MY NAME IS DAVID SHURTLEFF FOR
THE NATIONAL CENTER FOR
COMPLIMENTARY AND INTEGRATIVE
HEALTH AND IT'S MY PLEASURE TO
WELL CHILDRWELCOME EVERYONE ON
INTEROCEPTION FUNCTIONAL
NEUROCIRCUITS.
THIS IS THE INAUGURAL AND ANNUAL
INVESTIGATOR MEETING AND I MUST
SAY IT'S A PLEASURE TO BE
ACTUALLY HERE IN PERSON BEFORE A
LIVE AUDIENCE SEEING EVERYBODY
IN 3D RATHER THAN OUR TYPICAL
HOLLYWOOD SQUARES.
SO, INTEROCEPTION, THE PROCESS
BY WHICH OUR BODY SENSES,
INTERPRETS SIGNALS FROM WITHIN.
AS THE DEPUTY DIRECTOR OF NCCIH,
FOR THE PAST 10 YEARS NOW, I CAN
SAY NCCIH HAS BEEN INTERESTED IN
THE STUDY OF INTEROCEPTION
PROCESSES AS RELATES TO SELF
REGULATION, MAINTAINING
HOMEOSTASIS AND MEDICATION CAN
RESULT IN REFLECTION OF THESE
INTER ACCEPTIVE PROCESSES AND
PROMOTING ADAPTIVE BEHAVIOR AND
WELLBEING.
IT'S AN EXCITING AREA FOR NCCIH
FOR SURE OVER THESE MANY YEARS,
CERTAINLY, INTEROCEPTION
PROCESSES AND DIS-REGULATED
INTEROCEPTION PROCESSES IN
PARTICULAR, ARE ASSOCIATED WITH
MANY HEALTH CONDITIONS
ININCLUDEDDING PAIN, AND ANXIETY
DISORDERS, MOOD DISORDERS, PTSD,
OBSESSIVE COMPULSIVE BEHAVIOR,
AUTISM, EATING DISORDERS,
ADDICTION AND SOMATIC SYMPTOM
DISORDERS AND OF COURSE OTHERS.
WHICH GO WELL BEYOND NCCIH PER
HAVE YOU SPARKING CENTER ACROSS
CENTERS AT THE NIH.
IN ADDICTION ADDITION, THERE AE
UNDERSTANDING THE BASIC
MECHANISMS OF INTEROCEPTION THAT
COULD LEAD TO IMPROVED DISEASE
MODELS AND IMPROVE TREATMENT
STRAT GOES FOR MANY OF THE
HEALTH CONDITIONS THAT I JUST
MENTIONED.
IMPORTANTLY, THE NIH BLUE PRINT
FOR NEUROSCIENCE RESEARCH
COLLABORATIVE FRAMEWORK THAT
INCLUDES 14 NIH INSTITUTES IN
CENTERS AND OFFICES THAT SUPPORT
RESEARCH ON THE NERVOUS SYSTEM,
PROVIDES A GREAT OPPORTUNITY FOR
LIKE-MINDED INSTITUTES IN
CENTERS TO COME TOGETHER TO
ADDRESS COMMON INTERESTS AND
ADDRESS UNIQUE SCIENTIFIC
CHALLENGES AND CERTAINLY
INTEROCEPTION FALLS INTO THAT
CATEGORY.
JUST TO GIVE YOU A LITTLE
BACKGROUND, THE BLUE PRINT WAS
ESTABLISHED IN 2004 AND SOME 18
YEARS AGO.
AS THE FLAGSHIP PROGRAM TO BRING
TOGETHER MANY BRAIN INSTITUTES
ACROSS THE NIH TO ACCELERATE AND
TRANSFORM DISCOVERIES OF THE
BRAIN IN FUNCTION AND IN HEALTH
AND AGING AND DISEASE.
IN FACT, IT WAS A PRECURSOR TO
THE BRAIN INITIATIVE HAVING THE
BLUE PRINT HAVING CONTRIBUTED TO
THE BRAIN INITIATIVE EARLY ON.
WITH REGARD TO INTEROCEPTION IN
2008, THE BLUE PRINT SPONSORED A
WORKSHOP, THE SCIENCE OF
INTERCEPTION IT'S ROLE IN
NERVOUS SYSTEM DISORDERS AND
CONDUCT A GRANT PORTFOLIO WITH
FUNDED RESEARCH ON INTEROCEPTION
ACROSS THE NIH.
IT WAS QUITE CLEAR AND EVIDENCE
THAT MORE BASIC RESEARCH WAS
NEEDED IN THIS AREA SEEING THE
NEED AND EXCITED ABOUT THE
OPPORTUNITY, THE BLUE PRINT IN
SEPTEMBER OF 2020 ASKED A
REQUEST FOR APPLICATIONS TO
SUPPORT THE STUDY OF FUNCTIONAL
NERVE CIRCUITS OF INTEROCEPTION.
THAT LED TO SUBMISSION OF
FUNDING OF YOUR APPLICATIONS,
THE PEOPLE IN THIS ROOM, WHICH
BRINGS US HERE TODAY TO LEARN
ABOUT THE GREAT WORK YOU'VE DONE
AND WE'RE EXCITED TO HEAR ABOUT
IT THE NEXT COUPLE OF DAYS.
I WANT TO THANK YOU TO BE PART
OF THIS FOCUSING ON DISSECT AND
DETERMINING THE FUNCTION OF
NEUROCIRCUITS THAT CONNECT
ORGANS AND TISSUES WITH THE
CENTRAL NERVOUS SYSTEM.
CLEARLY IT'S AN IMPORTANT AREA
FOR THE NEUROSCIENCE BLUE PRINT
AND NIH AND WITH THAT I'LL TURN
IT BACK OVER TO MY COLLEAGUE FOR
THE NEXT STEPS.
THANK YOU AGAIN FOR COMING.
[APPLAUSE]
>>THANK YOU SO MUCH, DAVID AND
I WOULD LIKE NEXT TO INTRODUCE
Dr. WEN CHEN, THE BRANCH CHIEF
FROM THE DIVISION OF EXTRAMURAL
RESEARCH AT NCCIH AND SHE'S
GOING TO TALK TO US TODAY ABOUT
AN OVERVIEW AND UPDATE OF THE
NIH INTEROCEPTION PROGRAM.
>>THANK YOU Dr. SHURTLEFF
FOR YOUR INTRODUCTION.
WELCOME TO THE FIRST NIH
INVESTIGATOR MEETING ON
FUNCTIONAL NEUROCIRCUITS OF
INTEROCEPTION.
TODAY, I WILL PROVIDE SOME
UPDATES ON THE WORKING GROUP AND
THE HISTORY OF THE NIH
BLUEPRINTS FOR NEUROSCIENCE
RESEARCH INTEROCEPTION
INITIATIVE.
FUNDING OPPORTUNITIES WITH
ACKNOWLEDGMENT OF ANNUAL
INVESTIGATOR MEETINGS PLANNING
COMMITTEE.
SO THERE'S BEEN A STRONG AND
BROAD INTEREST IN SUPPORT WITHIN
THE NATIONAL INSTITUTE FOR
HEALTH AND OUR TRANS NIH
INTEROCEPTION RESEARCH WORKING
GROUP CONSISTS OF PROGRAM
OFFICIALS AND SCIENTIFIC REVIEW
OFFICERS ACROSS 15 NIH
INSTITUTES CENTERS AND OFFICES.
AND WE IMMEDIATE LEAST QUARTERLY
TO DISCUSS AND COORDINATE
TRANSPORTATION RELATED RESEARCH
INITIATIVES AND ACTIVITIES.
THE START MEMBERS HERE ARE THE
PROGRAM OFFICIALS WHO ORIGINALLY
WORKED TOGETHER TO KICKOFF THE
CONCEPT OF INTEROCEPTION WITHIN
THE NIH.
SOME OF YOU MAY BE FAMILIAR WITH
AT LEAST TWO ON GOING LARGE
INITIATIVES WITHIN THE NIH ONE
IS CALLED THE SPARK AND IT
STANDS FOR STIMULATING
PERIPHERAL ACTIVITIES TO RELIEF
CONDITIONS AND IT'S A 10-YEAR
COMMON FUND INITIATIVE WHICH
FOCUSED ON NEURO STIMULATION OF
THE PERIPHERAL ORGANS.
AND THE BRAIN INITIATIVE, THAT'S
AIMING AT REVOLUTIONARY OUR
UNDERSTANDING OF THE HUMAN
BRAIN.
IN 2018, WITH THE SUPPORT OF THE
NIH BLUEPRINTS FOR NEUROSCIENCE
RESEARCH WE LAUNCHED A NEW BLUE
PRINT INITIATIVE CALLED
INTEROCEPTION, AIMING TO CONNECT
THE BRAIN AND BODY AND FILL THE
KNOWLEDGE GAPS BETWEEN SPARC AND
BRAIN INITIATIVE.
AS Dr. SHURTLEFF MENTIONED
EARLIER, WE KICKED OFF THAT
EFFORT WITH A TWO-DAY WORKSHOP
IN 2019 AND THE WORKSHOP
FEATURED TWO KEYNOTE SPEAKERS
WHO MANY OF US HAVE FAMILIAR
WITH NOW AND WHO PROVIDED A LOOL
AND Dr. HUGO WHO GAVE US A
REVIEW ON THE NERVOUS SYSTEM
DISORDERS THAT ARE IMPACTED BY
DYSFUNCTIONS OF THE
INTEROCEPTION PROCESSES AND
PERIPHERAL ORGANS.
WE DECIDED TO HAVE
A PROGRESS OF REGULATING.
WE PUBLISHED A RFA AS Dr.
SHURTLEFF MENTIONED EARLIER AND
WITHIN THE BLUE PRINT WE DECIDED
TO FOCUS ON THE MAPPING,
FUNCTIONAL MAPPING OF THE
CONNECTIONS BETWEEN THE
PERIPHERAL ORGANS AND THE BRAIN
AS OUR VERY FIRST STEP TO
SUPPORT RESEARCH ON
INTEROCEPTION.
FOR THAT RFA, WE BASICALLY LAID
OUT THE NEURO PATHWAYS THAT
WE'RE HOPING THE SCIENTIFIC
COMMUNITY WILL BE ABLE TO MAP
OUT AND THAT INCLUDES THE
ASCENDING NEURO PATHWAYS AND
ACTUALLY THIS IS PROBABLY A GOOD
WAY TO -- IT'S NOT SENSING
ANYTHING.
BASICALLY WE WILL MAP NEURO
PATHWAYS ARE COMING FROM THE
PERIPHERAL ORGANS THAT GO
THROUGH EITHER THE VAGAL NERVES
AND GET INTO THE BRAIN OR GO
THROUGH THE DORRAL GANGLIA AND
THE SPINAL PATHWAY TO GET INTO
THE BRAIN AND WITHIN THE BRAIN,
WE WILL LIKE TO HAVE A MORE
IN-DEPTH UNDERSTANDING ABOUT THE
CIRCUS INVOLVED IN THE BRAIN OF
SENSING AND MOSTLY INTERPRETING
INTEGRATING THOSE INTERNAL
SIGNALS AND AS WELL AS THE
ACTUALLY GENERATING POTENTIALLY
REGULATING SIGNALS THAT WILL
THEN COME BACKOUT OF THE BRAIN
SO EITHER THE VAGAL PATHWAY OR
THE SPINAL PATHWAY AND TO
REGULATE THE INTERNAL SIGNALS OF
THE PERIPHERAL.
THOSE ARE THE SCOPE OF THE
PARTICULAR RFA THAT WE PUBLISHED
AND THAT RFA, I'M PLEASED TO SAY
THE RFA HAD ATTRACTED VERY LONG
PROPOSALS ACROSS THE SCIENTIFIC
COMMUNITY AND THE BLUE PRINT
INITIATIVE WAS ABLE TO SUPPORT
SEVEN OF THE AWARDS.
IF MY SLIDES WOULD SHOW YOU
WOULD BE ABLE TO SEE A NICE
DISTRIBUTION OF THOSE SEVEN
AWARDS AND ALL OF THE AWARDEES
ARE HERE TODAY AND WE WILL BE
HEARING THEIR INITIAL EFFORTS
FUNDED BY THIS INITIATIVE.
SO WITHIN THIS AMONG OF SEVEN FN
AWARDS WILL STUDY VAGAL PATHWAYS
AND THREE OF THEM STUDY SPINAL
PATHWAYS AND WITHIN THE BRAIN,
THE SEVEN AWARDS WILL
COLLECTIVELY TEST ALL THE
HYPOTHESIZED BRAIN AREAS
INVOLVED ON HUMAN IMAGING
STUDIES AND SOME OF THEM WILL GO
EVEN BEYOND TO TEST SOME OF THE
BRAIN AREAS THAT HAVE NOT BEEN
KNOWN, MAYBE INVOLVED IN
INTEROCEPTION AND YOU MAY HEAR
ABOUT SOME OF THOSE WORK TODAY.
AS THE BLUE PRINT RFA FOCUSED
MORE ON THE BASIC PHYSICAL
OWOLOGY OF PHYSIOLOGICAL PROCESS
OF INTEROCEPTION WE ALSO FOLLOW
THE PUBLICATION OF RFA WITH A
MULTI-IC FUNDING OPPORTUNITY
ANNOUNCEMENT IN THE FORM OF
NOTICE OF SPECIAL INTEREST
ISSUED BY 10 OFFICES INCLUDING
NCCH, NATIONAL INSTITUTE OF
AGING, DENTAL AND CRANIAL
RESEARCH, DRUG ABUSE,
ENVIRONMENTAL HEALTH AND
SCIENCES AND AT NIHS AND MENTAL
HEALTH AND CANCER INSTITUTE, AND
NATIONAL HEART LUNG AND SOCIAL
SCIENCES RESEARCH ON WOMEN'S
HEALTH.
THIS WILL LAST AT LEAST THROUGH
2024 AND RELEVANT TO THE
PARTICIPATING INSTITUTES AT NIH
AND I ENCOURAGE YOU THINK ABOUT
SUBMITTING THE APPLICATION
THROUGH THE NOTICE AND REACH OUT
TO THE SPECIFIC OFFICERS LISTED
IN THE ANNOUNCEMENT.
>>WE'RE GOING TO END UPTAKING
ANOTHER QUICK PAUSE AND WE'RE
GOING TO ACTUALLY SWITCH TO A
ZOOM MEETING AND THAT IS GOING
TO BE LIVE CASTED AS WELL SO THE
PEOPLE THAT ARE ON-LINE JUST
STAY TUNED AND THAT WILL GET
SWITCHED OVER.
>>OF COURSE, AGAIN, WE HAVE AN
ABUNDANCE OF OPTIONS AVAILABLE
TO US.
WE CAN GO ELECTRICAL STIMULATION
THAT USED IN CLINICS FOR DBS FOR
INSTANCE AND THERE WE HAVE TO
PRECISION BUT WE LACK THE CELL
TYPES SPECIFICITY AND IF WE NEED
THAT WE CAN TURN TO CONTROLLING
SPECIFIC CELLS WITH LIGHT
HOWEVER IT REQUIRES GENETIC
HARDWARE AND WE CAN TURN TO
PHARMACOLOGY TO GET ACCESS TO
SPECIFIC RECEPTORS AND THERE WE
MAY NOT HAVE ACCESS TO SPECIFIC
CELLS AND WE ALSO MAY HAVE
LIMITED PRECISION UNLESS WE
RESORT TO INVASIVE DEVICES THAT
MAYELING CHALLENGING.
WE HAVE VERSION OF PHARMACOLOGY
ENDOWING US STRUGGLING WITH THE
FAPHARMACOLOGY.
SO IF WE ARE THINKING ABOUT THE
SIMULTANEOUS RECORDINGS WE NEED
TO THINK OF INTEGRATION OF ALL
THE DIFFERENT MODALITY AND OUR
DEVICES ARE BULKY AND DIFFERENT
DESIGN CRITERIA NOT MET FOR
DIFFERENT TECHNOLOGY BUT ALSO,
THE ABILITY TO INTERFACE WITH
ORGANS WITHOUT DAMAGING THEM
DIMINISHES AND BECAUSE ALREADY
THEY ARE STRUGGLING A MISMATCH
WITHIN THE TISSUE THAT WE'RE
TRYING TO RECORD FROM OR
MODULATE AND THE DEVICE
AVAILABLE TO US SO HOW DO WE
SOLVE THOSE TWO CHALLENGES
SIMULTANEOUSLY AND COMBINE TOOLS
FOR RECORDING AND MODULATION IN
THE CONTEXT OF BRAIN ORGAN
CIRCUITS?
IN OUR GROUP, WE BORROW FROM
TELE COMMUNICATIONS AND WE
DESIGN FIBER-BASED DEVICES
CAPABLE OF SIMULTANEOUS
INTERROGATION AND RECORDING OF
NEURAL ACTIVITY AND THE WAY
FIBER WORKS, IT STARTS WITH THE
MAMACRO SCALE MODEL AND INTO THT
MACRO SCALE MODEL WE CAN
INCORPORATE ALL THE DESIRED
FEATURES, A POLYMER AND MICRO
FLUID FOR DRUG DELIVERY AND
ELECTRICAL CONDUCTIVE CHANNELS
FOR RECORDING AND TAKE THAT
STRUCTURE THAT IS IN THE MACRO
SCALE WITH THE NUMBER OF
CENTIMETERS OR INCHES AND HEAT
IT AND PULL IT DOWN AND THE
FEATURES TA STARTED OUT AS
CENTIMETERS BECOME MYCRONS SO
NOW WE HAVE A DEVICE AND CAN DO
UP DRUG DELIVERY RECORDING AND
WE CAN APPLY TO SIMULTANEOUS'
DELIVERED GENES AND ENDOW
OURSELVES WITH ON STICKAL
SENSITIVITY AND MONITOR WHEN THE
OPTICAL SENSITIVITY IS
SUFFICIENT FOR US TO MANIPULATE
BEHAVIOR SUCH AS IN THIS
EXPERIMENT WHERE WE SEE OPTICAL
CONTROL OF NEURAL ACTIVITY
BECAUSE POSSIBLE 11 DAYS AND
THEN IT BECOMES MORE AND MORE
ROBUST AS THE TIME GOES ON.
AND AS WE LEARN WHEN TO START
OUR BEHAVIOR BEHAVIORAL EXPERIE
CAN PROVIDE IT IN THE BRAIN AND
START UNDERSTANDING NOT ONLY
INDIVIDUAL REGIONS AND CELL
TYPES BUT CIRCUITS.
IF YOU LOOK AT AN EXAMPLE OF THE
PROJECTION BETWEEN HIPPOCAMPUS
AND BLA IMPLICATED IN ANNE
SIGHLY LIKE PATTERNS IN RODENTS,
WE CAN APPLY OUR DEVICES TO
MODULATE THIS PROJECTION IN A RA
VI TVARIETY OF WAYS IN AN OPEN D
TEST.
YOU CAN SEE AS A CONFIDENT MOUSE
EXPLORES THE CORNERS BUT THE
CENTER OF THE OPEN FIELD.
WHEN WE STIMULATE THE EXCITED
TERMINALS FROM AMYGDALA OUR
ANIMAL IS MORE ANXIOUS AND
STARTS STICKING TO THE CORNERS
BUT NOW, THIS EFFECT IS QUITE
ROBUST, BUT NOW WE CAN ACTUAL
LOW USE OTHER FEATURES OF OUR
DEVICE SUCH AS MICRO FLUIDICS
AND WE CAN INJECT A BLOCKER CNQX
AND COUPLE IT AND ABOLISH THE
EFFECT OF STIMULATION DURING
BEHAVIOR AND SHOWING US HOW WE
CAN APPLY ALL OF THESE
MODALITIES AND OF COURSE, THIS
DEVOICE IS I HAVE SHOWN YOU ARE
BASED ON POLYMER AND POLYMERS
STILL HAVE GIG A PASCALS RATHER
THAN THE ORGAN TISSUE THAT
ACTUALLY HAVE MECHANICS OF
JELL-O SO HOW CAN WE MAKE OUR
DEVICES SO SENSE THEY WILL BEND
EVEN WHEN THEY TOUCH JELL-O BUT
AT THE SAME TIME FUNCTIONAL.
WELL, LET'S MAKE THEM REALLY
SMALL AND INCORPORATE THEM INTO
ACTUAL JELL-O SUCH AS HYDRO GELS
SHOWN HERE.
HOW DOES IT WORK?
WE TAKE A TINY STRUCTURE ALL OF
WHICH CAPABLE OF RECORDINGS
STIMULATION DRUG DELIVER ROW AND
PUT THEM TOGETHER INTO ONE
STRUCTURE AND IMBED THEM INTO A
HIGHDRO GEL AND WE HAVE A DEVICE
AS THIN AS YOUR HAIR AND
MECHANICS OF A WET GOOD NOODLE.
WE LEARN FROM THE WORLD OF ART
AND THINK THE PAINT BRUSH
INDIVIDUAL BRISTLE ARE --
>>SO HOW IS IT HELPING US IN
OUR JOURNEY TO UNDERSTANDING
INTEROCEPTION.
HOW DO
>>SO, IF THE VIDEO ACTUALLY
PLAYED, WHICH YOU WOULD OBSERVE,
IS THAT THE GUT NOT ONLY IS VERY
THIN STRUCTURE, THAT HAS WALL
THICKNESS OF ABOUT 300 MYCRONS
IT'S UNDER A CONTINUOUS MOTION.
>>USE THEIR SOFT MECHANICS TO
ENABLE INTER FACES DIRECTLY INTO
THE SPACE.
WE CAN ASK OURSELVES IF WE'RE
ABLE TO MODULATE CELLS WITHIN
THE GUT WOULD THAT INFLUENCE
THIS ANIMALS BEHAVIOR IN THE
CONTEXT FIRST OF SOME BEHAVIORS
THAT ARE PARTICULARLY LINKED TO
THE GUT SUCH AS PREFERENCE FOR
NUTRIENTS.
AND FOR THIS WORK, WE
COLLABORATED THIS
SO WE THOUGHT CAN WE TEST THOSE
HYPOTHESIS IN THE CONTEXT OF OUR
ACTUAL BEHAVING ANIMAL BECAUSE
IT WAS ONLY POSSIBLE IN VITRO.
WORKING TOGETHER WITH DIEGO, WE
ASKED WHETHER THOSE ENDOCRINE
FOR SUGAR IN BEHAVING ANIMALS.
MICE VERY QUICKLY LEARN THAT
IT'S MORE VALUABLE THAN
SUCRALOSE AND IF HE THEY INHIBIT
THE CELLS AND IT'S DONE IN A
AWAKE, MOVING ANIMALS.
LET'S PUT THIS ALL TOGETHER.
CAN WE USE THOSE TYPES OF PROBES
AS I HAVE SHOWN YOU IN THE BRAIN
AND THE GUT TO INTERFACE WITH
BOTH OF THOSE SYSTEMS
SIMULTANEOUSLY.
CAN WE INTERFACE WITH THE BRAIN
TO RECORD WHAT HAPPENS IN THE
GUT AND VICE VERSA AND THEY'RE
MAKING INITIAL STEPS AND WE'RE
INTEGRATING SOPHISTICATED SOLID
STATE ELECTRONICS INTO OUR
FIBERS SO THAT WE CAN MANIPULATE
THEM WIRELESSLY AT THE DISTANCE
USING A SIMPLE COMPUTER
INTERFACE AND HERE YOU ARE
SEEING MANIPULATE OF DIFFERENT
COLOR LEDs AS WELL AS DRUG
INJECTIONS AND IF THIS VIDEO
PLAYS, YOU WOULD SEE BOTH OF
THOSE DEVICES IN REAL-TIME AND
SO LET'S TRY THIS ONCE.
SO, UNFORTUNATELY, WE ARE NOT
ABLE TO SEE THE VIDEOS BUT IF
YOU SAW THE VIDEO, WHAT YOU
WOULD SEE IS DEVIS THAT IS ABOUT
SEVERAL INCHES LONG THAT HAVE
BLINKING LEDs AND ON THE SAME
TIME OF THE INTERFACE YOU WOULD
SEE A BRAIN PROBE FOR A MOUSE
HAVING ITS LEDs CONTROLLED AT
THE DISTANCE AND LEDs ARE THE
ONLY FLASHY PART OF OUR DEVICE,
WE HAVE SENSORS THAT ARE NOT SO
VISUALLY APPEALING THAT WORK
WELL.
SO NOW, LET'S TRY THIS IN THE
CONTEXT OF AN ACTUAL BEHAVIOR
AND THE BEHAVE YEAR THAT WE ARE
GOING TO USE WILL BE A SIMPLE
REWARD TASK.
IF YOU WERE TO CELL REWARD AT
THE LEVEL OF THE BRAIN, YOU
WOULD IMPLANT A DEVICE INTO ONE
OF THE REWARD CENTERS AND SUCH
AS AREAS AND THAT HAS HIGH
POPULATION OF THE NEURONS AND
THEN IF WE EXCITE THOSE NEURONS
WE SEE AND WE CAN TEST IT IN THE
PREFFENS IF ONE SIDE OF THE
CHAMBER ANIMAL RESERVICE
SIMULATION ON THE OTHER IT
DOESN'T AND THEN IF THERE'S
DOPAMINE INVOLVED IT WILL PREFER
THIS STIMULATION SIDE AND THIS
IS EXACTLY WHAT WE SEE AND IT'SA
VERY ROBUST EFFECT.
LET'S TRY A MORE INTERESTING
EXPERIMENT.
INSTEAD, LET'S STIMULATE VAGAL
AT THE SMALL INTESTINE AND NOW
ASK OUR ANIMAL TO ALSO CONDUCT
THIS PLACE PREFERENCE ESSAY.
WE SEE THE SAME THING.
WE NOW SEE BY STIMULATING THIS
ANIMAL AT THE LEVEL OF VAGAL
AFFERANCE WE CAN MODULATE THEIR
BEHAVIOR.
THIS IS NOT NEWS TO SOME OF US
THAT THE DOCTOR WHO HAS
DISCOVERED A CIRCUIT THAT
CONNECTS FROM THE GUT TO REWARD
STRUCTURES IN THE BRAIN IN THE
BRAIN.
AND WE SEE CONSISTENT EFFECTS.
SO NOW WE HAVE TALKED A LITTLE
BIT ABOUT HOW WE CAN USE
NEUROTECHNOLOGIES TO MODULATE
NEURAL ACTIVITY AT THE LEVEL OF
CIRCUITS AND THE LEVEL OF
NEURONS AND WE CAN DO IT BOTH IN
THE BRAIN AS WELL AS FOR ORGANS
AND IF WE WERE TO UNDERSTAND
FUNDAMENTAL BLOCKS OF NEURO
COMMUNICATIONS, WE NEED TO START
THINKING ABOUT OUR CHANNELS AND
PROTEINS AND DO SO AT THE NANO
SCALE.
SO HOW DO WE MANIPULATE
ACTIVITIES OF THOSE MOLECULES AT
THEIR SCALE?
FOR THAT WE NEED TO BE ABLE TO
DELIVER A STIMULUS DEEP INTO THE
BODY WITHOUT ACTUALLY AFFECTING
THE BODY.
AND THE ONLY FIELD THAT IS
CAPABLE OF DOING THIS IS
MAGNETIC FIELDS.
IT'S THE ONLY FIELD THAT CAN
PENETRATE ARBITRARILY DEEP INTO
THE BODY AND IT'S NOT PERTURBED
BY THE SKULL O EPI -- THEY'RE
SMALLER THAN THE MRI MAGNATE
INTO SOMETHING THAT BIOLOGY CAN
UNDERSTAND.
WE CAN PROVIDE SMALL MAGNETIC
PART CALECHES THAT ABOUT 1/5,000
OF YOUR HAIR THAT CONVERTS THOSE
STIMULI INTO, FOR EXAMPLE,
THERMAL STIMULUS TO MODULATE
THERMO RECEPTORS AND THEY CAN
NEURO CHEMICALS TO CONTROL CHEEP
OWE RECEPTORS OR APPLY TENSION
FORCES AND MODULATE RECEPTORS
AND A NUMBER OF YEARS AGO, WE
HAVE STARTED EXPLORING THIS IDEA
BY FIRST DEMONSTRATING THAT WE
CAN SYNTHESIZE NANOPARTICLES OF
IRON OXIDE THAT HAVE A MAGNETIC
MOMENT AND IF THAT MAGNETIC
MOMENT IS SUBJECTED TO A
MAGNETIC FIELD IT WILL ALIGN IN
THE SAME DIRECTION AND WHEN WE
SWITCH THE DIRECTION OF THE
FIELD, THE MAGNETIC MOMENT WILL
TRY TO SWITCH THE DIRECTION AS
WELL AND IN THE PROCESS IT NEEDS
TO OVERCOME AN ENERGY BARRIERS
AND THAT GETS DISSIPATED AS HEAT
AND IT CONTROLS TRIP V1 WHICH IS
BROADLY EXPRESSED IN THE NERVOUS
SYSTEM BUT ALSO IS AVAILABLE IN
SOME PARTS OF THE CENTRAL
NERVOUS SYSTEM.
AND SO NOW, LET ME MAKE MY FINAL
ATTEMPT PLAYING THIS MOVIE WHERE
IF IT'S ACTUALLY WORKED, WHAT
YOU WOULD SEE ON THE SIDE WHERE
THE CELLS ARE SENSITIVE TO HEAT,
THE PRESENCE OF THE
NANOPARTICLES SENSITIVE THEM TO
THE INPUT.
IT ALLOWS US TO REMOTELY CONTROL
HEAT SENSITIVE CELLS FROM A
DISTANCE IN FREE LOW MOVING
ANIMALS.
NOW WE AND ALSO PRODUCES STRESS
HORMONES AND INTERESTINGLY
ENOUGH, BOTH COURT A KILL CELLS
THAT PRODUCE CORTISOL AS WELL AS
EPI NEFF RIN BOTH CONTAIN THE
HEAT SENSITIVE CHANNELS AND
THOSE HEAT SENSITIVE CHANNELS
ARE PERMYABLE SO WE CAN APPLY
OUR THERMAL STIMULATION TO
HIJACK THIS ENTIRE CIRCUIT AND
REMOTELY CONTROL RELEASE OF
THOSE HORMONES THROUGH THE
MAGNETIC FIELD AND IN DEED, WHAT
WE FIND IN TISSUE CULTURES THAT
IN THE PRESENCE OF MAGNETIC
PARTICLES, MAGNETIC FIELDS IS
STUFF AND TO EVOKE CALCIUM
INFLUX INTO THOSE CELLS AND IT
DEPENDS ON THE PRESENCE OF TRIP
YO VAN CHANNEL BECAUSE IT
ABOLISHES THIS EFFECT AND
HOWEVER IF WE USE NON MAGNETIC
PARTICLE CONTROLS WHICH DO NOT
DISSIPATE HEAT, WE DO NOT SEE AN
EFFECT OF MAGNETIC FIELD.
