GOOD AFTERNOON.
WELCOME TO THE WEDNESDAY
AFTERNOON LECTURE SERIES.
I'M MARGUERITE MATHEWS A PROGRAM
DIRECTOR AT THE NATIONAL
INSTITUTE OF NEUROLOGICAL
DISORDERS AND STROKE.
ON BEHALF OF NINDS AND OUR
SIBLING NEUROSCIENCE INSTITUTES
I'M THRILLED TO INTRODUCE
TODAY'S WALS SPEAKER, DR. KAFUI
DZIRASA WHO PIONEERED RESEARCH
AT THE INTERSECTION OF
NEUROSCIENCE PSYCHIATRY AND
NORTHEASTE
ENGINEERING.
BEFORE I GET INTO HIS RESUME THE
FIRST IS THE CODE FOR CONTINUING
EDUCATION CREDITS 57693.
I'LL REPEAT THAT.
57693.
FOR THOSE WATCHING REMOTELY, YOU
CAN SUBMIT QUESTIONS TO THE
SPEAKER ANYTIME DURING THE
LECTURE.
SIMPLY CLICK ON THE BUTTON THAT
SAYS SEND LIVE FEEDBACK BELOW
THE VIDEOCAST WINDOW.
TYPE YOUR MESSAGE AND WE'LL
RELAY IT TO THE SPEAKER AT THE
END.
KAF IS A MARIE WASHINGTON
PRESIDEN
PRESIDENTIAL DISTINGUISHED
PROFESSOR AT DUKE UNIVERSITY
SCHOOL OF MEDICINE AND HE HAS
OTHER TITLES AT DUKE.
THESE INCLUDE PROFESSOR OF
PSYCHIATRY AND PROFESSIONAL
SCIENCES AND PROFESSOR OF
NEUROSURGERY AND NEUROBIOLOGY
AND ASSISTANT PROFESSOR OF
MICROENGINEERING AND THE
PROFESSOR IN THE DUKE INSTITUTE
FOR BRAIN SCIENCES.
DANG, YOU'RE SIGNATURE MUST BE
LONG.
AT HIS CORE HE'S A NEURO
BIOLOGIST AND PSYCHOLOGIST
UNCODING DISEASE IN BRAIN AND
THE ESSENCE IS HOW
NEUROPSYCHIATRIC RISK GENES
MODIFY STRESS THAT UNDER LIE
NORMAL AND COGNITIVE FUNCTION.
HIS LAB USING ELECTROPHYSIOLOGY
AND OPTOGENETICS AND
QUANTITATIVE ANALYSIS OF
BEHAVIOR AND GENETICALLY
MODIFIED MICE.
THEY WERE THE FIRST TO IDENTIFY
PATTERNS OF ELECTRICAL ACTIVITY
ACROSS MULTIPLE BRAIN REGIONS
KNOWN AS BRAIN REGION OS LATORY
DESIGN DYNAMICS TO IMPROVE THE
UNDERSTANDING OF MOOD DISORDERS.
KAF EARNED A BS FROM UNIVERSITY
OF MARYLAND UP THE ROAD AND
PROFESSORED HIS Ph.D. IN NEU
NEUROBIOLOGY AND KAF ALSO
COMPLETED A PSYCHIATRY RESIDENCY
AND POSTDOCTORAL TRAINING AT
DUKE.
BEYOND HIS RESEARCH AND TRAINING
ACHIEVE CANMEN MENT -- ACHIEVEMS
HE RECEIVED NUMEROUS HONORS
INCLUDING THE NIH NEUROPIONEER
AWARD IN 2022 AND ELECTED TO THE
NATIONAL ACADEMY OF MEDICINE IN
2021.
HE'S A PASSIONATE ADVOCATE.
THE TITLE OF HIS LECTURE IS
TOWARDS PREVENTATIVE PSYCHO
THERAPEUTICS.
PLEASE WELCOME, KAF.
>> IT'S A REAL HONOR AND
PLEASURE.
I CALL HIS MY SECOND HOME AND
SPENT TIME AS A MEDICAL STUDENT
AND HAVE BEEN MULTIPLE TIMES
SINCE WITH FRIENDS AND
COLLEAGUES ACROSS THE
INSTITUTION.
I'LL GIVE A TALK TODAY ABOUT A
PROBLEM THAT I'VE BEEN TRYING TO
SOLVE FOR THE LAST 20 YEARS AND
WHEN MARGUERITE WAS GIVING MY
INTRODUCTION SHE MENTIONED THE
DIFFERENT DEPARTMENTS I WAS IN
AND ASSOCIATED WITH.
BECAUSE I REACHED INTO ALL THESE
DISCIPLINE TO TRY TO SOLVE THE
PROBLEM.
I HADN'T DONE THAT BECAUSE IT'S
BEEN FUN, BUT NECESSARY TO TRY
TO MAKE HEADWAY IN SOLVING THIS
PROBLEM.
THE TRAINEES HERE -- I ALWAYS
LIKE TO GIVE A DISCLAIMER FOR
TRAINEES WHICH IS YOU SHOULD NOT
GIVE A TALK LIKE THIS.
WE'RE GOING TO COURSE AND ZIP
THROUGH ALL KINDS OF
DISCIPLINES.
I'LL DO MY BEST TO ORIENT YOU IN
AND OUT OF THOSE SPACES BUT
TRYING TO SOLVE A PROBLEM THAT
TURNED OT -- OUT TO BE HARDER
THAN I THOUGHT IT WOULD.
THIS IS YEARS OF PRODUCTIVITY
LOSS WE EXPERIENCE FROM MENTAL
ILLNESS AND IN TERMS OF GLOBAL
LOSS OF PRODUCTIVITY, MENTAL
ILLNESS IS ON THE TOP OF THE
LIST.
I USED TO TAKE FOUR OR FIVE
SLIDES TO WALK PEOPLE THROUGH
THE TOPIC AFTER THE PANDEMIC WE
ALL APPRECIATE HOW DEEPLY
IMPACTFUL THESE ILLNESSES ARE
AND SEEING THEM IN FRIENDS AND
COLLEAGUES.
I WANTED TO SHOW THE DATA.
IT'S NOT JUST PANDEMIC.
THIS IS YOUTH.
YOU SEE THE SAME THING WITH
ANXIETY FEATURES.
THE INCIDENTS OF THE DISORDERS
HAVE BEEN GOING UP.
THEY WENT UP WITH THE PANDEMIC
BUT WERE INCREASING AS WELL.
SO A LITTLE BIT OF MY BACKGROUND
FOR THINKING HOW TO GET TRACTION
ON THE ILLNESSES.
I ALWAYS THOUGHT A REALLY GOOD
STARTING POINT WAS UNDERSTANDING
BIOLOGY AND THE GENETICS WITH
GOOD CLUES.
AS I WAS COMING UP IN MEDICAL
AND GRADUATE SCHOOL WE LAUNCHED
THE GWAS STUDIES THE GENOME WIDE
ASSOCIATED STUDIES.
THE IDEA WAS WE'D SEQUENCE THE
GENOME AND FIND HITS THAT GIVE
RISK FOR MENTAL ILLNESS AND FIND
THE GENE FOR DEPRESSION, THE
GENE FOR SCHIZOPHRENIA IN THE
SAME WAY WE FOUND THE GENE
PATHWAYS FOR CYSTIC FIBROSIS.
ONES WE FOUND THEM WE CAN FIX
THEM AND FIX ILLNESS.
IT TURNS OUT AS WE WERE DOING
THIS THE LANDSCAPE FOR
PSYCHIATRIC ILLNESSES WERE WAY
MORE COMPLEX.
THERE WERE LOTS OF RISK GENES
THAT COULD COME TOGETHER TO FORM
ILLNESS AND OVER TIME WHAT
HAPPENED WAS WE STARTED MAKE OUR
STUDIES LARGER AND LARGER AND
LARGER IN FINDING MORE AND MORE
AND MORE HITS.
SO AS A FIELD WE WANTED TO MAKE
SENSE OF THIS AND WHAT WE CAME
TO APPRECIATE OVER TIME WAS THAT
MANY OF THESE SORT OF BIOLOGICAL
RISK FACTORS SEEMS TO BE
CONVERGING ON A SPACE AT WHICH
BRAIN CELLS INTERACT CALL THE
SYNAPSE.
THE CONNECTIVITY SPACE BETWEEN
BRAIN CELLS.
I'LL SHOW AN IMAGE SUMMING UP
THE FINDINGS.
IN THE YELLOW COLOR AND RED
IDENTIFIED GENES AND PROTEINS
THAT INDICATE SCHIZOPHRENIA.
THE YELLOW AND AUTISM SPECTRUM
DISORDER AND DISABILITY THE HITS
WERE NOT JUST ONE ILLNESS THEY
WERE SHOWING UP ACROSS ILLNESSES
THAT IMPACT PSYCHIATRIC AND
EMOT
EMOTIONAL SPACES AND IT WAS MANY
PROTEINS AND THAT'S WHERE THE
IDEA FOR HOW WE COULD THINK OF
INTERVENING ON THESE CAME UP.
AS MARGUERITE MENTIONED I'M A
BIO MEDICAL ENGINEER.
SO I WONDERED IF WE COULD USE
TECHNOLOGY FOR A DISRUPTION IN
THIS COMMUNICATION PATHWAY
BECAUSE WE BASICALLY USED
TECHNOLOGY TO GO AROUND IT.
