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GOOD AFTERNOON.

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WELCOME TO THE WEDNESDAY 

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AFTERNOON LECTURE SERIES.

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I'M MARGUERITE MATHEWS A PROGRAM

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DIRECTOR AT THE NATIONAL 

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INSTITUTE OF NEUROLOGICAL 

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DISORDERS AND STROKE.

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ON BEHALF OF NINDS AND OUR 

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SIBLING NEUROSCIENCE INSTITUTES 

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I'M THRILLED TO INTRODUCE 

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TODAY'S WALS SPEAKER, DR. KAFUI 

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DZIRASA WHO PIONEERED RESEARCH 

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AT THE INTERSECTION OF 

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NEUROSCIENCE PSYCHIATRY AND 

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NORTHEASTE

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ENGINEERING.

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BEFORE I GET INTO HIS RESUME THE

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FIRST IS THE CODE FOR CONTINUING

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EDUCATION CREDITS 57693.

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I'LL REPEAT THAT.

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57693.

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FOR THOSE WATCHING REMOTELY, YOU

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CAN SUBMIT QUESTIONS TO THE 

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SPEAKER ANYTIME DURING THE 

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LECTURE.

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SIMPLY CLICK ON THE BUTTON THAT 

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SAYS SEND LIVE FEEDBACK BELOW 

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THE VIDEOCAST WINDOW.

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TYPE YOUR MESSAGE AND WE'LL 

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RELAY IT TO THE SPEAKER AT THE 

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END.

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KAF IS A MARIE WASHINGTON 

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PRESIDEN

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PRESIDENTIAL DISTINGUISHED 

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PROFESSOR AT DUKE UNIVERSITY 

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SCHOOL OF MEDICINE AND HE HAS 

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OTHER TITLES AT DUKE.

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THESE INCLUDE PROFESSOR OF 

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PSYCHIATRY AND PROFESSIONAL 

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SCIENCES AND PROFESSOR OF 

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NEUROSURGERY AND NEUROBIOLOGY 

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AND ASSISTANT PROFESSOR OF 

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MICROENGINEERING AND THE 

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PROFESSOR IN THE DUKE INSTITUTE 

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FOR BRAIN SCIENCES.

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DANG, YOU'RE SIGNATURE MUST BE 

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LONG.

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AT HIS CORE HE'S A NEURO 

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BIOLOGIST AND PSYCHOLOGIST 

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UNCODING DISEASE IN BRAIN AND 

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THE ESSENCE IS HOW 

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NEUROPSYCHIATRIC RISK GENES 

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MODIFY STRESS THAT UNDER LIE 

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NORMAL AND COGNITIVE FUNCTION.

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HIS LAB USING ELECTROPHYSIOLOGY 

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AND OPTOGENETICS AND 

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QUANTITATIVE ANALYSIS OF 

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BEHAVIOR AND GENETICALLY 

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MODIFIED MICE.

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THEY WERE THE FIRST TO IDENTIFY 

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PATTERNS OF ELECTRICAL ACTIVITY 

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ACROSS MULTIPLE BRAIN REGIONS 

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KNOWN AS BRAIN REGION OS LATORY 

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DESIGN DYNAMICS TO IMPROVE THE 

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UNDERSTANDING OF MOOD DISORDERS.

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KAF EARNED A BS FROM UNIVERSITY 

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OF MARYLAND UP THE ROAD AND 

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PROFESSORED HIS Ph.D. IN NEU

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NEUROBIOLOGY AND KAF ALSO 

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COMPLETED A PSYCHIATRY RESIDENCY

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AND POSTDOCTORAL TRAINING AT 

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DUKE.

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BEYOND HIS RESEARCH AND TRAINING

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ACHIEVE CANMEN MENT -- ACHIEVEMS

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HE RECEIVED NUMEROUS HONORS 

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INCLUDING THE NIH NEUROPIONEER 

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AWARD IN 2022 AND ELECTED TO THE

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NATIONAL ACADEMY OF MEDICINE IN 

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2021.

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HE'S A PASSIONATE ADVOCATE.

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THE TITLE OF HIS LECTURE IS 

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TOWARDS PREVENTATIVE PSYCHO 

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THERAPEUTICS.

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PLEASE WELCOME, KAF.

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>> IT'S A REAL HONOR AND 

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PLEASURE.

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I CALL HIS MY SECOND HOME AND 

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SPENT TIME AS A MEDICAL STUDENT 

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AND HAVE BEEN MULTIPLE TIMES 

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SINCE WITH FRIENDS AND 

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COLLEAGUES ACROSS THE 

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INSTITUTION.

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I'LL GIVE A TALK TODAY ABOUT A 

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PROBLEM THAT I'VE BEEN TRYING TO

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SOLVE FOR THE LAST 20 YEARS AND 

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WHEN MARGUERITE WAS GIVING MY 

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INTRODUCTION SHE MENTIONED THE 

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DIFFERENT DEPARTMENTS I WAS IN 

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AND ASSOCIATED WITH.

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BECAUSE I REACHED INTO ALL THESE

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DISCIPLINE TO TRY TO SOLVE THE 

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PROBLEM.

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I HADN'T DONE THAT BECAUSE IT'S 

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BEEN FUN, BUT NECESSARY TO TRY 

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TO MAKE HEADWAY IN SOLVING THIS 

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PROBLEM.

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THE TRAINEES HERE -- I ALWAYS 

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LIKE TO GIVE A DISCLAIMER FOR 

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TRAINEES WHICH IS YOU SHOULD NOT

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GIVE A TALK LIKE THIS.

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WE'RE GOING TO COURSE AND ZIP 

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THROUGH ALL KINDS OF 

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DISCIPLINES.

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I'LL DO MY BEST TO ORIENT YOU IN

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AND OUT OF THOSE SPACES BUT 

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TRYING TO SOLVE A PROBLEM THAT 

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TURNED OT  -- OUT TO BE HARDER 

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THAN I THOUGHT IT WOULD.

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THIS IS YEARS OF PRODUCTIVITY 

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LOSS WE EXPERIENCE FROM MENTAL 

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ILLNESS AND IN TERMS OF GLOBAL 

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LOSS OF PRODUCTIVITY, MENTAL 

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ILLNESS IS ON THE TOP OF THE 

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LIST.

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I USED TO TAKE FOUR OR FIVE 

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SLIDES TO WALK PEOPLE THROUGH 

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THE TOPIC AFTER THE PANDEMIC WE 

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ALL APPRECIATE HOW DEEPLY 

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IMPACTFUL THESE ILLNESSES ARE 

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AND SEEING THEM IN FRIENDS AND 

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COLLEAGUES.

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I WANTED TO SHOW THE DATA.

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IT'S NOT JUST PANDEMIC.

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THIS IS YOUTH.

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YOU SEE THE SAME THING WITH 

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ANXIETY FEATURES.

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THE INCIDENTS OF THE DISORDERS 

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HAVE BEEN GOING UP.

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THEY WENT UP WITH THE PANDEMIC 

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BUT WERE INCREASING AS WELL.

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SO A LITTLE BIT OF MY BACKGROUND

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FOR THINKING HOW TO GET TRACTION

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ON THE ILLNESSES.

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I ALWAYS THOUGHT A REALLY GOOD 

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STARTING POINT WAS UNDERSTANDING

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BIOLOGY AND THE GENETICS WITH 

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GOOD CLUES.

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AS I WAS COMING UP IN MEDICAL 

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AND GRADUATE SCHOOL WE LAUNCHED 

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THE GWAS STUDIES THE GENOME WIDE

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ASSOCIATED STUDIES.

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THE IDEA WAS WE'D SEQUENCE THE 

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GENOME AND FIND HITS THAT GIVE 

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RISK FOR MENTAL ILLNESS AND FIND

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THE GENE FOR DEPRESSION, THE 

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GENE FOR SCHIZOPHRENIA IN THE 

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SAME WAY WE FOUND THE GENE 

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PATHWAYS FOR CYSTIC FIBROSIS.

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ONES WE FOUND THEM WE CAN FIX 

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THEM AND FIX ILLNESS.

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IT TURNS OUT AS WE WERE DOING 

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THIS THE LANDSCAPE FOR 

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PSYCHIATRIC ILLNESSES WERE WAY 

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MORE COMPLEX.

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THERE WERE LOTS OF RISK GENES 

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THAT COULD COME TOGETHER TO FORM

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ILLNESS AND OVER TIME WHAT 

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HAPPENED WAS WE STARTED MAKE OUR

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STUDIES LARGER AND LARGER AND 

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LARGER IN FINDING MORE AND MORE 

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AND MORE HITS.

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SO AS A FIELD WE WANTED TO MAKE 

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SENSE OF THIS AND WHAT WE CAME 

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TO APPRECIATE OVER TIME WAS THAT

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MANY OF THESE SORT OF BIOLOGICAL

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RISK FACTORS SEEMS TO BE 

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CONVERGING ON A SPACE AT WHICH 

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BRAIN CELLS INTERACT CALL THE 

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SYNAPSE.

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THE CONNECTIVITY SPACE BETWEEN 

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BRAIN CELLS.

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I'LL SHOW AN IMAGE SUMMING UP 

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THE FINDINGS.

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IN THE YELLOW COLOR AND RED 

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IDENTIFIED GENES AND PROTEINS 

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THAT INDICATE SCHIZOPHRENIA.

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THE YELLOW AND AUTISM SPECTRUM 

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DISORDER AND DISABILITY THE HITS

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WERE NOT JUST ONE ILLNESS THEY 

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WERE SHOWING UP ACROSS ILLNESSES

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THAT IMPACT PSYCHIATRIC AND 

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EMOT

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EMOTIONAL SPACES AND IT WAS MANY

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PROTEINS AND THAT'S WHERE THE 

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IDEA FOR HOW WE COULD THINK OF 

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INTERVENING ON THESE CAME UP.

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AS MARGUERITE MENTIONED I'M A 

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BIO MEDICAL ENGINEER.

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SO I WONDERED IF WE COULD USE 

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TECHNOLOGY FOR A DISRUPTION IN 

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THIS COMMUNICATION PATHWAY 

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BECAUSE WE BASICALLY USED 

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TECHNOLOGY TO GO AROUND IT.

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IF THE LANDLINE FOR YOUR 

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TELEPHONE IS MESSED UP CAN WE 

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CREATE A CELL PHONE THAT AROUND 

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THE DISRUPTION.

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IMAGINE YOU HAVE TWO CELLS.

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ON THE TOP WE SEE PRESYNAPTIC 

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CELLS.

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THE POINTER WORKS.

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YOU HAVE PRESYNAPTIC AND POST 

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SYNAPTIC CELLS.

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IMAGINE HAVE YOU A BLOCKADE.

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CAN YOU PASS IT TO THE POST 

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SYNAPTIC CELL.

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THIS ISN'T A BIG GREAT GRAND 

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IDEA.

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THIS IS WHAT I SAW IN THE 

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CLINIC.

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THIS IS THE HEART AND IT HAS TO 

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BE SUPPLIED BY BLOOD AND THERE 

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CANNON CONDITIONS WHERE IT'S 

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BLOCKED AND BLOOD CAN'T GET TO 

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WHERE YOUR SENDING IT TO WHERE 

226
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YOU WANT TO RECEIVE ITS AND 

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THERE'S A TECHNIQUE CREATED WE 

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PROBABLY HEARD ABOUT THIS 

229
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CORONARY BIOPSY GRAPH AND YOU 

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PUT A BLOOD VESSEL IN FRONT OF 

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THE BLOCKADE AND ATTACH IT AND 

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IT CAN FLOW AROUND SO SIMPLE 

233
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CONCEPTUALLY.

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WE HAD THE IDEA OF CREATING A 

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BIOPSY TO BIOPSY THE SYNAPSE.

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WE USE A SET OF TOOLS AND HAD 

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PRESYNAPTIC POPULATION AND 

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IMPLANT ELECTRODE AND SAMPLE IT 

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UPSTREAM THEN FEED THE 

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INFORMATION IN THE COMPUTER AND 

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FIGURE OUT WHAT IT WAS SUPPOSED 

242
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TO BE SAYING AND THEN WE WOULD 

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PLAY THAT INFORMATION DOWN 

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STREAM AFTER THE SYNAPSE AND 

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WHEN WE PLAYED THAT INFORMATION 

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IN THE BRAIN WE'D USE A 

247
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TECHNIQUE CALLED OPTO GENETICS.

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CONCEPTUALLY IT WORKS THE SAME 

249
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WAY AS THE EYE, CHANGING LIGHT 

250
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TO CHEMICAL NEITHER AND HERE A 

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CHANNEL OPENS UP AND CLOSES AND 

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LIGHT CREATES STIMULATION OF 

253
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STEM CELLS AND WE DO THIS IN 

254
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1/50th OF A SECOND AND A GRAD IN

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MY LAB IS NOW APPLYING FOR A 

256
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FACULTY POSITION.

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WE CAME UP WITH THE SCHEMATIC TO

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CREATE THIS TECHNOLOGY.

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SO RECORD INFORMATION FROM THE 

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BRAIN, PROCESS IT IN THE 

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00:10:02,007 --> 00:10:04,543
COMPUTER AND FEED IT BACK IN 

262
00:10:04,543 --> 00:10:06,645
WITH HIGH FREQUENCY PULSES AND 

263
00:10:06,645 --> 00:10:10,182
THE CHANNELS OPEN UP WHEN YOU 

264
00:10:10,182 --> 00:10:15,153
STIMULATE WITH BLUE LIGHT AND 

265
00:10:15,153 --> 00:10:15,587
THA

266
00:10:15,587 --> 00:10:17,089
AND WE WANTED TO PICK A PARADIGM

267
00:10:17,089 --> 00:10:19,157
WHERE WE CAN TEST THIS 

268
00:10:19,157 --> 00:10:21,226
STIMULATION DEVICE AND MY LAB IS

269
00:10:21,226 --> 00:10:21,860
REALLY INTERESTED IN STRESS 

270
00:10:21,860 --> 00:10:25,430
BIOLOGY SO WE WANTED TO PICK A 

271
00:10:25,430 --> 00:10:28,100
CONTEXT ASSOCIATED WITH STRESS 

272
00:10:28,100 --> 00:10:28,367
BEHAVIOR.

273
00:10:28,367 --> 00:10:34,172
I ALWAYS THIS PICTURE UP AND 

274
00:10:34,172 --> 00:10:37,042
LIKE TO EXPLAIN IS.

275
00:10:37,042 --> 00:10:38,210
THE MODEL IS NOT DEPRESSED 

276
00:10:38,210 --> 00:10:39,911
THERE'S ONLY TWO THINGS I NEED 

277
00:10:39,911 --> 00:10:41,279
TO ACCEPT.

278
00:10:41,279 --> 00:10:43,715
SO WE CAN MOVE FORWARD IN HOW WE

279
00:10:43,715 --> 00:10:47,085
THEN TEST OUT THE TECHNOLOGY.

280
00:10:47,085 --> 00:10:57,629
THE FIRST THING MUST ONE ACCEPT 

281
00:10:58,130 --> 00:11:00,265
IS IF YOU DO THIS TO A MOUSE THE

282
00:11:00,265 --> 00:11:02,100
STRESS HORMONES GO UP.

283
00:11:02,100 --> 00:11:03,668
THE MOUSE'S BEHAVIOR IN THIS 

284
00:11:03,668 --> 00:11:06,171
ASSAY IS SENSITIVE TO HOW MUCH 

285
00:11:06,171 --> 00:11:07,572
STRESS IT'S PREVIOUSLY RECEIVED.

286
00:11:07,572 --> 00:11:09,408
IF YOU STRESS IT OUT AND PUT IT 

287
00:11:09,408 --> 00:11:12,010
IN THE ASSAY THE ANIMAL WIGGLES 

288
00:11:12,010 --> 00:11:13,078
AROUND LESS.

289
00:11:13,078 --> 00:11:16,048
SO THE ASSAY'S STRESSFUL AND 

290
00:11:16,048 --> 00:11:17,516
SENSITIVE TO THE ANIMAL'S PRIOR 

291
00:11:17,516 --> 00:11:17,949
STRESS.

292
00:11:17,949 --> 00:11:18,817
SO WE TOOK ADVANTAGE OF THIS 

293
00:11:18,817 --> 00:11:22,187
ASSAY BY RUNNING IT TWO DAYS IN 

294
00:11:22,187 --> 00:11:31,196
A ROW.

295
00:11:31,196 --> 00:11:34,599
AND THIS SECOND DAY IT HAD BEEN 

296
00:11:34,599 --> 00:11:37,169
EXPOSED ON THE FIRST DAY AND HOW

297
00:11:37,169 --> 00:11:38,170
THE COMPUTATION OF BEHAVIOR 

298
00:11:38,170 --> 00:11:40,005
CHANGE IN THE SAME CONTEXT WITH 

299
00:11:40,005 --> 00:11:41,373
THE SAME CONTEXT BETWEEN DAY ONE

300
00:11:41,373 --> 00:11:43,542
AND TWO BUT ON THE SECOND DAY 

301
00:11:43,542 --> 00:11:44,609
IT'S BEEN STRESSED ON THE 

302
00:11:44,609 --> 00:11:45,110
PREVIOUS DAY?

303
00:11:45,110 --> 00:11:49,047
SO WHEN YOU LOOK AT ANIMAL'S 

304
00:11:49,047 --> 00:11:50,415
BEHAVIORALLY BETWEEN DAY ONE AND

305
00:11:50,415 --> 00:11:54,152
TWO THEY'RE NOT ALL IDENTICAL.

306
00:11:54,152 --> 00:12:04,229
B

307
00:12:06,231 --> 00:12:07,666
BUT  AS A POPULATION THEY SHOW 

308
00:12:07,666 --> 00:12:08,266
LESS MOBILITY AND THAT'S HOW 

309
00:12:08,266 --> 00:12:08,867
THEY ADAPT AND WE'LL LOOK FOR 

310
00:12:08,867 --> 00:12:09,534
WHICH SYNAPSE WE SHOULD TARGET 

311
00:12:09,534 --> 00:12:10,035
FOR THE INTERVENTION.

312
00:12:10,035 --> 00:12:12,104
WE DID THIS BY IMPLANTING 

313
00:12:12,104 --> 00:12:13,205
ELECTRODES INTO THE BRAINS OF 

314
00:12:13,205 --> 00:12:15,774
MICE AND ONCE THEY RECOVER WE'RE

315
00:12:15,774 --> 00:12:17,742
ABLE TO RECORD ELECTRICAL 

316
00:12:17,742 --> 00:12:19,211
ACTIVITY FROM MANY BRAIN REGIONS

317
00:12:19,211 --> 00:12:24,449
AT THE SAME TIME.

