>> GOOD AFTERNOON, EVERYONE. WELCOME TO THE FIRST WEDNESDAY AFTERNOON LECTURE OF THE ACADEMIC YEAR. WE WERE SO EXCITED THAT WE HAD TO HAVE IT ON MONDAY. AND THERE WILL BE OF COURSE DURING THE COURSE OF THE YEAR ON WEDNESDAY AT 3 O'CLOCK IN THIS SPACE A LINEUP OF REMARKABLE SPEAKERS. TODAY'S REMARKABLE SPEAKER IS A PLEASURE TO BE ABLE TO INTRODUCE DR. CORI BARGMANN, HER CURRENT POSITION AT THE ROCKEFELLAR IS THE PROFESSOR AND HEAD OF THE LULU ANTHONY WANG CIRCUITS AND NEURAL BEHAVIOR AND SHELBY WHITE AND LEON LEVY CENTER FOR MIND AND BEHAVIOR. SHE BEGAIN TRAINING IN BS IN BIOCHEMISTRY UNIVERSITY OF GEORGIA THEN WENT ON TO Ph.D. AT MIT WITH BOB WINEBERG WHERE SHE DID VERY INTERESTING WORK ON THE GENE CALLED NU. DECIDING MAYBE CANCER WASN'T THE ANSWER TO EVERYTHING. SHE DID A POST-DOCTORAL RESEARCH PROGRAM WITH BOB HORVATH. SHE'S CHOSEN WELL IN TERMS OF LABORATORIES TO WORK WITHIN AND BECAME AS YOU WILL FIND OUT LATER CAPTIVATED BY WHAT ONE MIGHT BE ABLE TO LEARN FROM THE ROUND WORM C ELEGANS. SHE THEN SPENT TIME LIKE 13 YEARS AT THE UNIVERSITY OF CALIFORNIA SAN FRANCISCO, ALONG THE WAY BECAME INVESTIGATOR OF HHMI SHE CONTINUES TO BE TO THIS DAY AND THEN MOVED TO ROCKEFELLAR IN 2004. HER WORK HAS BEEN AT THE TOP OF THE FIELD OF UNDERSTANDING HOW NEURAL SYSTEMS WORK AND SHE HAS BEEN CLEANING UP HERE IN THE LAST COUPLE OF YEARS BEEN AWARDED THE CABLY PRIZE IN NEUROSCIENCE IN 2012 AND BREAK THROUGH PRIZE IN 2013 WHICH MAYBE SHE'LL TELL YOU THE EXPERIENCE HOW SHE FOUND OUT ABOUT IT BOTH WHICH ARE EXTREMELY WELL DESERVED. I HAVE TO SAY I'M PARTICULARLY GRATEFUL TO CORI FOR THE WAY IN WHICH SHE HAS PUT PROBABLY A CHUNK OF LAST EFFORTS ON HOLD OR PUSHED ASIDE FOR THE LAST THREE AND A HALF MONTHS AS SHE HAS BEEN CO-LEADING THE EFFORT NIH HAS ASKED FOR TO DEFINE THE GOALS OF THE BRAIN INITIATIVE ANNOUNCED BY THE PRESIDENT OF THE UNITED STATES ON APRIL 2ND AT A TIME WHERE THE GENERAL SCIENTIFIC IDEAS WHAT WE MIGHT DO WITH THIS INITIATIVE WERE A LITTLE IN NEED OF SPECIFICITY. AND CORI AND NEW CHAIR BILL NEWSOME ARE WORK WITH A DREAM TEAM OF NEUROSCIENTISTS TO PUT FORWARD WHAT WE EXPECT WILL BE A VERY EXCITING INTERIM PLAN THAT WILL GUIDE OUR EFFORTS TO GET THIS UNDERWAY IN FY 14 WHICH STARTS VERY SOON. SO KEEP YOUR EYE ON THE OUTPUT OF THIS DELIBERATIVE PROCESS AND THEY WILL GENERATE BY NEXT SUMMER A MORE DETAILED SOMEWHAT LONGER TERM PLAN FOR THE NEXT FIVE YEARS OR PERHAPS EVEN MORE. BECAUSE IT'S A CONSIDER SITING TIME IN NEUROSCIENCE. THE OPPORTUNITY WITH NEW TECHNOLOGY, NEW APPROACHES TO BE ABLE TO UNDERSTAND HOW CIRCUITS WORK IN REAL TIME. THERE'S NOBODY BETTER TO DESCRIBE HOW THAT'S ALREADY COMING THROUGH IN AN ORGANISM THAT WE KNOW A LOT ABOUT, NAMELY C ELEGANS THAN TODAY'S SPEAKER, CORI BARGMANN'S TITLE IS NEUROMODULATORY CIRCUITS AND MOTIVATED BEHAVIOR, PERSONAL PLEASURE TO HAVE HER HERE TODAY AND LET ME ASK YOU TO WELCOME DR. CORI BARGMANN. [APPLAUSE] >> SO I WOULD LIKE TO THANK MY COLLEAGUES HERE AT THE NIH PARTICULARLY NORA AND STORY FOR THIS INVITATION, THANK FRANCIS FOR THAT LOVELY INTRODUCTION AND THANK THE NIH IN GENERAL FOR ITS SUPPORT OF SCIENCE AND AT THIS POINT NEUROSCIENCE IN WAYS THAT EXCITED THE WHOLE FIELD. I'M GOING TO TALK ABOUT TRYING TO BREAK A PROBLEM DOWN TO ITS SIMPLEST ELEMENTS AND THE PROBLEM I'M GOING TO START WITH IS COMPLICATED BREAKING DOWN SIMPLE ELEMENTS AS MERITED. THAT IS THE BIOLOGICAL BASIS OF BEHAVIOR. SO WHEN WE LOOK AT ANIMALS EXPLORING THEIRÖ– ENVIRONMENT RECOGNIZING EACH OTHER, LEARNING EXPLORING, WHAT STRIKES US ABOUT THEM IS DIVERSITY OF DIFFERENT BEHAVIORS. WE LOOK AT HUMAN BEINGS WE ALSO SEE A GREAT DIVERSITY OF DIFFERENT BEHAVIORS. BUT GOING BACK TO THE 1930s T CLASSICAL NEUROPATHOLOGIST RECOGNIZED THAT BEHAVIOR HAS COMMON COMMON THEMES, EARN WHEN OUTWARD MANIFESTATIONS SEEM TO BE ALREADY DIFFERENT. THESE BIOLOGICALLY TRAINED PSYCHOLOGISTS VERY CAREFULLY EXAMINE BEHAVIORS OF ANIMALS AND SHOW IN PARTICULAR BEHAVIORS ASSOCIATED WITH KEY FUNCTIONS LIKE FEEDING AND REPRODUCTION TENDD TO HAVE ELEMENTS YOU CAN RECOGNIZE NOT ONLY FOR SPECIES BETWEEN MEMBERS OF DIFFERENT SPECIES. FOR EXAMPLE IF YOU LOOK AT COURTSHIP BEHAVIOR, AGGRESSIVE BEHAVIORS RELATED TO COURT SHIP AND DIFFERENT ANIMALS THE MANIFESTATIONS MIGHT BE DIFFERENT IN THE BEHAVIORS THEMSELVES BUT THERE WERE UNDERLYING RULES THAT DETERMINED WHEN THEY WERE EXPRESSED HOW THEY WERE EXPRESSED, WHEN BROKEN OFF AND WHAT THE APPROPRIATE TARGETS WERE. ANIMAL'S ABILITY TO RAISE OFFSPRING MIGHT APPEAR DIFFERENT FOR DIFFERENT ANIMALS BUT SIMPLE INVERTEBRATES TO OURSELVES, THE PROBLEM OF CARING FOR THE YOUNG SOMETHING THAT HAS A BIOLOGICAL BASIS AND CERTAIN FUNDAMENTAL PRINCIPLES UNDERLYING. THE NEUROPATHOLOGIST HAS NO IDEA WHAT MODERN BIOLOGY WAS AND HOW THAT MIGHT RELATE TO A MECHANISTIC BASIS BUT THIS CONCEPT OF