The depressed brain: sobering and hopeful lessons
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>>GOOD AFTERNOON, EVERYONE. WELCOME TO THE WEDNESDAY AFTERNOON LECTURE SERIES. GOT A DISTINGUISHED PRESENTATION TODAY FROM DR. HUDA AKIL. TOPIC IS DEPRESSED BRAIN: SOBERING AND HOPEFUL LESSONS. I’M ABLE TO LEARN BECAUSE SHE’S BEEN INTERVIEWED ABOUT THAT SHE WAS INSPIRED BY MARIE CURIE WHO MOVED FROM POLAND TO PARIS TO FOLLOW A DREAM TO BECOME A SCIENTIST. HEARING THOSE ASPIRATION, SHE DREAMED ABOUT GOING TO AMERICA. THAT SEEMS LIKE WHAT’S HAPPENING AND BEEN A GREAT CONTRIBUTION TO NEUROSCIENCE AS A RESULT. SHE GOT HER UNDERGRADUATE DEGREE AT THE AMERICAN UNIVERSITY OF BAY ROOT AND ALSO MASTERS DEGREE IN PSYCHOLINGUISTICS THEN CAME TO AMERICA TO GET A Ph.D. IN PSYCHOBIOLOGY APP AND NEUROSCIENCE AT UCLA. AFTER A POST DOC AT STANFORD WHERE I GATHERED SHE ENCOUNTERED OTHER PEOPLE, SHE THEN JOINED FACULTY AT UNIVERSITY OF MICHIGAN HAVE WHERE SHE’S BEEN SINCE 1978 RISING THROUGH THE RANGES RATHER QUICKLY AND NOW SERVING AS CODIRECTOR OF THE MOLECULAR AND BEHAVIORAL NEUROSCIENCE INSTITUTE. I WAS FORTUNATE TO BE AT MICHIGAN DURING NINE OF THOSE YEARS AND OVERLAPPING WITH HUDA WAS A PLEASANT EXPERIENCE INDEED BECAUSE OF THE OPEN COLLABORATIVE WAY IN WHICH SHE HAS APPROACHED ALL THE SCIENCE SHE HAS UNDERTAKEN. A MAJOR FOCUS OF HER CURRENT RESEARCH EFFORT IS BOTH TO DEVELOP ANIMAL MODELS TO UNDERSTAND GENETIC AND DEVELOPMENTAL BASISES OF DIFFERENCES IN TEMPERAMENT, ESPECIALLY IMPLICATIONS FOR ANXIETY AND DEPRESSION BUT ALSO TO STUDY HUMAN POSTMORTEM BRAINS AND IDENTIFY PATHWAYS SUCH AS FIBER GROWTH FACTORS THAT ARE INVOLVED IN MAJOR DEPRESSION AND I SUSPECT SHE’LL BE TALKING ABOUT SOMETHING ABOUT THAT. SHE’S MEMBER OF NATIONAL ACADEMY SCIENCES, WINNER OF — SHE’S BEEN PAST PRESIDENT OF THE AMERICAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY AND SOCIETY OF NEUROSCIENCE, AN NIH GRANTEE OVER MANY YEARS. I’M HAPPY TO SAY SHE’S CURRENTLY A MEMBER OF THE ADVISORY COMMITTEE TO THE DIRECTOR SO WE’LL BE KEEPING HER BUSY WITH THE CURRENT MEETING. PLEASE JOIN ME IN WELCOMING DR. HUDA AKIL. [APPLAUSE]>>THANK YOU. IT’S AN HONOR FOR ME TO BE GIVING THIS LECTURE. I SEE FRIENDS, STUDENTS, COLLEAGUES, COLLABORATORS, PEOPLE WHO HAVE AGREED WITH US SCIENCE TIFFLY AND PEOPLE WHO ARE DISAGREED AND I LOVE YOU ALL. SO I ALSO WANT TO, YOU KNOW, THANK MY ONGOING CONTINUING SUPPORT FOR 40 YEARS FROM THE NIH, ESPECIALLY THE NIMH, NIDA AND ALSO THE OFFICE OF NEIGHBOR RESEARCH AND THE PHYSICAL CONSORTIUM. I THINK I RECEIVED ONE OF THOSE VERY FIRST POST DOCTORAL FELLOWSHIP THAT THE NATIONAL INSTITUTES OF DRUG ABUSE EVER GAVE, SO MAYBE IT WAS MONEY NOT WASTED, I HOPE. WHILE I’M THANKING PEOPLE I DEFINITELY WANT TO THANK MY COLLABORATOR, STAN WATTSON WHO IS ALSO MY HUSBAND AND WE COLLABORATE OUR STUDENTS, TRAINEES, WE CALL THEM THE WAKEEANS AND I HOPE YOU WILL KEEP AN EYE ON THEIR NAMES IN THE CORNER OF EACH OF THE SLIDES, THE SCIENTIFIC SLIDES. I’M ALSO GOING TO TALK ABOUT THE RESULTS OF WORK FROM THIS VERY INTERESTING EXPERIMENT IN SCIENCE IN A WAY AND IT’S TEAM SCIENCE CALLED THE [INDISCERNIBLE] NEUROPSYCHIATRIC RESEARCH CONSORTIUM. FOR A WHILE WE ALSO HAD A COUNTY CENTER WHICH WAS GREAT AND THEY WERE VERY COMPLEMENTARY ARE KIND OF PUBLIC/PRIVATE COLLABORATION. THESE ARE THE UNIVERSITIES INVOLVED: MICHIGAN, UC IRVINE, STANFORD, COLONEL, AND THE HUDSON ALPHA INSTITUTE AND HERE ARE THE DIRECTORS AT EACH ONE OF THE SITES, AND IT’S BEEN REALLY FUN BECAUSE IT’S A MIX OF PSYCHIATRY, NEUROSCIENCE, GENETICS AND IT’S ABOUT A HUNDRED ACTUAL SCIENTISTS INVOLVED IN THIS AND IT’S KIND OF A — IT’S A LESSON NO — IN HOW TO DO THINGS IN A DIFFERENT DOMAIN. MY TOPIC IS ABOUT MOOD DISORDERS, ESPECIALLY DEPRESSION AND I DON’T NEED TO TELL YOU ALL THIS IS A HUGE BURDEN ON HUMANITY ALL TOGETHER AND ON THIS COUNTRY, IN PARTICULAR, AND IT’S A VERY PAINFUL AND HARD-TO-DEFINE IN THIS. IT’S ASSOCIATED WITH SEVERE PSYCHOLOGICAL PAIN AND A LOT OF DIMENSIONS OF CHANGES, SOME OF THEM ARE AFFECTIVE BUT SOME OF THEM ARE ALSO COGNITIVE, AUTONOMIC, MOTOR, BEHAVIORAL, LOTS OF BOTH PHYSICAL, COGNITIVE AND AFFECTIVE SYMPTOMS. MULTIPLE CLASSES, MOST OF YOU KNOW OF COURSE ABOUT BOTH UNIPOLAR AND BIPOLAR DEPRESSION. ONE REASON THE BURDEN IS HUGE IS BECAUSE THIS HAPPENS EARLY IN LIFE AND CAN BE LIFELONG IF NOT TREATED RIGHT. IT’S OFTEN UNDERDIAGNOSED. IT IS IS NOT HANDLED BY THE SOCIETY BY EVEN BY PHYSICIANS AND IT’S STIGMATIZED AND AS A RESULT WE REALLY STILL HAVE A LONG WAYS TO GO IN FINDING TREATMENT. A GOOD CHUMP OF THE PEOPLE HAVE TREATMENT — AS I WAS DISCUSSING WITH VARIOUS COLLEAGUES TODAY, IT’S NOT CLEAR HOW MUCH OF THIS IS GENETIC AND HOW MUCH OF THAT COMES ABOUT BECAUSE YOU RUN OUT OF NEUROMRAS TIS IS I AND THERE’S A LOT TO LEARN AND WE HAVE NOT HAD BRAND NEW TYPES OF ANTIDEPRESSANTS FOR A WHILE. A VERY BIG PART OF THE CHALLENGE IS THAT MOOD AS A CONCEPT IS NOT AS EASY TO WRAP YOUR BRAIN AROUND TO EVEN COMPARE TO ANOTHER BRAIN DISORDER LIKE A MOVEMENT DISORDER. IT’S A CONCEPT AND IT’S HARD TO EVEN DEFINE TEMP ROR RAILROADLY LIKE SOME PEOPLE SAY I HAVE THIS MOOD THIS MOMENT AND WE TALK ABOUT MOOD DISORDERS WE’RE TALKING ABOUT PROTRACTED CHANGES. I THINK OF IT OPERATIONALLY FOR ME AS A BIOLOGICAL MECHANISM THAT WE HAVE THAT IS ADRAPTIVE WAY OF TELLING US HOW WE ARE DOING IN THE WORLD. WHY SHOULD WE HAVE MOODS? WHAT’S THE POINT OF MOODS? AND TO ME IT’S A WAY OF INTEGRATING INFORMATION ABOUT WHEN WE ARE IN THE WORLD BOTH INTERNALLY HOW OUR BODY IS DOING AND HOW WE ARE DOING IN OUR ENVIRONMENT, A AND IF EVERYTHING IS HUMMING ALONG THEN WE’RE IN A GOOD MOOD AND IF SOMETHING IS EITHER HAPPEN THAT WAS MAD OR IS THREATENING TO BE BAD THEN OUR MOOD IS NOT SO GOOD. SO MOODS THEN CAN ALSO ORGANIZE BEHAVIOR, MOTIVATE YOU TO AVOID BAD THINGS, AND SUDDENLY START SHRINKING WITH ALL THESE OTHER FUNCTIONS THAT THE BRAIN HAS TO DO COGNITIVE MEMORY, AFFECTIVE AND THE LIKE. SO WHEN YOU HAVE A MOOD DISORDER YOU’RE PREVAILING EMOTIONAL TONE IS DISTORTED AND SIT NOT NECESSARILY WELL HOOKED TO REALITY, IT’S LOST THIS ABILITY TO GIVE YOU ACCURATE FEEDBACK ABOUT THE WORLD. SO IT’S EITHER STRUCK IN A NEGATIVE SITUATION AND THAT IS MAJOR DEPRESSION, OR IT’S ISOLATING IN ITS OWN RIGHT AND NOT COUPLED TO THE CURRENT REALITY OF THE SITUATION SO YOU CAN THINK OF IT AS AN