318
00:12:24,449 --> 00:12:28,120
IN THIS ASSAY WE'LL LOOK AT THE 

319
00:12:28,120 --> 00:12:38,163
DORSAL HIPPOCAMPUS AND PRELIMBIC

320
00:12:38,163 --> 00:12:40,732
CORTEX AND OTHERS AND IT'S NOT A

321
00:12:40,732 --> 00:12:43,168
FUNCTIONAL RESONANCE IMAGING, 

322
00:12:43,168 --> 00:12:45,470
THE WHOLE BRAIN, BUT THE SURVEY 

323
00:12:45,470 --> 00:12:47,639
OF LOTS OF BRAIN REGIONS 

324
00:12:47,639 --> 00:12:50,041
INVOLVED IN STRESS COMPUTATION 

325
00:12:50,041 --> 00:12:51,810
THEN ASK WHICH SHOW CHANGES 

326
00:12:51,810 --> 00:12:54,179
BETWEEN THE FIRST DAY AND THE 

327
00:12:54,179 --> 00:12:58,183
SECOND DAY.

328
00:12:58,183 --> 00:13:02,187
SOW  -- SO WHEN WE DO THAT ONLY 

329
00:13:02,187 --> 00:13:06,691
TWO SHOW CHANGES IN RECORDING.

330
00:13:06,691 --> 00:13:08,493
THE MOUSE PREFRONTAL CORTEX AND 

331
00:13:08,493 --> 00:13:13,098
THE SECOND IS THE MEDIAL DORSAL 

332
00:13:13,098 --> 00:13:15,300
THALAMUS AND ONLY IDENTIFIED TWO

333
00:13:15,300 --> 00:13:16,735
BRAIN AREAS CODING DIFFERENTLY 

334
00:13:16,735 --> 00:13:18,703
AND THE OTHERS WERE CODING FINE 

335
00:13:18,703 --> 00:13:21,940
BETWEEN ONE AND TWO AND ONE IN 

336
00:13:21,940 --> 00:13:23,308
GRAY, DAY TWO IN RED.

337
00:13:23,308 --> 00:13:24,609
WE FOCUSSED ON THE 

338
00:13:24,609 --> 00:13:25,310
INTERCONNECTED BRAIN REGIONS FOR

339
00:13:25,310 --> 00:13:31,883
THE REST OF OUR STUDY.

340
00:13:31,883 --> 00:13:33,952
WE WANTED TO UNDERSTAND HOW THEY

341
00:13:33,952 --> 00:13:35,120
WERE HAPPENING BETWEEN THE 

342
00:13:35,120 --> 00:13:35,554
AREAS.

343
00:13:35,554 --> 00:13:37,656
WE SEARCHED THROUGH A BUNCH OF 

344
00:13:37,656 --> 00:13:40,592
WAYS THE BRAIN AREAS CAN 

345
00:13:40,592 --> 00:13:42,093
COMMUNICATE OR SIN ROW 

346
00:13:42,093 --> 00:13:43,228
SYNCHRONIZE AND FOUND THIS 

347
00:13:43,228 --> 00:13:45,897
UNIQUE PATTERN BETWEEN THE 

348
00:13:45,897 --> 00:13:48,333
CORTEX AND MEDIAL DORSAL 

349
00:13:48,333 --> 00:13:49,234
THALAMUS.

350
00:13:49,234 --> 00:13:51,803
THE PATTERN WAS CALLED CROSS 

351
00:13:51,803 --> 00:13:52,237
FREQUENCY COUPLING.

352
00:13:52,237 --> 00:13:55,307
AND SO YOU CAN THINK OF THINGS 

353
00:13:55,307 --> 00:14:01,079
BEING SYNCHRONIZED LIKE THIS, 

354
00:14:01,079 --> 00:14:06,384
LIKE THIS OR ACROSS FREQUENCIES 

355
00:14:06,384 --> 00:14:12,157
LIKE THIS.

356
00:14:12,157 --> 00:14:15,227
SO WE TEST THE PATTERN AND FOUND

357
00:14:15,227 --> 00:14:17,462
THIS THE BRAIN THE LOWER 

358
00:14:17,462 --> 00:14:18,163
FREQUENCY AND RED HIGHER 

359
00:14:18,163 --> 00:14:20,665
FREQUENCY AND THE AMPLITUDE 

360
00:14:20,665 --> 00:14:21,666
WAVES OF THE RED OSCILLATION 

361
00:14:21,666 --> 00:14:23,235
TEND TO HAPPEN AT THE PART OF 

362
00:14:23,235 --> 00:14:25,937
THE CYCLE OF THE GREEN 

363
00:14:25,937 --> 00:14:26,238
OSCILLATION.

364
00:14:26,238 --> 00:14:27,372
THAT'S CALLED CROSS FREQUENCY 

365
00:14:27,372 --> 00:14:27,639
COUPLING.

366
00:14:27,639 --> 00:14:29,441
HERE'S ANOTHER WAY OF LOOKING AT

367
00:14:29,441 --> 00:14:30,542
THAT TYPE OF PLOT.

368
00:14:30,542 --> 00:14:32,410
YOU CAN SEE ON THE Y AXIS WE 

369
00:14:32,410 --> 00:14:33,812
HAVE THE AMPLITUDE OF THE 

370
00:14:33,812 --> 00:14:34,613
OSCILLATION OF THE RED.

371
00:14:34,613 --> 00:14:36,548
ON THE X AXIS WE HAVE THE PHASE 

372
00:14:36,548 --> 00:14:38,650
OF THE OSCILLATION OF THE BRAIN.

373
00:14:38,650 --> 00:14:40,619
BLUE MEANS NO COUPLING AND RED 

374
00:14:40,619 --> 00:14:41,653
MEANS HIGH COUPLING.

375
00:14:41,653 --> 00:14:45,490
WE SEE COUPLING BETWEEN THE TWO 

376
00:14:45,490 --> 00:14:52,063
BANDS OF FREQUENCYIES THE CORTE 

377
00:14:52,063 --> 00:14:58,169
IN 30s TO 60s AND THE MEDIAL 

378
00:14:58,169 --> 00:14:59,738
DORSAL CORTEX AND IT GETS 

379
00:14:59,738 --> 00:15:03,408
STRONGER ON THE SECOND DAY THEN 

380
00:15:03,408 --> 00:15:05,810
THE FIRST DAY.

381
00:15:05,810 --> 00:15:08,113
AS AN ENGINEER WE HAD A 

382
00:15:08,113 --> 00:15:08,380
QUESTION.

383
00:15:08,380 --> 00:15:10,181
WE THOUGHT THIS IS THE STRESS 

384
00:15:10,181 --> 00:15:12,584
CHANGE THAT MATTERS AND IF SO, 

385
00:15:12,584 --> 00:15:14,853
WE WANT TO FIGURE OUT HOW TO GET

386
00:15:14,853 --> 00:15:17,255
RID OF THIS AND MAKE THE ANIMALS

387
00:15:17,255 --> 00:15:19,257
MORE RESILIENT TO STRESSORS.

388
00:15:19,257 --> 00:15:22,160
ON THE OTHER HAND, MAYBE THE 

389
00:15:22,160 --> 00:15:23,528
SIGNATURE IS COMPENSATORY AND 

390
00:15:23,528 --> 00:15:25,797
THIS IS WHAT WE HAVE TO THINK 

391
00:15:25,797 --> 00:15:27,098
ABOUT AS ENGINEERS.

392
00:15:27,098 --> 00:15:29,200
IF I RUN UPSTAIRS MY HEART RUNS 

393
00:15:29,200 --> 00:15:30,669
FASTER BECAUSE IT'S A 

394
00:15:30,669 --> 00:15:31,169
COMPENSATION.

395
00:15:31,169 --> 00:15:35,373
SO IF WE HAVE COMPENSATION WHAT 

396
00:15:35,373 --> 00:15:38,576
I DON'T WANT IS MY HEART TO NOT 

397
00:15:38,576 --> 00:15:40,912
BEAT FASTER BECAUSE I WON'T BE 

398
00:15:40,912 --> 00:15:43,715
ABLE TO RUN BECAUSE THE HEART IS

399
00:15:43,715 --> 00:15:49,020
COMPENSATING TO KEEP MUSCLES 

400
00:15:49,020 --> 00:15:50,622
OXYGEN EI

401
00:15:50,622 --> 00:15:50,922
OXYGENATED.

402
00:15:50,922 --> 00:15:53,291
SO WHAT WE'LL DO IS TO FIGURE 

403
00:15:53,291 --> 00:15:55,827
OUT WE'LL PLAY THE SIGNATURE 

404
00:15:55,827 --> 00:15:57,329
BACK IN THE BRAIN.

405
00:15:57,329 --> 00:16:00,532
WE'RE GOING TO READ INFORMATION 

406
00:16:00,532 --> 00:16:03,268
AND IF IT'S PRIMARY IT WILL MAKE

407
00:16:03,268 --> 00:16:05,837
ME ANIMAL'S BEHAVIOR WORSE AND 

408
00:16:05,837 --> 00:16:07,205
IF COMPENSATORY IT WILL MAKE IT 

409
00:16:07,205 --> 00:16:07,439
BETTER.

410
00:16:07,439 --> 00:16:10,542
YOU SEE THE DATA ON THE LEFT.

411
00:16:10,542 --> 00:16:12,410
ANIMALS ON THE ASSAY, BLUE LIGHT

412
00:16:12,410 --> 00:16:13,311
IS OUR EXPERIMENTAL GROUP, 

413
00:16:13,311 --> 00:16:14,746
YELLOW IS OUR CONTROL.

414
00:16:14,746 --> 00:16:17,916
YOU CAN SEE THE BLUE GROUP IS 

415
00:16:17,916 --> 00:16:18,783
LESS IMMOBILE.

416
00:16:18,783 --> 00:16:20,952
PLANTING A SIGNATURE IN THEIR 

417
00:16:20,952 --> 00:16:24,556
BRAIN REVERSED THE PHENOTYPE.

418
00:16:24,556 --> 00:16:26,157
IN OTHER WORDS, IT'S A 

419
00:16:26,157 --> 00:16:26,658
COMPENSATORY SIGNATURE.

420
00:16:26,658 --> 00:16:28,727
IT'S NOT PRIMARY.

421
00:16:28,727 --> 00:16:30,095
SO BY PLAYING THIS COMPENSATORY 

422
00:16:30,095 --> 00:16:34,165
END WE INCREASE THE ANIMAL'S 

423
00:16:34,165 --> 00:16:35,166
REACHES TO AN EXTERNAL STRESSOR.

424
00:16:35,166 --> 00:16:36,201
IN OTHER WORDS, STRENGTHENING 

425
00:16:36,201 --> 00:16:36,701
THE PATHWAY.

426
00:16:36,701 --> 00:16:38,436
WE DID A SERIES OF CONTROLS 

427
00:16:38,436 --> 00:16:39,904
WHICH WE ALSO THOUGHT WERE 

428
00:16:39,904 --> 00:16:41,806
REALLY IMPORTANT AND THESE WERE 

429
00:16:41,806 --> 00:16:42,173
INSTRUCTIVE.

430
00:16:42,173 --> 00:16:45,443
YOU CAN SEE ON THE RIGHT WE'RE 

431
00:16:45,443 --> 00:16:47,579
BASICALLY STIMULATING TIME TO 

432
00:16:47,579 --> 00:16:49,314
THE OSCILLATION IN THE CORTEX, 

433
00:16:49,314 --> 00:16:52,283
IN OTHER WORDS, WE'RE DOING OUR 

434
00:16:52,283 --> 00:16:52,751
BYPASS.

435
00:16:52,751 --> 00:16:55,053
FOR THE FIRST CONTROL WE SAID 

436
00:16:55,053 --> 00:16:56,888
MAYBE IT'S BECAUSE WE'RE 

437
00:16:56,888 --> 00:16:57,422
STIMULATING THALAMUS.

438
00:16:57,422 --> 00:16:59,224
LET'S TAKE THE SAME NUMBER OF 

439
00:16:59,224 --> 00:17:01,025
PULSES BUT STIMULATE IN THE SAME

440
00:17:01,025 --> 00:17:02,727
WAY THAT ISN'T RESTORING THE 

441
00:17:02,727 --> 00:17:03,895
TIME IN THE CIRCUIT.

442
00:17:03,895 --> 00:17:05,263
WE'LL RESTORE A NORMAL PATTERN 

443
00:17:05,263 --> 00:17:06,998
PEOPLE USE ALL THE TIME IN THE 

444
00:17:06,998 --> 00:17:07,999
ANIMAL RESEARCH LITERATURE, SAME

445
00:17:07,999 --> 00:17:10,835
NUMBER OF LIGHT PULSES AND MADE 

446
00:17:10,835 --> 00:17:12,504
THE ANIMALS BEHAVIOR WORSE.

447
00:17:12,504 --> 00:17:14,038
THE FIRST MADE IT BETTER, THE 

448
00:17:14,038 --> 00:17:15,140
SECOND MADE IT WORSE.

449
00:17:15,140 --> 00:17:17,142
IT'S NOT JUST THE CELLS.

450
00:17:17,142 --> 00:17:18,643
THEN WE THOUGHT MAYBE IT'S THE 

451
00:17:18,643 --> 00:17:20,178
BURST OF THREE THAT ARE 

452
00:17:20,178 --> 00:17:20,445
IMPORTANT.

453
00:17:20,445 --> 00:17:21,880
SO WE STIMULATED WITH THE BURST 

454
00:17:21,880 --> 00:17:23,348
OF THREE AND GOT A PATTERN THAT 

455
00:17:23,348 --> 00:17:24,382
LOOKED LIKE THIS.

456
00:17:24,382 --> 00:17:25,483
THE BEHAVIOR DIDN'T CHANGE AT 

457
00:17:25,483 --> 00:17:25,650
ALL.

458
00:17:25,650 --> 00:17:27,652
WE THINK WHAT'S HAPPENING IS 

459
00:17:27,652 --> 00:17:30,088
IT'S AN ISSUE THAT ENGINEERS CAN

460
00:17:30,088 --> 00:17:31,589
APPRECIATE CALLED SIGNAL TO 

461
00:17:31,589 --> 00:17:31,856
NOISE.

462
00:17:31,856 --> 00:17:33,958
SO IN THE FIRST CASE, YOU TIME 

463
00:17:33,958 --> 00:17:36,995
THE SIGNAL CORRECTLY, YOU'VE 

464
00:17:36,995 --> 00:17:39,097
INCREASED THE SIGNAL.

465
00:17:39,097 --> 00:17:42,434
IN THE SECOND CASE YOU TIME IT 

466
00:17:42,434 --> 00:17:43,067
INCORRECTLY YOU INCREASE THE 

467
00:17:43,067 --> 00:17:45,870
NOISE AND SOME PULSES ARE AT THE

468
00:17:45,870 --> 00:17:47,372
RIGHT PHASE OF THE OSCILLATION 

469
00:17:47,372 --> 00:17:49,240
AND YOU INCREASE THE SIGNAL AND 

470
00:17:49,240 --> 00:17:53,812
THE NOISE AND NOTHING HAPPENS.

471
00:17:53,812 --> 00:17:59,517
IF WE WANT TO THINK OF DOING THE

472
00:17:59,517 --> 00:18:00,652
SYNAPTIC BYPASS WE NEED IT TO 

473
00:18:00,652 --> 00:18:01,586
READ AND PLAY THE INFORMATION 

474
00:18:01,586 --> 00:18:04,022
BACK IN WITH THE RIGHT TIMING.

475
00:18:04,022 --> 00:18:06,591
SO SO, THIS WAS GOING TO BE THE 

476
00:18:06,591 --> 00:18:07,058
SOLUTION.

477
00:18:07,058 --> 00:18:08,426
I SET OUT TO SOLVE A MAJOR 

478
00:18:08,426 --> 00:18:09,661
PROBLEM AND WE WERE EXCITED 

479
00:18:09,661 --> 00:18:11,796
BECAUSE WE FINISHED AND FIGURED 

480
00:18:11,796 --> 00:18:13,064
OUT THE SOLUTION TO THE MAJOR 

481
00:18:13,064 --> 00:18:14,866
PROBLEM THAT WE WERE TRYING TO 

482
00:18:14,866 --> 00:18:16,301
SOLVE.

483
00:18:16,301 --> 00:18:19,304
AND I WAS SO EXCITED THAT I WENT

484
00:18:19,304 --> 00:18:22,440
BACK TO MY HOME, HOME.

485
00:18:22,440 --> 00:18:25,210
MY FAMILY IS FROM GHANA AND WEST

486
00:18:25,210 --> 00:18:27,245
AFRICA AND MY MOTIVATION FOR 

487
00:18:27,245 --> 00:18:31,049
THIS WORK I DO, THE BOTTOM ROW 

488
00:18:31,049 --> 00:18:33,184
IS MY MOM AND HER SIBLINGS AND 

489
00:18:33,184 --> 00:18:38,156
FOUR OF FIVE CARRIES A MAJOR 

490
00:18:38,156 --> 00:18:40,492
PSYCHIATRIC DIAGNOSIS WHETHER A 

491
00:18:40,492 --> 00:18:42,894
BIPOLAR DISORDER OR DEPRESSION 

492
00:18:42,894 --> 00:18:44,929
OR PSYCHIATRIC DISORDER.

493
00:18:44,929 --> 00:18:46,197
IT'S NOT CURIOSITY IT'S LOVE FOR

494
00:18:46,197 --> 00:18:47,932
MY FAMILY MEMBERS AND WANTED TO 

495
00:18:47,932 --> 00:18:49,100
HEAL THEM AND HEAL THE NEXT 

496
00:18:49,100 --> 00:18:51,436
GENERATION OF MY FAMILY.