IDEAS OR THEMES IN BEHAVIOR IN PARTICULAR FOR INSTICTIVE BEHAVIOR ARE EXPRESSEDDED AT A MOLECULAR LEVEL AND I WOULD LIKE TO MENTION EXAMPLE OF THAT AT THING BEGINNING OF MY TALK. AND THAT IS THE SMALL MOLECULE NEUROPEPTIDEOXI TOE SIN SUPPRESSION, NON-AMINO ACID PEPTIDE CLOSELY RELATED TO EACH OTHER, THE FIRST PEPTIDE NEUROPEPTIDE IS TO BE PURIFIED AN SYNTHESIZED FOR MAMMALS WHERE THEY WERE RECOGNIZEDDED EARLY ON IMPORTANT ROLES IN REPRODUCTIVE BEHAVIOR SO WHEN A MAMMAL GIVES BIRTH, HER HYPOTHALAMUS RELEASESOXI TOE SIN INTO THE BLOODSTREAM. IT CAUSE IT IS UTERUS TO CONTRACT DRIVING THE BIRTH OF THE OFFSPRING, IT ALSO CAUSES A MILK LET DOWN RESPONSE THE TO ALLOW NURSING TO TAKE PLACE. OXI TOE SIN IS REELED TO THE FEMALE IS RELEASED TO THE FEMALE MA MA'AM BRAIN AND RELEASE PROVIDES A STRONG STIMULUS TO FORMATION OF MATERNAL BEHAVIOR AND MOTHER PUP BONDING. SOOXI TOE SIN IS ONE STOP SHOPPING OF MAMMALIAN BEHAVIOR, IT GETS THE OFFSPRING BORN, GETS THE OFFSPRING FED AND TAKEN CARE OF. IN A VARIETY OF MAMMALIAN SPECIES. A GRADUATE STUDENT IN MY LAB EVAN NOTICED THE GENE OF A NEMATODE WORM C ELEGANS HAD A MOLECULE THAT LOOKED LIKE OXYTOCIN. I HAVE TO SAY YOU HAVE TO BE A VERY GOOD FRIEND TO BELIEVE THIS MOLECULE WAS REALLY OXYTOCIN, IT DIDN'T LOOK LIKEOXI TOASTING BUT WE WERE ENCOURAGED BECAUSE THERE WERE TWO POTENTIAL RECEPTORS THAT LOOKED LIKE OXYTOCIN VASOPRESSIN RECEIVE FROMSORS. SO FOLLOWING THAT ON CESSATION JENNIFER GARY SON A POST DOC WHO JOINED THE LAB PROVED THIS PEPTIDE IS MADE PURIFIED FROM WORM, AND SHOWEDDED THAT IT ACTIVATES THESE TWO RECEPTORS, IN HETEROLOGOUS CELL SYSTEMS SYNDICATING THERE IS A CONSERVED PEPTIDE AND CONSERVED RECEPTOR THAT BELONG TO THIS PARTICULAR FAMILY OF C PEPTIDE VEEPTOR SYSTEM. SO THIS IS A BIOCHEMICAL RELATIONSHIP BUT WHAT'S INTERESTING IS A BIOLOGICAL RELATIONSHIP, WE OBTAIN MUTATIONS IN THIS MOLECULE NEMATODE OXYTOCIN AND RECEPTORS. AND JENNIFER EXAMINED THEM FOR A WIDE VARIETY OF DIFFERENT RESPONSES AND THESE ANIMALS WERE VIABLE, THEY WERE SUPERFICIALLY HEALTHY, ABLE TO SOLVE TASKS BUT THERE WERE THERE WAS ONE TASK THAT DIDN'T FALL VERY WELL, THAT IS THAT THE MALES, THE SKINNY GUYS HERE, WERE INEFFECTIVE WHEN PLACED IN A SITUATION WITH A MATING PARTNER T LARGER HER HALF INDICT AND ASKING TO CARRY OUT A MATING ROUTINE. THEY DIDN'T FAIL COMPLETELY, THEY FAILED HALF THE TIME REGARDLESS WHETHER THE PEPTIDE WAS MISSING OR RECEPTORS WERE MISSING. AND CONSISTENT WITH THIS FUNCTION, WHEN YOU LOOK AT THE MALE TAIL WITH SPECIALIZED NEURONS AND CIRCUITS REQUIRED FOR MATING BEHAVIORS BOTH NEMATODES AND RESTOPS WERE EXPRESSED IN SUBSETS OF NEURONS. WHAT IS INTERESTING ABOUT THIS, FROM THE POINT OF VIEW OF THE BIOLOGY, HAVING A SYSTEM LIKE THIS, ENABLES JENNIFER TO LOOK CAREFULLY AND ASK WHAT IS THE LOGIC BY WHICH THIS REPRODUCTIVE NEUROPEPTIDE IS REGULATING REPRODUCTIVE BEHAVIOR? IS IT REQUIRED FOR THE NEURONS TO FUNCTION AT ALL? IS IT REQUIRED FOR MATE RECOGNITION, REQUIRED FOR SOME PARTICULAR STEP OF THE PROCESS? SO BY USING QUANTITATIVE ASSAYS WHICH MEASURED MANY ASPECTS OF MATING, AND ALSO BY MEASURING THINGS LIKE OVERALL MATING SUCCESS AND NUMBER OF PROGENY, AND BY MEASURING A COMPLETELY DIFFERENT SET OF BEHAVIORS RELATED TO REPRODUCTION WHICH WERE FOOD SEEKING BEHAVIORS THAT MANIFEST THEMSELVES OVER TIME PERIODS OF HOURS, JIM FOUND THAT EVERY ASPECT OF REPRODUCTIVE MATING BEHAVIOR IN MALES WAS BUT REDUCED IN ANIMALS LIKE LACKING THE NEUROPEPTIDE. THEY ACT AS GLOBAL REGULATORS BUT COORDINATED MATING BEHAVIOR ON SHORT TIME SCALE AND LONG TIME SCALE, A PARTICULAR MOTOR ACTION AND EVEN SPERM TRANSFER. INSTEAD OF ONE LEVEL, THIS NEUROPEPTIDE IS ONE ELEMENT OF MATING BEHAVIOR I INCLUDES MANY NEURONS AND SIGNALS. ANOTHER LEVEL IS ELEMENT OF ALL ASPECTS OF MATING BEHAVIOR WE CAN EVALUATE. THE TAKE HOME MESS LEST SON, IT TELLS ABOUT A RELATIONSHIP BETWEEN A MOLECULE AND BEHAVIOR WE CAN EXAMINE HIGH RESOLUTION QUANTITATIVELY BUT THE REAL TAME HOME LESSON THAT STRIKES US ABOUT THIS IS IT SUGGESTS SOMETHING REMARKABLE. WHICH IS THESE MOLECULES RELATED TO OXYTOCIN AND VASOPRESSIN MAY HAVE BEEN LOCKED INTO A PARTICULAR FUNCTION EARLY IN ANIMAL EVOLUTION. BECAUSE WORK FROM A VARIETY OF PEOPLE IN MAMMALIAN SYSTEMS CAN'T BE HERE AT NIH WITHOUT MENTIONING TOM INSEL'S WORK, OXYTOCIN AND VASOPRESSIN ARE IMPORTANT REGULATORS OF REPRODUCTIVE BEHAVIORS INCLUDING MATING. WORK FROM BILL KRISTEN'S LAB AT UCSD SHOWED A OXYTOCIN PEPTIDE IS INVOLVED IN THE MATING REGIME OF LEECHES AND OUR WORK INDICATES THAT IT'S INVOLVED IN THE MATING BEHAVIOR OF NEMATODE. SO ACROSS ALL THREE MAJOR BRANCHES OF ANIMALS THE SAME MOLECULAR PATHWAYS ARE USED AS GLOBAL REGULATORS THE SAME KINDS OF BEHAVIOR. THESE -- DESPITE THE DIFFERENT MATING BEHAVIOR, APPEARANCE AND QUEUES OF THESE ANIMALS, PART OF THE INNER