ALTERED FEEDBACK FUNCTION AND YOU CAN THINK OF IT AS INTERFERING WITH WHAT I CALL EMOTIONAL EXECUTIVE FUNCTION, YOUR ABILITY TO PRIORITIZE, YOUR ABILITY TO DECIDE WHAT SHOULD BE IN THE FOREFRONT RIGHT NOW, WHAT YOU SHOULD BE DOING AS USING YOUR BRAIN AS AN EXECUTIVE VERSUS WHAT CAN SHOULD SAY BECAUSE IT’S NOT SO CRITICAL? SO OUR EFFORTS AT UNDERSTANDING THESE ILLNESSES HAVE BEEN RATHER DIFFICULT. I LIKE THE CHARACTERIZATION THAT MOOKERGI GAVE OF THE SEARCH FOR ANSWERS FOR CANCER IN THE EMPEROR OF ALL MALLTIES. HE TALKS ABOUT THE HIP NO TICK DRIVE FOR UNIVERSAL SOLUTION WHICH IS WE HAVE DEFINITELY SUFFERED FROM AND THE QUESTION SI [INDISCERNIBLE] BETWEEN DEFEATISM AND HOPE WHICH WE CONTINUE TO SUFFER FROM. SO WE REALLY NEED TO FIGURE OUT HOW TO WRAP OUR BRAIN AROUND STUDYING THIS COMPLEX ILLNESS OR PROBABLY SETS OF ILLNESSES — IT’S NOT ONE — AND UH HOW TO GO ABOUT IT IN A REALISTIC WAY, NOT TRYING TO FIND EASY UNIVERSAL SOLUTIONS BUT ALSO NOT BECOMING DEFEATED ABOUT IT, AND AS A BASIC SCIENTIST WHO’S BEEN IN THE BUSINESS FOR OVER 40 YEARS YOU GET TO THIS PHASE WHERE YOU ASK YOURSELF SOME QUESTIONS AND TO ME IT’S VERY SIFSHLING SO I’VE WONDERED HOW DO WE REALLY HELP AS BASIC SCIENTISTS. AS NEUROSCIENCE GENETICS HAVE WE OFFERED PSYCHIATRY ENOUGH INFORMATION, ENOUGH SUBSTANTIAL HELP IN UNDERSTANDING ALL DISORDERS BUT IN THIS CASE THIS ONE AND IF SO, WHY NOT? ARE WE DEPLOYING THE RIGHT KIND OF ANIMAL MODELS? ARE WE REALLY MODELLING WHAT WE PRETEND TO BE MODELLING NOT JUST TO GET THE GRANT MONEY BUT TO ACTUALLY UNDERSTAND AND SOLVE THE PROBLEMS? DO WE HAVE SOME BLIND SPOTS? THINGS THAT WE DON’T THINK ABOUT THAT WE SHOULD BE THINKING ABOUT EVEN IF THEY ARE HARD? ONE OF THEM, I WILL GIVE YOU IS VARIABILITY I FEEL THAT BASIC SCIENTISTS HATE VARIABILITITY. THEY THINK OF IT AS 124I7K TO BE ASHAMED OF WHEREAS CLINICIANS THINK OF IT A AS SOMETHING THAT IS TO BE UNDERSTOOD AND EMBRACED SO I WILL HAVE DONE SOMETHING ABOUT THAT BY THE END OF THE TALK, I HOPE, AND THEN I E PEOPLE LIKE WE ARE TOO DIE COT NISTS, WE WANT GENE VERSUS ENVIRONMENT AND I THINK WE NEED TO COME UP ESPECIALLY FOR THESE KINDS OF DISORDER WITH A MORE INTEGRATED VIEW AND WE NEED TO USE ALL OF THIS TO TRY AND UNDERSTAND MORE ABOUT CAUSES AND ACTUAL CURES, BUT OF COURSE THE MOST HUMBLING QUESTION OF ALL IS, ARE WE SMART ENOUGH? AM I SMART ENOUGH? VERY QUESTIONABLE, BUT IT’S WORTH A TRY. SO ONE OF THE QUESTIONS IN WHETHER WE HAVE BEEN SMART ENOUGH IS HAVE WE OVERREDUCED THE PROBLEM? SO WE’VE BEEN, YOU KNOW, IN NEUROSCIENCE WE ARE ALWAYS FIGHTING THE BATTLE OF STIGMA AND ONE OF THE WAYS THAT WE HAVE RESPONDED TO THE ISSUE OF STIGMA IS THAT WE HAVE TO TELL PEOPLE, IT’S BIOLOGY, IT’S NOT SOMEBODY’S FAULT. THEY’RE NOT BEING LAZY, THEY’RE NOT BEING JUST NOT MOTIVATED BECAUSE THEY’RE TRYING TO GIVE YOU A HARD TIME, BUT THIS IS A BRAIN ILLNESS AND SO THAT IS DEFINITELY TRUE, BUT THEN IT’S EASY TO SAY, IT’S THIS CHEMICAL IMBALANCE OR THAT CHEMICAL IMBALANCE AND SOMETIMES WE BELIEVE OUR OWN PR, AND THE OTHER THING THAT I THINK WE TEND TO FORGET IS HOW DYNAMIC THIS IS, THAT PEOPLE AREN’T LIVING A LIFE THAT LIVING A LIFE WITH CERTAIN FEELINGS, CHANGE IN BEHAVIOR, BEHAVIOR CHANGES THE BRAIN, IT CHANGES FEELINGS, AND THERE IS A CYCLE THAT DEVELOPS OVER A LIFE COURSE AND AS A BASIC SCIENTIST, I DON’T FEEL LIKE WE HAVE TAKEN CARE TO MODEL THIS WELL ENOUGH IN OUR OWN ANIMAL MODELS. SO THIS IS MY USUAL KIND OF WAY OF SAYING, WE CAN’T JUMP FROM ARE GENES TO BEHAVIOR, WE CAN’T JUMP FROM GENE TO CLINICAL. IF THERE IS A BRAIN IN THE MIDDLE OF YOUR BUSINESS, IT’S THERE. YOU KNOW, IT HAS A LIFE OF ITS OWN SO OF COURSE IT IS IMPACTED BY E GENES, IT IS CHANGED BY DEVELOPMENT, IT’S NOT APPLIED BY HORMONES. IN THE ENVIRONMENT IT SITS IN THE CASE OF DEPRESSION OFTEN TIMES YOU NEED MULTIPLE SENSORS BEFORE YOU SEE EPISODE BUS THEN THIS CAN TAKE ON A LIFE OF ITS OWN AND EVENTUALLY EPISODES START TO HAPPEN EVERYBODY IF YOU CAN’T IDENTIFY AN EXTERNAL STRESSOR BUT VERY IMPORTANT PARTICULAR IS THAT THE BEHAVIOR GOES BACK AND REMODELS THE BRAIN AND THESE REMODELLING ISSUES ARE NOW THE FEW STEPS AWAY FROM THE ORIGINAL GENETICS AND OWL OF THIS IS KIND OF COMING TOGETHER IN ISSUES OF DIAGNOSIS AND PREDICTION AND TREATMENT. SO THIS IS REALLY WHY — SHOULD WE STUDY GENES, SHOULD WE STUDY THE BRAIN? A FEW YEARS AGO A FEW OF US TRIED TO KIND OF GET TOGETHER AND WRITE THIS ARTICLE ABOUT THE FACT THAT MAYBE THE AREA WHERE WE SHOULD ALL BE FOCUSING IS MORE ON NEUROCIRCUIT AS AN INTERMEDIARY IN THE BRAIN BETWEEN WHERE THE GENES AND CELLS ARE, YOU KNOW, INTEGRATING THE ACTIVITY AND THEN WHAT’S DRIVING THE BEHAVIOR. THAT IT’S IMPORTANT TO NOT DO AN EITHER OR BUT TO FIND WAYS OF INTEGRATION AND I CANNOT TELL YOU ALL HOW HAPPY I AM THAT THE BRAIN INITIATIVE FOCUSES ON NEUROCIRCUIT. I THINK YOU GOT IT RIGHT. IT IS VERY CLEAR THAT DIFFERENT COMBINATIONS OF GENETIC VARIANCE CAN CAUSE DISRUPTION AT THE NEUROCIRCUIT LEVEL THAT CAN LOOK THE SAME BEHAVIORAL AND CLINICALLY. IT’S FAIR BY NOW THAT UH YOU CAN HAVE THE SAME GENETIC VARIABILITITY AS FAR AS WE CAN SEE BUT GET DIFFERENT OUTCOME AND WE CANNOT GET AWAY FROM NEEDING TO LOOK AT IT AT A D DIFFERENT LEVEL OF INTEGRATION. SO WE HAVE BEEN INVOLVED IN CONSORTIUM IN A NUMBER OF STUDIES AND WHAT YOU’LL SEE IS THAT FOR ME IN THIS TALK IT’S NOT AN EITHER/OR, BUT WE NEED TO THINK ABOUT GENES, WE NEED TO THINK ABOUT ENVIRONMENT AND ANIMAL MODELS AND REALLY MY HOPE IS TO CONVINCE THAT KIND OF THINKING START. SO YOU CAN SEE — CAN YOU SEE ME? YEAH. [LAUGHTER] I’M VERY IMPORTANT. [LAUGHTER] SO THIS IS ONE OF THOSE PAPERS WITH PSYCHIATRIC GENOMICS CONSORTIUM THAT HAS STUDIED 60,000 PSYCHIATRIC SUBJECTS AND IT’S BEEN INTERESTING TO WATCH WHAT COMES OUT OF IT BUT WHAT IE LOVED IN THE LATEST ANALYSIS WHICH HAS BEEN THOUGHTFUL AND INTERESTING IS THAT THERE ARE PATHWAYS THAT ARE EMERGING THAT ARE SHARED BETWEEN DIFFERENT PSYCHIATRIC DISORDERS AND ONE OF THEM IS HISTONE METHODLATION. THESE ARE EPIGENETIC MODIFICATIONS AND THEY’RE EVEN [INDISCERNIBLE] IS TO SAY THAT THERE IS A GENETICS OF EPIGENETICS WHICH TELLS YOU THERE IS A JE TI NE TICK OF RESPONSIVENESS TO THE ENVIRONMENT WHICH MIGHT BE REALLY AT THE HEART OF THE MATTER OF WHAT WE’RE DEALING WITH IN PSYCHIATRY. HERE IS EXAMPLE OF ENTIRE PATHWAYS. [INDISCERNIBLE] I DON’T EXPECT TO YOU BE ABLE TO READ THEM