IF THE LANDLINE FOR YOUR
TELEPHONE IS MESSED UP CAN WE
CREATE A CELL PHONE THAT AROUND
THE DISRUPTION.
IMAGINE YOU HAVE TWO CELLS.
ON THE TOP WE SEE PRESYNAPTIC
CELLS.
THE POINTER WORKS.
YOU HAVE PRESYNAPTIC AND POST
SYNAPTIC CELLS.
IMAGINE HAVE YOU A BLOCKADE.
CAN YOU PASS IT TO THE POST
SYNAPTIC CELL.
THIS ISN'T A BIG GREAT GRAND
IDEA.
THIS IS WHAT I SAW IN THE
CLINIC.
THIS IS THE HEART AND IT HAS TO
BE SUPPLIED BY BLOOD AND THERE
CANNON CONDITIONS WHERE IT'S
BLOCKED AND BLOOD CAN'T GET TO
WHERE YOUR SENDING IT TO WHERE
YOU WANT TO RECEIVE ITS AND
THERE'S A TECHNIQUE CREATED WE
PROBABLY HEARD ABOUT THIS
CORONARY BIOPSY GRAPH AND YOU
PUT A BLOOD VESSEL IN FRONT OF
THE BLOCKADE AND ATTACH IT AND
IT CAN FLOW AROUND SO SIMPLE
CONCEPTUALLY.
WE HAD THE IDEA OF CREATING A
BIOPSY TO BIOPSY THE SYNAPSE.
WE USE A SET OF TOOLS AND HAD
PRESYNAPTIC POPULATION AND
IMPLANT ELECTRODE AND SAMPLE IT
UPSTREAM THEN FEED THE
INFORMATION IN THE COMPUTER AND
FIGURE OUT WHAT IT WAS SUPPOSED
TO BE SAYING AND THEN WE WOULD
PLAY THAT INFORMATION DOWN
STREAM AFTER THE SYNAPSE AND
WHEN WE PLAYED THAT INFORMATION
IN THE BRAIN WE'D USE A
TECHNIQUE CALLED OPTO GENETICS.
CONCEPTUALLY IT WORKS THE SAME
WAY AS THE EYE, CHANGING LIGHT
TO CHEMICAL NEITHER AND HERE A
CHANNEL OPENS UP AND CLOSES AND
LIGHT CREATES STIMULATION OF
STEM CELLS AND WE DO THIS IN
1/50th OF A SECOND AND A GRAD IN
MY LAB IS NOW APPLYING FOR A
FACULTY POSITION.
WE CAME UP WITH THE SCHEMATIC TO
CREATE THIS TECHNOLOGY.
SO RECORD INFORMATION FROM THE
BRAIN, PROCESS IT IN THE
COMPUTER AND FEED IT BACK IN
WITH HIGH FREQUENCY PULSES AND
THE CHANNELS OPEN UP WHEN YOU
STIMULATE WITH BLUE LIGHT AND
THA
AND WE WANTED TO PICK A PARADIGM
WHERE WE CAN TEST THIS
STIMULATION DEVICE AND MY LAB IS
REALLY INTERESTED IN STRESS
BIOLOGY SO WE WANTED TO PICK A
CONTEXT ASSOCIATED WITH STRESS
BEHAVIOR.
I ALWAYS THIS PICTURE UP AND
LIKE TO EXPLAIN IS.
THE MODEL IS NOT DEPRESSED
THERE'S ONLY TWO THINGS I NEED
TO ACCEPT.
SO WE CAN MOVE FORWARD IN HOW WE
THEN TEST OUT THE TECHNOLOGY.
THE FIRST THING MUST ONE ACCEPT
IS IF YOU DO THIS TO A MOUSE THE
STRESS HORMONES GO UP.
THE MOUSE'S BEHAVIOR IN THIS
ASSAY IS SENSITIVE TO HOW MUCH
STRESS IT'S PREVIOUSLY RECEIVED.
IF YOU STRESS IT OUT AND PUT IT
IN THE ASSAY THE ANIMAL WIGGLES
AROUND LESS.
SO THE ASSAY'S STRESSFUL AND
SENSITIVE TO THE ANIMAL'S PRIOR
STRESS.
SO WE TOOK ADVANTAGE OF THIS
ASSAY BY RUNNING IT TWO DAYS IN
A ROW.
AND THIS SECOND DAY IT HAD BEEN
EXPOSED ON THE FIRST DAY AND HOW
THE COMPUTATION OF BEHAVIOR
CHANGE IN THE SAME CONTEXT WITH
THE SAME CONTEXT BETWEEN DAY ONE
AND TWO BUT ON THE SECOND DAY
IT'S BEEN STRESSED ON THE
PREVIOUS DAY?
SO WHEN YOU LOOK AT ANIMAL'S
BEHAVIORALLY BETWEEN DAY ONE AND
TWO THEY'RE NOT ALL IDENTICAL.
B
BUT AS A POPULATION THEY SHOW
LESS MOBILITY AND THAT'S HOW
THEY ADAPT AND WE'LL LOOK FOR
WHICH SYNAPSE WE SHOULD TARGET
FOR THE INTERVENTION.
WE DID THIS BY IMPLANTING
ELECTRODES INTO THE BRAINS OF
MICE AND ONCE THEY RECOVER WE'RE
ABLE TO RECORD ELECTRICAL
ACTIVITY FROM MANY BRAIN REGIONS
AT THE SAME TIME.
IN THIS ASSAY WE'LL LOOK AT THE
DORSAL HIPPOCAMPUS AND PRELIMBIC
CORTEX AND OTHERS AND IT'S NOT A
FUNCTIONAL RESONANCE IMAGING,
THE WHOLE BRAIN, BUT THE SURVEY
OF LOTS OF BRAIN REGIONS
INVOLVED IN STRESS COMPUTATION
THEN ASK WHICH SHOW CHANGES
BETWEEN THE FIRST DAY AND THE
SECOND DAY.
SOW -- SO WHEN WE DO THAT ONLY
TWO SHOW CHANGES IN RECORDING.
THE MOUSE PREFRONTAL CORTEX AND
THE SECOND IS THE MEDIAL DORSAL
THALAMUS AND ONLY IDENTIFIED TWO
BRAIN AREAS CODING DIFFERENTLY
AND THE OTHERS WERE CODING FINE
BETWEEN ONE AND TWO AND ONE IN
GRAY, DAY TWO IN RED.
WE FOCUSSED ON THE
INTERCONNECTED BRAIN REGIONS FOR
THE REST OF OUR STUDY.
WE WANTED TO UNDERSTAND HOW THEY
WERE HAPPENING BETWEEN THE
AREAS.
WE SEARCHED THROUGH A BUNCH OF
WAYS THE BRAIN AREAS CAN
COMMUNICATE OR SIN ROW
SYNCHRONIZE AND FOUND THIS
UNIQUE PATTERN BETWEEN THE
CORTEX AND MEDIAL DORSAL
THALAMUS.
THE PATTERN WAS CALLED CROSS
FREQUENCY COUPLING.
AND SO YOU CAN THINK OF THINGS
BEING SYNCHRONIZED LIKE THIS,
LIKE THIS OR ACROSS FREQUENCIES
LIKE THIS.
SO WE TEST THE PATTERN AND FOUND
THIS THE BRAIN THE LOWER
FREQUENCY AND RED HIGHER
FREQUENCY AND THE AMPLITUDE
WAVES OF THE RED OSCILLATION
TEND TO HAPPEN AT THE PART OF
THE CYCLE OF THE GREEN
OSCILLATION.
THAT'S CALLED CROSS FREQUENCY
COUPLING.
HERE'S ANOTHER WAY OF LOOKING AT
THAT TYPE OF PLOT.
YOU CAN SEE ON THE Y AXIS WE
HAVE THE AMPLITUDE OF THE
OSCILLATION OF THE RED.
ON THE X AXIS WE HAVE THE PHASE
OF THE OSCILLATION OF THE BRAIN.
BLUE MEANS NO COUPLING AND RED
MEANS HIGH COUPLING.
WE SEE COUPLING BETWEEN THE TWO
BANDS OF FREQUENCYIES THE CORTE
IN 30s TO 60s AND THE MEDIAL
DORSAL CORTEX AND IT GETS
STRONGER ON THE SECOND DAY THEN
THE FIRST DAY.
AS AN ENGINEER WE HAD A
QUESTION.
WE THOUGHT THIS IS THE STRESS
CHANGE THAT MATTERS AND IF SO,
WE WANT TO FIGURE OUT HOW TO GET
RID OF THIS AND MAKE THE ANIMALS
MORE RESILIENT TO STRESSORS.
ON THE OTHER HAND, MAYBE THE
SIGNATURE IS COMPENSATORY AND
THIS IS WHAT WE HAVE TO THINK
ABOUT AS ENGINEERS.
IF I RUN UPSTAIRS MY HEART RUNS
FASTER BECAUSE IT'S A
COMPENSATION.
SO IF WE HAVE COMPENSATION WHAT
I DON'T WANT IS MY HEART TO NOT
BEAT FASTER BECAUSE I WON'T BE
ABLE TO RUN BECAUSE THE HEART IS
COMPENSATING TO KEEP MUSCLES
OXYGEN EI
OXYGENATED.
SO WHAT WE'LL DO IS TO FIGURE
OUT WE'LL PLAY THE SIGNATURE
BACK IN THE BRAIN.