WE CAN MOVE THIS IN VIVO AND TO
GENETICALLY INTACT COMPLETELY
UNMODIFIED RATS AND BASED ON OUR
INJECTIONS, WHETHER INTO CORTEX
OR THE MEDULLA, WE CAN RELEASE
ON DEMAND EITHER COURTIC IN
THOSE ANIMALS USING MAGNETIC
FIELD NOTHING TOUCHES THOSE
ANIMALS.
WE CAN TAKE IT ONE STEP FURTHER
AND LINK IT TO A RELEASE FROM
NEURO CHEMICALS FROM LIPOSOMAL
VAGAL AND ENDOW HEMO GENETICS SO
BY LOADING TO DESIGNER
RECEPTORS, INTO THOSE LINE SEEM
IT WILL OPEN FORCED TO RELEASE
THE DRUG.
SO NOW WE CAN APPLY THIS METHOD
TO CONTROL AGAIN, A RO REWARD
CIRCUIT.
WE FOR FOR A SWIM AT THE TEST.
I WILL TELL WHAT YOU THIS VIDEO
IS GOING TO LOOK LIKE.
THIS VIDEO DEPICTS A MOUSE THAT
IS HEAD AND SHOULDERS INSIDE A
MAGNETIC COIL AND SWIMMING IN A
BUCKET.
YOU CANNOT SEE IT'S HEAD AND
SHOULDERS BECAUSE THEY'RE NOT
TRANSPARENT AND YOU WILL HAVE TO
TAKE MY WORD FOR IT THAT THERE'S
NOTHING TOUCHING THIS ANIMAL.
IT LOOKS LIKE A WILD TYPE MOUSE.
IT'S COMPLETELY FREE OF HARDWARE
WITH THE EXCEPTION OF HAVING
INJECTIONS.
NOW, IF YOU TAKE A MOUSE AND PUT
THEM NO A CUP OF WATER ON THE
FIRST TRY THEY'RE MOTIVATED AND
THEY'RE STRUGGLING TO GET OUT
BUT IF YOU KEEP DOING THIS DAY
AFTER DAY, THEY LEARN THAT THEY
DON'T DROWN AND INSTEAD THEY
JUST WAIT FOR RESEARCHER TO TAKE
THEM OUT.
THIS PROCESS IS CALLED
ADAPTATION.
SO IN THIS VIDEO YOU HAVE ONE OF
THESE ADAPTED MICE THAT IS
LITERALLY SITTING THERE IN A CUP
OF WATER A RESEARCHER TO TAKE
THEM OUT.
INTO THEIR DOPAMINE BRAIN
STRUCTURE AREAS AND DOPAMINE
STARTS TO FLOW INTO THIS BRAIN
AND THE MOUSE BECOMES
EXCEPTIONALLY MOTIVATED TO SWIM
OUT OF THE BUCKET.
AND THIS IS QUITE REPRODUCE ABLE
AND WE CAN REPEAT IT MULTIPLE
DAYS IN THE ROW APPLIED TO
DIFFERENT ESSAYS NOT ONLY ESSAYS
SUCH AS FORM SWIM TEST BUT
SOCIAL ESSAYS AND PREFFENS ESSAY
ASK WE'LL SEE THE SAME RESULTS
CONSISTENT WITH THE FUNCTION IN
THE VTA.
SO FINALLY, WE HAVE TALKED A LOT
ABOUT MODULATING THERMO
RECEPTORS AND CHEMO RECEPTORS
AND HOW WE CAN TRANSLATE THOSE
TOOLS TO THE ORGANS BEYOND THE
BRAIN AND WE HAVE NOT TALKED
ABOUT TRANSLATING MAGNETIC FIELD
INTO MECHANICAL STIMULI WHICH
MAY BE OF IMPORTANCE GIVEN THE
FACT THAT THE RECEPTORS ARE
EXPRESSED AT GREAT DEGREE IN
ORGANS SUCH AS THE GUT AND MAY
CONTROL PHENOMENON SUCH AS GUT
PAIN OR SENSING THE SYSTEM.
FOR THAT WE NEED TO LEARN TO
APPLY FRACTIONS OF FORCE AND IT
MAY SOUND SMALL TO YOU BUT IT'S
HUGE AND THE MOLECULAR SCALE AND
YOU NEED EITHER VERY LARGE
MAGNETIC FIELD GRADIENTS SUCH AS
THOSE USED IN MAGNETIC 1-888- MR
WE NEED TO USE LARGE MAGNETIC
PARTICLES AND THOSE ARE MAGNETS
SO IF YOU TRY TO PUT THEM NO A
SOLUTION, WHAT YOU THINK WILL
HAPPEN THEY WILL ALL STICK TO
EACH OTHER AND FORM GIANT BALLS
THAT WILL BE USE LESS.
HOW DO WE OVERCOME THIS PROBLEM?
WE LEARN FROM MAGNETIC MEMBER
ROW FIELDS WHERE IT'S KNOWN THAT
WE CAN CREATE STRUCTURES WERE IN
THE ABSENCE OF MAGNETIC FIELDS,
ALL THE ATOMS LINEUP IN A CIRCLE
AND THAT STATE IS CALLED THE
VORTEX WHICH MEANS IN THE
ABSENCE OF THE MAGNETIC FIELD,
THEY'RE NOT ATTRACTED TO EACH
OTHER AND WHEN WE HEAR FROM THE
MAGNETIC FIELD IF IT'S VERY WEAK
AND THE PARTICLES AND THE LINEUP
IN PLANE AND NOW YOU HAVE A
PEDESTRIAPETAL TO ACHIEVE THIS L
MODULATION AND WE CAN TAKE THE
DISK AND TARGET THEM TO THE
MEMBRANES OF NEURONS IN THIS
CASE TO SENSOR NEWER ALS FROM
DOR SAL ROAD GANGLIA WHICH HAVE
SCEPTER EXPRESSED IN THEM AND WE
CAN APPLY WHAT IS GOING ON
THE SIDE THAT CONTAINS NANO
DISKS, YOU WILL SEE INFLUXES,
FLASHES OF NEURONS IN RESPONSE
TO A MAGNETIC FIELD WHILE IN THE
ABSENCE OF A NANO DISK NOTHING
HAPPENS AND INTERESTING THING
ABOUT THIS EXPERIMENT IS UNLIKE
EXPERTS I HAVE SHOWN YOU WITH
THERMAL MODULATIONS WITH
SOPHISTICATED ELECTRONICS, THIS
CAN BE DONE WITH THE GUITAR
AMPLIFIER AND WIRE.
SO IT'S MUCH, MUCH SIMPLER.
AND ANOTHER INTERESTING THING
ABOUT MECHANICAL STIMULATION
IT'S FAST.
WE NO LONGER HAVE TO WAIT FOR
HEAT DIS A PRECIPITATION OR DRUG
DELIVERY WE GET AN EFFECT OF
PULLING ON NEURONAL MEMBRANES
AND ACTUALLY INFLUXES EVOKED ON
MEDIATED BY THOSE SENSITIVE
CHANNELS.
SO NOW, WE HAVE FINALLY MADE IT
TO THE END AND HOPEFULLY I HAVE
CONVINCED YOU THAT BY LEVERAGING
NEURO TECHNOLOGY EITHER AT THE
MACRO AND MICRO SCALE SUCH AS
MULTI FUNCTIONAL FIBERS WE'RE
GOING FURTHER DOWN AND USING
MAGNETIC TO MODULATE RECEPTORS
WE CAN UNDERSTAND THE MULTITUDE
OF SIGNALING SCALES IN THE
ORGANS AND THE BRAIN AND
ACTUALLY STARTING APPLYING IT TO
OUR STUDIES OF INTEROCEPTION.
I WOULD LIKE TO THANK MY
TALENTED AND HARD-WORKING GROUP
OF TRAINEES AS WELL AS THE
GENEROUS SUPPORT FROM.
>>ESPECIALLY PILING THROUGH
WITH ALL THE TECHNICAL
DIFFICULTIESES.
WE DID HAVE ONE QUESTION FROM
ON-LINE.
AND REGARDING HEATING DAMAGE AND
THEY WANTED TO KNOW IF YOU CAN
FURTHER EXPLAIN HOW YOUR
MAGNETIC HEATING MECHANISM
SELECTIVE WITHOUT DAMA DAMAGINGR
CELLS WITH THE ENERGY OR HEAT
YOU ARE DISSIPATING, DOES THE
TECHNIQUE ONLY WORK WHERE
THERE'S SUBSTANTIAL AMOUNT OF
TRP1 HEAT SENSITIVE CELLS?
>>THAT'S A GREAT QUESTION SO IN
FACT, WEOPERATE OUR MODULATION
TO REACH TRIP V1 THRESHOLD
>>IN THOSE EXPERIMENTS AND THEY
HAVE OR OF COURSE CAN BE FULLY
DISCOUNTED THAT IF YOU
CONTINUOUSLY KEEP RAISING THE
TEMPERATURE IN A GIVEN ORGAN,
THAT YOU WILL START SEEING
LONG-TERM EFFECTS TO LONG-TERM
REMODELING, HOWEVER IN TERMS OF
SHORT TERM DAMAGE OR ACTUALLY
CLOSING, THIS IS NOT SOMETHING
THAT IS GOING TO HAPPEN BECAUSE
YOU WILL HAVE KEEP THE HEAT AT
THAT LEVEL FOR 30 MINUTES TO
START ACTUALLY KILLING NEURONS.
>>MY QUESTION IS, WITH REGARDS
TO REMOTE CONTROL TRANSDUCTION
HOW FOCUSED CAN YOU MAKE THE
MAGNET AND CAN YOU CONTROL FOR
EXAMPLE DIFFERENT PARTS OF THE
GI TRACT?
>>THAT'S A WONDERFUL QUESTION,
THANK YOU.
THIS IS THE LOCALE TEE OF THE
MAGNETIC STIMULATION DEPENDS ON
TWO THINGS, THE PRESENCE OF
CHANNEL MEDIATOR IN THE GIVEN
TISSUE AND THAT YOU CAN BRING IN
GENETICALLY OR RELY ON
ENDOGENOUS EXPRESSION AND WHERE
YOU PLACE THE PARTICLES AND SO
THE WHOLE POINT OF MAGNETIC
STIMULATION IS IT IS A EMPLOYED
TO A MAN MALL PERFORMING A TASK
IN AN ARENA AND ONLY THE CELLS
THAT HAPPENED TO BE IN THE
VICINITY ARE TARGETED BY THE
PARTICLES WILL GET STIMULATED
AND TARGETING IS A CHALLENGING
QUESTION AND THAT IS WHY I WAS
VERY FORTUNATE TO RECEIVE THE
PIONEER AWARD TO SOLVE THAT
PROBLEM AT THE ENABLE THIS SORT
OF CELL TYPE SPECIFIC AND.
>>I KNOW WE'RE BEHIND SCHEDULE
AND I'LL LIKE TO INTRODUCE OUR
OPERATOR, Dr. HEIKE
MUENZBERG-GRUENING.
>>WELCOME TO SESSION 1,
EVERYONE.
SO THIS IS ABOUT THE DIGESTIVE
SYSTEM BRAIN CONNECTIONS AND
WE'RE GOING TO HAVE FOUR
SPEAKERS HERE AND SO THEY'RE
GOING TO GO ONE AFTER THE OTHER
AND I'M JUST GOING TO GO THROUGH
THE HAWKS THAT WE HAVE RIGHT NOW
AND EVERY PRESENTATION IS GOING
TO BE 15 MINUTES IF WE HAVE TIME
AND OTHERWISE WE'LL COLLECT
QUESTIONS UNTIL THE END OF THE
SESSION SO WE'RE GOING TO BE A
JOINT QUESTION FOR 25 MINUTES.
AND THE FIRST SPEAKER IS
FUNCTIONAL NEUROCIRCUIT OF THOM
AK BRAIN INTER OWE EXCEPTION
WHICH IS ZHONGMING LIU AND THE
SECOND FROM Dr. IVAN DE ARAUJO
FROM THE ICAHN SCHOOL OF
MEDICINE AT MOUNT SINAI AND THE
NEXT IS GUT-TO-BRAIN CIRCUITS
UNDER LIG FLUID FROM Dr. YUKI
OKA AND THE FOURTH SPEAKER IS
GOING TO ABOUT FUNCTIONAL
IDENTIFICATION OF VAGAL SENSORY
NEURONS INNER RATE ISING THE
LIVER FROM Dr. YOUNG-HWAN JO.
PLEASE, TAKE THE FLOOR.
FOR ON-LINE QUESTIONS WHICH
REFER TO EACH SPEAKER YOU ASK
THE QUESTION FOR THE END
QUESTION AND ANSWER SO MAYBE
IT'S ONE FOR SPEAKER ONE THAT
WOULD BE GREAT.
>>THANK YOU FOR THE
INTRODUCTION, I HOPE THE SLIDES
DISPLAY PROPERLY ON THE ZOOM
SIDE.
IT'S MY GREAT PLEASURE TO BE A
PART OF THIS MEETING AND I HAVE
RECEIVED A FUND TO GO DO THIS
PROJECT AND THE PROJECT FUNCTION
NEUROCIRCUITS OF STOMACH-BRAIN
INTEROCEPTION.
WE BOTH OF US WILL BE HAPPY TO
ANSWER QUESTIONS AND JOINING ME
IS JIANDE AN CHEN.
OUR PROJECTS ARE TRYING TO
ADDRESS THE QUESTIONS OF HOW THE
BRAIN AND INTERACTS WITH THE
STOMACH AND WE ARE LOOKING AT
THIS FROM THE LEVEL OF FUNCTION
NEUROCIRCUITS AND
IT'S PROPAGATING ALONG THE
STOMACH AND ALSO THE
ACCOMMODATION THAT ALLOWS THE
STOMACH TO STORE THE FOODS AND
HOW TO STOMACH AND HANDLES
DIFFERENT NUTRIENTS.
AND THEN, THIS TYPE OF PROJECTS
THAT INVOLVES A LOT OF DIFFERENT
EXPERTISE, WE HAVE EXPERTS IN
MRI AND ELECTRIC
PHYSIOLOGY AND.
>>CAN BE CONFIRMED WITH RESPECT
TO THE DEFERENTIAL
CONSTITUTIONAL VAGAL AND WE CAN
CUT THE VEGAS NERVE SO SEE HOW
MUCH THE ACTIVATION WOULD
DIMINISH AND WOVE FOUND A
SUBSTANTIAL LESS BRAIN
ACTIVATION WHEN WE CUT THE NERVE
AND IT WILL BE USED OVER THE
COURSE OF OUR PROJECT AND WE
ALSO ACTUALLY LOOK AT THE
INTRINSIC BRAIN NETWORKS AND
AGAIN THIS IS USING A TECHNIQUE
CALLED RESTING STATE FUNCTIONAL
CONNECTIVELY AND USED IN HUMANS
AND AND HOWEVER IT'S NOT BEEN
RELATED TO THE INTRO PROCESSES
AND WE ACTUALLY FURTHER ACTUALLY
LOOKED AT THIS AND THE WAKE
ANIMALS USING A PRODUCT
ESTABLISHED IN OUR COLLABORATOR
JOB AT PEN STATE AND WE TRAINED
ANIMALS TO STAY AWAKE IN MRI
WHILE WE SCAN THEM AND IT TAKES
ONE WEEK OF TRAINING AND OVER
THE COURSE OF ONE WEEK THE
ANIMAL IS RELATIVELY STILL AND
RELATIVE AND LOW AND INSIDE OF
MRI FOR AN HOUR.
AND SINCE THE START OF THIS
PROJECT WE LOOKED AT THIS
INTRINSIC FUNCTIONAL AND IS THE
DORRAL VAGAL COMPLEX IN THE
BRAIN STEM WHERE THE INFLOW AND
OUTFLOW INFORMATION AND A LOT OF
VISCERAL ORGANS AND THEY WILL
PASS THROUGH AND WE LOOK AT THE
INTRINSIC FUNCTIONAL ACTIVITY TO
THE AND WE HAVE IDEA NUMBER OF
AREAS SIMILAR AND WE UNDERSTOOD
ABOUT AND THE NET WICK AND
INVOLVING THE SINGLE CORTEX
HYPOTHALIMUS, THALAMUS AND SOME
OF THE BRAIN STEM NUCLEUS AND
WE'RE TRYING TO UNDERSTAND THE
FUNCTIONAL ROWS.
IT GIVES US ANOTHER AND WE CAN
SEE THE STOMACH MOVEMENT THAT
THE MOVEMENT OF THE ENTIRE GI
TRACT USING MRI AND FORTUNATELY
THIS TIME THE VIDEO PLAYS.
WE CAN LOOK AT NERVE ACTIVITY
AND ONE WAY TO LOOK AT THEN
INJECT THE CONTRAST AGENT INTO
THE GANGLION AND TO THIS TYPE OF
CONTRAST CONTAINS AND WE TEST
THE FEASIBILITY OF THIS BY
SAYING THAT IF WE INJECTED THE
CONTRAST AGENT INTO THE LEFT
GANGLION WE'LL SEE THE LEFT
LIGHT UP AND WE ALSO SEE SOME OF
THE DOWNSTREAM NUCLEUS LIGHT UP
SO WE'LL CONTINUE EXPLORING THIS
TECHNIQUE FOR MAPPING THE
CENTRAL CIRCUITS THROUGH THE
ASCENDING PATHWAYS.
AND THIS IS NOT JUST A TRACING
BUT IT'S ALSO A FUNCTION MATCHES
OF THE NERVE TECH TO HAVE WHEN
WE UP REGULATE THE VEGAS NERVE
STIMULATING THE VEGAS NERVE
THERE'S MORE UPTAKE AND LEVEL OF
NTS AND WE ALSO ANTICIPATE THAT
WHEN WE ACTUALLY PERTURBED THE
CIRCUITS IN DIFFERENT WAYS WE'LL
MATCH OUT DIFFERENT FUNCTIONS OF
CIRCUITS IN THE BRAIN.
WE CAN ALSO RECORD FROM THE NTS
NEURONS AND RESPONDING TO THE
GASTRIC INTEROCEPTION SO WE CAN
LOOK AT IT IN THE MULTI UNIT
LEVELS AND WHAT IS OF PARTICULAR
INTEREST WHEN WE APPLY THE
STIMULATION TO A TYPE OF VAGAL
AVENUE REASONS ON THE STOMACH,
THE ACTIVITIES AND WE APPLY THE
STIMULATION AND SURPRISINGLY WE
FIND THIS TYPE OF NEURONS ARE
HIGHLY SENSITIVE TO THE OREN
TAKE OF THE STIMULATION AND
STIMULATE THE STOMACH AND MAP
OUT THE FUNCTIONAL CIRCUITS
INVOLVED IN THE GASTRO
INTEROCEPTION.
AND THIS IS A TRUE FOR TWO
DIFFERENT AND ONE IS THE VAGAL
FOR THE MUSCLE AND THE OTHER IS
THE CIRCULAR MUSCLES AND FOR
THOSE CASES, THE ORIENTATION
SELECTIVITY IS TRUE.
NOW LOOKING AT THE SPONTANEOUS
STOMACH IN THE BRAIN
INTERACTIONS THAT WITHOUT ANY
STIMULATION THAT ACTUALLY THE
STOMACH AND THE BRAIN INTERACTS
IN REAL-TIME AND THIS IS A HUMAN
STUDY BY A GROUP IN FRANCE AND
LED AND THEY RECORD THE GASTRIC
SLOW WAVE IN THE STOMACH THE
BRAIN ACTIVITY IS FACE LOCKED TO
THE GASTRO RHYTHMS AND WE'RE
INSPIRED BY THAT SO WE END UP
REPLICATING THIS STUDY IN THE
RAT MODEL SO WE RECORD A GASTRIC
SLOW WAVE AND REASON AND PROFESR
JIANDE CHEN IS AN EXPERT IN
THIS.
WHAT PEOPLE REPORT IN HUMANS
THERE'S A REAL-TIME GUT RING
INTERACTION AND ITSELF THE
STOMACH BRAIN COHERENCE IN TERMS
OF THE SIGNALS.
AND WE ARE INTERESTED IN WHAT IS
THIS INTERACTION SO WE ACTUALLY
CUT THE NERVE AND TRIED TO SEE
HOW MUCH THE VEGAS AFTER
CONTRIBUTING TO INTERSECTION.
THE SURPRISINGLY WHEN WE CUT THE
NERVE THIS INTERACTION IS ALMOST
GONE AND SO THIS ACTUALLY
SUGGESTS A CENTRAL ROLE OF THE
VEGAS IMMEDIATE STOMACH AND
BRAIN AND WHEN WE CUT THE NERVE
AND WE SEE THE STOMACH STILL CON
TRACTS AND THE REASON IT EXISTS
SO THIS RHYTHM IS REALLY A
REASON THAT THE PASSING FROM THE
STOMACH INTO THE BRAIN AND NOT
THE OTHER WAY AROUND.
NOW WE'RE LOOKING AT THE GASTRIC
SLOW WAVES AND WE'RE LOOKING AT
THE ACTIVITY IN THIS CASE THAT
WE PUT THE THE CON VAXES IN
REAL-TIME AND IT'S THE WE'RE
GOING TO BEGIN TO LOOK AT A
MECHANICAL ACTIVITY AND HOW IT'S
SYNCHRONIZED WITH BRAIN ACTIVITY
IN REAL-TIME.
I RAN OUT OF TIME.
THIS TECHNOLOGY ARE TRANSLATABLE
TO HUMANS AND ACTUALLY AS PART
OF TRYING TO LOOK AT THIS IN A
HUMANS AS WELL AND RECORDING A
LOT OF ORGAN FUNCTIONS THE
HEART, LUNG AND THE AROSAL
SIGNALS AND EMOTIONAL RESPONSES
AND HOW THEY'RE MAPPED OUT INTO
THE BRAIN.
WITH THAT I'D LIKE TO CONCLUDE.
I HOPE I CONVINCED YOU THAT WE
HAVE A NUMBER OF DIFFERENT
TECHNOLOGIES AND FOR STUDYING
THE STOMACH-BRAIN INTERACTION
FROM REAR TIME AND THE VAGUS AND
GASTRIC NEURONS AT THE NTS ARE
OR'EN TAKE SELECTIVE AND WE CAN
DO IT IN AWAKE ANIMALS AND WE'RE
LOOKING FORWARD TO THE
OPPORTUNITY TO DO THIS IN HUMANS
AS WELL.
[APPLAUSE]
THANK YOU, I THINK WE HAVE TIME
FOR ONE QUESTION AND IF Dr.
ARAUJO IS ALREADY MOVING UP AND
OPEN HIS PRESENTATION SO WE CAN
HAVE ONE QUESTION FOR Dr. LIU.
ANY QUESTIONS IN THE ROOM OR IN
THE CHAT ROOM?
I HAVE A QUESTION.
WHAT DO YOU THINK WOULD BE THE
FUNCTION OF THE -- FOR EXAMPLE,
FOR BARIATRIC SURGERY, WHAT
WOULD THAT TRANSLATE?
WOULD IT MODIFY THE AMOUNT OF
FOOD INTAKE?
BODY WEIGHT, WHAT IS YOUR
SUGGESTION HERE?
>>THE SURGICAL PROCESS HAS
DEFINITELY IMPLICATIONS AND WE
ACTUALLY, SOME OF THE STUDIES IN
ACUTE SETTINGS AND WE HAVE A
SHAM CONTROL AND SOME OF THIS
ARE INVOLVING THE CHRONICLE
IMPLANTATION SO HOPEFULLY IN
THOSE CHRONIC SITUATIONS, THE
IMPACT OF THE SURGERY IS MORE
CONTROLLABLE AND IT WILL BE LESS
OF A CONCERN.
>>IT'S AMAZING HOW PRECISE YOU
CAN ALSO PINPOINT THESE BRAIN
AREAS AND I MEAN, IT WAS USUALLY
YOU CANNOT GO THAT DEEP, RIGHT.
>>WEST RESOLUTION ABOUT A
$.2 MILLION RESOLUTION RAT
BRAIN.
IT'S NOT HIGH ENOUGH BUT IT WILL
GIVE US AN IDEA OF WHICH WILL BE
INVOLVED IN THE GASTRO
INTEROCEPTION.
>>VERY EXCITING.
>>GO AHEAD.
>>SO, THANK YOU SO MUCH FOR THE
INVITATION AND FOR BEING PART OF
THIS PROGRAM.
SO, I'LL BE SPEAKING A LITTLE
BIT ABOUT THE SPINAL GUT-BRAIN
PATHWAY.
SO, IN TERMS OF RATIONALE, OVER
THE LAST 50 OR 60 YEARS, WE
FORMED THE FIRM IMPRESSION THAT
THE MAIN CONDUCT OF INFORMATION
FROM THE GUT TO THE BRAIN IS THE
HAVING US NERVE.
WITH BLOATING AND FULLNESS THAT
IS PRESUMABLY A FUNCTIONAL UNIT
IN THE CONTROL OF FOOD INTAKE.
HOWEVER, MORE CAREFUL ANALYSIS
OF THE DATA ON THE VAGUS NERVE
ON VAGUS NERVE LESIONS OVER THE
YEARS, DO NOT SHOW AT ALL
ACTUALLY THAT DISRUPTING THE
NERVE WILL LEAD TO A GREATER
INTAKE OR TO AN ACCESS OF
GASTRIC FULLNESS AS WOULD BE
EXPECTED, IF THE SYSTEM WOULD BE
PERFORMING SUCH FUNCTIONS.
SO, ONE POSSIBILITY TO EXPLAIN
HOW WE FORM THIS CONSCIOUS CLEAR
PERCEPTION OF FULLNESS AND
GASTRIC DISTINCTION IS THAT
ANOTHER LESS STUDIED GUT BRAIN
PATHWAY THE SPINE AT SENSORY
PATHWAY MAY BE INVOLVED IN
CESSATION.
ARGUING FOR THIS POSSIBILITY IS
ANOTHER ORGAN, THE BLADDER.
SO THE BLADDER IS VERY SIMILAR
TO THE STOMACH IN SENSORY TERMS
IN MANY WAYS.
SO, WE HAVE A CONSCIOUS
PERCEPTION OF THE STATE OF THE
BLADDER AND IT CAN GO FROM MILD
FULLNESS TO HARD FULLNESS AND
EVEN TO A STATE OF VERY
UNCOMFORTABLE SENSATION OR THE
CEASE SESSION ARE ARRIVING FROM
THE BLADDER ARE CONVEYED FROM
THE SPINAL SYSTEM.
IT'S A SPINAL CORD FROM THERE
VIA THE SPINAL CORD IT REACHES
THE BRAIN AND PRESUMABLY
CORTICAL CENTERS THAT WOULD GIVE
ACCESS TO CONSCIOUSNESS THAT
WOULD GIVE ACCESS TO THE
SENSATIONS AND IN TERMS OF
CONSCIOUS PERCEPTION.
SO, A SIMILAR CASE, I BELIEVE,
MAY BE MADE FOR THE STOMACH, THE
STOMACH AND THEY ARE CONVEYED
THROUGH THE SPINAL CORD TO EQUAL
OR EQUIVALENT CORTICAL CENTERS
LIKE THESE CORTEX TO FULLNESS
AND DISCOMFORT.
MANY OF THE SENSATIONS,
ESPECIALLY SENSATIONS THAT WE
ATTRIBUTE TO THE VAGUS NERVE ARE
ACTUALLY MEDIATED BY SENSORY
GANGLIA AND SENSORY SPINAL
GANGLIA.
SO, WE HAVE BEEN PERFORMING SOME
ATOMICAL STUDIES THAT ARE
EQUIVALENT TO WHAT WE HAVE
PERFORMED FOR THE VEGAS SYSTEM
AND IN ORDER TO ACHIEVE A ORGAN,
A SPECIFIC MAPPING OF THE SPINAL
INNERRIZATINTERINVESTIGATION ANE
ORGAN OF INTEREST IN THIS CASE
THE STOMACH AND THE VIRUS STRAIN
THAT IS RETROGRADE AND CARRIES
AND THIS WILL RETROGRADE AND GO
BACKWARDS TO ALL NEURONS
INNOVATING THE STOMACH AND WE
PERFORM A SECOND INJECTION
DIRECTLY IN THE GANGLIA OF A PRE
DEPEND APARTMENT VIRUS THAT IS
ON THEY ARE OWE GRADE SO THE
IDEA HERE IS THAT WE USE THE
DORRAL ROUTE GANGLIA CELLS THAT
INNOVATE THE STOMACH AS IT
STARTER CELLS TO MAP THE GUT
BRAIN SPINAL PATHWAYS.
AND IN OUR STUDIES, WE SEE AS
EXPECTED, LABELING OF DORRAL
ROUTE GANG GANGLIA AT THE SPINAL
CODE SO THE VIRUS STARTS
SPREADING TO THE SPINAL CORD AND
ESPECIALLY ON LAYER 10 WITH VIS
ESHAL SEC SESSION AND IT HAS THE
NUCLEUS THAT IS ASSOCIATED WITH
SENSATIONS LINKED TO
TRANSMISSION OF OF THE MUSS LIEU
CAR SYSTEM VIA THE SPINAL CORD
SO HERE WE HAVE A PROPER PEW
KULAR TYPE OF BRAIN CENTER
APPARENTLY ALSO MEDIATING
SENSATIONS FROM INTERNAL ORGANS.
THIS IS INTERESTING THAT FROM
THE HOUR IN THERE'S LABELING OF
THE PARA SYMPATHETIC NEURONS OF
THE VAGUS COMPLEX BUT ALSO NO
LABELING OF THE VAGAL TARGETS IN
THE KNEE CLUE US OF THE SOLITARY
TRACT PROPER SHOWING THAT THE
SPINAL PATHWAYS IS TO A GREAT
EXTENT, SEPARATING FROM THE
VAGAL PATHWAY EVEN THOUGH THEY
MAY CONVERGE LATER ON IN CERTAIN
AREAS OF THE HYPOTHALIMUS FOR
EXAMPLE.