BUT [INDISCERNIBLE] CHARACTERISTIC OF EITHER BIPOLAR, SCHIZOPHRENIA OF MAJOR DEPRESSION AND WHAT YOU SEE IS THERE ARE SOME PATHWAYS UNIQUE TO THE CLASSICAL DIAGNOSIS LIKE POST SYNAPTIC DENSITIES POPS UP HIGH IN SCHIZOPHRENIA BUT NOT OTHERS BUT THERE ARE PATHWAYS THAT ARE SHARED WHERE THOSE ARROWS ARE ALL POINTED TO HISTONE METHODLATION AS A PATHWAY THAT’S A ALTERED. EVEN WHEN YOU DO COMBINE ANALYSES OF INDIVIDUAL GENES AND YOU DO NETWORK BASED ON DEVELOPMENT — I DON’T HAVE TIME TO GO INTO IT — AND EXPRESSION, THERE ARE SOME INTERESTING GENES THAT POP UP THAT I WANT TO POINT OUT TO YOU BECAUSE THEY’RE GOING TO COME BACK. WE CLING TO THOSE GENES THROUGH OUR ANIMAL MODELS AND HUMAN STUDIES. THIS [INDISCERNIBLE] IS 2015 SO OBVIOUSLY IT DIDN’T DRIVE THE RESEARCH BUT I LOVE THE FACT THAT WE HAVE SOME CONVERGENCE. THESE ARE CALCIUM GENES THAT POP UP AS BEING CRITICAL AMONG THOSE SHARED GENES BETWEEN THE PSYCHIATRIC DISORDERS, MORE IMPORTANT IN SOME THAN OTHERS. YOU CAN SEE [INDISCERNIBLE] RECEPTOR R 1 IS ANOTHER ONE THAT I JUST HIGHLIGHTED, AND YOU CAN ALSO SEE HDAK FOUR. SO I JUST KIND OF KEEP THEM IN THE BACK OF YOUR MIND, I’LL COME BACK TO THEM LATER. SO HOW DO WE GO ABOUT TAKING SOMETHING ON LIKE THIS? AND VERY BROADLY SPEAKING IN OUR GROUP, WE HAVE LOOKED AT TWO APPROACHES; ONE IS MORE HYPOTHESIS-DRIVEN. WHAT IS IT WE KNOW ABOUT BIOLOGY STRESS GENE INTERACTION, YOU KNOW T CREATURE IN THEIR ENVIRONMENT? CAN WE COME UP WITH SPECIFIC HIGH POT SOOES SOOES AND MODEL THEM. THE OTHER IS MORE DISCOVERY-DRIVEN. IN ALL CASES WE GO BETWEEN ANIMAL AND HUMAN BOTH POST MORTEM AND LIVING AND WE CAN START IN THE ANIMAL OR HUMAN BUT THE HOPE IS TO ALWAYS GO INTO THE LIVING VIJ. SO I’M GOING TO TAKE JUST — INDIVIDUAL. SO I’M GOING TO TAKE A UH FEW MINUTES TO TELL YOU ABOUT AN EXAMPLE OF HYPOTHESIS-DRIVEN MODEL AND I LIKE TO GIVE YOU JUST A COUPLE OF MESSAGES OUT OF IT. THIS IS AN INDUCIBLE ANIMAL WHERE WE OVEREXPRESSED THE STRESS REACCEPT SOR ONLY IN THE FOREBRAIN — RECEPTOR ONLY IN THE FOREBRAIN, AND IT IS INDUCIBLE SO WE CAN TURN IT ON AND OFF AT WILL. AND SO YOU CAN SEE THAT THE INDUCTION WORKS AND IT’S VERY SELECTIVE. THIS IS THE HIPPOCAMPUS, NOT EYE BROUS AND EYES. YOU CAN SEE IT’S SELECTIVE WHEN WE DO TURN IT ON. WE DID THIS STUDY WHERE WE TURNED IT ON AT DIFFERENT TIME NPS IS THE LIFE SPAN OF THE ANIMAL AND THEIR AGES AND YOU CAN TURN IT ON EITHER THROUGHOUT THE LIFE. WE HAD A MOD SOL WE KNEW WHAT TO EXPECT SO WE REPLICATED IT BY TURNING ON THE OVEREXPRESS PRESENTATION IN THIS INDUCIBLE ONE THROUGHOUT THE LIFE OR ONLY BEFORE WEANING, OR STARTING AT WEANING THROUGHOUT THE LIFE. ALL THE TESTING IS ON ADULTS. SO THESE ANIMALS AND THESE ANIMALS BOTH HAVE OVEREXPRESSING GLUCOCORTICAL RECEPTOR. THESE GUYS HAVEN’T SEEN IT FOR A FEW WEEKS. SO WHAT WE SEE IS WITH THE LIFELONG OVEREXPRESSION WE REPLICATE SOMETHING WE’VE SEEN BEFORE THAT IF YOU OVEREXPRESS THE STRESS RECEPTOR IN THE HIPPOCAMPUS YOU MAKE ANIMALS MORE ANXIOUS WHICH IS NOT THAT SHOCKING IN THAT YOU KNOW THIS IS SOMETHING THAT STRESS AND YOU SHOULD BE NERVOUS IF YOU HAVE A MORE ACTIVE MOLECULES THAT STRESS. SO YOU CAN SEE LESS ENTRY IN THE OPEN ARMS, ELEVATED [INDISCERNIBLE] MORE LATENT IS I TO ENTER MULTIPLE MEASURES SHOWING. ACTUALLY ANIMALS ARE MORE PRONE TO DEPRESSION [INDISCERNIBLE]. THEY ARE ALSO VERY REACTIVE TO ANTIDEPRESSANTS SO IN THAT WAY THEY’RE MORE [INDISCERNIBLE] OF BIPOLAR PATIENT, ANXIOUS BUT [INDISCERNIBLE] AND REACTIVE. THIS IS WHAT HAPPENS IF YOU EXPRESS THE RECEPTOR ONLY BEFORE WEANING AND THEN SHUT IT OFF AND IT’S COMPLETELY GONE WHEN YOU ARE DOING ADULT TESTING. IT IS JUST AS STRONG A PHENOTYPE AS THE LIFE-LONG EXPRESSION. AND THIS IS WHAT HAPPENS WHEN YOU DO IT AFTER WEANING. THEY LOOK MUCH MORE LIKE THE WISE-TYPE ANIMALS. SO THERE IS A WINDOW IN WHICH YOU OVEREXPRESS THE RECEPTOR AND YOU GET A LIFE-LONG PHENOTYPE. AFTER THAT, THE SYSTEM IS SET AND THE ANIMAL SEEMS PROTECTED. WHEN WE DO GENE EXPRESSION PROFILING ON THESE ANIMALS AND WE’VE DONE IT IN A COUPLE OF WAYS. ONE PLACE WE SEE BIGGEST CHANGES IS IS HIPPOCAMPUS IN [INDISCERNIBLE] AS OPPOSED TO THIS OTHER AREA [INDISCERNIBLE] AND WE SEE SOME GENES THAT ARE UP REGULATED, SOME ARE DOWN REGULATED, AND A LOT OF THEM ARE SHARED BETWEEN THE LIFE-LONG AND EARLY LIFE MODEL. SO TELLING US THAT THESE MIGHT BE ACTUALLY REALLY IMPORTANT IN THE PHENOTYPE, THE UNSHARED ONES DON’T, YOU KNOW, MAY NOT REPLICATE THE PHENOTYPE. HERE’S WHAT’S INTERESTING IS A LOT OF THE GENES THAT COME UP ALSO HAVE COME UP IN SOME OF THE BIPOLAR GENETIC STUDIES. THIS IS ONE GENE I HIGHLIGHTED FOR YOU IN THE NETWORK THAT I SHOWED YOU BEFORE. IT’S ONE OF THOSE GENES THAT IS SIGNIFICANTLY L ALTEREDED IN THE LIFE-LONG ANIMAL AND IN THE EARLY-LIFE ANIMAL BUT NOT DIFFERENT BETWEEN EARLY-LIFE AND LIFE-LONG. SO SIT A GENE THAT MIGHT BE IMPORTANT. SO AND WE HAVE DONE INTERVENTION IN THESE ANIMALS TO SHOW IT’S FUNCTIONALLY IMPORTANT OR NOT, BUT THE POINT IS THAT WE CAN START FROM SPECIFIC GENES WHERE WHETHER WE THINK ABOUT THEM OR BRING THEM FROM THE GENETIC STUDIES, WE CAN CREATE VERY BRAIN-SPECIFIC MODELS AND START TO STUDY THE FUNCTION AND I’VE SHOWN YOU AN EXAMPLE GREATER ANXIETY DEPRESSION RESPONSIVENESS TO DRUG AND VERY EARLY LIFE INDUCTION WHICH I I REALLY WAS NOT EXPECTING IT TO BE NEARLY THAT CLEAR-CUT AS IT TURNED OUT TO BE. SO FOR THE REST OF THE TALK, I’M GOING TO SWITCH OVER AND TALK TO YOU ABOUT A MORE DISCOVERY APPROACH WHERE WE DIDN’T HAVE A HYPOTHESIS. WE WENT IN OPEN-ENDED IN THE CONTEXT OF THE PHYSICAL CONSORTIUM. THERE WE ARE INVOLVED IN THIS ON THE GENETIC AND GENOMIC STUDY THAT ARE PART OF THIS BIG CONSORTIA SO WE HAVE ACCESS TO A BRAIN AING AT UC IRER VINE WHERE WE DO ANALYSIS WITH DIFFERENT TYPES OF PROFILING STUDIES. WHEN WE STARTED WITH THIS APPROACH WE DIGIT PRETEND WE KNEW WHERE DEPRESSION OR SCHIZOPHRENIA OR BY POLAR WERE. WE HAVE THESE THREE TYPES, WE JUST TOOK ALL BRAIN REGIONS WE COULD GET OUR HANDS ON AND THEN WE DID MUCH BETTER DISSECTION. SO THE WATTSON LAB IS GOOD AT TAKING HUMAN BRAIN AND MARKING IT WITH VARIOUS MARKERS AND DISSECTING SPECIFIC GROUP WITH LASERER CAPTURE AND DOING ANALYSIS, SOMETIMES DISSECTIONS ARE BLOTTERED WITH THAT AND MORE AND MORE WE’RE TRYING TO ADAPT OF THE CLARITY METHOD TO TRY AND GET A LOT MORE BANG OUT OF OUR BUCK AND 3-D. THIS IS WORKING WELL IN ANIMALS. IT’S STILL IN THE WORKS FOR THE HUMAN BRAIN. SOAR VERY EARLY ON ONE OF THE THINGS WE SAW IS THAT [INDISCERNIBLE] DOES SEEM SEVEN WITH OLD MICRORAY TECHNOLOGY THERE IS A DIFFERENT SIGNATURE OF THE ILLNESS ON THE BRAIN. 