497
00:18:51,436 --> 00:18:54,072
AND THE OPEN CHAIR, THERE'S MY 

498
00:18:54,072 --> 00:18:55,874
UNCLE WITH BIPOLAR DISORDER AND 

499
00:18:55,874 --> 00:18:59,410
THIS IS A PICTURE OF MY 

500
00:18:59,410 --> 00:19:00,378
GRANDMOTHER'S FUNERAL AND THE 

501
00:19:00,378 --> 00:19:02,680
STRESS CAUSED HIM TO BE UNABLE 

502
00:19:02,680 --> 00:19:03,648
TO COMPENSATE AND WASN'T ABLE TO

503
00:19:03,648 --> 00:19:07,118
MAKE IT AND THE REST OF THE 

504
00:19:07,118 --> 00:19:08,453
CONVERSATION WILL BE FROM 

505
00:19:08,453 --> 00:19:10,188
TALKING TO HIM AND I SHOWED HIM 

506
00:19:10,188 --> 00:19:11,456
THE DESIGN AND EXPLAINING IT TO 

507
00:19:11,456 --> 00:19:14,025
HIM AND HE SAID THIS IS GOOD THE

508
00:19:14,025 --> 00:19:16,528
FAMILY'S SO PROUD OF YOU AND 

509
00:19:16,528 --> 00:19:19,330
FEEL THE FAMILY ILLNESS REACHED 

510
00:19:19,330 --> 00:19:21,533
YOU AND YOU'RE DOING SOMETHING 

511
00:19:21,533 --> 00:19:23,268
GOOD FOR THE WORLD AND TELL ME 

512
00:19:23,268 --> 00:19:26,137
HOW YOU THINK THIS IS GOING TO 

513
00:19:26,137 --> 00:19:27,539
GETTING TO THE THIRD WORLD.

514
00:19:27,539 --> 00:19:30,141
I NEVER THOUGHT OF WHAT I WAS 

515
00:19:30,141 --> 00:19:32,610
CREATING WOULD NEVER GOING TO 

516
00:19:32,610 --> 00:19:35,113
GET TO THE THIRD WORLD OR SCALE 

517
00:19:35,113 --> 00:19:36,981
AND WOULD ONLY REQUIRE 

518
00:19:36,981 --> 00:19:39,417
NEUROSURGEONS OF WHICH THERE'S 

519
00:19:39,417 --> 00:19:41,953
NOT ENOUGH AND THE GLOBAL 

520
00:19:41,953 --> 00:19:44,122
DISORDER OF SCHIZOPHRENIA AND 

521
00:19:44,122 --> 00:19:47,959
MENTAL ILLNESS SO LARGE UNLESS 

522
00:19:47,959 --> 00:19:50,161
IT'S SOMETHING THAT'S SCALABLE 

523
00:19:50,161 --> 00:19:53,064
IT WON'T GET TO THE ILLNESS AND 

524
00:19:53,064 --> 00:19:56,834
THE REMAINDER OF MY TALK WILL BE

525
00:19:56,834 --> 00:20:01,239
ON HOW WE THINK OF MAKING THE 

526
00:20:01,239 --> 00:20:02,340
BYPASS DEVICE SCALABLE.

527
00:20:02,340 --> 00:20:05,944
NOW I'VE RUN OUT OF ALL MY 

528
00:20:05,944 --> 00:20:07,312
ENGINEERING AND NEUROSCIENCE AND

529
00:20:07,312 --> 00:20:08,746
HERE BECOMES OUR JOURNEY THROUGH

530
00:20:08,746 --> 00:20:10,014
DIFFERENT FIELDS TO TRY TO SOLVE

531
00:20:10,014 --> 00:20:12,984
THIS PROBLEM.

532
00:20:12,984 --> 00:20:17,088
SO SO AT THE TIME I WRESTLED 

533
00:20:17,088 --> 00:20:18,156
WITH THE QUESTION OF WHAT IS 

534
00:20:18,156 --> 00:20:18,656
SCALABLE.

535
00:20:18,656 --> 00:20:19,757
I WILL THOUGHT OF TWO THINGS 

536
00:20:19,757 --> 00:20:21,259
THAT SCALED.

537
00:20:21,259 --> 00:20:23,728
THE FIRST IS ANTIBIOTICS AND THE

538
00:20:23,728 --> 00:20:25,330
SECOND IS VACCINES.

539
00:20:25,330 --> 00:20:26,397
IN PRINCIPLE WHAT ANTIBIOTICS DO

540
00:20:26,397 --> 00:20:29,734
IS THEY TARGET THINGS THAT ARE 

541
00:20:29,734 --> 00:20:35,873
NOT SELF, TO MAKE SELF MORE 

542
00:20:35,873 --> 00:20:37,208
SUSTAINABLE OR RESILIENT IN AN 

543
00:20:37,208 --> 00:20:40,278
ENVIRONMENT AND I SAID WELL, OUR

544
00:20:40,278 --> 00:20:42,146
ILLNESS IS OF SELF.

545
00:20:42,146 --> 00:20:43,848
THAT CONCEPT WITH AN ANTIBIOTIC 

546
00:20:43,848 --> 00:20:44,849
DOESN'T MAKE SENSE.

547
00:20:44,849 --> 00:20:47,318
ON THE OTHER HAND WHAT A VACCINE

548
00:20:47,318 --> 00:20:50,555
DOES IS TARGET SELF TO MAKE SELF

549
00:20:50,555 --> 00:20:51,222
MORE RESILIENT IN THE 

550
00:20:51,222 --> 00:20:53,358
ENVIRONMENT.

551
00:20:53,358 --> 00:20:54,993
AND I LOVE THE CONCEPT OF 

552
00:20:54,993 --> 00:20:57,261
FIGURING OUT HOW TO MAKE SELF 

553
00:20:57,261 --> 00:20:58,162
MORE RESILIENT TO THINGS IN THE 

554
00:20:58,162 --> 00:20:58,496
ENVIRONMENT.

555
00:20:58,496 --> 00:21:00,965
SO WE CAME UP WITH THIS CONCEPT 

556
00:21:00,965 --> 00:21:03,067
OF WELL, WHAT IF WE COULD MAKE A

557
00:21:03,067 --> 00:21:06,738
VACCINE FOR MENTAL ILLNESS AND 

558
00:21:06,738 --> 00:21:07,405
SKETCHED THIS DOWN WHICH MADE NO

559
00:21:07,405 --> 00:21:10,074
SENSE AT ALL AT THE TIME.

560
00:21:10,074 --> 00:21:12,844
BUT I WAS INVITED TO JOIN THE 

561
00:21:12,844 --> 00:21:14,045
WORKING GROUP FOR THE BRAIN 

562
00:21:14,045 --> 00:21:14,345
INITIATIVE 

563
00:21:14,345 --> 00:21:16,080
THEY WERE IN THE SECOND HALF.

564
00:21:16,080 --> 00:21:18,349
THE GOAL WAS TO UNDERSTAND THE 

565
00:21:18,349 --> 00:21:20,351
HUMAN BRAIN TO TREAT DISEASES 

566
00:21:20,351 --> 00:21:22,153
LIKE DEPRESSION AND BIOPSY 

567
00:21:22,153 --> 00:21:29,360
DISORDER A-- BIPOLAR DISORDER.

568
00:21:29,360 --> 00:21:32,830
THERE WAS THE HUMAN CELL ATLAS.

569
00:21:32,830 --> 00:21:34,932
THEY WOULD TAKE THE BRAIN AND 

570
00:21:34,932 --> 00:21:37,435
BILLIONS OF CELLS AND SEQUENCE 

571
00:21:37,435 --> 00:21:38,770
THEM AND FIND THE GENE 

572
00:21:38,770 --> 00:21:39,437
EXPRESSION SEQUENCE FOR EACH OF 

573
00:21:39,437 --> 00:21:41,105
THE BRAIN CELLS TO TARGET IT.

574
00:21:41,105 --> 00:21:43,441
THESE ARE SORT OF THE SAME 

575
00:21:43,441 --> 00:21:45,410
PATTERNS WE USED TO TARGET BRAIN

576
00:21:45,410 --> 00:21:46,844
CELLS IN MICE IN THE LAB.

577
00:21:46,844 --> 00:21:48,246
YOU LEARN THESE ABOUT HUMANS.

578
00:21:48,246 --> 00:21:50,148
THAT WAS THE FIRST TECHNOLOGY.

579
00:21:50,148 --> 00:21:54,018
THE SECOND TECHNOLOGY THESE WERE

580
00:21:54,018 --> 00:21:56,254
TECHNOLOGIES DONE BY MY 

581
00:21:56,254 --> 00:22:00,625
COLLEAGUE AND THERE ARE AAVs 

582
00:22:00,625 --> 00:22:06,597
WHICH CROSS THE BLOOD BRAIN 

583
00:22:06,597 --> 00:22:11,002
BARRIER AND YOU AND A SYSTEM 

584
00:22:11,002 --> 00:22:13,705
LIKE THIS WITH HUMAN BRAIN CELL 

585
00:22:13,705 --> 00:22:16,240
ATLAS AND YOU CAN DELIVER 

586
00:22:16,240 --> 00:22:17,408
PROTEINS TO SPECIFIC CELLS IN 

587
00:22:17,408 --> 00:22:18,176
THE BRAIN.

588
00:22:18,176 --> 00:22:20,912
AND ONCE I LEARNED ABOUT THE 

589
00:22:20,912 --> 00:22:21,913
TRANSFORMATIVE TECHNOLOGIES THE 

590
00:22:21,913 --> 00:22:24,682
FIELD WAS WORKING ON CREATING, I

591
00:22:24,682 --> 00:22:27,118
REALIZES THE PROBLEM I HAD TO 

592
00:22:27,118 --> 00:22:28,853
SOLVE WAS TAKE THE COMPUTERIZED 

593
00:22:28,853 --> 00:22:29,687
CLOSED-LOOP STIMULATION DEVICE 

594
00:22:29,687 --> 00:22:31,255
AND TURN IT INTO PROTEINS.

595
00:22:31,255 --> 00:22:34,125
IF I CAN TURN IT INTO PROTEINS 

596
00:22:34,125 --> 00:22:36,427
WE CAN DELIVER IT TO BRAIN CELLS

597
00:22:36,427 --> 00:22:37,261
PAIRS OF INTEREST.

598
00:22:37,261 --> 00:22:39,497
THAT BECAME THE CHALLENGE WE 

599
00:22:39,497 --> 00:22:42,166
NEEDED TO SOLVE IN ORDER TO MOVE

600
00:22:42,166 --> 00:22:43,434
THIS FORWARD.

601
00:22:43,434 --> 00:22:44,869
IT TURNS OUT IT WASN'T FAR 

602
00:22:44,869 --> 00:22:45,303
FETCHED.

603
00:22:45,303 --> 00:22:47,739
AS I SAID WENT TO MEDICAL SCHOOL

604
00:22:47,739 --> 00:22:50,174
AND I SPENT A LOT OF TIME 

605
00:22:50,174 --> 00:22:52,376
THINKING ABOUT WAYS THAT BRAIN 

606
00:22:52,376 --> 00:22:54,312
CELLS AND OTHER CELL TYPES 

607
00:22:54,312 --> 00:22:55,747
TRANSFERRED INFORMATION FROM ONE

608
00:22:55,747 --> 00:22:56,781
CELL TO ANOTHER.

609
00:22:56,781 --> 00:22:58,816
ONE OF THE SYSTEMS USED TO 

610
00:22:58,816 --> 00:22:59,717
TRANSFER ELECTRICITY IN THE 

611
00:22:59,717 --> 00:23:01,819
HEART ARE WHAT WE CALL THROUGH 

612
00:23:01,819 --> 00:23:04,589
ELECTRICAL SYNAPSES AND THEY'RE 

613
00:23:04,589 --> 00:23:06,824
BASICALLY CHANNELS THAT CONNECT 

614
00:23:06,824 --> 00:23:09,026
TO BRAIN CELLS AND ALSO CALLED 

615
00:23:09,026 --> 00:23:10,561
GAP JUNCTIONS AND ALLOW IONS TO 

616
00:23:10,561 --> 00:23:12,263
FLOW FROM ONE CELL TO ANOTHER.

617
00:23:12,263 --> 00:23:15,967
IT'S WHY YOUR HEART IS SO 

618
00:23:15,967 --> 00:23:17,268
SYNCHRONIZED THEY CAN MOVE 

619
00:23:17,268 --> 00:23:21,305
ELECTRICITY FROM ONE CELL TO 

620
00:23:21,305 --> 00:23:22,173
ANOTHER.

621
00:23:22,173 --> 00:23:24,242
ABOUT WHAT IT'S DOING IS 

622
00:23:24,242 --> 00:23:26,944
TRANSFERRING ELECTRICAL IONS 

623
00:23:26,944 --> 00:23:29,480
FROM ONE TO ANOTHER AND THROUGH 

624
00:23:29,480 --> 00:23:31,449
CONNEXINS AND THEY COME TOGETHER

625
00:23:31,449 --> 00:23:36,287
TO FORM A GAP JUNCTION.

626
00:23:36,287 --> 00:23:38,623
THEY ARE EXPRESSED IN MOST HUMAN

627
00:23:38,623 --> 00:23:42,160
TISSUES AND BECAUSE THE IONS CAN

628
00:23:42,160 --> 00:23:48,800
MOVE BACK AND FORTH THEY'RE BYE 

629
00:23:48,800 --> 00:23:59,310
DIRECTIONAL AND SOME USED C. 

630
00:24:03,014 --> 00:24:08,019
ELEGANS AND YOU CAN PUT THESE 

631
00:24:08,019 --> 00:24:11,322
CONNEX INS IN SPECIFIC CELLS IN 

632
00:24:11,322 --> 00:24:17,962
A C. ELEGANS AND IT MOVED 

633
00:24:17,962 --> 00:24:19,463
ELECTRICAL ACTIVITY FROM ONE TO 

634
00:24:19,463 --> 00:24:21,499
THE NEXT AND CHANGED THE 

635
00:24:21,499 --> 00:24:21,766
BEHAVIOR.

636
00:24:21,766 --> 00:24:25,469
YOU COULD BASICALLY REWIRE OR 

637
00:24:25,469 --> 00:24:35,980
CREATE A BYPASS IN C. ELEGANS.

638
00:24:37,148 --> 00:24:39,851
AND THEY HAVE ONE CELL TYPE.

639
00:24:39,851 --> 00:24:41,485
THAT'S NOT THE SAME WITH HUMANS.

640
00:24:41,485 --> 00:24:45,256
IMAGINE WE WANTED TO DO THIS AND

641
00:24:45,256 --> 00:24:48,025
THE GAP JUNCTIONS ARE PINK HERE 

642
00:24:48,025 --> 00:24:52,630
CONNECTING THE IONS TO FLOW TO 

643
00:24:52,630 --> 00:24:53,297
CREATE OUR BYPASS.

644
00:24:53,297 --> 00:24:54,632
SAY THIS IS WHAT WE WERE TRYING 

645
00:24:54,632 --> 00:24:56,467
TO ACHIEVE.

646
00:24:56,467 --> 00:24:58,202
THE FIRST PROBLEM YOU'D RUN INTO

647
00:24:58,202 --> 00:25:01,505
BECAUSE WE HAVE MANY BRAIN CELL 

648
00:25:01,505 --> 00:25:05,910
TYPES OF EACH, YOU'D GET THE GAP

649
00:25:05,910 --> 00:25:08,813
JUNCTIONS EXPRESSED THERE.

650
00:25:08,813 --> 00:25:12,083
AS YOU HAVE THE SIGNAL UP STREAM

651
00:25:12,083 --> 00:25:14,151
WAS SCRAMBLED BECAUSE IT GOES 

652
00:25:14,151 --> 00:25:17,889
SIDE WAYS INSTEAD OF UP AND 

653
00:25:17,889 --> 00:25:18,155
DOWN.

654
00:25:18,155 --> 00:25:19,156
PROBLEM ONE.

655
00:25:19,156 --> 00:25:22,159
THE GAP JUNCTION ARE CORES SO 

656
00:25:22,159 --> 00:25:26,163
ELECTRICITY CAN FLOW IN BOTH 

657
00:25:26,163 --> 00:25:27,331
DIRECTIONS AND GET SCRAMBLING 

658
00:25:27,331 --> 00:25:29,166
LIKE THIS LIKE WHEN YOU'RE 

659
00:25:29,166 --> 00:25:30,201
TRYING TO TALK TO SOMEBODY AND 

660
00:25:30,201 --> 00:25:32,036
THEY'RE YELLING AT YOU IS LIKE 

661
00:25:32,036 --> 00:25:33,237
WHAT YOU GET.

662
00:25:33,237 --> 00:25:36,207
I LIKE TO GIVE THINGS A TRY AND 

663
00:25:36,207 --> 00:25:40,111
WHAT IF WE TRY THEM OUT AND PUT 

664
00:25:40,111 --> 00:25:42,146
THEM IN MICE AND SEE WHAT 

665
00:25:42,146 --> 00:25:43,814
HAPP

666
00:25:43,814 --> 00:25:44,048
HAPPENS.

667
00:25:44,048 --> 00:25:53,157
WE MADE THE GAP JUNCTIONS AND 

668
00:25:53,157 --> 00:25:59,864
PUT THEM IN AND WE INJECTED THEM

669
00:25:59,864 --> 00:26:01,866
WITH TWO DOSES AND MEAN DOSE IN 

670
00:26:01,866 --> 00:26:03,334
THE MIDDLE AND FOUR AND FIVE 

671
00:26:03,334 --> 00:26:05,636
DAYS LATER THE ANIMALS STARTED 

672
00:26:05,636 --> 00:26:06,170
TO DIE.

673
00:26:06,170 --> 00:26:07,305
MY GRADUATE STUDENT SAID THERE'S

674
00:26:07,305 --> 00:26:08,806
NO PHENOTYPE.

675
00:26:08,806 --> 00:26:09,774
I SAID THERE'S NO PHENOTYPE IN 

676
00:26:09,774 --> 00:26:13,377
THE WORLD WHEN YOU THINK OF 

677
00:26:13,377 --> 00:26:13,678
TRANSLATION.

678
00:26:13,678 --> 00:26:14,679
THERE'S NOTHING MORE IMPORTANT 

679
00:26:14,679 --> 00:26:18,149
THAN THE ANIMALS DON'T SURVIVE.

680
00:26:18,149 --> 00:26:20,117
IT'S A CLEAR PHENOTYPE.

681
00:26:20,117 --> 00:26:23,354
THE HIPPOCAMPUS SEIZED AND DIED.

682
00:26:23,354 --> 00:26:24,555
IT'S THE PROBLEM ON THE LEFT.

683
00:26:24,555 --> 00:26:26,924
INFORMATION MOVING FORWARD, 

684
00:26:26,924 --> 00:26:28,726
BACKWARDS AND SIDE WAYS.

685
00:26:28,726 --> 00:26:31,629
SO THEY HAD A CLEAR PHENOTYPE.