MOTIVATIONAL MECHANISMS REPRESENTED BY A PARTICULAR NEUROPEPTIDE ARE LINKED TO THESE SYSTEMS. AND WE CAN RECOGNIZE THEIR ACTION ACROSS THE SYSTEM. THIS PRESENTS FOR ME THE REASON FOR THE JUSTIFICATION FOR STUDYING THE NEMATODE WORM C ELEGANS AS A MODEL SYSTEM FOR UNDERSTANDING THE BRAIN. LIKE NEUROSCIENTISTS I WOULD LIKE TO UNDERSTAND THE HUMAN BRAIN PARTICULARLY MY HUSBAND. THE HUMAN BRAIN IS IMMEASURABLY COMPLEX, IT CONSISTS OF BILLIONS OF NEURONS CONNECTED BY TRILLIONS OF SYNAPSES. SOMETIMES IT'S THE MOST COMPLICATED OBJECT THAT WE KNOW OF. GETTING TO THE LEVEL OF GENES WHICH IS WHAT I'M TALKING ABOUT, THERE'S ROUGHLY 25, 30,000 OF THEM, QUITE A NUMBER OF COMPONENTS IN THAT STRUCTURE. I WANT TO MENTION HUMANS HAVE ABOUT A HUNDRED GENES THAT INNEUROPEPTIDES, OXYTOE SIN AND VASOPRESSIN. HERE WE LOOK AT NEMATODE C ELEGANS. THE NERVOUS SYSTEM OF THIS ANIMAL CONSISTS OF JUST 302 NEURONS IF HE MA FLOW DIET SO ANATOMICALLY THIS IS A MUCH SIMPLER PLACE TO GO. IF WE LOOK AT THE LEVEL OF THE GENETIC CIRCUITRY, IT'S ALMOST AS COMPLEX AS NUMBER OF GENES, IT HAS ABOUT THE SAME NUMBER OF NEUROPEPTIDE GENES SOME WHICH HAVE ORTHO LOGS ACROSS THE STRAIN. THIS PART OF THE PUZZLE WE SHOULD UNDERSTAND IN C ELEGANS AND CONTEXT OF HAVING ANIMAL WHERE YOU HAVE IDENTIFIED NEURONS, THAT YOU CAN RECOGNIZE IN EVERYONE, KNOWN CONNECTIVITY, BECAUSE WE KNOW THE SYNAPTIC CONNECTIONS BETWEEN THESE NEURONS FROM WORK ON JOHN WHITE AND COLLEAGUE, POWERFUL GENETIC TOOLS COMBINED WITH A THREE DAY LIFE CYCLE. HERE IS ANOTHER ILLUSTRATION OF THAT POINT. THIS IS THE WIRING PROGRAM SHOWING THE MAJOR CLASSES OF NEURONS IN C ELEGANS, CATEGORIZED ACCORDING TO CONNECTIONS WITH EACH OTHER INDICATED BY THESE EDGES BETWEEN DIFFERENT NODES. THERE'S A STRUCTURE HERE, DIFFERENT NEURONS CONNECTED IN PARTICULAR PATTERNS, GROUPS OF NEURONS THAT TEND TO BE INTERCONNECTED. THIS IS WHAT WE HAVE TO UNDERSTAND, TO UNDERSTAND HOW NEMATODE BEHAVIOR WORKS. WE HAVE TO UNDERSTAND TO UNDERSTAND HOW HUMAN BEHAVIOR WORKS. TREMENDOUSLY MORE PLEX, COMPLEX, THESE ARE LARGE CONNECTIONS USING DIFFUSION TENSOR IMAGING COMPARED TO ACTUAL INDIVIDUALLY ANATOMICALLY DEFINEDDED MAPS THAT WE CAN LOOK AT. P AS A PROVISIONAL IN BETWEEN STEP THIS WILL HELP ALONG THE PATH WITH THIS. WHAT I WANT TO TALK ABOUT TODAY IN PARTICULAR ARE A CLASS OF MOLECULES THAT REPRESENT ONE OF THE WAYS THAT NERVOUS SYSTEMS HAVE OF COMMUNICATING AND THOSE ARE NEUROPEPTIDES AND NEUROMODULATORS. SO TO CLASSICAL TOOL OF NEUROPHYSIOLOGY AND NEUROANATOMY HAVE FOCUSED ON ONE OF THE WAYS THAT NEVER CELLS COMMUNICATE WHICH IS THROUGH FAST CHEMICAL TRANSMISSION. GLUTAMATE OR GAP BE OR ACETYLCHOLINE SYNAPSES. THERE'S THE SECOND MODE USED LESS OF USING ELECTRICAL SYNAPSES AN GAP JUNCTION. SUPERIMPOSED ON THESE THIS IS MOLECULES ARE CO-RELEASED WITH CLASSICAL TRANSMITTERS LESS ACCESSIBLE TO THE POWER OF TOOLS ANATOMY AND PHYSIOLOGY, THEY'RE NOT ALWAYS RELEASED EXACTLY AT SYNAPSES SO NOT SO STRAIGHT FORWARD TO DETERMINE THE TARGETS WITHOUT TESTING DIRECTLY. THEY ACTIVATE G PROTEIN COUPLED RECEPTORS FOR THE MOST PART AND THAT MEANS THAT IT IT IS NOT EASY TO MEASURE ACTION POTENTIAL WHAT THESE MOLECULES HAVE DONE TO THE TARGET NEURONS WITHIN THE CIRCUIT. HOWEVER, IT'S CLEAR THEY HAVE IMPORTANT BIOLOGICAL FUNCTIONS THAT INCLUDES REGULATION OF BEHAVIORS SUCH AS SLEEP AND WAKING, HUNGER, PAIN PATHWAYS, BONDING AFFILIATED BEHAVIOR AND PRODUCTION, MOOD REGULATIONND ADDICTION WHICH HAVE BEEN ASSOCIATEDDED WITH MOLECULES FROM WITHIN THE FAMILY. THEIR ROLE BEHAVIOR INDICATED PHARMACO LOGICALLY OR GENETICALLY THROUGH THESE KINDS OF MECHANISMS INCLUDING HUMAN BEHAVIOR IS FIRM. HERE IS THE QUESTION TO ADDRESS AT MICROSCOPIC LEVEL. HOW DO THESE CIRCUITS INTERACT WITH CHEMICAL CIRCUIT? WHAT IS THE STRUCTURE OF THE CIRCUITS, WHAT DISTANCES DO THEY ACT OVER, WHAT TIME SCALES. HOW CAN WE PUT TOGETHER WAYS OF VIEWING ONE EASTERNER SLOWS SYSTEM. I WILL TALK ABOUT THOSE IN THE CONTEXT OF A PARTICULAR KIND OF BEHAVIOR FORAGING BEHAVIOR, EXEMPLOYERTORY THE BEHAVIOR. IT'S BUILT ON A CLASSICAL OBSERVATION FROM NEUROPATHOLOGY WHEN YOU LOOK AT FORGING ANIMALS WHETHER THOSE ARE DROSOPHILA FLYING IN THEIR CAGE OR MICE MOTORING AROUND IN THEIR HOME CAGES OR HERE IN THIS CASE WILD TURNS FORAGING ON DIFFERENT ISLANDS OR TODDLERS IN A PLAYGROUNDS, YOU SEE THE SAME KINDS OF PATTERNS OF BEHAVIOR. BEHAVIOR THAT IS STRUCTURED IN BOUGHT OF HIGH ACTIVITY AND BOUGHT OF LOW ACTIVITY. I AM SHOWING YOU CIRCADIAN RHYTHM TO STRUCTURE ON LONG TIME SCALES THE ENTIRE 24 HOUR CYCLE, BUT EVEN WITHIN AN INTERVAL OF THE CYCLE YOU SEE THERE'S BOUGHT OF HIGH ACTIVITY SHOWN BY THESE PATCH MARKS AN BOUGHT OF QUIETER PERIODS. THESE KINDS OF ACTIVITY STATES ARE SOMETIMES CALLED ACTIVE STATES OR EXPLORATORY STATES VERSUS QUITE YET RESTING OR WAKEFULNESS, FOR