23 YOU TOOK THE BLUE PEOPLE THAT WERE MAJOR DEPRESSION, YOU SAW AND YOU JUST LOOKED ACROSS MULTIPLE BRAIN REGION YOU SAW HIPPOCAMPUS AND MA LIG DO LA HAD MSH HIGHLY [INDISCERNIBLE] EVEN THOUGH BY POLAR PATIENTS WERE DEPRESSED AT TIME OF DEATH, THE BIGGER SIGNATURE WAS IN THE NUCLEUS [INDISCERNIBLE]. WE HAVE REPLICATED THIS IN A VIERLT OF WAYS WITH BETTER AND BETTER TECHNIQUES INCLUDING FROM RICK MEYER’S LAB DOING RNA SEEK LOOKING IN MUCH GREATER DETAIL BUT THIS IS JUST A GENERAL SLIDES THAT SHOWS THAT FIRST OF ALL YOU CAN CLUSTER THE ANTERIOR [INDISCERNIBLE] AND PREFRONTAL CORTEX TOGETHER, VERY NICELY SEPARATED FROM THE NEW UHICALLY YUS [INDISCERNIBLE] SO THAT GIVES YOU SOME KIND OF FAITH THAT IT’S NOT CLEAT GARBAGE, IT MAKES BIOLOGICAL SENSE, AND AT THE SAME TIME WE CAN BEGIN TO LOOK AT CORONATION ACROSS THREE DISORDERS. L I’M SHOWING YOU THREE REGIONS AND I’M SAYING OUR BANK CORRELATIONS AND YOU CAN SEE THAT, FOR EXAMPLE, THE ANTERIOR SINGULAR IN THE SCHIZOPHRENIC VERSUS THE BY POLAR HAVE A LOT OF SHARED TRANSCRIPTS THAT ARE ALTERED. FEWER ARE SHARED BETWEEN THESE TWO DISORDERS THERE ARE SOME BUT FEWER ARE HIGHLY SIGNIFICANTLY SHARED IN THE DORSAL LATERAL PREFRONTAL CORTEX AND LESS IN THE NUCLEUS COMPASS. DEPRESSION, LESS SHARING, LESS EVIDENCE OF WHAT THAT WE CAN SEE BIG CHANGES. I THINK IT’S A LOT NOISIER. SO LET’S KIND OF BACK UP AND ASK WHETHER IN THE OLDER DATA OR NEWER DATA ARE THERE THINGS WE CAN SEE RELIABLY AND EVERYONE IN VERY OLD DATA WE STARTED IT WAS CLEAR WITH THESE DIFFERENTIAL SIGNATURES THAT IN DEPRESSION WHAT WE SAW MOST ALTERED WERE GROWTH-RELATED, SENSE SURVIVAL, CELL SIGNALALING, CELL DEATH, CELL CYCLE. THEY WERE IN EVERY BRAIN REGION WE LOOKED AT AND SOME WERE VERY PROFOUND CHANGES EVEN THOUGH THE HIPPOCAMPUS AND MA LIG DA LA WERE MOST ALTERED, IT WAS NOT RESTRICTED TO ANY NEUROARE TRANSMITTER SYSTEM. IT WAS VERY WIDE-RANGING. AND SOME PLACES IN THE MA LIG DA LA YOU CAN SEE DIFFERENCES IN THE AMOUNT OF RNA WE CAN PICK UP. THESE ARE CONTROLS MAJOR DEPRESSIVE PATIENT WHO IS DIED BUT NOT OF SUICIDE AND SUICIDE AND YOU CAN SEE JUST A VERY GROSS LEVEL WHERE THIS DIFFERENCES IN WHAT WE CAN CAPTURE FROM THEM DONE AT THE SAME TIME IN A BLIND WAY. SO, YOU KNOW, SO VERY BROADLY, WHAT IS REALLY CLEAR FROM 60,000 KIND OF POINT OF VIEW IS THAT THE DISREGULATION IS WIDE. NOTHING IS LIKE PENCIL DIFFERENT, THINGS ARE TWO-FOLD DIFFERENT, BUT THERE’S A LOT OF CHANGES AND A LOT OF THEM ARE IN GENES THAT I WILL TELL YOU ABOUT FOR EXAMPLE IN NEW GENES BUT WHAT IS REALLY REMARKABLE IS THAT I HAVE TRIED WITH ANIMAL MODELS TO REPLICATE THIS LEVEL OF REGULATION, WE NEVER SEE NIT OUR ANIMAL MODEL. THIS IS LIKE AN END-STAGE REGULATION WE’RE SEEING AND IT MAY HAVE ARE TO DO WITH TREATMENT RESISTANCE. MAYBE THESE ARE REALLY SICK PEOPLE. OBVIOUSLY IF THEY DIED OF SUICIDE THEY PROBABLY WERER NOT DOING ALL THAT WELL, BUT, YOU KNOW, WHAT WE SEE IS ANTIDEPRESSANTS ACTUALLY CHANGE THE GENE EXPRESSION, THEY CHANGE IT CLOSER TO NORMAL BUT THEY NEVER NORMALIZE THEM BECAUSE [INDISCERNIBLE] PEOPLE REMAIN DEPRESSED. SO ON THE WHOLE POSITIVE SIDE WE HAVE IDENTIFIED SOME THINGS THAT WE WERE NOT EXPECTING TO SEE, AND THESE INCLUDE — I DON’T KNOW WHAT IS DOING THIS BUT — BEEPING, DO YOU KNOW, ANYBODY? SO WE’VE IDENTIFIED FAMILIES OF GENE, IMMUNE GENES, CIRCADIAN CLOCK GENES, AND GLUE FACTORS THAT SEEM TO BE VERY CLEARLY DIFFERENT IN THE BRAINS OF NDB VERSUS CONTROL. I AM NOT GOING TO GO INTO ALL OF THEM I’M GOING TO TAKE A MINUTE TO TALK ABOUT THE CIRCADIAN GENES BECAUSE THEY’RE INTERESTING TO ME. SOMETHING IS BEEPING. IF SOMEBODY COULD HELP ME WITH THAT THAT WOULD BE GOOD BECAUSE IT’S DRIVING ME A LITTLE CRAZY. CAN YOU FIGURE OUT WHAT THAT IS? OKAY. THANK YOU. APPRECIATE IT. THIS IS A KIND OF DUMB EXPERIMENT IN A WAY BUT WE DID IT ANYHOW. IT WAS ONE OF THOSE DUMB EXPERIMENTS THAT ACTUALLY REVEALED SOMETHING. SO WE LITERALLY JUST LINED UP PEOPLE AROUND THE CLOCK BASED ON WHEN THEY DIED AND THAT’S THANKS TO [INDISCERNIBLE] WHO KEEPS GOOD RECORDS FOR HIS BRAIN BANK. WHEN YOU SEE A NUMBER IT MEANS SOMEBODY DIED ONE HOUR AFTER SUNRISE, EIGHT HOURS AFTER SUNRISE, 12 HOURS AFTER SUNRISE, LIKE THAT. AND THEN YOU JUST SIMPLY GO TO A GENE EXPRESSION DATA AND YOU LOOK TO SEE IF THERE IS ANY EVIDENCE OF CHANGE AS A FUNCTION OF WHEN SOMEBODY DIEDED. AND WHAT YOU SEE IS REMARKABLE. FOR EXAMPLE, HERE’S [INDISCERNIBLE] WHICH IS A CLOCK GENE AND YOU CAN SEE THAT IT HAS A SIGNIFICANT CIRCADIAN RHYTHM, JUST SIMPLY THESE ARE DIFFERENT PEOPLE DIED AT DIFFERENT TIMES, ALL CONTROLLED, BUT YOU CAN SEE THERE IS EIGHT OF THEM THAT YOU CAN FIT AND YOU CAN FIT IT WAY BETTER 24 HOURS AND 12 HOURS AND YOU UH CAN DO A LOT OF CONTROLS AND ALL THE CLOCK GENES ACTUALLY COME UP WITH SOME KIND OF SICKNESS EVEN YOU SHOULD THESE UNIDEAL CONDITIONS, AND EVEN THEIR RELATIONSHIPS ARE RIGHT LIKE WHEN ONE PEAKS RELATIVE TO THREE. THAT TIME DIFFERENCE IS EXACTLY WHAT THE ANIMAL MODELS PREDICT. FIRST PEOPLE BEING SEEN IN GENE EXPRESSION IN THE HUMAN BRAIN. MOREOVER, THERE IS ABOUT A THOUSAND GENES IN THE BRAIN THAT SHOW A 24-HOUR RHYTHM DISTRIBUTED ALL OVER THE BRAIN. THIS IS NOT JUST IN THE SUPER CHARISMATIC NUCLEUS, WE’RE TALKING OUTSIDE OF THE SCN. AND WHAT IS ALSO INTERESTING IS THAT NOW YOU NOW CAN ASK, IS THERE SOMETHING WRONG IN THEIR ETHNICITY IN ANY OF THE DISORDERS? AND WE’RE STARTING TO LOOK AT IT IN BY DI POLARS AND SKITSZ FRIN YEAH. HERE IS A PAPER BY BONN ANY ET AL IN MOLECULAR PSYCHIATRY LAST YEAR. WHEN SOMETHING IS SIGNIFICANT IT MEANS IT HAS SIGNIFICANT ETHNICITY. YOU CAN SEE THESE ARE CLASSICAL GENES THAT ARE PART OF THE MOLECULAR CLOCK AND ALL HIGH ELY SIGNIFICANTLY CYCLING IN THE CONTROL AND THE MATCHED MDD MATCHED BY ALL KINDS OF CRITERIA, ALL HAVE NOTED THEM EXCEPT THIS [INDISCERNIBLE] ALPHA THAT HAS SOME OF THEM LEFT BUT EVERYBODY ELSE LOST THEIR RIM ARE RHYTHM. BASED ON PATTERN OF GENE EXPRESSION ACROSS BRAIN AREAS, WE CAN ACTUALLY TIME THE TIME OF DEATH OF THE GIVEN INDIVIDUAL. WE CAN SAY BASED ON THE SIGNATURE IN CONTROL BRAIN, THEY DIED AT 10 IN THE MORNING AND WE ARE WITHIN AN HOUR OF THE ACTUAL