686
00:26:31,629 --> 00:26:38,002
SO SO CONNEX INS STICK TOGETHER 

687
00:26:38,002 --> 00:26:39,770
AND LET INFORMATION FLOW.

688
00:26:39,770 --> 00:26:41,672
I SAID WHAT IF CHANGE WHAT WE 

689
00:26:41,672 --> 00:26:43,140
WERE DOING CONCEPTUALLY AND 

690
00:26:43,140 --> 00:26:45,276
TURNED THEM INTO MAGNETS.

691
00:26:45,276 --> 00:26:48,279
INSTEAD OF FUNCTIONING LIKE 

692
00:26:48,279 --> 00:26:52,850
STICKERS THEY'RE LIKE MAGNETS 

693
00:26:52,850 --> 00:26:54,151
AND THERE'S A GREEN CONNECTION 

694
00:26:54,151 --> 00:26:55,586
AND RIGHT CONNECTION.

695
00:26:55,586 --> 00:26:59,690
IMAGINE ONE'S A POSITIVE END AND

696
00:26:59,690 --> 00:27:04,562
ONE'S POSITIVE AND THE POSITIVE 

697
00:27:04,562 --> 00:27:06,163
THOUGH IT'S PRESYNAPTIC CELL 

698
00:27:06,163 --> 00:27:07,598
TYPES BUT THE POSITIVE AND 

699
00:27:07,598 --> 00:27:09,100
NEGATIVE CAN COME TOGETHER.

700
00:27:09,100 --> 00:27:13,404
AND JUST FOR KICKS, WHAT IF WE 

701
00:27:13,404 --> 00:27:15,272
CAN MAGICALLY FLOW ONE DIRECTION

702
00:27:15,272 --> 00:27:16,607
OVER ANOTHER?

703
00:27:16,607 --> 00:27:18,075
THIS WAS CONCEPTUALLY WHAT WE 

704
00:27:18,075 --> 00:27:18,943
ADVISORY OF WERE TRYING TO 

705
00:27:18,943 --> 00:27:19,343
ACHIEVE.

706
00:27:19,343 --> 00:27:21,345
I PULLED TOGETHER WHAT I LIKE TO

707
00:27:21,345 --> 00:27:22,213
CALL MY DREAM TEAM.

708
00:27:22,213 --> 00:27:24,181
I CALL THEM THAT BECAUSE IT'S A 

709
00:27:24,181 --> 00:27:29,754
GROUP OF UNDERUNDERGRADSS  -- 

710
00:27:30,087 --> 00:27:31,489
UNDERGRADS THAT HAD NO IDEA THIS

711
00:27:31,489 --> 00:27:34,425
COULD WORK AND START WITH THE 

712
00:27:34,425 --> 00:27:35,893
MAGICAL BELIEF THE ANSWER'S OUT 

713
00:27:35,893 --> 00:27:39,397
THERE AND SEARCHED THROUGH CON 

714
00:27:39,397 --> 00:27:44,602
EX  IN  -- CONNEXINS PROTEINS A 

715
00:27:44,602 --> 00:27:48,839
CAME UP WITH THIS PAIR IN 

716
00:27:48,839 --> 00:27:52,643
GOLDFISH AND THE CONNEXINS ARE 

717
00:27:52,643 --> 00:27:55,546
LABELLED BY THEIR WEIGHT AND THE

718
00:27:55,546 --> 00:27:56,580
PAIR HAD A REALLY INTERESTING 

719
00:27:56,580 --> 00:27:57,882
SET OF FEATURES.

720
00:27:57,882 --> 00:28:00,351
FIRST OF ALL IT'S TWO THAT CAN 

721
00:28:00,351 --> 00:28:01,685
COME TOGETHER.

722
00:28:01,685 --> 00:28:06,157
SO MAYBE IT WILL GET US OUR 

723
00:28:06,157 --> 00:28:08,092
FWREEN AND RED.

724
00:28:08,092 --> 00:28:09,827
THEY'RE IN NATURE AND THAT'S 

725
00:28:09,827 --> 00:28:10,027
COOL.

726
00:28:10,027 --> 00:28:13,097
THEY TEND TO RECTIFY AND CURRENT

727
00:28:13,097 --> 00:28:15,266
FLOWS IN MORE IN ONE DIRECTION 

728
00:28:15,266 --> 00:28:16,667
THAN THE OTHER AND WONDERFULLY 

729
00:28:16,667 --> 00:28:18,769
ENOUGH THEY TEND TO CONDUCT 

730
00:28:18,769 --> 00:28:21,839
CURRENT AT EXACTLY THE 

731
00:28:21,839 --> 00:28:23,040
PHYSIOLOGICAL RANGE YOU'D WANT 

732
00:28:23,040 --> 00:28:23,974
FOR HUMAN NEURONS.

733
00:28:23,974 --> 00:28:25,042
WE SELECT THE PAIR AND DECIDED 

734
00:28:25,042 --> 00:28:26,811
TO MOVE FORWARD WITH IT.

735
00:28:26,811 --> 00:28:28,312
THE PROBLEM WITH THIS PAIR IS 

736
00:28:28,312 --> 00:28:31,182
THAT IT DOES WHAT WE WANT IT TO 

737
00:28:31,182 --> 00:28:33,284
DO, IN OTHER WORDS, IT WORKS 

738
00:28:33,284 --> 00:28:36,487
LIKE A MAGNET BUT ALSO LIKE 

739
00:28:36,487 --> 00:28:36,754
STICKERS.

740
00:28:36,754 --> 00:28:41,759
THE 34.7 AND THE 35 WILL DOCK 

741
00:28:41,759 --> 00:28:42,460
LIKE 35.

742
00:28:42,460 --> 00:28:46,197
SO WE'VE NOW GONE FURTHER AND 

743
00:28:46,197 --> 00:28:52,970
TOUCHED C. ELEGANS A LITTLE BIT 

744
00:28:52,970 --> 00:28:58,876
AND THE DOCKING IS CONTROLLED BY

745
00:28:58,876 --> 00:29:01,612
RESIDUES ON THE EXTRA CELLULAR 

746
00:29:01,612 --> 00:29:04,415
LOOPS OF THE CONNEXIN PROTEINS.

747
00:29:04,415 --> 00:29:06,550
ALL THESE WORDS I CAN'T KNOW 

748
00:29:06,550 --> 00:29:10,054
WHAT THEY MEANT WHEN WE STARTED 

749
00:29:10,054 --> 00:29:10,621
DOWN THIS ADVENTURE.

750
00:29:10,621 --> 00:29:13,624
WE REALIZED WE COULD MUTATE THE 

751
00:29:13,624 --> 00:29:14,992
RESIDUES AND IF WE COULD DO THAT

752
00:29:14,992 --> 00:29:16,961
MAYBE WE CAN FIGURE OUT WHICH 

753
00:29:16,961 --> 00:29:18,662
ARE NEGATIVE AND POSITIVES IN 

754
00:29:18,662 --> 00:29:20,498
THE RIGHT COMBINATION AND 

755
00:29:20,498 --> 00:29:21,699
ESSENTIALLY CREATE A PAIR WHERE 

756
00:29:21,699 --> 00:29:23,167
THEY DON'T FUNCTION LIKE 

757
00:29:23,167 --> 00:29:24,668
STICKERS ANYMORE BUT CONTINUE TO

758
00:29:24,668 --> 00:29:25,436
FUNCTION LIKE MAGNET.

759
00:29:25,436 --> 00:29:27,471
SO THAT'S WHAT WE'LL TRY TO 

760
00:29:27,471 --> 00:29:27,705
ACHIEVE.

761
00:29:27,705 --> 00:29:30,040
AND I'M GOING TO FAST FORWARD 

762
00:29:30,040 --> 00:29:31,208
THROUGH THE NEXT SLIDE BECAUSE 

763
00:29:31,208 --> 00:29:33,444
THIS IS YEARS OF WORK BUT THE 

764
00:29:33,444 --> 00:29:36,013
WAY WE SOLVED IT WAS COME UP 

765
00:29:36,013 --> 00:29:37,615
WITH A NOVEL SCREENING ASSAY IN 

766
00:29:37,615 --> 00:29:38,649
THE LAB.

767
00:29:38,649 --> 00:29:41,785
I HIRED A BIO CHEMIST TO RAPIDLY

768
00:29:41,785 --> 00:29:44,455
SCREEN THE INTERACTION BETWEEN 

769
00:29:44,455 --> 00:29:46,857
CONNEXIN PROTEIN PAIRS.

770
00:29:46,857 --> 00:29:50,060
I HAD A COMPUTER SCIENCE MAJOR 

771
00:29:50,060 --> 00:29:54,165
JOIN MY LAB AND CREATED A 

772
00:29:54,165 --> 00:29:54,865
COMPUTATIONAL PROBLEMS AND 

773
00:29:54,865 --> 00:29:57,268
NEITHER COULD SOLVE ON THEIR OWN

774
00:29:57,268 --> 00:30:01,639
BUT THEY INNOVATED TOGETHER AND 

775
00:30:01,639 --> 00:30:05,042
IT ITERATED THROUGH AN IN VITRO 

776
00:30:05,042 --> 00:30:06,377
SCREEN AND CRACK THE CODE HOW 

777
00:30:06,377 --> 00:30:09,480
THE RESIDUES INTERACT TO CREATE 

778
00:30:09,480 --> 00:30:11,415
THE BINDING BETWEEN CONNEXIN 

779
00:30:11,415 --> 00:30:13,617
PROTEINS AND IT LOOKS LIKE THIS.

780
00:30:13,617 --> 00:30:14,185
THERE'S ESSENTIALLY FOUR 

781
00:30:14,185 --> 00:30:15,286
IMPORTANT RESIDUES AND THE 

782
00:30:15,286 --> 00:30:18,155
SECOND ONE FROM THE TOP ON EACH 

783
00:30:18,155 --> 00:30:20,558
SIDE INTERACTS WITH THREE ON THE

784
00:30:20,558 --> 00:30:22,159
OTHER SIDE ESSENTIALLY FORMING A

785
00:30:22,159 --> 00:30:23,060
CONNECTION MECHANISM.

786
00:30:23,060 --> 00:30:30,167
SO WHAT WE REALIZED WE COULD DO 

787
00:30:30,167 --> 00:30:34,171
IS SYSTEMATICALLY MUTATE THEM 

788
00:30:34,171 --> 00:30:36,507
AND 35 WE MADE ALMOST ALL 

789
00:30:36,507 --> 00:30:39,143
NEGATIVE AND THE MAGNET CONCEPT 

790
00:30:39,143 --> 00:30:40,344
OF BIOLOGY AND WE WERE 

791
00:30:40,344 --> 00:30:42,146
ULTIMATELY ABLE TO IDENTIFY A 

792
00:30:42,146 --> 00:30:47,484
PAIR WITH OUR FEATURES OF 

793
00:30:47,484 --> 00:30:47,751
INTEREST.

794
00:30:47,751 --> 00:30:49,220
HERE'S WHAT IT LOOKS LIKE.

795
00:30:49,220 --> 00:30:50,854
WE EXPRESSED THE PROTEINS IN HEX

796
00:30:50,854 --> 00:30:53,958
CELLS AND THEN WE WERE ABLE TO 

797
00:30:53,958 --> 00:30:55,626
DUAL PATCH.

798
00:30:55,626 --> 00:31:00,431
CONNECTING A PIPETTE TO BOTH AND

799
00:31:00,431 --> 00:31:03,067
MEASURE THE FLOW OF ELECTRICITY 

800
00:31:03,067 --> 00:31:05,135
AND FOUND WE COULD SEND 

801
00:31:05,135 --> 00:31:07,004
ELECTRICITY FROM ONE CELL TO 

802
00:31:07,004 --> 00:31:08,739
ANOTHER AND THEY WERE CONDUCTING

803
00:31:08,739 --> 00:31:12,710
ELECTRICITY AND WE WERE EXCITED 

804
00:31:12,710 --> 00:31:15,980
BECAUSE THOUGH WE COULD MUTATE 

805
00:31:15,980 --> 00:31:18,148
THEM THEY COULD DO THIS AND ONE 

806
00:31:18,148 --> 00:31:20,317
HAS 35.  7 AND ONE HAS 35 AND 

807
00:31:20,317 --> 00:31:23,520
WHEN WE EXPRESSED 37 IN BOTH THE

808
00:31:23,520 --> 00:31:26,056
LOCK AND LOCKED, NO CURRENT 

809
00:31:26,056 --> 00:31:26,924
PASSED BETWEEN THE CELLS AND 

810
00:31:26,924 --> 00:31:28,559
WHEN WE EXPRESSED THE KEY IN THE

811
00:31:28,559 --> 00:31:30,060
KEY, NO CURRENT PASS BETWEEN 

812
00:31:30,060 --> 00:31:30,261
CELLS.

813
00:31:30,261 --> 00:31:33,230
SO WE HAVE IT WORKING LIKE A 

814
00:31:33,230 --> 00:31:34,164
MAGNET AND IT DOESN'T WORK LIKE 

815
00:31:34,164 --> 00:31:37,768
A STICKER.

816
00:31:37,768 --> 00:31:39,970
SO WE REACHED OUT TO COLLEAGUES.

817
00:31:39,970 --> 00:31:45,175
WE MENTIONED THE C. ELEGANS 

818
00:31:45,175 --> 00:31:47,578
LITERATURE AND WE DON'T DO THAT 

819
00:31:47,578 --> 00:31:50,147
WORK IN THE LAB AND I HAVE A 

820
00:31:50,147 --> 00:31:53,417
FRIEND IN YALE AND HIS LAB DOES 

821
00:31:53,417 --> 00:31:56,086
WORK IN C. ELEGANS AND I SAID 

822
00:31:56,086 --> 00:31:58,455
CAN YOU TEST IT TO SEE IF THEY 

823
00:31:58,455 --> 00:32:00,924
CAN CHANGE BEHAVIOR AND 

824
00:32:00,924 --> 00:32:02,226
PHYSIOLOGY IN A LIVING INTACT 

825
00:32:02,226 --> 00:32:02,493
SYSTEM.

826
00:32:02,493 --> 00:32:04,428
SO WE SENT HIM THESE PROTEINS.

827
00:32:04,428 --> 00:32:07,231
THE C. ELEGANS IS NICE FOR 

828
00:32:07,231 --> 00:32:07,631
MULTIPLE REASONS.

829
00:32:07,631 --> 00:32:11,302
THEY HAVE ONE CELL OF EACH CELL 

830
00:32:11,302 --> 00:32:13,771
TYPE BUT WHAT'S ALSO COOL IS 

831
00:32:13,771 --> 00:32:15,472
NEUROSCIENTISTS WORKED HARD TO 

832
00:32:15,472 --> 00:32:16,807
FIGURE OUT THE BEHAVIORS IN 

833
00:32:16,807 --> 00:32:17,007
THESE.

834
00:32:17,007 --> 00:32:19,777
THERE'S A SET OF BEHAVIORS 

835
00:32:19,777 --> 00:32:25,783
MAPPED ON TO CELL TYPES IN THE 

836
00:32:25,783 --> 00:32:26,817
C. ELEGANS.

837
00:32:26,817 --> 00:32:35,125
NAR CLEAR  

838
00:32:38,796 --> 00:32:41,799
SO HERE'S THE ASSAY THAT WE'RE 

839
00:32:41,799 --> 00:32:43,967
TO USE IN C. ELEGANS AND I'LL 

840
00:32:43,967 --> 00:32:45,469
WALK YOU THROUGH THIS QUICKLY.

841
00:32:45,469 --> 00:32:48,305
I LIKE TO SAY THEY'RE LIKE 

842
00:32:48,305 --> 00:32:48,906
GRADUATE STUDENTS.

843
00:32:48,906 --> 00:32:49,973
WHEREVER YOU FEED THEM, THEY 

844
00:32:49,973 --> 00:32:51,975
WILL RETURN.

845
00:32:51,975 --> 00:32:55,245
SO THIS BEHAVIOR IS CONTROLLED 

846
00:32:55,245 --> 00:32:58,148
AT LEAST IN PART BY TWO NEURONS.

847
00:32:58,148 --> 00:33:01,051
THERE'S AFD, WHICH YOU CAN SEE 

848
00:33:01,051 --> 00:33:03,721
IS THE LARGE GREEN NEURON OVER 

849
00:33:03,721 --> 00:33:07,758
THERE ON THE TOP AND THEN AIY.

850
00:33:07,758 --> 00:33:09,426
AFD IS A SENSORY NEURON.

851
00:33:09,426 --> 00:33:13,364
IN THIS CASE IT SENSES 

852
00:33:13,364 --> 00:33:13,764
TEMPERATURE.

853
00:33:13,764 --> 00:33:17,935
SO THE WARMER THE C. ELEGANS THE

854
00:33:17,935 --> 00:33:20,137
MORE THE NEURON FIRES.

855
00:33:20,137 --> 00:33:23,307
IF YOU FEED THEM AT WARM 

856
00:33:23,307 --> 00:33:23,941
TEMPERATURES AND TEST THEM IT 

857
00:33:23,941 --> 00:33:26,744
WILL GO BACK TO WARM AND FEED 

858
00:33:26,744 --> 00:33:28,412
THEM AT COLD IT WILL PREFER COLD

859
00:33:28,412 --> 00:33:30,147
TEMPERATURE LATER.

860
00:33:30,147 --> 00:33:36,820
SO IN THE CASE OF FEEDING A C. 

861
00:33:36,820 --> 00:33:39,156
ELEGANS IT RESPONDS TO 

862
00:33:39,156 --> 00:33:39,456
TEMPERATURE.

863
00:33:39,456 --> 00:33:41,558
SO UNDER THE BIG GREEN NEURON 

864
00:33:41,558 --> 00:33:43,794
YOU CAN SEE A TRACE IN WHICH 

865
00:33:43,794 --> 00:33:45,162
WE'RE INCREASING TEMPERATURE AND

866
00:33:45,162 --> 00:33:46,730
RAMPING TEMPERATURE UP AND 

867
00:33:46,730 --> 00:33:49,566
SHOWING YOU ACROSS 60 OR SO 

868
00:33:49,566 --> 00:33:51,135
ANIMALS WHAT HAPPENS TO THE 

869
00:33:51,135 --> 00:33:52,403
NEURON AS WE INCREASE 

870
00:33:52,403 --> 00:33:54,138
TEMPERATURE AND IT GETS MORE RED

871
00:33:54,138 --> 00:33:55,773
AS YOU SLIDE TO THE RIGHT 

872
00:33:55,773 --> 00:33:59,276
BECAUSE IT'S RESPONDING TO 

873
00:33:59,276 --> 00:34:00,043
TEMPERATURE.