EXAMPLE. SO WE SEE THIS ACROSS A VARIETY OF DIFFERENT ANIMAL SPECIES, SEEMS TO BE A WAY BEHAVIOR IS ORGANIZED ON RELATIVELY LONG TIME SCALES OF MINUTES OR HOURS. STEVE A POST-DOC IN MY LAB DECIDED TO ADDRESS IN THE CONTEXT OF BEHAVIOR DESCRIBED PREVIOUSLY BY (INDISCERNIBLE) STEVE MCENTYRE'S LAB, THAT'S A BEHAVIOR THAT HAS THE SAME KIND OF PUNCTUATED STRUCTURE WITH C ELEGANS CALLED ROAMING AND DWELLING BEHAVIOR. IT REPRESENTS BEHAVIORS ANIMALS SHOW ON FOOD WHILE FEEDING. BY LOOKING AT THE TRACK THE SINGLE ANIMAL LEFT IN A ONE HOUR PERIOD COLOR CODED DEPENDING ON WHAT IT WAS DOING AN HOW LONG IT WAS DOING. WHAT YOU CAN SEE FOR THE FIRST 40 MINUTES OF THE TRACK HERE IN RED THIS ANIMAL MOVED AROUND IN A SMALL AREA NOT FAR, TURNING RAPIDLY, STAYING IN THAT AREA. FOR OTHER INTERVALS LIKE THIS TEN MINUTE BLUE INTERVAL HERE, IT TEARS AROUND ON THE FOOD EXPLORING THE FOOD WIDELY BEFORE TURNING TO SPEND ANOTHER TIME AT THE HOME RESTING PLACE. WE CAN CATEGORIZE BEHAVIORS MOVING DURING BEHAVIORS, FEEDING, LAYING EGGS, RESPONSIVE TO SENSORY QUEUES SO NOT SLEEPING, THESE ARE WAKING BEHAVIORS. WE CAN SEPARATE THEM OUT EASILY. ANIMALS THAT ARE DWELLING AT LOW SPEED AND TURNING FREQUENTLY AS THEY EAT ON THE FOOD, GRAZE ON THE FOOD, ANIMALS ROAMING AT HIGHER SPEED ALLOWING THE SCATTER SO FAR. THIS IS WHAT THAT LOOKS LIKE. HERE IS A MOVIE, THERE IS A WORM AROUND HERE IF THINGS GO WELL THAT YOU CAN SEE. STARTING IN DWELLING STATE, STAYING IN ONE AREA, IT JUST ROAMD. NOW IT'S DWELLING, ROAM. DWELL, DWELL, ROAM. DWELL. SPEEDING UP WORM MOVIES MAYBES THEM MUCH MORE EXCITING. BUT WE CAN SEE INDIVIDUAL ANIMALS MOVING BETWEEN STATES WHICH YOU CAN QUITE READILY RECOGNIZE BY I USING THIS APPROACH. AND MORE IMPORTANTLY YOU CAN RECOGNIZE IT THROUGH ANALYTICAL APPROACH MEASURING TWO BASIC PARAMETERS ANGULAR SPEED, HOW OFTEN IT CHANGES DIRECTION AND ITS LOCOMOTION SPEED, HOW QUICKLY IT'S MOVING, IT'S CLEAR WHEN YOU SUPER IMPOSE THESE ON TOP OF EACH OTHER, THAT THERE ARE BEHAVIORAL STATES HIGH AND BEHAVIORAL STATES WHERE SPEED IS LOW AND THERE'S MANY, MANY TURNS. SO THESE STATES CAN BE CADGERRIZED USING A HIDDEN MODEL WHICH BASICALLY SAYS YOU CAN CATEGORIZE STATES IN A FAIRLY STRAIGHT FORWARD WAY THAT THE COMPUTER DETERMINES ON ITS OWN INTO BEHAVIORAL STATES. SO THIS IS SOMETIMES CALLED IN FORAGING LITERATURE, EXPLORATION VERSUS EXPLOITATION ACCESS WHICH IS FUN. AND THIS IS A BEHAVIOR THAT REFLECTS THE ANIMAL'S INTERNAL STATE AS WELL AS EXTERNAL QUEUES. SO ANIMALS ARE IN GOOD CONDITION THEY SPEND MOST TIME DWELLING. BUT WHEN FOOD QUALITY IS LOW OR WHETHER -- FOOD IS LIMITING OR IF THEY'RE ENVIRONMENTAL IRRITANTS THE ANIMALS SPEND MORE TIME ROAMING. DWELLING IS A MARKER OF A GOOD SITUATION FOR THE WORM AND ROAMING MORE OF EXPLORATORY ACTIVITY TO SEE IF THERE MIGHT BE SOME BETTER SITUATIONS. SO STEVE SET OUT TO DEVELOP RIGOROUS WAYS OF ANALYZING THE BEHAVIOR, CLASSIFYING THEM, AND ASKING WHAT THE STRUCTURE WAS AND WHAT HE DID WAS TO VIDEOTAPE HUNDREDS OF HOURS MOVING THROUGH THE ENVIRONMENT AND ASK THE STRUCTURES OF THE BEHAVIORS. DWELLING STATE HAS SINGLE EXPONENTIAL WITH AVERAGE DWELL TIME OF 8 MINUTES. ROPING STATE HAVE A DISTRIBUTION SUGGESTING THEY HAVE TWO EXPONENTIALS. THERE'S SHORT ROAMING STATES ABOUT AIMING LONG THAT ARE -- MINUTE LONG THAT ARE 80% OF TOTAL AND CLASS OF ROAMING STATES MUCH LONGER, ABOUT NINE MINUTES LONG, 15% OF THE TOTALMENT THE SIGNIFICANCE IS THAT IT TELLS US WE CAN DESCRIBE THESE BEHAVIORS, THEY'RE RELIABLE, FIT THEM INTO A MODEL AND SEE IF THEY CHANGE AND ALSO THAT THESE ARE NOT RHYTHMIC OR CYCLIC BEHAVIOR. THEY PN'T DON'T HAVE A REGULAR STRUCTURE LIKE CIRCADIAN RHYTHM, EXPONENTIAL STRUCTURE SAYS THEY CAN START AND END AT RANDOM SO WE HAVE TO TAKE THAT INTO ACCOUNT WHEN THEY'RE GENERATED. I WON'T TELL YOU ABOUT TWO MOLECULES IMPORTANT IN REGULATING BEHAVIORAL TRANSITIONS AN STATES. THE FIRST MOLECULE, I'M GOING TO TALK ABOUT IS SMALL MOLECULE NEUROMODULATOR SEROTONIN FOR ROLE IN BIOLOGICAL PROCESSES AND ANCIENT NEUROTRANSMITTERS BY ALL ANIMALS. OUR STUDY OF SEROTONIN HOW TO SEE DYNAMIC CHANGES IN CIRCUIT ACTIVITIES THAT UNDERLIE THIS BEHAVIOR. AND P MUCH MORE BRIEFLY AS SECOND PART OF THE MY TALK, I'LL TALK NEUROPEPTIDE THE 18 AMINO ACID PIGMENT DISPERSING FACTOR OR PDF AND I'LL RELATE THESE TOGETHER TO UNDERSTAND SWITCHING AND RELATIONSHIPS TO EACH OTHER. HOW DO WE GET HERE? STEVE DESCRIBING THE BEHAVIOR SYSTEMATICALLY EXAMINE MUTANTS HE THOUGHT MIGHT HAVE INTERESTING ROLES IN CIRCUITRY OF BEHAVIOR WHICH IN OUR CASE INVOLVE TAKING CLASSES OF MUTANTS THAT AFFECT NEUROTRANSMITTER, REACCEPTERTOR, G COUPLED PROTEIN RECEPTOR, GAP JUNCTION SUBUNITS AND OTHER MOLECULES THAT HAVE REGULATORY FUNCTIONS AN NERVOUS SYSTEM. FROM THIS HE IDENTIFIED TWO MOLECULES WITH STRONG EFFECTS ON DURATION AND LENGTH AND DURATION