WE'RE GOING TO READ INFORMATION
AND IF IT'S PRIMARY IT WILL MAKE
ME ANIMAL'S BEHAVIOR WORSE AND
IF COMPENSATORY IT WILL MAKE IT
BETTER.
YOU SEE THE DATA ON THE LEFT.
ANIMALS ON THE ASSAY, BLUE LIGHT
IS OUR EXPERIMENTAL GROUP,
YELLOW IS OUR CONTROL.
YOU CAN SEE THE BLUE GROUP IS
LESS IMMOBILE.
PLANTING A SIGNATURE IN THEIR
BRAIN REVERSED THE PHENOTYPE.
IN OTHER WORDS, IT'S A
COMPENSATORY SIGNATURE.
IT'S NOT PRIMARY.
SO BY PLAYING THIS COMPENSATORY
END WE INCREASE THE ANIMAL'S
REACHES TO AN EXTERNAL STRESSOR.
IN OTHER WORDS, STRENGTHENING
THE PATHWAY.
WE DID A SERIES OF CONTROLS
WHICH WE ALSO THOUGHT WERE
REALLY IMPORTANT AND THESE WERE
INSTRUCTIVE.
YOU CAN SEE ON THE RIGHT WE'RE
BASICALLY STIMULATING TIME TO
THE OSCILLATION IN THE CORTEX,
IN OTHER WORDS, WE'RE DOING OUR
BYPASS.
FOR THE FIRST CONTROL WE SAID
MAYBE IT'S BECAUSE WE'RE
STIMULATING THALAMUS.
LET'S TAKE THE SAME NUMBER OF
PULSES BUT STIMULATE IN THE SAME
WAY THAT ISN'T RESTORING THE
TIME IN THE CIRCUIT.
WE'LL RESTORE A NORMAL PATTERN
PEOPLE USE ALL THE TIME IN THE
ANIMAL RESEARCH LITERATURE, SAME
NUMBER OF LIGHT PULSES AND MADE
THE ANIMALS BEHAVIOR WORSE.
THE FIRST MADE IT BETTER, THE
SECOND MADE IT WORSE.
IT'S NOT JUST THE CELLS.
THEN WE THOUGHT MAYBE IT'S THE
BURST OF THREE THAT ARE
IMPORTANT.
SO WE STIMULATED WITH THE BURST
OF THREE AND GOT A PATTERN THAT
LOOKED LIKE THIS.
THE BEHAVIOR DIDN'T CHANGE AT
ALL.
WE THINK WHAT'S HAPPENING IS
IT'S AN ISSUE THAT ENGINEERS CAN
APPRECIATE CALLED SIGNAL TO
NOISE.
SO IN THE FIRST CASE, YOU TIME
THE SIGNAL CORRECTLY, YOU'VE
INCREASED THE SIGNAL.
IN THE SECOND CASE YOU TIME IT
INCORRECTLY YOU INCREASE THE
NOISE AND SOME PULSES ARE AT THE
RIGHT PHASE OF THE OSCILLATION
AND YOU INCREASE THE SIGNAL AND
THE NOISE AND NOTHING HAPPENS.
IF WE WANT TO THINK OF DOING THE
SYNAPTIC BYPASS WE NEED IT TO
READ AND PLAY THE INFORMATION
BACK IN WITH THE RIGHT TIMING.
SO SO, THIS WAS GOING TO BE THE
SOLUTION.
I SET OUT TO SOLVE A MAJOR
PROBLEM AND WE WERE EXCITED
BECAUSE WE FINISHED AND FIGURED
OUT THE SOLUTION TO THE MAJOR
PROBLEM THAT WE WERE TRYING TO
SOLVE.
AND I WAS SO EXCITED THAT I WENT
BACK TO MY HOME, HOME.
MY FAMILY IS FROM GHANA AND WEST
AFRICA AND MY MOTIVATION FOR
THIS WORK I DO, THE BOTTOM ROW
IS MY MOM AND HER SIBLINGS AND
FOUR OF FIVE CARRIES A MAJOR
PSYCHIATRIC DIAGNOSIS WHETHER A
BIPOLAR DISORDER OR DEPRESSION
OR PSYCHIATRIC DISORDER.
IT'S NOT CURIOSITY IT'S LOVE FOR
MY FAMILY MEMBERS AND WANTED TO
HEAL THEM AND HEAL THE NEXT
GENERATION OF MY FAMILY.
AND THE OPEN CHAIR, THERE'S MY
UNCLE WITH BIPOLAR DISORDER AND
THIS IS A PICTURE OF MY
GRANDMOTHER'S FUNERAL AND THE
STRESS CAUSED HIM TO BE UNABLE
TO COMPENSATE AND WASN'T ABLE TO
MAKE IT AND THE REST OF THE
CONVERSATION WILL BE FROM
TALKING TO HIM AND I SHOWED HIM
THE DESIGN AND EXPLAINING IT TO
HIM AND HE SAID THIS IS GOOD THE
FAMILY'S SO PROUD OF YOU AND
FEEL THE FAMILY ILLNESS REACHED
YOU AND YOU'RE DOING SOMETHING
GOOD FOR THE WORLD AND TELL ME
HOW YOU THINK THIS IS GOING TO
GETTING TO THE THIRD WORLD.
I NEVER THOUGHT OF WHAT I WAS
CREATING WOULD NEVER GOING TO
GET TO THE THIRD WORLD OR SCALE
AND WOULD ONLY REQUIRE
NEUROSURGEONS OF WHICH THERE'S
NOT ENOUGH AND THE GLOBAL
DISORDER OF SCHIZOPHRENIA AND
MENTAL ILLNESS SO LARGE UNLESS
IT'S SOMETHING THAT'S SCALABLE
IT WON'T GET TO THE ILLNESS AND
THE REMAINDER OF MY TALK WILL BE
ON HOW WE THINK OF MAKING THE
BYPASS DEVICE SCALABLE.
NOW I'VE RUN OUT OF ALL MY
ENGINEERING AND NEUROSCIENCE AND
HERE BECOMES OUR JOURNEY THROUGH
DIFFERENT FIELDS TO TRY TO SOLVE
THIS PROBLEM.
SO SO AT THE TIME I WRESTLED
WITH THE QUESTION OF WHAT IS
SCALABLE.
I WILL THOUGHT OF TWO THINGS
THAT SCALED.
THE FIRST IS ANTIBIOTICS AND THE
SECOND IS VACCINES.
IN PRINCIPLE WHAT ANTIBIOTICS DO
IS THEY TARGET THINGS THAT ARE
NOT SELF, TO MAKE SELF MORE
SUSTAINABLE OR RESILIENT IN AN
ENVIRONMENT AND I SAID WELL, OUR
ILLNESS IS OF SELF.
THAT CONCEPT WITH AN ANTIBIOTIC
DOESN'T MAKE SENSE.
ON THE OTHER HAND WHAT A VACCINE
DOES IS TARGET SELF TO MAKE SELF
MORE RESILIENT IN THE
ENVIRONMENT.
AND I LOVE THE CONCEPT OF
FIGURING OUT HOW TO MAKE SELF
MORE RESILIENT TO THINGS IN THE
ENVIRONMENT.
SO WE CAME UP WITH THIS CONCEPT
OF WELL, WHAT IF WE COULD MAKE A
VACCINE FOR MENTAL ILLNESS AND
SKETCHED THIS DOWN WHICH MADE NO
SENSE AT ALL AT THE TIME.
BUT I WAS INVITED TO JOIN THE
WORKING GROUP FOR THE BRAIN
INITIATIVE
THEY WERE IN THE SECOND HALF.
THE GOAL WAS TO UNDERSTAND THE
HUMAN BRAIN TO TREAT DISEASES
LIKE DEPRESSION AND BIOPSY
DISORDER A-- BIPOLAR DISORDER.
THERE WAS THE HUMAN CELL ATLAS.
THEY WOULD TAKE THE BRAIN AND
BILLIONS OF CELLS AND SEQUENCE
THEM AND FIND THE GENE
EXPRESSION SEQUENCE FOR EACH OF
THE BRAIN CELLS TO TARGET IT.
THESE ARE SORT OF THE SAME
PATTERNS WE USED TO TARGET BRAIN
CELLS IN MICE IN THE LAB.
YOU LEARN THESE ABOUT HUMANS.
THAT WAS THE FIRST TECHNOLOGY.
THE SECOND TECHNOLOGY THESE WERE
TECHNOLOGIES DONE BY MY
COLLEAGUE AND THERE ARE AAVs
WHICH CROSS THE BLOOD BRAIN
BARRIER AND YOU AND A SYSTEM
LIKE THIS WITH HUMAN BRAIN CELL
ATLAS AND YOU CAN DELIVER
PROTEINS TO SPECIFIC CELLS IN
THE BRAIN.
AND ONCE I LEARNED ABOUT THE
TRANSFORMATIVE TECHNOLOGIES THE
FIELD WAS WORKING ON CREATING, I
REALIZES THE PROBLEM I HAD TO
SOLVE WAS TAKE THE COMPUTERIZED
CLOSED-LOOP STIMULATION DEVICE
AND TURN IT INTO PROTEINS.
IF I CAN TURN IT INTO PROTEINS
WE CAN DELIVER IT TO BRAIN CELLS
PAIRS OF INTEREST.
THAT BECAME THE CHALLENGE WE
NEEDED TO SOLVE IN ORDER TO MOVE
THIS FORWARD.
IT TURNS OUT IT WASN'T FAR
FETCHED.
