCTIONS THAT
JARVIS GAVE TO HIS SUBJECTS SO
EITHER TO EXAMINE THE PAINTING
FREELY OR ESTIMATE THE MATERIAL
CIRCUMSTANCES OF OUR FAMILY.
SO YOU CAN SEE THE DRAMATIC
DIFFERENCE IN THE EYE MOVEMENTS
MANY THE SCAN PATH HERE SHOWN IN
WHITE.
IN OUR WORK WE ALSO IDENTIFIED
CHANGES IN EYE MOVEMENTS THAT
REFLECT MEMORY FOR PARTICULAR
SCENES.
IN MANY EXPERIMENTS WE TRAIN
MONKEYS TO SIT IN FRONT OF
COMPUTER MONITOR AND WE HAVE
ALLOWED THEM TO FREELY VIEW A
SERIES OF COMPLEX SCENES WHILE
WE RECORDED NEURAL ACTIVITY IN
THE HIPPOCAMPUS AND THE
INTRONNAL CORTEX.
WHILE WE WERE EXAMINING NEURAL
SIGNALS RELATED TO MEMORY FROM
VISUAL SCENES, AND THE SCAN PACK
FOR MONKEY VIEWING THIS SCENE IS
SHOWN HERE OVER LAID IN BLUE.
AS WE OBSERVE THE WAY MONKEYS
VIEW THESE SCENES WE HAD THE
IDEA THAT MAYBE PRIMATES USE EYE
MOVEMENT TO EXPLORE SPACE
SIMILAR TO THE WAY RODENTS
EXPLORE THEIR ENVIRONMENT BY
MOVING AROUND.
FROM THE STUDIES OF
ENVIRONMENTAL EXPLORATION IN
RODENTS, SEVERAL PRIMARY CELL
TYPES HAD BEEN DISCOVERED.
SO JOHN O'KEEFFE WHO I MENTIONED
EARLY WHERE REAR DISCOVERED
HIPPOCAMPAL PLACED CELLS, THESE
ARE CELLS IN THE HIPPOCAMPUS
THAT RESPOND WHENEVER THE RAT IS
IN ONE LOCATION WITHIN THE
ENVIRONMENT.
THEN IN THE EARLY 2000s WITH
STUDENTS DISCOVERED GRID CELLS
IN THE ADJACENT INTERRAL CORTEX
THESE ARE CELLS THAT RESPOND TO
MULTIPLE LOCATIONS IN THE
ENVIRONMENT AND FIELDS FOR THESE
NEURONS PERFORM A PERFECTED GRID
IN THE ENVIRONMENT.
THESE ARE BORDER CELLS THAT FIRE
WHEN RAT IS MOVE ALONG ONE EDGE
OF THE ENVIRONMENT AND HEAD
DIRECTION CELLS WERE DISCOVERED
SO THESE ARE CELLS THAT FIRE
SELECTIVELY WHEN THE RAT IS
FACING OR MOVING IN A PARTICULAR
DIRECTION AND THESE CELLS ARE
IDENTIFIED IN THE ENTERONNAL
CORTEX AND THE THALAMUS AND
THESE KINDS OF RESPONSES HAVEN'T
BEEN IDENTIFIED IN PRIMATES.
SO IN OUR WORK THIS IS WITH
NATHAN KILLIAN WHO HAS HIS HONE
LAB AT EINSTEIN BUT WHEN HE WAS
A GRADUATE STUDENT IN MY LAB HE
WORD RECORDED FROM THE ENTERAL
CORE EXAND IDENTIFIED GRID LIKE
ACTIVITY RELATED TO THE MONKEY
SCAN PATH.
IN THE LEFT THE YEAH LINES
REPRESENT THE MONKEY SCAN PATH
VIEWED HUNDREDS OF COMPLEX
IMAGES, SO ALL THE SCAN PATHS
ARE OVERLAID.
AND THE RED DOTS INDICATE WHERE
THE MONKEY WAS LOOKING ON THE
SCREEN WHEN THIS PARTICULAR VIR
RON FIRED ACTION POTENTIAL.
SO THE MIDDLE PLOT SHOWS THE
FIRING RATE OF THE HEAT MAP AND
THEN THE RIGHT PLOT SHOWS THE
AUTOCORRELATION OF FIRING RATE
MAP WHICH HIGHLIGHTS THE GRID
LIKE ACTIVITY.
SO THIS IS A PRETTY SURPRISING
FINDING FOR US IN THE LAB.
AND I WOULD SAY IT REALLY
CHANGED THE FOCUS OF MY RESEARCH
FOR A WHILE.
SO THIS SLIDE SHOWS A SUMMARY OF
WORK OVER THE PAST DECADE SINCE
THAT FIRST PUBLICATION.
DURING THAT TIME WE HAVE BEEN
ABLE TO IDENTIFY ALL OF THE SAME
KINDS OF SPATIAL REPRESENTATIONS
THAT HAVE BEEN IDENTIFIED IN
RODENTS.
SO GRID CELLS AND BORDER CELLS
MANY THE ENTERONNAL CORTEX,
CELLS CALLED BECAUSE THEY WERE
SELECTED FOR ANGLE OF TRAJECTORY
OF THE EYE MOVEMENT AND WHICH
MAYBE ANALOGOUS TO HEAD
DIRECTION CELLS AND THEN MOST
RECENTLY PLACE CELLS IN THE
HIPPOCAMPUS.
SO AGAIN ALL THESE KINDS OF
REPRESENTATIONS WERE IDENTIFIED
WHEN THE MONKEYS WERE ENGAGED IN
VISUAL EXPLORATION SO MOVING
THEIR EYES AROUND.
TO EXPLORE COMPLEX SCENES.
BUT WE WERE ALSO INTERESTED IN
WHAT EXTENT THESE
REPRESENTATIONS MIGHT BE PRESENT
APART FROM EYE MOVEMENTS AND
MIGHT INSTEAD REFLECT THE
LOCATION OF ATTENTION.
SO VISITING STUDENT IN THE LAB
NICHOLAS DECIDED TO TEST THIS
IDEA BY TRAINING MONKEYS TO
FIXATE A CENTRAL CROSS WHILE HE
PRESENTED A STIMULUS MOVING MANY
THE THE PERIPHERY.
THE MONKEYS WERE REWARD FOR
MAINTAINING CENTRAL FIXATION SO
THEY COULDN'T MOVE THEIR EYES
BUT THEY WERE REWARDED FOR
COVERTLY ATTENDING TO THAT
PERIPHERAL STIMULUS AND THEN
RESPONDING BY RELEASING THEIR
HOLD ON A BAR, PLACED INSIDE
THEIR CHAIR WHEN THERE WAS A
SUBTLE LUMINESCE CHANGE IN THE
STIMULUS.
WE CAN TITRATE THAT CHANGE TO
MAKE SURE THE MONKEYS WERE
MAINTAINING ATTENTION IN ORDER
TO PERFORM WELL IN THE TASK.
SURPRISINGLY IN THIS EXPERIMENT
WHILE NICHOLAS RECORDED THE
ACTIVITY OF NEURONS IN THE
INTERNAL CORTEX HE FOUND
EVIDENCE FOR GRID LIKE ACTIVITY
AND EXAMPLE IS SHOWN HERE AT THE
BOTTOM WITH THE HEAT MAP ON THE
LEFT AND THE AUTOCORRELATION ON
THE RIGHT.
SO THIS ACTIVITY REFLECTED THE
LOCATION OF ATTENTION WITHOUT
PHYSICAL MOVEMENT SO WHILE THE
MONKEYS WERE MAINTAINING CENTRAL
FIBBIZATION THIS ACTIVITY
REFLECTED WHERE THE NEURON WAS
FIRING RELATIVE TO THE LOCATION
OF COHORT ATTENTION.
I THINK THERE WAS A CONCERN AT
LEAST IN OUR MINDS MAYBE THESE
FLAT TWO DIMENSIONAL
REPRESENTATIONS ARE NOT
ANALOGOUS TO CASE OF RODENTS
MOVING IN SPACE.
THEY CAN WHEN LEARN MORE TO
TRAIN MONKEYS TO PLAY VIDEO
GAMES IN VIRTUAL REALITY SO WE
TRAIN THEM TO USE A JOY STICK TO
NAVIGATE A VIRTUAL SPEISES
EXAMINE THE RESPONSES UNDER
THESE CONDITIONS.
SO I WANT TO SHOW YOU FIRST AN
OLD VIDEO, THIS IS ONE MONKEY
GUISEPPE USING THE JOY STICK TO
MOVE AROUND THE VIRTUAL ARENA.
SO EVERY TIME HE COLLIDES WITH A
VIRTUAL BANANA HE RECEIVES A
FOOD REWARD AND THAT IS
DELIVERED THROUGH A TUBE THAT IS
POSITIONED IN FRONT OF HIS
MOUTH.