OF DWELL STATES. THERE'S TWO RELATED MOLECULES ARE SEROTONIN RECEPTOR THE CHLORIDE CHANNEL ONE AND TPH 1 THE MAJOR BIOCINCH THETIC ENZYME FOR SEROTONIN SYNTHESIS. THE PHENOTYPE WAS SIMILAR, AND THAN WAS SHOWN HERE FOR ONE OF THEM. THAT INSTEAD OF SPENDING 80% OF THE TIME DWELLING AND 20% ROAMING UNDER PARTICULAR CONDITIONS THESE GUYS ONLY SPEND 40% DWELLING AND 60% ROAMING. STEVE BROKE THAT DOWN LOOKING AT TWO STATES INDEPENDENTLY AND DWELL DURATIONS WERE SHORTER AND ROAM DURATIONS WERE LONGER BUT WHEN HE LOOKED WITHIN THESE ROAM AND DWELL STATES THEIR STRUCTURES WERE NORMAL. THERE WERE NORMAL PATTERNS OF TURNS AND SPEEDS SO THE MICROSTRUCTURES OF THESE BEHAVIORS ON THE SECOND LEVEL WAS INDISTINGUISHABLE FROM THAT OF WILD TYPE BUT THE LARGER STRUCTURE ON THESE BEHAVIORS CHANGED FROM TWO MINUTES WILD TYPE ROAMING TO AVERAGE OF MORE LIKE 6 OR 7 MINUTES SO SEEMED TO BE SOMETHING ACTING ON A LONGER DURATION. HERE IS WORKING ON C ELEGANS IS HELPFUL, SEROTONIN IS IMPORTANT AND C ELEGANS IS EXPRESSED IN 11 NEURONS IN SIX CLASSES. THESE INCLUDE NEURONS IN THE FEIGN RINK, THE FEEDING STRUCTURE, SENSORY NEURONS INNER NEURONS AN MOTOR NEURONS. SO PREVIOUS WORK DONE BY MY POST DOC ADVISER BOB ORVITZ AND (INDISCERNIBLE) WE KNOW ABOUT SEROTONIN FUNCTION IN C ELEGANS. IT MIMICS OR IMMATE AT A TIMES RESPONSES TO FOOD. IT INEXCUSES EGG LAYS AN LOCAL MOTION BEHAVIORS AND FEEDING BEHAVIORS THAT ANIMALS SHOW ON FOOD. THAT FITS WHAT WE SEE HERE, WE SEE IT STRENGTHENING RESPONSE TO GOOD FOOD, DWELLING BEHAVIOR. ASTERISK HERE, MIGHT SAY MIMICS GOOD RESPONSE TO GOOD FOOD SOURCES AN MULTIPLE RECEPTORS WE LOOKED ALL A OF THEM, MULTIPLE G COUPLED PROTEIN RECEPTORS THAT ARE IMPORTANT FOR OTHER BEHAVIORS NOT IMPORTANT FOR ROAMING AND DWELLING BUT THE MOD 1 RECEPTOR WAS. SINCE WE HAVE ONLY SIX CLASSES OF NEURONS THESE CONNECTS ASK WHAT'S THE CIRCUIT HERE. WHERE DOES SEROTONIN HAVE TO BE MADE FOR ROAMING AND DWELLING AND HE DID IT USING THE SAME METHODS YOU WOULD USE IN A MOUSE TO FIRST APPROXIMATION. HE HAD BIOSYNTHETIC SEROTONIN SWINGED BY PHLOX SITES THAT ALLOW RECOMBINATION SO EXPRESSED CRE TRANSGENES IN PARTICULAR CELL TYPES HE WOULD DELETE EXPRESSION OF SEROTONIN AND CELL TYPES. HE ASKED WHICH CELLS ARE IMPORTANT? THIS REPRESENTS A SIMPLER EXPRESSION OF DWELLING AND ROAMING BEHAVIOR. WILD TYPE ANIMALS ROAM ABOUT 60% OF THE TIME LET'S CALL IT SEROTONIN MUTANTS 80% OF THE TIME, IF HE INACTIVATED THE BIOSYNTHETIC ENZYME OF TWO NEURONS MSN AND HSN, CAUTION THE SAMPLES TO BE CONVERTD TO MUTANT BEHAVIOR, SEVERAL OTHER NEURONS WERE NOT IMPORTANT. PRETTY MUCH THE SAME EXPERIMENT. SLIGHTLY DIFFERENT STRATEGY. LOOK AT THE SEROTONIN RECEPTOR. WHERE IS THAT RECEPTOR ACTING TO REGULATE THE SAME BEHAVIOR? SO THREE DIFFERENT NEURONS EMERGED FROM THIS STUDY, CRE LOX RECOMBINATION IMPORTANT FOR ROAMING AND DWELLING REGULATION EACH CONTRIBUTED TO THE COMBINED BEHAVIOR. SO WE CAN ASSEMBLE THOSE IN THIS CIRCUIT HERE, SEROTONIN FOR TWO NEURONS IS IMPORTANT IN REGULATING ROAMING AND DWELLING BEHAVIOR AND ACTS ON AT LEAST THREE TARGET NEURONS THROUGH THE MOD 1 RECEPTOR. TOGETHER THIS LEADS TO THE ACTIVITY OF THE CIRCUIT MODIFIES THE LENGTH OF ROAMING AND DWELLING STATES. SO JUST LOOKING AT THE CIRCUIT WE CAN TELL SOMETHING THAT'S PRETTY INTERESTING TO SOMEONE WHO SPENT A LONG TIME AT THE C ELEGANS WIRING DIAGRAM. THIS CIRCUIT DOESN'T RESPECT THAT WIRING DIAGRAM AT ALL. NOT ONLY ARE THE NEURONS NOT CONNECTED BY CLASSICAL SYNAPSES IN THE WIRING DIAGRAM, THIS VIOLATE AS FEATURE OF THE DIAGRAM COMMENTED ON BY EVERYONE WHO HAS SEEN IT, STRONGLY FEET FORWARD FROM SENSORY NEURONS TO INTERNEURONS AND IMMIGRATING NEURONS TO MOTOR NEURONS. BUT IN THIS CASE WE HAVE A MOTOR NEURON IN THE PHARYNX AND THEY'RE FEEDING BACK ON INNER NEURONS AN EVEN ON SENSORY NEURONS SO RUNNING IN REVERSE COMPARED TO THE STRUCTURE OF THE WORM WIRING DIAGRAM. THIS IS DIFFERENT FROM THE CLASSICAL WIRING. NEXT QUESTION. WHAT DOES ONE MOLECULE LIKE THIS DO IN REAL TIME? CAN WE RELATE TO ACTIVITY OF THE NEURONS IN CIRCUIT WHAT IS THE ANIMAL IS DOING? CALCIUM AND FORAGING ANIMAL IS A SURROGATE FOR NEURAL ACTIVITY BY EXPRESSING THE G CAMP CALCIUM INDICATOR, SPECIFICALLY IN THE NSM NEURONS IN THE SEROTONIN NEURONS IN THE HEAD OF THE WORM WITH AN IMAGING SYSTEM BY DURK ALBRECHT IN THE LAB, THAT LETS US SIMULTANEOUSLY MONITOR CALCIUM ACTIVITY AND ANIMAL MOVEMENT SO WHEN WE LOOK AT THAT LITTLE NEURON IN THE HEAD, WE CAN WATCH THE WORM MOVING AROUND, WE CAN SEE A CHANGE IN OR ORIENTATION, ASSOCIATED WITH A LITTLE BIT OF ACTIVITY OF THAT NEURON. WE CAN TRACK THE ANIMAL HERE, WE CAN TRACK FLORS ARE SENSE AND CALCIUM ACTIVITY OF THE UNDERLYING NEURON AND RELATE THOSE TOGETHER. THE IMAGE NSM CALCIUM SEROTONIN IN FORAGING ANIMALS, AND HE SAW THERE WERE EVENTS FLUORESCENCE INCREASED AND