SO TO START GROBEING ON THE
FUNCTIONALITY OF THIS SYSTEM
WE'VE BEEN LOOKING OF THE
ACTIVITY AND A LOT OF INVE OWE
AND THESE HAVE FIXED WAKE
ANIMALS AND WE CHOSE TO USING
SINGLE CELL RECORDING IN ORDER
TO ACHIEVE THE SAME TYPE OF
TEMPORAL RESOLUTIONS AS THE
ELECTRICITY MIO GRAMS AND A
LARGE AMOUNT OF UNITS IN THE
NUCLEUS SEEMS TO BE VERY
RESPONSIVE TO CHANGES IN GASTRIC
MOW TILL TEE SO WE SEE MANY
UNITS BEING EITHER INHIBITED OR
EXCITED UPON DETECTION OF
CONTRACTIONS ELICITED BIT
INFLATION OF THE STOMACH OF THE
ANIMALS IN SUCH A WAY THAT MANY
OF THESE UNITS, FOR EXAMPLE,
THEY MAY BE IN SYNCHRONY WITH
THE EVENTS OBSERVED IN THE
STOMACH AND MANY OF THEM ARE
ACTUALLY INHIBITED AND IT'S
CONSISTENT WITH THE LITERATURE
ON OUR UNITS AND RESPONDING TO
PRO ACCEPTIVE CUES AND THE
NUMBER OF KUNITZ HAVE BEEN FOUND
TO BE RESPONSIVE TO EVENTS
LOCALIZED THIS SHE THOM AK AND
THE VERY BRIEFLY, I WILL JUST
DESCRIBE ONE EXPERIMENT WHERE WE
LOCKED AT IN BEHAVING ANIMALS,
WE LOOKED AT THE FUNCTIONAL ROLE
OF THE DRGs INNOVATING THE
STOMACH SO IN THIS CASE, WE USED
MICE ON THE IDTR BACKGROUND
MEANING THEY'VE CONTINUALLY
EXPRESSED THE TOXIN RECEPTORS
AND IT'S NOT NORMALLY EXPRESSED
IN MICE AND SO WE HAVE AGAIN
INJECTED IT TO THE STOMACH AND
IT TRAVELED BACK TO THE DORRAL
ROUTE GANGLIAL AND THE VAGAL
GANGLIA AND WE A SUPPLIED A
SALINE INJECTION, WHAT WE SEE IS
UPON INFLATING A BALLOON ON THE
STOMACH, WE SEE AS EXPECTED A
DRASTIC REDUCTION IN FOOD
INTAKE, HOWEVER, WHEN WE INJECT
INSTEAD THE TOXIN ITSELF WHICH
IS GOING TO CUE ONLY CREE
EXPRESSING NEURONS, DUE TO THE
BACKGROUND OF THE ANIMAL, WHAT
WE SEE IS THAT THERE'S A GREAT A
TIN TEN YOUATION MEANING THE DOL
ROUTE GANGLIA SEEMS TO BE
IMPORTANT FOR MEDIATING THE
SUPPRESSION OF APPETITE AT LEAST
BY THE PERCEPTION OF AN INFLATED
STOMACH.
AND WHEN WE REPEATED THESE
EXPERIMENTS, EXACTLY THE SAME
WAY, ALTHOUGH THIS TIME,
PERFORMING THE LESIONS INTO THE
VAGAL SENSORY GAGLY A AND THE
NO-DOSE GANGLIA WE SEE UPON
INFLATING THE BALLOON, WE SEE
AGAIN THE DRASTIC REDUCTION IN
FOOD INSTAKE AFTER SALINE
INFUSION, HOWEVER.
WHETHER IT'S INJECTED IN THE
NO-DOSE GANGLIA WE DID NOT SIGH
FIFTH CLEAR OF THE EFFECT OF THE
BALLOON AND MEANING THAT IN
PRINCIPLE, THE SUPPRESSION OF
APPETITE CAUSED BY THE
PERCEPTION OF A BLOATED STOMACH
IS MUCH MORE HEAVILY DEPENDENT
ON A SPINAL TRANCE WAY
TRANSMITTING FROM THE STOMACH TO
THE BRAIN THEY GO PATHWAYS.
THE VAGUS IS GOING TO PERFORM A
NUMBER OF OTHER FUNCTIONS
PROBABLY SECRETARY FUNCTIONS
LIKE ACID RELEASE UPON GASTRIC
DISTINCTION BUT THIS BEHAVIORAL
READ OUT DOES NOT SEEM TO BE
HEAVILY DEPENDENT ON THE VAGUS
NERVE.
SO, TO SUMMARIZE, OUR TRACING
AND FUNCTION OF THE STUDIES
SEEMS TO SUGGEST THAT DORRAL
ROUTE GANGLIA AND THE SPINAL
SYSTEMS THEY DETECT INFORMATION
OF OCCURRING IN THE STOMACH AT
THE LEAST MECHANISM CESSATION
AND MEET THAT INFORMATION TO
LOWER CENTERS IN THE BRAIN STEM
AND FROM THERE THIS IS SOMETHING
THAT WE ARE INTERESTED IN ALSO
AND WE ALSO SOME LOCALIZED BUT
INTERESTING LABELING IN SOME
PARTS OF THE SOMATO SENSORY
CONTEXT KNOWN TO MEDIATE
CONSCIOUS PERCEPTIONS OF BODY
PARTS IN AT LEAST IN TERMS OF
THE MUSCULAR SYSTEM.
SO IN OVER ALL, WE BELIEVE THAT
THE IT MAY CONTRIBUTE TO THIS
MORE GENERAL SENSATION AND IT
MAY HELP THE BRYN TO PERFORM
COMMUTATIONS LIKE POSITIONING IN
SPACE AND YOUR ORIENTATION OF
THE BODY SINCE OUR INTERNAL
ORGANS, FOR EXAMPLE, THEY
STOMACH AND THE BLADDER, ACCESS
TO CONSCIOUSNESS AND PERFORM OR
PROVIDE SOME CUE IN TERMS OF
WHERE WE ARE IN SPACE AND HOW
OUR BODIES ARE ORIENTED.
AND I WOULD LIKE TO END BY
THANKING MY COLLEAGUES WHO DID
ALL THIS WORK ESPECIALLY THE
SURGICAL AND FUNCTIONAL APPROACH
AND MATTHEW WHO IS DOING GREAT
WORK ON ELECTRIC PHYSIOLOGY AND
THANK YOU.
[APPLAUSE]
THANK YOU, WHILE THE NEXT
SPEAKER Dr. OKA IS COMING UP,
WE'LL HAVE ROM FOR QUESTIONS.
ANYONE HAVE A QUESTION HERE?
WE HAVE SOMETHING IN THE CHAT?
IT'S VERY INTERESTING AND MY
QUESTION IS THAT WHICH PRESSURE
DID YOU USE WHEN YOU DISTEND THE
STOMACH?
>>WHICH PRESSURE?
>>YEAH.
>>WELL I MEAN -- WE TRIED A
RANGE OF PRESSURES.
SO IT'S A LITTLE COMPLICATED
BECAUSE I CAN EXPLAIN TO YOU
LATER BUT BASICALLY WE
DETERMINED IT BY BEHAVIORAL
ASIZATIOAASSAYS SO WE LOCKED ATH
PRESSURE THE BALLOON WOULD
PREVENT FURTHER FOOD INTAKE IN A
PARTICULAR ANIMAL AND WE
REAPPLIED THAT DURING THE
BEHAVIORAL ASSAY.
>>THE REASON I'M ASKING IS THE
PATHWAY IS DEPENDENT ON THE
PRESSURE OF FOOD ATTENTION SO
PROBLEM VAGUS IS MORE INVOLVED
BUT IF IT'S GOES THROUGH THE
SYMPATHETIC PATHWAY LIKE YOU
REPORTED.
>>YEAH, THAT'S RIGHT.
I MEAN, YEAH, EXACTLY.
WE COULD LOOK AT THE POSSIBILITY
FOR OUR NAUSEA OR PAIN AND WE
DID A NUMBER OF BEHAVIORAL ASSAY
I DON'T HAVE THE TIME TO EXPLAIN
TO VERIFY THAT THE ANIMALS ARE
PERFORMING OTHER FUNCTIONS
NORMALLY.
THEY ARE JUST NOT INTERESTED IN
FOOD, YEAH.
BUT THAT'S A GOOD POINT.
>>THAT'S A GREAT QUESTION TO
CONTINUE AT THE END.
SO, PLEASE GO AHEAD.
>>GREAT, YEAH.
THANK YOU SO MUCH FOR IN
INVITING ME AND I'M VERY HAPPY
TO SHARE OUR RECENT RESULTS.
I'M GOING TO TALK ABOUT THE
GUT-TO-BRAIN NEUROCIRCUIT.
FOR THE MAIN FOCUS OF OUR
LABORATORY IS TO UNDERSTAND HOW
THE WHOLE BOD OH NOT JUST THE
BRAIN BUT THE GUT AND BRAIN,
REGULATES THE INTERNAL FLUID
BALANCE SO THE FLUID BALANCE IS
REALLY BALANCED BY TWO CO
FACTORS, ONE IS WATER AND TO THE
LEFT AND ONE IS SODIUM.
SO UNLIKE FOOD OR HUNGER, WHICH
HAS A LOT OF COMPONENTS, SUGAR,
FAT AND PROTEIN, THESE TWO PURE
COMPONENTS, WATER AND SODIUM, IS
REALLY IMPORTANT FOR OUR BODIES
FLUID BALANCE AND IT'S NOT JUST
EATING A LOT, SO PROBABLE
BECAUSE IF YOU EAT A LOT OF
SODIUM, EVEN IF YOU NEED IT, IT
WILL MAKE YOU HYPERTENSION AND
SO YOU NEED TO HAVE APPROPRIATE
AMOUNT AND HAVE TO GET THE
SPECIFIC FACTOR TO MAINTAIN THE
BALANCE AND THEN LIKE I SAID,
IT'S NOT JUST THE BRAIN, IT
TURNED OUT THAT THE REGULATION
OF INTAKE OF WATER AND SODIUM
HAS A LOT OF MODULATION FROM THE
GUT AND THE BODY RIGHT.
THE ONE EXAMPLE IS A SENSE TOM
LIKE AND ALSO SOME SENSATION IN
THE SWALLOWING STUFF AND THEN
ALSO GUT SENSATION AFTER EATING
AND DRINKING.
SO, AND THEN FOR THIRST THE
REGULATION IN THE BRAIN SO THE
MAIN STRUCTURE THAT REGULATES
THIRST IS A THIN LAYER STRUCTURE
THAT HAS THREE NEWLY EYE AND THE
SENSORY OF AND EXPOSED TO THE
BLOOD AND AND P.O. IS
INCOMPETENT GREAT TIVE NUCLEUS
SENSITIVE INFORMATION FROM AND
CENTS THE INFORMATION BACK TO
THE REST OF THE BRAIN.
WHEN YOU LOSE VOLUME IN THE
BLOOD OR THE CHANGE AND THAT
ACTIVATES SPECIFIC TYPE OF
NEURONS AND STIMULATION WITH
SOME ACTIVATION TOOLS AND I CAN
SHOW YOU IN THIS CASE -- I CAN'T
SHOW YOU THE VIDEO UNFORTUNATELY
BUT IT'S LINKED TO
THE BEHAVIOR BECAUSE YOU CAN
IMMEDIATELY DRY THE FEELING AND
WE SEE IT IN ONE SECOND.
AND ININCLUDEDDING MY LABORATORY
AND MANY OTHER LABORATORY, WE
FOUND THAT THIS INTRA ACCEPTIVE
NEURONS THAT ARE A BRAIN SENSOR
NEURONS, NOT JUST MONITOR OUR
INTERNAL BODY STATE BUT MONITOR
REALLY SORT OF OUR BEHAVIOR
STATE OR NUTRIENT REPLENISH FROM
THE GUT TO THE BRAIN.
SO ALSO, INTERESTING ABOUT IT,
THE DIFFERENT MUTANT FACT LIKE
WATER RAPIDS AND FOOD AND THESE
RECEIVE DIFFERENT TYPE OF
SENSORY FEEDBACK AND IN THE CASE
GULPING AND OSMOLAITY AND IN
HUNGER CASE AND TASTE SMELL,
SIGHT OR C OR CALORIC VALUE ANDE
ACTIVITY OF THE INTER ACCEPT
NEURONS BEFORE DIFFERENT TIMES
OF NUTRIENT FACTOR.
SO WE FOCUSED ON THE SENSING AND
HOW THAT SIGNAL, YOU KNOW, GIVES
MODULATION TO THE BRAIN AND WHEN
YOU DRINK WATER, YOU DRINK WATER
GETS TO THE STOMACH HERE AND IT
GOES THROUGH THE INTESTINE AND
IT'S ABSORBED THROUGH THE LARGE
VESSEL CALLED THE PORTAL VEIN
AND THAT IS WATER GOES THROUGH
THE CIRCULATION.
SO IN THESE ORGANS, ARE
INNOVATED BY TWO DISTINCT
SYSTEMS LIKE ONE IS THE SPINAL
PATHWAY AND ANOTHER ONE IS A
VAGAL PATHWAY SO WE LOOKED FOR
THE POSSIBILITY AND HOW THEY
RESPOND THROUGH CHANGE THE GUARD
AND FOR THE FIRST ONE WE LOOKED
AT THE DRG PATHWAY AND THE
CONTROL OF THE SKIN PINCH
BECAUSE IT'S SENSITIVE TO
(INAUDIBLE) SO WE FOUND THAT FEW
POPULATION OF DRG NEURONS
RESPONSE TO ANY NUTRIENT FACTORS
IN THEN ADVERTISE TIN LIKE
WATER, SODIUM, AND THEY
RESPONDED BUT IT'S NOT VERY TIME
LOCKED.
SO WE LOOKED INTO THE ANOTHER
SUBSYSTEMS WHICH IS THE VAGUS
SYSTEM AND WE STARTED TO RECORD
THE NERVE ACTIVITY FROM THE
ENTIRE NERVE AND INTERESTINGLY
WE FOUND THAT THESE NERVES
RESPOND VERY STRONGLY TO THE
HYPO STIMULI IN THE INTESTINE
AND IN FACT, FROM THE BOTTOM
BLACK LINE AND IT'S 150 MILL
MALL AND TO SO THIS IS REALLY
NOT THE SINGLE CELL RESOLUTION
AND IF YOU LOCK AT THE SINGLE
CELL RESOLUTION, AGAIN, IT
DOESN'T REALLY, YOU KNOW, PLAY
SO WE HAVE TO TAKE MY WORD.
SO YOU CAN SEE REALLY SPARSE AND
STRONG CALCIUM RESPONSES EFFECT
BY JUST PUTTING WATER INTO THE
INTESTINE AND SO, AGAIN, THIS IS
JUST THE WATER RESPONSE BUT IF
WE NOW TEST DIFFERENTLY LIKE
WATER AND HIGH SODIUM STIMULUS,
AND ALSO SUGAR AND WE SAW A
MOSTLY POPULATION BUT SOME BUT
POPULATION LIGHT UP AND BY
DIFFERENT FACTORS.
SO NOW WE ASK FOR POPULATION AND
WE FOUND WHO GENETIC LINE WITH A
CONTRASTING RESPONSE AND ONE IS
A TAC-1-CRE AI AND STIMULUS AND
THE OTHER NTS-CRE IS A DIFFERENT
TYPE OF SEC SET NEURONS AND THEY
DIDN'T SHOW RESPONSE AND SO IT'S
JUST A MARKER BUT IT DOESN'T
REALLY -- IT'S NOT VERY CLEAN
MARKER BUT IT GAVE ME SORT OF A
HINT WHERE TO LOOK AT AND SAYING
THAT WHERE THAT THEY SENSING
HAPPENS AND SO, THE BIGGEST
DIFFERENCE WE FOUND AND IS THE
INNOVATION TO THE TIP ATTIC
BRAIN AND FOR THE LIVER AREA AND
AS YOU CAN SEE HERE TO THE
RIGHT, YOU CAN SEE A STRONG
LABELING OF INNOVATION IN THE
VAGAL NEURONS BUT NOT IN THE
NTS-CRE.
THIS IS A MOST PROMINENT
DIFFERENCE.
WE HIGH POTH A SIZE THAT MAYBE
THOSE INNOVATION FROM HPA MIGHT
BE IMPORTANT FOR OS MOW SENSEING
AND WHEN WE CUT THIS SMALL
BRANCH TO THE VEIN, HERE, THE
LEFT SIDE IS WATER RESPONSE
BEFORE AND THE RIGHT SIDE IS
AFTER THE INNOVATION AND IT'S
ALMOST COMPLETELY GONE BUT THE
TACTICS -- TACTILE DID NOT
CHANGE.
THERE'S A LOT OF HYPE TONIC
RESPONSES AND THEN THE QUESTION
IS, WE KNOW WHERE TO LOOK AT
SENSING OR THE RESPONSES BUT THE
KEY IF WE -- IF THESE RESPONSES
ARE IMPORTANT FOR REGULATION OF
THE BRAIN, RIGHT, SO WE COMBINE
THE OPERATION AND THEN CALCIUM
RECORDING FROM THE INTEROCEPTION
NEURONS IN THE BRAIN.
SO HERE IS THE SFO, WE RECORD IT
AND AT THE SAME TIME WE OPERATE
IT IN THE GUT SO THIS GRAPH, THE
BLACK LINE IS GENERAL NORMAL
RESPONSE AND BEFORE AND AFTER
DRINKING.
SO BEFORE DRINKING, YOU FEEL A
TIGHT ACTIVITY LEVEL OF CALCIUM
BUT WHEN YOU START DRINKING
WATER AND THIS ACTIVITY DROPS
VERY RAPIDLY.
AFTER THE INNOVATION OF THIS
SPECIFIC BRANCH OF THE VEIN,
THEN, THE SORT OF QUENCHING
EFFECT THE SUPPRESSION OF THE
NEURONS IS LARGELY GONE.
THE IMPORTANT PART AS I SAID, SO
THERE ARE TWO COMPONENTS.
ONE IS THE GULPING AND ANOTHER
(INAUDIBLE).
THE GOOD CONTROL IS THAT THE
GULPING PART IS NOT AFFECTED,
RIGHT.
SO I NOW IN LARGE SO IF I LOOK
AT THE INITIAL SEPARATION OF
THESE NEURONS WHICH IS BEING
USED BY GULPING IS UNCHANGED,
RIGHT.
THE ONLY CHANGE IS THIS
PROLONGED SEPARATION AND AGAIN
INDICATES THIS CHANGES
SEPARATION AND SO FAR, I HAVE
TALKED ABOUT THE AREA IS
IMPORTANT FOR TRANSMITTING
OSMOLAITY TO THE BRAIN BUT ONE
THING THAT WASN'T CLEAR IS THE
HPA DIRECTLY SENSING OSMOLALITY
CHANGE AND DIRECT THREE THROUGH
SOMETHING ELSE.
THIS IS ONE OF THE FINDINGS FOR
US BUT WE TEST THIS AND WE DID
MORE COMPLICATED SURGERY IN THE
SAME ANIMAL WE CHANGED THE OS
MOWALITY IN THE TESTING AND
CHANGING IT IN THE PORTAL VEIN
SO WE HAVE TOO MANY TUBES IN THE
GUT AND THEN WE DID ALL THESE
EXPERIMENTS SO THIS IS THE
RESULT HERE.
WE FIRST INFUSE THE WATER IN THE
INTESTINE AND YOU GET A LOT OF
RESPONSE RIGHT.
WE DILUTED THE BLOOD INTO THE
HPV SO THERE'S NO RESPONSE OF
THAT.
WE EXPECT THIS IS DILUTION OF
BLOOD BUT IT'S NOT THE CASE AND
IT'S NOT PER SE IT'S OX SEDATING
SO NOW WE NOW ASK THE NEXT
HYPOTHESIS.
MAYBE THIS IS IS SOMETHING THAT
SECRETED FROM THE INTESTINE THAT
ACTIVATES THESE NEURONS.
THERE ARE MANY PEPTIDES KNOWN TO
BE SECRETED FROM THE INTESTINE
BASED ON FOOD AND WATER AND ONE
OF THEM WAS LIKE V.I.P. AND
THESE RESPONSE WHEN WE INFUSE
VIP NO THE VEIN, IT'S NOT LIKE
PERFECT OVER ALL BUT AT LEAST
PARTIAL NUMBERS AT LEAST VIP IS
CONTRIBUTING TO THE RESPONSE OF
THE OSMOLALITY AND SO, AS
EXPECTED, ONE OF THE VIP
RECEPTORS, VIP RECEPTORS TYPE 2
IS STRONGLY PRESSED IN THE HPA
AREA AND THEN WHAT OUR RESPONSE
AND ALSO VIP RESPONSES OF BOTH
SEPARATE IN THE HIP ATTIC IN VE
OWE EXPERIMENTS SO FROM THIS
RESULT NOW, WE CAN NOW CONCLUDE
AT LEAST SO FARTHER BRAIN HAS A
LOT OF RAPID MODULATION FROM THE
GUT AND THEN ONE FACTORS IS THE
CHANGING THE GUT WHICH IS NOW
TRANSMITTED THROUGH THE VAGUS
AND THIS IS NOW THE TRANSLATED
INTO HORMONAL SITUATION TO
ACTIVATE THE NEURONS.
THIS IS CREATING A LOT OF
DIFFERENT QUESTIONS THAT WE NEED
TO CHALLENGE SO, LIKE I SAID,
VIP IS ONE OF THE MANY FACTORS
MAYBE AND IT DOESN'T EXPLAIN THE
ENTIRE RESPONSE SO WHAT OTHER
MOLECULES ARE INVOLVED?
AND THEN THE MAIN QUESTION
ACTUALLY HAS NOT BEEN SOLVED SO
OS MOLE TESTING WE DO KNOW WHAT
CELLS ARE SENSING IT AND HOW VIP
DETECTION IN THE VEIN WE KNOW
THAT THE RECEPTORS BUT HOW DOES
THE RECEPTORS ACTIVATE THIS
VAGAL KNEW ON BECAUSE THEY DON'T
EXPRESS THE VIP RECEPTORS SO HOW
DO THEY COMMUNICATE EACH OTHER
SO THERE ARE MANY QUESTIONS WE
ARE TRYING TO CHALLENGE THOSE
AND I'D LIKE TO THANK MY LAB
MEMBERS AND ESPECIALLY THE WORK
AND HE IS AN EXCELLENT SURGEON
AND SHE GOT COMMISSIONED IN
JAPAN AND OTHER MEMBERS AND
THANK YOU.
[APPLAUSE]
THANK YOU AND NICE PRESENTATION.
AS Dr. JO IS COMING UP WE HAVE
ROOM FOR ONE MORE QUESTION.
ANYONE HAVE A QUESTION HERE IN
THE ROOM?
>>IS THERE A POSSIBILITY YOU
CONSIDER GIVEN THE RESULTS THAT
WE HAVE ACTUALLY A MECHANISM FOR
SENSING WATER LIKE IMAGINE THIS
SAME IS FOR SENSING SUCROSE THAT
IT'S NOT EVEN, IT'S IMPORTANT
THAT YOU WOULD BE SOME KIND OF
SIGNALING MECHANISM THAT IT
DOESN'T NEED TO DETECT
OSMOLARIS?
>>IT'S TRUE.
I SAID OSMOLALITY AS A GENERAL
STIMULUS THAT WATER IF IT'S SELF
IS SENSED BY SOME CHANNEL.
AND SO THAT'S FASCINATING
POSSIBILITY AND WE'RE LOOKING
INTO THAT.
YEAH, DEFINITELY.
THANK YOU.
>>NEXT SPEAKER, PLEASE.
MY PRESENTATION IS FUNCTIONAL
IDENTIFICATION OF VAGAL SENSORY
NEURONS INNERVATING THE LIVER.
SO, THE VITAL ORGANS THEY
CONTROL DIVERSE FUNCTIONS AND
SUCH AS ENERGY AND HOMEOSTASIS
AND THE BRAIN FUNCTION AS WELL.
SO TO CATCH ON THE IDEAS OF
FUTURE REGULATED BY THE BRAIN.
IF SO, THE INTEROCEPTION
SIGNALING BETWEEN THE VIVA AND
VAGAL SENSORY NEURONS.
SO OUR AIM IS ANY ONE TO
DETERMINE THE MOLECULAR AND
CELLULAR IDENTITY OF LIVER
PROJECT IN SENSORY NEURONS AND
IS THE FUNCTION CONSISTS OF LOSS
OF FUNCTION OF RIVER-BRAIN
NEURAL CIRCUIT.
WE USE THE TWO MODEL ONE IS A
LABEL TO ANIMAL AND SENSE ROW ON
SPECIFIC BIND IN PROTEINS SO
MOST IS THE OTHER IS CALCA AND
THE WE USE RETROGRADE AAV AND
SUCH AS LIVER PROTECTING AND THE
TO REGULATE THEIR ACTIVITIES AND
PROTEIN TO RECORD THE ACTIVITY
OF THE LIVER PROTECT NEURON AND
IT TO A TO CELL ACTIVELY AND
PROJECTING SENSORY NEURONS.
SO I'LL SHOW YOU THE VIVO
PROJECT IN NEURONS AND IT'S USED
WITH THE CALCA AND SENSORY
ANIMAL AND WE INJECTED THE
RETROGRADE AA HAVE AND THE
PROTEINS AND SO YOU CAN PROBE
THE LIVER PROJECT AND YOU SEE
HERE WE FOUND VERY SMALL NEURON
AND PROJECTED TO THE LIVER.
WE FOUND IT VERY STRONG AND
SIGNAL INTO THE SITE AND YOU SEE
HERE THE POSITIVE KNOB PRESENT
OF THE NEURONS.
SO SOME OF THE INNOVATION AND
MORE IMPORTANT REALLY SO THEY
LOCATED AROUND THE PROTEIN AND
THEY SEE SNAP INNOVATIONS.
WE FOUND THE.
>>Commissioner Rubio: AND THIY
IMPORTANT AND THEY CONTAIN
NUTRIENTS AND THE WATER IS
SENSORY INNOVATION AND CAN SENSE
AND DETECT TO THE SIGNAL AND SO
WE FOUND THAT THIS IS IT'S'
UNIQUE AND SO IT'S NETWORK SO
THIS IS THE SYNAPSIS AND THIS IS
FORCED THE DEM ON STRAW STATION
AND AND WE WANT TO MAKE SURE
THAT THIS IS A TRUE AND SYNAPSIS
AND WE CHANGED THE TRANSPORT AND
YOU SEE HERE AND THIS IS THE
SAME SO THEY MAKE THE SNAP TEAM
NETWORK AND THE NEURONS BUT ALSO
WE FOUND THAT MAKE PERCENT SAME
SNAP SIS SO THIS IS INDICATE
THAT IN CONTRAST TO THE SEPTIC
SENSATION AFTER INPUT AND OUR
DATA SUGGESTS THAT THE
SIGNIFICANT UPDATE INPUT SO NEXT
THERE IS A COMMUNICATION BETWEEN
THE LIVER AND THE VAGAL SENSORY
NEURONS SO STUDY THIS PROBLEM
THIS POSSIBILITY AND WE
SELECTIVELY PRESSED SENSING AND
ON IN NEURON AND THE LIVER AND
WE ALSO DEVELOPED AAV VIRUS SO
WE EXPRESSED THE TODAY THE
RECEPTOR ONLY IN BY USING THE
PROMOTER WHICH IS THE
SPECIFICITY SO WE CAN EXPRESS
THE GS COUPLED RECEPTORS AND WE
EXPRESS SENSING PROTEIN IN
NEURONS AND DOING MAJOR
SIGNALING FROM THE GANGLIA AND
WE SEE HERE, THIS IS THE WAY THE
IP INJECTION AND THIS IS
ACTIVATION OF RECEPTORS
INCREASES SIGNALING THE LIVER
REDICTIONARYING AND SO FROM IS
SOCIETY AND AND I SENSES.
BUT SO WE USE THE SAME PROTOCOL
WE FOUND LARGE ENOUGH INNOVATION
IN THE AREA AND SO YOU FOUND THE
AREA THAT CAN THE SAMPLE AS YOU
SEE HERE, SOME OF THE NEURON
RECEIVER AND FROM THE PROJECTING
THAT ASSOCIATED NEURONS SO THIS
INDICATES THIS SHOULD ALSO SEND
BACK THE LIVER AND OTHER ORGANS.
WE CAN FUNCTION THE SENSORY
NEURON SO TO STUDY THIS
POSSIBILITY WE USED THIS TIME
LIVER ANIMAL AND TEST PAGE 3 SO
WE EXPRESSED THE ONLY IN VIVO
PROTECTING SENSITIVE NEURONS AND
THEN WE KEPT DIET TO SEE THE
SENSE ROW NEURON AND TO ACCESS
OUR KNEE TREE ENTERS AND YOU SEE
HERE, SO THEY BECOME OVER
HOWEVER WE FOUND THAT MICE
WITHOUT THE PREDICTING AND
ACCESSORY NEURONS THEY AND AND
THIS IS TO THE INCREASING
BECAUSE THERE IS NO DIFFERENCE
IN THE MESS BETWEEN THE GROWTH.
WE FOUND THE SAME RESULT IN
FEMALE ANIMALS.
WE GET THAT EFFORT IN THE LIVER
SO THIS IS A CONTROL ANIMAL WE
DID THE SAY LIPID AND WE SEE
HERE, MANY EMPTY SPACES IN THE
PLASMA OF THE AND THE
ACCUMULATION IN THE WE FOUND
LARGE ACCUMULATION AROUND THE
CENTER EVENT AND THIS IS THE
LIVER AND WE FOUND ACCUMULATION
IN THE LIVER AND ALSO WE MAJOR
THE LIVER WE FOUND A SIGNIFICANT
DECREASE AND IN THE LIVER SO
THIS INDICATES THE LIVER.
AND THEN WHEN I START WITH THIS
STUDY I PROMISE AND I'M GOING TO
HOW THIS SIGNAL ON THE REGULATOR
THE FRAME FUNCTION AND WE HAVE A
TESTER SO CHANGE FROM TESTING TO
ACCESS INGEST LIKE BEHAVIOR OR
WILLINGNESS.