874
00:34:00,043 --> 00:34:01,678
SO THE NEURON FIRES THE SENSORY 

875
00:34:01,678 --> 00:34:01,912
NEURON.

876
00:34:01,912 --> 00:34:05,082
WHEN YOU FEED ANIMALS IN COLD 

877
00:34:05,082 --> 00:34:07,918
THE CONNECTION BETWEEN AFD AND 

878
00:34:07,918 --> 00:34:09,453
AIY IS WEAK.

879
00:34:09,453 --> 00:34:11,755
THE SECOND CELL BECAUSE THE 

880
00:34:11,755 --> 00:34:14,258
CONNECTION IS WEAK THE CELL 

881
00:34:14,258 --> 00:34:15,859
DOESN'T FIRE MORE WHEN FED AT 

882
00:34:15,859 --> 00:34:16,794
COLD TEMPERATURES IF YOU TEST 

883
00:34:16,794 --> 00:34:18,162
THEM OUT THEY PREFER COLD.

884
00:34:18,162 --> 00:34:20,664
BUT IN THE CASE WHERE YOU FEED 

885
00:34:20,664 --> 00:34:21,465
THE ANIMALS AT WARM 

886
00:34:21,465 --> 00:34:23,000
TEMPERATURES, NOW THE CONNECTION

887
00:34:23,000 --> 00:34:26,737
BETWEEN THE TWO NEURONS IS 

888
00:34:26,737 --> 00:34:27,838
STRONG.

889
00:34:27,838 --> 00:34:35,946
IT'S CHANGED.

890
00:34:35,946 --> 00:34:37,414
WHEN YOU INCREASE TEMPERATURE 

891
00:34:37,414 --> 00:34:38,882
THE POST SYNAPTIC NEURON STARTS 

892
00:34:38,882 --> 00:34:39,950
FIRING MORE BECAUSE THE 

893
00:34:39,950 --> 00:34:42,152
CONNECTION BETWEEN THE TWO IS 

894
00:34:42,152 --> 00:34:46,190
STRONG AND THE ANIMALS PREFER 

895
00:34:46,190 --> 00:34:46,390
WARM.

896
00:34:46,390 --> 00:34:48,292
SO YOU CAN MEASURE HOW STRONGLY 

897
00:34:48,292 --> 00:34:49,226
THEY'RE CONNECTED BY TWO 

898
00:34:49,226 --> 00:34:49,793
FEATURES.

899
00:34:49,793 --> 00:34:53,096
ONE, DOES THE ANIMAL PREFER COLD

900
00:34:53,096 --> 00:34:55,165
OR PRESERVE WARM?

901
00:34:55,165 --> 00:34:56,934
AND SECONDLY, HOW MUCH CALCIUM 

902
00:34:56,934 --> 00:34:58,068
RISE IS THERE AS YOU INCREASE 

903
00:34:58,068 --> 00:34:58,535
TEMPERATURES?

904
00:34:58,535 --> 00:34:59,636
IT'S AN EASY WAY OF MEASURING 

905
00:34:59,636 --> 00:35:01,472
THE CONNECTION BETWEEN THE TWO 

906
00:35:01,472 --> 00:35:01,672
CELLS.

907
00:35:01,672 --> 00:35:05,042
SO THAT'S WHAT WE'RE GOING TO DO

908
00:35:05,042 --> 00:35:05,409
EXPERIMENTALLY.

909
00:35:05,409 --> 00:35:07,277
WE'LL PUT THE LOCK IN ONE CELL 

910
00:35:07,277 --> 00:35:08,278
AND LOCK IN THE OTHER CELL OR 

911
00:35:08,278 --> 00:35:10,347
PUT THE KEY IN ONE CELL AND KEY 

912
00:35:10,347 --> 00:35:13,250
IN THE OTHER CELL.

913
00:35:13,250 --> 00:35:17,621
AND THEN WE'LL MEASURE CALCIUM 

914
00:35:17,621 --> 00:35:19,056
CHANGE AND ANIMAL WARM OR COLD 

915
00:35:19,056 --> 00:35:20,324
AND THE LOCK AND LOCK IN THE 

916
00:35:20,324 --> 00:35:23,327
MIDDLE AND KEY AND KEY THERE'S 

917
00:35:23,327 --> 00:35:25,863
NO POST SYNAPTIC CALCIUM RISE.

918
00:35:25,863 --> 00:35:27,965
WE'RE NOT STRENGTHENING THE 

919
00:35:27,965 --> 00:35:29,466
CONNECTION BETWEEN THE TWO DOING

920
00:35:29,466 --> 00:35:30,667
LOCK-LOCK OR KEY-KEY.

921
00:35:30,667 --> 00:35:33,036
BUT WHEN WE PUT THE LOCK AND KEY

922
00:35:33,036 --> 00:35:34,271
AND LOCK IN THE FIRST AND KEY IN

923
00:35:34,271 --> 00:35:36,340
THE SECOND CELL NOW YOU CAN SEE 

924
00:35:36,340 --> 00:35:38,308
A POST SYNAPTIC CALCIUM RISE AS 

925
00:35:38,308 --> 00:35:42,079
IF WE STRENGTHENED THE 

926
00:35:42,079 --> 00:35:43,247
CONNECTION THOUGH THE ANIMAL 

927
00:35:43,247 --> 00:35:44,481
NEVER GOT FOOD AT A WARM 

928
00:35:44,481 --> 00:35:44,882
TEMPERATURE.

929
00:35:44,882 --> 00:35:45,616
SO WE'RE CHANGING THE WIRING 

930
00:35:45,616 --> 00:35:49,520
BETWEEN THE TWO CELLS.

931
00:35:49,520 --> 00:35:54,191
NOW WE'LL LOOK AT WHAT GOES ON 

932
00:35:54,191 --> 00:35:54,525
BEHAVIORALLY.

933
00:35:54,525 --> 00:35:56,994
THE ANIMALS WITH THE LOCK AND 

934
00:35:56,994 --> 00:35:59,663
LOCK PREFER COLD AND ANIMALS KEY

935
00:35:59,663 --> 00:36:00,764
IN THE KEY PREFER COLD.

936
00:36:00,764 --> 00:36:04,001
BUT WHEN WE PUT THE LOCK AND KEY

937
00:36:04,001 --> 00:36:06,803
IN ALL OF A SUDDEN THEY PREFER 

938
00:36:06,803 --> 00:36:07,838
WARM TEMPERATURES SO YOU CHANGE 

939
00:36:07,838 --> 00:36:10,140
THE PHYSIOLOGY AND BEHAVIOR 

940
00:36:10,140 --> 00:36:13,710
ESSENTIALLY CREATING A SYNAPTIC 

941
00:36:13,710 --> 00:36:16,780
BYPASS THAT WORKS IN C. ELEGANS.

942
00:36:16,780 --> 00:36:19,750
AND FOR KICKS BECAUSE MY UNCLE 

943
00:36:19,750 --> 00:36:22,152
SHAMED ME WITH THE QUESTION, WE 

944
00:36:22,152 --> 00:36:24,655
TESTED THIS WITH CONNECTION 

945
00:36:24,655 --> 00:36:27,624
PROTEINS IN THE HUMAN BRAIN AS 

946
00:36:27,624 --> 00:36:28,725
WELL BECAUSE THIS TIME WE 

947
00:36:28,725 --> 00:36:34,164
THOUGHT WE BETTER THINK OF LONG 

948
00:36:34,164 --> 00:36:37,834
TERM AND THEY DIDN'T INTERACT 

949
00:36:37,834 --> 00:36:44,474
WITH CONNEX IN IN HUMANS.

950
00:36:44,474 --> 00:36:45,976
NOW WE'RE EXCITED.

951
00:36:45,976 --> 00:36:47,644
WE GOT THIS AND PLAYING AROUND 

952
00:36:47,644 --> 00:36:49,713
WITH IT AND SEEMS TO BE WORKING 

953
00:36:49,713 --> 00:36:52,983
IN C. ELEGANS AND I'LL TAKE YOU 

954
00:36:52,983 --> 00:36:55,419
AROUND BACK TO THE BEGINNING OF 

955
00:36:55,419 --> 00:36:56,286
MY TALK.

956
00:36:56,286 --> 00:36:58,322
IF YOU REMEMBER I PUT UP THE 

957
00:36:58,322 --> 00:37:01,291
DIAGRAM ABOUT THE GENOME-WIDE 

958
00:37:01,291 --> 00:37:02,859
ASSOCIATION STUDIES AND SHOWED 

959
00:37:02,859 --> 00:37:07,130
THE GENE ALTERATIONS IN HUMANS 

960
00:37:07,130 --> 00:37:08,599
WERE MAPPING ON TO SYNAPTIC 

961
00:37:08,599 --> 00:37:08,899
PROTEINS.

962
00:37:08,899 --> 00:37:11,368
I'LL SPEND THE REST OF THE TALK 

963
00:37:11,368 --> 00:37:14,838
FOCUSSING IN ON ONE OF THESE 

964
00:37:14,838 --> 00:37:15,105
PROTEINS.

965
00:37:15,105 --> 00:37:17,708
IT'S CALLED SAP APP AND YOU CAN 

966
00:37:17,708 --> 00:37:18,642
SORT OF SEE IT.

967
00:37:18,642 --> 00:37:20,510
I WISH I COULD GET IT TO WORK 

968
00:37:20,510 --> 00:37:22,613
BUT FOR THOSE AT HOME YOU GET TO

969
00:37:22,613 --> 00:37:24,448
ENJOY THIS POINTER.

970
00:37:24,448 --> 00:37:27,184
IT'S THE GREEN LINK OVER THERE 

971
00:37:27,184 --> 00:37:29,786
THAT'S HOLDING UP THE RECEPTORS.

972
00:37:29,786 --> 00:37:31,488
AND PEOPLE HAD MADE A MOUSE 

973
00:37:31,488 --> 00:37:34,124
MODEL WHERE THEY'D REMOVED THE 

974
00:37:34,124 --> 00:37:36,660
PROTEIN SO THEY REMOVED SAPP APP

975
00:37:36,660 --> 00:37:37,060
3.

976
00:37:37,060 --> 00:37:40,163
AND THE WORK WAS FIRST PUBLISHED

977
00:37:40,163 --> 00:37:43,100
IN 2007 AND WHEN IT GOT 

978
00:37:43,100 --> 00:37:43,867
PUBLISHED THERE WAS AN 

979
00:37:43,867 --> 00:37:44,534
INTERESTING PHENOTYPE.

980
00:37:44,534 --> 00:37:47,037
AS THEY AGED AND PASSED THROUGH 

981
00:37:47,037 --> 00:37:49,740
WHAT IS MOUSE ADOLESCENCE PEOPLE

982
00:37:49,740 --> 00:37:54,144
STARTED NOTICING THEY HAD 

983
00:37:54,144 --> 00:37:59,516
REPETITIVE BEHAVIOR AND GR GROOD

984
00:37:59,516 --> 00:38:01,885
AND GROOMED AND GROOMED SOME 

985
00:38:01,885 --> 00:38:05,288
MORE THAN A WILD TYPE AND 

986
00:38:05,288 --> 00:38:06,923
SOMETIMES FOUR AND FIVE TIMES AS

987
00:38:06,923 --> 00:38:08,659
MUCH AND THE CONSEQUENCES OF THE

988
00:38:08,659 --> 00:38:10,961
GROOMING CAN BE QUITE SEVERE.

989
00:38:10,961 --> 00:38:12,462
I'M SHOWING THE WILD TYPE MOUSE 

990
00:38:12,462 --> 00:38:16,833
ON TOP AND ON BOTTOM A SAP APP 

991
00:38:16,833 --> 00:38:17,034
MOUSE.

992
00:38:17,034 --> 00:38:19,469
A MOUSE THAT'S LOST THE PROTEINS

993
00:38:19,469 --> 00:38:21,338
AND CAN GROOM UNTIL IT HAS HUGE 

994
00:38:21,338 --> 00:38:22,139
FACIAL LESIONS BECAUSE IT'S 

995
00:38:22,139 --> 00:38:26,143
GROOMING SO MUCH.

996
00:38:26,143 --> 00:38:30,681
I'LL QUANTIFY THAT FOR YOU.

997
00:38:30,681 --> 00:38:32,916
SEE THE LESION SIZE ON BOTH OF 

998
00:38:32,916 --> 00:38:35,352
ITS FACE AVERAGED TOGETHER.

999
00:38:35,352 --> 00:38:40,290
ZERO MEANS NO LESIONS AND 5 

1000
00:38:40,290 --> 00:38:44,761
MEANS TWO 5 MILLIMETER LESIONS 

1001
00:38:44,761 --> 00:38:47,064
AND IN THE KNOCKOUT YOU SEE THE 

1002
00:38:47,064 --> 00:38:48,365
LESIONS AND MOST THE ANIMALS 

1003
00:38:48,365 --> 00:38:49,232
HAVE IT.

1004
00:38:49,232 --> 00:38:53,036
85% OF THE ANIMALS BY THE END WE

1005
00:38:53,036 --> 00:38:54,337
TRACKED THEM FOR 10 WEEKS.

1006
00:38:54,337 --> 00:38:56,106
85% OF THE ANIMALS SO 25 WEEKS 

1007
00:38:56,106 --> 00:38:59,543
OF AGE WE'RE TRACKING FROM 15 TO

1008
00:38:59,543 --> 00:39:01,611
25 HAVE LESIONS.

1009
00:39:01,611 --> 00:39:03,947
SO WHAT'S INTERESTING ABOUT THIS

1010
00:39:03,947 --> 00:39:05,949
IS THAT MULTIPLE LABS HAVE TRIED

1011
00:39:05,949 --> 00:39:10,353
TO MAP THIS BEHAVIOR ON TO 

1012
00:39:10,353 --> 00:39:12,856
CIRCUITS IN THE BRAIN AND 

1013
00:39:12,856 --> 00:39:14,858
IMPLICATED TWO BRAIN REGIONS 

1014
00:39:14,858 --> 00:39:16,693
PARTICULARLY IMPORTANT.

1015
00:39:16,693 --> 00:39:21,064
ONE IS ORBITAL FRONTAL CORTEX 

1016
00:39:21,064 --> 00:39:25,302
AND THE OTHER IS IT THE 

1017
00:39:25,302 --> 00:39:25,569
STRIATUM.

1018
00:39:25,569 --> 00:39:29,339
AND THE WAY IT'S SET UP YOU HAVE

1019
00:39:29,339 --> 00:39:35,612
CELLS IN ORBITAL FRONTAL CORTEX 

1020
00:39:35,612 --> 00:39:40,484
TO STRIATUM AND THIS IS 

1021
00:39:40,484 --> 00:39:42,519
UNIDIRECTIONAL AND PEOPLE USED 

1022
00:39:42,519 --> 00:39:49,926
THAT TOOL, OPTOGENETICS TO DO 

1023
00:39:49,926 --> 00:39:51,728
EXPERIMENTS AND IT'S REDUCED 

1024
00:39:51,728 --> 00:39:53,029
GROOMING.

1025
00:39:53,029 --> 00:39:55,465
AND PEOPLE HAVE DONE EXPERIMENTS

1026
00:39:55,465 --> 00:39:59,669
TARGETING THE PV NEURONS IN THE 

1027
00:39:59,669 --> 00:40:03,573
STRIATUM AND STIMULATED THEM AND

1028
00:40:03,573 --> 00:40:06,143
THAT REDUCED GROOMING AND 

1029
00:40:06,143 --> 00:40:07,144
THERE'S PROBABLY THE CIRCUIT IN 

1030
00:40:07,144 --> 00:40:09,780
THE MIDDLE NOT THE LEFT OR RIGHT

1031
00:40:09,780 --> 00:40:11,481
THAT'S IMPORTANT.

1032
00:40:11,481 --> 00:40:13,083
BUT THERE HAVEN'T BEEN GREAT 

1033
00:40:13,083 --> 00:40:14,484
NEUROSCIENCE TOOLS TO STIMULATE 

1034
00:40:14,484 --> 00:40:17,554
PART OF THAT BUT NOT THE OTHER 

1035
00:40:17,554 --> 00:40:19,890
PART SO YOU SORT OF HAVE TO BE 

1036
00:40:19,890 --> 00:40:21,191
ABLE TO HIT THE PRESYNAPTIC 

1037
00:40:21,191 --> 00:40:23,760
NEURON FOR THIS TO WORK.

1038
00:40:23,760 --> 00:40:27,230
SO THE IDEA WAS WE CREATED THIS 

1039
00:40:27,230 --> 00:40:28,832
LOCK AND KEY GAP JUNCTION TOOL.

1040
00:40:28,832 --> 00:40:30,901
CAN WE JUST TEST THIS OUT ON THE

1041
00:40:30,901 --> 00:40:33,470
CIRCUIT AND SEE WHAT IT WILL DO?

1042
00:40:33,470 --> 00:40:36,640
SO, WHAT WE'RE GOING TO DO IS 

1043
00:40:36,640 --> 00:40:40,210
PUT THE LOCK AND ORBITAL FRONTAL

1044
00:40:40,210 --> 00:40:43,880
CORTEX AND PUT IT IN THE D1 

1045
00:40:43,880 --> 00:40:45,182
EXPRESSING NEURONS OR THE D2 

1046
00:40:45,182 --> 00:40:47,484
EXPRESSING NEURONS OR THE PB 

1047
00:40:47,484 --> 00:40:50,987
NEURONS AND SEE WHAT IT DOES.

1048
00:40:50,987 --> 00:40:53,957
CAN WE REWIRE THE CIRCUIT AND 

1049
00:40:53,957 --> 00:40:55,358
CREATE A SENSE OF VIRAL VECTORS.

1050
00:40:55,358 --> 00:40:57,060
I'LL WALK YOU THROUGH THIS ON 

1051
00:40:57,060 --> 00:40:57,627
THE NEXT SLIDE.

1052
00:40:57,627 --> 00:41:00,330
WE'LL HAVE A SERIES OF VIRAL 

1053
00:41:00,330 --> 00:41:05,435
VECTORS AND TAG GREEN.