RECORD ARE OF DEATH. SO THERE IS A TIME STAMP ON THE BRAIN AS ITS DIES BASED ON THE CIRCADIAN CLOCK AND THAT IS COMPLETELY LOST IN THE MDV. IT’S LIKE THEY’VE BEEN TRAVELLING IN A DIFFERENT TIME ZONE. THOSE KINDS OF STUDIES REALLY START TO TELL YOU THAT WE ARE LOOKING AT BIG ORCHESTRATED CHANGES IN THE BRAIN AT EVERY LEVEL, LEVELS OF EXPRESSION IN THEIR NISTY IN PUT APPROXIMATELY CIRCUMSTANCES WE NEED TO THINK ABOUT. MY EXAMPLE FOR THE REST OF THE TALK IS GOING TO FOCUS ON JUST SYSTEM WHERE IT WAS ONE OF THE FIRST DISCOVERIES WE MADE WHERE WE SAW THAT THIS FAMILY WHICH I KNEW NOTHING ABOUT WAS THE MOST DISREGULATED IN THE CORTEX OF THE DEPRESSED PEOPLE. IT WAS MORE DISREGULATED THAN IN BIPOLAR OR IN SCHIZOPHRENIA. SINCE THEN WE’VE SEEN SOME EFFECT BUT NOT NEARLY AS PROFOUND. IT’S A COMPLEX SYSTEM. IT HAS 22 LIGANDS AND A LOT OF PARTNERING PROTEINS A HANDFUL OF RECEPTORS BUT THEY’RE VERY COMPLICATED, THEY HAVE SPLICE ISSUES AND PARTNERS. COMPLICATED SYSTEM. THESE TEN YEARS AGO, MORE THAN, THESE ARE SIMPLE FINDINGS, AGAIN, NOTHING HUGELY PROFOUND, BUT FOR EXAMPLE HERE IS ONE LIGAND OF THE FAMILY SIGNIFICANTLY DECREASED IN DEPRESSION AT R 2, R 3 AND IF YOU LOOK AT PEOPLE WHO HAD A HISTORY OF ANTIDEPRESSANT TREATMENT AND YOU CAN MEASURE ANTIDEPRESSANTS IN THEIR BRAIN SO WE DO THAT IN THE TALK, YOU CONTINUE THAT THEY SIT/LIE RIGHT IN BETWEEN THE CONTROL AND UNTREATED PATIENT. VERY EARLY ON WE NOTICED THAT THERE ARE A BUNCH OF DISREGULATION. IT’S NOT JUST ONE FACTOR THAT WAS DISREGULATED BUT THE WHOLE FAMILY WAS DISREGULATED. SO BUT ONE OF THE THINGS THAT CAUGHT OUR ATTENTION IS BECAUSE THERE WAS LITTLE BIOLOGY DONE ABOUT YOU KNOW IN OTHER MODELS OF FGF AND SOME OF ITS REFLECTORS. WE DECIDED TO START WITH THAT BECAUSE THERE WERE MORE TOOLS AND WE NOTICED JUST TO REMIND YOU BOTH FTF 2 AND FGF RECEPTOR 3 IT’S SELECTIVE, IT’S INTERACT WITH OTHER RECEPTORS AS WELL BUT THEY ARE DECREASED IN SEVERAL AREAS OF THE BRAIN. SINCE THEN OTHER PEOPLE HAVE REPLICATED THAT AND WE HAVE DONE MANY MORE BRAIN A AREAS. AND SO ASKED, DOES THAT MEAN ANYTHING? IS THIS ACTUALLY FUNCTIONALLY RELEVANT IN ANY WAY OR IS THIS SORT OF A MARKER OF SOMETHING? SO WE WENT BACK TO OUR MODEL BUT IN ANIMALS AND WE TRIED TO LOOK AT EACH ONE OF THE FACETS OF THIS SKI MA AND SAID COULD IT BE A VULNERABLE GENE IS A DEVELOPMENTAL GENE IS IT INVOLVED IN ENVIRONMENTAL INTERACTION, INVOLVED IN REMODELLING? I’M GOING QUICKLY GO THROUGH A LOT OF THIS HAS BEEN PUBLISHED AND THE ANSWER IS WE CAN USE SOCIAL REPEATED SOCIAL DEFEAT AS AN ANIMAL MODEL OF DEPRESSION, ANIMALS THAT LOSE REPEATEDLY EVEN IF IT’S A BRIEF LOSS AND ETCH IF THERE IS NO PHYSICAL DAMAGE CAN START ACTING DIFFERENTLY, THEY HAVE FEWER SOCIAL XER ACTIONS, THEY DON’T LIKE SUCROSE — INTERACTIONS, THEY DON’T LIKE SUCROSE AND THEY SHOW E DEPRESS SIEVE FEATURES AND WE USE THAT MODEL AND LOOK AT FGF IN THEIR BRAIN LOOKING A AT HI E POE CAMPUS WHICH YOU SEE IS SIGNIFICANT DECREASE IN OF FGF 2 AND SOME FGF RECEPTORS. SOME OF THOSE DECREASES ARE QUITE DRAMATIC AND OTHERS MILDER BUT AFTER A FEW DAYS OF SOCIAL DEFEAT. WHAT WAS INTERESTING IS WE THEN ASKED, COULD IT BE AN ENDOGENOUS ANTIDEPRESSANT? WE DID A DUMB STUDY WHERE WE TOOK FGF AND GAVE IT TO AN L MALLS AND WE GAVE IT PERIPHERALLY AND CENTRALLY. LOOKED A AT MULTIPLE MODELS OF DEPRESSION. THIS IS THE SWIM TEST WHICH IS BRAET-AND-BUTTER BORING TEST BUT WHAT YOU SEE IS IN FACT FGF TWO ACTS LIKE AN ANTIDEPRESSANT. MORE IMMOBILITY MEANS GREATER DEPRESSIVE-LIKE BEHAVIOR IN THIS TEST. MORE SWIM MEANS LESS DEPRESSIVE BEHAVIOR. THOSE WITH FGF SHOWS GREATER SWIM. INTERESTINGLY IF YOU COMPETE IT WITH A SMALL PEPTIDE EVEN ONLINE IN THAT MOMENT, YOU COULD INCREASE DEPRESSIVE BEHAVIOR SUGGESTING THAT REALLY ANY — IN THE MOMENT THAT THE ANIMAL IS BEHAVING, FGF IS PLAYING A ROLE BECAUSE IF YOU COMPETE WITH IT, IT CHANGES THE BEHAVIOR. AND SO THEN WE ASK, CAN WE ACTUALLY KNOCK DOWN THE INGOJ NOUS MATERIAL AND SEE THE DIFFERENCE IN BEHAVIOR AS OPPOSED TO GIVING ITS? CAN WE KNOCK IT DOWN? WE AIMED OUR KNOCK-DOWN THROUGH SPECIFICALLY THE GYRUS OF THE HIPPOCAMPUS AND SO THE GREEN IS THE ANTIVIRAL VECTOR AND YOU CAN SEE THE RED IS THE NEWICALLY E EYE AND BLUE IS [INDISCERNIBLE] AND IT’S MOSTLY IN THE NEURONS THAT IT GOES INTO THE NEURONS AS OPPOSED TO THE G GLIAL. WHEN WE DO KNOCKDOWN WE GET SIGNIFICANT BUT NOT COMPLETE KNOCKDOWN OF THE ENDOGENOUS IN THAT REGION, NO OTHER REGION, VERY SPECIFIC. AND WHEN WE DO THAT WHAT WE SEE, WE SEE SOME CHANGES IN DEPRESSION BUT WE SEE MOSTLY CHANGES IN ANXIETY BEHAVIOR. THIS MIGHT BE BECAUSE THIS IS VERY LOCALIZED AND THIS AREA IS IMPORTANT AND ANXIETY SO YOU SEE THESE ANIMALS ARE SPENDING A LOT MORE TIME NOW IN THE CLOSE ARMS OF AN ELEVATED MAZE AND LESS TIME IN THE MORE AREAS OF THE CLASSMATES. SO WE SUGGEST HERE THAT IN FACT IT SEEMS TO BE IMPORTANT IN THE SENSE OF IN ADULT ANIMALS, IT’S PART OF THE STRESS RESPONSIVENESS WHICH I SHOWED YOU SOCIAL DEFEAT. I SHOWED YOU THAT IT’S ACTING AND MODULATING BEHAVIOR IN ADULTS BUT IT IS A GENETIC FACTOR, A DEVELOPMENTAL FACTOR? IN OTHER WORDS TO ADDRESS THAT WE TURN TO THIS ANIMAL MODEL THAT WE HAVE DEVELOPEDED BASED ON THIS IDEA THAT, YOU KNOW THAT THERE ARE GENES FOR — THERE IS NO GENES FOR DEPRESSION ARE, NO GENES FOR ANY ONE OF THOSE — PROBABLY GENES THAT PREDISPOSE TO CERTAIN STYLES OF INTERACTING WITH ENVIRONMENT THAT WE CALL PERRAL PERRALTY — PERSONALITY IN REAL LIFE. ONE OF THE MAJOR KIND OF DIMENSIONS IS SO-F CALLED INTERNALIZING VERSUS EXTERNALIZING FILE. WHEN PEOPLE FALL APART GET AN ILLNESS, THEY GET AN ILLNESS THAT ARE BIASSED BY WHETHER YOU HAVE AN INTERNALIZING TEMP MENTAL OR EXTERNALIZING TEMPERAMENT. EXTERNAL DISORDERER IS ONE ASSOCIATED WITH SO-CALLED BEHAVIORAL UNDER CONTROL WHERE PEOPLE FEEL SOMEWHAT LESS INHIBITED. THEY’RE MORE CONFRONTATIONAL, MORE CONDUCT DISORDERS, MAY HAVE ATTENTION PROBLEMS, MORE PRONE TO ANTISOCIAL BEHAVIOR, SUBSTANCE ABUSE. ON THE OTHER HAND, PEOPLE WHO ARE MORE PRONE TO INTERNALIZING DISORDERS ARE MOREBROKEN TO BE OVERCONTROL DEPRESSION, ANXIETY AND THE LIKE. SO WE ASKED, CAN WE MODEL THAT IN ANIMALS AND BEGIN TO USE THAT IN UNDERSTAND — AND I’M GOING GET BACK TO FGF, BUT YOU HAVE TO UNDERSTAND THE MODEL. SO WE STARTED WITH THIS VERY SIMPLE EXPERIMENT WHERE YOU TAKE AN ANIMAL — I DON’T KNOW IF YOU CAN SEE THE RED BUT THIS IS