SO IT'S THIS IS A CONTROL ANIMAL
AS YOU SEE HERE, CONTROL ANIMAL
STAY IN THE AREA CLOSE TO WHERE
HOWEVER MOUSE WITHOUT PRO
DICTION NEURONS AND THEY WILL
LINK TO EXPLORE IN THE CENTRAL
AREA SO WE FOUND THAT THERE'S AN
INCREASE OF ACTIVITY AND THE
MOUSE STAYED LONGER IN CENTER
AREA.
SO THIS IS PROJECT IN SENSE ROW
NEURONS INCREASE IN ACTIVITY AND
WHILE REDUCING ANXIETY LIKE
BEHAVIOR.
WE FOUND IT SIGNIFICANT INPUT
FROM THE SENSORY NEURONS AND
ACTIVATION AND THE RECEPTORS AND
ON THE AND THIS SUBSEQUENT TO
THE ACTIVATED THE SENSE ROW
NEURON THIS SIGNALING AND THIS
WORK CANNOT BE DONE WITH HALF
THE DOCTOR SCHWARTZ AND MY
POSTDOCS.
THANK YOU SO MUCH FOR YOUR
ATTENTION.
[APPLAUSE]
>>THANK YOU TO ALL SPEAKERS.
WE HAVE ONE QUESTION.
>>VERY INTERESTING DATA AND
EVEN -- OF VAGAL INNOVATION TO
THE LIVER.
SO, YOU SHOWED THAT THE LIVER
PROJECTION CAN ALLEVIATE THE
PHENOTYPE BUT YOU SHOW THAT
LOCAL MOTION FOR INCREASE SO CAN
YOU EXPLAIN THAT INCREASED
LOCOMOTION?
>>THAT'S THE DIFFERENCE.
THIS IS ACTIVITY AND WE DID OPEN
TO THE TEST.
THEY HAVE INCREASED THE ACTIVITY
BUT WHEN YOU LOOK AT WHO LOCO
ACTIVITY THERE'S A SIGNIFICANT
INCREASE IN DECREASE IN THE
ACTIVITY.
>>WE'RE GOING TO HAVE NOW AN
OVER ALL QUESTION FOR 10 MINUTES
BECAUSE WE'RE GOING TO SHORTEN
IT A LITTLE BIT SO MAYBE YOU CAN
START YOUR QUESTIONS.
>>THAT'S GREAT.
>>LET ME INTRODUCE I HAVE A
QUESTION.
SO WHEN YOU APPLY THE LIVER
PROJECTION SENSORY VAGUS
NEURONS.
WHAT HAPPENS WITH THE ANIMALS?
DOES ANIMAL EAT LESSOR BE MORE
ACTIVE?
>>THAT'S A GOOD QUESTION.
WE LOOK AT SENSORY NEURONS AND
ALSO WE DID SUPPRESS THE
RECEPTORS COUPLED WITH THE
RECEPTOR IN CGIP.
WHEN YOU ARE ACTIVATING THE
SHORT TERM WITH RECEPTORS, THEY
EAT MORE.
THEY EAT MORE, YEAH.
IN THIS HYPER FEEDING BECAUSE
THERE'S BIG DIFFERENCE SO YOU
CANNOT MEASURE HOW MUCH THEY EAT
BECAUSE THE DIFFERENCE IS VERY
BIG IN TERMS OF EVALUATED SO WE
SHOULD CALCULATE NORMALIZE IT
AND THEN WHEN YOU GET -- WHEN
YOU NORMALIZE THE FOOD INTAKE,
THEY EAT THE SAME.
THIS CALORIES.
>>SO YOU ARE CHANGING THE
METABOLISM?
>>SORRY?
>>THE INTERVENTION, YOU DID
CHANGE THE METABOLISM?
>>YEAH.
ACTUALLY, WE ARE DOING THAT THE
CALORIE EXTREME WAS SO WE FOUND
VERY BIG DIFFERENCE OF ACTIVITY
AND ENERGY EXPENDITURE.
>>WE ARE GOING TO READ SOME
QUESTIONS FROM THE CHAT RIGHT
NOW.
SO IF YOU WANT YOU CAN SIT DOWN
BUT YOU CAN ALSO STAY THERE
BECAUSE IT'S GOING TO BE FOR
EVERYONE.
THE FIRST QUESTION IS TO Dr.
LIU AND Dr. CHEN.
HAVE YOU CONSIDERED UNILATERAL
VAGOTOMY WHETHER SENDING INPUTS
PROJECT TO BOTH SIDES OF THE
BRAIN?
>>WE DID BILATERAL.
WE HAVE NOT TRIED UNILATERAL BUT
THAT'S A GOOD SUGGESTION AND
WE'LL EXPLORE THAT.
>>NEXT QUESTION IS FOR Dr.
ARAUJO.
THE WORK OF Dr. LIU SUGGESTS
THAT STOMACH TO BRAIN
INTEROCEPTION IS ALMOST
COMPLETELY ABOLISHED SUGGESTING
A CRITICAL ROLE OF THE ARM OF
THE VAGUS NERVE IN SIGNALING
THESE FINDING APPEARS TO BE AT
ODDS WITH THE DATA BY Dr.
ARAUJ SO SAYING IT DOES NOT
CONTROL FULLNESS TO THE BRAIN.
PLEASE DISCUSS WHAT KIND OF
LEVEL OF SENSORY WERE ABLATED IN
THE DTX APPROACH.
THOSE GO TO BOTH BASICALLY.
Dr. OKA AND Dr. LIU.
>>SO, IF WE UNDERSTOOD THE
FINDINGS CORRECTLY WHAT WAS
ABOLISHED IS THE SYNCHRONY IN
SIGNAL BETWEEN STOMACH MOVEMENT
AND THE BRAIN OSCILLATION,
RIGHT.
SO THIS IS A VERY INTERESTING
QUESTION.
WE DON'T KNOW EXACTLY WHAT THIS
SYNCHRONY MEANS IN TERMS FOR THE
BRAIN AND WHAT FUNCTIONS IT MAY
BE PERFORMING SO I THINK THAT IT
DOES NOT MEAN OSCILLATIONS AND
TOOKING FOR THEY MAY BE MOR
COMPLEX BECAUSE OF GUT MOVEMENT
AND THE FACT OF THAT YOU WILL
HAVE THIS CONSCIOUS PERCEPTION
OF DISTINCTION MEDIATED BY
DORRAL ROUTE GANGLIA IS MORE
CONSISTENT WITH WHAT WE KNOW
ABOUT THE BLADDER, WHICH
PRODUCES VERY SIMILAR SENSATIONS
AND VERY SIMILAR TYPES OF
BEHAVIOR WITH IN THIS CASE WE
KNOW IT'S ENTIRELY DEPENDENT ON
THE DORRAL ROUTE GANGLIA SO I
THINK IT'S A QUESTION TO BE
INVESTIGATED IN THE FUTURE FOR
THE DORRAL ROUTE GANGLIA
LESIONS, IN WITHIN WAY WE
INJECTED DIRECTLY INTO THE
THORACIC DOR SO ROUTE GANGLIA
WHERE MOST OF THE INTEROCEPTION
TARGETING THE STOMACH IS LOCATED
AND WE ALSO PERFORMED INJECTIONS
OF THE TOXIN AND THEY SEEM TO
PRODUCE VERY SIMILAR EFFECTS.
SO, WE USED A BALLOON THAT CAUSE
A CERTAIN PRESSURE ABOUT
10 MILLIGRAMS MERCURY THAT WE
KNOW IS THE THRESHOLD IN ANIMALS
WILL STOP EAT NORTH A FREELY
BEHAVING SETING AND THE VAGAL
LESIONS DID NOT DISRUPT THE
ABILITY OF THE ANIMALS TO
INFLATE THE BALLOON UP TO
10 MILLIGRAMS MERCURY.
SO IT'S AN OPEN QUESTION TO
INTERPRET THE FUNCTIONALITY OF
THE CORRELATION BETWEEN GUT AND
BRAIN, WHICH IS VERY
INTERESTING.
IT MAY NOT BE SIMPLY JUST
DETECTING DISTINCTION ON ORGAN
VALUE PER SE.
>>I DEGREE THESE ARE TWO
DIFFERENT SET OF PHENOMENON AND
ONE IS THE MOW TILL TEE AND THE
OTHER REGARDING THE GAS TICK GAS
TENSION.
AND WE THINK THAT THE INTRINSIC
AND SPONTANEOUS IN REAL-TIME
BRAIN-GUT SYNCHRONY, IS AN
INTRIGUING PHENOMENON.
IT'S LIKELY VERY USEFUL MARKER
OF THE GUT-BRAIN INTERACTION.
IT REFLECTS MUCH MORE REGARDING
MOW TILL TEE AND THE A ARYTHMIC
CHANGES OF GASTRIC MOVEMENTS AND
HOW IT'S SENSED BY AND LIKELY
POTENTIALLY REGULATED BY THE
BRAIN.
AND THAT IS DIFFERENT FROM THE
FINDINGS YOU JUST REPORTED
REGARDING THE DORRAL ROAD
GANGLIA FOR GASTRIC DIS TENSION.
THAT'S MY COMMENT AND I KNOW MY
COLLEAGUES WOULD HAVE OTHER
INPUT AS WELL.
>>JUST ONE QUICK NOTE, IN FACT
THEY MAY NEED THE OPPOSITE
BECAUSE DURING DISTINCTION THE
MOW DILL TEE IS DISRUPT SO
PROBABLY DURING THE DISTINCTION
THIS MAY BE DISRUPTED IN TERMS
OF SYNCHRONY BETWEEN THE TWO?
>>WHEN WE ARE DOING THIS
INTEROCEPTION GRANT WE DID
SEVERAL STUDIES WITH GASTRO
DETENTION IS TRICKERY.
WHEN YOU HAVE THE STOMACH AT THE
PRESSURE OF 10 MERCURY IT'S
PHYSIOLOGICAL.
IF YOU ENHANCED CONTRACTION OF
THE STOMACH.
IF YOU INCREASE UP TO 20 MERCURY
AND YOU WILL DIS LAPSE THE
CONTRACTION AND MY IMPRESSION IS
THAT UNDER PHYSIOLOGICAL
CONDITIONS, SO THEN WE JUST HAVE
A NORMAL EARTH.
DON'T OVER EAT.
WHEN YOU OVER EAT YOU WILL FEEL
BLOAT AND PAIN.
SO WHEN YOU DISTANCE STOMACH TOO
MUCH, THEN YOU WILL GENERATE
PAIN AND UNDER THEIR CONDITION,
PROBABLY THE DOR SAL THE SIGNAL
WILL GO TO SYMPATHETIC PATHWAY
AND UNDER PHYSIOLOGICAL
CONDITIONS, MOST OF THE TIME,
SIGNAL WILL GO THROUGH THE VAGAL
PATHWAY BUT THAT'S NOT THE 100%
SO THERE'S BOTH PATHWAYS BUT
LOGICALLY, IT'S MORE VAGAL.
AND IT IS MORE SYMPATHETIC AND
ALSO, THE STOMACH HAS ADAPTATION
PROCESS SO WE HAVE TO BE CAREFUL
WHEN YOU DIS TENT THE STOMACH
BECAUSE WE RELAX AND YOUR
PRESSURE WILL DECREASE AND YOU
HAVE TO THINK WHETHER 10MAO OR
WITH 5MAO OR WHATEVER AT
BEGINNING THE PRESSURE IS HIGH
AND AFTERWARDS THE PRESSURE IS
GONE.
SO WE HAVE TO BE A LITTLE BIT
CAREFUL WHEN YOU DO DETENTION IF
IF YOU DO SMALL, IT'S EVEN MORE
COMPLICATED BECAUSE SMALL WILL
KEEP RELAXING AND THEN YOU CAN
KEEP PUSHING MORE AIR TO
MAINTAIN THE PRESSURE.
>>WE NEVER WENT ABOVE
10 MILLIGRAMS MERCURY BUT ALSO,
WE SEE THE SAME RESULTS IF WE
INDUCE RELAXATION WITH GOP1 SO
IT DOES NOT SEEM TO DEPEND ON
THE CONTRACTION OR GOING THE
PHYSIOLOGICAL RANGE.
>>ONE MORE QUICK QUESTION.
>>QUESTION.
I THINK THIS IS VERY INTERESTING
AND WE NEED TO BE A LITTLE BIT
MORE OPEN.
SO EVOLUTIONARILY, OF COURSE,
DRG SENSE INCEPTION ALL OVER THE
BODY AND IT DOESN'T MAKE SENSE
THAT IT'S JUST FOR MUSCLES.
AND THE RESULTS ARE THE LESION
ACTUALLY, IF IT WOULD BE PAIN,
YOU KNOW, OVER EATING, RIGHT,
YOU WOULD EXPECT THAT THEY
WOULDN'T BE NECESSARILY OVER
EATING AND IN THE CASE OF VAGUS,
SO MAYBE THEY'RE SIGNALING
DIFFERENT ASPECTS AND MECHANIC
SENSATION, I MEAN WE KNOW IT
EXISTS IN THE VRG TO SPINAL CORD
AND I'LL TALK IN THE END ABOUT
THE MOTOR ASPECT AND YOU WILL
SEE IT'S VERY SIMILAR WITH MOTOR
CORTEX INNOVATING INTERNAL
ORGANS SO MAYBE, UNLESS THERE'S
SOME TECHNICAL ISSUES WITH MY,
MAYBE WE'VE OVERLOOKED AND WE'VE
THOUGHT EVERYTHING IN TERMS OF
SENSING AND CONTROL THAT GOES
THROUGH THE CORD IS FOR OVERT
MOVEMENT BUT IT MAY BE FOR
PHYSIOLOGY.
>>WE NEED TO STOP HERE.
THERE ARE A FEW MORE QUESTIONS
AND MAYBE THOSE INDIVIDUALS, WE
CAN KIND OF PASS THAT ONTO THE
SPEAKERS.
SO GRATEFUL FOR THE LIVELY
DISCUSSION.
THANK YOU.
>>WE WILL HAVE A BRIEF BREAK.
IF YOU WANT TO GIVE UP AND MOVE
AROUND AND WE'LL BE BACK HERE AT
2:35 TO GET STARTED.
WELCOME BACK.
WE'LL STARTED WITH SESSION 2 AND
I'D LIKE TO GO AHEAD AND
INTRODUCE OUR SESSION 2
MODERATOR, Dr. MARK ANDERMANN.
>>WE'VE NOT EXCITING LINEUP FOR
THE SECOND SESSION HERE AND THE
SESSION IS ON PULMONARY CARD
VASCULAR SYSTEM AND BRAIN
CONNECTIONS AND THERE'S FOUR
SPEAKERS AND I'LL GOING TO READ
OUT THEIR TITLES AND NAMES IT'S
A 15-MINUTE TALK AT THE END
WE'LL HAVE 10 MINUTES FOR
QUESTIONS AND WE MIGHT REMEMBER
IF YOU END YOUR QUESTIONS
ON-LINE TO EXPLAIN WHICH SPEAKER
THE QUESTION IS DIRECTED TO.
SO, WE'RE GOING TO START WITH A
TALK BY Dr. XIN SUN FROM UCSD
DISSECT THE INTEROCEPTION KIRK
ET THAT CONTROLS AIRWAY AND
WE'LL HEAR FROM ARLIN BLOOD AND
CHRISTOPHER WILSON WITH
UNRAVELING LUNG INTEROCEPTION
AND ITS FUNCTIONAL CONSEQUENCE
IN THE DEVELOPING OWE VINE LUNG
AND DISSECT KNEW OWE CIRCUITS
FOR BREATHING PATTERNS AND Dr.
AJIJOLA FROM UCLA WILL TALK
ABOUT DEFINING SUBSETS OF SI
SYMPATHETIC NEURONS MEDIATING
CARDIAC NEURO TRANSMISSION.
WITH THAT I'LL PASS IT OVER.
I'D LIKE TO START BY THANKING
DAVID AND WEN AND THE NCCIH
LEADERSHIP FOR SUPPORTING THIS
WORK AND I'M HERE TO GIVE YOU A
PROGRESS REPORT OF OUR WORK ON
THE AIRWAY CIRCUITS.
SO SINCE I'M THE FIRST SPEAKER
IN THIS CARDIO PULMONARY SESSION
I'D LIKE TO START WITH THIS
SLIDE TO SAY THAT THE LUNG IS
NOT JUST A VITAL AND BEAUTIFUL
ORGAN BUT IT'S ALSO A BEAUTIFUL
ORGAN TO STUDY INTEROCEPTION AND
GIVEN IT'S HUGE SURFACE AREA AN
AVERAGE ADULT PERSON HAS ABOUT A
HALF A SIZE OF A TENNIS COURT
PACKED INTO OUR CHEST AND IN
ADDITION, AN AVERAGE PERSON
RESTING FIVE TO EIGHT LITERS OF
AIR THAT COMES IN AND OUT OF OUR
LUNGS.
SO THIS AIR CAN CONTAIN A
DIVERSITY OF SIGNALS INCLUDING
ALLERGANS, POLLUTANTS, INCREASE
AND DECREASING OXYGEN AND ALSO A
DIFFERENT SYSTEM MECHANICAL
TENSION.
THE LUNG IS A BEAUTIFUL ORGAN TO
STUDY THE INTEROCEPTION
CIRCUITS.
I'M TRAINED DEVELOPMENTAL
BIOLOGY STUDIED SO I'LL ENTRY
POINT INTO STUDY THE LUNG STARTS
WITH ANATOMICAL MAPPING SO THIS
IS A WHOLE MOUSE LUNG CLEARED AN
IMAGED WITH THE SENSORY NERVES
THAT RUNS ALONG MOST OF THE
AIRWAYS THAT REACHES DEEP INTO
THE LUNG.
SO WE USED TO ADDRESS WHERE THE
SENSORY NERVES, THE CELL BODIES
AS WELL AS THEIR UPWARDS
PROJECTIONS INTO THE BRAIN STEM
WHEN USED THE GRADE APPROACHED
SOME OF THE ALREADY MENTIONED IN
THE FIRST SESSION, THE
RETROGRADE AAV AND WE HAVE USED
IT INTO THE LUNGS SO WE GET
WIDESPREAD INFECTION IN THE LUNG
INCLUDING IN THE NERVE TERMINALS
AND MOST OF THE CELL BODIES ARE
IN THE VAGAL GANGLIA AND WITH
VERY FEW NEURONS LABELED IN THE
DRG AND SO THE UPWARD PROJECTION
GOES INTO THE BRAIN STEM AND
THIS IS THE WHOLE BRAIN STEM
CLEARED AND AS YOU CAN SEE HERE
NOT SURPRISINGLY MOST OF THE
PROJECTIONS GOES TO THE NTS
REGION.
SO, WITH THIS SET UP, WE ASKED
WHAT ARE THE SPECIFIC SIGNALS
TRANSMITTED FROM THE LUNGS SO
THE FIRST SIGNAL WE LOOKED AT IS
ALLERGANS.
WHY?
IT'S A COMMON INHALED IRRITANT
COMING INTO THE LUNG AND IT
INDUCES SEVERAL TYPES OF
ADAPTIVE RESPONSES INCLUDING
AIRWAY CONSTRICTION, A TH2
IMMUNE INFILTRATION RESPONSE AS
WELL AS META PLAY SHA IN THE
AIRWAY AND IT'S EXCITING TO STUY
ALLERGEN RESPONSE BECAUSE AS
SHOWN HERE, IT'S AN IDEAL
SETTING TO LOOK AT NERVE, THE
PINK CELLS ARE IMMUNE CELLS AS
WELL AS LUNG SENSORY CELL TYPES
AND SENSORY CELL TYPES THE
ENDOCRINE CELLS HIGHLIGHTED HERE
AND INNOVATED BEAUTIFULLY BY
NERVES AND SO THESE NEURON
ENDOCRINE CELLS MENTIONED IN THE
FIRST TALK ARE WIRED BY NERVES
AS WELL AS THERE ARE IMMENSELY
SENSITIVE TO ALLERGAN RESPONSE
AND REALLY IMPORTANT FOR
TRANSMITTING THAT RESPONSE.
ALLERGAN RESPONSE IS DISEASE
RELEVANT IN PARTICULAR, ASTHMA
BEING A DISEASE THAT IS
TRIGGERED BY CHRONIC ALLERGAN
EXPOSURE.
SO TO STUDY ALLERGAN RESPONSE, I
MENTIONED THAT SINCE THE LUNG
INNOVATING SENSORY NERVE MOSTLY
PROJECT TO THE NTS REGION, WE'VE
USED FOUR-DOSE HOUSE DUST MIGHT
ALLERGY INDEX REGIME THAT IS
COMMONLY USED IN THE LUNG TO
STUDY ALLERGY RESPONSE AND
ADDRESSED THE NEURONAL
ACTIVATION IN THE NTS REGION YOU
CAN SEE HERE THERE'S A
BEAUTIFULLY STATISTICALLY
SIGNIFICANT INCREASE OF NEURON
TIVE TAIZATION IN THE THE NTS
REGION AND I WANT TO POINT OUT,
THIS IS RESPONSE HAPPENING AFTER
FOUR DOSES OF ALLERGAN CHALLENGE
AND IT'S NOT SEEING WITH THE
EARLY ADULTS SUGGESTING THAT
THERE'S A CHALLENGE AND
POTENTIAL PLASTICITY BUILT INTO
THE SYSTEM.
SO THE NEXT QUESTION IS WHICH
SUBSET OF THE NTS NEURONS MUTATE
IN THIS RESPONSE AS MANY OF YOU
STUDIED THE NTS FOR AN
INTEGRATING CENTER FOR MULTIPLE
ORGANS SO WE DID SINGLE NUCLEUS
BOTH AT THE BASELINE AS WELL AS
AFTER ALLERGAN CHALLENGE AND IN
BOTH SETTINGS, THE NTS NEURONS
SEGREGATE INTO CERTAIN CLUSTERS
IN OUR HANDS AND ALONG THOSE
CLUSTERS WE FOUND ONE OF THIS
CLUSTER MARKED BY THE DBH AS A
MARKER, IS SELECTIVELY ENRICHED
BY RESPONSE TIVE NOOSE OWNS AND
NEURONS.SO THE NEXT QUESTION WIN
ADDRESSED ARE THESE POSITIVE
NEURONS DBH FOR TRANSMITTING THE
ALLERGAN RESPONSE DOWNSTREAM?
SO TO DO THIS, WE USED THREE
DIFFERENT APPROACHES AND FIRST A
TOXIN TO ABATE THE POSITIVE
NEURONS AND SECOND WE USED THE
DTR SYSTEM IN COMBINATION WITH
THE DBH SPECIFIC THE THIRD ONE I
WILL SHOW YOU DATA FOR THE DREDD
SYSTEM WHICH WHEN WE INFECTED
THE AAV CARRYING THE FLEX INHIB
TREE VIRUS INTO THE NTS REGION
AND SO WITH THE INHIBITION OF
THOSE NEURONS IN THE PRESENCE OF
HDM WE FOUND IS THAT NEITHER OF
THE IMMUNE RESPONSE CELLS ARE
EFFECTED BUT THE AIRWAY
CONSTRICTION RESPONSE AND THE
MAJOR RESPONSE THAT BLOCKS AIR
FLOW IS EFFECTED SO BEFORE I
SHOW YOU THAT AND TELL YOU THAT
RESULT I WANT TO TELL YOU HOW WE
ESSAY FOR AIRWAY CONSTRICTION SO
WE USED A SYSTEM CALLED TO FOR
AIR FLOW AND THROUGH THE AIRWAY
AND THIS IS AFTER THE HDM
CHALLENGE SHOWN IN BOTH OF THESE
MEASUREMENTS AND SIMILAR
MEASUREMENTS FOR AIRWAY RESPONSE
SHOWN ON THE TOP ORANGE LINE
HERE IS AN ANIMAL AFTER THE
ALLERGAN CHALLENGE AND THIS
LEADS TO A PRODUCT ADAPTER SONS
TO THE CIRCUIT AS WELL AS THE
AIRWAY SMAIR SMOOTH MUSCLE SO WN
WITH ACUTE MESSAGE THAT ACUTELY
CONSTRICTS THE AIRWAY SO YOU SEE
THE EXACERBATED RESPONSE TO
AIRWAY CONSTRICTION COMPARED TO
THE SALINE CONTROL SO THIS IS
SIMILAR TO WHAT HAPPENS TO
ASMATIC PATIENTS YOU GET
EXACERBATED RESPONSE.
SO THIS IS HOW WE ASSAY FOR IT
AND WHEN WE HAVE THE DREDD
SYSTEM COMPARED TO CNL OR
WITHOUT IT SO WITH THE CNO
STIMULATION OF THE INHIBITORY
DREDD, WE VERY MUCH BLUNTED THAT
HYPER REACTIVITY RESPONSE
COMPARED TO THE CONTROL
SUGGESTING THE NTH NEURON
ACTIVATION IS NECESSARY FOR A
HYPER REACTIVITY RESPONSE.
WHAT WILL THE FLIP SIDE?
WE USE THE ACTIVATION DREDD
SYSTEM INJECTED INTO THE AND
THEY DIRECTLY INNOVATE THE --
>>THEY ARE INNOVATED BY NERVE
TERMINALS AND IT'S THESE AND
CONSTRICTION.
SO, WITH THIS NEURO MAP WE KNOW
THAT IT'S PART OF THE PATHWAY SO
OUR THE NEURONS REQUIRED FOR THE
ALLERGAN RESPONSE AND SO HERE,
USING THE INHIB TREE DREAD AS
WELL AS THE ACTIVATION DREDD WE
SHOWED THAT LIKE THE NTS
DEVIATION NEURONS THE NA NEURONS
ARE NECESSARY AND STUFF FOR
ALLERGAN INDUCED AREA HYPER
ACTIVITY SO THE FINAL DATA SITE
I'M GOING TO SHOW YOU ABOUT IS
TO GET TO THE SIGNAL OF
TRANSMISSION AND IT'S A VERY
SMALL CLUSTER OF NEURONS AND
THEY CLUSTER OUT TO THREE
DIFFERENT SUB TYPES AND WE CAN
THEN LOOK AT RECEPTORS PAIRING
WITH THOSE DIFFERENT NODES AND
FROM THOSE INFORMATION WE
HYPOTHESIZED THAT THE DBH
NEURONS MIGHT ACT AS CAPABLE OF
PRODUCING NOR EPINEPHRIN WITH
THE RECEPTORS OF BEING PRESENT
IN THE NEURONS SO THAT MIGHT BE
A TRANSMITTER AND WHAT WE DID IS
TO COME IN AND INFUSE INTO THE
NA REGION SPECIFICALLY
ANTAGONIST FOR THE AND SO WITH T
I'D LIKE TO THANK AND IT'S
SPEARHEADED THIS WORK AND I'M
VERY GRATEFUL FOR MY FUNDING AND
VERY GRATEFUL FOR OUR NEWER OLE
BIOLOGIST COLLABORATORS.
THANK YOU.
[APPLAUSE]
THANK YOU, VERY MUCH.
OK, WE HAVE TIME FOR ONE QUICK
QUESTION.
I THINK THE SECOND PERSON FROM
THE END.
CONGRATULATIONS.
SO, YOU MENTIONED THE DBH
NEURONS IN THE HYPER SENSITIVE
>>I HAVEN'T DONE THAT PART OF
THE CONTROL FOR GETTING WHEN WE
DID MANIPULATE THE NA REGION WE
LOOKED AT THE BRAIN CONTROL AND
THE BASELINE.
WE DID NOT SEE AN EFFECT.
>>I SEE.
THANK YOU.
>>THAT'S AN IMPORTANT QUESTION.
THANK YOU.
>>LET'S MOVE ON TO THE NEXT
SPEAKER.
>>THERE'S A INTER PLAY BETWEEN
THE BRAIN AND.
>>WE WANT TO DETERMINE WHETHER
OR NOT TRAFFIC CHANGES IN THE
VAGUS DURING THE COURSE OF
DEVELOPMENT SO WE HAVE -- WE CAN
IMPLANT AND WE DID INVASIVE
MEASUREMENTS JUST.
>>SHORTLY AFTER BIRTH.
WE'RE LOOKING AT THE FUNCTIONAL
EFFECTS OF THE VAGUS NERVE AND
HOW IT ORCHESTRATES THE
CARDIOVASCULAR TRANSLATION THAT
HAPPENS AT BIRTH SO WE WILL AN
EARLY STAGE ABOUT 100 DAYS IN
GESTATION AND LET THEM PRE GRES
TO THE TERM AND DO A C-SECTION
WHILE WE MEASURE CARDIO
PULMONARY PARAMETERS AND THIS
WAS KIND OF TYPICAL RESPONSE TO
BIRTH FOR A HUGE INCREASE IN
PULMONARY BLOOD FLOW AND A
DECREASE IN RESISTANCE AND BLOOD
FLOW WE CAN MEASURE SO WE'LL
INSTRUMENT THE ANIMAL TO MEASURE
THESE AND TREASURE AND GO
THROUGH A C-SECTION AND
FOLLOWING THIS PROTOCOL AND
WE'LL SUBJECT THEM TO A HYPOXIC
STIMULUS AND WATCH THE LUNGS AND
BASAL CONSTRICT AGAINST THE
HYPOXIA AND WATCH THE HEART RATE
RESPONSE AND THIS IS DONE IN
ANIMALS THAT HAVE A VAGUS
COMPARED THAT THOSE HAVE BEEN
DENERVATED TO SEE HOW THEY
RESPOND.
SOME PRELIMINARY DATA, NOT TOO
SURPRISING, IF THEY ARE
DEINNERVATED ANIMALS THEY COME
IN WITH A RESTING HEART RATE
THAT IS HIGHER THAN OUR SHAM
CONTROL ANIMALS AND THIS IS AN
PROJECT BUT THIS IS
REPRESENTATIVE OF 30 OR 40
ANIMALS WE'VE DONE WITH THIS
PROTOCOL.
PULMONARY VASCULAR RESISTANCE IS
ELEVATED IN THE THROW ANIMALS
THAT WE'VE DEINNERVATED AND
STUDIED SO FAR SO WE'LL FOCUS ON
HOW INNERRIZATION OF THE
PULMONARY MIGHT BE CHANGED BY
THIS AND PULMONARY COMPLIANCE IS
DECREASED IN OUR DENERVATED
ANIMALS AND THIS IS WHAT A PRE
TERM WOULD LOOK LIKE AND THESE
ARE TERM LAMBS.
I'LL TURN IT OVER TO Dr.
WILSON TO TALK.