I WENT FORWARD THERE.
SEE IF HE IS GOING TO PLAY.
HE'S RECEIVING FOOD REWARD INTO
A TUBE THAT IS POSITIONED IN
FRONT OF HIS MOUTH EVERY TIME HE
COLLIDES WITH A BANANA.
WE WERE ALSO TRACKING HIS EYE
MOVEMENT, THAT IS REPRESENTED IN
THIS VIDEO WITH THE WHITE
CIRCLE.
WE SAW LOTS OF INTERESTING
BEHAVIORS IN THIS OPEN FIELD
FORAGING SO MONKEYS TENDED TO
SORT OF EXPLORE THE ENVIRONMENT
FOR A BIT BEFORE THEY FOUND
BANANAS CLUSTERED AND MOVE
FORWARD FOR THOSE CLUSTERED
BANANAs.
HERE IS AN EXAMPLE OF THIS HERE
IN THE VIDEO.
AND THEN MONKEYS ALSO SHOW
EVIDENCE FOR REMEMBERING THE
LOCATION OF THE NEXT CLOSEST
BANANA WHEN IT WAS OFF THE
SCREEN, SO SORT OF A MEMORY FOR
AT LEAST THE MOST RECENT LAY OUT
OF THE BANANAs.
AT THE SAME TIME WE ALSO WANTED
TO INCREASE OUR ABILITY TO
RECORD FROM A LARGER NUMBER OF
NEURONS SIMPLY COLLABORATED WITH
CHARLIE GRAY IN MONTANA TO
DEVELOP A MULTI-CHANNEL
MICRODRIVE THAT ALLOWED US TO
CHRONICALLY RECORD FROM 124
SINGLE WIRES DIRECTED TOWARDS
THE HIPPOCAMPUS AND THE
ENTERONNAL CORTEX AND I WANT TO
HIGHLIGHT ACKNOWLEDGE AGAIN MANY
ASPECT OF THE DEVELOPMENT OF
THIS NEW RECORDING TECHNOLOGY
WERE MADE POSSIBLE THROUGH BRAIN
INITIATIVE FUNDING.
SO WHILE WE WERE RECORDING FROM
THIS MULTI-DRIVE WE TRAIN
MONKEYS TO PERFORM SPATIAL
MEMORY TASKS SIMILAR TO THOSE
USED IN RODENT EXPERIMENTS ONE
TASK WAS SPATIAL DELAYED AL
MATERIAL TEAR NATION TASK USING
A EYE MAZE, I WILL SHOW YOU A
VIDEO HOW THIS TASK WORKS.
SO NOW THE VIDEO IS PLAYING HERE
MONKEY IS REWARRED FOR CENTER
STEM OF THIS Y MAZE ALTERNATING
TRIALS TURNING LEFT OR RIGHT IN
ORDER TO FIND THE HIDDEN BANANA
AT THE END OF THE ARM HIDDEN IN
THIS STICKY HUT, WE ARE
MONITORING EYE MOVEMENTS, THERE
WAS A FOUR SECOND INTERTRIAL
INTERVAL SHOWN THERE IN THE DARK
SCREEN AND NOT SURE IF YOU CAN
HEAR THE SOUND THAT WE ARE
RECORDING IN THIS VIDEO YOU CAN
HOPEFULLY HEAR THE SOUND OF
SINGLE HIPPOCAMPAL NEURON FIRING
AND THIS NEURON ALONG WITH MANY
OTHERS THAT I WILL SHOW YOU IN A
MINUTE SHOWED A SPATIAL
SELECTIVITY.
SO THIS NEURON TENDED TO FIRE
WHEN THE MONKEY WAS AT THE END
OF THAT CHOICE -- AT THE CHOICE
POINT AT END OF CENTER ARM AND
FIRED A LOT AT THE END OF THE
LEFT WARD ARM BUT NOT THE END OF
THE RIGHT WARD ARM.
SO LET ME SHOW YOU NOW SOME DATA
FROM NEURONS RECORDED WHILE THE
MONKEY WAS PERFORMING THIS TASK.
WHAT YOU CAN SEE HERE ARE THE
TRIALS SEPARATED BY LEFT WARD
GOING AND RIGHT WARD GOING
TRIALS EACH ROW REPRESENTS A
DIFFERENT TRIAL AND BLACK MARKS
INDICATE TICK MARKS INDICATE A
SINGLE ACTION POTENTIAL SO YOU
CAN SEE FOR THIS EXAMPLE NEURON
TENDED TO FIRE QUITE A BIT DOWN
THE LEFT WARD ARM.
IN ORDER TO QUANTIFY THIS
BEHAVIOR FIRST WE CAN VISUALLY
LOOK AT INSPECT BY LOOKING AT
THE HEAT MAP SHOWN ON THE LEFT
WHERE YOU SEE INCREASE FIRING
RATE DOWN THE LEFT WARD ARM
INTUITIVELY FOR SPILL TO BE
SPATIALLY RESPONSIVE, WE WANTED
TO NULLIFY TWO REMAINING CRY
TIERIA. THE SPIKING NEEDS
AVENUE TARS SPATIAL LOCATION AND
ALSO MUST DO THIS CONSISTENT LID
SO MUST BE RELIABLE.
SO WE CAN QUANTIFY WHETHER EACH
CELL CARRIES MORE INFORMATION
ABOUT SPACE THAN WE EXPECT A
CHANCE BY PERFORMING A MONTE
CARLO SIMULATION WE SHUFFLE EACH
NEURON SPIKE TRAIN WITHIN AND
BETWEEN TRIALS TO BUILD A CHANCE
DISTRIBUTION AND THEN WE TAKE
ONLY THOSE CELLS WHERE THE
INFORMATION OBSERVED IS HIGHER
THAN EXPECT BY CHANCE.
SO HERE IN THIS DISTRIBUTION OF
THE POPULATION IN ORANGE I'M
SHOWING YOU ONE OF THESE
INFORMATION METRICS FOR
SPATIALLY RESPONSIVE CELLS AND
IN BLUE YOU CAN SEE DISTRIBUTION
FOR CELLS THAT DIDN'T PASS
CRITERION.
TO ASSESS THE CELL STABILITY WE
CAN ASK WHETHER PAIRS OF TRIALS
ACROSS EACH RECORDING SESSION
WHERE CORRELATED FIRING RATES
THAN YOU WOULD EXPECT WHEN
COMPARED TO A SIMILARLY SHUFFLED
DISTRIBUTION.
SO NOW SHOWING YOU HERE IN
ORANGE AGAIN THE POPULATION THAT
SHOWED SIGNIFICANT RELIABILITY
IN ORANGE AND ONES IN BLUE THAT
DID NOT.
WE CAN LOOK AT BOTH MEASURES
ACROSS THE POPULATION AND TAKE
HOME MESSAGE WITH E SEE A WE SEE POPULATIO N
OF NEURONS RELIABLE AND
INFORMATIVE ABOUT SPATIAL
LOCATION.
WHILE LOCATION IS THOUGHT TO BE
PRIMARY ROLE OF THE HIPPOCAMPUS
GOING BACK TO THE WORK OF ROLLS
IN THE '90s PRIMATE STUDIES
HAVE SHOWN IT CAN BE INTERPRETED
IN TO GAZE LOCATION AND THIS
MIXED ENCODING IS UNDERSCORED BY
RECENT WORK IN RODENTS THAT
SHOWS THAT MULTIPLE
ENVIRONMENTAL FACTORS CONTRIBUTE
TO THE POPULATION RESPONSES.
BUT HERE WE ALSO TESTED THE
EXTENT TO WHICH RESPONSES ARE
SENSITIVE TO GAZE LOCATION.
WE USE EYE TRACKING TO
RECONSTRUCT THE 3-D LOCATION OF
GAZE VIDEO ON THE LEFT SIDE WHAT
THIS LOOKS LIKE.
AT THE SAME TIME SHOWN HERE THE
ENVIRONMENT CONSISTS OF OBJECTS
SO TREES BUSHES BANANAs SO WE
CAN ALSO TEST WHETHER THE
RESPONSES COULD BE INTERPRETED
AS OBJECT SENSITIVITY.
ON THE RIGHT YOU CAN SEE TWO
EXAMPLES OF CELLS THAT SHOWED
GAZE CORRELATES, HIGHER FIRING
RATES WHEN MONKEY WAS LOOKING AT
A PARTICULAR OBJECT IN THE
ENVIRONMENT HOWEVER TAKEN AS
WHOLE THESE POPULATIONS WERE
MORE MINORITY WHAT WE OBSERVE
THROUGHOUT THE POPULATION.