THERE WERE EVENTS DIFFERENT BEHAVIORS OCCURRED. THERE WAS OBVIOUSLY COMPLEXITY FOR THE STRUCTURE. SO HE TOOK 100 TRACES WHERE HE TRACKED ANIMALS FOR 30 MINUTES OR AN HOUR. AND HE ALIGNED THEM TO EACH OTHER USING TWO CRITERIA. I SEE A SET OF EVENTS WHICH NSM HAS CALCIUM PEEKS SO HE ALIGNED BASED ON WHEN A CALCIUM PEAK WAS PRESENT AND PASSIVELY WHAT HAPPENED TO SPEED AND EVENT TRIGGERED AVERAGING APPROACH. WHAT HE SAW WAS THAT THESE CALCIUM PEAKS WERE ASSOCIATED WITH THE DROP IN LOCAL MOTION THAT RECOVERED ON A SIMILAR TIME FRAME NOTE THESE ARE SLOW. THEY ARE TWO MINUTES LONG WHICH IS C ELEGANS NEURONS ARE SLOW OPERATING ON THE TIME SCALE OF A SECOND. C ELEGANS NEURONS. CONVERSELY, ALIGNED ALL THE TRACES BASED ON WHEN ANIMALS STARTED ROAMING WHICH MEANS MOVING QUICKLY, HE SAW THE CALCIUM DECREASE IN THE NSM NEURON BEFORE ROAM AND RECOVERED AT THE ROAM -- AS THE ROAM ENDED. IS THIS RELATED TO SEROTONIN OR IS IS THIS A COINCIDENCE? TO GET AT THAT, STEVE LOOKED IN THE SEROTONIN MUTANTS USING THE SAME APPROACH AND FOUND THAT NSM ACTIVITY WAS A MUCH POORER PREDICTION OF ROAMING BEHAVIOR IN THESE MUTANTS COMPARED TO WILD TYPE. SO THERE'S STILL WERE CALCIUM PULSES NOT AS WELL SYNCHRONIZED, SPEED DECREASE, THERE WERE ROAMING EVENTS BUT NOW YOU NO LONGER SAW A DIP IN CALCIUM WHERE ROAMING OCCURRED SO SEROTONIN HAS A CAUSATIVE ROLE IN THE BEHAVIOR. ALIGNED ON THESE TIME SCALES. FINALLY, CHANNEL RHODOPSIN EXPRESSING THE OPTO GENETIC TOOL WITHIN THE NSM NEURONS TO STIMULATE THE RELEASE OF SEROTONIN FROM THE NEURONS OR USE OPT TOE GENETICS TO MIMIC SEROTONIN ON THE TARGET NEURON. THIS IS AN INHIBITOR CONNECTION, A CHLORIDE CHANNEL, SO THE TOOL USED HERE WAS ARCH INHIBITOR TRANSMITTER TO IMITATE WHAT INHIBITOR CHANNELS WHAT SEROTONIN WOULD DO. IN EITHER CASE HE SAW THE SAME RESULT, TO BE THE POPULATION OF ANIMALS WHICH HE ALIGNED FOR THOSE ROAMING WHEN HE TURNED THE LIGHT ON. TURNING THE LIGHT ON LED TO TRANSMISSION OF ANIMALS TO A DWELLING STATE COMPARED TO CONTROL ANIMALS INDICATING ACTIVATING THESE NEURONS OR INACTIVATING THESE NEURONS WAS SUFFICIENT TO DRIVE DWELLING. INTERESTKLY THE DWELLING STATE CONTINUED FOR A MINUTE AFTER THE LIGHT CAME BACK OFF. IS THE DWELLING STATE OUTLASTD THE STIMULUS THAT TRIGGERED IT. THIS NEXT EXPERIMENT IS ANOTHER OPTO GENETIC EXPERIMENT IN THIS CASE WHAT STEVE DID IS TOOK ANIMALS THAT WERE DWELLING AND HE ACTIVATED THE SEROTONIN SYSTEM WITH CHANNEL RHODOPSIN OR INHIBITED THE TARGET NEURON AND ASKED WHAT THAT DID TO THE STRUCTURE OF THE BEHAVIOR. HE FOUND IF ANIMALS WERE DWELLING AND HE ACTIVATED THESE NEURONS OR INHIBITED THESE, THE NEXT DWELLING STATE WAS GREATLY PROLONGED BUT ONE MINUTE OF LIGHT LED TO A DWELLING STATE THAT WAS 6 MINUTES LONGER ON AVERAGE THAN THOSE SEEN IN THE ABSENCE OF SO IT SEEMED NOT ONLY TO INITIATE DWELLING STATES BUT PROLONG IF THEY'RE PRE-EXISTING. SO THIS IS REALLY THE CONCLUSION OF THIS PART OF THE TALK. WE CAN SAY THAT NEUROMODULATORY TRANSMITTERS INDUCES AN EXTENDS DWELLING STATES. THESE ARE LONG LASTING BEHAVIORAL STATES, THEY LAST ABOUT 8 MINUTES LONG AN SEROTONIN IS CAPABLE OF -- AT LEAST THE LEVEL PROLONGING DWELLING STATE ON SIMILAR TIME SCALE OF ABOUT SIX MINUTES OR SO. SO THE OTHER BEHAVIOR, ASSOCIATED WITH DWELLING, QUICK MOTOR ACTIONS ARE TAKING PLACE ON TIME SCALE OF SECONDS. THIS MUCH LOWER EFFECT IS BEING MEDIATED THROUGH DYNAMIC CHANGES IN MODULATORY STATES. COUPLE OF OTHER THINGS TO SAY ABOUT THIS. I MENTION ROAMING AN DWELLING WERE REGULATED BY NUTRITIONTRITIONAL QUEUES AND VARIOUS SENSORY KEY COUNTIES. MANY NEURONS IN THE CIRCUIT WITH KNOWN TO DETECT SUBSETS OF DIFFERENT KINDS OF EXTERNAL ENVIRONMENTAL QUEUES SO POSSIBLE THE CIRCUIT REPRESENTS A PLACE INFORMATION ABOUT THE ENVIRONMENT IS CONVERGING WITH INFORMATION ABOUT MODULATORY STATES TO REGULATE BEHAVIOR. BUT NONE OF THAT IS TESTED YET. NOW ON TO THE SECOND TRANSMITTER. THE PIGMENT DISPERSING FACTOR OR PDF. PDF WAS FIRST IDENTIFIED IN CRUSTACEANS AND DROSOPHILA AND ONE RESULT WE THINK IS RESONANT WITH WHAT WE'RE SETTING AS A RESULT OF PAUL THAT CANNER'S LAB HE NOTICED DROSOPHILA PDF IS IMPORTANT IN COUPLING CIRCADIAN RHYTHMS TO ACTIVITY LEVELS SO IF YOU LOOK AT A WILD TYPE SLIDE OR PTDF MUTANT YOU CAN SEE THAT MUTANTS HAVE CIRCADIAN RHYTHM, BOUGHT OF ACTIVITY IN THE CYCLE BUT THE STRUCTURE OF THE RITE.S IS DISRUPTED SO IN WILD TYPE THERE WOULD BE A LOT OF ACTIVITY COUPLED AT THIS PARTICULAR TIME IN THE CLOCK AND DISTRIBUTED ALL OTHER HERE SO THERE SEEMS TO BE SOMETHING ABOUT ACTIVITY LEVELS ABBOTS AND PDF THAT'S IMPORTANT IN CROSS FLORIDA IN C ELEGANS WHAT PDF IS IMPORTANT FOR IS ROAMING BEHAVIOR. WHEN STEVE LOOKED AT MUTANTS IN THE C ELEGANS PDF PEPTIDE OR RECEPTOR, ANIMALS SPENT ALMOST ALL TIME OF DWELLING, AND ALMOST NONE OF THEIR TIME ROAMING. THAT REPRESENTS 95% DWELLING