>>SO IT'S FOCUSED ON A MORE
SIGNAL THEORY KIND OF APPROACH
TO VAGUS NERVE AND THE OTHER WAY
AROUND, CNS TO THE LUNG SINCE WE
GET TWO FOR TREE THERE.
DURING GESTATION OF BIRTH IN THE
SENSE WE'RE USING LONG-TERM
RECORDINGS THAT WE HAVE HOOKED
UP TO A RADIO SYSTEM.
IF YOU LOOK AT THE IMPLANT HERE,
ABOUT 95 DAYS OF GESTATION WE
CAN DO RECORDINGS OUT TO 150
DAYS WHICH IS TERM.
NORMALLY WHEN WE THINK ABOUT
PHYSIOLOGICAL WINDOWS WE TAKE
SNAPSHOTS JUST LIKE STOP-MOTION
ANIMATION WHERE WE GET LITTLE
WINDOWS OF PHYSIOLOGICAL
ACTIVITY BUT NOW WE'RE ABLE TO
DO LONG-TERM RECORDING AND
INDUCE SIGNAL ANALYSIS ON THAT
PARTICULAR SIGNAL AND WE GET ECG
SO WE HAVE ECG AS WELL AS VAGUS
ACTIVITY SO WE CAN CROSS
CORRELATION OF ECG AND VAGUS
NERVE ACTIVITY AND WE CAN LOOK
AT HEART RATE VARIABILITIES
METRICS BASED ON SDNN, SDANN,
NM50 AND LOOK AT FREQUENCY SEW
MAIN ANALYSIS USING FAT FORWARD
TRANSFORMS WITH TIME VARIANT AND
INFRASTRUCTURE RACE ANALYSIS AND
ANY OF THOSE THINGS AND ON THESE
SIGNALS.
IT ALLOWS TO LOOK AT BALANCE AS
WELL AND OUR DATA ANALYSIS TOOLS
STACK IS PYTHON, NON PYTHON AND
JUPYTER NOTEBOOKS THAT LITTLE
SCRABBLE AAVAILABLE TO EVERYONE.
SO HERE IS JUST AN EXAMPLE OF
SOME OF OUR PRELIMINARY DATA,
THIS WAS ACQUIRED WITH HOOK
ELECTRODES NOT OUR NEW CUFF
ELECTRODES.
HERE IS AN FFT OF THE VAGUS
NERVE ACTIVITY, WE SEE IN B AND
TIME SPECTRUM OVER MULTIPLE
MINUTES HERE SO WE'RE JUST AT
THE BEGINNING OF DOING THIS
ANALYSIS IN THE SMALL NUMBER OF
ANIMALS THAT WE'VE RECORDED DATA
FROM BUT WE HAVE SOME OF THAT
DATA.
NOW I'M JUST GOING TO SUMMARIZE
A FEW OF THE ARE
GOING ON WITH THE PROJECT AND
SOME OF THE -- WE'RE HONORED TO
COLLABORATE WITH HER AND DENISE
AND JAMIE WORKS WITH Dr. SUN
AND OUR POSTDOC WHO IS DOING A
HUGE AMOUNT OF THE WORK IS
KARINA MAYAGOLITA WHO WORKS WITH
US AT LLU.
>>THANK YOU.
>>THANK YOU VERY MUCH.
>>NEURONS AND OTHERS SO DID YOU
THINK OF LOOKING INTO OTHER
NERVES, FOR EXAMPLE, THE -- THE
CARROTTED THAT MAY GIVE A
STRONGER SIGNALS IN RESPONSE TO
HYPOXIA.
>>CERTAINLY.
WE'RE NOT FOCUS ON HYPOXY EXCEPT
A CHALLENGE TO MAKE SURE WE HAVE
INPUTS UP TO THE BRAIN STEM THAT
EFFECT BREATHING CONTROL SO
WE'RE FOCUSED ON INSENATORS FORR
THE LUNG.
WE HOPE TO DO THAT WORK AS WELL
OF COURSE AND TALK ABOUT MORE OF
THE REST OF THE CONTROL CIRCUIT
TREE WITHIN THE BRAIN STEM.
GREAT POINT.
WE'D LIKE TO DO IT AND WE'LL
KEEP WORKING.
>>THANK YOU.
>>THANK YOU VERY MUCH AND NOW
WE'LL MOVE TO THE NEXT TALK.
GOOD AFTERNOON, EVERYONE.
MY NAME IS PENG LI AND I'M FROM
THE UNIVERSITY O MICHIGAN, GO
BLUE.
I'D LIKE TO THANK THE BLUE PRINT
FOR FUNDING OUR PROJECT AND
THANK YOU TO THE ORGANIZERS FOR
HAVING ME HERE TO SHARE OUR
WORK.
OUR LAB IS INTERESTING SHOWING
HOW OUR BRAIN INTEGRATE SENSORY
STIM YOU LIGHT AND CONTROLLING
BEHAVIOR SO WITH THE FOCUS ON
BREATHING.
BECAUSE BREATHING -- SO, BECAUSE
BREATHING IS A VITAL BODY
FUNCTION IN HOMEOSTASIS AND IT'S
EFFECTED AND WITH CONSEQUENCES.
BREATHING A CRITICAL PROCESS IN
LINKING OR MEDIATING THE
INTERACTION BETWEEN THE BRAIN
ANDED BOW OAND BODY AND THE ONLC
BODY FUNCTION THAT CAN BE
CONTROLLED BOTH OF VOLUNTARILY
AND THE INVOLUNTARILY.
AND IT'S A BEHAVIOR BREATHING IS
ALSO APP TRACTABLE AND WE CAN
SIMPLY TRACE DIFFERENT
PARAMETERS TO A MATTER OF
BREATHING WHAT IS SHOWING HERE
IS A BREATHING FROM THE RESTING
STATE BECAUSE YOU HAVE A
BREATHING PATTERN OR A REGULAR
BREATH AND IN ADDITION TO THESE
REGULAR BREATHING PATTERNS, WE
ALSO HAVE OTHER BREATHING
PATTERNS WHICH HAVE SIMULATED
WE STARTED BY DESECTING THE
NEURONS SO FIRST WE CARRY OUT A
SINGLE CELL OF THE NTS REGION OF
THE FROM THERE WE IDENTIFY THE
DIFFERENT CELL TYPES AND
INCLUDING NEURONS AND OTHER CELL
TYPES IN THIS.
>>WE ACTIVATED THE CELLS AND AS
SUBSET AND SO BECAUSE NTS IS
ESSENTIAL INTO MEDIATING
BREATHING IT'S NOT SURPRISING
THAT WE SAW BREATHING IS
EFFECTING WHEN WE ACTIVATED
DIFFERENT SUBSETS SO WHEN WE
ACTIVATED THE ACCESS OF THE
NEURONS WE OFTEN SEE A
INSPIRATION INDUCED AND WHEN WE
ACTIVATE THE INWILL TO BE
NEURONS WE SAW THE BREATHING AND
LEN WE ZOOM INTO THE SUBSET OF
THE NEURONS AND FOR EXAMPLE HERE
WHEN WE ACTIVATE A SMALL SUBSET
OF THE NEURONS SPECIFICALLY
EXPRESSING RELEASING PEP TIGHTS
REPRESENTING THE TWO AND THROW
AND WE SAW A SIGH IS INDUCED SO
WHAT IS A SIGH?
THE WE OFTEN TALKED ABOUT IT
LONG LARGE DEEP BREATHE SEWATED
TO EMOTION AND STRESS, RELIEF
AND SADNESS.
BUT AS CAN YOU SEE HERE IT'S A
INSPIRATION FOLLOWED BY A
ELONGATED EXPIRATION AND IT
TURNS OUT THAT WE SAW
SPONTANEOUSLY AND WE CALL THIS A
BASAL SIZE AND HUMAN SIZE FIVE
TO 10 MINUTES AND EVERY TWO
MINUTES SO YOU PAY ATTENTION TO
YOUR OWN BREATHING, YOU WILL
NOTICE ONE TO TWO SIZE IN THE
REST OF IT AND THIS SIZE ARE
ESSENTIAL INFORM THE COM APPS
AND THE DOCTORS PROGRAM THESE
SIDES INTO THE VENTILATOR TO
MAINTAIN THE TELL MINUTE TARRY
FUNCTIONS OF THE PATIENTS AND IT
CANNING REGULATED BY DIFFERENT
STIMULI AND SUCH AS HYPOXIA
WHICH SO I STRONG STIMULUS IN
ENTHUSING SIZE.
THERE ARE OTHER CONDITIONS WITH
ELEVATED SIZE AND INCLUDING
CHRONIC DISORDERS AND THE PANIC
DISORDERS AND WE CAN ALSO
VOLUNTARY SIGH BECAUSE IT'S HOW
WE CAN VOLUNTARILY CONTROL OUR
OTHER BREATHING PATTERNS.
SO, HOW IS A SIDE CONTROL.
A COUPLE YEARS AGO WE IDENTIFIED
SMALL SUBSET OF NEURONS IN THE
ONE SIDE OF THE BRAIN STREAM AND
CONNECTING TWO KEY BREATHING
CONTROL CENTERS AND
>>FOR THE RHYTHM GENERATION.
THIS NEURONS ONLY THE SIGH IS
EFFECTED AND NOW THE BREATHING
AND SO SUGGEST THEY PLAY A
DEDICATED CONTROL IN CONTROLLING
THESE BREATHING PATTERNS AND WE
FOLLOW THIS UP LOOKING INTO THE
EMOTIONAL SIDE AND WE FOUND THE
STRESS WE ALSO CALL IT CLASS
CLAUSE TRACLAUSTROPHOBIA AND FRE
NEURONS WE IDENTIFY THE DOZEN
REGIONS INCLUDING -- WE CAN INDE
STRESS RELATED BEHAVIOR SIMILAR
TO THE RESPONSE ELEVATED AND
WHEN WE SILENCE THIS PATHWAY,
>>IT'S SUFFICIENT IN INDUCING
WE NEXT WONDER IF THERE'S A
CIRCUIT OF FEEDING INTO THIS
NEURON IN REGULATING THE
HYPOTHESIS AREA RESPONSE AS
PEOPLE MENTIONED EARLIER, IT'S A
MAJOR OX DEPART OXY DENT SO WE E
NEURONS AND USE A RETRO TRADE
TRACING IN COMBINATION THERE'S
TRACING FROM THE BODY AND IN
DEED, WE FOUND A CO LOCALIZATION
OF THIS IN THE VAGUS NIH SO VAG.
AND THE NEXT WE USE A GENETICS
TO SILENCING THE GPR NEURONS AND
IN DEED, THE HYPOXY INDUCES IS A
SPECIFICALLY REDUCED AND I'M NOT
SHOWING YOU HERE IS THE BASAL
SIDE OR OTHER RESPONSE WAS NOT
EFFECTED.
SO SUGGESTING THESE NEURONS HAVE
A SPECIFIC CONTROL IN MEDIATING
HIGH TOXIA SO WE LOOK AT NEURONS
AND LET'S LOOK AT ANOTHER
POPULATION WHICH IS A NEURONS IN
THE NTS SO WHEN WE ACTIVATED
THESE CLASS NEURONS, WE SAW A
STEREO TYPE BRACKET BREATHING SS
THIS BREATHING PATTERNS.
SO WE LOOKED INTO LITERATURE
FROM HUMAN AND OTHER SPECIES AND
IT LOOKS SIMILAR TO A COUGH.
SO WHAT IS A COUGH?
A COUGH IS A PROTECTIVE
BREATHING RESPONSE TO THE USE OF
YOUR AIRWAYS.
IT'S TRIGGERED BY THESE COUGH
INDUCING STIMULUS.
AND IT STARTED BY A COMPRESSION
PHASE WHICH IS A CLOSE AIR
PRESSURE BUILDUP IN OUR AIRWAYS
AND BECAUSE OF THE SUDDEN
OPENING OF THE AREA IT RUSHES
OUT FROM OUR AIRWAY WHICH IS
COUPLED WITH BODY MOVEMENT.
HOWEVER, WHETHER MOUTH COUGHS
HAVE BEEN DEBATED IN THE FIELD,
BECAUSE THEY'RE TINY AND IT'S
HARD TO DETECT THE BREATHING
PATTERN.
WE DECIDED TO CHECK OURSELVES.
SO WE NUMBER YOU LIESED THE
EXACT INTEREST WHICH IS KNOWN AS
A PASSIVE AGENT IN PATIENTS SO
DOCTORS USED THESE IN PATIENTS.
SO WE APPLIED THESE CHALLENGE TO
THE ANIMALS AND WE INDUCES IT
WITH INSPIRATION, COM OPERATION
PHASE AND EXPLOSIVES PHASE AND
IT'S A COUPLED WITH THE SUM AND
THE OTHER PHYSIOLOGICAL
MATTERMENTS SO THEN, WE PULL THE
ANIMAL, THE ANIMALS INTO THIS
PARADIGM AND IN DEED WE SAW THE
IDENTICAL PATTERN WAS INDUCED.
AND THEN WE SILENCEDDED THESE
NEURONS AND WE FOUND COUGH IS
DRAMATICALLY REDUCED SO THESE
SUGGEST THAT THESE NEURONS IS
BOTH NECESSARY AND SUFFICIENT
FOR COUGH.
AND IN THE MEANTIME, WE ALSO
OBSERVE THE OTHER BREATHING
POTTENS AND RESPONSE AND NOW
THOSE WERE EFFECTED, BUT THESE
MANIPULATION.
NEXT WE TRACE THE UPSTREAM AND
DOWNSTREAM OF THESE NEURONS AND
WE FOUND THAT THEY RECEIVED THE
MEET EIGHTING THE PASSIVE
STIMULUS AND THEY PROJECT TO
DIFFERENT DOWNSTREAM REGIONS IN
THE BRAIN STEM IN CONTROLLING
THE COMPLIMENTARY AND THE
SEQUENTIAL MOTOR OUT MODES OF A
TOUGH.
SO WE HAVE HIGH POTH A SIS THESE
NEURONS AS PART OF THE IMPORTANT
PART OF THE TOUGH CENTRAL AND
GENERATOR AND SO IN SUMMARY, WE
STARTED MOLECULAR AND FUNCTIONAL
ANALYSIS OF NTS NEURONS AND
IDENTIFIED TWO SMALL SUBSETS OF
NEURONS THAT GRP NEURONS AND THE
THEY ARE REGULATING TWO DISTINCT
BREATHING PATTERNS AS A SIGH AND
A COUGH.
WHICH ARE ALSO IMPORTANT IN THE
PATHOLOGICAL CONDITIONS.
WE FOUND THAT THEY'RE MEDIATING
HYPOXY INDUCED SIGH AND CHARGING
INDUCING THE COUGH RESPECTIVELY
AND BY TRACING TH CIRCUIT, WE
IDENTIFIED MEDIATING THESE TWO
BEHAVIORS AND WE ALSO PROPOSE TO
CHECK AND TO TRACE THEIR DOWN
STREAMS THROUGH OUT THE BRAIN TO
FIGURE OUT THE BRAIN MAP
REPRESENTING THESE INTRO
ACCEPTIVE STATES.
WITH THAT, I'D LIKE TO THANK MY
LAB.
AND OUR COLLABORATORS AND THE
FUNDING AGENTS.
ESPECIALLY THE BLUE PRINT NEURO
INTERCEPTION ON INTEROCEPTION
AND THE WORK THAT I PRESENTED
TODAY.
THANK YOU.
[APPLAUSE]
>>THANK YOU, VERY MUCH.
WE HAVE ONE QUESTION.
>>NICE WORK.
I WANTED TO YOU ASK IF YOU SAW
PHRG NEURO GROUPS.
THEY PROJECT AND THE GRPR
NEURONS AND FOR THE NEURONS
PROJECTED TO THE REGION AND ALSO
THE RFRG TO REGULATE DIFFERENT
ASPECTS OF THE COST.
>>THANK YOU.
>>YEAH.
>>JUST ONE OTHER QUICK
QUESTION.
SO YOU MENTIONED THAT BREATHING
IS UNDER VOLUNTARY CONTROL AND
I'M WONDERING WHEN YOU THINK
THAT ONE COULD TRAIN A MOUSE TO
COUGH?
>>THAT'S A GOOD QUESTION MANY
OF IT'S ON OUR WISH LIST.
WE HOPE WE CAN TRAIN AN ANIMAL.
IF YOU HAVE ANY SUGGESTIONS, LET
US KNOW.
[LAUGHTER]
>>THANK YOU.
>>WE'LL MOVE ON TO THE NEXT
SPEAKER.
>>GOOD AFTERNOON.
I WOULD LIKE TO START BY
THANKING THE MEETING ORGANIZING
COMMITTEE AND Dr. CHEN, AND
MANY OTHERS FOR THE KIND
INVITATION TO BE HERE TODAY.
MY LAB GROUP IS INTERESTED IN
UNDERSTANDING THE DESCENDING OR
THE EFFECTER LYMPH INTEROCEPTION
CIRCUITS THAT REGULATE THE
HEART.
HERE ARE MY DISCLOSURES AND
FUNDING SOURCES.
AS WELL AS AN ACKNOWLEDGMENT OF
MY COLLEAGUES IN UCLA AND I'M IN
A LARGE GROUP OF PHYSICIAN
SCIENTISTS INTERESTED IN WHAT
WE'RE TALKING ABOUT TODAY.
SO, MY GROUP IS PARTICULARLY
INTERESTED IN THIS -- THIS VIDEO
IS NOT GOING TO PLAY.
WE'RE INTERESTED IN ARRHYTHMIA
IS THE LEADING CAUSE OF DEATH IN
DEVELOPED NATIONS AND OUR LAB
GROUP IS PARTICULARLY INTERESTED
IN THE DEFENDING CONTROLS SO
WITHIN THE SYMPATHETIC NERVOUS
SYSTEM THAT REGULATES CARDIAC
FUNCTION AND WE USE MODELS,
MICE, PIGS AND EVEN HUMANS, YES,
HUMANS ARE MODEL ORGANISM IN OUR
LAB GROUP AND WE USE
MULTI-STALE, MULTI MODAL
APPROACHES FOR SYMPATHETIC SAM
BOLLING IN CARDIAC PATHOLOGY AND
ARRHYTHMIA.
HEART DISEASE IS THE LEADING
CAUSE OF DEATH AND 34 PEOPLE DIE
EVERY MINUTE OF SUDDEN CARDIAC
DEATH AND THIS RESEARCH AREAS IS
PARTICULARLY IMPORTANT BECAUSE
OF ALL THE PATIENTS AT RISK FOR
SUDDEN DEATH, IF YOU LOOK AT
THIS BLUE OVAL HERE AND PATIENTS
WHO HAVE SUDDEN DEATH WERE ONLY
ABLE TO RECOGNIZE A VERY, VERY
PREPORTION OF THEM AT RISK FOR
SUDDEN DEATH SO, RESEARCH INTO
THIS AREA IS CRITICALLY NEEDED.
WE GOT INTERESTED IN THIS AREA
BECAUSE OF A THERAPY THAT WE
FOUND OUT OF DESPERATION WHICH
IS OUR PATIENTS WITH SEVERE
ARRHYTHMIA WERE OFFERED THERAPY
CARDIAC REMOVAL OF THE PART THE
GANGLION AND THE SECOND AND
THIRD AND FOURTH AUTHORIZE AS
TICK BODIES OF THE SYMPATHETIC
CHAIN WHICH REPRESENTS THE POST
GANGLION I CAN SYMPATHETIC
CONTROL OF THE HEART.
IT SAVED LIVES AND PATIENTS WENT
ON TO DO WELL.
THIS TURNED OUR ATTENTION TO
CARDIAC NEURAL CONTROL.
MOST OF YOU NEED NO INTRODUCTION
TO THE FACT THAT THE HEART IS
DENSELY INNERVATED AND THIS IS
PLAYING SO I'LL START IT AGAIN.
IT'S A IMAGE OF A MOUSE HEART
JUST SHOWING HOW DENSELY
INNERVATED THE HEART IS.
IN ADDITION TO THAT, THERE ARE
NEURONS THAT SIT WITHIN EPI CARD
Y'ALL GANGLIA AND TOGETHER
REGULATE THE HEART AS SHOWN
HERE.
THATESSENTIALLY WE LOOK AT THE T
OF A SERIES OF FEEDBACK LOOPS
WHERE INFORMATION FROM THE HEART
IS PROCESSED BY NEURONS WITHIN
THE EPI CARDIAL GANGLIA AND
INFORMATION IS TAKEN UP TO THE
WE'RE TAKING OUT OF PATIENTS AND
THROUGH THE DRG SPINAL CORD AND
BACK TO THE HEART AND TO BRAIN
STEM AND BACK TO THE HEART.
WE ARE FOCUSING DOWN TO THE
HEART AND THE REASON FOR THAT,
AGAIN, IS THE FACT THAT WE KNOW
THAT IT IS A CAUSE OR A DRIVER
OF ARRHYTHMIA IN PATIENTS.
IF YOU TAKE A PATIENT WITH A
HEART ATTACK WE'VE LEARNED OVER
THE YEARS THAT THERE ARE
MEDIATED ALTERATIONS THAT HAPPEN
TO NEURONS WITHIN THE GANGLION
AND AT THE LEVEL OF THE HEART
THAT TOGETHER TRIGGERED THOSE
DANGEROUS ARRHYTHMIAS THAT I
JUST SPOKEN ABOUT.
IN ADDITION TO THAT, WHEN THE
HEART IS CHRONICALLY INJURED,
THESE NEURONS UNDERGO A REALLY
LARGE AMOUNT OF ENCLOUD OX DAY
TIVE STRESS AND ACTIVATION OF
GLEE OWE CELLS AND ALTERATION IN
NEURO TRANSMITTER USE BUT
CONTROL OF THE HEART ARE MAVOR
OR DRIVERS THAT CAUSE PATIENTS
TO DIE OF MORTALITY AND
MORBIDITY.
WE ARE TACKLING FUNDAMENTAL
QUESTIONS THAT ARE ADDRESS TO
THE LIMB OF THE CIRC SECRETARY'S
ASPECTS OF THE CIRCUIT AS WELL
BUT WE'VE BEEN FOCUSING ON THE
SYMPATHETIC CARDIAC CIRCUIT AND
ASKING QUESTIONS SUCH AS, YOU
KNOW, WHAT ARE THE CARDIAC
SYMPATHETIC EFFECTOR NEURONS ARE
THEY DISTINCT FROM NEURONS THAT
HAVE OTHER TISSUES AND HOW MANY
SUCH SUB TYPES ARE THERE AND HOW
DO THEY CHANGE IN DISEASE?
>>SO TO ADDRESS THIS QUESTION
OF POSTDOC IN MY LAB AND IN
CONVERSATIONS WITH Dr. XI SUN
WHO SPOKE EARLIER ON THAT WE
SPOKE ON THE SIDELINES OF A NIH
MEETING AND THIS LED TO THIS
NICE PROJECT COMING OUT OF THE
LAB AND THE IDEA TO USE A
SIMILAR TRACING APPROACH TO
WHICH MOST OF YOU HAVE USED AND
IT'S TO INJECT IN THE HEART AND
HAVE IT TRACE BACK TO THE
GANGLION AND WHAT IS INTERESTING
IS THAT WE CAN IDENTIFY THE
TRANSCRIPT FOR THESE FLUORESCENT
PROTEINS TO IDENTIFY CARDIAC
NEURONS AND WE'VE DONE THE SAME
THINGS IN OTHER TISSUES AND SO
WE CAN TAKE THIS APPROACH TO
IDENTIFY CARDIAC SUB TYPES AND
PROFILE THEM USING SIMILAR
APPROACHES ASK TECHNIQUES THAT
YOU ARE ALL DOING.
HERE IS AN EXAMPLE OF OUR
TRACING, YOU SEE NICELY THAT WE
HOLE EYES TO THE CARN Y'ALL
MEDIAL SPOL AT THE CARDIO
PULMONARY POLE AND FROM OUR
SINGLE CELL RNA SEQUENCING DATA
WE IDENTIFY SEVEN SUB TYPES AND
THREE OF THEM WE SEE INNERVATE
THE HEART.
WE VALIDATED THE BECAUSE OF OUR
INTEREST IN TRANSLATING OUR
STUDIES TO HUMANS WE PROBE THESE
SAME CELL TYPES AND PIGS AND
HUMANS AND IDENTIFIED THEM FROM
THESE TWO MODELS AS WELL.
NOW LOOKING AT THE GENES ACROSS
THE SUBTYPES PARTICULARLY
FOCUSED ON THE ONES WE KNOW
INNERVATE THE HEART, ONE GENE
THAT JUMPED OUT WAS NEURO PEP
TYPE 1.
IT EXPRESSES A VERY HIGH LEVELS
OF NEURO PEPTIDE Y BUT SUBTYPE
NA1B IS MUCH LOWER LEVELS AND
AND THEY HAVE NO EXPRESSION OF
NEURO PEPTIDE Y AS WELL.
THE REASON IS JUMP OUTSIDE AT US
IS THERE'S A CONCEPT THAT
NEUROPEPTIDES OR NEURO
TRANSMITTER RE LEASE IN THE
HEART IS OCCURS AS SHOWN HERE
WHERE THE VES KELS THAT CONTAIN
NEUROPEPTIDES HAVE RELEASE
PATTERNS SO UNDER BASAL STATES
OR VERY LOW STRESS ONLY CERTAIN
GRANULES ARE RELEASED,
PARTICULARLY THOSE FOR CAT A A
COLEMAN BUT YOU UNDER THIS
DOESN'T REALLY SEEM TO FIT VERY
MUCH WITH THE FACT THAT SOME
NEURONS HAVE IN NEURO PEPTIDE
BUT INNERVATE THE HEART AND IN
ADDITION TO THAT IN PATIENTS
WITH SEVERE HEART FAILURE WE'VE
IDENTIFIED CIRCULATING LEVELS AS
WELL AS CORONARY SINUS LEVELS
AND LEVELS IN THE HEART AS BEING
PREDICTED OF PATIENTS WHO WILL
HAVE ADVERSE OUTCOMES.
FOR EXAMPLE, IF YOU SAMPLE
CORONARY SINUS NEURO PEPTIDE Y
LEVELS IN HAITIANS THEY'RE LOW
AND IF YOU LOOK AT PATIENTS WITH
INCREASES OF CARDIAC INJURY YOU
SEE THAT NERVE LEVELS ARE
DRAMATICALLY ELEVATED AND
FURTHER IF YOU ACTUALLY TAKE A
THRESHOLD APPROACH AND LOOK AT
PATIENTS WITH VERY HIGH NERVE
PEPTIDE Y LEVELS, MOST OF THOSE
PATIENTS WHO WERE STABLE, WERE
ALMOST DECEASED BY THROW AND A F
YEARS.
IT MADE US CRYSTALIZE ON NEURO
PEPTIDE Y.
TO VALIDATE THE SEQUENCING DATA
AND SHARE THAT IN DEED THERE ARE
NEWERRANCE THAT DO NOT EXPRESS
THAT INNERVATE THE HEART SO
THERE WAS A CLEVER EXPERIMENT
WHERE THEY COMBINED RETROGRADE
TRACING WITH SPACIAL TRACING
FROM THE HEART SO HE INJECTED
TWO DIFFERENT TRACERS AND TRACED
THEM BACK TO THE GANGLION TO
IDENTIFY ONE, THE SUBTYPES OF
NEURONS THAT INNERVATE THE HEART
AND THIS WAS DONE IN THE MPYGFT
ANIMAL AND LOOK AT THE
ESSENTIALLY THE SPACIAL CONTROL
IN THE HEART OF THE GANGLION.
AND SURE ENOUGH, THERE ARE
NEURONS SO GRO GREEN NEURONS HEE
HAVE MPY AND NEURONS THAT DO NOT
HAVE GFP DO NOT EXPRESS NPY AND
YOU CAN SEE IT FROM THE HEART
WHERE THEY DO NOT EXPRESS MPY AS
WELL AS NEURONS THAT DO
EXPRESSION MPY AND THE SAME FROM
THE BASE HERE IN BLUE, YOU SEE
THAT THERE ARE NEURONS THAT
AGAIN DO NOT HAVE ANY MPY BUT
INNERVATE THE HEART AS WELL AS
NEURONS THAT DO HAVE MPY SO IT'S
CORRECT THAT MPY AS WELL AS NPY
HIGH NEURONS INNERVATE THE
HEART.
IN ADDITION TO THAT WHEN WE
COMPARE THEM, WE FIND THAT MOST
NEURONS THAT INNERVATE THE HEART
EXPRESSION MPY BUT THERE'S A
PREPORTION THAT DON'T AND
INTERESTINGLY THE NEURONS THAT
EXPRESSION MPY AND INNERVATE THE
HEART ARE LARGER THAN THOSE THAT
DO NOT.
NEXT WE MOVED ON TO ELECTRO
PHYSICAL LOGIC PROFILING OF
THESE TWO DIFFERENT SUBTYPES
WHEN WE LOOKED AT THE TRANCE
SCRIP TOMB THERE ARE DIFFERENCES
IN SPECIFIC EXPRESSIONS SUCH AS
KSNQ AND THE 1A AND B SUBTYPES
OF THE CALCIUM CHANNELS AS WELL
AS CHLORIDE CHANNELS AND WE
PROFILED THIS USING AN IN VITRO
PREP AS SHOWN HERE WHERE WE CAN
TAKE THE ENTIRE GANGLION AND
REALLY PLUCK OUT A SINGLE NEURON
TO RECORD AND WE CAN BACK FILL
THOSE NEURONS WHEN WE'RE DONE
AND TO ESSENTIALLY LOCK AT THE
PROPERTIES AND VERIFY THAT WE
DID RECORD FROM A SINGLE NEURON
AND HERE ARE SOME OF THE
FINDINGS FROM THESE NEURONS
ESSENTIAL LOW LONG STORY SHORT
WE FIND THAT MPY HIGH NEURONS
ARE A LOT MORE EXCITE ABLE THAN
NEURONS THAT ARE LOW AND DO NOT
EXPRESS MPY.