SO THIS SLIDE SHOWS THE RATE
RESPONSES OF EACH OF O OUR
SPATIAL CELLS AND SO EACH ROW
REPRESENTS A DIFFERENT NEURONS
AND WHAT I HAVE DONE HERE IS
LINED THEM UP OR SORT BY
LOCATION OF PEAKIER FIRING AND
WE GET RESPONSES THAT ARE
SELECTIVE, CELLS THAT PASSED
CRITERION A COUPLE OF SLIDES AGO
AND THEY SPAN THE FULL RANGE OF
THE TASK OR AT LEAST IN THIS
SLIDE THE MAZE.
I'M SHOWING YOU THE LEFT WARD
ARM AND THE RIGHT WARD ARM WE
CAN LOOK AT METRIC HOW SIMILAR
EACH ARM IS TO ITSELF SO TO DO
THIS WE CAN COMPUTE THE
CORRELATION FOR THE POPULATION
VECTORS IN THE FIRST AND SECOND
HALF OF OUR RECORDING SESSION.
FOR EACH POINT AND SPACE.
BEFORE I SHOW YOU THE DATA I
GIVE YOU A SENSE WHAT IT MIGHT
LOOK LIKE.
SO YOU WILL RECALL ONE OF THE
REQUIREMENTS IN ORDER TO BE
INCLUDED IN THIS PLOT IS THAT
THE FIRST AND SECOND HALF OF THE
DATA MUST HAVE A SIGNIFICANT
CORRELATION.
SO WHAT THIS MEANS IS THAT WE
ARE GUARANTEED TO SEE THIS
YELLOW BAND INDICATING HIGH
CORRELATION DOWN DIAGONAL OF
CORRELATION DOWN THE MATRIX BUT
THE WIDTH TELLS US SOMETHING
IMPORTANT.
IF EACH LOCATION GETS A UNIQUE
REPRESENTATION THEN IN BAND WILL
BE NARROW.
BUT AS THE POPULATION RESPONSE
GETS LESS SPECIFIC THAN THIS
BAND GETS WIDER.
SO I DRAW YOUR ATTENTION TO
EXTREME CASE OF THIS.
IF ETHICS OF OUR TASK EACH HAVE
DISTINCT REPRESENTATION BUT
WITHIN ETHIC CODING IS
RELATIVELY NON-SPECIFIC, THEN WE
WOULD EXPECT TO SEE HIGH
CORRELATION ACROSS THE ENTIRETY
OF THE ETHIC.
SO HERE THEN SO H IS THE
CORRELATION BETWEEN THE LEFT ARM
AND ITSELF AND WHAT I HOPE YOU
IMMEDIATELY RECOGNIZE IS THAT
WHAT YOU SEE IMPOSED IS THE
STRUCTURE OF THE TASK REFLECTED
IN THIS CORRELATION MATRIX.
MEANING THAT THE POPULATION
REPRESENTATION IS BROADLY
SIMILAR WITHIN AN ARM BUT US
SIMILAR ACROSS ARMS.
AT ANOTHER WAY OF SAYING THIS IS
THAT -- SORRY.
ANOTHER WAY OF SAYING THIS IS
THAT EVEN THOUGH THERE'S NO
DISCONTINUITY IN SPACE BETWEEN
THE ARMS, ALL THAT HAPPENED WAS
THE MONKEY STOPPED TO TURN.
WE STILL SEE A DISCONTINUITY IN
NEURAL REPRESENTATION SO THIS
SUGGESTS IT IS THE STRUCTURE OF
THE TASK THAT'S SHAPING THIS
POPULATION LEVEL REPRESENTATION.
SO SPACE IS SEPARATED IN TO
THESE BEHAVIORALLY MEANINGFUL
CHUNKS.
WE ALSO IDENTIFIED VIRIONS THAT
RESPONDED TOKER FADESES OF THE
TASK SO APARTS FROM THE POSITION
IN THE MAZE, THESE INCLUDED
CELLS THAT RESPONDED TO THE
REWARDS, HERE ARE TWO EXAMPLE
CELLS SHOWN HERE.
THE DIFFERENT COLORS REPRESENT
THE LEFT WARD AND RIGHT WARD
GOING TRIALS.
CELLS THAT RESPONDED DURING THE
INNER TRIAL INTERVAL.
HERE IS TWO ADDITIONAL EXAMPLES
THAT SHOWED DISTINCT KINDS OF
RESPONSES BUT WITHIN THE INNER
TRIAL INTERVAL.
SO NOW IF WE LOOK AT THIS
POPULATION CORRELATION ACROSS
THE FULL RANGE OF THE TASK,
INCLUDING THE MAZE AS WELL AS
REWARD PERIOD AND THE INNER
TRIAL INTERVAL, IT IS CLEAR
AGAIN THAT THIS RESPONSE
POPULATION RESPONSE IS BEST
CHARACTERIZED AS EPIC LIKE SO
CHUNKING BEHAVIORALLY RELEVANT
PHASES OF THE TASK.
YOU CAN ALSO SEE IMPOSED A
HIERARCHICAL STRUCTURE WITHIN
THE DIFFERENT ASPECT OF THE
TASK.
BECAUSE WE ARE WORKING IN
VIRTUAL REALITY WE CAN ALSO
PRETTY EASILY EXAMINE THESE
RESPONSES IN VISUALLY DISTINCT
ENVIRONMENTS, WE TRAIN THE
MONKEYS IN ONE ENVIRONMENT LIKE
I SHOWED IN VIDEO, AND THEN
WITHIN A GIVEN RECORDING
SESSION, WE CAN EXAMINE NEURAL
RESPONSES IN THAT ORIGINAL
ENVIRONMENT AS WELL AS IN
DIFFERENT ENVIRONMENTS.
HERE IS SOME EXAMPLES OF WHAT WE
FOUND.
RESPONSES CAN BE CONTEXT
DEPENDENT.
JUST TO GIVE YOU A SENSE OF HOW
WE DID THESE RECORDINGS, WE
FIRST RECORD NEURAL ACTIVITY
WHILE MONKEY PERFORMED TASK IN
ONE ENVIRONMENT AND WE WOULD
MOVE THE MONKEY VIRTUALLY IN A
SECOND ENVIRONMENT AND MOVE THEM
BACK INTO THE ORIGINAL
ENVIRONMENT SO WE CAN COMPARE
THE ACTIVITY WHEN MONKEY WAS
RECORDING OR PERFORMING THE TASK
ACROSS TWO VERSIONS OF THAT
ORIGINAL SESSION WRITTEN FOR
THIS NEURON WE SEE IDENTICAL
RESPONSES ACROSS THE TWO BLOCKS
OF TRIALS IN ENVIRONMENT A.
WE SEE A DIFFERENT RESPONSE WHEN
THE MONKEY PERFORMED THE SAME
TASK WITHIN A DISTINCT
ENVIRONMENT.
THESE CONTEXT DEPENDENT NEURONS
REPRESENTED A SMALL MINORITY OF
OUR OVERALL RESPONSES, ABOUT 17%
OF THE NEURONS SHOWED THIS
CONTEXT DEPENDENT, REMAPPED IN
THE DIFFERENT ENVIRONMENTS.
WHILE THE VAST MAJORITY OF THE
NEURONS SHOWED CONTEXT THEY WERE
NOT CONTEXT DEPENDENT.
THEY SHOW THE SAME RESPONSE
ACROSS -- THE SLIDES WENT TOO
FAR.
THEY SHOWED THE SAME RESPONSE IN
EACH OF THE DIFFERENT
ENVIRONMENTS.
SO WE WILL GO TO AN INTERIM
SUMMARY HERE WHAT HE IS DATA
DEMONSTRATE IS THAT HAVING A
LITTLE TROUBLE WITH THE SLIDE
CHANGER HERE.
GO BACK.
SO WHAT THESE DATA SUGGEST IS
THAT -- WHAT THEY SHOW IS FIRST
MONKEY HIPPOCAMPAL CELLS DO SHOW
SPATIAL CORRELATES IN THIS
STRUCTURED TASK IN VIRTUAL
REALITY.
AND THAT THE RESPONSES APPEAR TO
BE BETTER TUNED TO ETHICS OF OUR
TASK THAN TO SPECIFIC SPATIAL
LOCATIONS.
WE ALSO FOUND NEURONS THAT
REPRESENT NON-SPATIAL TASK
EVENTS LIKE REWARD PERIOD AND
INNER TRIAL INTERVAL BUT OVERALL
RESPONSES ARE PREDOMINANTLY CON
INVARIANT SO THEY DON'T CHANGE
AS WE MOVE MONKEY TO DISTINCT
ENVIRONMENTS.
SO TOGETHER WE WOULD SUGGEST
THESE DATA INDICATE HIPPOEXAMPLE
NEURONS REPRESENT BEHAVIORALLY
RELEVANT FEATURES OF ONGOING
EXPERIENCES.
THIS STARTS TO UNCOVER MORE
ABOUT THE NATURE OF THE PRIMATE
COGNITIVE MAP THAT WHAT IT IS
INVOLVED IN IS CARVING
EXPERIENCE INTO BEHAVIORALLY
RELEVANT ETHICS.