VISION JUST TRACKING THE MOVEMENT OF ANIMALS AND I’M SORRY YOU CAN’T SEE IT BUT THIS ANIMAL IS ALL OVER THE PLACE INVESTIGATIONING THIS LITTLE OBJECT IN NEW ENVIRONMENT AND NEW FIELD WITH A NEW OBJECT AND HE’S ALL OVER IT AND THIS ANIMAL IS JUST HUGGING THE WALL, KIND OF LITTLE SCARRED DI CAT. HOW MUCH DO THEY INVESTIGATE SOMETHING. WE TOOK THIS AS DIMENSION AND STARTED BREEDING THESE ANIMALS FOR OVER 45 GENERATION ARES NOW AND THEY SEPARATE LIKE NOBODY’S BUSINESS VERY QUICKLY, VERY CLEARLY. SO BY NOW WE HAVE 100% CERTAINTY WHAT THEIR PHENOTYPE IS GOING TO BE BASED ON THEIR LINEAGE. THIS IS NOT IMBREEDING AND WE DON’T BREED BETWEEN FAMILIES BUT IT SEPARATES, AND THE NORM RL SOMEWHERE IN-BETWEEN AND WE HAVE LINEAGES ON THESE ANIMALS AND WE HAVE CHARACTERIZED THEM ON A WHOLE BUNCH OF BEHAVIORS EVEN THOUGH WE BRED THEM ON THIS ONE DIMENSION AND IT’S REMARKABLE THAT A LOT OF BEHAVIORS COME ALONG WITH THIS SIMPLE BREEDING DESIRE SUGGESTING THAT WE’RE TAPPING INTO SORT OF ENVIRONMENTAL REACTIVITY STYLE AND, YOU KNOW, SO AGGRESSION, DEPRESSION, FEAR CONDITIONING AND SO ON ALL DIFFERS. HERE IS ELEVATED PLUS MAZE, THE ANIMALS WE CALL HIGH RESPONDERS SPEND A LOT OF TIME IN OPEN ARM OF THE ELEVATED PLUS MAZE. LOW RESPONDERS DON’T. IT’S NOT JUST BECAUSE OF MOTOR BEHAVIOR, WE CONTROL FOR THAT. EXPOSE THEM TO STRESS AND LOOK AT THEIR SOCIAL INTERACTIONS. HIGH RESPONDERS ARE REALLY RESILIENT, YOU CAN’T HARDLY BUDGE THEM, THEY STAY GREGARIOUS, WHEREAS THESE TWO GUYS PLUMMET PRETTY QUICKLY AND IT’S RESPONSIVE TO ANTIDEPRESSANT. FEAR CONDITIONING, THEY HAVE VERY BIG DIFFERENCES WITH ACQUISITION AND EXTINCTION OF FEAR CONDITIONING. THOSE LOW RESPONDERS LIKE INTERNALIZING ANIMALS ARE EXTINGUISH THEIR FEAR. I’M GOING QUICKLY JUST TO KIND OF GIVE YOU A SENSE. THIS IS WHERE THE OUTBRED ANIMALS SIT. THEY TYPICALLY SIT JUST IN-BETWEEN THE TWO WE’RE JUST KIND OF GRABBING THE TAIL ENDS OF THE NORMAL DISTRIBUTION AND HIGH RESPONDERS LOVE TO TAKE DRUGS, THEY LOVE NEW THINGS AND THEY TAKE THE DRUGS WITH GREAT JOY AND THE LOW RESPONDERS IT TAKES EITHER A LONG TIME OR SOME STRESS AND THEN THEY WILL TAKE DRUGS. MORE IMPORTANTLY, IF WE ADDICT THEM EVEN TO THE SAME EXTENT MAKING SURE THEY TAKE THE SAME AMOUNT OF DRUGS AND NOW WE LOOK AT RELAPSE USING VARIOUS TYPES OF TRICKS LIKE AFTER ONE MONTH OF ABSTINENCE WE GIVE THEM A QUEUE ASSOCIATED WITH THE DRUG AND WE LOOK AT THEM, WE SEE BIG DIFFERENCES IN THEM SO THESE ANIMALS HIGH RESPONDERS LOVE AS SOON AS THEY SEE THE CUE THEY WANT TO START POKING AND TAKING THE DRUG. SO THEY SHOW DIFFERENCES IN ADDICTION AND RELAPSE BETWEEN THEM. WE HAVE BEEN, WE’VE BEEN COLLABORATING WITH DAVID GOLDMAN HERE AT NIH AS KIND OF A JOINT PROJECT WITH NIA AND NIDA WITH OTHERS TO DO XOEM SEQUENCING ON THESE ANIMALS AND WE HAVE DATA AND MULTIPLE GENES THAT ARE INTERESTING. WE ALSO HAVE RNA SEQUENCE ON THESE ANIMALS SO WE’RE JUST GETTING OUR BRAIN WRAPPED AROUND THIS. SO IT’S VERY CLEAR THERE IS A GENETIC DIFFERENCES. WE’VE ELIMINATED THAT IT’S NOT SIMPLY DUE TO MATERNAL BEHAVIOR. WE KNOW THERE IS GENETICS INVOLVED. SO THE QUESTION IS, IF YOU HAVE DIFFERENCES IN TEMPERAMENT, DO YOU NEED DIFFERENT TREATMENTS? WHAT I CALL MY PRECISION MEDICINE FOR RATS AND WHAT ABOUT FGF? AND THE ANSWER IS, FGF IS DIFFERENT NATIVELY IN THESE ANIMALS SO THE LOW RESPONDERS HAVE LESS FGF 2 THAN THE HIGH RESPONDERS AND THERE’S A CORRELATION BETWEEN HOW MUCH FGF YOU HAVE IN CERTAIN PARTS OF THE HIPPOCAMPUS AND HOW MUCH THIS CUE WOULD TAKE IN A NEW PLACE OR AN THE ELEVATED PLUS MAZE. MOREOVER IF YOU GIVE FGF 2 CHRONICALLY YOU RESCUE THESE ANIMALS, YOU DON’T TOUCH THE HIGH RESPONDER ANIMALS, THEY’RE ALREADY FINE, THEY’RE NOT SCARED. THE ONES THAT ARE SCARED YOU GIVE THEM CHRONIC FGF, YOU RESCUE THEM AND THEY BECOME LESS SCARED AND YOU ALSO INDUCE NEW TOE GENESIS IN THE PROCESS. OUR HYPOTHESIS THEN IS THAT THIS IS A KEY MOLECULE IN TEMPERAMENT, THAT YOU CAN DIAL IN THE LEVEL OF INTERNALIZING AND EXTERNALIZING DISORDER BASED ON MANY MOLECULAR PLAYERS BUT THAT THIS COULD BE ONE OF THEM AND ONE OF THE QUESTION IS, IS IT CHANGEABLE OR IS IT SET IN PLACE FOREVER? SO I SHOWED YOU WE CAN RESCUE IT IN ADULTS BUT CAN WE DO ANYTHING DEVELOPMENTALLY? AND WHAT WE DID IS WE GAVE IT ONCE ON THE SECOND DAY OF LIFE, WE GAVE ONE SHOT OF FGF 2 TO BOTH HIGH AND LOW RESPONDERS AND THEN WATCH THEM AT DIFFERENT STAGES OF LIFE DURING DEVELOPMENT AND IN ADULTHOOD. WE LOOKED AT NEUROGENESIS SAND WE CAN SEE FGF 2 ACCELERATES IT IN ANIMALS EVEN OUTBRED BRED ANIMALS, AND BUT THE MOST INTERESTING THING IS THIS FINDING THAT SAYS THAT SO HERE ARE [INDISCERNIBLE] HOW MUCH TIME WE SPEND ON THE OPEN ARMS OF THE ELEVATED PLUS MAZE. HOW MUCH THEY SPEND WILLING TO TAKE OR HOW ANXIOUS THEY ARE. THIS IS LATER GENERATION, YOU CAN SEE HOW DIFFERENT THE HIGH AND LOW RESPONDERS ARE IN THE FALL OF LINE. THESE GUYS ARE SPENDING A A GOOD CHUNK OF TIME OUT ON A LIMB AND THESE GUYS HARDLY EVER. NOW IF YOU’VE GIVEN THEM FGF, NOTHING HAPPENS TO THESE HIGH RESPONDERS, THEY’RE ALREADY OUT THERE, BUT THE LOW RESPONDERS ACTUALLY CHANGE. NOW WE’RE TESTING THEM AS ADULTS AND THEY HAD ONE SHOT OF FGF WHEN THEY WERE BORN, BUT NOW THEY ARE SOMEWHERE IN-BETWEEN. SO YOU CAN RESCUE A BIG PIECE OF THE PHENOTYPE AND WE’VE LOOKED AT THEY’RE ADDICTION I MEAN THEIR DRUG-TAKING BEHAVIOR AND THEY JUST SIMPLY SHIFTS THEM, MAKES THEM ALSO WANT TO TAKE MORE COCAINE. I’M NOT NECESSARILY RECOMMENDING THAT’S WHAT EVERYBODY — WHAT I’M SAYING IS THAT IT’S LIKE YOU ARE SOMEWHERE ON THAT PHENOTYPE DIAL AND FGF 2 MOVES YOU AWAY FROM THE MORE DEPRESSIVE TOWARDS THE MORE RISK-TAKING PHENOTYPE AND YOU CAN DO IT ONCE DURING DEVELOPMENT AND CHANGE THE PROGRAM, AND WE HAVE A WHOLE BUNCH OF MOLECULES THAT WE’VE LOOKED THROUGH, UM, YOU KNOW, PROFILING, THAT ARE MEDIATORS OF THESE CHANGES, YOU KNOW, THAT WE ARE STUDYING THAT ARE DOWN TROOEM FROM FGF THAT WE THINK ARE MEDIATING. THE OTHER THING I WANT TO SAY IS THAT EVEN THOUGH THE HIGH RESPONDERS DON’T SEEM TO PROFIT FROM EARLY LIFE FGF, IF YOU DO STRESS THEM NOW YOU PROTECT THEM SO THIS THE INHIBITED ASSOCIATE — INHIBITED BECAUSE THEY’RE BEING SOCIALLY DEFUTED. EVERYBODY’S BEEN INHIBITED BY SOCIAL DEFEAT. BOTH LOW RESPONDERS AND HIGH RESPONDERS ARE MADE MORE RESILIENT AGAINST SOCIAL DEFEAT BY HAVING HAD FGF EARLY IN LIFE. SO ALTHOUGH YOU DON’T SEE THE