IT WILL DRIVE A CRE DEPENDENT
EXPRESSION AND DELETE NEURONS AS
SHOWN HERE AND THEN WE INJECTED
A CONTROL VIRUS JUST EXPRESSING
GFP AND YOU CAN SEE THE
DIFFERENCES HERE AND AT BASELINE
INTERESTINGLY THERE'S NO
DIFFERENCE IN HEART RATES
SUGGESTING THAT NPY NEURONS ARE
NOT REQUIRED FOR BASAL HEART
RATE CONTROL AND THEN THEY PREP
RATED HERE STIMULATING THE GANG
LOW ON AND WE KNOW THESE NEURONS
INNERVATE THE HEART AND WE CAN
MEASURE HEART RATE AND WHAT WE
FIND IS THAT WHEN WE DELETE MPY
NEURONS, THESE ANIMALS JUST ARE
NOT ABLE TO GET THE HEART RATES
UP AS HIGH AND ESPECIALLY AS WE
ESCALATE THE STIMULATION
FREQUENCY.
SO, THIS PREPARATION HERE WOULD
MIMIC HIGH STATES OF SYMPATHETIC
STRESS AT HIGHER END OF
SYMPATHETIC STIMULATION AND
LOWER LEVELS OF SYMPATHETIC
STRESS AS THE LOWER LEVELS OF
STIMULATION SO CLEARLY IT LOOKS
LIKE MPY NEURONS ARE FOX MAXIMUM
STRESS.
YOU SAY YOU DELETED NEURONS IS
WHY IS IT THAT YOU WOULD EXPECT
MAXIMAL SYMPATHETIC STRESS SO
MAXIMAL RESPONSE SO WE LOOKED AT
THAT ASPECT OF THINGS AND MPY
MICE AND COMPARED THE KNOCK OUT
TO HOMO SIGH DO NOT HAVE NPY AND
WE ROW PETEED AND FOUND THAT IN
DEED THE LOSS OF MPY WAS
ASSOCIATED WITH THE INABILITY TO
ACHIEVE MAXIMUM SYMPATHETIC
STRESS.
AGAIN, WE WANTED TO ALSO REALLY
HONE IN ON THIS BECAUSE WE KNOW
THAT THE MPY1R RECEPTORS IS THE
MAJOR RECEPTORS FOR NEURO
PEPTIDE Y SIGNALING IN THE HEART
SO WE KNOCKED THAT OUTCOME
PAIRING HETERO SIGH GUS AND THE
SAME PREPARATION AND YOU SEE
THAT MICE NOW WITH THE HOMO SIGH
GUS DELETION COMPARED TO THE
DELETED ANIMALS.
SO WHAT THIS IS REALLY TELLING
US IS THAT AT LEAST IN THE
DESCENDING LYMPH THIS CIRCUIT
CONTROL IS THAT THERE'S TIERED
CONTROL BY THE NEURONS WHERE AT
LOW LEVELS OF WHEN HIGHER
CITATION IS NEEDED IT'S
CONTROLLED BY DIFFERENT SUBTYPES
OF CELLS AND NA1 AND NA3 IN
PREPARATION SO I'LL STOP BY
SUMMARIZING WE FIND THREE
SUBTYPES OF SYMPATHETIC NEURONS
AND THEY APPEAR CONSERVED ACROSS
MOUSE AND UNIQUE AND ELECTRIC
PHYSICAL LOGIC PROPERTIES AND
THEY APPEAR TO BE FUNCTION IN
TIERED CONTROL MANNER WHERE ONE
SUBTYPE OF NEURONS MEDIATES THE
LOW CITATION AND TWO OTHER
SUBTYPES MEDIATE HIGH CITATIONS
AND WITH THAT I'LL STOP AND
ACKNOWLEDGE MY COLLEAGUES AT
UCLA AND THE MEMBERS OF MY LAB
THAT DO THIS.
THANK YOU.
[APPLAUSE]
>>THANK YOU, VERY MUCH.
WE'LL TAKE ONE QUESTION AND
WE'LL MOVE TO A GENERAL Q&A
SESSION.
DOES ANYONE HAVE ANY QUESTIONS
IN THE ROOM FIRST?
>>VERY NICE PRESENTATION.
I'M A LITTLE BIT SURPRISED THAT
YOU DID NOT LOOK INTO INNOVATION
OF ARTERIES.
I KNOW THAT MPY IS VERY WELL
KNOWN TO GO WITH ARTERY
INNOVATION SO DID YOU EXCLUDE
THAT?
>>NO, WE DIDN'T.
WE WERE JUST FOCUSED FOR OUR
INITIAL STUDIES JUST ON HEART
RATE CONTROL BUT YOU ARE
ABSOLUTELY RIGHT THAT MPY
NEURONS DO DENSELY INTER RATE IS
ARTERIES AND THAT WILL BE THE
FOCUS OF A FUTURE WORK BUT
PARTICULARLY WE'RE JUST LOOKING
HERE AT CONTROL OF THE HEART.
THANK YOU.
>>I THINK WE HAD ANOTHER
QUESTION FOR YOU.
WHILE YOU ARE HERE.
>>IT'S NOT TOTALLY DIRECTLY TO
YOUR TALK BUT ONE OF THE MAIN
INTRO ACCEPTIVE TASKS IN HUMANS
IS TO ASK THEM TO COUNT THEIR
HEART BEATS RIGHT.
>>WE CAN ACTUALLY TARGET THE
SPINAL SYMPATHETIC PATHWAY WITH
OUR SYMPATHETIC IN PATIENTS SO
THE ANSWER TO THAT IS TBD.
I DO SUSPECT THAT BOTH THE VAGAL
PATHWAY AND SPINAL PATHWAYS ARE
IMPORTANT BUT THE CON TRIB
BUYINGS OF ONE RCON INTETHEY WI.
>>DOES ANYONE HAVE QUESTIONS
FOR THE FOUR SPEAKERS IN THIS
SESSION IN THE ROOM?
>>IF NOT, PLEASE.
>>FIRST, THANK YOU FOR ALL THE
GREAT TALKS AND REALLY I'M
LEARNING SO MUCH AND I REALLY
ENJOYED IT AND THIS IS A
QUESTION FOR THE TWO LUNG
SPEAKERS.
WHAT I'M THINKING ABOUT WHEN
LISTENING TO YOUR TALKS IS
COVID.
HOW COULD THE VIRUS IN THE LUNG
POTENTIALLY AFFECT THE BRAIN AND
HAVE AN IMPACT ON BEHAVIOR ON
NEWER LOGIC FUNCTION SO ARE
THERE ROOTS THAT YOU THOUGHT
ABOUT OR MECHANISMS BY WHICH
THIS COULD OCCUR?
>>SO, ACTUALLY, WITH WEN WE
HAVE A COVID SUPPLEMENT ON THIS
GRANT LOOKING AT EXACTLY THAT,
ESPECIALLY LONG COVID RESPONSES.
WHETHER IT'S A INFECTION IN THE
BRAIN OR WHETHER IT'S INFECTION
IN THE LUNG AND OTHER INTERNAL
ORGANS THAT GETS TRANSMITTED TO
THE BRAIN THROUGH THE VAGAL
NEURONS SO ACTUALLY THE OTHER
PART OF MY LAB WORK ON LUNG STEM
CELL ACTIVATION AFTER INJURY
RESPONSE SO WE HAVE THOSE
WORKING ON THE COVID MOUSE MODEL
BUT WE HAVE THE FLU MODEL THAT
WE'RE STARTING TO WORK ON.
>>SO, NICK WHO WORKS WITH Dr.
BLOOD AND Dr. SUN AND I HAVE
SHOWN THERE'S ACE 2 IN THE COR
OTED BODY AND THE NTS SO THAT
VECTOR FOR COVID TO GET INTO
THOSE CELLS IS THERE.
THERE MAY BE CHANGES IT'S
SOMETHING WE'RE STILL WORKING ON
WITH ANOTHER COLLEAGUE AT UCSD
ON BRAIN.
GAINING TO THAT CIRCUIT WOULD
ALTER BREATHING CONTROL.
>>YEAH AND I WANT TO ADD THAT
APPARENTLY COUGH IS ONE OF THE
MAJOR SYMPTOMS OF COVID AND NOW
WE ARE NOT WORKING ON THE COVID
MODELEL YET BUT WHEN WE PICK OPT
CIRCUIT, IT'S WORTH CHECKING HOW
IT'S EFFECTING.
>>
>>SO MAYBE, A QUESTION FOR ALL
BUT MAYBE, THEY COULD START AND
ABOUT THE GRANULARITY OF CONTROL
SO WE SAW IN TWO TALKS, FOR
EXAMPLE, DIFFERENT POPULATIONS
CONTROLLING DIFFERENT RESPONSES
OF SIMILAR MUSCLES SO I MEAN,
THERE'S A SENSORY ASPECT THAT
YOU ARE FOCUSING BUT THE
RESPONSE ASPECTS AND THEN WE SAW
IN THE SYMPATHETIC, I MEAN
THERE'S LOW AND HIGH BUT THEY
COULD BE MODULATING DIFFERENT
PHYSIOLOGICAL RESPONSES SO
THERE'S MUCH MORE GRANULARITY IN
THE SYSTEM IN TERMS OF NOT ONLY
SPECIFIC SENSING BUT SPECIFIC
CONTROL OF THE RESPONSES.
WOULD YOU COMMENT ON THIS?
>>YEAH, I THINK IN TERMS OF
BREATHING, MANY OF THE MUSCLES
ARE SHARED BY DIFFERENT BEHAVE
YEARS INCLUDING BREATHING AND
AWE RESPIRATORY RELATED
BEHAVIORS OR VOCALIZATIONS AND
ALL THE CRANIAL FACIAL FUNCTIONS
SO REALLY UNDERSTANDING LIKE
WHAT ARE THE MOTOR CONTROLS
MODULES OF THESE BEHAVIORS WOULD
BE VERY IMPORTANT AND IT THEN I
THINK THAT WILL ALSO PROVIDE US
PARADIGM LIKE HOW EVOLUTIONARY
WE DEVELOPED THIS NEUROCIRCUITS
USING THE SAME KIND OF MUSCLE
AND MOTOR OUTPUT AND COMBINE
THEM TOGETHER AND TO GENERATE A
DIFFERENT PATTERN.
>>I THINK IT'S A FASCINATING
QUESTION.
FOR THE HEART, IT'S ACTUALLY
PARTICULARLY IMPORTANT AND
EXACTLY WHAT ARE SAYING BECAUSE
THE HEART REQUIRES THIS VERY
HIGHLY COORDINATED PATTERN OF
CONTRACTION AND ELECTRICAL
PROPAGATION AND THAT'S ONE OF
THE REASONS WE'RE INTERESTED IN
THIS AREA IS THAT THE SUDDEN
CHANGE IN ELECTRICAL PROPERTIES
OF THE HEART CAN ACTUALLY LEAD
TO SUDDEN DEATH SO IT'S ONE OF
THE MECHANISMS OF DEATH THAT
WORE INTERESTED IN.
I COMPLETELY AGREE WITH YOU.
I THINK IT'S SOMETHING THAT WE
REALLY NEED TO PROBE IS TO
ACTUALLY LOOK AT DIFFERENT WAYS
OF, I DON'T WANT TO SAY INJURY
TO THE HEART BUT DIFFERENT
STIMULI TO THE HEART SO THINGS
LIKE EITHER ISCHEMIA OR
SIMULATING AN AN ARRHYTHMIA ANDE
WHETHER THEY MEDIATE THAT SORT
OF RESPONSE BACK DOWN TO THE
HEART.
OTHER QUESTIONS FROM THE ROOM?
>>CAN I ANSWER THAT FURTHER?
WHEN YOU TALK ABOUT GRANULARITY
YOU HAVE BREATH TO BREATH AND
BEAT TO BEAT BUT COUGH IS THE
DIAPHRAGM INVOLVED BUT YOU HAVE
INCOMPETENTER COSTAL INVOLVEMENT
AS WELL AND YOU HAVE TO BE ABLE
TO CONTROL THAT SUITE OF MUSCLE
ACTIVITY IN ORDER TO GET THE PRO
PRO AT RESPONSE FOR A NORMAL
SIGH OR COUGH OR SOMETHING LIKE
THAT SO IT'S HIGHLY CONTROLLED.
RAPIDLY ADAPTING RECEPTORS FROM
THE LUNG CAN PROVIDE
BREATH-TO-BREATH CONTROL AND
DEPTH OF INSPIRATION AND OF
COURSE WE GET BREATH-TO-BREATH
CONTROL AND IT DRYS RESPIRATORY
RHYTHM SO IT'S GRANULAR AND
HIGHLY DETAILED.
>>I JUST WANTED TO ADD ON TOP
OF THAT WITH THE REPEATED INPUT
AND THERE'S ADAPTATION THAT
COULD CHANGE ON THE LEVEL OF
CONNECTIVITY AND TRANSCRIPTIONAL
DIFFERENCES OF TRANSMITTERS AND
RECEPTORS THAT COULD ACT AS THE
DIVERSITY AND SPECIFICITY.
>>LET ME ADD ONE OTHER THING,
NOT TO GO THE OTHER WAY BUT JUST
SORT OF TO PLAY DEVIL'S ADVOCATE
IS THROUGH AT LEAST ON THE
SYMPATHETIC SIDE OF THINGS THE
COORDINATION BETWEEN THE HEART
AND THE LUNGS WAS ACTUALLY IN
SOME LARGE ANIMAL EXPERIMENTS WE
DID WHERE WE WERE RECORDING FROM
THE GANGLION AND LOOKING AT
SINGLE-UNIT AND MULTI-UNIT
ACTIVITY, THEY WERE STRUCK BY
HOW MUCH MODULATION OF NEURONS
THAT INTENDED TO RESPOND TO
CARDIAC ACTIVITY BY LUNG
FUNCTION SO ALTHOUGH THERE'S
THIS VERY GRANULAR CONTROL SORT
OF AT A HIGH LEVEL OF THESE
SYSTEMS ARE STILL VERY HIGHLY
INTEGRATED AND I THINK THAT THE
SYSTEM DOES RECOGNIZE THIS SORT
OF DIS CO DINNATED ACTIVITY.
>>WE HAVE TIME FOR ONE MORE
QUESTION AND WE'LL TAKE IT FROM
THE CHAT.
Dr. BLOOD AND WILSON ARE
ASKED, ANALOGOUS HEART, WHAT ARE
THE REGULATORY FUNCTIONS OF THE
INTRINSIC NEUROCIRCUITS OF LUNG?
>>YEAH, WE'D LIKE TO FIGURE
THAT OUT.
IF YOU THINK ABOUT AIRWAY
CONTROL AND SMOOTH MUSCLE TONE,
IN THE UPPER AIRWAYS, THAT IS
SOMETHING THAT IS PROBABLY
CLOSELY REGULATED AND THIS IS
SOMETHING THAT DOCTOR SUN AND
Dr. BLOOD AND I HAVE TALKED
ABOUT TRYING TO EXPLORE FURTHER.
WHEN IT IT COMES TO INS INSCEPTI
DON'T KNOW THAT ANYBODY KNOWS
THAT WHETHER OR NOT THERE'S AN
IMPACT SO IT'S SOMETHING THAT
WOULD BE FASCINATING TO PURSUE.
GREAT QUESTION FROM JEFF.
>>SO I THINK ANY OTHER
QUESTIONS AND THE CHAT WE WILL
RELAY TO THE SPEAKERS AND MOVE
ONTO THE NEXT SESSION AND.
>>GREAT, THANK YOU, IT'S MY
PLEASURE AND HONOR TO MODERATE
THIS SESSION AND SESSION 3,
METABOLIC IMMUNE MUSS YOU LAR
AND BRAIN CONNECTIONS.
OUR SPEAKERS I'LL JUST READ THEM
OUT AND THEY'RE TALKS -- AND
CHUNG FROM UNIVERSITY OF TEXAS
AND UNIVERSITY OF MARYLAND AND
BOLT MORE RESPECTIVELY AND Dr.
COSTA AND.
>>IT DEPENDS ON THE INTERNAL
STATE OF THE BODY AND WHETHER OR
NOT THOSE OBJECTS ARE VALUABLE.
IT'S A SITE OF SENSORY INPUTS
FROM THE BODY BOTH SPINAL AND
VAGAL AND OTHER AND SO AN
IMPORTANT THEORY FROM THE DRUG
ADDICTION LITERATURE TRIED TO
INTEGRATE THESE TOGETHER AND IN
THE CONTEXT OF THINKING ABOUT
FEEDING AND DRINKING, ONE THING
THAT IT MIGHT BE DOING IS
CREATING A PREDICTION OF FUTURE
PHYSIOLOGICAL STATES.
SO IN PARTICULAR, HOW WILL
EATING THIS FOOD OR DRINKING
THIS WATER MAKE ME FEEL?
AND WE WANTED TO ADDRESS THIS
QUESTION IN OUR STUDIES IN MICE
AND THE WORK WAS LED BY A FORMER
POSTDOC IN THE LAB AND CARRIED
ON BY SEVERAL OTHERS IN THE LAB.
I'M GOING TO FOCUS FIRST ON FOOD
CRUISE IN THE MOUSE A VISUAL
FOOD CREW HAS TO BE TRAINED.
WE TRAIN THE MOUSE AND ONE
PICTURE IS ASSOCIATED WITH FOOD
AND IN THIS CASE A DROP OF MILK
SHARE AND ANOTHER PICTURE MEANS
NOTHING WILL HAPPEN AND THE MICE
LEARN THAT WHEN THEY SEE ONE
PICTURE, THEY START TO LICK IN
RESPONSE TO THAT PICTURE TO
INDICATE THEY WANT THE FOOD AND
THEY WILL EAT SEVERAL MILL
LITERS AND THEY'LL JUST STOP
RESPONDING AND IF YOU SILENCE
INSULAR CORTEX WHAT YOU FIND IS
THAT WHILE IT ABOLISHES THIS
BEHAVIOR ENTIRELY, WE WERE
SURPRISED THAT IT REALLY DIDN'T
EFFECT HOME CAGE FEEDING AND IT
DIDN'T EVEN EFFECT THE
CONSUMPTION OF THE SAME MILK
SHAKE WHEN IT WASN'T ASSOCIATED
WITH ANY LEARNED CUES SO WE
REALLY THINK THAT THE CONTROL OF
THE INSULAR CORTEX AS AN
ADDITIONAL LAYER ON TOP OF THE
STUDIES PEOPLE HAVE DEMONSTRATED
TODAY MIGHT BE A PLACE THAT'S
IMPORTANT FOR LEARNED
ASSOCIATIONS AND PREDICTIONS OF
FUTURE OUTCOMES.
NOW TO GET A BETTER SENSE OF
WHETHER THAT MIGHT BE THE CASE,
WE WANTED TO RECORD FROM THE
NEURONS AND INSULAR CORTEX SO
YOU HAVE ANOTHERS THAT DEVELOPED
A PARA SCOPE APPROACH WHERE WE
COULD USE CUL CALCIUM IMAGING A
WAKE HOUSE.
I'LL SHOW YOU AN INDIVIDUAL
NEURON AND INSULAR CORTEX IN
RESPONSE TO THE PRESENTATION OF
A FOOD CUE, YOU CAN SEE THIS
NEURON IN ORANGE IS INCREASING
ITS ACTIVITY AS THE FOOD CUE IS
PRESENTED WHEN THE MOUSE IS
HUNGRY BUT AFTER THE MOUSE
BECOMES SATED THE SAME NEURON NO
LONGER RESPONDS TO THE FOOD.
IN EARLY PRIMARY VISUAL CORTEX
WHERE THE VISUAL CUES MATTER THE
RESPONSES ARE SIMILAR WHETHER OR
NOT THE MOUSE IS HUNGRY OR
SATED.
AND SO, THE VALUE OF SORT OF
RECAPITULATING THIS FROM EARLY
VISUAL CORTEX NOT BEING
SENSITIVE TO HUNGER IN THE WAY
WHICH IS KNOWN IN HUMAN SUDDEN S
WHAT ARE THE MECHANISMS THAT
MIGHT REGULATE THE PROCESSING OF
SPECIFIC OBJECTS IN THE WORLD
DEPENDING ON WHETHER WE'RE
HUNGRY OR THURS THIRSTY OR SATE.
THE VERSUS OF HUNGRY OR SATED
HAS A DIVERSE SET OF CHANGES IN
THE BODY THAT ARE ASSOCIATED.
AND FOR PURPOSES OF GETTING
STARTED WE FOCUS ON THE MEDIA
BASAL HYPE A THALAMUS AND THE
PEP TIGHT NEURONS BECAUSE IN THE
ASSAUSATED NEURONS IF YOU TURN N
THE ANIMAL WILL EAT ANOTHER 10%
OR MORE OF ITS BODY WEIGHT.
AND SO TO SUMMARIZE THE SERIES
OF EXPERIMENTS THIS IS A MODEL
WHAT WE THINK MIGHT BE
HAPPENING.
THE MOUSE SEES A PICTURE OF FOOD
AND THE VISUAL ASPECTS ARE
PROCESSED IN THE CORTEX AND
THALAMUS AND ROW LAID TO THE
AMYGDALA ONTO ON TO CORTEX.
THERE'S A BLOCK IN THE SATED
STATE.
WHEN THE ANIMAL IS HUNGRY AND
THESE AGRP NEURONS ARE ACTIVE
SOMEHOW IN A WAY THAT WORE STILL
WORKING ON, UNBLOCKS THIS
PATHWAY AND THE VISUAL
INFORMATION ABOUT FOOD IS NOW
GOING TO BE ABLE TO FLOW TO THE
INSEWALL AR CORTEX AND THAT
SHOULD IN TURN BE PART OF A
NETWORK THAT DRIVES FOOD SEEKING
AND ALSO AS IS SHOWN PERHAPS MY
PREPARE THE BODY FOR FO FO FORN
AND SO ON.
IT MIGHT UNBLOCK WATER RELATED
CUES IN THE INSULAR CORTEX.
AND FINALLY, IN A DIFFERENT SET
OF EXPERIMENTS IN OUR LAB, WE'VE
BEEN TRYING TO UNDERSTAND
SOMETHING ABOUT THE NATURE OF
CRAVINGS AND THOUGHTS REGARDING
FOOD AND TO TROY TO DO THIS IN A
MOUSE WE PRESENT THE NICE WITH
THESE PICTURES OF FOOD AND WE
TURN ON THE TV SCREEN AND RECORD
FROM THESE SAME NEURONS AN HOUR
LATER IN THE DARK AND WE CAN SEE
THAT THE SAME PATTERNS OF
NEURONS THAT WERE ACTIVATED BY
FOOD ARE REACTIVATED OVER AND
OVER OVER THE COURSE OF SEVERAL
HOURS AND WE THINK THAT THIS MAY
BE AT LEAST AN ENTRY POINT TO
STUDYING FOOD CRAVINGS.
SO, THAT WAS ABOUT FOOD CUES AND
WATER CUES AND WHAT ABOUT
REPRESENTATION OF FOOD AND WATER
AND HUNGER AND THIRST.
WE KNOW IN THE THIRSTY ANIMAL OR
A SATED ANIMAL, IN BOTH CASES
THERE'S LOTS OF NEURAL ACTIVITY
IN THE INSULAR CORTEX AND SOME
NEURONS ARE ACTIVE IN THE
THIRSTY STATE BUT NOT THE
QUENCHED STATE AND ARREST ACTIVE
IN THE SAME RECORDING IN THE
QUENCHED STATE BUT NOT THE
THIRSTY STATE AND IF YOU JUST
SUMMARIZE THIS DATA FROM 200
NEURONS RECORDED IN THE SAME
IMAGING SESSION SO YOU SEE THAT
SOME OF THE NEURONS IN ORIGINAL
ARE ACTIVE EARLY AND LESS ACTIVE
AS THE MOUSE BECOMES QUENCHED
OVER A FEW HOURS AND OTHER
NEURONS ARE QUIET AND THEY
BECOME ACTIVE IN IN OTHER WORDS,
THE PATTERN OF ACTIVITY ACROSS
THESE NEURONS IS CHANGING OVER
TIME AND NOT ONLY THE PEOPLE MEY
AND THIS IS NOT IN A MULTI
DIMENSIONAL SPACE WHERE EACH DOT
IN THE SPACE IS A PATTERN OF
ACTIVITIES SO THE BLUE DOTS ARY
PATTERNS HERE AND THE YELLOW
REPRESENT LATE PATTERNS OF
ACTIVITIES AFTER THE MOUSE
BECOMES QUENCHED.
AND WE FOUND THAT THESE CHANGES
IN THIS SLOW PATTERNS OF
ACTIVITIES OVER HOURS, REALLY I
THINK RELATES TO INTRA EXCEPTION
AND SOMEHOW AS REFLECTING THE
HYDRATION STATE OF THE ANIMALS
AND NOT CHANGES IN MOTOR
BEHAVIOR AS WE'VE SHOWN IN THESE
RECENT STUDIES.
WE CAN DECODE LOOKING AT THE
ACTIVITY THE SAME NEURONS OVER
DAYS SO WE THINK THAT THERE'S A
LOT OF INFORMATION BEYOND THESE
TWO DIMENSIONS IN THE SAME
REGION OF INSULAR CORTEX.
IF YOU LOCK AT THIS IN THE
CONTEXT OF THESE TWO DIMENSIONS,
HYDRATIONS AND FUEL LEVEL, YOU
CAN CONCEIVE OF A POINT IN THIS
SPACE AS JUST A STATE OF THE
CORTEX.
WHEN THE MOUSE IS HUNG ROW YOU
HAVE A PATTERN OF ACTIVITY
REFLECTED OF FOOD DEFICIT AS I
SAID AND WHEN THE MOUSE SEES A
PICTURE OF FOOD, WE FOUND WHICH
WAS REALLY STRIKING WAS THAT
ACTUALLY THIS PATTERN OF
ACTIVITY MOVES OVER THE COURSE
OF A FEW SECONDS TOWARDS THIS
SATED STATE THAT IS ONLY GOING
TO BE EXPERIENCED TWO HOURS
LATER AND THEN COMES BACK TO THE
HUNGRY STATE.
IS THE MOUSE IS AING WHETHER
SEATING A SINGLE DROP IS FOOD IS
GOING TO EVENTUALLY MOVE IT
TOWARDS THIS FUTURE SATED STATE.
WHEN THE MOUSE IS SATED THE
CORTEX BASELINE ACTIVITY
REFLECTS THAT SAY TEE AND WHEN
THE MOUSE SEES A PICTURE OF
FOOD, NOTHING HAPPENS BECAUSE IT
KNOWS THIS WON'T PUT THE FOOD IN
ITS MOUTH.
WHEN YOU TURN ON THE NEURONS
THAT COMPEL THE MOUSE TO PUT THE
FOOD IN THE MOUTH WE SEE THAT
NOW THIS TRIGGERS A MOVEMENT OF
THE INSULAR CORTEX TO THE FUTURE
STATE OF FOOD SURPLUS VERY MUCH
LIKE YOU FINISHING A HUGE MEAL
AND SEEING THE DESSERT TRAY
COMING OVER TO YOUR TABLE.
WE THINK THAT THE INSULAR CORTEX
CAN CREATE PREDICTIONS OF WHERE
YOU SHOULD BE AFTER LET'S SAY A
MEAL.
IF YOU ARE A PATIENT WITH AN
ANOREXIA AND YOU'VE EATEN 200
MEALS WITH 10% OF THE NEEDED
CALORIES THIS MAY LEAD TO A
PREDICTION YOU ARE GOING TO BE
ABLE TO STOP EATING AFTER A FEW
BITES.
AND SO, IT MAY REQUIRE
RECONFIGURING CORTICAL PLASTIC
TEE THROUGH THERAPY WHICH IS ONE
OF THE MOST COMMON THERAPIES FOR
ANOREXIA TO ANTICIPATE A MEAL
SETS A FULL SET OF CALORIES N
OBESITY IT MAY BE THE PREDICTION
AFTER MANY MONTHS OF OVER EATING
IS THAT FOOD SURPLUS SHOULD BE
THE END POINT OF YOUR MEAL.
AND THAT IT WILL REQUIRE
SIMILARLY PLASTICITY IN THE
CORTEX AND ELSEWHERE THAT WILL
EVENTUALLY DRIVE A CHANGE IN
THIS COMPASS IN THE CORTEX, A
CHANGE IN THE SETTLING POINT SO
WE CAN ACTUALLY CREATE
EXPECTATIONS OF WHAT A MEAL
SHOULD BE AND FINALLY, THERE ARE
DIFFERENT OTHER ACTIONS
REPRESENTED IN THE INSULAR
CORTEX IN A DISTRIBUTED MANNER
WITH BODY TEMPERATURE AND PAIN
AND SO ON.
HOW DO ALL THESE SIGNALS GET
INTO THE INSULAR CORTEX WE CAN'T
STUDY OR MANIPULATE THE PATTERNS
UNTIL WE KNOW WHERE THOSE
PATTERNS ARE COMING FROM AND I
THINK THIS IS WHERE THIS BRIDGES
WITH ALL THE BEAUTIFUL WORK
WE'VE SEEN SO FAR AND COMING
FROM THIS SPINAL AND VAGAL
INPUTS TO CONVERGENT FOR EXAMPLE
THE PARA NUCLEUS AND ELSEWHERE
AND SO THE NUCLEUS IS A REGISTER
ON IN THE BRAIN STEM THAT
RECEIVES INPUTS FROM SPINAL
VAGAL AND ELSEWHERE TO INTEGRATE
THE INTRA ACCEPTIVE STATE OF THE
BODY AND WITH THE INPUTS TO THE
TBN.
IF YOU LOOK AT THIS MOUSE THAT
IS DRINKING DROPS OF WATER YOU
CAN SEE OVER SEVERAL SECONDS,
THE DROPS OF HEAVY WATER ARE
MOVING THROUGH THE
GASTROINTESTINAL TRACK SO WE
THINK THAT SOMETHING IS SIMILAR
IS HAPPENING WHEN THE MOUSE
DRINKS A DROP OF MILK SHAKE YOU
CAN FIRST SEE A SET OF NEURONS
RESPONDING AT THE MOMENT THE
MOUSE LICKS BUT THERE ARE OTHER
NEURONS THAT RESPOND IN A WAVE A
CROSS THE LATERAL PART OF THE
NUKELY US AND SOME OF THEM ARE
RESPONDING FIVE SECONDS AFTER
THE MOUSE HAS INGESTED THE MILK
SHAKE SUGGESTING THAT THERE
MAYBE NEURONS IN CODING EACH
PART OF THE G.I. TRACT.
AT THE SAME TIME, WE CAN
INTERETRACK MILDTAIL SHOCKS ANDO
STIMULATION OF FEEDBACK FROM THE
INSULAR CORTEX BACK TO THE PBM
WHICH IS STRONG AND DRIVES
PATRONS RESPONSE AND WE THINK
MIGHT BE IMPORTANT FOR IN EXTRA
ACCEPTIVE STATES WHEN THEY'RE
NOT HAM.