INTERESTINGLY IN OUR TASK THESE
BEHAVE I DON'T RECALLLY RELEVANT
ETHICS ENCOMPASS TIME SO IT
TAKES THE MONKEY OVER TEN
SECONDS TO COMPLETE A SINGLE
KRILL MANY THE TASK.
SO WE WERE ALSO INTERESTED IN
WHETHER THERE WAS ANY STRUCTURE
TO THE NEURAL SIGNALS WHEN
LOOKING AT FINER TIME SCALE.
WE KNOW FROM RODENT STUDIES
HIPPOCAMPAL NEURONS INHIBIT
PRECISE TIMING RELATIVE TO
NETWORK THETA OSCILLATION SO IT
DEPICT AS RAT MOVING DOWN A
LINEAR TRACK, THE RED OVAL
REPRESENT IT IS PLACE FIELD FOR
SINGLE HIPPOCAMPAL NEURON,
HIPPOCAMPUS HAS A NETWORK RHYTHM
OBSERVED IN FIELD POTENTIAL WITH
HIGH AMPLITUDE OSCILLATIONS IN
THEE DA FREQUENCY SO 8 TO 12
HERTZ FOR RODENTS.
HIPPOCAL KIDNAP PAL NEURONS
OCCUR IN THE TRANCHE AND EARLIER
THEY FIRE EARLY PHASES OF THETA
AS THE RAT MOVES THROUGH THE
FIRING FIELD SO THIS IS CALLED
THETA PHASE PROCESSION.
WHEN YOU LOOK AT A POPULATION
VIRIONS RECORDED SIMULTANEOUSLY
EACH SHOWING THEIR OWN PHASE
PROCESSION YOU FIND WITHIN EACH
THETA CYCLE A SEQUENCE OF
NEURONS FIRING THAT REFLECT IT
IS CURRENT LOCATION ALONG WITH
THE PREVIOUS AND FUTURE
LOCATIONS IN THIS REALLY
BEAUTIFUL PRECISE SEQUENCE THAT
MOVES THROUGH AS YOU GO THROUGH
EACH THETA CYCLE.
I THINK DATA LIKE THESE REALLY
HIGHLIGHT THE IMPORTANCE OF THE
THETA BAND OSCILLATION FOR
STRUCTURING THE FINE TIMING OF
HIPPOCAMPAL TIFTED.
SO WHAT ABOUT THETA BAND
ACTIVITY IN PRIMATES, I WOULD
SAY AT LEAST IN OUR HANDS IT IS
COMPLETELY DIFFERENT FROM WHAT
HAS BEEN RECORDED IN RODENTS.
JOHN ROBINGMAN, RESEARCH
PROFESSOR AT UDUB AND ERIC
GARCIA, WORKED WITH ME ON THIS
ISSUE AND FUNDED THROUGH A BRAIN
GRANT.
ON THE LEFT YOU CAN SEE DATA
JOHN RECORDED FROM RAT
HIPPOCAMPUS A TRAINEE IN
HOWARD'S LAB, YOU CAN SEE DATA
FROM A MONKEY HIPPOCAMPUS
RECORDED IN MY LAB, I THINK IT
IS PRETTY EASY TO SEE THE
PRIMATES DON'T SHOW THE SAME
STABLE HIGH AMPLY THETA BAND
OSCILLATION DESCRIBED IN
RODENTS. HOWEVER WHEN WE LOOK
AT BEHAVIOR OF THE MONKEYS BACK
TWO DIMENSIONAL PREVIEWING
VISUAL EXPLORATION TASK WE FOUND
THE AYE MOVEMENTS THEMSELVES HAD
A RHYTHMIC, MONKEYS AND HUMANS,
WE MOVE OUR EYES AT A LOW THETA
FREQUENCY WITH FIXATIONS BETWEEN
IS A CADS LASTING ABOUT 200
MILLISECONDS SO THAT MEANS THE
EYES ARE MOVING AT A RATE OF 5
HERTZ, A DISTRIBUTION OF
FIXATION DURATION.
SO GIVEN THIS WE WONDERED IF
THERE WAS RELATIONSHIP BETWEEN
THIS RHYTHMIC BEHAVIOR OF
SENSING THE WORLD AND
OSCILLATIONS IN THE HIPPOCAMPAL
LOCAL FIELD POTENTIAL.
WHAT I'M SHOWING YOU HERE EACH
ROW OR EACH TRACE IS A DIFFERENT
-- RELATED TO A DIFFERENT EYE
MOVEMENT SO THE RED REPRESENTS
THE RAW LOCAL FIELD POTENTIAL
DATA RECORDED FROM HIPPOCAMPUS
AND THE BLUE IS THE SIGNAL
FILTERED IN THETA.
AND WHAT YOU CAN SEE DOTTED LINE
IS THE TIME OF THE EYE MOVEMENT,
PRIOR TO EYE MOVEMENT THERE WAS
NO IMMEDIATE TO BE ANY PHASE
RELATIONSHIP IN THE LOCAL FIELD
POTENTIAL.
BUT AFTER THE EYE MOVEMENT THERE
APPEARED A PHASE RESET SO NOW
THERE WAS STRONGER ALIGNMENT OF
THIS PHASE ACROSS TRIALS.
THIS RELATIONSHIP BETWEEN
HIPPOCAMPAL ACTIVITY AND THIS
ACTIVE SENSING BEHAVIOR HAVE
BEEN DESCRIBED BEFORE IN
RODENTS, THIS IS WHERE -- EARLY
WORK FROM -- HOWARD'S LAB AT THE
TOP, ARE WHERE PHASE LOBBING IS
QUESTION DEMONSTRATED BETWEEN
PHASE OF SNIFFING AND RHYTHMIC
ACTIVITY AND THE HIPPOCAMPUS.
AS WELL AS PHASE LOCKING BETWEEN
WHISKING BEHAVIOR AND THE
HIPPOCAMPUS.
THIS IS WORK FROM MATTHEW
DIAMOND'S LAB AND BOTH OF THESE
BEHAVIORS IN RODENTS SNIFFING
AND WHISKING OCCUR THETA
FREQUENCY AND IN OUR STUDIES
AGAIN WE FOUND THAT THERE WAS A
RELATIONSHIP BETWEEN EYE
MOVEMENTS AND THE HIPPOCAMPAL
RHYTHM IN THIS LOW DATA
FREQUENCY WITH A PHASE RESET OF
THE OSCILLATORY ACTIVITY AROUND
THE TIME OF THE EYE MOVEMENT.
THEN YOU SEE THE LOW FREQUENCY
ALIGNMENT IN LOTS OF STUDIES.
THESE -- WHAT I AM SHOWING YOU
HERE ARE TWO FIGURES FROM WORK
OF DAVID POPAL AND OTHERS
SHOWING THE SPEECH PATTERNS
FOLLOW A THETA BAND RHYTHM IN
TERMS OF MODULATION SPECTRUM
ACROSS A VARIETY OF LANGUAGES
AND ACROSS DIFFERENT FORMS OF
PRESENTATION.
THEN I WAS REALLY STRUCK -- FIST
THIS IS SHOWING DISTRIBUTION IN
MONKEYS ON THE LEFT AND HUMANS
ON THE RIGHT SHOWING WE MOVE OUR
EYES ABOUT THE SAME RATE WITH A
PEAK AROUND 200 MILLISECONDS FOR
EACH FIXATION.
AND I WAS REALLY STRUCK WHEN I
FOUND OUT ABOUT THIS CASE REPORT
OF 21-YEAR-OLD WOMAN, SHE WAS A
FEMALE UNDERGRADUATE AND AS A
RESULT OF APPARENTLY CONGENITAL
EXTRA OCULAR MUSS SKEW ALREADY
FIBROSIS WHICH RESULTED IN
PARALYSIS OF EYE MUSCLES SHE HAD
NO EYE MOVEMENTS SINCE BIRTH.
HOWEVER VISUAL PERCEPTION IS
SURPRISINGLY NORMAL AND SHE WAS
ABLE TO READ AT HIGH SPEEDS AND
IT TURNED OUT SHE USED MOVEMENTS
OF THE HEAD TO COMPENSATE FOR
THE ABSENCE OF EYE MOVEMENTS,
AND HER HEAD MOVEMENTS BETWEEN
DURING READING HAD A PSYCHOTIC
CHARACTER AND SHOWED THE SAME
FEATURES THAT CHARACTERIZE EYE
MOVEMENTS INCLUDING AS SHOWN
HERE MEDIAN DURATION OF ABOUT
200 MILLISECONDS.
SO AGAIN IN THE THETA RANGE.
SO ALONG WITH LOCAL FIELD
POTENTIALS THEN RECENT GRADUATE
STUDENT IN MY LAB HAD LOOKED AT
SINGLE UNIT RESPONSES TO EYE
MOVEMENTS.