IMPACT OF FGF ON THE HIGH RESPONDERS ON THE BASIL CONDITION, YOU PUSH THEM, YOU START SEEING IT. SO IT SEEMS TO REALLY BE PROTECTIVE AND KIND OF TO BE A RESILIENCE PATHWAY AND THIS IS FOR TOM. ONE OF THE DOWN TROOEM MOLECULES IS OXI TOE SIN. SO WHEN WE GIVE THEM EARLY LIFE FGF AND LOOK AT THEM IN A ADULTHOOD AND SEE THEM THIS IS ONE OF THE MOLECULES THAT REALLY IS INDUCED ONLY IN THE LOW RESPONDERS IS OXI TOE SIN THAT USED TO BE LOW AND NOW BECOMES INDUCED IN VARIOUS PARTS OF THE BRAIN. IT’LL BE INTERESTING TO KNOW HOW THE WHOLE PROGRAM PLAYS OFF AND, YOU KNOW, PART OF THIS STORY IS E P PI GENETICS SO HOW DO THESE CHANGES OCCUR? WE KNOW ONE OF THE THINGS WE’RE DOING DEVELOPMENTALLY IS IS THAT WE ARE MEDIATING MAJOR LONG-LASTING EPIGENETIC CHANGES IN THESE ANIMALS AND I DON’T HAVE TIME TO GET INTO THE READS ABOUT IT BUT I THINK THEY BOTH SEEM TO BE IMPORTANT IN THE INDUCTION OF RESILIENCE. ONE OF THE TARGETS WE HAVE LOOKED AT ESPECIALLY IS IS THIS H 3 HISTONE, IT’S NOT H 4 BUT IT’S 3 CANINE AT THAT SITE AND WE LOOKED AT IT BECAUSE WE SAW SOME EVIDENCE THAT BASALLY JUST GLOBALLY THERE WERE DIFFERENCES BETWEEN OUR LINES AND THE LEVELS OF THIS SYSTEM AND WE WONDERED IF THERE WERE PARTNERING MOLECULES THAT WERE IMPORTANT. WE LOOKED AT EXAMPLES WITH CHIP ASSAYS AT TWO MOLECULES THAT I TALKED TO YOU ABOUT TODAY, FGF 2 AND GU TOE CORD CODE RECEPTOR. REMEMBER ARE IT’S NATIVELY HIGHER IN THE HIGH-RISK-TAKING ANIMALS. GR IS NOWHERE IN THESE HIGH RISK-TAKING ANIMALS. WHAT WE SEE IS SIGNATURES EPIGENETIC SIGNATURE ON THESE THAT ARE DIFFERENTIAL BETWEEN OUR LINES IN MULTIPLE BRAIN REGIONS WHERE, FOR EXAMPLE, FOR FGF 2 THE INHIBITORY HISTONE MODIFIED HISTONE IS LOWER IN THE HIGH RESPONDERS WHEREAS THE ACTIVATING ONE IS HIGHER, AND EXACTLY THE MIRROR IMAGE FOR THE GLUCOCORD CODERECEPTORS. THERE ARE EPIGENETIC MARKS THAT ARE NATIVE BEFORE WE DO ANYTHING TO THESE ANIMALS THAT GO A ALONG WITH THE DIFFERENTIAL EXPRESSION. IMPORTANT THING IS THAT WE CAN CHANGE THEM. SO IF WE GIVE FGF 2 IN EARLY LIFE WE CAN FLIP THEM SO THAT ANIMALS THAT WERE MORE REPRESSED BECOME LESS DEPRESSED. THE LR ANIMALS NOW HAVE LESS OF THE REPRESSIVE HISTONE FOR EXAMPLE IN THE NUCLEUS AND IN THE HI E POE CAMPUS THEY BECOME MORE LIKE THE RISK-TAKING ANIMALS. REMEMBER THEIR ANXIETY IS ALSO CHANGING. AND MORE IMPORTANTLY WHEN WE DO KNOCKDOWN STUDIES OF FGF 2, WE INCREASE ANXIETY IN THE HIGH RISK-TAKING ANIMALS AND WE ALSO CHANGE THE EPIGENETIC PROFILE ACCORDINGLY. WHAT WE NEED TO DO IS INTERFERE WITH THAT HISTONE AND SHOW WHAT HAPPENS BEHAVIORALLY, BUT OUR CURRENT HYPOTHESIS IS THAT FGF DOES A LOT OF THINGS, INDUCES A LOT OF THINGS BUT PART OF WHAT IT DOES IS IT INDUCES DURING DEVELOPMENT EPI NE GENETIC CHANGES THAT ARE THEN LONG-LASTING AND CHANGE THE TEMPLE MENTAL REACTIVITY OF THE ANIMAL TOWARDS THE ENVIRONMENT. SO I WANT TO JUST WRAP UP BY TELLING YOU IN THIS SORT OF A MODEL THERE IS MORE THAN FGF TWO, WE HAVE A WHOLE STORY WITH FGF 9 WHICH SEEMS TO BE A FUNCTIONAL ANTAGONIST, EXACTLY THE OPPOSITE OF FGF 2. WE’RE ABOUT TO PUBLISH THIS WORK. MORE THAN ONE TARGET AND THERE ARE OTHER FGFs IN THIS STORY THAT ARE VERY INTERESTING AND PARTNERING MOLECULES. SO THERE ARE MULTIPLE TARGETS IN THIS FAMILY TO STUDY, BUT THE POINT IS THAT HERE WE STARTED FROM THE DEPRESSED HUMAN BRAINS, UNCOVERED THE NEW MOLECULAR ANTISEE DANT AND WE TRIED TO TAKE IT TO BECOME KIND OF TO ASK ABOUT ITS FUNCTIONAL ROLE AND WHAT I REALLY LIKE IS THAT A LOT OF THIS WORK HAS BEEN REPLICATED BY OTHERS INCLUDING YOUR COLLEAGUE HERE IN A BEAUTIFUL STUDY SHOWING ROLE ARE OF FGF ALLEVIATING SOME EFFECTS OF ROSY HERE [INDISCERNIBLE]. SHE SHOWED EXACTLY THE SAME KIND OF THING THAT WE SHOWED ABOUT FGF BEING AN IMPORTANT ANTIDEPRESSANT AND AN IMPORTANT MEDIATOR OF SO ANTIDEPRESSOR AND MEDIATOR OF NEUROGENESIS. I KNOW I’M NOT DOING ANY JUSTICE TO HER WORK BUT I JUST WANTED TO SIGNAL IT IF YOU WANT SOMEBODY LOCAL TO TALK TO, SHE KNOWS A LOT ABOUT IT MORE THAN I DO. BUT IT’S VERY GOOD TO KNOW THAT PEOPLE WHO DO HUMAN WORK IN DIFFERENT ANIMAL MODELS ARE CONTINUING SOME OF THIS EFFORT AND SHOWING THAT IT IS APPLICABLE IN MULTIPLE WAYS IN MULTIPLE PLACES. I SORT OF CAME AWAY FROM ALL THIS WORK WITH IDEA THAT THERE MIGHT BE BE THESE SWITCH GENES THAT ARE NOT CLASSICAL BUT ARE A LOT OF THINGS. THEY CAN BE GENETIC FACTORS, CAN BE MEDIATORS OF ENVIRONMENTAL RESPONSIVENESS, THEY CAN BE GROWTH FACTORS, THEY CAN BE THAT INTERFACE BETWEEN THE ANIMAL AND THE WORLD OUTSIDE AND SORT OF RIGHT THESE BLOTTER PROGRAM WITHIN WHICH OTHER REGULATION OR DISREGULATION HAPPENS, AND WE’RE VERY INTERESTED IN THE INTEREST OF TIME AND I’M GOING TO SKIP SOME HUMAN STUDIES TO TELL YOU THAT WE’RE MOVING TOWARDS TRYING TO USE THEM AS BIOMARKERS IN VARIOUS STRESS CONDITIONS. SO THE LESSONS I HAVE TAKEN IS THAT MOOD DISORDER LEAD TO VERY PERSISTENT AND WIDE-SPREAD PATTERNS OF DISREGULATION THROUGHOUT THE BRAIN THAT WE’RE NOT REALLY MODELLING WELL SO WE DON’T REALLY UNDERSTAND VERY WELL. BUT THERE IS A UNIQUE SIGNATURE THAT COULD BE SECONDARY, BUT THE POINT IS THAT WE NEED TO THINK BEYOND ONE TRANSMITTER. I MEAN I’M NOT SPIK PUKING ON SEROTONIN — I LOVER IS TOEN ANYONE — BUT I THINK WE NEED TO THINK AWE BOUT WHOLE ENSEMBLE OF THIS GOING ON. THINK ABOUT WHICH ASPECTS WE NEED TO BEGIN TO ANALYZE IN A SEPARATE WAY AND THAT THE SAME MOLECULE IS NOT AN EITHER/OR, IT COULD BE A GENETIC AND ENVIRONMENTAL MEDIATOR. BUT, YOU KNOW, THE GOOD NEWS IS THAT YOUR GENES AREN’T YOUR DESTINY. I’VE SHOWN YOU AN EXAMPLE WHERE SOMETHING IS VERY GENETIC BUT WE COULD CHANGE IT WITH SOME VERY EARLY-LIFE MANIPULATIONS AND I FEEL THESE MOLECULAR ORGANIZERS MIGHT ACTUALLY BE VERY COOL TARGETS FOR FURTHER DRUG DEVELOPMENT AND I STILL FEEL WE NEED TO UNDERSTAND MORE ABOUT THE DYNAMICS OF SEQUENCES OF THINGS AND HOW TO TAP INTO IT. IN OTHER WORDS, SOME OF THESE GENES, I THINK, ARE WORTHY OF GOING BACK NOW AND STUDYING THEM BUT THINKING ABOUT THEM IN MORE DYNAMIC WAY AND WITH BETTER MODELS THAN WE HAD IN THE PAST. YOU KNOW, MY WHOLE THING IS THAT WE NEED TO FACE THE MUSIC ABOUT THE COMPLEXITY OF THE BRAIN AND EMBRACE IT INSTEAD OF FINDING IT’S JUST A HEADACHE AND DESPAIRING FROM EVER FIGURING IT OUT. THANK YOU. [APPLAUSE]>>TERRIFIC. THANK YOU. WE HAVE TIME FOR SOME QUESTIONS. MIKES ARE IN THE AISLES SO IF YOU HAVE A QUESTION, PLEASE GO THE MIKES SO PEOPLE WATCHING BY VIDEO CAN HEAR.