AS I SAID WENT TO MEDICAL SCHOOL
AND I SPENT A LOT OF TIME
THINKING ABOUT WAYS THAT BRAIN
CELLS AND OTHER CELL TYPES
TRANSFERRED INFORMATION FROM ONE
CELL TO ANOTHER.
ONE OF THE SYSTEMS USED TO
TRANSFER ELECTRICITY IN THE
HEART ARE WHAT WE CALL THROUGH
ELECTRICAL SYNAPSES AND THEY'RE
BASICALLY CHANNELS THAT CONNECT
TO BRAIN CELLS AND ALSO CALLED
GAP JUNCTIONS AND ALLOW IONS TO
FLOW FROM ONE CELL TO ANOTHER.
IT'S WHY YOUR HEART IS SO
SYNCHRONIZED THEY CAN MOVE
ELECTRICITY FROM ONE CELL TO
ANOTHER.
ABOUT WHAT IT'S DOING IS
TRANSFERRING ELECTRICAL IONS
FROM ONE TO ANOTHER AND THROUGH
CONNEXINS AND THEY COME TOGETHER
TO FORM A GAP JUNCTION.
THEY ARE EXPRESSED IN MOST HUMAN
TISSUES AND BECAUSE THE IONS CAN
MOVE BACK AND FORTH THEY'RE BYE
DIRECTIONAL AND SOME USED C.
ELEGANS AND YOU CAN PUT THESE
CONNEX INS IN SPECIFIC CELLS IN
A C. ELEGANS AND IT MOVED
ELECTRICAL ACTIVITY FROM ONE TO
THE NEXT AND CHANGED THE
BEHAVIOR.
YOU COULD BASICALLY REWIRE OR
CREATE A BYPASS IN C. ELEGANS.
AND THEY HAVE ONE CELL TYPE.
THAT'S NOT THE SAME WITH HUMANS.
IMAGINE WE WANTED TO DO THIS AND
THE GAP JUNCTIONS ARE PINK HERE
CONNECTING THE IONS TO FLOW TO
CREATE OUR BYPASS.
SAY THIS IS WHAT WE WERE TRYING
TO ACHIEVE.
THE FIRST PROBLEM YOU'D RUN INTO
BECAUSE WE HAVE MANY BRAIN CELL
TYPES OF EACH, YOU'D GET THE GAP
JUNCTIONS EXPRESSED THERE.
AS YOU HAVE THE SIGNAL UP STREAM
WAS SCRAMBLED BECAUSE IT GOES
SIDE WAYS INSTEAD OF UP AND
DOWN.
PROBLEM ONE.
THE GAP JUNCTION ARE CORES SO
ELECTRICITY CAN FLOW IN BOTH
DIRECTIONS AND GET SCRAMBLING
LIKE THIS LIKE WHEN YOU'RE
TRYING TO TALK TO SOMEBODY AND
THEY'RE YELLING AT YOU IS LIKE
WHAT YOU GET.
I LIKE TO GIVE THINGS A TRY AND
WHAT IF WE TRY THEM OUT AND PUT
THEM IN MICE AND SEE WHAT
HAPP
HAPPENS.
WE MADE THE GAP JUNCTIONS AND
PUT THEM IN AND WE INJECTED THEM
WITH TWO DOSES AND MEAN DOSE IN
THE MIDDLE AND FOUR AND FIVE
DAYS LATER THE ANIMALS STARTED
TO DIE.
MY GRADUATE STUDENT SAID THERE'S
NO PHENOTYPE.
I SAID THERE'S NO PHENOTYPE IN
THE WORLD WHEN YOU THINK OF
TRANSLATION.
THERE'S NOTHING MORE IMPORTANT
THAN THE ANIMALS DON'T SURVIVE.
IT'S A CLEAR PHENOTYPE.
THE HIPPOCAMPUS SEIZED AND DIED.
IT'S THE PROBLEM ON THE LEFT.
INFORMATION MOVING FORWARD,
BACKWARDS AND SIDE WAYS.
SO THEY HAD A CLEAR PHENOTYPE.
SO SO CONNEX INS STICK TOGETHER
AND LET INFORMATION FLOW.
I SAID WHAT IF CHANGE WHAT WE
WERE DOING CONCEPTUALLY AND
TURNED THEM INTO MAGNETS.
INSTEAD OF FUNCTIONING LIKE
STICKERS THEY'RE LIKE MAGNETS
AND THERE'S A GREEN CONNECTION
AND RIGHT CONNECTION.
IMAGINE ONE'S A POSITIVE END AND
ONE'S POSITIVE AND THE POSITIVE
THOUGH IT'S PRESYNAPTIC CELL
TYPES BUT THE POSITIVE AND
NEGATIVE CAN COME TOGETHER.
AND JUST FOR KICKS, WHAT IF WE
CAN MAGICALLY FLOW ONE DIRECTION
OVER ANOTHER?
THIS WAS CONCEPTUALLY WHAT WE
ADVISORY OF WERE TRYING TO
ACHIEVE.
I PULLED TOGETHER WHAT I LIKE TO
CALL MY DREAM TEAM.
I CALL THEM THAT BECAUSE IT'S A
GROUP OF UNDERUNDERGRADSS --
UNDERGRADS THAT HAD NO IDEA THIS
COULD WORK AND START WITH THE
MAGICAL BELIEF THE ANSWER'S OUT
THERE AND SEARCHED THROUGH CON
EX IN -- CONNEXINS PROTEINS A
CAME UP WITH THIS PAIR IN
GOLDFISH AND THE CONNEXINS ARE
LABELLED BY THEIR WEIGHT AND THE
PAIR HAD A REALLY INTERESTING
SET OF FEATURES.
FIRST OF ALL IT'S TWO THAT CAN
COME TOGETHER.
SO MAYBE IT WILL GET US OUR
FWREEN AND RED.
THEY'RE IN NATURE AND THAT'S
COOL.
THEY TEND TO RECTIFY AND CURRENT
FLOWS IN MORE IN ONE DIRECTION
THAN THE OTHER AND WONDERFULLY
ENOUGH THEY TEND TO CONDUCT
CURRENT AT EXACTLY THE
PHYSIOLOGICAL RANGE YOU'D WANT
FOR HUMAN NEURONS.
WE SELECT THE PAIR AND DECIDED
TO MOVE FORWARD WITH IT.
THE PROBLEM WITH THIS PAIR IS
THAT IT DOES WHAT WE WANT IT TO
DO, IN OTHER WORDS, IT WORKS
LIKE A MAGNET BUT ALSO LIKE
STICKERS.
THE 34.7 AND THE 35 WILL DOCK
LIKE 35.
SO WE'VE NOW GONE FURTHER AND
TOUCHED C. ELEGANS A LITTLE BIT
AND THE DOCKING IS CONTROLLED BY
RESIDUES ON THE EXTRA CELLULAR
LOOPS OF THE CONNEXIN PROTEINS.
ALL THESE WORDS I CAN'T KNOW
WHAT THEY MEANT WHEN WE STARTED
DOWN THIS ADVENTURE.
WE REALIZED WE COULD MUTATE THE
RESIDUES AND IF WE COULD DO THAT
MAYBE WE CAN FIGURE OUT WHICH
ARE NEGATIVE AND POSITIVES IN
THE RIGHT COMBINATION AND
ESSENTIALLY CREATE A PAIR WHERE
THEY DON'T FUNCTION LIKE
STICKERS ANYMORE BUT CONTINUE TO
FUNCTION LIKE MAGNET.
SO THAT'S WHAT WE'LL TRY TO
ACHIEVE.
AND I'M GOING TO FAST FORWARD
THROUGH THE NEXT SLIDE BECAUSE
THIS IS YEARS OF WORK BUT THE
WAY WE SOLVED IT WAS COME UP
WITH A NOVEL SCREENING ASSAY IN
THE LAB.
I HIRED A BIO CHEMIST TO RAPIDLY
SCREEN THE INTERACTION BETWEEN
CONNEXIN PROTEIN PAIRS.
I HAD A COMPUTER SCIENCE MAJOR
JOIN MY LAB AND CREATED A
COMPUTATIONAL PROBLEMS AND
NEITHER COULD SOLVE ON THEIR OWN
BUT THEY INNOVATED TOGETHER AND
IT ITERATED THROUGH AN IN VITRO
SCREEN AND CRACK THE CODE HOW
THE RESIDUES INTERACT TO CREATE
THE BINDING BETWEEN CONNEXIN
PROTEINS AND IT LOOKS LIKE THIS.
THERE'S ESSENTIALLY FOUR
IMPORTANT RESIDUES AND THE
SECOND ONE FROM THE TOP ON EACH
SIDE INTERACTS WITH THREE ON THE
OTHER SIDE ESSENTIALLY FORMING A
CONNECTION MECHANISM.
SO WHAT WE REALIZED WE COULD DO
IS SYSTEMATICALLY MUTATE THEM
AND 35 WE MADE ALMOST ALL
NEGATIVE AND THE MAGNET CONCEPT
OF BIOLOGY AND WE WERE
ULTIMATELY ABLE TO IDENTIFY A
PAIR WITH OUR FEATURES OF
INTEREST.
HERE'S WHAT IT LOOKS LIKE.
WE EXPRESSED THE PROTEINS IN HEX
CELLS AND THEN WE WERE ABLE TO
DUAL PATCH.