AND THE IDEA WAS TO TRY TO
UNDERSTAND WHETHER THESE EYE
MOVEMENTS WERE ORGANIZING NOT
JUST LOCAL FIELD POTENTIAL BUT
SINGLE UNITS IN THE HIPPOCAMPUS.
WHAT SETH FOUND ALIGNING THE
FIRING OF INDIVIDUAL NEURONS TO
THE ONSET OF MONKEY FIXATION IN
INDIVIDUAL CELLS HE FOUND THEY
WOULD FIRE PREFERENTIALLY AT
FIXED INTERVALS AFTER FIXATION
ONSET SO LET ME UNPACK THESE TWO
FIGURES HERE.
THESE ARE TWO SEPARATE NEURONS,
EACH ROW ON THE TOP FIGURE
INDICATES DIFFERENT EYE MOVEMENT
SO THE GREEN DOTTED LINE
INDICATES THE START OF THE
FIXATION.
AND THE BLACK MARKS INDICATE THE
ACTION POTENTIAL SO YOU CAN SEE
THESE NEURONS FIRE AT PARTICULAR
TIME AFTER THAT EYE MOVEMENT.
THEN BECAUSE THIS IS IN FREE
VIEWING MON KISS WERE
FICTIONISTING FOR DIFFERENT
AMOUNTS OF -- MONKEYS WERE FIX
SATING, AND SORTED FROM BOTTOM
TO TOP DURING DURATION OF
FIXATION WITH THE SHORTER AT THE
BOTTOM AND THE LONGER FIXATIONS
AT THE TOP SO THE RED LINE
INDICATES THE END OF THAT
FIXATION.
SO THEN YOU CAN SEE THAT THE
RESPONSE OF THE NEURONS FIRING
AGAIN AFTER THE NEXT EYE
MOVEMENT.
SO WHAT THESE DATA SUGGEST IS
THAT EACH FIXATION REFLECTS THE
MONKEY SAMPLING ELEMENT OF
SCENE, VISITING A NEW PLACE AND
THIS VISUAL SAMPLING IS
REFLECTED IN THE FINE TIME SCALE
ACTIVITY IN THE HIPPOCAMPUS.
NOW, HERE ARE MOM EXAMPLES
SHOWING THAT THIS SACAD RELATED
ACTIVITY CAN BE DEPENDENT ON
LOCATION.
HERE ARE TWO NEURONS IN THE
HIPPOCAMPUS IN THE TOP AND THE
BOTTOM.
YOU CAN SEE THE TOP NEURONS
FIRED WHENEVER THE MONKEY WAS
LOOKING UP AT THE UPPER RIGHT
CORNER OF THE SCREEN.
YOU CAN SEE NEXT THE HEAT MAP OF
THAT RESPONSE AND THEN THE
RESPONSE OF THE NEURON WHENEVER
THE MONKEY IN RED WAS LOOKING
INTO THAT FIELD, THAT FIRING
FIELD YOU CAN SEE THE ROSTER
PLOT ON THE RIGHT.
WE LOOKED CAREFULLY AT MANY OF
THESE NEURONS THAT HAVE THESE
PLACE PREFERENCES WE NOTICE THE
LATENCY OF THE RESPONSE RELATIVE
TO START OF FIXATION COULD BE
VARIABLE ACROSS NEURONS.
SOME CELLS SHOWING -- SOME CELLS
RESPONDING RIGHT AFTER THE
FIXATION AND OTHERS SHOWING A
MUCH LONGER LATENCY.
SO ACROSS POPULATION OF NEURONS
WE FOUND THAT THE LATENCY IS
COMPLETELY TILED TIME OF
FIXATION OF 200 MILLISECONDS SO
EACH ROW REPRESENTS A DIFFERENT
NEURON AGAIN SORTED BY TIMING OF
THEIR RESPONSE.
AND YOU CAN SEE THAT WE GET
RESPONSES THAT FILL THE ENTIRE
TIME OF THE FIXATION.
SO IF WE THINK OF THE FIXATION
PERIOD AS IN SOME WAY ANALOGOUS
TO A THETA BAND OSCILLATION OR
PROVIDING A SIMILAR STRUCTURE
FOR THE NEURAL ACTIVITY, THESE
DATA SUGGEST NEURONAL SEQUENCES
MAY BE IDENTIFIED RELATIVE TO
THIS EYE MOVEMENT STRUCTURE.
WE ALSO FOUND THAT THESE SACAD
RELATED RESPONSES COULD BE
DEPENDENT ON OTHER FACTORS SO
THIS WAS WORK DONE BY YONI
BROWNING A GRADUATE STUDENT IN
THE LAB WITH JOHN ROBINGMAN
WHILE RECORDING MONKEYS SPATIAL
DELAYED ALTERNATION GAME THEY
REPORTED FROM THE SAME NEURONS
WHILE MONKEY WAS DOING A FREE
VIEWING TASK AND FOUND NEURONS
SHOWED THIS SACAD RELATED
ACTIVITY THAT MIGHT HAVE A
DIFFERENT LATENCY DEPENDING
WHICH TASK THE MONKEY WAS
PERFORMING.
THIS MODULATION CAN BE DEPENDENT
ON THE PRECISE ENVIRONMENT.
SO IT CAN SHOW A REMAPPING OF
THE ENVIRONMENT SO HERE IS
EXAMPLE NEURONS THAT SHOW
DIFFERENT RESPONSES IN TERMS OF
THIS FINE TIME SCALE SACADIC
ACTIVITY RELATIVE TO THE
DIFFERENT VISUAL ENVIRONMENTS.
AND SO JUST TO SUMMARIZE THIS --
THESE RESPONSES IN TERMS OF THE
MODULATION BY VISUAL SAMPLING,
WHAT THESE DATA SHOWED IS THAT
FIRST HIPPOCAMPAL NEURONS SHOW
FINE TIME SCALE EYE MOVEMENT
MODULATION SO THEY SHOW THIS
PRECISE FIRING RELATIVE TO THE
EYE MOVEMENT BUT THESE RESPONSES
CAN CHANGE ACROSS DIFFERENT
EXPERIMENTS.
THEY CAN DEPEND ON THE LOCATION
OF EYE MOVEMENT, SO WHERE THE
MONKEY IS LOOKING WITHIN THE
SCENE, THEY CAN DEPEND ON THE
TASK AND ON THE VIRTUAL
ENVIRONMENT.
SO THEY CAN HAVE DIFFERENT
RESPONSES WHEN THE MONKEY IS
PLAYING THE SAME GAME IN
DIFFERENT ENVIRONMENTS.
SO HOW DO WE MAKE SENSE OF THIS
FINE TIME SCALE ACTIVITY?
IN THINKING HOW THE EYE
MOVEMENTS MIGHT STRUCTURE THE
SEQUENTIAL NEURAL ACTIVITY WE
WERE STRONGLY MOTIVATED BY
RECENT REVIEW ARTICLE BY
(INDISCERNIBLE).
THE TOP GRAPH HERE, I WILL SHOW
YOU A FIGURE FROM REVIEW
ARTICLE, THE TOP GRAPH
DEMONSTRATES THE FIRING OF A
POPULATION OF HIPPOCAMPAL
NEURONS RELATIVE TO DISTANCE
ALONG THE LINEAR TRACK.
THIS FIGURE EACH ROW REPRESENTS
A DIFFERENT TRIAL, AND EACH
COLOR INDICATES A DIFFERENT
NEURON.
SO LOOKING AT THIS POPULATION,
YOU CAN CERTAINLY DECODE THE
DISTANCE THE RAT HAD MOVED DOWN
THE TRACK.
THEN IN THE SECOND GRAPH THE
DATA THE SAME DATA ARE PLOTTED
RELATIVE TO TIME IN THE TRIAL.
SO YOU CAN ALSO CERTAINLY USE
THESE DATA TO DECODE TIME THAT
HAD A LAPSE SINCE THE BEGINNING
OF TRIAL.
HOWEVER WHEN YOU PLOT THE DATA
RELATIVE TO THE THETA BAND
OSCILLATION A MUCH MORE PRECISE
PICTURE EMERGES SO HERE IT IS
CLEAR THESE NEURONS ARE FIRING
IN SEQUENCE AND THAT THE
SEQUENCE PROGRESSES THROUGH EACH
CYCLE OF THETA BAND OSCILLATION.