1054
00:41:05,435 --> 00:41:08,939
I WARNED YOU YOU'D SEE GREEN AND

1055
00:41:08,939 --> 00:41:10,106
RED A LOT AND 35 IS TAGGED TO 

1056
00:41:10,106 --> 00:41:12,976
THE RED AND HAVE A SERIES OF 

1057
00:41:12,976 --> 00:41:17,881
CONTROLS GFP GREEN PROTEIN OR 

1058
00:41:17,881 --> 00:41:20,650
RFP JUST RED AND TARGET THE CELL

1059
00:41:20,650 --> 00:41:21,418
TYPES.

1060
00:41:21,418 --> 00:41:23,119
THIS IS A PICTURE OF THE 

1061
00:41:23,119 --> 00:41:24,855
STRIATUM AND SEE THE GREEN IS 

1062
00:41:24,855 --> 00:41:27,290
SORT OF THE AXONS COMING IN AND 

1063
00:41:27,290 --> 00:41:28,892
THE TERMINALS COMING IN TO 

1064
00:41:28,892 --> 00:41:30,994
STRIATUM AND THE RED IN THIS 

1065
00:41:30,994 --> 00:41:33,396
CASE IS A PV NEURON AND ON THE 

1066
00:41:33,396 --> 00:41:35,232
BOTTOM ON THE RIGHT YOU CAN SORT

1067
00:41:35,232 --> 00:41:37,467
OF SEE THERE'S LIKE A YELLOW 

1068
00:41:37,467 --> 00:41:39,536
SPOT IN THERE THAT'S LIKE THE 

1069
00:41:39,536 --> 00:41:41,738
GREEN AND SORT OF YELLOW.

1070
00:41:41,738 --> 00:41:43,874
IT MEANS THESE TWO COLORS ARE 

1071
00:41:43,874 --> 00:41:46,176
SOMETIMES COMING CLOSE TOGETHER.

1072
00:41:46,176 --> 00:41:50,947
SORT ARGUING WE'RE CREATING A 

1073
00:41:50,947 --> 00:41:51,181
SYNAPSE.

1074
00:41:51,181 --> 00:41:52,315
HERE'S GROUPS WE'RE GOING TO 

1075
00:41:52,315 --> 00:41:52,515
TEST.

1076
00:41:52,515 --> 00:41:54,618
WE'LL START OFF WITH A STRAIN OF

1077
00:41:54,618 --> 00:41:55,151
MICE.

1078
00:41:55,151 --> 00:41:57,254
THE SAP UP MICE.

1079
00:41:57,254 --> 00:41:58,622
WE CROSSED IT TO MICE THAT WILL 

1080
00:41:58,622 --> 00:42:02,158
ALLOW US TO TARGET PV NEURONS.

1081
00:42:02,158 --> 00:42:07,030
SO THIS ALLOWS YOU TO TARGET THE

1082
00:42:07,030 --> 00:42:09,633
CELLS THAT EXPRESS CREE WITH THE

1083
00:42:09,633 --> 00:42:13,703
VIRUS AND PUT THE LOCK IN THE 

1084
00:42:13,703 --> 00:42:19,910
FRONTAL CORTEX AND KEY IN THE 

1085
00:42:19,910 --> 00:42:21,678
STRIATUM AND THE NEXT THE LOCK 

1086
00:42:21,678 --> 00:42:24,814
WILL BE OFC AND KEY WILL BE 

1087
00:42:24,814 --> 00:42:27,817
SPECIFICALLY IN THE CELLS IN 

1088
00:42:27,817 --> 00:42:31,321
STRI JATAL AND THE NEXT TARGET L

1089
00:42:31,321 --> 00:42:32,589
CELL TYPES.

1090
00:42:32,589 --> 00:42:36,993
THE THIRD IS THE LOCK OFC COLOR 

1091
00:42:36,993 --> 00:42:38,762
AND STRIATUM AND COLOR AND LOCK 

1092
00:42:38,762 --> 00:42:42,165
KEY AND STRIATUM AND ON THE 

1093
00:42:42,165 --> 00:42:44,334
BOTTOM WE'LL TARGET EVERYTHING 

1094
00:42:44,334 --> 00:42:45,168
EXCEPT FOR THOSE CELLS.

1095
00:42:45,168 --> 00:42:47,804
I'LL SHOW YOU ON THE NEXT SLIDE 

1096
00:42:47,804 --> 00:42:49,372
WHAT HAPPENS WITH GROOMING.

1097
00:42:49,372 --> 00:42:51,041
YOU CAN KEEP YOUR EYE ON THE 

1098
00:42:51,041 --> 00:42:55,245
DATA AND HOW THE ANIMALS LOOK.

1099
00:42:55,245 --> 00:42:56,813
SO I'M SHOWING YOU GROOMING AND 

1100
00:42:56,813 --> 00:42:58,148
THE AMOUNT OF TIME SPENT 

1101
00:42:58,148 --> 00:42:59,783
GROOMING.

1102
00:42:59,783 --> 00:43:01,651
WE PUT THE VIRUS IN AT EIGHT 

1103
00:43:01,651 --> 00:43:03,353
WEEKS AND MEASURED THEM FIVE 

1104
00:43:03,353 --> 00:43:06,156
WEEKS AND 10 WEEKS AND 15 WEEKS 

1105
00:43:06,156 --> 00:43:06,856
LATER.

1106
00:43:06,856 --> 00:43:08,591
ON THE LEFT ABOUT WHAT YOU'RE 

1107
00:43:08,591 --> 00:43:11,027
SEEING IS IN THE LIGHT GRAY YOU 

1108
00:43:11,027 --> 00:43:11,995
SEE THE ANIMALS THAT ONLY HAVE 

1109
00:43:11,995 --> 00:43:15,432
COLORS NO PROTEINS JUST CONTROL 

1110
00:43:15,432 --> 00:43:16,566
COLORS AND THEY'RE RUNNING HOT 

1111
00:43:16,566 --> 00:43:18,168
BUT IN THE ANIMALS WE PUT THE 

1112
00:43:18,168 --> 00:43:20,337
LOCK AND THE KEY, THE KEY 

1113
00:43:20,337 --> 00:43:21,171
SPECIFICALLY IN THE INDIVIDUAL 

1114
00:43:21,171 --> 00:43:23,406
CELLS IT REDUCES GROOMING ACROSS

1115
00:43:23,406 --> 00:43:24,674
THE ENTIRE COURSE OF THE 

1116
00:43:24,674 --> 00:43:25,008
EXPERIMENT.

1117
00:43:25,008 --> 00:43:26,176
SO WE CAN BY PUTTING INTO THE 

1118
00:43:26,176 --> 00:43:28,478
CELL TYPES REDUCE THE BEHAVIOR.

1119
00:43:28,478 --> 00:43:31,114
THEN WE'LL LOOK AT OUR CONTROL 

1120
00:43:31,114 --> 00:43:31,481
GROUPS.

1121
00:43:31,481 --> 00:43:32,682
IN THE MIDDLE YOU SEE THE GROUP 

1122
00:43:32,682 --> 00:43:34,617
WHERE WE TARGET OFC.

1123
00:43:34,617 --> 00:43:39,189
THE LOCK IN OFC AND KEY IS 

1124
00:43:39,189 --> 00:43:42,192
EVERYWHERE IN STRIATUM NOT JUST 

1125
00:43:42,192 --> 00:43:43,526
CELLS OF INTEREST BUT EVERYWHERE

1126
00:43:43,526 --> 00:43:46,096
BUT BLUE GROUP AND IF WE TARGET 

1127
00:43:46,096 --> 00:43:47,630
ALL THE GROOMING INCREASES OVER 

1128
00:43:47,630 --> 00:43:47,831
TIME.

1129
00:43:47,831 --> 00:43:49,699
IT'S ONLY THE CASE WE HIT THE 

1130
00:43:49,699 --> 00:43:51,634
INDIVIDUAL SIDES NOT ALL CELLS.

1131
00:43:51,634 --> 00:43:54,104
AND THEN IN THE PURPLE WE HAVE A

1132
00:43:54,104 --> 00:43:55,538
CASE WHERE WE HIT EVERYTHING 

1133
00:43:55,538 --> 00:43:57,240
EXCEPT FOR THE PV NEURONS AND 

1134
00:43:57,240 --> 00:43:57,607
STRIATUM.

1135
00:43:57,607 --> 00:43:59,809
WE'RE FORMING THE CONNECTIONS AT

1136
00:43:59,809 --> 00:44:00,877
THE WRONG PLACE AND GROOMING 

1137
00:44:00,877 --> 00:44:01,978
INCREASES OVER TIME.

1138
00:44:01,978 --> 00:44:03,646
IT'S ONLY WHEN YOU HIT THE CELL 

1139
00:44:03,646 --> 00:44:04,047
TYPE PAIR.

1140
00:44:04,047 --> 00:44:06,216
THEN ALL THE WAY ON THE RIGHT 

1141
00:44:06,216 --> 00:44:08,418
YOU HAVE ONLY THE LOCK IN 

1142
00:44:08,418 --> 00:44:09,919
STRIATUM OR ONLY THE LOCK IN 

1143
00:44:09,919 --> 00:44:11,621
CORTEX AND ONLY THE KEY IN 

1144
00:44:11,621 --> 00:44:11,988
STRIATUM.

1145
00:44:11,988 --> 00:44:13,923
ONLY HALF THE PROTEIN AND AGAIN 

1146
00:44:13,923 --> 00:44:15,225
THE GROOMING INCREASES OVER 

1147
00:44:15,225 --> 00:44:15,458
TIME.

1148
00:44:15,458 --> 00:44:18,194
IT'S ONLY IF YOU PUT IT AT THE 

1149
00:44:18,194 --> 00:44:19,462
RIGHT CONNECTION AND BYPASS THE 

1150
00:44:19,462 --> 00:44:19,996
RIGHT PLACE.

1151
00:44:19,996 --> 00:44:21,664
HERE'S WHAT THE ANIMALS LOOK 

1152
00:44:21,664 --> 00:44:23,833
LIKE IN TERMS OF THEIR FACIAL 

1153
00:44:23,833 --> 00:44:24,067
LESIONS.

1154
00:44:24,067 --> 00:44:27,537
I'LL WALK YOU FROM TOP TO 

1155
00:44:27,537 --> 00:44:27,771
BOTTOM.

1156
00:44:27,771 --> 00:44:29,906
SO SO ONLY COLORED PROTEINS, 

1157
00:44:29,906 --> 00:44:31,574
THEY DEVELOP FACIAL LESIONS IT'S

1158
00:44:31,574 --> 00:44:32,809
LIKE 90%.

1159
00:44:32,809 --> 00:44:34,010
THAT'S THE CONTROL GROUP.

1160
00:44:34,010 --> 00:44:36,513
IF YOU PUT THE LOCK AND THE KEY 

1161
00:44:36,513 --> 00:44:38,915
IN, TWO-THIRDS OF THE ANIMALS 

1162
00:44:38,915 --> 00:44:40,350
NEVER DEVELOP ANY LESION 

1163
00:44:40,350 --> 00:44:40,884
WHATSOEVER.

1164
00:44:40,884 --> 00:44:43,620
SO NOT ONLY DECREASED THE 

1165
00:44:43,620 --> 00:44:46,189
GROOMING, THEY DEVELOP NO LESION

1166
00:44:46,189 --> 00:44:46,489
WHATSOEVER.

1167
00:44:46,489 --> 00:44:47,624
IF YOU PUT THE LOCK IN CORTEX 

1168
00:44:47,624 --> 00:44:51,294
AND KEY IN ALL THE CELLS, YOU'RE

1169
00:44:51,294 --> 00:44:54,197
TARGETING ALL THE CELLS, THOSE 

1170
00:44:54,197 --> 00:44:55,999
ANIMALS DEVELOP LESIONS ALSO AND

1171
00:44:55,999 --> 00:44:57,634
IN FACT THE MAJORITY DEVELOP 

1172
00:44:57,634 --> 00:44:57,901
LESIONS.

1173
00:44:57,901 --> 00:44:59,636
IF YOU PUT ONLY THE LOCK IN, THE

1174
00:44:59,636 --> 00:45:02,005
FOURTH FROM THE TOP, THOSE 

1175
00:45:02,005 --> 00:45:12,849
ANIMALS DEVELOP LESIONS, TAKE Y 

1176
00:45:23,927 --> 00:45:27,530
AND DID A SERIES OF CONTROL 

1177
00:45:27,530 --> 00:45:28,965
EXPERIMENTS TARGETING THE D1 OR 

1178
00:45:28,965 --> 00:45:31,901
D2 NEURON.

1179
00:45:31,901 --> 00:45:35,371
WE USE A D1 PRE MOUSE OR ONE 

1180
00:45:35,371 --> 00:45:45,281
THAT OVERLAP THE STRIATUM AND 

1181
00:45:45,281 --> 00:45:46,116
THEY DEVELOPED LESIONS AS WELL.

1182
00:45:46,116 --> 00:45:48,618
YOU HAVE TO HIT THE CELL TYPE 

1183
00:45:48,618 --> 00:45:50,653
PAIR OF INTEREST OR IT DOESN'T 

1184
00:45:50,653 --> 00:45:51,688
WORK.

1185
00:45:51,688 --> 00:45:54,023
YOU HAVE TO BYPASS THE SYNAPSE 

1186
00:45:54,023 --> 00:45:54,691
OF CHOICE.

1187
00:45:54,691 --> 00:45:56,292
OF COURSE WE'RE ALSO EXCITED 

1188
00:45:56,292 --> 00:45:58,161
BECAUSE IT TURNS OUT YOU CAN 

1189
00:45:58,161 --> 00:46:00,130
BYPASS THE SYNAPSE AND KEEP THE 

1190
00:46:00,130 --> 00:46:01,097
ANIMALS FROM GROOMING THEIR FACE

1191
00:46:01,097 --> 00:46:03,967
OFF IF YOU HIT THE RIGHT THING.

1192
00:46:03,967 --> 00:46:04,400
OKAY.

1193
00:46:04,400 --> 00:46:06,136
SO WE'RE SORT OF LEFT AND I'LL 

1194
00:46:06,136 --> 00:46:08,104
SPEND THE LAST TWO OR THREE 

1195
00:46:08,104 --> 00:46:09,539
SLIDES FOR ALL THE PHYSIOLOGISTS

1196
00:46:09,539 --> 00:46:10,473
IN THE ROOM BECAUSE AT SOME 

1197
00:46:10,473 --> 00:46:12,542
POINT I HAVE TO COME BACK TO MY 

1198
00:46:12,542 --> 00:46:13,643
OWN DISCIPLINE, RIGHT?

1199
00:46:13,643 --> 00:46:16,012
SO WE WENT THROUGH AND WE WANTED

1200
00:46:16,012 --> 00:46:17,947
TO RECORD LIKE WHAT WAS 

1201
00:46:17,947 --> 00:46:19,349
HAPPENING WITH THE CODE IN THIS 

1202
00:46:19,349 --> 00:46:19,849
BRAIN AREA.

1203
00:46:19,849 --> 00:46:23,586
AND I APOLOGIZE TO ALL THE 

1204
00:46:23,586 --> 00:46:25,021
NON-PHYSIOLOGISTS IN HERE.

1205
00:46:25,021 --> 00:46:28,091
IT GETS NUANCED.

1206
00:46:28,091 --> 00:46:31,928
WE IMPLANTED A TYPE OF RECORDING

1207
00:46:31,928 --> 00:46:33,796
ELECTRODE THAT ALLOWS US TO 

1208
00:46:33,796 --> 00:46:35,098
RECORD LOTS OF NEURAL ACTIVELY.

1209
00:46:35,098 --> 00:46:39,903
WE'LL DO VERY HIGH DENSITY 

1210
00:46:39,903 --> 00:46:42,705
NEURORECORDING ACTIVITY FROM 

1211
00:46:42,705 --> 00:46:45,508
STRIATUM AND GET THE SAME 

1212
00:46:45,508 --> 00:46:49,379
INFORMATION FROM FRONTAL ORBITAL

1213
00:46:49,379 --> 00:46:50,947
CORTEX FROM ME MOUSE AND COLLECT

1214
00:46:50,947 --> 00:46:54,184
LOTS OF CELLS ABOUT 900 TOTAL 

1215
00:46:54,184 --> 00:46:55,518
NEURONS AND RECORD OSCILLATIONS 

1216
00:46:55,518 --> 00:46:58,188
FROM THE ORBITAL CORTEX IN THE 

1217
00:46:58,188 --> 00:47:00,423
SAME CELL AND THEN SPLIT THE 

1218
00:47:00,423 --> 00:47:01,224
NEURONS IN THE TWO GROUPS AND 

1219
00:47:01,224 --> 00:47:04,427
FOR THOSE WHO STUDY THE STRIATUM

1220
00:47:04,427 --> 00:47:06,196
YOU YOU'LL DIGEST THIS QUICKLY.

1221
00:47:06,196 --> 00:47:08,431
WE HAVE NEURONS ON THE RIGHT 

1222
00:47:08,431 --> 00:47:10,600
WITH NARROW WAVE FORMS.

1223
00:47:10,600 --> 00:47:15,205
THESE WILL BE THE PV NEURONS AND

1224
00:47:15,205 --> 00:47:18,508
ON THE LEFT ARE GOING TO BE WHAT

1225
00:47:18,508 --> 00:47:25,114
WE CALL STRIATAL PROJECTION 

1226
00:47:25,114 --> 00:47:27,116
NEURONS AND WE'LL ASK HOW 

1227
00:47:27,116 --> 00:47:27,984
THEY'RE DIFFERENT UNDER NORMAL 

1228
00:47:27,984 --> 00:47:30,186
CONDITIONS AND WHEN WE DO THE 

1229
00:47:30,186 --> 00:47:30,653
BYPASS.

1230
00:47:30,653 --> 00:47:32,956
AND SO ON THE LEFT I'M JUST 

1231
00:47:32,956 --> 00:47:35,758
SHOWING YOU A NORMAL ANIMAL AND 

1232
00:47:35,758 --> 00:47:41,431
THE KNOCKOUT ANIMAL AND WHEN WE 

1233
00:47:41,431 --> 00:47:44,100
LOOK THERE'S NO BYPASS HERE 

1234
00:47:44,100 --> 00:47:46,402
THERE'S BASICALLY THE STRIATAL 

1235
00:47:46,402 --> 00:47:48,271
OR MEDIUM NEURONS FIRE LESS.

1236
00:47:48,271 --> 00:47:50,139
SO THERE'S A DECREASE IN THEIR 

1237
00:47:50,139 --> 00:47:50,440
FIRING.