CONNECTING A PIPETTE TO BOTH AND
MEASURE THE FLOW OF ELECTRICITY
AND FOUND WE COULD SEND
ELECTRICITY FROM ONE CELL TO
ANOTHER AND THEY WERE CONDUCTING
ELECTRICITY AND WE WERE EXCITED
BECAUSE THOUGH WE COULD MUTATE
THEM THEY COULD DO THIS AND ONE
HAS 35. 7 AND ONE HAS 35 AND
WHEN WE EXPRESSED 37 IN BOTH THE
LOCK AND LOCKED, NO CURRENT
PASSED BETWEEN THE CELLS AND
WHEN WE EXPRESSED THE KEY IN THE
KEY, NO CURRENT PASS BETWEEN
CELLS.
SO WE HAVE IT WORKING LIKE A
MAGNET AND IT DOESN'T WORK LIKE
A STICKER.
SO WE REACHED OUT TO COLLEAGUES.
WE MENTIONED THE C. ELEGANS
LITERATURE AND WE DON'T DO THAT
WORK IN THE LAB AND I HAVE A
FRIEND IN YALE AND HIS LAB DOES
WORK IN C. ELEGANS AND I SAID
CAN YOU TEST IT TO SEE IF THEY
CAN CHANGE BEHAVIOR AND
PHYSIOLOGY IN A LIVING INTACT
SYSTEM.
SO WE SENT HIM THESE PROTEINS.
THE C. ELEGANS IS NICE FOR
MULTIPLE REASONS.
THEY HAVE ONE CELL OF EACH CELL
TYPE BUT WHAT'S ALSO COOL IS
NEUROSCIENTISTS WORKED HARD TO
FIGURE OUT THE BEHAVIORS IN
THESE.
THERE'S A SET OF BEHAVIORS
MAPPED ON TO CELL TYPES IN THE
C. ELEGANS.
NAR CLEAR
SO HERE'S THE ASSAY THAT WE'RE
TO USE IN C. ELEGANS AND I'LL
WALK YOU THROUGH THIS QUICKLY.
I LIKE TO SAY THEY'RE LIKE
GRADUATE STUDENTS.
WHEREVER YOU FEED THEM, THEY
WILL RETURN.
SO THIS BEHAVIOR IS CONTROLLED
AT LEAST IN PART BY TWO NEURONS.
THERE'S AFD, WHICH YOU CAN SEE
IS THE LARGE GREEN NEURON OVER
THERE ON THE TOP AND THEN AIY.
AFD IS A SENSORY NEURON.
IN THIS CASE IT SENSES
TEMPERATURE.
SO THE WARMER THE C. ELEGANS THE
MORE THE NEURON FIRES.
IF YOU FEED THEM AT WARM
TEMPERATURES AND TEST THEM IT
WILL GO BACK TO WARM AND FEED
THEM AT COLD IT WILL PREFER COLD
TEMPERATURE LATER.
SO IN THE CASE OF FEEDING A C.
ELEGANS IT RESPONDS TO
TEMPERATURE.
SO UNDER THE BIG GREEN NEURON
YOU CAN SEE A TRACE IN WHICH
WE'RE INCREASING TEMPERATURE AND
RAMPING TEMPERATURE UP AND
SHOWING YOU ACROSS 60 OR SO
ANIMALS WHAT HAPPENS TO THE
NEURON AS WE INCREASE
TEMPERATURE AND IT GETS MORE RED
AS YOU SLIDE TO THE RIGHT
BECAUSE IT'S RESPONDING TO
TEMPERATURE.
SO THE NEURON FIRES THE SENSORY
NEURON.
WHEN YOU FEED ANIMALS IN COLD
THE CONNECTION BETWEEN AFD AND
AIY IS WEAK.
THE SECOND CELL BECAUSE THE
CONNECTION IS WEAK THE CELL
DOESN'T FIRE MORE WHEN FED AT
COLD TEMPERATURES IF YOU TEST
THEM OUT THEY PREFER COLD.
BUT IN THE CASE WHERE YOU FEED
THE ANIMALS AT WARM
TEMPERATURES, NOW THE CONNECTION
BETWEEN THE TWO NEURONS IS
STRONG.
IT'S CHANGED.
WHEN YOU INCREASE TEMPERATURE
THE POST SYNAPTIC NEURON STARTS
FIRING MORE BECAUSE THE
CONNECTION BETWEEN THE TWO IS
STRONG AND THE ANIMALS PREFER
WARM.
SO YOU CAN MEASURE HOW STRONGLY
THEY'RE CONNECTED BY TWO
FEATURES.
ONE, DOES THE ANIMAL PREFER COLD
OR PRESERVE WARM?
AND SECONDLY, HOW MUCH CALCIUM
RISE IS THERE AS YOU INCREASE
TEMPERATURES?
IT'S AN EASY WAY OF MEASURING
THE CONNECTION BETWEEN THE TWO
CELLS.
SO THAT'S WHAT WE'RE GOING TO DO
EXPERIMENTALLY.
WE'LL PUT THE LOCK IN ONE CELL
AND LOCK IN THE OTHER CELL OR
PUT THE KEY IN ONE CELL AND KEY
IN THE OTHER CELL.
AND THEN WE'LL MEASURE CALCIUM
CHANGE AND ANIMAL WARM OR COLD
AND THE LOCK AND LOCK IN THE
MIDDLE AND KEY AND KEY THERE'S
NO POST SYNAPTIC CALCIUM RISE.
WE'RE NOT STRENGTHENING THE
CONNECTION BETWEEN THE TWO DOING
LOCK-LOCK OR KEY-KEY.
BUT WHEN WE PUT THE LOCK AND KEY
AND LOCK IN THE FIRST AND KEY IN
THE SECOND CELL NOW YOU CAN SEE
A POST SYNAPTIC CALCIUM RISE AS
IF WE STRENGTHENED THE
CONNECTION THOUGH THE ANIMAL
NEVER GOT FOOD AT A WARM
TEMPERATURE.
SO WE'RE CHANGING THE WIRING
BETWEEN THE TWO CELLS.
NOW WE'LL LOOK AT WHAT GOES ON
BEHAVIORALLY.
THE ANIMALS WITH THE LOCK AND
LOCK PREFER COLD AND ANIMALS KEY
IN THE KEY PREFER COLD.
BUT WHEN WE PUT THE LOCK AND KEY
IN ALL OF A SUDDEN THEY PREFER
WARM TEMPERATURES SO YOU CHANGE
THE PHYSIOLOGY AND BEHAVIOR
ESSENTIALLY CREATING A SYNAPTIC
BYPASS THAT WORKS IN C. ELEGANS.
AND FOR KICKS BECAUSE MY UNCLE
SHAMED ME WITH THE QUESTION, WE
TESTED THIS WITH CONNECTION
PROTEINS IN THE HUMAN BRAIN AS
WELL BECAUSE THIS TIME WE
THOUGHT WE BETTER THINK OF LONG
TERM AND THEY DIDN'T INTERACT
WITH CONNEX IN IN HUMANS.
NOW WE'RE EXCITED.
WE GOT THIS AND PLAYING AROUND
WITH IT AND SEEMS TO BE WORKING
IN C. ELEGANS AND I'LL TAKE YOU
AROUND BACK TO THE BEGINNING OF
MY TALK.
IF YOU REMEMBER I PUT UP THE
DIAGRAM ABOUT THE GENOME-WIDE
ASSOCIATION STUDIES AND SHOWED
THE GENE ALTERATIONS IN HUMANS
WERE MAPPING ON TO SYNAPTIC
PROTEINS.
I'LL SPEND THE REST OF THE TALK
FOCUSSING IN ON ONE OF THESE
PROTEINS.
IT'S CALLED SAP APP AND YOU CAN
SORT OF SEE IT.
I WISH I COULD GET IT TO WORK
BUT FOR THOSE AT HOME YOU GET TO
ENJOY THIS POINTER.
IT'S THE GREEN LINK OVER THERE
THAT'S HOLDING UP THE RECEPTORS.
AND PEOPLE HAD MADE A MOUSE
MODEL WHERE THEY'D REMOVED THE
PROTEIN SO THEY REMOVED SAPP APP
3.
AND THE WORK WAS FIRST PUBLISHED
IN 2007 AND WHEN IT GOT
PUBLISHED THERE WAS AN
INTERESTING PHENOTYPE.
AS THEY AGED AND PASSED THROUGH
WHAT IS MOUSE ADOLESCENCE PEOPLE
STARTED NOTICING THEY HAD
REPETITIVE BEHAVIOR AND GR GROOD
AND GROOMED AND GROOMED SOME
MORE THAN A WILD TYPE AND
SOMETIMES FOUR AND FIVE TIMES AS
MUCH AND THE CONSEQUENCES OF THE
GROOMING CAN BE QUITE SEVERE.
I'M SHOWING THE WILD TYPE MOUSE
ON TOP AND ON BOTTOM A SAP APP
MOUSE.
A MOUSE THAT'S LOST THE PROTEINS
AND CAN GROOM UNTIL IT HAS HUGE
FACIAL LESIONS BECAUSE IT'S
GROOMING SO MUCH.
I'LL QUANTIFY THAT FOR YOU.
SEE THE LESION SIZE ON BOTH OF
ITS FACE AVERAGED TOGETHER.
ZERO MEANS NO LESIONS AND 5
MEANS TWO 5 MILLIMETER LESIONS
AND IN THE KNOCKOUT YOU SEE THE
LESIONS AND MOST THE ANIMALS
HAVE IT.