SO WE KNOW MOVEMENT IN RODENTS
PLAY AS STRONG ROLE STRUCTURING
HIPPOCAMPAL ACTIVITY SO THIS
THETA RHYTHM IS APPARENT
PREDOMINANTLY WHEN RATS ARE
PHYSICALLY MOVING OR ACTIVELY
SNIFFING OR WHISTING TO SAMPLE
ENVIRONMENT AND FROM OUR DATA IN
MONKEYS, EYE MOVEMENTS ARE
SIMILARLY STRUCTURE HIPPOCAMPAL
ACTIVITY SO I THINK A REALLY
INTERESTING QUESTION FOR FUTURE
STUDIES WOULD BE AN
INVESTIGATION OF THE CIRCUIT
THAT SUPPORTS THIS, YOU WILL
REMEMBER FROM A FEW SLIDES AGO
THE DATA THAT I SHOWED YOU FOR
THESE RESPONSES START SOMETIMES
EVEN BEFORE THE IF YOU
CANNIZATION SO MIDDLE OF THE
SACAT.
SO UNDERSTANDING THE SIGNALS THE
HIPPOCAMPUS IS GETTING AND AGAIN
THE CIRCUIT THAT MIGHT SUPPORT
THIS TIME SCALE RESPONSE.
HOW THIS CIRCUITRY IS IMPACTED
DURING LEARNING.
I THINK IT IS ALSO REALLY
INTERESTING QUESTION FOR FUTURE
STUDIES.
SO I WILL SUMMARIZE HERE SOME
CONCLUSIONS THEN ALSO HIGHLIGHT
SOME ADDITIONAL FUTURE
QUESTIONS.
THIS LAST PART I SHOWED THE
HIPPOCAMPAL NEURONS SHOW FINE
TIME SCALE PERISACATIC ACTIVITY
AND FROM THE EARLIER PART
HIPPOCAMPAL NEURONS REPRESENT
BEHAVIORALLY RELEVANT FEATURES
OF ONGOING EXPERIENCES.
AND I THINK FROM DECADES OF
STUDIES IN RODENTS WE HAVE
LEARNED A LOT ABOUT HIPPOCAMPUS.
MOST STUDIES HAVE STARTED WITH
FOUNDATION OF GUARANTEED PLACE
CELL RESPONSE THAT COULD BE
MODULATED OR EXPLORED UNDER
VARIETY OF CONDITIONS.
DATA I PRESENTED TODAY GAVE
HANDLE IN THE PRIMARY
HIPPOCAMPUS TO USE TO
INVESTIGATE OTHER INFLUENCES ON
HIPPOCAMPAL CODING AND I SAY
SOME LOW HANGING FRUIT
EXPERIMENTS THAT WE ARE EXCITED
TO START INCLUDE IMPACT OF
NOVELTY ON REPRESENTATIONS SO
WHAT HAPPENS TO THESE
REPRESENTATIONS WHEN WE PUT
MONKEY INTO DISTINCT ENVIRONMENT
FOR THE FIRST TIME ALSO LOOKING
AT LEARNING SO HOW DOES
BEHAVIORAL STRUCTURE OR THE
INTERNAL MAP OF EXPERIENCE
BECOME SOLIDIFIED AND HOW DOES
IT SUPPORT ADDITIONAL LEARNING
MAYBE MORE RAPID LEARNING IN THE
FUTURE.
ALSO WE WANT TO LOOK AT THE
INFLUENCE OF TIMING SO
STRETCHING OR COMPRESSING THIS
EXPERIENCE AND ALSO LOOKING FOR
MARKERS OF REPLAY DURING REST OR
SIGNIFICANT MOMENTS IN THE
EXPERIENCE THAT MIGHT SUPPORT
MEMORY CONSOLIDATION.
CRITICAL QUESTION WILL BE TO
UNDERSTAND HOW RESPONSES ARE
COORDINATED ACROSS TIME SCALES
TO FROM THE VERY FINE
PERISARKSCATIC RESPONSES TO THE
COURSE MORE BEHAVIORALLY ETHIC
RESPONSES.
IN CASE I DIDN'T MAKE IT CLEAR,
THE SAME NEURON CAN SHOW THIS
KIND OF TIMING, THESE TWO KINDS
OF TIMING RESPONSES CAN
PARTICIPATE BOTH IN THE
PERISACATIC TIMING AS WELL AS
BEHAVIORAL TIME SCALE TIMING SO
UNDERSTANDING HOW RESPONSES ARE
COORDINATED IS SOMETHING WE ARE
INTERESTED IN PURSUING.
SO I JUST WANT TO END WITH ONE
FINAL VIDEO.
TO MOTIVATE AGAIN WHERE WE WANT
TO GO IN THESE FUTURE
EXPERIMENTS.
I STARTED BY SETTING UP THIS
DICHOTOMY BETWEEN SPATIAL
RESPONSES AND EPISODIC MEMORY
AND ONE THING WE LIKE TO DO IS
USE THE VR TO PROKE MORE ABOUT
EPISODIC MEMORY.
SO I WANT TO SHOW YOU A VIDEO,
THIS SHOWS TIME WHEN MONKEY WAS
PLAYING OPEN FIELD FORAGING GAME
SO TRAINED ON COLLECTING BANANAS
FOR REWARD.
ONE OF THE LAB TECHNICIANS HAD
MADE A COMPLETELY NEW
ENVIRONMENT, PROGRAMMED THIS
REALLY INTRICATE NEW ENVIRONMENT
FOR THE MONKEY.
I WANT TO SHOW YOU HOW THEY
PERFORMED THE FIRST TIME HE WAS
IN THIS NEW ENVIRONMENT.
YOU CAN SEE THE WHITE DOT SHOWS
WHERE MONKEY WAS LOOKING, HE
STARTS OUTGOING FOR BANANAs.
THEN NOT TO ANTHROPOMORPHIC TOO
MUCH BUT HE REALIZED HE WAS IN A
NEW ENVIRONMENTS WHAT I CAN SAY
BEHAVIORALLY IS HE SHIFTED FROM
LOOKING FOR BANANAs TO
EXPLORING THIS NOVEL ENVIRONMENT
HE SPENDS TIME LOOKING AROUND
THEN DECIDES TO MOVE FORWARD TO
EXPLORE MORE.
AND THE MONKEY WAS READY TO GET
FOOD, SO WE WANT TO BE ABLE TO
GET LIEU THE WALL TO EXPLORE
MORE.
HOPEFULLY THIS IS STILL PLAYING.
SORRY WAS HAVING TROUBLE WITH
THE MOUSE THERE.
SO THIS IS STARTING OVER BUT THE
MONKEY REALLY IN THIS FIRST TIME
OF BEING IN THIS ENVIRONMENT THE
MONKEY SPENT ABOUT AN HOUR JUST
EXPLORING THE SCENE.
EVERY ONCE IN A WHILE HE
COLLECTS BANANAs AND GET
REWARD BUT REALLY WAS HIGHLY
MOTIVATED BY THIS NOVEL SCENE.
SO THESE ARE THINGS WE ARE
INTERESTED IN EXPLORING, THIS
BEHAVIOR AND I THINK THROUGH
CONTINUED SUPPORT FROM THE BRAIN
INITIATIVE IN TERMS OF TOOL
BUILDING, TO ENABLE INCREASINGLY
LARGE SCALE RECORDINGS, FROM
THESE STRUCTURE DEEP IN THE
BRAIN HARD TO GET TO, ALONG WITH
THE DEVELOPMENT OF NOVEL
ANALYSES AND COMPUTATIONAL
MODELING TOOLS, WE NEED A LOT OF
ANALYSES TO TRY TO GET AT THIS
EPISODIC MEMORY BEHAVIOR.
BUT WE ARE GETTING CLOSER TO THE
POSSIBILITY OF BEING ABLE TO
UNDERSTAND THE NEURAL MECHANISMS
THAT MIGHT SUPPORT COMPLEX
NATURALISTIC BEHAVIORS LIKE
THESE.
I WANT TO END THERE BY
ACKNOWLEDGING THIS INCREDIBLE
TEAM WHO REALLY PERFORMED ALL
THE WORK THAT I HAVE THE HON
MORE TO SHOW YOU TODAY.
HIGHLIGHTED MANY INDIVIDUALS
DURING THE TALK BUT I WANT TO
POINT OUT AGAIN THOSE WHO ARE
WORKING ON THE VIRTUAL REALITY
NOW, INCLUDING JOHN ROBINGMAN
AND YONI BROWNING A RECENT GRAD
STUDENT IN THE LAB, SETH WHO
START WITH EYE MOVEMENTS,
NICHOLAS DID THE ATTENTION AND
NATHAN DID THE EARLY WORK WITH
LOOKING AT THE GRID CELLS.
I ALSO WANT TO HIGHLIGHT OUR
INCREDIBLE LACK TECHNICIANS
MEGHAN AND AJ IAN AND BRIAN WHO
REALLY -- AND NATALIE AND ELLA
WHO PLAY A SIGNIFICANT ROLE
CARING FOR THE ANIMALS AND
REALLY MOVING THIS WORK FORWARD.
MY LAST ACKNOWLEDGMENT SLIDE, I
WANT TO THANK THIS INCREDIBLE
TEAM, THIS IS THE TEAM THAT
MAKES UP OUR U 19 GROUP FUND
THROUGH THE BRAIN INITIATIVE.