1238
00:47:50,440 --> 00:47:54,177
BUT WHEN WE LOOK AT THE NARROW 

1239
00:47:54,177 --> 00:47:56,379
SPIKING UNITS, THOUGH LIKE 

1240
00:47:56,379 --> 00:47:58,815
THERE'S LESS OF THEM, THERE'S NO

1241
00:47:58,815 --> 00:48:05,088
STATISTICAL DIFFERENCE IN THAT 

1242
00:48:05,088 --> 00:48:05,421
DISTRIBUTION.

1243
00:48:05,421 --> 00:48:07,490
BUT IN TERMS OF THE MEAN FIRING 

1244
00:48:07,490 --> 00:48:08,791
RATE THERE'S NO DIFFERENCE.

1245
00:48:08,791 --> 00:48:11,527
WE HAVE LOTS OF CELLS THERE.

1246
00:48:11,527 --> 00:48:13,196
WE EXPECTED LIKE A LOWER FIRING 

1247
00:48:13,196 --> 00:48:15,932
RATE OF THE NEURONS AND THOUGHT 

1248
00:48:15,932 --> 00:48:17,300
THAT'S WHAT WE'D HAVE 

1249
00:48:17,300 --> 00:48:17,767
EXPERIMENTALLY.

1250
00:48:17,767 --> 00:48:19,669
WE THEN MOVED ON TO STUDY WHAT'S

1251
00:48:19,669 --> 00:48:21,304
GOING ON IN THE ANIMALS WHEN WE 

1252
00:48:21,304 --> 00:48:22,071
DO THE BYPASS?

1253
00:48:22,071 --> 00:48:23,906
YOU'LL LIKELY SEE THE CONTROL 

1254
00:48:23,906 --> 00:48:24,107
GROUP.

1255
00:48:24,107 --> 00:48:26,943
ON THE RIGHT HAND FOR EACH OF 

1256
00:48:26,943 --> 00:48:29,412
THE TWO PLOTS YOU'LL SEE THE 

1257
00:48:29,412 --> 00:48:32,015
LENGTHS THE BYPASS.

1258
00:48:32,015 --> 00:48:35,151
WHEN WE PUT THIS BYPASS IN 

1259
00:48:35,151 --> 00:48:36,452
THERE, THE FIRING OF THE NEURONS

1260
00:48:36,452 --> 00:48:37,186
GOT LOWER.

1261
00:48:37,186 --> 00:48:39,555
YOU SORT OF HAVE THE DISEASE 

1262
00:48:39,555 --> 00:48:40,757
CASE THE FIRING RATE IS LOWER 

1263
00:48:40,757 --> 00:48:43,960
AND THEN WE FIX IT AND THE 

1264
00:48:43,960 --> 00:48:45,128
FIRING RATE GETS EVEN LOWER 

1265
00:48:45,128 --> 00:48:46,195
WHICH IS SUPER CONFUSING TO US 

1266
00:48:46,195 --> 00:48:48,898
AND THEN WE LOOK AT THE NARROW 

1267
00:48:48,898 --> 00:48:50,166
SPIKING UNITS WE THOUGHT WERE 

1268
00:48:50,166 --> 00:48:52,402
THE PV NEURONS AND THOUGH IT 

1269
00:48:52,402 --> 00:48:53,936
TENDED TO INCREASE THE FIRING 

1270
00:48:53,936 --> 00:48:56,105
RATE THERE WEREN'T A LOT OF PV 

1271
00:48:56,105 --> 00:48:57,240
NEURONS THERE.

1272
00:48:57,240 --> 00:48:59,542
THERE WAS -- WE'RE DOING DEEP 

1273
00:48:59,542 --> 00:49:00,343
RECORDINGS AND BARELY GETTING 

1274
00:49:00,343 --> 00:49:03,680
ANY PV NEURONS OR THINGS THAT 

1275
00:49:03,680 --> 00:49:04,914
HAVE WAVES THERE.

1276
00:49:04,914 --> 00:49:06,749
WE WERE STRUCK BY THIS.

1277
00:49:06,749 --> 00:49:08,551
WE JUST QUANTIFIED LIKE WHAT 

1278
00:49:08,551 --> 00:49:11,354
PERCENTAGE OF NEURON TYPES DO WE

1279
00:49:11,354 --> 00:49:12,588
HAVE AND IT GOT INTERESTING.

1280
00:49:12,588 --> 00:49:15,825
ON THE LEFT YOU SEE OUR NORMAL 

1281
00:49:15,825 --> 00:49:18,161
ANIMALS, THE PLUS AND THE 

1282
00:49:18,161 --> 00:49:19,696
KNOCKOUT ANIMALS THE NEGATIVE 

1283
00:49:19,696 --> 00:49:21,864
AND WHAT WE COULD CLEARLY SEE 

1284
00:49:21,864 --> 00:49:24,801
WHEN WE QUANTIFIED THIS ACROSS 

1285
00:49:24,801 --> 00:49:26,169
ANIMALS THERE WERE LESS NEURAL 

1286
00:49:26,169 --> 00:49:29,806
SPIKING UNITS LESS OF WHAT WE 

1287
00:49:29,806 --> 00:49:31,908
THOUGHT WERE PV NEURONS IN THE 

1288
00:49:31,908 --> 00:49:32,575
MUTANT CASE.

1289
00:49:32,575 --> 00:49:35,011
AND WHEN WE LOOKED AT THE MUTANT

1290
00:49:35,011 --> 00:49:38,681
ANIMALS WHAT WE COULD SEE WAS WE

1291
00:49:38,681 --> 00:49:41,551
INCREASED THE PROPORTION OF PV 

1292
00:49:41,551 --> 00:49:43,653
EXPRESSING NEURONS OR SPIKING 

1293
00:49:43,653 --> 00:49:43,853
UNITS.

1294
00:49:43,853 --> 00:49:45,655
YOU SEE THE RED AND ON THE RIGHT

1295
00:49:45,655 --> 00:49:46,689
THE SLICE GETS BIGGER.

1296
00:49:46,689 --> 00:49:48,291
INTERESTINGLY ENOUGH ON THE 

1297
00:49:48,291 --> 00:49:50,593
RIGHT, THE TOTAL NUMBER OF PV 

1298
00:49:50,593 --> 00:49:51,361
NEURONS WAS WAY LESS.

1299
00:49:51,361 --> 00:49:54,163
WE THINK IT HAS TO DO WITH THE 

1300
00:49:54,163 --> 00:49:56,065
CREE LINE WHICH JUST DECREASED 

1301
00:49:56,065 --> 00:49:58,935
THE FUNCTIONALITY OF THE PV 

1302
00:49:58,935 --> 00:49:59,702
NEURONS THERE.

1303
00:49:59,702 --> 00:50:02,205
BUT WE THINK THERE'S ESSENTIALLY

1304
00:50:02,205 --> 00:50:03,139
A SILENCING.

1305
00:50:03,139 --> 00:50:09,512
THE NEURONS BASICALLY GO SILENT 

1306
00:50:09,512 --> 00:50:13,349
SO IF YOU'RE DOING ELECTRICAL 

1307
00:50:13,349 --> 00:50:14,484
RECORDINGS THEY DROP OFF AND YOU

1308
00:50:14,484 --> 00:50:15,451
CAN'T SEE THEM BECAUSE THEY'RE 

1309
00:50:15,451 --> 00:50:17,453
NOT FIRING.

1310
00:50:17,453 --> 00:50:20,123
THERE'S A SILENCING AND WHEN WE 

1311
00:50:20,123 --> 00:50:24,293
BYPASS THEM IT RECOVERED THEM.

1312
00:50:24,293 --> 00:50:26,496
WILL I'LL FAST FORWARD THROUGH 

1313
00:50:26,496 --> 00:50:27,864
THE LAST TWO SLIDES AND GIVE YOU

1314
00:50:27,864 --> 00:50:28,931
THE TAKE HOME OF WHAT WE THINK 

1315
00:50:28,931 --> 00:50:32,468
IS GOING ON.

1316
00:50:32,468 --> 00:50:34,504
SO IN THE END, WE TAKE THESE 

1317
00:50:34,504 --> 00:50:36,305
NEURONS FIRING AND ASK HOW WELL 

1318
00:50:36,305 --> 00:50:39,242
ARE THEY CONNECTED TO OFC?

1319
00:50:39,242 --> 00:50:45,348
SO WE CAN QUANTIFY THE FIRING 

1320
00:50:45,348 --> 00:50:47,717
RELATIONSHIP IN THE STRIATUM TO 

1321
00:50:47,717 --> 00:50:50,019
THE OSCILLATING INFORMATION IN 

1322
00:50:50,019 --> 00:50:50,186
OFC.

1323
00:50:50,186 --> 00:50:52,855
ON THE LEFT WE SEE WHEN YOU LOOK

1324
00:50:52,855 --> 00:50:54,190
AT THE KNOCKOUT ANIMALS THEIR 

1325
00:50:54,190 --> 00:50:56,058
CELLS BASICALLY SHOW THEY FIRE 

1326
00:50:56,058 --> 00:50:58,060
IN A WAY THAT HAS LESS OF A 

1327
00:50:58,060 --> 00:51:00,029
RELATIONSHIP TO OFC.

1328
00:51:00,029 --> 00:51:02,432
IT LOOKS LIKE THERE'S A 

1329
00:51:02,432 --> 00:51:03,065
DISCONNECTION IN THE CIRCUIT 

1330
00:51:03,065 --> 00:51:08,471
BECAUSE THE CELLS DON'T HAVE 

1331
00:51:08,471 --> 00:51:10,173
ASA 

1332
00:51:10,173 --> 00:51:15,411
SASIN  -- ASYNCHRONOUS TIMING AD

1333
00:51:15,411 --> 00:51:16,979
WE RESTORE THE FIRING 

1334
00:51:16,979 --> 00:51:17,947
RELATIONSHIP AND THE CELLS IN 

1335
00:51:17,947 --> 00:51:19,782
THE STRIATUM ARE FIRING WITH THE

1336
00:51:19,782 --> 00:51:22,151
BETTER RELATIONSHIP WITH THE 

1337
00:51:22,151 --> 00:51:25,488
CONNECTIVITY IN OFC.

1338
00:51:25,488 --> 00:51:27,657
AND SO WE THINK ULTIMATELY WHAT 

1339
00:51:27,657 --> 00:51:30,693
WE'VE GOT AND I'M SUMMARIZE THIS

1340
00:51:30,693 --> 00:51:34,163
IS THAT OUR GOAL WE SET OUT TO 

1341
00:51:34,163 --> 00:51:35,965
BYPASS THE SYNAPSE.

1342
00:51:35,965 --> 00:51:40,470
AND WE THOUGHT THAT IN THE CASE 

1343
00:51:40,470 --> 00:51:43,172
OF MAMMALIAN SPECIES WE CAN 

1344
00:51:43,172 --> 00:51:45,808
TARGET A HOUSE IN WHICH THERE'S 

1345
00:51:45,808 --> 00:51:47,610
A GENETICALLY INDUCED 

1346
00:51:47,610 --> 00:51:49,378
DYSFUNCTION IN THE SYNAPSE.

1347
00:51:49,378 --> 00:51:51,547
SO WE GOT THE SYNAPSE, WE GOT 

1348
00:51:51,547 --> 00:51:55,051
THE BREAK AND WANT TO KNOW IF WE

1349
00:51:55,051 --> 00:51:55,985
CAN BYPASS THE BREAK?

1350
00:51:55,985 --> 00:51:59,489
WE CAME UP WITH THE SOLUTION OF 

1351
00:51:59,489 --> 00:52:01,290
BASICALLY GENERATING BYPASS 

1352
00:52:01,290 --> 00:52:02,191
PROTEIN CHANNELS WE TURNED INTO 

1353
00:52:02,191 --> 00:52:06,162
MAG

1354
00:52:06,162 --> 00:52:07,430
MAGNETS.

1355
00:52:07,430 --> 00:52:10,166
WE TESTED THEM IN C. ELEGANS AND

1356
00:52:10,166 --> 00:52:13,002
WENT TO THE DISEASE MODEL WHERE 

1357
00:52:13,002 --> 00:52:16,405
THE MICE REPETITIVELY GROOM TO 

1358
00:52:16,405 --> 00:52:18,174
THE POINT THEIR FACE IS 

1359
00:52:18,174 --> 00:52:19,642
SCRATCHED OFF AND HAVE A 

1360
00:52:19,642 --> 00:52:21,477
SPECIFIC CONNECTION OF INTEREST,

1361
00:52:21,477 --> 00:52:23,913
PUT THE BYPASS IN THERE AND IT 

1362
00:52:23,913 --> 00:52:26,549
RESTORED BOTH THE PHYSIOLOGY OF 

1363
00:52:26,549 --> 00:52:32,522
THE CIRCUIT AND NORMALIZED 

1364
00:52:32,522 --> 00:52:35,258
BEHAVIOR AND GOT RID OF THE 

1365
00:52:35,258 --> 00:52:35,892
PATHOLOGICAL OUTCOMES.

1366
00:52:35,892 --> 00:52:37,560
IT'S NOT HUMAN TRANSLATION.

1367
00:52:37,560 --> 00:52:39,929
THE STORY'S NOT OVER WE'RE STILL

1368
00:52:39,929 --> 00:52:41,497
DOING WORK TO GET THERE BUT 

1369
00:52:41,497 --> 00:52:42,198
WANTED TO TAKE THE LAST MINUTE 

1370
00:52:42,198 --> 00:52:42,999
AND A HALF TO TALK ABOUT THE 

1371
00:52:42,999 --> 00:52:45,835
PEOPLE THAT DID THE WORK.

1372
00:52:45,835 --> 00:52:48,004
AND I ALWAYS END MY TALKS WITH 

1373
00:52:48,004 --> 00:52:49,138
THE SLIDE THAT LOOKS LIKE THIS 

1374
00:52:49,138 --> 00:52:51,240
BECAUSE I THINK WHAT IS SO 

1375
00:52:51,240 --> 00:52:52,475
FUNDAMENTAL TO WHAT WE'RE TRYING

1376
00:52:52,475 --> 00:52:54,377
TO ACHIEVE IS TO GET THE 

1377
00:52:54,377 --> 00:52:56,078
SMARTEST, MOST TALENTED PEOPLE 

1378
00:52:56,078 --> 00:52:56,946
WORKING ON THE HARDEST PROBLEMS 

1379
00:52:56,946 --> 00:52:59,815
AND FOR ME WHEN I WAS GIVEN THE 

1380
00:52:59,815 --> 00:53:02,518
OPPORTUNITY TO COME TO NIH I 

1381
00:53:02,518 --> 00:53:03,352
WANTED TO TAKE THE OPPORTUNITY 

1382
00:53:03,352 --> 00:53:05,121
TO THANK NIH FOR ALL THE WORK IT

1383
00:53:05,121 --> 00:53:07,957
DOES TO REMOVING BARRIERS TO THE

1384
00:53:07,957 --> 00:53:09,525
SMARTEST PEOPLE WORKING ON THE 

1385
00:53:09,525 --> 00:53:10,826
HARDEST PROBLEMS.

1386
00:53:10,826 --> 00:53:13,829
THAT'S ME ON THE LEFT HAND 

1387
00:53:13,829 --> 00:53:14,063
CORNER.

1388
00:53:14,063 --> 00:53:17,233
BELIEVE IT OR NOT I OWN MORE 

1389
00:53:17,233 --> 00:53:18,901
THAN ONE OUTFIT.

1390
00:53:18,901 --> 00:53:21,571
NEXT TO ME IS LIZ THAT CAME UP 

1391
00:53:21,571 --> 00:53:24,340
WITH THE SCREENING POSITION AND 

1392
00:53:24,340 --> 00:53:30,580
STARTED HER LAB AT CARNEGIE 

1393
00:53:30,580 --> 00:53:34,183
MELON AND THE NEXT ONE I MET IN 

1394
00:53:34,183 --> 00:53:36,085
MY UNDERGRAD AND THOUGHT HE WAS 

1395
00:53:36,085 --> 00:53:37,720
SUPER WEIRD AND WASN'T PAYING 

1396
00:53:37,720 --> 00:53:41,824
ATTENTION AND IS NOW GETTING HIS

1397
00:53:41,824 --> 00:53:52,368
MASTER'S AT CARNEGIE MELLON AND 

1398
00:53:53,035 --> 00:53:55,605
TATIANA RODRIGUEZ GREW UP IN THE

1399
00:53:55,605 --> 00:53:56,505
APPALACHIAN MOUNTAINS IN 

1400
00:53:56,505 --> 00:53:59,075
MARYLAND, SUPER RURAL AREA, CAME

1401
00:53:59,075 --> 00:54:03,346
TO MY LAB AS A TECHNICIAN AND 

1402
00:54:03,346 --> 00:54:07,550
NOW DOING HER Ph.D. IN NYU AND 

1403
00:54:07,550 --> 00:54:08,784
ANOTHER DID Ph.D. WORK IN PENN 

1404
00:54:08,784 --> 00:54:11,454
AT THE AREA OF ADDICTION AND 

1405
00:54:11,454 --> 00:54:14,190
CAME TO MY LAB AND HELPS RUN IT.

1406
00:54:14,190 --> 00:54:20,296
HANNAH DID MOST HER WORK ON TA 

1407
00:54:20,296 --> 00:54:30,172
MODEL SPENT TIME IN DUBAI AND 

1408
00:54:30,172 --> 00:54:35,444
THE OTHER IS WORKING FON A BIO 

1409
00:54:35,444 --> 00:54:38,180
TECH TO TREAT MENTAL ILLNESS AND

1410
00:54:38,180 --> 00:54:44,086
ANOTHER HAS A LAB AT YALE AND 

1411
00:54:44,086 --> 00:54:46,188
ANOTHER DID A Ph.D. IN BIO 

1412
00:54:46,188 --> 00:54:47,857
CHEMISTRY IN DUKE AND HAD TWO 

1413
00:54:47,857 --> 00:54:49,225
KIDS DURING THE PANDEMIC AND 

1414
00:54:49,225 --> 00:54:50,826
REALIZED HOW IMPORTANT IT WAS TO

1415
00:54:50,826 --> 00:54:51,927
THINK ABOUT CHILDCARE IN 

1416
00:54:51,927 --> 00:54:53,095
SUPPORTING YOUNG SCIENTISTS AS 

1417
00:54:53,095 --> 00:54:55,064
THAT I WERE DOING THEIR 

1418
00:54:55,064 --> 00:54:56,499
IMPORTANT WORK.