85% OF THE ANIMALS BY THE END WE
TRACKED THEM FOR 10 WEEKS.
85% OF THE ANIMALS SO 25 WEEKS
OF AGE WE'RE TRACKING FROM 15 TO
25 HAVE LESIONS.
SO WHAT'S INTERESTING ABOUT THIS
IS THAT MULTIPLE LABS HAVE TRIED
TO MAP THIS BEHAVIOR ON TO
CIRCUITS IN THE BRAIN AND
IMPLICATED TWO BRAIN REGIONS
PARTICULARLY IMPORTANT.
ONE IS ORBITAL FRONTAL CORTEX
AND THE OTHER IS IT THE
STRIATUM.
AND THE WAY IT'S SET UP YOU HAVE
CELLS IN ORBITAL FRONTAL CORTEX
TO STRIATUM AND THIS IS
UNIDIRECTIONAL AND PEOPLE USED
THAT TOOL, OPTOGENETICS TO DO
EXPERIMENTS AND IT'S REDUCED
GROOMING.
AND PEOPLE HAVE DONE EXPERIMENTS
TARGETING THE PV NEURONS IN THE
STRIATUM AND STIMULATED THEM AND
THAT REDUCED GROOMING AND
THERE'S PROBABLY THE CIRCUIT IN
THE MIDDLE NOT THE LEFT OR RIGHT
THAT'S IMPORTANT.
BUT THERE HAVEN'T BEEN GREAT
NEUROSCIENCE TOOLS TO STIMULATE
PART OF THAT BUT NOT THE OTHER
PART SO YOU SORT OF HAVE TO BE
ABLE TO HIT THE PRESYNAPTIC
NEURON FOR THIS TO WORK.
SO THE IDEA WAS WE CREATED THIS
LOCK AND KEY GAP JUNCTION TOOL.
CAN WE JUST TEST THIS OUT ON THE
CIRCUIT AND SEE WHAT IT WILL DO?
SO, WHAT WE'RE GOING TO DO IS
PUT THE LOCK AND ORBITAL FRONTAL
CORTEX AND PUT IT IN THE D1
EXPRESSING NEURONS OR THE D2
EXPRESSING NEURONS OR THE PB
NEURONS AND SEE WHAT IT DOES.
CAN WE REWIRE THE CIRCUIT AND
CREATE A SENSE OF VIRAL VECTORS.
I'LL WALK YOU THROUGH THIS ON
THE NEXT SLIDE.
WE'LL HAVE A SERIES OF VIRAL
VECTORS AND TAG GREEN.
I WARNED YOU YOU'D SEE GREEN AND
RED A LOT AND 35 IS TAGGED TO
THE RED AND HAVE A SERIES OF
CONTROLS GFP GREEN PROTEIN OR
RFP JUST RED AND TARGET THE CELL
TYPES.
THIS IS A PICTURE OF THE
STRIATUM AND SEE THE GREEN IS
SORT OF THE AXONS COMING IN AND
THE TERMINALS COMING IN TO
STRIATUM AND THE RED IN THIS
CASE IS A PV NEURON AND ON THE
BOTTOM ON THE RIGHT YOU CAN SORT
OF SEE THERE'S LIKE A YELLOW
SPOT IN THERE THAT'S LIKE THE
GREEN AND SORT OF YELLOW.
IT MEANS THESE TWO COLORS ARE
SOMETIMES COMING CLOSE TOGETHER.
SORT ARGUING WE'RE CREATING A
SYNAPSE.
HERE'S GROUPS WE'RE GOING TO
TEST.
WE'LL START OFF WITH A STRAIN OF
MICE.
THE SAP UP MICE.
WE CROSSED IT TO MICE THAT WILL
ALLOW US TO TARGET PV NEURONS.
SO THIS ALLOWS YOU TO TARGET THE
CELLS THAT EXPRESS CREE WITH THE
VIRUS AND PUT THE LOCK IN THE
FRONTAL CORTEX AND KEY IN THE
STRIATUM AND THE NEXT THE LOCK
WILL BE OFC AND KEY WILL BE
SPECIFICALLY IN THE CELLS IN
STRI JATAL AND THE NEXT TARGET L
CELL TYPES.
THE THIRD IS THE LOCK OFC COLOR
AND STRIATUM AND COLOR AND LOCK
KEY AND STRIATUM AND ON THE
BOTTOM WE'LL TARGET EVERYTHING
EXCEPT FOR THOSE CELLS.
I'LL SHOW YOU ON THE NEXT SLIDE
WHAT HAPPENS WITH GROOMING.
YOU CAN KEEP YOUR EYE ON THE
DATA AND HOW THE ANIMALS LOOK.
SO I'M SHOWING YOU GROOMING AND
THE AMOUNT OF TIME SPENT
GROOMING.
WE PUT THE VIRUS IN AT EIGHT
WEEKS AND MEASURED THEM FIVE
WEEKS AND 10 WEEKS AND 15 WEEKS
LATER.
ON THE LEFT ABOUT WHAT YOU'RE
SEEING IS IN THE LIGHT GRAY YOU
SEE THE ANIMALS THAT ONLY HAVE
COLORS NO PROTEINS JUST CONTROL
COLORS AND THEY'RE RUNNING HOT
BUT IN THE ANIMALS WE PUT THE
LOCK AND THE KEY, THE KEY
SPECIFICALLY IN THE INDIVIDUAL
CELLS IT REDUCES GROOMING ACROSS
THE ENTIRE COURSE OF THE
EXPERIMENT.
SO WE CAN BY PUTTING INTO THE
CELL TYPES REDUCE THE BEHAVIOR.
THEN WE'LL LOOK AT OUR CONTROL
GROUPS.
IN THE MIDDLE YOU SEE THE GROUP
WHERE WE TARGET OFC.
THE LOCK IN OFC AND KEY IS
EVERYWHERE IN STRIATUM NOT JUST
CELLS OF INTEREST BUT EVERYWHERE
BUT BLUE GROUP AND IF WE TARGET
ALL THE GROOMING INCREASES OVER
TIME.
IT'S ONLY THE CASE WE HIT THE
INDIVIDUAL SIDES NOT ALL CELLS.
AND THEN IN THE PURPLE WE HAVE A
CASE WHERE WE HIT EVERYTHING
EXCEPT FOR THE PV NEURONS AND
STRIATUM.
WE'RE FORMING THE CONNECTIONS AT
THE WRONG PLACE AND GROOMING
INCREASES OVER TIME.
IT'S ONLY WHEN YOU HIT THE CELL
TYPE PAIR.
THEN ALL THE WAY ON THE RIGHT
YOU HAVE ONLY THE LOCK IN
STRIATUM OR ONLY THE LOCK IN
CORTEX AND ONLY THE KEY IN
STRIATUM.
ONLY HALF THE PROTEIN AND AGAIN
THE GROOMING INCREASES OVER
TIME.
IT'S ONLY IF YOU PUT IT AT THE
RIGHT CONNECTION AND BYPASS THE
RIGHT PLACE.
HERE'S WHAT THE ANIMALS LOOK
LIKE IN TERMS OF THEIR FACIAL
LESIONS.
I'LL WALK YOU FROM TOP TO
BOTTOM.
SO SO ONLY COLORED PROTEINS,
THEY DEVELOP FACIAL LESIONS IT'S
LIKE 90%.
THAT'S THE CONTROL GROUP.
IF YOU PUT THE LOCK AND THE KEY
IN, TWO-THIRDS OF THE ANIMALS
NEVER DEVELOP ANY LESION
WHATSOEVER.
SO NOT ONLY DECREASED THE
GROOMING, THEY DEVELOP NO LESION
WHATSOEVER.
IF YOU PUT THE LOCK IN CORTEX
AND KEY IN ALL THE CELLS, YOU'RE
TARGETING ALL THE CELLS, THOSE
ANIMALS DEVELOP LESIONS ALSO AND
IN FACT THE MAJORITY DEVELOP
LESIONS.
IF YOU PUT ONLY THE LOCK IN, THE
FOURTH FROM THE TOP, THOSE
ANIMALS DEVELOP LESIONS, TAKE Y
AND DID A SERIES OF CONTROL
EXPERIMENTS TARGETING THE D1 OR
D2 NEURON.
WE USE A D1 PRE MOUSE OR ONE
THAT OVERLAP THE STRIATUM AND
THEY DEVELOPED LESIONS AS WELL.
YOU HAVE TO HIT THE CELL TYPE
PAIR OF INTEREST OR IT DOESN'T
WORK.
YOU HAVE TO BYPASS THE SYNAPSE
OF CHOICE.
OF COURSE WE'RE ALSO EXCITED
BECAUSE IT TURNS OUT YOU CAN
BYPASS THE SYNAPSE AND KEEP THE
ANIMALS FROM GROOMING THEIR FACE
OFF IF YOU HIT THE RIGHT THING.
OKAY.
SO WE'RE SORT OF LEFT AND I'LL
SPEND THE LAST TWO OR THREE
SLIDES FOR ALL THE PHYSIOLOGISTS
IN THE ROOM BECAUSE AT SOME
POINT I HAVE TO COME BACK TO MY
OWN DISCIPLINE, RIGHT?
SO WE WENT THROUGH AND WE WANTED
TO RECORD LIKE WHAT WAS
HAPPENING WITH THE CODE IN THIS
BRAIN AREA.