THEY ARE SCATTERED THROUGHOUT
MANY DIFFERENT UNIVERSITIES, AND
BUT WE HAVE HAD A GREAT TIME
GETTING TOGETHER, WE WERE ABLE
TO SUCCESSFULLY SWITCH TO ZOOM
AND KEEP THINGS GOING DURING THE
PANDEMIC AND REALLY THIS GROUP
HAS INFORMED A LOT OF OUR
THINKING AND PLAYED A BIG ROLE
IN A LOT OF THESE EXPERIMENTS.
SO THANK YOU TO THEM.
AND TO OUR FUNDING SOURCES.
I'M HAPPY TO TAKE QUESTIONS.
>> THANKS SO MUCH ELIZABETH.
THAT WAS AMAZINGLY INTERESTING I
HI IT IS PERTINENT TO OUR
EXPERIENCES ON ZOOM THE LAST TWO
YEARS.
FIXATING THE VIRTUAL ENVIRONMENT
LIKE MONKEY SAYS.
FOR THE FIRST QUESTION, IS A
LITTLE BIT RELATED TO THAT, THE
QUESTION IS YOUR MONKEYS IN THE
VIRTUAL REALITY ENVIRONMENT HAVE
SIGNALS WERE SO POTENT THEY
DON'T ACTUALLY MOVE, WHAT DO YOU
THINK THEY HAVE MOREAU DENT LIKE
THETA IF THEY WERE FREELY
MOVING?
>> THAT IS AN EXCELLENT
QUESTION.
WILL IS A GROUP OF RESEARCHERS
WHO ARE WORKING NOW RECORDING IN
THE HIPPOCAMPUS AND SOME OF THEM
HAVE NOW LOOKED AT ACTIVITY IN
MONKEYS ACTUALLY MOVING AROUND
IN REAL SPACE.
PREDOMINANTLY I WOULD SAY ADORA
WITH (INDISCERNIBLE) HAVE PAPER
OUT RECENTLY LOOKING AT THAT.
SO THEY RECORDED MANY MONKEYS
THAT WERE DOING THE OPEN FIELD
FORAGING I WOULD SAY, IN AN OPEN
MAZE AND WHAT IS INTERESTING IS
IN THAT ENVIRONMENT THEY DIDN'T
FIND A LOT OF CLEAR PLACE CELLS,
THEY FOUND HEAD DIRECTION CELLS,
SORT OF TURNING CELLS, STRONGER
RESPONSES BUT NOT A LOT OF PLACE
CELLS WITH THE REAL PHYSICAL
MOVEMENT.
CAROL BARNES IS ALSO DONE THIS
WORK LOOKING AT RECORDING FROM
FREELY MOVING MONKEYS AND KAREN
OFMAN SO THERE IS RESEARCHERS
WORKING ON THAT BUT I THINK EVEN
WITH THE ACTUAL VESTIBULAR
INFORMATION THAT YOU GET IN
THOSE EXPERIMENTS THAT NOT
ENOUGH TO DRIVE THESE PLACE
CELLS.
I THINK WHAT IS CONSISTENT
ACROSS THOSE STUDIES AND OUR
STUDY AND ALSO INCLUDING SYLVIA
WORTH AND MARTYNA, A LOT OF
RESEARCHERS HAVE DONE GREAT WORK
ON THIS SHOWING WHAT SEEMS TO BE
IMPORTANT IS BEHAVIORAL TASK THE
MONKEY IS PERFORMING AND THESE
RESPONSES ARE RELATING TO THE
STRUCTURE OF EXPERIENCE THE
ANIMAL HAS.
>> NEXT ONE IS KIND OF GETTING
-- TEASING OUT ACTUAL SACAD
VERSUS CONTEXT, HAVE YOU EVER
TRIED TO INTEGRATE SAC AD OR
CREATE THEM TO SEE HOW THIS
ALTERS PHYSIOLOGY AND
OSCILLATORY VOLATILE
ENVIRONMENT?
THERE IS A FUNCTION OF SACAD OR
SOMETHING ELSE RELATED TO --
>> YEAH THAT IS A GOOD QUESTION.
THIS IS WORK THAT I DIDN'T GET
TO INCLUDE IN THE PRESENTATION
TODAY BUT SETH DID SO WHILE HE
RECORDED FROM MONKEYS DOING THE
FREE VIEWING VISUAL EXPLORE RACE
TASK HE ALSO RECORDED FROM THE
SAME NEURONS WHILE MONKEYS WERE
PERFORMING DIRECTED SACAD TASK
SO THE IDEA OF ARTIFICIALLY
PRODUCING A SACAD OR ASKING THE
MONKEY TO MAKE A SACAD TO A
PARTICULAR LOCATION TO A
STIMULUS.
AND WHAT HE FOUND WAS THAT FOR
MANY CELLS THEY SHOWED THIS
PERISACADIC ACTIVITY BUT IT WAS
MODULATED BASED ON WHAT MONKEY
WAS DOING.
SO SOME NEURONS SHOWED THIS
ACTIVITY ONLY IN THE FREE
VIEWING CASE.
EVEN WHEN MONKEY WAS LOOKING AT
THE SAME LOCATION ON THE SCREEN
IN THE DIRECTED SACAD TASK.
AND FOR OTHER NEURONS THEY MIGHT
SHOW THAT SAME RESPONSE BUT IT
WAS MODULATED BASED ON WHAT TASK
THE MONKEY WAS PERFORMING.
IT DOES APPEAR RELATED TO SOME
ASPECT OF COGNITION APART FROM
JUST THE EYE MOVEMENT.
>> A LITTLE QUESTION IN THERE
SOMEWHAT RELATED, I MAY BE OFF
BASE BUT GUESSING THAT ALL
SACADES ARE NOT EQUAL IN TERMS
OF CONTEXT AND SO SOME OF THE
SACAD MAY GO TO FEATURES THAT
ARE MORE SALIENT, WHAT THE TASK
IS THAN OTHERS.
SO WONDERING IS THAT SOMETHING
YOU CAN EVER PARSE OUT FROM THE
DATA THAT YOU HAVE?
>> THAT IS A GOOD QUESTION.
ONE THING -- I THINK WE COULD,
WE HAVEN'T LOOKED AT THAT
CAREFULLY SO I KNOW IN SOME WORK
THAT YONI BROWNING IS LOOKING
AT, THE GRAD WATT STUDENT
WORKING ON THE VR TASK HE
IDENTIFIED THERE WERE TIMES WHEN
THE MONKEY WAS LOOKING AT THE
GAME AND WHENEVER THE MONKEY
LOOKED OFF THE SCREEN HE OFTEN
WOULD LOOK DOWN AT HIS HANDS AND
LOOK AT THE JOY STICK.
HE FOUND DIFFERENT KIND OF
SACADIT RESPONSES WHEN MONKEY
WAS WITHIN THE GAME VERSUS
LOOKING DOWN AT THE JOY STICK.
HE ALSO STARTED SOME PRELIMINARY
ANALYSES LOOKING AT THE EYE
MOVEMENTS WHEN THE MONKEY IS
PLACED IN A ANY ENVIRONMENT FOR
THE FIRST TIME IN THE VR GAME.
WE HAVEN'T FINISHED ANALYSES,
THERE ARE THINGS TO PULL OUT
WHETHER THE EYE MOVEMENTS
THROUGH LEARNING BECOME MORE
STEREOTYPED AROUND BEHAVIORALLY
SALIENT PARTS OF THE
ENVIRONMENT.
THEN ALSO LOOKING AT THE
HIPPOCAMPAL RESPONSES RELATIVE
TO THOSE EYE MOVEMENTS.
>> THANKS VERY MUCH, ELIZABETH.
SO THE NEXT ONE I GUESS IS MAYBE
A SUGGESTION WITH A QUESTION.
CLEARLY THAT THE GREAT BENEFIT
OF SETTING THE PRIMATES IS IT IS
CLOSER TO HUMANS, THE QUESTION
IS, WHY COULDN'T YOU OR WITH
NEUROSURGEON DO SAME EXPERIMENTS
IN HUMANS?
VIRTUAL REALITY.
(OVERLAPPING SPEAKERS)
>> THAT IS A REALLY GREAT
QUESTION.
SO I ACKNOWLEDGED OUR EWE U 19
TEAM AT THE END AND THE WORK
FROM THIS GROUP IS REALLY
FOCUSED ON TRYING TO MAKE THESE
DIRECT COMPARISONS.
SO WE HAVE A RANGE OF DIFFERENT
BEHAVIORAL TASKS THAT WE USED
FOR THE FIRST ROUND OF OUR U 19
BUT WHERE WE WERE ABLE TO TRAIN
MONKEYS TO PERFORM THE SAME TASK
WE WERE TESTING IN HUMAN
EPILEPSY PATIENTS, WHO HAVE
ELECTRODES IMPLANTED IN THE
MEDIAL TEMPORAL LOBE INCLUDING
THE HIPPOCAMPUS A AS WELL AS
SOME PARTS OF PREFRONTAL CORTEX.