1419
00:54:56,499 --> 00:55:00,136
NEXT I HAVE NICOLE AN Ph.D. IN 

1420
00:55:00,136 --> 00:55:06,208
DUKE IN NEUROLOGY AND ANOTHER IS

1421
00:55:06,208 --> 00:55:10,513
AT OREGON HEALTH SCIENCES 

1422
00:55:10,513 --> 00:55:14,183
ANOTHER WAS PART OF A DREAM TEAM

1423
00:55:14,183 --> 00:55:17,653
IN CRACKING THE CODE IS NOW A 

1424
00:55:17,653 --> 00:55:19,722
CARDIOLOGY FELLOW AT DUKE.

1425
00:55:19,722 --> 00:55:22,525
AND GWEN FINISHED WITH HER Ph.D.

1426
00:55:22,525 --> 00:55:24,827
IN NEURO BIOLOGY AT DUKE AND NOW

1427
00:55:24,827 --> 00:55:26,629
WORKING FOR A FOUNDATION.

1428
00:55:26,629 --> 00:55:28,497
AND THE FIRST PERSON I TOLD 

1429
00:55:28,497 --> 00:55:31,600
ABOUT THIS IDEA WAS FACULTY IN 

1430
00:55:31,600 --> 00:55:34,170
BIOMEDICAL ENGINEERING WORKING 

1431
00:55:34,170 --> 00:55:36,372
IN CARDIOLOGY AND FAMILY WAS 

1432
00:55:36,372 --> 00:55:38,207
ORIGINALLY THERE SERBIA AND CAME

1433
00:55:38,207 --> 00:55:40,443
ON BOARD TO HELP AND ANOTHER WAS

1434
00:55:40,443 --> 00:55:42,178
A Ph.D. STUDENT AND DID THE 

1435
00:55:42,178 --> 00:55:44,380
COMPUTATIONAL MODELLING NOW A 

1436
00:55:44,380 --> 00:55:45,548
POSTDOC AT STANFORD.

1437
00:55:45,548 --> 00:55:48,751
HALF HIS FAMILY MIGRATED FROM 

1438
00:55:48,751 --> 00:55:50,486
RUSSIA, THE OTHER HALF FROM 

1439
00:55:50,486 --> 00:55:52,054
UKRAINE.

1440
00:55:52,054 --> 00:55:56,559
FINALLY, RAINBOW HOTMAN FOUND 

1441
00:55:56,559 --> 00:55:58,494
THE RIGHT MUTATIONS IN THE CODE 

1442
00:55:58,494 --> 00:56:01,764
OF THE CONNEXIN PROTEINS.

1443
00:56:01,764 --> 00:56:04,734
THE DEVELOPED DEBILITATING 

1444
00:56:04,734 --> 00:56:05,768
MIGRAINES SO MUCH SO SHE 

1445
00:56:05,768 --> 00:56:10,172
COULDN'T LOOK AT A COMPUTER AND 

1446
00:56:10,172 --> 00:56:13,943
IS NOW RUNNING A LAB IN IOWA AND

1447
00:56:13,943 --> 00:56:16,879
AWARDED A NIH NEW INNOVATOR 

1448
00:56:16,879 --> 00:56:20,649
AWARD TO STUDY THE 

1449
00:56:20,649 --> 00:56:21,984
NEUROPHYSIOLOGY OF MIGRAINES.

1450
00:56:21,984 --> 00:56:23,385
THANK YOU AND I'M HAPPY TO TAKE 

1451
00:56:23,385 --> 00:56:23,652
QUESTIONS.

1452
00:56:23,652 --> 00:56:26,055
>> WE HAVE TIME FOR
QUESTIONS.

1453
00:56:26,055 --> 00:56:29,125
THE CME CODE FOR PEOPLE WHO MAY 

1454
00:56:29,125 --> 00:56:32,128
NOT HAVE CAUGHT IT, 57693.

1455
00:56:32,128 --> 00:56:34,930
LOOKS LIKE WE HAVE A QUESTION 

1456
00:56:34,930 --> 00:56:38,167
COMING -- NO.

1457
00:56:38,167 --> 00:56:39,001
YOU'VE GOT ONE RIGHT HERE.

1458
00:56:39,001 --> 00:56:42,138
>> THAT WAS AN ABSOLUTELY 

1459
00:56:42,138 --> 00:56:43,773
WONDERFUL LECTURE FOR MANY 

1460
00:56:43,773 --> 00:56:46,208
REASONS BUT I'M GOING TO BE 

1461
00:56:46,208 --> 00:56:53,349
SPECIFIC ON YOUR THOUGHTS ON THE

1462
00:56:53,349 --> 00:56:56,685
PATHWAY IN THE COMPULSIVE 

1463
00:56:56,685 --> 00:56:59,455
BEHAVIOR WHICH IS WHERE WE'RE 

1464
00:56:59,455 --> 00:57:00,623
SEEING HAVE YOU ADDED GIVING IT 

1465
00:57:00,623 --> 00:57:02,691
TO THE ANIMALS DO THEY ESCALATE 

1466
00:57:02,691 --> 00:57:05,261
FASTER?

1467
00:57:05,261 --> 00:57:08,230
>> WE HAVEN'T DONE THIS.

1468
00:57:08,230 --> 00:57:09,431
THE DATA'S ABOUT THREE MONTHS 

1469
00:57:09,431 --> 00:57:10,032
OLD.

1470
00:57:10,032 --> 00:57:12,501
I DO HAVE A GRADUATE STUDENT 

1471
00:57:12,501 --> 00:57:13,736
SUPPORTED BY YOU ALSO, THANK YOU

1472
00:57:13,736 --> 00:57:17,273
VERY MUCH, WHO IS LOOKING AT 

1473
00:57:17,273 --> 00:57:18,207
FENTANYL CONSUMPTION AND COCAINE

1474
00:57:18,207 --> 00:57:21,443
CONSUMPTION AND THINKING HOW TO 

1475
00:57:21,443 --> 00:57:22,778
REWIRE CIRCUITRY TO CHANGE THAT 

1476
00:57:22,778 --> 00:57:26,182
BEHAVIOR AS WELL.

1477
00:57:26,182 --> 00:57:36,659
WE DON'T HAVE AN ANSWER YET.

1478
00:57:37,593 --> 00:57:38,861
>> I DON'T KNOW IF ANYBODY
HAS 

1479
00:57:38,861 --> 00:57:44,700
LOOKED AT THE SPECIFIC ANIMALS.

1480
00:57:44,700 --> 00:57:45,034
I'M NOT SURE.

1481
00:57:45,034 --> 00:57:46,168
YEP.

1482
00:57:46,168 --> 00:57:50,172
>> KAF, GREAT TALK.

1483
00:57:50,172 --> 00:57:51,607
I APPRECIATE IT.

1484
00:57:51,607 --> 00:57:54,443
I HAVE A QUESTION ABOUT THE 

1485
00:57:54,443 --> 00:57:54,810
PHYSIOLOGY.

1486
00:57:54,810 --> 00:57:58,180
HAVE YOU GUYS -- THE FUNCTION OF

1487
00:57:58,180 --> 00:58:00,182
THE LENS Z WILL DEPEND ON WHERE 

1488
00:58:00,182 --> 00:58:02,184
IT FORMS ITS CONNECTIONS TO 

1489
00:58:02,184 --> 00:58:03,586
DENDRITES AND CELL BODY AND HAVE

1490
00:58:03,586 --> 00:58:05,521
YOU GUYS LOOKED AT WHERE IT 

1491
00:58:05,521 --> 00:58:07,223
FORMS THE CONNECTIONS AND WHAT 

1492
00:58:07,223 --> 00:58:08,991
IT DOES TO THE PHYSIOLOGY OF THE

1493
00:58:08,991 --> 00:58:09,925
CELL?

1494
00:58:09,925 --> 00:58:13,295
>> YEAH, NO, IF ONLY I HAD
A 

1495
00:58:13,295 --> 00:58:15,664
COLLABORATOR WHO STUDIED THAT 

1496
00:58:15,664 --> 00:58:19,935
AND WAS INTERESTED.

1497
00:58:19,935 --> 00:58:21,837
WE HAVEN'T DONE THAT.

1498
00:58:21,837 --> 00:58:23,505
FOR US THERE'S SO MUCH TO 

1499
00:58:23,505 --> 00:58:24,540
EXPLORE WITH A TOOL LIKE THIS 

1500
00:58:24,540 --> 00:58:25,741
AND SO MUCH TO LEARN AND A LOT 

1501
00:58:25,741 --> 00:58:27,543
OF IT FALLS OUT OF THE RANGE OF 

1502
00:58:27,543 --> 00:58:29,812
WHAT MY LAB DOES.

1503
00:58:29,812 --> 00:58:31,914
WE'RE HAPPY TO SHARE THE TOOL.

1504
00:58:31,914 --> 00:58:34,250
WE SHARED IT WITH A LOT OF LABS 

1505
00:58:34,250 --> 00:58:37,419
BUT IF THAT'S SOMETHING WE'RE 

1506
00:58:37,419 --> 00:58:39,388
INTERESTED IN TACKLING WE'LL GET

1507
00:58:39,388 --> 00:58:39,889
IT TO YOU.

1508
00:58:39,889 --> 00:58:42,992
>> COOL, MAN, THANK YOU.

1509
00:58:42,992 --> 00:58:46,962
>> A DOUBLE QUESTION HERE.

1510
00:58:46,962 --> 00:58:49,431
FIRST, CURIOUS ABOUT THE TIME 

1511
00:58:49,431 --> 00:58:49,632
LINE.

1512
00:58:49,632 --> 00:58:51,166
HOW LONG DID THIS TAKE?

1513
00:58:51,166 --> 00:58:52,668
YOU SAID A LONG TIME.

1514
00:58:52,668 --> 00:58:54,603
>> ARE YOU REFERRING TO
THE MICE

1515
00:58:54,603 --> 00:58:58,173
OR THE ENTIRE SCOPE OF THE 

1516
00:58:58,173 --> 00:58:58,908
PROJECT -- 

1517
00:58:58,908 --> 00:58:59,475
>> THE SCOPE.

1518
00:58:59,475 --> 00:59:00,976
HOW LONG IT TOOK TO GET TO THE 

1519
00:59:00,976 --> 00:59:04,113
MICE BECAUSE THE FOLLOW-UP 

1520
00:59:04,113 --> 00:59:07,950
QUESTION IS WHAT'S NEXT VIS A 

1521
00:59:07,950 --> 00:59:08,584
VIS ANIMALS?

1522
00:59:08,584 --> 00:59:13,188
>> IT WAS 2014 OR '15 WE
KNEW 

1523
00:59:13,188 --> 00:59:14,690
WHAT WE WERE DOING WASN'T GOING 

1524
00:59:14,690 --> 00:59:15,457
TO BE SCALABLE.

1525
00:59:15,457 --> 00:59:18,160
IT WAS 2018 WHEN I STARTED ON 

1526
00:59:18,160 --> 00:59:19,361
THE BRAIN INITIATIVE PANEL.

1527
00:59:19,361 --> 00:59:20,763
THAT ANCHORS THE MIDDLE OF THE 

1528
00:59:20,763 --> 00:59:21,196
TALK.

1529
00:59:21,196 --> 00:59:26,168
EVERYTHING UP TO THAT POINT WAS 

1530
00:59:26,168 --> 00:59:34,209
PROBABLY 2005 TO LIKE 2013.

1531
00:59:34,209 --> 00:59:37,880
>> AFTER MICE WHAT'S THE
NEXT 

1532
00:59:37,880 --> 00:59:41,583
ANIMAL MODEL?

1533
00:59:41,583 --> 00:59:43,752
>> I WON'T INTRODUCE THAT
NOW 

1534
00:59:43,752 --> 00:59:44,653
BECAUSE WE'LL BE HERE ANOTHER 

1535
00:59:44,653 --> 00:59:46,789
HOUR AND IT'S ANOTHER TALK THAT 

1536
00:59:46,789 --> 00:59:47,690
REQUIRES A LOT OF BACKGROUND 

1537
00:59:47,690 --> 00:59:48,590
INFORMATION SO I WON'T ANSWER 

1538
00:59:48,590 --> 00:59:51,327
THAT BUT IF YOU ASK ME AT THE 

1539
00:59:51,327 --> 00:59:53,128
RECEPTION I'M HAPPY TO GET INTO 

1540
00:59:53,128 --> 00:59:54,196
THAT BUT WE'RE ALREADY TESTING 

1541
00:59:54,196 --> 00:59:56,532
THAT ON HUMAN ORGANOIDS AS WELL 

1542
00:59:56,532 --> 00:59:58,167
TO MAKE SURE HUMAN BRAIN CELLS 

1543
00:59:58,167 --> 01:00:00,869
CAN TOLERATE THE PROTEIN AND 

1544
01:00:00,869 --> 01:00:02,371
CHANGE PHYSIOLOGY THERE AS WELL.

1545
01:00:02,371 --> 01:00:03,105
>> EXCELLENT.

1546
01:00:03,105 --> 01:00:04,373
>> ANY OTHER QUESTIONS?

1547
01:00:04,373 --> 01:00:05,007
ONE MORE.

1548
01:00:05,007 --> 01:00:05,975
>> VERY NICE TALK.

1549
01:00:05,975 --> 01:00:08,043
I HAD A QUESTION ABOUT THE 

1550
01:00:08,043 --> 01:00:08,477
STRESS.

1551
01:00:08,477 --> 01:00:10,879
SO THE MOUSE IS HANGING 

1552
01:00:10,879 --> 01:00:11,847
UPSIDE-DOWN, THAT'S THE ANXIETY.

1553
01:00:11,847 --> 01:00:14,650
SO YOU DID IT FOR ONE DAY AND 

1554
01:00:14,650 --> 01:00:18,721
THEN ANOTHER DAY.

1555
01:00:18,721 --> 01:00:20,155
WHOSE TO SAY THE THIRD DAY IT 

1556
01:00:20,155 --> 01:00:21,423
WOULDN'T BE DIFFERENT OR FOURTH 

1557
01:00:21,423 --> 01:00:22,157
DAY?

1558
01:00:22,157 --> 01:00:25,394
>> PEOPLE TESTED THAT.

1559
01:00:25,394 --> 01:00:26,962
THE ANIMAL'S BEHAVIOR KEEPS 

1560
01:00:26,962 --> 01:00:28,497
LOOKING MORE AND MORE STRESSED 

1561
01:00:28,497 --> 01:00:31,667
WHEN PEOPLE CHECKED FIVE AND SIX

1562
01:00:31,667 --> 01:00:34,169
DAYS IN A ROW.

1563
01:00:34,169 --> 01:00:38,173
THERE ARE OTHER MORE ROBUST WAYS

1564
01:00:38,173 --> 01:00:39,174
ECOLOGICALLY ANCHORED WAYS OF 

1565
01:00:39,174 --> 01:00:40,309
STRESSING MICE.

1566
01:00:40,309 --> 01:00:42,077
WE JUST LIKE THE SIMPLICITY 

1567
01:00:42,077 --> 01:00:47,516
BECAUSE WE CAN RECORD ELECTRICAL

1568
01:00:47,516 --> 01:00:49,418
ACTIVITY TO IDENTIFY THE 

1569
01:00:49,418 --> 01:00:50,019
CIRCUITRY.

1570
01:00:50,019 --> 01:00:52,521
FOR TESTING AND IF WE ULTIMATELY

1571
01:00:52,521 --> 01:00:54,890
STRESS IN OTHER STRESS PARADIGMS

1572
01:00:54,890 --> 01:00:56,892
WHETHER IT'S CHRONIC OR 

1573
01:00:56,892 --> 01:00:57,826
UNPREDICTABLE STRESS BUT THE 

1574
01:00:57,826 --> 01:01:02,197
IDEA IS YOU SHOULD BE ABLE TO 

1575
01:01:02,197 --> 01:01:05,067
TARGET THE SAME CIRCUIT.

1576
01:01:05,067 --> 01:01:06,969
>> COULDN'T THE MOUSE GET
USED 

1577
01:01:06,969 --> 01:01:08,570
TO BE HANGING UPSIDE-DOWN?

1578
01:01:08,570 --> 01:01:12,174
>> SO THIS IS WHY I DON'T
WANT 

1579
01:01:12,174 --> 01:01:15,244
TO MAKE CLAIMS ABOUT WHETHER THE

1580
01:01:15,244 --> 01:01:17,546
MOUSE'S BEHAVIOR IS GOOD OR NOT.

1581
01:01:17,546 --> 01:01:19,448
BECAUSE THERE'S LOTS OF WAYS AN 

1582
01:01:19,448 --> 01:01:21,183
ANIMAL CAN ADAPT TO AN 

1583
01:01:21,183 --> 01:01:22,451
ENVIRONMENT AND SOME MIGHT 

1584
01:01:22,451 --> 01:01:24,887
ERRING IT MAKES SENSE TO STOP 

1585
01:01:24,887 --> 01:01:30,526
LIKE FIGHTING SO HARD ABOUT A 

1586
01:01:30,526 --> 01:01:33,195
SITUATION AND SAVE TIME AND THE 

1587
01:01:33,195 --> 01:01:34,830
INVESTIGATOR WILL TAKE YOU DOWN 

1588
01:01:34,830 --> 01:01:37,800
AND DON'T WANT TO MAKE CLAIMS 

1589
01:01:37,800 --> 01:01:39,668
WHETHER IT'S GOOD OR BAD SO YOU 

1590
01:01:39,668 --> 01:01:41,804
DON'T BELIEVE IT'S DEPRESSION 

1591
01:01:41,804 --> 01:01:42,671
BUT IT'S STRESS AND IT DOES 

1592
01:01:42,671 --> 01:01:43,906
CAUSE A CHANGE IN BEHAVIOR AND 

1593
01:01:43,906 --> 01:01:47,142
CAN USE THAT AS A WAY TO 

1594
01:01:47,142 --> 01:01:47,943
IDENTIFY CIRCUITRY.

1595
01:01:47,943 --> 01:01:49,745
>> SO IF THERE'S NO MORE 

1596
01:01:49,745 --> 01:01:50,779
QUESTIONS, LET'S THANK THE 

1597
01:01:50,779 --> 01:01:54,383
SPEAKER ONE MORE TIME.

1598
01:01:54,383 --> 01:01:56,819
>> THERE'S A RECEPTION AS 

1599
01:01:56,819 --> 01:01:57,152
MENTIONED OUTSIDE.