AND I APOLOGIZE TO ALL THE
NON-PHYSIOLOGISTS IN HERE.
IT GETS NUANCED.
WE IMPLANTED A TYPE OF RECORDING
ELECTRODE THAT ALLOWS US TO
RECORD LOTS OF NEURAL ACTIVELY.
WE'LL DO VERY HIGH DENSITY
NEURORECORDING ACTIVITY FROM
STRIATUM AND GET THE SAME
INFORMATION FROM FRONTAL ORBITAL
CORTEX FROM ME MOUSE AND COLLECT
LOTS OF CELLS ABOUT 900 TOTAL
NEURONS AND RECORD OSCILLATIONS
FROM THE ORBITAL CORTEX IN THE
SAME CELL AND THEN SPLIT THE
NEURONS IN THE TWO GROUPS AND
FOR THOSE WHO STUDY THE STRIATUM
YOU YOU'LL DIGEST THIS QUICKLY.
WE HAVE NEURONS ON THE RIGHT
WITH NARROW WAVE FORMS.
THESE WILL BE THE PV NEURONS AND
ON THE LEFT ARE GOING TO BE WHAT
WE CALL STRIATAL PROJECTION
NEURONS AND WE'LL ASK HOW
THEY'RE DIFFERENT UNDER NORMAL
CONDITIONS AND WHEN WE DO THE
BYPASS.
AND SO ON THE LEFT I'M JUST
SHOWING YOU A NORMAL ANIMAL AND
THE KNOCKOUT ANIMAL AND WHEN WE
LOOK THERE'S NO BYPASS HERE
THERE'S BASICALLY THE STRIATAL
OR MEDIUM NEURONS FIRE LESS.
SO THERE'S A DECREASE IN THEIR
FIRING.
BUT WHEN WE LOOK AT THE NARROW
SPIKING UNITS, THOUGH LIKE
THERE'S LESS OF THEM, THERE'S NO
STATISTICAL DIFFERENCE IN THAT
DISTRIBUTION.
BUT IN TERMS OF THE MEAN FIRING
RATE THERE'S NO DIFFERENCE.
WE HAVE LOTS OF CELLS THERE.
WE EXPECTED LIKE A LOWER FIRING
RATE OF THE NEURONS AND THOUGHT
THAT'S WHAT WE'D HAVE
EXPERIMENTALLY.
WE THEN MOVED ON TO STUDY WHAT'S
GOING ON IN THE ANIMALS WHEN WE
DO THE BYPASS?
YOU'LL LIKELY SEE THE CONTROL
GROUP.
ON THE RIGHT HAND FOR EACH OF
THE TWO PLOTS YOU'LL SEE THE
LENGTHS THE BYPASS.
WHEN WE PUT THIS BYPASS IN
THERE, THE FIRING OF THE NEURONS
GOT LOWER.
YOU SORT OF HAVE THE DISEASE
CASE THE FIRING RATE IS LOWER
AND THEN WE FIX IT AND THE
FIRING RATE GETS EVEN LOWER
WHICH IS SUPER CONFUSING TO US
AND THEN WE LOOK AT THE NARROW
SPIKING UNITS WE THOUGHT WERE
THE PV NEURONS AND THOUGH IT
TENDED TO INCREASE THE FIRING
RATE THERE WEREN'T A LOT OF PV
NEURONS THERE.
THERE WAS -- WE'RE DOING DEEP
RECORDINGS AND BARELY GETTING
ANY PV NEURONS OR THINGS THAT
HAVE WAVES THERE.
WE WERE STRUCK BY THIS.
WE JUST QUANTIFIED LIKE WHAT
PERCENTAGE OF NEURON TYPES DO WE
HAVE AND IT GOT INTERESTING.
ON THE LEFT YOU SEE OUR NORMAL
ANIMALS, THE PLUS AND THE
KNOCKOUT ANIMALS THE NEGATIVE
AND WHAT WE COULD CLEARLY SEE
WHEN WE QUANTIFIED THIS ACROSS
ANIMALS THERE WERE LESS NEURAL
SPIKING UNITS LESS OF WHAT WE
THOUGHT WERE PV NEURONS IN THE
MUTANT CASE.
AND WHEN WE LOOKED AT THE MUTANT
ANIMALS WHAT WE COULD SEE WAS WE
INCREASED THE PROPORTION OF PV
EXPRESSING NEURONS OR SPIKING
UNITS.
YOU SEE THE RED AND ON THE RIGHT
THE SLICE GETS BIGGER.
INTERESTINGLY ENOUGH ON THE
RIGHT, THE TOTAL NUMBER OF PV
NEURONS WAS WAY LESS.
WE THINK IT HAS TO DO WITH THE
CREE LINE WHICH JUST DECREASED
THE FUNCTIONALITY OF THE PV
NEURONS THERE.
BUT WE THINK THERE'S ESSENTIALLY
A SILENCING.
THE NEURONS BASICALLY GO SILENT
SO IF YOU'RE DOING ELECTRICAL
RECORDINGS THEY DROP OFF AND YOU
CAN'T SEE THEM BECAUSE THEY'RE
NOT FIRING.
THERE'S A SILENCING AND WHEN WE
BYPASS THEM IT RECOVERED THEM.
WILL I'LL FAST FORWARD THROUGH
THE LAST TWO SLIDES AND GIVE YOU
THE TAKE HOME OF WHAT WE THINK
IS GOING ON.
SO IN THE END, WE TAKE THESE
NEURONS FIRING AND ASK HOW WELL
ARE THEY CONNECTED TO OFC?
SO WE CAN QUANTIFY THE FIRING
RELATIONSHIP IN THE STRIATUM TO
THE OSCILLATING INFORMATION IN
OFC.
ON THE LEFT WE SEE WHEN YOU LOOK
AT THE KNOCKOUT ANIMALS THEIR
CELLS BASICALLY SHOW THEY FIRE
IN A WAY THAT HAS LESS OF A
RELATIONSHIP TO OFC.
IT LOOKS LIKE THERE'S A
DISCONNECTION IN THE CIRCUIT
BECAUSE THE CELLS DON'T HAVE
ASA
SASIN -- ASYNCHRONOUS TIMING AD
WE RESTORE THE FIRING
RELATIONSHIP AND THE CELLS IN
THE STRIATUM ARE FIRING WITH THE
BETTER RELATIONSHIP WITH THE
CONNECTIVITY IN OFC.
AND SO WE THINK ULTIMATELY WHAT
WE'VE GOT AND I'M SUMMARIZE THIS
IS THAT OUR GOAL WE SET OUT TO
BYPASS THE SYNAPSE.
AND WE THOUGHT THAT IN THE CASE
OF MAMMALIAN SPECIES WE CAN
TARGET A HOUSE IN WHICH THERE'S
A GENETICALLY INDUCED
DYSFUNCTION IN THE SYNAPSE.
SO WE GOT THE SYNAPSE, WE GOT
THE BREAK AND WANT TO KNOW IF WE
CAN BYPASS THE BREAK?
WE CAME UP WITH THE SOLUTION OF
BASICALLY GENERATING BYPASS
PROTEIN CHANNELS WE TURNED INTO
MAG
MAGNETS.
WE TESTED THEM IN C. ELEGANS AND
WENT TO THE DISEASE MODEL WHERE
THE MICE REPETITIVELY GROOM TO
THE POINT THEIR FACE IS
SCRATCHED OFF AND HAVE A
SPECIFIC CONNECTION OF INTEREST,
PUT THE BYPASS IN THERE AND IT
RESTORED BOTH THE PHYSIOLOGY OF
THE CIRCUIT AND NORMALIZED
BEHAVIOR AND GOT RID OF THE
PATHOLOGICAL OUTCOMES.
IT'S NOT HUMAN TRANSLATION.
THE STORY'S NOT OVER WE'RE STILL
DOING WORK TO GET THERE BUT
WANTED TO TAKE THE LAST MINUTE
AND A HALF TO TALK ABOUT THE
PEOPLE THAT DID THE WORK.
AND I ALWAYS END MY TALKS WITH
THE SLIDE THAT LOOKS LIKE THIS
BECAUSE I THINK WHAT IS SO
FUNDAMENTAL TO WHAT WE'RE TRYING
TO ACHIEVE IS TO GET THE
SMARTEST, MOST TALENTED PEOPLE
WORKING ON THE HARDEST PROBLEMS
AND FOR ME WHEN I WAS GIVEN THE
OPPORTUNITY TO COME TO NIH I
WANTED TO TAKE THE OPPORTUNITY
TO THANK NIH FOR ALL THE WORK IT
DOES TO REMOVING BARRIERS TO THE
SMARTEST PEOPLE WORKING ON THE
HARDEST PROBLEMS.
THAT'S ME ON THE LEFT HAND
CORNER.
BELIEVE IT OR NOT I OWN MORE
THAN ONE OUTFIT.
NEXT TO ME IS LIZ THAT CAME UP
WITH THE SCREENING POSITION AND
STARTED HER LAB AT CARNEGIE
MELON AND THE NEXT ONE I MET IN
MY UNDERGRAD AND THOUGHT HE WAS
SUPER WEIRD AND WASN'T PAYING
ATTENTION AND IS NOW GETTING HIS
MASTER'S AT CARNEGIE MELLON AND
TATIANA RODRIGUEZ GREW UP IN THE
APPALACHIAN MOUNTAINS IN
MARYLAND, SUPER RURAL AREA, CAME
TO MY LAB AS A TECHNICIAN AND
NOW DOING HER Ph.D. IN NYU AND
ANOTHER DID Ph.D. WORK IN PENN
AT THE AREA OF ADDICTION AND
CAME TO MY LAB AND HELPS RUN IT.