IN ONE PLACE. WHEN ANIMALS WERE ROAMING THE BEHAVIOR WAS NORMAL. NOT THEY COULDN'T MOVE, THEY MOVED QUICKLY AND SHOWED NORMAL OFF FOOD BEHAVIOR. SEEMS TO BE THE TRANSITION HERE. WE CAN SEE THAT TRANSITION IN DURATION OF ROAM AND DWELL STATE ON LONG MINUTE LONG TIME SCALES. THAT PDF RECEPTOR MUTANTS DWELL FOR 15 MINUTES AT A STRETCH LONGER THAN WILE TYPE ANIMALS AND CONVERSELY RECEPTOR MUTANTS SHOW SHORT ROAMING STATES SO ONLY ABOUT A MINUTE OR SO WHEREAS WILD TYPE ROAMS SEVERAL MINUTES AT A TIME. SO THESE ARE EXACTLY THE RECIPROCAL EFFECTS FROM THOSE IN THE SEROTONIN MUTANT EXPRESSED IN THE SAME SET OF BEHAVIORS. THE CONCLUSIONS OUT OF SEROTONIN RECEPTOR MUTANT AND SEROTONIN MUTANT WERE ECHOED BY THE CONCLUSION STEVE DREW FROM MAKING THE SAME CELL SPECIFIC KNOCK OUTS AND RESCUES OF PDF AND PDF RECEPTOR. HE FOUND PDF IS EXPRESSED FROM MULTIPLE NEURONS AND A SUBSET OF OF THOSE ARE IMPORTANT IN REGULATING ROAMK BEHAVIOR. PDF RECEPTOR IS EXPRESSED IN MANY NEURONS BUT AGAIN, A SMALL SUBSET OF THOSE NEURONS ARE IMPORTANT IN REGULATING ROAMING BEHAVIOR. SO IN EACH CASE IT'S NOT ONE NEURON THAT'S IMPORTANT, NOT ALL THE NEURONS THAT ARE IMPORTANT, IT'S SOME. BUT THAT PARTICULAR PATTERN REGULATES THE TRANSITIONS. STEVE ADDRESSED THE FUNCTION OF THE SYSTEM USING ONTY GENETIC APPROACHES. IT'S A CLASSICAL NEUROPEPTIDE AND NEUROPEPTIDE RECEPTOR SHOWN IN LET ROLAGS SYSTEMS THAT ACTIVATES GS ADENLYL CYCLIC -- USING OPTO GENETICS TO HYPERPOLAR NEURONS WOULDN'T NECESSARILY AFFECT THE CYCLIC AMP ON THE CELLS SO TO USE THE OPTO GENETIC INTERVENTIONS STEVE TOOK ADVANTAGE OF BACTERIA LIGHT ACTVATED CYCLASE TO PERFORM OPTO GENETIC ACTIVATION AND TARGET CELLS, PLANNING TO IMITATE FUNCTIONS OF PDF IN THE TARGET CELLS. WHAT HE SHOWED WAS IF HE TOOK ANIMALS DWELLING AND INDUCED ADEN LITTLE CYCLASE IN THE NEURONS THAT APRESSED THE PDF RECEPTOR HE SAW A RAPID INCREASE IN SPEED AND DECREASE IN TURNING THAT INDICATED A TRANSITION FROM DWELLING BEHAVIOR TO ROAMING BEHAVIOR. AS WAS SEEN FOR SEROTONIN AND THE OPPOSITE BEHAVIOR, THE ROAMING BEHAVIOR OUTLASTED THE STIMULUS THAT INDUCED IT, IT WAS EVIDENT FOR AT LEAST TWO MINUTES AFTER THE STIMULUS WAS REMOVED SO TWO DIFFERENT NEUROMODULATORS ONE NEUROPEPTIDE, ONE SMALL MOLECULE, TWO OPPOSITE EFFECTS ON BEHAVIOR, HOW DO THESE RELATE TO EACH OTHER? ARE THEY IN SERIES THAT ONE REGULATES THE OTHER OR IN PARALLEL. TO ADDRESS THIS STEVE USED THE TECHNIQUE OF DOUBLE MUTANT ANALYSIS THAT MAKE ANIMALS LAST BOTH SEROTONIN RECEPTOR AND THE PDF RECEPTOR AND LOOK AT THEIR BEHAVIORS AN ROAMING AND DWELLING ASSAYS. AT FIRST GLANCE BEHAVIOR OF DOUBLE MUTANTS SEEMS SORT OF LIKE WILD TYPE, THEY ROAM ABOUT 70% OF THE TIME, THEY ROAMED ABOUT 30% OF THE TIME AND DWELLED ABOUT 70% OF THE TIME. CLOSER INSPECTION REVEALED SOMETHING DIFFERENT. SO WHEN STEVE LOOKED AT THESE ANIMALS IN DETAIL DOUBLE MUTANTS HAD A SHORT DWELLING STATE CHARACTERISTIC OF SEROTONIN USE. AND THEY HAD THE VERY IMPORTANT ROAMING STATE CHARACTERISTIC OF PDF MUTANT SO THESE HAVE UNSTABLE BEHAVIORS THEY RAPIDLY SWITCH BACK AND FORTH, UNABLE TO MAINTAIN A BEHAVIORAL STATE. LOOK AT THE DOUBLE MUTANT OUR INTERPRETATION IS FOLLOWS, THE RYE MARE ROLE OF THE MODULATORY SYSTEMS IS TO EXTEND THE BEHAVIOR STATES. THE BEHAVIORAL STATES EXIST WITHOUT THEM, THEY CAN EVEN PERCOLATE ALONG A MINUTE OR SO WITHOUT THEM BUT IF YOU WANT TO HAVE A LONG LASTING 8 OR 10 MINUTE LONG BEHAVIOR STATE YOU NEED THE PARALLEL MODULATORY SYSTEM TO MAINTAIN IT. AND IN ADDITION THEY INHIBIT EACH OTHER TO HELP SET THE OVERALL LEVEL OF THE DIFFERENT STATES. IN CONCLUSION WHAT WE FOUND HERE ARE TWO DISTRIBUTED CIRCUITS FOR FORAGING BEHAVIOR. WE CALL THESE WIRELESS CIRCUITS. BECAUSE THE NEURONS THAT MAKE SEROTONIN ARE NOT CONNECTED BY CLASS CALL SYNAPSES TO THE NEURONS THAT RESPOND TO IT AND THE NEURONS THAT MAKE PDF NOT CONNECTED WITH CLASSICAL SYNAPSE TO THEIR TARGET. SO THIS THE CLASSCLE WIRING DIAGRAM LINKS ELEMENTS WITHIN THE CIRCUITS BUT NOT IN THE SAME PATTERN AS MODULATORS SO WIRELESS NOT WIRED. FUNCTIONALLY EACH EXTENDS ONE BEHAVIORAL STATE. THE EFFECT OF KILLING ANY OF THESE NEURONS IS MUCH STRONG ESCAMBIA STRONGER THAN EFFECT OF REMOVING THE MODULATOR. SO IF WE KILL FOR EXAMPLE THE ASI NEURON THAT'S A MUCH MORE SERIOUS DEFECT THAN JUST HYPERPOLARIZING THE ASI NEURON WITH THE AHRQ THROUGH THIS PATHWAY THESE NEURONS ARE DOING OTHER THINGS IN ADDITION TO WHAT THE MODULATORS ARE DOING. PRESUMABLY THROUGH OTHER EFFECTS IN THE CLASSICAL WIRING DIAGRAM. HERE I SUPER IMPOSE THOSE CIRCUMSTANCES BACK ON THE WIRING DIAGRAM C ELEGANS WE STARTED WITH, THE CLASSICAL ANATOMICALLY DEFINEDDED WIRING DIAGRAM. AND THE POINT -- SO WHAT I HAVE DONE IS CIRCLE THE SEROTONIN AND PDF CIRCUITS HERE IN BLUE. AND THE POINT TO MAKE SHEER IS THAT -- HERE IS YOU COULD NOT HAVE CHOSEN