>>HI. SOMETIMES VIRUSS CAN USE CELL SURFACE MOLECULES LIKE FGF PER ACCEPT TOR.>>YES.>>IS ANYBODY LOOKING AT INFECTION IN MOOD?>>YEAH, I MEAN PEOPLE DO AND WE HAVE A WHOLE IMMUNE STORY AND THE STORY ABOUT THE IMMUNE SYSTEM IN THE PERIPHERY OF THE BRAIN ARE NOT NECESSARILY THE SAME SO WE ARE JUST STARTING TO LOOK AT SIDE-BY-SIDE WHAT THE MEASURES AND THE BRAIN SHOW. BUT SPECIFICALLY YOU’RE RIGHT FGF HAVE ARE BEEN REPLICATED IN VIRAL AND INFECTION AND ESPECIALLY AIDS AND THIS IS BEYOND BY KIN BUT I WOULD LOVE SOMEBODY TO DO WORK ON IT.>>HOW YOU COULD TRANSLATE RESULTS IN HUMAN PATIENTS? [INDISCERNIBLE].>>IS THIS TRANSMITTABLE? YEAH. OBVIOUSLY AS YOU CAN TELL IT’S PART OF A HUMAN SO I’M PRETTY SURE IT’S RELEVANT TO HUMAN. SO THAT NUMBER ONE IS ONE THAT WAY BY WORKING BACKWARDS. SO WE HAVE — WE AND OTHERS — HAVE SHOWN THAT THERE ARE SOME VARIANCE THAT ARE ALSO VERY PREDICTIVE. MY COLLEAGUE HAS GENOTYPED PEOPLE BASED ON SOME VARIOUS BIOMARKERS INCLUDING SOME I’VE MENTIONED TO PROTECT WHO’S GOING TO BE DEPRESSION PRESSED DURING THEIR INTERNSHIP YEAR BUT I THINK IT’S A COOL MODEL. SO AS BIOMARKERS, I THINK WE’RE STARTING — WHAT I SKIPPED OVER WAS A TREE OF SOCIAL STRESS TEST YOU GIVE TO HUMANS AND WE’RE TRYING TO PREDICT WHO’S GOING TO RESPOND IN WHAT WAY AT THE ENDOCRINE LEVEL BASED ON BIOMARKERS. I THINK BIOMARKERS ARE IS FAIRLY PROXIMAL. WE SHOULD BE ABLE TO GET AT THOSE IF WE ASK THE QUESTIONS RIGHT. IN TERMS OF DRUGS, WE KNOW IT WORKS IF WE GIVE IT TO ANIMALS, BUT GIVING IT TO HUMANS IS WHOLE OTHER BALL GAME. ONE OF MY CONCERNS IS THAT FGF 2 IS VERY POWERFUL AND IT MAY BE THAT IT’S TOO MUCH TO GIVE, AND ONE REASON I SHOWED YOU FGF 9 IS BECAUSE IT IS WORKING IN THE OPPOSITE DIRECTION AND IT’S BETTER TO GIVE ANTAGONISTS THAN AGONISTS SO THIS IS ONE DIRECTION WE’RE GOING. THE OTHER DIRECTION WE’RE GOING IS TO LOOK AT PARTNERS OF THESE MOLECULES THAT ARER LIKE MORE BRAIN-SPECIFIC. SO WE WOULD LIKE TO TRANSLATE IT BUT KIND OF INTELLIGENTLY HOPEFULLY BY TRYING TO AVOID SOME OF THE POTENTIAL PERIPHERAL SIDE EFFECTS BECAUSE THESE ARE VERY POWERFUL AGENTS THROUGHOUT THE BODY.>>ALSO LOOKING AT HUMAN VAIN POSTMORTEM. DO YOU SEE EFFECT OF [INDISCERNIBLE] SHOULD BE INCLUDING GROWTH OF [INDISCERNIBLE]? SO DO YOU SEE ANY CHANGES BECAUSE OF THE FGF 2?>>IN HUMAN POSTMORTEM WE HAVEN’T DONE THAT, WE CAN’T DO THAT. ONE OF THE REASONS THAT THE WATTSON LAB IS FOCUSING SO MUCH OF CLARITY IS TO BE ABLE TO TAKE THE THOSE BRAINS ARE VERY, YOU KNOW, PRECIOUS AND IF YOU TAKE THEM AND GRIND THEM UP FOR ONE KIND OF STUDY, SO WE GET ONE HALF TO DO ONE THING, OTHER HALF TO KEEP FOR MORE ANALYSES AND IT WOULD BE REALLY IMPORTANT TO GET FROM THE SAME BRAIN AS MUCH DATA AS WE CAN GET AS MANY MARKERS INCLUDING SOME ADULT STEM CELLS AND OTHER THINGS AND CERTAIN OTHER MARKERS AND SO ON IN AN AN ATOM CALL SURFACE CONTEXT WHILE WE’RE DOING GENETICS AND GENE EXPRESSION PROFILING AND IF WE COULD GET UH ALL THAT TOGETHER I THINK THAT WOULD BE GOOD.>>YOU MENTIONED ABOUT THE POSTMORTEM WHEN YOU DO THE BRAINS AND SAY YOU FOUND DIFFERENT GENOMIC PROFILES DEPENDING ON TIME OF DEATH.>>YES.>>THERE’S AN AN AWFUL LOT OF MEDICAL LIT KRA CHUR DEDICATED TO CIRCADIAN RHYTHMS AND DISEASE AND I CAN TELL YOU FROM EXPERIENCE A SERIES WHICH I PUBLISHED IN THE ARCHIVES OF PATHOLOGY ON ASTHMA DEATHS IS THAT ONE OF THE MAJOR FINDINGS WAS ASTHMA ATTACK BEGAN IN THE EARLY A.M., THAT WAS CAUSE OF DEATH. INCIDENTALLY IN THAT STUDY WE FOUND ONE RELATION WAS BETWEEN PEOPLE WHO EITHER ABUSED DRUGS OR HAD AT THE TIME OR HAD DONE IT IN THE PAST WHICH IS NOW BECOMING VERY BIG IN LITERATURE. THE POINT IS, THAT YOUR CIRCADIAN RHYTHM SEEMS TO BE EVEN THOUGH YOU POINTED IT OUT AS INCIDENTAL FINDING MIGHT BE A MAJOR THING TO FOCUS ON.>>YEAH. I MEAN MY COLLEAGUE HAS BEEN TALKING ABOUT CIRCADIAN RHYTHMS AND ROLE IN AFFECTIVE DISORDERS FOR MANY YEARS WHICH IS WHAT DROVE US TO LOOK AT THIS THING AROUND THE CLOCK AND LOOK AT POTENTIAL TARGET FOR INTERVENTION. I AM NOT SURE THAT THE CLOCK PER SE IS BROKEN IN THESE PEOPLE, YOU KNOW, AT THE MOLECULAR LEVEL, BUT I THINK DEFINITELY THE REGULATION AND SOMETHING — THERE IS SOMETHING TO LEARN A LOT ABOUT THE PATTERNS OF CHANGE ACROSS THE BRAIN AND HOW THAT MIGHT BE INFLUENCING. BY THE WAY, WHAT IS REALLY INTERESTING IS THAT WHEN WE LINED UP THE DEPRESSED PEOPLE AROUND THE CLOCK, THEY WERE NOT AS DISTRIBUTED AROUND THE CLOCK AS THE CONTROLS, AND I DON’T KNOW WHAT IT MEANS WHEN PEOPLE DIE, SUICIDE OR NON-SUICIDE, THE TIMING OF WHEN PEOPLE DIE IS INTERESTING. SO WHAT WE HAVE TO DO IS THEN GO BACK TO CONTROLS AND PICK ONLY ONES THAT DIED AT ABOUT THE SAME TIME AND MAKE SURE THAT IS NOT BIASSED. SO EVEN IN DEPRESSION, MY POINT IS, THAT PEOPLE DIE AT DIFFERENT TIMES THAN KIND OF RANDOMLY, AND I DON’T KNOW WHAT THAT HAS TO DO WITH CIRCADIAN RHYTHM BUT MAYBE.>>OKAY. THANK YOU VERY MUCH.>>HUDA YOU SHOWED THIS LOVELY DATA ABOUT GENE EXPRESSION AND MODIFICATION OF HISTONE METHYLATION, BUT OF COURSE MUCH OF YOUR DATA HAS BEEN FOCUSED ON TAKING A PIECE OF BRAIN TISSUE — WE’RE ALL EXCITED ABOUT THE IDEA OF BEING ABLE TO GO TO SINGLE CELLS — IS THAT SOMETHING THAT YOU THINK COULD CHANGE THIS PICTURE SUBSTANTIALLY ‘CUZ YOU’RE OBVIOUSLY PUTTING A LOT OF DIFFERENT CELL TYPES TOGETHER HERE? WHAT’S THE FUTURE OF THAT?>>RIGHT. ABSOLUTELY. SO WE’VE BEEN WORKING BY SUCCESSIVE APPROXIMATION. THE FIRST ONE WAS BRAIN REGION AND THEN I I SHOWED SOME SLIDE WHERE IS WE WERE TRYING TO SEE IF WE CAN GRAB LIKE, YOU KNOW, MOLECULARLY-DEFINED LIKE [INDISCERNIBLE] VERSUS RH NEURONS OR WHATEVER, BUT I THINK EVENTUALLY BEING ABLE TO LOOK MORE AT — ESPECIALLY GIVEN THE LEVEL OF THE [INDISCERNIBLE]ISM IN THE HUMAN CORTEX, ASKING IF IF THAT IS IN FACT IN ITSELF A VARIABLE, YOU KNOW, WHETHER YOU GET MORE NOISE, FOR EXAMPLE, WITH SOME OF THESE ILLNESSES OR LESS,; AND TRYING TO SEE IF WE CAN CAPTURE THAT. ONE OF MY JR. COLLEAGUE WE HIRED IS NOW PART OF THE CONSORTIUM IS VERY INTERESTED IN CORTEX AND GENETIC TO LOOK AT THAT. HOPEFULLY IT WILL YIELD SOMETHING USEFUL.>>YEAH. WELL WE CAN CONTINUE THE CONVERSATION AT THE RECEPTION WHICH IS IN THE LIBRARY. PLEASE COME AND JOIN IF YOU WANT COFFEE, COOKIES AND CONVERSATION, BUT PLEASE LET’S THANK HER FOR A WONDERFUL PRESENTATION.

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