SO IF YOU WANT THE HYPOTHALIMUS
AND THE BRAIN STEAM MAY ALLOW
THE BRAIN TO LON HOW TO BEST
ANTICIPATE KEEFEATIONS FROM HOME
YO STAY ADVERTISE AND TO
STIMULATE HOW THE BODY FEELS ON
UPCOMING ACTIONS AND ADAPT
DECISION MAKING AND TO MAKE
PROGRESS IN TRYING TO UNDERSTAND
THESE CENTRAL CIRCUITS, INVOLVED
IN INTRA DECISION MUCH HAS BEEN
THE CASE IN OTHER SENSORY
SYSTEMS LIKE VISION WHERE THE
KNOWLEDGE OF GENETIC CELL TYPES
IN THE RETINA HAVE MADE HUGE
CONTRIBUTION TO OUR ABILITY TO
UNDERSTAND CENTRAL CIRCUITS FOR
VISION AND IT'S GOING TO BE
CRITICAL TO FORGE COLLABORATIONS
AND MANY OF THE LABS HERE IN
ELSEWHERE THAT STUDY IT MORE
PERIPHERALLY AND USE THESE
ENTRIES POINTS TO BETTER
UNDERSTAND CENTRAL PROCESSING
AND WITH THAT, I WANT TO THANK
OUR MEMBERS OF THE LAB PAST AND
PRESENT WHO ARE PUSHING HARD
TOWARDS THIS GOAL AND OUR
COLLABORATORS AND A BIG THANK
YOU AT THE NCCIH AND TO OTHER
SOURCES OF FUNDING AND THANK YOU
VERY MUCH FOR YOUR ATTENTION.
PLOWS.
>>WE COULD TAKE ONE QUESTION IF
THERE'S ONE.
IF NOT I CAN TAKE THE
OPPORTUNITY TO ASK A QUESTION
QI.
YOU START TODAY GET TO THIS
TOWARDS THE END OF YOUR TALK AND
REALLY HONING IN ON THE OTHER
SOURCE OF INPUTS AND ONE OF
WHICH IS CARDIAC AND DUNG HUNGER
AND SATE, HOW WOULD YOU INDICATE
THAT INTO THE WORKING PARADIGM
YOU HAVE?
>>OUR HOPE IS TO BASICALLY BE
ABLE TO TRACK DIFFERENT
PHYSIOLOGICAL STATES WITH AND
WITHOUT SILENCING OF VARIOUS
LET'S SAY SPINAL AND DO THIS IN
A SUBTLE WAY SO WE DON'T KIND OF
FREAK OUT THE ANIMAL WHICH I
THINK IS A CONFOUND IN A LOT OF
THESE STUDIES TRYING TO
UNDERSTAND AND OVER ALL STATE
AND WHAT IS CON TRIB TO USE THE.
>>I WOULD LIKE TO THANK NIH
STAFF FOR ORGANIZING THIS
MEETING AND THE OPPORTUNITY TO
PRESENT AND MY LAB IS INTERESTED
IN THE INTEROCEPTIVE FORM OF
LEPTIN THAT IS PRODUCED AND
RELEASED FROM ADDIE POSE TISSUE
IN A CIRCULATION WHICH IT
REACHES THE BRAIN THE HYPE A
THALAMUS AND AND IT REGULATES
BODY TISSUE AND LEPTIN LEVELS
ARE HIGHLY RESPONSES TO CHANGES
IN FOR EXAMPLE EX TER OWE
EXCEPTION AND AS WELL AS TO
ENERGY STATES LIKE FASTING OR
OVER FEEDING.
AND LEPTIN OVER ALL IS NO ONE TO
ACT ON FUNCTIONS AND IT'S ALSO
ASSOCIATED WITH A BUNCH OF
DISEASES AND ILLNESSES AND WHERE
PARTICULARLY WE'RE INTERESTED IN
OBESITY AND DIABETES.
WE ARE INTERESTED ALSO IN THE
ROLE OF LEPTIN AND ENERGY
EXPENDITURE AND FOR FOOD TAKE
AND OVER ALL PEOPLE ASSUME THAT
LEPTIN INCREASES ENERGY
EXPENDITURE BUT IT SHOES IT'S
NOT EXACTLY TRUE IF YOU MEASURE
METABOLIC RATE AND INJECT LEPTIN
IN FAT ANIMALS THERE'S NO EFFECT
ON ENERGY EXPENDITURE
WHATSOEVER.
FASTING AND FOOD RESTRICTION
CAUSE A AND IT'S HYPO METABOLIC
STATE AND THAT'S ALSO TRUE IN
HUMANS AND VERY DIFFERENT
SITUATION IS AMY AN TEMPERATURE
AND FOR LEPTIN DEFICIENT MICE
THEY HAVE A DECREASE BODY
TEMPERATURE AND IF YOU EXPOS
THEM TO COLD THEY ARE UNABLE TO
MAINTAIN THEIR BODY TEMPERATURE
EVEN THOUGH THEY HAVE NO
PROBLEMS TO DO THAT AND THAT IS
CURIOUS BECAUSE IT DECREASED
LEPTIN LEVELS EVEN MORE DRAMATIC
THAN FASTING AND IN A WAY THEY
HAVE THE SAME LOW LEPTIN LEVELS
BUT THEY RESPOND VERY
DIFFERENTLY THAT WE DON'T REALLY
UNDERSTAND NOWADAYS.
AND ALSO MET WITH LEPTIN LEVELS
UNKNOWN TO BE IMPORTANT FOR
ADIPOSE TISSUE INNERRIZATION AND
LEPTIN CAN RECOVER THAT.
TO START TO UNDERSTAND THESE
ASSOCIATIONS, WE INITIALLY
IDENTIFIED LEPTIN RECEPTORS IN
THE BRAIN AND THE REOPTIC AREA
THAT MODULATE ENERGY EXPENDITURE
AND THESE IS PART OF A
REGULATORY CIRCUIT THAT
INNOVATION TO BROWN ADIPOSE
TISSUE AND IF WE CAN STIMULATE
WE INCREASE ENERGY EXPENDITURE
SIMILAR TO CODE EXPOSURE AND IF
WE STIMULATE PRO OPTIC AREA
NEURONS WE DECREASE ENERGY
EXPENDITURE SIMILAR TO WARM
EXPOSURE OR FASTING.
AND WE ALSO WANTED TO TEST IF
THIS IS REALLY BY SYMPATHETIC
ADIPOSE TISSUE AND WE USE THE
BATTLE 3 TO BLOCK THE EFFECT AND
TO SEE HERE THAT WE CAN
SUCCESSFULLY SUPPRESSION THE
INDUCTION OF ENERGY EXPENDITURE
WITH A ANTAGONIST BUT YOU CAN
ALSO APPRECIATE WITH STILL
MAINTAIN A GOOD A LOT OF THE
RESPONSE.
AND SIMILARLY HERE, WE TRIED TO
BLOCK THE SUPPRESSION OF ENERGY
EXPENDITURE WITH AGONIST AND WE
DO IT AND WE STILL HAVE A
SIGNIFICANT SUPPRESSION OF
ENERGY EXPENDITURE AND WHAT THAT
SAYS IS THAT THREE ALONE CANNOT
FULLY EXPLAIN THE EFFECT ON
ENERGY EXPENDITURES AND ALSO IT
DOESN'T REALLY TELL US IF BROWN
FAT ACTIVATION ALONE IS
SUFFICIENT FOR THE ENERGY
EXPENDITURE ADAPTATION WHICH IS
THE DARK MAGIC SO IN 1997, BRAD
LILLY'S GROUP HAD DATA ON THAT
SO HERE THEY HAVE WHOLE BODY
KNOCK OUT ANIMALS AND THAT FULLY
SUPPRESSED THE EFFECT OF CL BY
THE THREE AGO NISTS TO INCREASE
ENERGY EXPENDITURES AND THEN
THEY REEXPRESSED BETTER 3
RECEPTORS AND BROWN AND THAT IS
NOT ABLE TO RECOVER THE EFFECT
ON ENERGY EXPENDITURE HOWEVER,
THE BROWN AND WHITE FULLY COULD
RECOVER THIS EFFECT.
ALREADY HINTING THAT YOU MAY
NEED BOTH SYMPATHETIC BROWN AND
WHITE FOR ACTIVATION.
NOW MORE RECENTLY, IT HAS BEEN
SHOWN THAT BLOCKING GENES IN
BROWN AND ALSO NOT ESSENTIAL FOR
CODE INDUCED AND AGAIN
QUESTIONING THE DOGMATIC VIEW WE
HAVE NOWADAYS THAT BROWN
ACTIVATIONS FROM ITSELF IS ABLE
TO DRIVE ENERGY EXPENDITURE SO
WE WANTED TO IDENTIFY IF
ISOLATED SYMPATHETIC ACTIVATION
IS THAT SUFFICIENT FOR SOME
AGENDA AND LEPTIN AND TO
SUPPRESSION LEPTIN EXPRESSION.
TO DO THAT WE NEEDED TO TARGET
SELECTIVELY IBAT AND WE USED AN
RETROGRADE INJECT NOD BROWN
ADIPOSE TISSUE AND WITH A REPORT
AMOUNTS ARE LINE WE CAN NICELY
SEE THE SYMPATHETIC NEURONS THAT
ARE BROWN FED ELATED AND THE
DISTRIBUTION OF THOSE FROM
CELLULAR TO T5 WHICH IS
CONSISTENT TO WHAT WE HAD
PUBLISHED BEFORE USING WE CAN
ALSO COUNT THESE CELLS AND WE
GET A FAIR AMOUNT OF NEURONS IN
EACH GANGLION AND WE ALSO CAN
LOOK AT SENSORY NEURONS SO EVEN
THOUGH WE GET FAR LESS SENSORY
NEURONS WE HAVE A SMALL AND
CONSISTENT NUMBER OF SENSORY
NEURONS THAT WE TARGET AS WELL.
AND NEXT, WE USE THE MOUSE LINE
TO BE ABLE TO SPECIFICALLY
ACTIVATE THESE NEURONS.
NOW, IT'S COMMON IN THE CENTRAL
NERVOUS SYSTEM AND WE USE THE
GOLD STANDARD TO VERIFY OUR
SYSTEM OVER ALL WORKS AND WE USE
RECORDING IN COLLABORATION WITH
OUR INSTITUTE SO WE ATTACH ON TO
THESE GREEN NEURONS AND YOU ARE
CERTIFY THE IS ABLE TO CHANGE
THE MEMBRANE POTENTIAL IN OUR
BROWN FAT SYMPATHETIC AND YOU
CAN SEE THE VAST MAJORITY OF
THOSE NEURONS RESPOND VERY
ROBUSTLY.
CONFIRMING THE SET UP WORKS VERY
WELL.
IF WE LOOK IN VIVO AND ACUTE
ANESTHESIAIA MOUSE MODEL, WE
RECORD BROWN TEMPERATURE HERE
AND INITIALLY WE USE VERIFY TO
WE CAN SEE INCREASED TEMPERATURE
AND YOU SEE HERE A NICE INCREASE
IN TEMPERATURE AND HOWEVER IT
WOULD STIMULATE SYMPATHETICS WE
DON'T GET AN EFFECT ON THE
TEMPERATURE TO THE CONTRARY WE
SEE IN THE SECOND FACE AFTER 30
MINUTES IT DECREASE IN BROWN FAT
TEMPERATURE AND TO VERY FINE
MAYBE WE DO NEED MORE COMPLEX
SYMPATHETIC STIMULATION MAYBE OF
WHITE AND BROWN ADIPOSE TISSUE
AND WE USED ANOTHER MOUSE MODEL
WHERE WE HAVE TH CREED DRIVING
RECEPTORS EXPRESSION SO HERE WE
CAN STIMULATE ALL THE
SYMPATHETIC NEURONS AND IN DEED
IN THIS MOUSE MODEL WE SEE
NICELY AN INCREASE IN BROWN FAT
TEMPERATURE BUT STILL WE
MAINTAIN IN THE SECOND PHASE THE
SUPPRESS I HAVE EFFECT ON BROWN
FAT TEMPERATURE AND HERE IN THE
FOURTH MOUSE MODEL, WE COMBINE
TL INJECTIONS WITH OUR
SYMPATHETIC IBAT STIMULATION AND
WE MAINTAIN THE INCREASE IN
TEMPERATURE HERE BUT THEN AGAIN
INHIBITORY EFFECT AND WE CAN
ALSO DO THAT IN FRO MOVING
ANIMALS USING A MILLIMETER
SYSTEM TO MEASURE CORE
TEMPERATURE AND CL INCREASES
CORE TEMPERATURE AND THEN THE
COMBINED EFFECT OF CL AND CNO
INITIALLY IS SUPPRESSING THE
EFFECT OF CL HOWEVER INTERESTING
SURPRISINGLY IN THE LONG-TERM,
WE ACTUALLY FEEL SYNERGISTIC
EFFECT WHERE BROWN FAT CORE
TEMPERATURE STAYS ELEVATED
COMPARED TO CL ALONE AND IN DEED
WE ALSO NOTICED THAT AFTER 24
HOURS, IT WAS SUPPRESSED WHICH
IS NOT OBSERVED AND THE
INDIVIDUAL INJECTION AND THE
DIRECT.
WE SEE HERE BETTER SIGNALING
AGAINST ARE VASTLY INTENSE IN
THIS CO EXPRESSION STIMULATION
OF CL AND BRONZE FAT
SYMPATHETICS THAT WE DO NOT SEE
IN THE INDIVIDUAL STIMULATIONS
AND IF YOU LOOK AT GENES THAT
ARE UP REGULATED BY BROWN FAT
SYMPATHETIC ALONE THIS IS FROM
THE COMPLIMENT IN IMMUNE SYSTEM
IT SEEMS TO BE INVOLVED SO WE
LOOKED AT LEPTIN EXPRESSION AND
BRONZE SYMPATHETICS TO NOT
SUPPRESSION LEPTIN LEVELS AND TO
THE CONTRARY THEY SEEM TO
INCREASE IT BUT THEY DO NOT
PREVENT THE SUPPRESSION OF
LEPTIN BY BETTER THREE ADD INOID
STIMULATION AND INTERESTINGLY WE
ALSO SEE SOME OTHER
INTEROCEPTIVE SIGNALS THAT ARE
ENHANCED WITH THE COMBINED
EFFECT AND SEEM TO BE AND COULD
BE INVOLVED IN THE EFFECT ON
BODY WEIGHT.
SO IN SUMMARY, SYMPATHETIC
ACTIVATION IN ISOLATES MAY BE
NECESSARY FOR SOME BUT IT'S NOT
SUFFICIENT TO INDUCE SOME ALONE.
AND SYMPATHETIC IBAT ACTIVATION
COUNTER SIGNALING IN THE SHORT
TERM BUT LONG-TERM, IT ENHANCES
ALPHA AND BETA SIGNALING AND
WEIGHT LOSS.
AND LEPTIN mRNA EXPRESSION IS
SUPPRESSED BY THROW ACCUMULATION
BUT WAS INCREASED BY ISOLATED
IBAT ACTIVATION.
AND SO LAST BUT NOT LEAST I
WOULD LIKE TO THANK FORMER AND
CURRENT LAB MEMBERS AS WELL AS
COLLABORATORS.
AND I WOULD ALSO LIKE TO THANK
NIH FOR THE FUNDING OVER THE
YEARS AND SPECIFICALLY FOR THIS
PROJECT FOR NIH BLUE PRINT AND
INTEROCEPTION.
THANK YOU.
[Please stan [APPLAUSE]
>>THANK YOU, THA ANY QUESTIONS?
MAYBE IN THE INTEREST OF TIME WE
CAN MOVE ON AND THEN WE'LL TAKE
QUESTIONS FROM THE AUDIENCE IN
THE Q&A, THANK YOU.
>>HI, EVERYONE, THANK YOU FOR
ORGANIZING THIS NICE MEETING AND
IT'S A GREAT PLEASURE AND I
WANTED TO TALK ABOUT MY RESEARCH
HERE AT NIH INTEROCEPTION.
TODAY, I'M GOING TO TALK ABOUT
THIS FUNCTIONAL FUNCTIONAL
PERIPHERAL AND CENTRAL VAGAL
NEURAL CIRCUITS OF INTRO
EXCEPTION INHIBITING PAIN.
IT'S DIFFERENT THAN THE PHYSICAL
OLE TEE IN THE ORGAN.
SO VAGAL INTRO EXCEPTION IS
INTERSECTION WITH PATHWAYS TO
PAIN FROM TEMPORAL JOINTS WHICH
IS SECOND TO JOINT IN OUR BODY.
HERE.
SO IN ONE, WE WILL WILL
DELINEATE VAGAL THAT MEDIATES --
IT'S DEFINABLE VAGAL AND MEDIATE
THE PAIN FROM TMJ INFLAMMATION
SO WE WILL DETERMINE VAGAL
STIMULATION IN THIS AND TMJ PAIN
BY OVERLAYING SUBSET AND OUR
ACTIVATION USING THE ACTIVATION.
SO IN DAY TWO WE WILL DETERMINE
RECEPTION TO VAGAL AND SO OUR
WALKING HYPOTHESIS IS THE
PROJECT INTO TMJ ACTUALLY
ELEVATES PAIN AND ALSO RECEPTION
TO SIGNALING AND TMJ AND SO WE
WILL WILL TERM THE ROLE OF THE
DOPAMINE RELEASED FROM THE VAGUS
AND WE WILL NOW HAVE THAT
BEHAVIOR AND PERFORM IN VIVO
GANGLION NEURON AND THE
ACTIVATIONAL DOPAMINE.
FOR AIM 3, OUR MULTI P.I. HERE
IN HE AND HIS TEAM WILL
DETERMINE CENTRAL VAGAL
ANESTHESIAIA FOR TMJ PAIN SO OUR
WALKING IS THAT VAGAL INPUT INTO
NTS NUKELIAL WHICH IS THE
CENTRAL FROM (INAUDIBLE) AND THE
PAIN TO A DIRECT PROJECTION OF
NTS NEURONS TO DIFFERENT BRAIN
REGIONS AND INVOLVED IN AFFECTED
TRANSMISSION AND PAIN MODULATION
AND SO THE ACTIVATION TEST
NEURON ASSOCIATED WITH THE VAGAL
STIMULATION PAIN AND ALSO THE
NTS NEURON THAT IS PROJECTED TO
THE CRITICAL FOR EFFECTING PAIN
AND ALSO THE PAIN (INAUDIBLE) SO
WE FOUND THAT THERE IS VAGAL ON
THOSE COMMON IN THIS TMJ AREA SO
YOU CAN SEE CORE THE OR I C TMJT
TO THIS EAR AREA AND OVER THE
BONE AND FROM THE TMJ AND IT'S
ACTUALLY HAVING THESE RED COLOR
ON THE RECEPTORS AND THEY
ACTUALLY INTERSECT SO WE HAVE
THIS RELEASED DOPAMINE AND YOU
SEE THIS CENTRAL PATHWAYS SO I
WAS REALLY SURPRISED TODAY THAT
ALL THE PHYSIOLOGICAL BRAIN
REGION TO THE PAIN EFFECTIVE
PATHWAYS AND SO YOU CAN SEE, WE
SEE IT GOES TO AND THIS ALL US
AND ACC AND SENSITIVE ORGANIZE
TEXT AND AND ALSO WE PRODUCT
POCKETS AND IT'S PAIN AND IT IS
IN THE PRIMARY EFFORT BY THE
MEET EIGHT OR AND THERE'S STILL
TO SIGNALING FROM THE VAGAL
NEURON TO THE PRIMARY SENSORY
AND IT'S VERY NOVEL AND SO NOW
WE PERFORM IN VIVO AND YOU CAN
CATCH AND TRY GANGLION NEURON
AND' USED THE MULTI LINE IN
VAGAL AND AND LABELED AND ALSO
WE ACTUAL DEPENDS ON LABELING ON
BRAIN NEURON AND AND ALSO WE DO
THE GENETIC OPERATIONS AND SO WE
DO TWO LAB COLLABORATIONS AND
Dr. KIM WHICH IS ME AND ALSO
Dr. CHUNG WE USED OUR
EXPERTISE FOR THIS AND THE
FOURTH WE INJECT CFA WHICH IS TO
TMJ AND IT CAN INDUDES
MECHANICAL HYPER TENSE TEE AND
YOU CAN SEE HERE IN THE MEANS
THAT ANIMAL SHARING A LOT OF
EXPERTISE MEANS THAT A LOT OF
PAIN AND THEN WE EXPLODED THE
VAGAL IN CHECK THE AREA AND THEN
ELECTRIC STILL WE CAN SEE THIS
PAIN AND YOU CAN SEE IN THE
BLUE, AFTER THE VAGAL
STIMULATION WE CAN SEE WE CAN GO
DRAMATICALLY REDUCED AND IT'S
BEEN FOR SEVERAL DAYS AND THEN
WE BUILDUP THE NEW MOUSE MODEL
WHICH IS CALLED FORCE OPENING
MODEL AND AS YOU CAN SEE HERE.
IT LASTS ABOUT AND FORCE NOT
OPENING AND THIS ACTUALLY DIS
LOCATES THE ENTER POSITION TO
WHICH ACTUALLY IN THIS VERY
STRONG PAIN AND AREA AND THEN WE
CHECK THE BY FORCE ANIMAL
ACTUALLY BY WE WILL AND BECAUSE
OF THE THE PAIN AND SO IT CAN
LAST ABOUT THREE WEEKS AND ALSO
WE CHECKED THE ANIMAL FACIAL
PAIN EXPRESSION AND CALLED IT
AND IT'S LIKE 20 DAYS AND THEY
CHECKED WITH THE CFA MODEL AND
OPEN FIELD TEST AND THE ANIMAL
AND THERE'S A HYPER WORKING
ACTIVITY WITH THE INFORMATION
NOW WE ARE TESTING THE CONDITION
PREFERENCE TEST TO SEE IF THEY
HAVE ANY PREFERENCE WITHOUT THIS
PAIN AND WE FOUND THIS DDC AND
IT'S HIGH IN NEURONS AND SO THIS
IS ACTUALLY CRITICAL TO MAKING
THE DOPAMINE IN THE BODY AND SO
WE INJECT A RETROGRADED RED DYE
INTO THE TMJ AND THERE'S A LOT
OF VAGAL LABELING THIS RED DYE
SO THIS MEANS THAT VAGAL
ACTUALLY INNOVATING TO THE TMJ
AND THEN ANOTHER RETROGRADE DYE
THROUGH OUR INJECTED AND THEN A
STANDARD DVC AND YOU CAN SEE
THERE'S MANY VAGAL OVERLAPPED
WITH THIS MEANS THAT THE TMJ
NEURONS WHICH IS THE NEURONS
FROM VAGAL AND THEN AFTER WE
MAKE FMO WE INJECT DOPAMINE SO
WHEN WE INJECT THE DOPAMINE INTO
TMJ WE CAN SEE OUR PAIN AND WE
CAN REPEAT THESE SEVERAL TIMES
AND THEN WE TROY TO IMAGE IN
VIVO THIS PRIMARY SENSORY
NEURON, ESPECIALLY WITH A NEURON
IS WE MADE THIS CALLED IT
CREATING POINT SO THE POT
ACTUALLY DRIVES THIS EXPRESSION
SO WHY WE CHOSE POT BECAUSE POT
IS ONLY EXCLUSIVELY EXPRESSED IN
PRIMARY SENSORY AND NOT IN ANY
OTHER BRAIN SO WE CAN HAVE A
VERY STRONG EXPRESSION AND ONLY
IN PRIMARY SENSORY NEURONS IS WE
CAN DO A LOT OF PAIN MODELING.
MIGRAINE, HEADACHE AND TRY THE
TMJ AND PAIN HERE AND ALSO TOOTH
PAIN AND ORAL FACIAL PAIN.
THE TWO IMAGES WE PURCHASED THIS
NICE HIGH REGULATION UNDER THIS
WE MADE A CUSTOM THIS PLATFORM
AND SO IN THE PLATFORM ANIMAL IS
LAID DOWN AND ANIMAL'S HEAD IS
HOLD O HE CAN MINIMIZE ANIMAL
MOVEMENT ARROWS.
IT STABILIZED ANIMAL BODY
TEMPERATURE AND THE WE HAVE A
VERY TINY CRANIAL RENAL TO LET
IT WE MADE A HOLE SO BY CORTICAL
TISSUE AND SO THEN, LET'S MOVE
ON, SO THEN, AS YOU CAN SEE
HERE, ALL THROUGH THE CRANIAL
WINDOW YOU CAN REACH OUT TO THE
LOCATED UNDER THE BRAIN AREA AND
WE CAN FOR THE FIRST TIME CAN
HAVE 3,000 NEURONS
SIMULTANEOUSLY SO WE CAN IMAGE
IT OVER HERE A TINY SMALL SIDE
CALLED RE SCEPTERS AND THEY CAN
SENSE PAIN AND WE CAN IMAGE IT
WHICH WE CAN TOUCH AND WE V1 OR
T AND P AND WE CAN EASILY
IDENTIFY AND THEN USING THIS
TOOL,
THERE'S A LOT GOING ON AFTER
THIS FMO AND THEN WE APPLIED
DOPAMINE ON TOP OF THIS AS YOU
CAN SEE THIS ACTUALLY IS HERE.
AND THEN WE ACTUAL LOW ALSO
INJECTED A CFA INTO THE TMJ AND
WE GET THE ACTIVITY AND THE CFA
AND THE ANIMAL YOU SEE THERE'S A
LOT OF THIS SPONTANEOUS GOING ON
AND COMPARED TO SHAM AND AFTER
WE SEE THIS SPONTANEOUS
ACTIVITY, WE ARE APPLYING
DOPAMINE WE CAN ALLEVIATE THIS
SPONTANEOUS ACTIVITY AND WE
TRIED TO DO A TRAP ON THIS
NEURON AND IT'S THE VAGAL NEURON
ACTUALLY HAVING THIS CENTRAL
TERMINAL USING THE FORCE BY ON
TEE GENETICS AND ALSO A
COMMUNITY ACTIVATION FOR THE
FIRST STEP AND WE EXPLODED THE
VAGAL AND ELECTRICALLY STIMULATE
AND THEN WE GET THE NTS AREA
HERE YOU CAN SEE THERE ARE
POSITIVE NEURONS THAT WE CAN
IDENTIFY HERE AND WE ALSO
ACTIVATE THE VAGAL CELL IN
MOLECULAR AREA AND WE LOCK AT
THE NTS AREA YOU CAN SEE A LOT
OF THE NEURONS AND WE CAN
IDENTIFY AND WE CAN SEE HERE SO
NEXT STAGE OF WE WANT TO USE THE
FIRST TREE TO ACTUALLY LABEL AND
THE CORTEX AREA.
I WOULD LIKE TO THANK OUR LAB
MEMBERS AND OUR PI.
AND HIS TEAM AND I WOULD LIKE TO
THANK ALL OUR COLLABORATORS ASK
AND I WOULD LIKE TO THANK OUR
FUNDING SOURCE.
THANK YOU, VERY MUCH.
[APPLAUSE]
>>ANY QUESTIONS?
I ASK ASK A QUICK ONE.
YOU MIGHT BE AWARE OF
NON-INVASIVE STIMULATION OF THE
OR I CAN YOU LAR BRANCH THE
VAGUS HAVE BEEN USED FOR CARDIAC
APPLICATIONS.
I'M JUST CURIOUS IF YOU THINK A
NON-INVASIVE APPROACH OF A
TEMPORAL NERVE COULD BE
SIMILARLY USED TO ACTUALLY
SUPPRESS PAIN GIVEN THE CIRCUIT
YOU ARE DESCRIBING?
>>THAT'S REALLY GOOD QUESTION
SOLSO WE ACTUALLY -- I HONESTLYI
DIDN'T KNOW THERE WAS ACTUALLY
(INAUDIBLE) BUT YEAH, WE WILL
TRY TO INDIFFERENT SPECIFIC
SUBSET AREAS TO ACTIVATE IT.
THANK YOU.
LAST TALK Dr. COSTA.
>>HI, THERE, EVERYONE.
IT'S REALLY A PLEASURE TO BE
HERE AND I'VE BEEN LEARNING A
LOT AND THERE'S A LOT OF
QUESTIONS AND THIS IS VERY
EXCITING AND SO TODAY I'M GOING
TO TALK ABOUT THE PART OF
CONTROL AS WE HEARD ALREADY A
LITTLE BIT AND ABOUT THE
DESCENDING INNERRIZATION AND
CONTROL OF INTERNAL ORGAN
FUNCTION.
OUR LAB AND THERE WE GO.
OUR LAB AND MUCH OF THE WORLD
HAS BEEN STUDYING ANIMAL
BEHAVIOR IN THE OVERT SENSE AND
ALSO HOW ANIMALS LEARN TO
CONTROL WHICH BEHAVIOR, WHICH
MOVEMENT IS APPROPRIATE IN A
PARTICULAR CONTEXT OR UPON
CERTAIN SYSTEMS AND WE KNOW FOR
BODILY MOVEMENTS OF THE MAIN
BODY IT'S THE INN INAND THEY'RE
QUIETLY TIGHTLY CONTROLLED IN
THE SPINAL CORD AND THAT IT CAN
INNOVATE MUSCLES, FROM MOVEMENT
AND MEDIATE REFLEX MOVEMENT SO
FOR VOLUNTARY MOVEMENTS WE NEED
THE DESCENDING INPUT FROM THE
BRAIN AND A LOT OF INPUT TO THE
EXECUTIVE AND WE KNOW THAT THIS
IS SPECIFIC POPULATION THAT
INNOVATED THE SPINAL SPECIFIC
SPINAL CIRCUITS TO SPECIFIC
MUSCLE CONTROL PATTERNS AND WE
HAVE ALSO FOUND CORTICAL INPUT
TO SPINAL CORD IS PERHAPS LARGER
THAN WE PREVIOUSLY ACKNOWLEDGED
AND ALSO SPECIFIC POPULATIONS OF
COURTI CANAL NEURONS AND TO REIE
AND CIRCUITS AND INDUCED OR
WANGING INDUCES PLASTIC TEE AND
THIS IS FOR OVERT BEHAVIOR BUT A
LOT OF WHAT WE CONSIDER BEHAVIOR
IN NEURAL SPACE IS NOT ONLY
THROUGH MULLS.