HANNAH DID MOST HER WORK ON TA
MODEL SPENT TIME IN DUBAI AND
THE OTHER IS WORKING FON A BIO
TECH TO TREAT MENTAL ILLNESS AND
ANOTHER HAS A LAB AT YALE AND
ANOTHER DID A Ph.D. IN BIO
CHEMISTRY IN DUKE AND HAD TWO
KIDS DURING THE PANDEMIC AND
REALIZED HOW IMPORTANT IT WAS TO
THINK ABOUT CHILDCARE IN
SUPPORTING YOUNG SCIENTISTS AS
THAT I WERE DOING THEIR
IMPORTANT WORK.
NEXT I HAVE NICOLE AN Ph.D. IN
DUKE IN NEUROLOGY AND ANOTHER IS
AT OREGON HEALTH SCIENCES
ANOTHER WAS PART OF A DREAM TEAM
IN CRACKING THE CODE IS NOW A
CARDIOLOGY FELLOW AT DUKE.
AND GWEN FINISHED WITH HER Ph.D.
IN NEURO BIOLOGY AT DUKE AND NOW
WORKING FOR A FOUNDATION.
AND THE FIRST PERSON I TOLD
ABOUT THIS IDEA WAS FACULTY IN
BIOMEDICAL ENGINEERING WORKING
IN CARDIOLOGY AND FAMILY WAS
ORIGINALLY THERE SERBIA AND CAME
ON BOARD TO HELP AND ANOTHER WAS
A Ph.D. STUDENT AND DID THE
COMPUTATIONAL MODELLING NOW A
POSTDOC AT STANFORD.
HALF HIS FAMILY MIGRATED FROM
RUSSIA, THE OTHER HALF FROM
UKRAINE.
FINALLY, RAINBOW HOTMAN FOUND
THE RIGHT MUTATIONS IN THE CODE
OF THE CONNEXIN PROTEINS.
THE DEVELOPED DEBILITATING
MIGRAINES SO MUCH SO SHE
COULDN'T LOOK AT A COMPUTER AND
IS NOW RUNNING A LAB IN IOWA AND
AWARDED A NIH NEW INNOVATOR
AWARD TO STUDY THE
NEUROPHYSIOLOGY OF MIGRAINES.
THANK YOU AND I'M HAPPY TO TAKE
QUESTIONS.
>> WE HAVE TIME FOR QUESTIONS.
THE CME CODE FOR PEOPLE WHO MAY
NOT HAVE CAUGHT IT, 57693.
LOOKS LIKE WE HAVE A QUESTION
COMING -- NO.
YOU'VE GOT ONE RIGHT HERE.
>> THAT WAS AN ABSOLUTELY
WONDERFUL LECTURE FOR MANY
REASONS BUT I'M GOING TO BE
SPECIFIC ON YOUR THOUGHTS ON THE
PATHWAY IN THE COMPULSIVE
BEHAVIOR WHICH IS WHERE WE'RE
SEEING HAVE YOU ADDED GIVING IT
TO THE ANIMALS DO THEY ESCALATE
FASTER?
>> WE HAVEN'T DONE THIS.
THE DATA'S ABOUT THREE MONTHS
OLD.
I DO HAVE A GRADUATE STUDENT
SUPPORTED BY YOU ALSO, THANK YOU
VERY MUCH, WHO IS LOOKING AT
FENTANYL CONSUMPTION AND COCAINE
CONSUMPTION AND THINKING HOW TO
REWIRE CIRCUITRY TO CHANGE THAT
BEHAVIOR AS WELL.
WE DON'T HAVE AN ANSWER YET.
>> I DON'T KNOW IF ANYBODY HAS
LOOKED AT THE SPECIFIC ANIMALS.
I'M NOT SURE.
YEP.
>> KAF, GREAT TALK.
I APPRECIATE IT.
I HAVE A QUESTION ABOUT THE
PHYSIOLOGY.
HAVE YOU GUYS -- THE FUNCTION OF
THE LENS Z WILL DEPEND ON WHERE
IT FORMS ITS CONNECTIONS TO
DENDRITES AND CELL BODY AND HAVE
YOU GUYS LOOKED AT WHERE IT
FORMS THE CONNECTIONS AND WHAT
IT DOES TO THE PHYSIOLOGY OF THE
CELL?
>> YEAH, NO, IF ONLY I HAD A
COLLABORATOR WHO STUDIED THAT
AND WAS INTERESTED.
WE HAVEN'T DONE THAT.
FOR US THERE'S SO MUCH TO
EXPLORE WITH A TOOL LIKE THIS
AND SO MUCH TO LEARN AND A LOT
OF IT FALLS OUT OF THE RANGE OF
WHAT MY LAB DOES.
WE'RE HAPPY TO SHARE THE TOOL.
WE SHARED IT WITH A LOT OF LABS
BUT IF THAT'S SOMETHING WE'RE
INTERESTED IN TACKLING WE'LL GET
IT TO YOU.
>> COOL, MAN, THANK YOU.
>> A DOUBLE QUESTION HERE.
FIRST, CURIOUS ABOUT THE TIME
LINE.
HOW LONG DID THIS TAKE?
YOU SAID A LONG TIME.
>> ARE YOU REFERRING TO THE MICE
OR THE ENTIRE SCOPE OF THE
PROJECT --
>> THE SCOPE.
HOW LONG IT TOOK TO GET TO THE
MICE BECAUSE THE FOLLOW-UP
QUESTION IS WHAT'S NEXT VIS A
VIS ANIMALS?
>> IT WAS 2014 OR '15 WE KNEW
WHAT WE WERE DOING WASN'T GOING
TO BE SCALABLE.
IT WAS 2018 WHEN I STARTED ON
THE BRAIN INITIATIVE PANEL.
THAT ANCHORS THE MIDDLE OF THE
TALK.
EVERYTHING UP TO THAT POINT WAS
PROBABLY 2005 TO LIKE 2013.
>> AFTER MICE WHAT'S THE NEXT
ANIMAL MODEL?
>> I WON'T INTRODUCE THAT NOW
BECAUSE WE'LL BE HERE ANOTHER
HOUR AND IT'S ANOTHER TALK THAT
REQUIRES A LOT OF BACKGROUND
INFORMATION SO I WON'T ANSWER
THAT BUT IF YOU ASK ME AT THE
RECEPTION I'M HAPPY TO GET INTO
THAT BUT WE'RE ALREADY TESTING
THAT ON HUMAN ORGANOIDS AS WELL
TO MAKE SURE HUMAN BRAIN CELLS
CAN TOLERATE THE PROTEIN AND
CHANGE PHYSIOLOGY THERE AS WELL.
>> EXCELLENT.
>> ANY OTHER QUESTIONS?
ONE MORE.
>> VERY NICE TALK.
I HAD A QUESTION ABOUT THE
STRESS.
SO THE MOUSE IS HANGING
UPSIDE-DOWN, THAT'S THE ANXIETY.
SO YOU DID IT FOR ONE DAY AND
THEN ANOTHER DAY.
WHOSE TO SAY THE THIRD DAY IT
WOULDN'T BE DIFFERENT OR FOURTH
DAY?
>> PEOPLE TESTED THAT.
THE ANIMAL'S BEHAVIOR KEEPS
LOOKING MORE AND MORE STRESSED
WHEN PEOPLE CHECKED FIVE AND SIX
DAYS IN A ROW.
THERE ARE OTHER MORE ROBUST WAYS
ECOLOGICALLY ANCHORED WAYS OF
STRESSING MICE.
WE JUST LIKE THE SIMPLICITY
BECAUSE WE CAN RECORD ELECTRICAL
ACTIVITY TO IDENTIFY THE
CIRCUITRY.
FOR TESTING AND IF WE ULTIMATELY
STRESS IN OTHER STRESS PARADIGMS
WHETHER IT'S CHRONIC OR
UNPREDICTABLE STRESS BUT THE
IDEA IS YOU SHOULD BE ABLE TO
TARGET THE SAME CIRCUIT.
>> COULDN'T THE MOUSE GET USED
TO BE HANGING UPSIDE-DOWN?
>> SO THIS IS WHY I DON'T WANT
TO MAKE CLAIMS ABOUT WHETHER THE
MOUSE'S BEHAVIOR IS GOOD OR NOT.
BECAUSE THERE'S LOTS OF WAYS AN
ANIMAL CAN ADAPT TO AN
ENVIRONMENT AND SOME MIGHT
ERRING IT MAKES SENSE TO STOP
LIKE FIGHTING SO HARD ABOUT A
SITUATION AND SAVE TIME AND THE
INVESTIGATOR WILL TAKE YOU DOWN
AND DON'T WANT TO MAKE CLAIMS
WHETHER IT'S GOOD OR BAD SO YOU
DON'T BELIEVE IT'S DEPRESSION
BUT IT'S STRESS AND IT DOES
CAUSE A CHANGE IN BEHAVIOR AND
CAN USE THAT AS A WAY TO
IDENTIFY CIRCUITRY.
>> SO IF THERE'S NO MORE
QUESTIONS, LET'S THANK THE
SPEAKER ONE MORE TIME.
>> THERE'S A RECEPTION AS
MENTIONED OUTSIDE.