SO THIS IS WORK WITH BOB KNIGHT
AND JACQUELINE AND OTHERS WHERE
WE GET AT THAT -- WHAT WE ARE
PLANNING IN THE NEXT PHASE
HOPEFULLY OF THE U 19 IS TO BE
ABLE TO INCORPORATE EYE
TRACKING.
SO THAT WE CAN LOOK AT THESE
SAME RESPONSES NOW IN HUMANS
SINGLE UNITS.
SO THAT IS DEFINITELY WHERE WE
ARE MOVING.
>> NEXT ONE IS GETTING TO THE
CORTEX.
SO THE QUESTION IS HOW SHOULD WE
THINK ABOUT EYE MOVEMENT RELATED
HIPPOCAMPAL ACTIVATIONS IN
RELATION TO THE CODING OF VISUAL
SPACE IN THE VISUAL CORTEX, HOW
IS THAT INFLAMMATION FLOW IS
THERE BLOW BACK?
>> THIS SOMETHING WE ARE
INTERESTED IN, I MENTION LOOKING
AT THE CIRCUITRY OF THESE --
THIS EYE MOVEMENT RESPONSE.
ONE THING THAT IS DIFFERENT
ABOUT WHAT WE SEE IN HIPPOCAMPUS
IS THAT EVEN THOUGH WE SEE
SPATIAL REPRESENTATION ALREADY
RELATIVE TO WHERE THE EYE IS.
SO THEY ARE NOT RETINA TOPIC SO
THAT IS REALLY DIFFERENT FROM
WHAT YOU WOULD SEE IN EARLY
VISUAL CORTEX.
THAT BEING SAID WE SEE IN THE
INTERNAL CORTEX THESE SACAD
RELATED RESPONSES THAT ARE
SELECTIVE FOR THE TRAJECTORY OF
THE SACAD.
WHICH SEEMS MORE SIMILAR TO
RESPONSES THAT YOU MIGHT SEE IN
THIS FOLIC ALSO OR FUNNEL EYE
FIELDS.
NOT TOO FAR OFF FIELD BUT
THERE'S INTERESTING NEW RESULTS
SUGGESTING IN SUPERIOR
COLLICULUS, YOU SEE NOT ONLY
MOTOR EYE MOVEMENT RESPONSES BUT
YOU ALSO SEE RESPONSES THAT ARE
MODULATED BY COGNITION THAT CAN
SHOW DIFFERENCES BASED ON
LEARNING OR EXPERIENCE OF THE
ANIMAL AND SO THIS IS ANOTHER
LINE WE ARE EXCITED TO PURSUE,
WITH OUR U 19 TEAM, TRYING TO
UNDERSTAND THE CIRCUIT OF THIS
AND WHY WE WOULD SEE THESE MOTOR
TYPE RESPONSES SACAD RELATED
RESPONSES IN HIGHER ORDER
COGNITIVE AREA HIPPOCAMPUS AND
SEE THESE COGNITIVE TYPE
RESPONSES IN WHAT HAVE BEEN
CONSIDERED EYE MOVEMENT AREAS
LIKE THE SUPERIOR COLLICULUS.
>> THANKS, ELIZABETH.
NEXT QUESTION IS TECHNICAL
QUESTION THAT I DON'T QUITE HAVE
IN MY HEAD STRAIGHT BUT MAYBE
YOU UNDERSTAND THE QUESTION IS
IN THE Y MAZE WHAT WOULD YOU
EXPECT TO CHANGE THE RULES OF
THE TASK BUT NOTHING ELSE SUCH
AS SWITCHING BETWEEN ARMS AFTER
EACH TRIAL THE USUAL YES TASK
VERSUS SWITCHING AFTER EVERY TWO
TRIALS.
>> I THINK SO, WHAT WE HAVE
SHOWN WAS FOR MOST CELLS THERE
WASN'T A LOT OF CONTEXT
DEPENDENCE SO IF WE MOVE THE
MONKEY TO VISUALLY DISTINCT
ENVIRONMENT, THE NEURONS AS A
POPULATION SHOWED THE SAME
RESPONSE IN TERMS OF RESPONDING
AT PARTICULAR BEHAVIORAL ETHICS
OF TASK EVEN THOUGH IT WAS A
TOTALLY DIFFERENT ENVIRONMENT.
SO I THINK IT IS A REALLY GOOD
QUESTION SO WHAT WOULD HAPPEN IF
WE KEPT THE VISUAL PART OF THE
ENVIRONMENT THE SAME, BUT CHANGE
RULES OF THE GAME.
FOR THAT MY GUESS IS THAT WE
WOULD SEE THE POPULATION WOULD
CHANGE, THE RESPONSES WOULD
CHANGE BASED ON THE TASK.
IT WOULD BE INTERESTING TO TRAIN
MONKEYS TO DO THIS IN BLOCK TO
DO ONE RULE THEN NEXT RULE THEN
BACK TO FIRST RULE, MY GUESS IS
WE SEE A CHANGE IN THE REMAPPING
BASED ON COGNITIVE ASPECT OF THE
TASK.
WHILE KEEPING SPACE ENTIRELY THE
SAME.
REALLY GOOD QUESTION.
>> NEXT ONE MAYBE SIMILAR IS
THERE EVIDENCE DYNAMIC REMAPPING
IN THE PRIMATES AS THEY TRAVERSE
THE SAME PATH AS OCCURS IN THE
RODENT?
>> ONE THING IS WE HAVE LOOKED A
LITTLE BIT AT POTENTIAL WHAT ARE
CALLED SPLITTER CELLS SO THIS IS
THE WORK BY EMMA WOOD, WITH
HOWARD IKENBALM, THEY INITIALLY
SHOWED THIS WHEN THE RAT IS
GOING DOWN A CENTER STEM IT IS
GOING TO HAVE A DIFFERENT
RESPONSE WHEN GETTING READY TO
TURN LEFT VERSUS GETTING READY
TO TURN RIGHT.
WE DO FIND SOME EVIDENCE FOR
THAT, IT IS JUST NOT A LARGE
PERCENTAGE OF OUR POPULATION.
>> NOW WE ARE GOING BACK TO THE
LOCOMOTION STORY AGAIN.
BEAUTIFUL WORK PRESUMABLY ONE
COULD MAP OUT CELLS IF MONKEY
PHYSICALLY NAVIGATE THE
ENVIRONMENT, THROUGH AN
EXPERIMENT YOU EXPECT CELLS TO
MAP ON TO THE PATTERN FOUND WHEN
THE MONKEY OBSERVES A SPACE
THROUGH ITS SACAD?
THE MAPPING WITH LOCOMOTION AND
MAPPING WITH VIRTUAL
ENVIRONMENT.
YOU THINK YOU COULD PUT THEM IN
THE SAME EXPERIMENT SEE SAME
MAP, WOULD IT BE DIFFERENT?
>> GOOD QUESTION.
FOR THE -- IT IS HARD TO SAY, I
GUESS IN TERMS OF WHAT THE --
WHAT ED WOULD MEAN FOR THE MAT
TO BE THE SAME IN THE 2D CASE
COMPARED TO THE 3-D ENVIRONMENT,
WHAT YOU WOULD EXPECT IS IT
WOULD HAVE THE SAME SPACING
AMONG THE FIELDS OF THE GRID
CELL.
WHAT WE FIND -- WE HAVEN'T YET
RECORDED THE CORTEX OR HAVEN'T
LOOKED CAREFULLY AT THE DATA SO
IT WOULD BE INTERESTING TO SEE
WHAT WE FIND.
FOR THE HIPPOCAMPUS I CAN TELL
YOU THAT WHEN WE AGAIN LOOK AT
THE SAME NEURONS RECORDED IN THE
VIRTUAL ENVIRONMENT VERSUS 2D
SPACE, WE SEE DIFFERENT KINDS OF
RESPONSES, SOME EXAMPLES THAT I
SHOWED TODAY, EVEN PERISACATIC
RESPONSES WERE DIFFERENT.
MY GUESS IS WE LIKELY SEE
SOMETHING DIFFERENT FOR THE
ENTERONNAL, BUT WOULD BE A GOOD
EXPERIMENT TO DO.
>> THAT WAS FANTASTIC.
WE APPRECIATE YOUR TAKING THE
QUESTION GOT GRILLED TODAY.
ALL GOOD QUESTIONS AND GREAT
TALK.
GREAT WAY TO END THE FIRST DAY
OF THE BRAIN INITIATIVE MEETING.
SO THANKS EVERYONE FOR
ATTENDING.
THANK YOU ELIZABETH SO MUCH.
HAVE A GOOD EVENING NOW.