IF I REACH FOR AN APPLE OR A
APPROACH A FOOD SOURCE AND WE
HEARD HERE AND I SHOULD BE
STARTING TO PREPARE FOR THE FACT
THAT I'M GOING TO GET IMMUNE AND
WE KNOW THAT ALSO THERE'S
DESCENDING INNERRIZATION OF
OTHER ORGANS AND THE PAN
CREATION THAT WE'LL START
INCREASING THE RELEASE OF
INSULIN AND DECREASE THE RELEASE
OF NOT ONLY THAT REFLECTIVELY
AFTER YOU EAT BUT WITH TIME IN
PREPARATION FOR THE MEAL AND FOR
EXAMPLE, THE DESCENDING
INNOVATION OF THE SPLEEN AND AND
WE KNOW A LITTLE BIT ABOUT THE
HYPOTHALIMUS AND THE REGIONS,
ARE IMPORTANT FOR THESE AND WE
WANTED TO TAKE A MORE SYSTEMATIC
APPROACH TO THESE AND SO THERE
ARE -- FIRST, HOW DO WE STUDIES
THOSE CONTROL OF INTERNAL ORGAN
FUNCTIONS FOR PREDICTIVE CONTROL
OF PAN CROW ATTIC FUNCTION AND
THIS RELEASE OF INSULIN AND
DECREASED THAT WE'VE SEEN WE CAN
USE PAVLOVIAN CONTINUING THAT
HAS BEEN AROUND FOR 100 YEARS
AND PAVLOV HAD A LOT OF INSIGHTS
TO THESE WHERE YOU PRESENT A
NEUTRAL STIMULUS PREPARED FOR A
CERTAIN FOOD FOR EXAMPLE,
SUCROSE AND JUST PREVENTING OF
THAT CONTINUE STIMULUS OR
CONTINUAL STIMULUS AS IT SHOULD
BE AND I WILL IS ITS ACTUALLY
THE PHYSIOLOGICAL RESPONSE EVEN
IN THE ABSENCE OR AHEAD OF FOOD.
AND THIS IS WELL-KNOWN AND
PERHAPS NOT SURPRISING BUT YOU
KNOW, WHAT IS INTERESTING IS
THIS IS MUCH MORE GENERALIZABLE
SO FOR EXAMPLE, NOW, IF YOU PAIR
A PARTICULAR CONTINUAL STIMULUS
LET'S SAY SACCHARIN, WHICH IS AN
IMMUNOSUPPRESS ENTER FOR A
WHILE, THEN YOU CAN PRESENT JUST
THE CONDITIONAL STIMULUS AND
JUST THE CS AND THAT IS
SUFFICIENT TO GET A CONDITION
IMMUNO SUPPRESSION IN RESPONSE
TO FOR EXAMPLE INJECTIONS WITH
LPS.
SO THESE, WE KNOW, REQUIRES
DESCENDING INO INNOVATION AND
THERE'S STUDIES OF THE HIPPO
THALAMUS AND THE INNOVATION OF
SPLEEN IN THIS CASE.
AND PANCREAS AND SPLEEN AND
THESE ARE TH POSITIVE NEURONS
AND YOU SEE THE PANCREAS MORE
DIFFUSED AND IN THE SPLEEN AND
IT'S MORE ORGANIZED AND IT IS
JUST MARVELOUS TO LOOK AT THESE
ORGANIZATIONS AND SO THESE
INNOVATIONS COMES FROM THE
GANGLION AND ONE THE FIRST
EXPERIMENT WAS INJECTED ALCOHOL
TOXIN B WITH DIFFERENT COLORS IN
SPLEEN AND PANCREAS AND LOCK AT
THE CELL BODIES IN CMG THAT WERE
INNERVATING THESE TWO ORGANS AND
PERHAPS NOT SURPRISINGLY FOR
THIS CROWD HERE BUT CERTAINLY A
BIT SURPRISING FOR US WHEN WE
FIRST SAW IT, IT SEEMS THAT
THESE ARE MOSTLY DIFFERENT
POPULATIONS OF NEURONS WITHIN
CMG AND THERE'S SOME, IN THIS
FIELD, ONE NEURON, HAD POTENTIAL
LOW INNERVATED BOTH BUT IT SEEMS
THAT DIFFERENT POPULATIONS ARE
INNERVATING THIS TWO ORGANS AND
IT AGAIN COULD POINT TO THAT
GRANULARITY THAT WE WERE
SPEAKING ABOUT WHAT THEY WILL
BEEN DOING IN COLLABORATION AT
THE ALLEN INSTITUTION IS
ACTUALLY SEQUENCING THESE
NEURONS SO HOPEFULLY IT'S GOING
TO NOW ACTUALLY START OUR
SPECIFIC MOLECULAR IDENTITY.
AND THE NEXT STEP WHAT LEONE
O'ER WANTED TO KNOW WAS WHAT IS
THE INPUT TO THE GANGLION
NEURONS AND TO DO THESE, SHE
USED A CYTO TYPE OF RABIES BUT
IT DOESN'T JUMP BACK TO JUST
LABORED THE NEURONS THAT THE
AXONS OF AND WHAT SHE SAYS IS
THAT YOU KNOW, SHE HAD NEURONS
IN THE INTER IMMEDIATE LATERAL
COLON OF THE CORD AND THE INTER
ELECTED NUCLEUS BUT IT ALSO IF
SEEMS THAT THE INNOVATION FROM
THE SPINAL CORD IS ALSO NOT
COMING JUST IF THEY ARE
TARGETING THE TYPES AND WE DON'T
KNOW THAT YET AND SO, AFTER
MAPPING THE SECOND NEURONS, LEO
NOWHERE AND LINDA IN THE LAB AND
THESE EXPERIMENTS WHICH WAS NOW
AGAIN WITH THE RABIES AND NOW
COMPLIMENTING WITH THE HELPER
THAT HAVE GLYCO PROTEIN IN THE
SPINAL CORD SO YOU GET THE THIRD
OR THE NEURONS WHICH ACTUALLY
INPUT TO THE CORD NEURONS THAT
THE GANGLIA AND WHAT WAS AMAZING
IS OF COURSE NOW USING SPINAL
WAS DEVELOPED BY THE DOCTOR AND
YOU COULD SEE WHERE VIRTUALLY
ALL CELL BODIES OR MANY OF THE
CELL BOD OTH BODIES ARE IN THE D
YOU SEE THE HYPOTHALAMUS BUT I
WANT TO DRAW YOUR ATTENTION TO
THE VERY STRONG CORTICAL INPUT D
YOU CAN SEE IT IN THE THE FIRST
TIME SLIDE AND COMING UP ONLY
FROM AREAS OF THE INSULIN FROM
THE COX TEXT WE SAW BUT IN CASE
FROM THE MOR MOTOR CORTEX WHERE
SEE THE TYPICAL CORTICAL SPINAL
TRACT AND THE SENSORY COURSES
AND WHICH ALSO, EVEN FOR MUSCLE
ALSO DESCENDING INPUT AND NOW,
SOME OF THESE AREAS ARE, WE
STILL NEED TO DO MORE CONTROLS
BUT THESE ARE AREAS OF THE
SPINAL CORD VERY DIFFERENT THAN
THE AREAS THAT ARE RESPONSIBLE
FOR MOTOR INNOVATION AND SO THIS
WAS EXCITING BUT SURPRISING SO
WE THOUGHT WHAT ABOUT OTHER
ORGANS THAT HAVE A LITTLE BIT OF
A DIFFERENT INNOVATION SO FOR
EXAMPLE, THE ADRENAL GLAND THAT
STORES EPINEPHRIN IT ALSO
RECEIVES INPUT FROM THE CORD BUT
DIRECT INPUT SO IT DOESN'T GO
NECESSARILY THROUGH A GANGLIA
AND SO, JOSH GROWN DID A SIMILAR
AND HERE YOU SEE AGAIN, MANY
CORTICAL NEURONS IN AND OTHERS
FOR THE TAKE OF TIME I'M LEAVE
IT FOR DISCUSS BUT HOW DO WE GO
ABOUT STUDYING THESE CONNECT WE
WANT TO LOOK THE ALL THE BRAIN
DESCENDING NEURONS BUT MAYBE WE
NEED TO START GOING FROM THE
PERIPHERY BACK AND SO, SHEERAN
EX FORMENT THAT THEY NEED AND
DOING ONE PHOTO IMAGING OF G
CAMP ACTIVITIES AND AFTER
INJECTION OF PLS AND I WANT TO
MAKE ONE POINT WHICH IS THERE
ARE A FEW NEURONS THAT DO
RESPOND MUCH BUT IF YOU HEAR THE
GREEN NEURONS THAT INCREASES IN
ACTIVITIES AND DAYS FOR A LONG
TIME AND THIS IS WHAT WE
TYPICALLY THINK OF OF THE
NERVOUS SYSTEM RESPONSE BUT FOR
EXAMPLE, THIS BLUE HAS A TRANCE
SEE ENTER HERE AND YOU WILL SEE
I MEAN THIS IS A SPED UP VIEW
BUT TOWARDS THE END OF THE
VIDEO, IT'S A TRANCE SEE ENTER
INCREASING ACTIVITY.
THIS IS HEAVILY MOTION
CORRECTED, YOU WILL SEE IT NOW,
BOOM.
GO UP AND SO THERE'S PATTERNS OF
ACTIVITIES THAT ARE VERY
DIFFERENT AND VERY CLOSE TO THE
PERIPHERY AND SO WE DO NEED TO
UNDERSTAND THESE PATTERNS AND IN
THE REFLECT OR THE HOMEOSTATIC
CONDITIONS BUT ALSO IN THE
LEARNED CONDITIONS AND OF
COURSE, I MEAN, WE, LIKE
EVERYONE HERE, WE HAVE BEEN MORE
METHODS TO ACTUALLY MEASURE AND
CONTROL THINGS WHEN YOU GET INTO
THE BRAIN AND EVEN BRAIN STEM
BUT I DO THINK THAT WE NEED TO
DEVELOP A LOT OF MORE METHODS TO
MEASURE THINGS AND CONTROL IN
THE PERIPHERY.
SO, WE WANT TO LEAVE A MESSAGE
HERE IS THAT MAYBE THESE MOTOR
SYSTEMS THAT WE TALK ABOUT
ACTUALLY DIDN'T EVOLVE ONLY TO
CONTROL MUSCLE WHICH WOULDN'T
MAKE SENSE AND WE HEARD ABOUT
THE SENSORY SYSTEMS THAT ARE
ACTUALLY SIMILAR BUT ARE
ACTUALLY CONTROLLED SYSTEMS AND
THEY CONTROL THE ADAPTIVE
BEHAVIOR OF THE ORGANISM AND
MAYBE BEFORE WE EVEN SENSE THE
INTERACTIVE WITH THE WORLD, AS
WE BECAME MULTI CELLULAR
ORGANISMS THROUGHOUT THE
EVOLUTION, THE MAIN
PREOCCUPATION OF THE NERVOUS
SYSTEM WAS A FAST SENSOR OF
THINGS INSIDE AND RESPONSES AND
THE BEAUTIFUL OF THE PAVLOVIAN
SYSTEM WHERE IT'S NOT JUST THE
CLOSE LOOK REFLEX.
NOW AN INPUT THROUGH AN EYE CAN
ACTUALLY CONNECT AND THE
ASSOCIATE THROUGH WHAT WE THINK
MAY BE THE REFLEX IS SYSTEM THAT
CONTROLS, YOU KNOW, METABOLISM
OR THE IMMUNE SYSTEMS SO, I
THINK THIS IS THE SUPER EXCITING
FOR NEUROSCIENCE AND I THINK
CONCEPTUALLY AND UNFORT LOW WHEN
WE READ PAVLOV HE GOT MOST OF IT
ALREADY BUT SOME OF THE NEW
TOOLS AND THIS COLLABORATIVE
EFFORT LIKE WHAT WE HAVE HERE
IT'S A PLEASURE.
I JUST WANT TO THANK EVERYONE IN
THE LAB AND IN PARTICULAR LOW IL
OF YOU.
[APPLAUSE]
THANK YOU Dr. COSTA.
ANY QUESTIONS?
>>THAT WAS GREAT.
SO, WE HAVE REALLY COOL
EXPERIMENTS SHOWING THAT
SPECIFIC DEEP LAYER NEURONS IN
MOTOR CORTEX DRIVE COMPLEX
HAND-TO-MOUTH BEHAVIOR SIMILAR
TO WHAT WAS SHOWN.
I WONDER WHETHER OR NOT LIKE
WHEN YOU ARE AT THE POINT WHERE
YOU HAVE A COMPLEX
HAPPENED-TO-MOUTH BEHAVIOR FOR
BRINGING FOOD TO YOUR MOUTH
WOULD YOU USE THE SAME NEURONS
TO CREATE INSULIN.
>>THIS IS A SUPER INTERESTING
QUESTION.
OF COURSE, I MEAN, I KNOW THIS
STUDIES AND WE'VE SUM YOU LATED
IN OTHER AREAS BUT WE
CONCEPTUALLY ALWAYS THOUGHT OF
IT AS DIFFERENT CIRCUITS THAT
WOULD BE COORDINATED INTO
SOMEWAY.
BUT AGAINST MY ANALOGY OF
REACHING FOR FOOD, BUT WOULDN'T
IT BE INTERESTING IF ACTUALLY SO
OBVIOUSLY IT'S NOT NECESSARILY
LEARNED AND IF WE GO INTO A
CERTAIN AREA OF THE BASAL
GANGLIA, WE IT FOR EXAMPLE
INDUCE THE WHOLE FACIAL MOVEMENT
OF LEAKING, RIGHT, WITHOUT ANY
TRAINING AND IN A FREELY MOVING
ANIMALS FOR THE FIRST TIME.
SO, NOW WE'RE STARTING TO THINK
MAYBE, COULD IT BE IF THESE WERE
SELECTED THROUGH OUT THE
EVOLUTION, TO PRODUCE A CERTAIN
BEHAVIORAL PATTERN THEY ALSO,
YOU KNOW, THROUGH COLLATERAL,
THESE NEURONS AS THEY DESCEND
THEY DON'T JUST PROTECT TO ONE
SPECIFIC TYPE MANY OF SO THESE
WOULD BE, SUPER EXCITING IF
THERE WERE COORDINATED MODULES
THAT ARE NOT ONLY FOR ADVERSE
BEHAVIOR BUT FOR ADVERSE
BEHAVIOR AND -- THE ENTIRE
PHYSIOLOGICAL RESPONSE WHICH IS
NOT THE ONLY MUSCULAR.
>>IT'S KNOWN FOR EXERCISE,
ISN'T IT.
OF COURSE IT'S TRUE AND ANIMALS
START TO RUN THAT IT'S GOING TO
REGULATE IT'S HEART RATE AND
BLOOD PRESSURES IN WAYS THAT ARE
COORDINATED.
I DON'T KNOW WHETHER PEOPLE IN
THE ROOM WHETHER NO WHETHER IT
HAS COLLATERALS THAT ARE CONTROL
TAG?
ING THAT.>>THIS COULD BE A GOOO
START A DISCUSSION.
IMAGINE IF YOU START MUSCULAR --
I MEAN, RUNNING AND ACTIVATING
YOUR MUSCLES, DOES YOUR HEART
START TO PREPARE FOR THAT IN
ANTICIPATION?
I MEAN, CERTAINLY THE LUNGS WITH
NO RESPIRATION STARTS.
>>RESPIRATION STARTS FIRST SO
IT GOES UP DUE TO VAGAL
INTERFERENCE AND CARDIAC
CONTROLS COMES ON LATER SO YOU
GET A LAG.
BUT YOU ALSO HAVE CENTRAL
DESCENDING CONTROLS.
>>AND IF IT COORDINATED IN THE
SENSE THAT IT STIMULATES ONE
THING.
>>YOU GET THAT IMMEDIATE UP
REGULATION RESPIRATION AND THEN
YOU GRADUALLY GET REFLEX AS YOU
PRODUCE METABOLITES AND YOU GET
TIE POINT WHERE YOU LEVEL OFF ON
YOUR WORKLOAD.
THE IMMEDIATE CHANGES ARE
CENTRALLY DRIVEN.
>>THAT'S COOL.
WE START A POPULATIONS IN THE
BRAIN STEM AND IT CAN BE IN USED
STIMULATION VERY QUICKLY AND
IT'S INTERESTING BEFORE OR AND
AND IF YOU HAVE THESE, YEAH.
>>YOU ARE A URF HERE?
>>
[LAUGHTER]
>>I WOULD SIT DOWN.
>>WE HAVE A COUPLE OF QUESTIONS
AND THE FIRST Dr. FOR Dr.
ANDERMANN.
I HAVE A COUPLE OF QUESTIONS FOR
Dr. ANDERMANN.
HAVE YOU INVESTIGATED THE
QUESTION UNDERLINE PATHOLOGICAL
EATING DISORDERS AND ALSO WHAT
FEATURES IN THE SIGNAL DID YOU
USE TO UNDERSTAND WHETHER THE
ACTIVITIES INDICATED FOOD
DEFICIT VERSUS FOOD SURPLUS,
IT'S A VERY INTERESTING TALK.
THANK YOU.
>>THANK YOU FOR THE QUESTION
AND THIS IS THE SECOND ONE BUT
THE FIRST QUESTION WAS REGARDS
TO THE INSULAR CORTEX IN EATING
DISORDERS.
ACTUALLY, THE MOST INTERESTING
LITERATURE THAT IS QUITE
COMPELLING TO ME IN HUMANS WITH
LAUCHANCE OR STROKES TO THE
CORTEX ACTUAL LOW HAD TO DO WITH
THE FACT THAT IT'S EASIER TO
QUIT SMOKING AND TO QUIT OTHER
ADDICTIONS IN THAT CONTEXT AND
SO I THINK IN SOME WAYS, THIS IS
CONSISTENT WITH WHAT I WAS
PROPOSING IN THE TALK WHICH IS
THAT THE INSULAR CORTEX MAY BE
PART OF A NETWORK THAT
INTEGRATES THE GOOD FEELINGS AND
THE BAD FEELINGS OF TAKING
INACTION AND IF THERE'S SOMEWAY
OF PER SEVER ANSON MOTOR BEHAVE
YEARS THAT MAINTAIN A STATE SUCH
AS A STATE OF NICOTINE
DEPENDENCE, DESPITE THE TASTE OF
NICOTINE AND SO ON THAT MIGHT
REQUIRE THE CORTEX TO KIND OF
EXERT ITS CONTROL AND THAT WHEN
YOU TAKEAWAY THE INSULAR CORTEX,
IT'S EASIER TO QUIT THE SMOKING
BECAUSE YOU DON'T HAVE THE SORT
OF WANTING TO PERSIST.
DIDN'T CATCH THE SECOND
QUESTION.
>>THAT'S GOOD.
THANK YOU.
>>THE NEXT QUESTION FOR Dr.
HEIKE MUENZBERG-GRUENING.
CAN YOU CHANGE IT TO FAT TISSUE
IN TH DRIVEN.
HOW DO YOU ELIMINATE THE VAGAL
AND SPINAL TH POSITIVE SENSORY
NEURONS?
HAVE YOU TRIED LOCAL AV
DELIVERY, HM3DQ?
>>THE TH3 MOUSE MODEL WE WERE
USING SAUL SYMPATHETIC AND IT'S
TRUE THAT VAGAL IS TO IT'S
EXPRESSED IN THE VAGAL AND SO WE
DON'T DISTINGUISH THAT SO WE
WANT AID SYSTEM WHERE WE HAVE A
MORE BROAD STIMULATION OF
SYMPATHETIC AND COULD WE GET A
SIMULATION OF TEMPERATURES
BECAUSE OF A SURPRISING TO US
THAT THAT IS THE THAT SHOULD
INCREASE FROM THE TEMPERATURE
AND IT DOES NOT.
SO WHAT IT SHOWS US WAS
BASICALLY THAT YEAH, IT'S
POSSIBLE TO GET ACTIVATED
TEMPERATURES IS JUST NOT
SUFFICIENT IF YOU ONLY ARE
DRIVER TO BRONZE FED.
>>Dr. COSTA, THE NEXT
QUESTION IS FOR YOU.
DO YOU SEE DRG NEURONS THAT
PROJECT DIRECTLY INTO THE
PANCREAS?
>>SO, WE HAVE NOT EXPLORED SO
MUCH OF THE SENSORY SIDE.
WE KNOW THE STOMACH, RIGHT.
I WOULD IMAGINE THAT YES.
I DON'T KNOW IF IT'S THE SAME
ONE OF THE STOMACH WE KNOW.
ONE INTERESTING THING SO ON THE
DRG SIDE ON THE SENSORY SIDE, WE
DON'T HAVE AS MUCH MAPPING.
ONE INTERESTING THING I MEAN,
BECAUSE WE TALK ABOUT
SYMPATHETIC AND HERE AS TWO
DIFFERENT SYSTEMS BUT FOR
EXAMPLE, TO THE GANG LEANNE AND
THAT THE SPLEEN DOES NOT SEEM TO
HAVE DIRECT VAGAL INNOVATION AND
THERE IS INNOVATION OF THE
GANGLIA BY THE VAGUS WHICH IS
SUPPOSEDLY A SYMPATHETIC SYSTEM
SO ON THE PANCREAS, YOU GET BOTH
SYMPATHETIC AND SO YOU KNOW,
MAYBE INSTEAD OF SYSTEMS THESE
ARE NEURONS AND WE HAVE A
CERTAIN TYPE OF NEURO
TRANSMITTERS AND EXPRESSIONS
THAT ARE COORDINATED FOR
RECEIVING AND AGAIN I THINK THAT
NOT DRG BUT THE DORRAL MOTOR
VAGUS NUCHAVING NUCLEUS.
I DON'T KNOW IF YOU HAVE THE
DATA HERE.
>>D RG INNERVATING THE PANCREAS
IT'S CLEAR.
ONE INTERESTING THING ABOUT SOME
OF THIS INTERNAL ORGANS,
ESPECIALLY THE PANCREAS IS
SOMETHING IN HUMANS CALLED
REFERRAL PAIN WHICH IS THAT
PEOPLE WITH SAY PROBLEMS IN THE
PANCREAS, THEY PERCEIVED PAIN IN
DIFFERENT AREAS OF THE BODY AND
SO THE WAY THAT THE ARRANGEMENTS
OF THE CIRCUITRY USED IS UNCLEAR
BUT THERE'S INNER HA PANCREATIC
PAIN IN CANCER IS A PROBLEM.
>>IN THE SPLEEN, WHEN THERE'S
THE CON TRACKTURE MANY OF YOU
PROBABLY HAVE NOTICED.
>>YEAH, EXACTLY.
AND IT'S ALSO TRUE THAT MANY
TERMINALS INNERVATE CELIAC SOME
NEURONS COME FROM THE INTESTINE
AND THERE'S SOME VAGAL WITH THE
NEURONS OF THE SPINAL CORD SO
IT'S A VERY COMPLICATED GAME FOR
SURE.
IT'S VERY INTERESTING.
>>WELL, THAT, WE'LL END THIS
SESSION.
THANK YOU ALL VERY MUCH AND MOVE
ON TO CLOSE REMARKS BY Dr.
VALENTINO.
>>THANK YOU, IT'S A DIFFICULT
TASK.
I HAVE TO SAY THAT THIS WAS A
VERY ENTA ELECTRIC ACTUALLY
ENERGIZING MEETING AND IT WAS
JUST A LOT OF FUN AND I FIRST
WANT TO THANK EVERYONE TODAY.
I WANT TO THANK ALL OF THE
SPEAKERS, ALL OF THE ORGANIZERS
AND THOSE WHO WORKED WITH THE
LOGISTICS EVEN THOUGH WE HAD
GLITCHES, WE'RE ENDING ON TIME
AND DOING GREAT.
AND I PARTICULARLY WANT TO
ACKNOWLEDGE, WHEN, FOR RALLY
TAKING ON THIS VISION AND YOU
KNOW, AND YOU CAN HAVE A
PARTICULAR VISION BUT AN
IMPORTANT THING IS FINDING THE
RIGHT TIME TO PRESENT IT AND I
THINK THAT'S ONE OF THE THINGS
THAT SHE DID.
SHE RECOGNIZED THAT THE TIMING
WAS RIGHT TO DEVELOP AND PROMOTE
THIS INITIATIVE AND I THINK WE
HAD 2019, A COUPLE YEARS AGO, WE
HAD THE FIRST MEETING AND WE
TALKED ABOUT THE CHALLENGES AND
IT WAS VERY EXCITING AND I THINK
PRIOR TO THAT, I KNOW A LOT OF
IS IS THAT KIND OF WORKED ON THE
BRAIN ADVISER A INTERACTIONS
FELT LIKE THE WORK WAS ON THE
FRINGE AND IT WAS FALLING
BETWEEN THE CRACKS OF
INSTITUTES.
I KNOW THAT I FELT THAT WAY.
AND TWO YEARS AFTER THIS MEETING
OUR KEYNOTE SPEAKER WAS A NOBLE
LAUREATE AND THAT'S REAL FIFTH Y
IMPORTANT.
WE DISCUSSED WHEN PRESENTED
EARLIER HOW THIS INITIATIVE
LANDS BETWEEN BRAIN AND LINKS
BETWEEN THE BRAIN INITIATIVE AND
THE SPARC INITIATIVE
INNERRIZATION OF PERIPHERAL
ORGANS SO IT'S TRUE WE'RE
BEGINNING TO IDENTIFY RECIPROCAL
COMMUNICATIONS, WAYS OF
RECIPROCAL COMMUNICATION BETWEEN
THE BRYN AND PERIPHERAL ORGANS.
THIS IS REALLY A STORY OF
MULTI-SYSTEM INTEGRATION AND HOW
DOES THE ADVIS -- HOW IS IT HARD
WITH ALL THE OTHER SOUNDS?
UNDERSTANDING THIS IS REALLY
INFORMS US OF HOW MULTI SYSTEMS
ORGANISMS, WE CAN REALLY BEGIN
TO NAVIGATE OUR UNIVERSE OR OUR
ENVIRONMENT AND ALSO INFORMS US
HOW PATHOLOGY CAN PRESENT AS CO
MORBID CENTRAL AND PERIPHERAL
FEATURES, WE'RE LEARNING FROM
THE BRAIN INITIATIVE AND SPARC
THE IMPORTANCE OF TECHNOLOGY AND
HOW THIS ADVANCES KNOWLEDGE AND
OUR KEYNOTE SPEAKER TODAY,
REALLY REINFORCED THIS IDEA AND
IN THE INTERCEPTION PROGRAM.
SHE ALSO PRESENTED AND SHOWED
THERE WERE UNIQUE CHALLENGES IN
ACCESSING TISSUE AND VISUALIZING
AND RECORDING AND MANIPULATING
AND I THOUGHT THAT WAS VERY
IMPORTANT AND THE NEED TO
INCORPORATE BIO ENGINEERING, NEW
BIO ENGINEERING APPROACHES TO
OVERCOME THE CHALLENGES.
ALL THE SCIENCE PREVENTED NEW
KNOWLEDGE AND OPENED UP, AS GOOD
RESEARCH DOES, IT OPENS UP NEW
QUESTIONS SOFI.WE LEARNED THE UF
MULTI-PRONGED APPROACH AND HOW
THE BRAIN REGULATES THE STOMACH
AND THE NEED TO UNDERSTAND THE
INNER PLAY BETWEEN VAGAL AND
SPINAL NETWORKS AND DISPLAYING
GASTRO INFORMATION TO THE BRAIN.
THE RECOGNIZE T -- THIS CAN EVEG
BEHAVIOR IS FASCINATING AND IT'S
IMPORTANT TO UNDERSTAND HOW AND
WHEN THIS WOULD BE ENGAGE AND
HOW IT INTERACTS WITH HAVINGEL
OUT PUTS.
IT REVEALED CIRCUITS AND REFLEX
RESPONSES AND RELATED TO
BREATHING AND RELATED TO CARDIAC
FUNCTION AND RELATE TODAY
METABOLISM AND THIS IS
INFORMATION THAT IS CRITICAL TO
UNDERSTANDING THE BIGGER
QUESTION OF HOW ARE THESE
REFLEXES LINKED TO COGNITIVE AND
EMOTIONAL FUNCTION.
HOW DO THEY INTERACT WITH THESE
FUNCTIONS?
I ONLY HEARD THE WORD AMYGDALA
ONCE TODAY I WAS SHOCKED AND IT
WAS IN PASSING.
HOW DOES THAT HAPPEN?
I THOUGHT IT WAS GOOD BECAUSE IT
MEANS THINGS ARE CHANGING AND
OTHER THINGS ARE COMING INTO
PLAY.
SO TO ME, THE STRESS RESPONSES
ARE A BEAUTIFUL EXAMPLE OF HOW
ALL OF THESE PERIPHERAL
RESPONSES, BREATHING, CARDIAC
CHANGES, GASTROINTESTINAL
CHANGES, CHANGES IN BLADDER
FUNCTION AND IMMUNE FUNCTION AND
METABOLISM, THEY ALL HAVE TO BE
COORDINATED AND VERY PRECISE
FASHION WITH BEHAVIOR AND
COGNITIVE FUNCTION AND TO BE
ABLE TO ADAPT TO
LIFE-THREATENING ST STIMULUS AND
ANY DISREGULATION OF THAT
COORDINATION RESULTS IN STRESS
RELATED DISORDERS AND STRESS
RELATED DISEASES SO I THINK WHAT
WE'RE TRYING TO UNDERSTAND HERE
IS HOW, THAT'S JUST AN EXAMPLE
TO ME OF HOW THINGS ARE KIND OF
SUPPOSED TO WORK TOGETHER AND I
THINK WHAT I LIKE ABOUT THIS
INITIATIVE AND ALL THE RESEARCH
THAT YOU ALL ARE DOING IS IT'S
GOING TO BEGIN TO ANSWER THOSE
QUESTIONS AND TO REALLY, AT THE
END.
GIVE US A PICTURE OF HOW THIS
WORKS AND OF THIS COORDINATION
THAT REALLY ALLOWS US TO
SURVIVE.
SO I EXPECT THAT WE'LL GET EVEN
MORE ADVANCED TECHNOLOGIES THAT
ALLOW HIGHER RESOLUTION ACCESS
AND MANIPULATION AND GET US
CLOSER TO THIS BIG PICTURE.
THANK YOU FOR COMING AND I'M
LOOKING FORWARD TO TOMORROW.
[APPLAUSE]