A MORE RANDOM SUBSET OF NEURONS FROM THE WIRING DIAGRAM IN TERMS OF CONNECTIONS, LOCATION, APPARENT FUNCTIONS. THIS IS REALLY A SEPARATE LOGIC. THE LOGIC OF THE NEUROMODULATORS IS A LOGIC THAT WILL HAVE TO BE SOLVED INDEPENDENTLY OF MODULATORS OF FAST CIRCUMSTANCES LOCOMOTIVE PATTERNS. THEY OVERLAP WITH GREEN NEURONS HERE FOR EXAMPLE, ULTIMATELY THESE TARGETS ARE THE SAME. BUT THE CONNECTIONS BETWEEN TARGETS ARE DIFFERENT. THE CONCLUSIONS INTELLECTUALLY MULTIPLE NEURONS MAKE MODULATORS MULTIPLE NEURONS MAKE RECEPTORS. EACH HAS INDEPENDENT FUNCTIONS. SO IF WE LOOK AT NEURONS AND MODULATOR AND RECEPTOR AS A VIN DIAGRAM, NONE ARE SUBSETS OF THE OTHER. EACH HAS TO BE SOLVED AS A SEPARATE PROBLEM. SECOND, THE SIGNALS ARE NOT IN THE BACK, THEY'RE ACTUALLY INSTRUCTIVE FOR GENERATING NEW BEHAVIOR. THEY INDUCE BEHAVIORAL STATES AND STABILIZE PRE-EXISTING BEHAVIORAL STATES. OUR WAY OF THINKING ABOUT WHAT THESE GUYS ARE DOING PARTICULARLY IN THE STABILIZING STATE IS CONVERTING TIME TO BIOHEMCAL TIME. FAST CIRCUITS MAINTAIN VERSUS STATES FOR TENS OFS BUT WHEN YOU GET INTO TENS OF MINUTES G PROTEIN PATHWAYS AND PROTEIN CORRELATION ARE BETTER WAYS TO STABILIZE THE WHOLE BIOLOGICAL INFORMATION. THAN RAPIDLY CHANGING NEURAL ACTIVITY PATTERN. LITTLE CONNECTION WITH THE DIRECT CONNECTIONS IN THE PROGRAM, SEPARATE ORTHOGONAL CIRCUITS. THESE ARE THE LESSONS WE HAVE FOR C ELEGANS, SHOULD YOU HAVE TO THINK ABOUT THEM, IF YOU WERE IN OTHER KINDS OF NERVOUS SYSTEMS. THE ROLES OF MODULATORS ARE VERY CLEAR ACROSS THE NERVOUS SYSTEM IN VERTEBRATES AND I WOULD LIKE TO POINT OUT THE MORE WE UNDERSTAND ABOUT FUNCTIONS OF VERTEBRATE NERVOUS SYSTEM THE MORE WE UNDERSTAND THE ROLES OF MODULATORS BEING HIGHLY IMPORTANT. SO WITHIN THE VERTEBRATE RETINA, DOPAMINE NEUROMODULATOR IS PRESENT AS REGULATOR OF CIRCUIT STATE. RETINA FUNCTIONS IN DIFFERENT WAYS DURING THE LIGHT WHEN CONE PHOTO RECEPTORS DOMINATE CIRCUITS AND DURING THE DARK WHEN ROD PHOTO RECEPTORS DOMINATE THEY'RE MORE SENSITIVE BUT CIRCUITS HAVE LESS SPECTRAL SPECIAL RESOLUTION. THE SWITCH ACTING AT MULTIPLE POINTS TO SWITCH BETWEEN NIGHT AND DAY VISION. SO THESE ARE AGAIN, LONG LASTING CIRCUIT STATES HAPPENING IN PARALLEL WITH COMPUTATION WITH A SYNAPTIC CONNECTION OF THE RETINA. SINCE SOMEONE WAS AT A TALK WITH RECENTLY SAID THAT THE RETINA WAS AN HONORARY INVERTEBRATE I THOUGHT SPECIAL PLEADING, I WANT TO POINT OUT WHATEVER PART OF THE BRAIN YOU'RE INTERESTED IN, THERE ARE NEUROPEPTIDES AND NEUROMODULATORS THAT ACT IN THAT PART OF THE BRAIN. THAT INCLUDES THE HIGHEST BRAIN AREA. THEY ARE PROMINENT IN CORTICAL CIRCUITS. I STARTED WITH OXYTOCIN AND HERE I'M ENDING WITH OXYTOCIN ON A RECENT PAPER FROM DICK CHEN'S LAB LOOKING AT THE ROLE OF OXYTOCIN IN HIPPOCAMPUS WHERE THERE ARE THOUGHT TO BE ROLES IN MEMORY FORMATION. WHERE HE SHOWED OXYTOCIN ACTING ON OXYTOCIN VEEPTOR SPECIFICALLY MODULATE FAST INNER NEURONS TO CHANGE TRANSMISSION TO REGULATE THE FLOW OF INFORMATION THROUGH THE CLASSICAL CIRCUITS. ON THIS SLIDE BELOW HERE IS A RECENT MAPPING SLIDE FROM (INDISCERNIBLE) LAB IN WHICH HE WAS LOOK AT THE ROLES OF DIFFERENT INHIBITOR NEURONS, CONNECTIONS WITH ONE ANOTHER AND CONNECTIONS WITH EXCITATORY NEURONS, MAPPED OUT THROUGH OPTO GENETICS. THE POINT I WANT TO MAKE SURE IS THEY'RE SO PROMINENT IN THE CORTEX, WE NAME CELL CLASSES BY THE NEUROPEPTIDE THEY EXPRESS. PEOPLE CALL THESE GUYS HERE THE SOMATOSTATIN INNER NEURON AND THE VII INNER NEURONS. BECAUSE THAT'S THE BEST WAY TO IDENTIFY THEM. IT HASN'T BEEN CHARACTERIZED WHAT THE NEUROPEPTIDES ARE DOING IN THESE NEURON WHICH IS EXPRESS THE NEUROTRANSMITTER GABBA BUT EXPRESSION HERE IS QUITE PROMINENT AND PREPRODUCIBLE. I WOULD LIKE TO HIGHLIGHT VASOACTIVE INTESTINAL PEPTIDE HERE, THEY HAVE AN INTERESTING PLACE IN CORTICAL CIRCUITS, THEY'RE A PLACE THAT SUBCORTICAL INFORMATION ABOUT AROUSAL AND COLYNERGIC COMES IN TO REGULATE ACTIVITY OF LOCAL CIRCUITS HERE, IN ADDITION VIP ITSELF AND RECEPTOR VIPER TWO ARE RECENT HITS THAT EMERGE FROM LARGE SCALE GENETIC STUDIES OF HUMAN SCHIZOPHRENIA AS RISK FACTORS PRE-DISPOSING A CERTAIN NUMBER OF HUMANS TO ALTERATIONS IN COGNITIVE STATE. SO I DON'T THINK IT'S A GOOD IDEA TO IGNORE THE MOLECULES, WE HAVE MUCH TO LEARN FROM THEM. AS THEY ARE IMBEDDED WITHIN THE CIRCUIT THAT WE HAVE STUDIED POWERFULLY FOR SO LONG BUT PERFORMING PERHAPS DIFFERENT FUNCTIONS. WITH THAT, I WILL THANK YOU FOR YOUR ATTENTION AND SHOW YOU THE PICTURES OF PEOPLE IN THE LAB WHO WORKED ON THIS PROJECT. I HAVE ALWAYS THOUGHT THE SECRET TO MY SUCCESS IN SCIENCE IS MY GOOD TASTE IN PEOPLE AND I FELT THAT'S REFLECTED BY THE SCIENTIST WHOSE HAVE DONE THIS WORK. THE WORK I TALKED ABOUT WAS ALMOST ENTIRELY THE WORK OF STEVE FLAVELL POST-DOC IN THE LAB EXPLORING QUANTITATIVE METHODS OF I ADDRESSING PODSLATORY CIRCUITS. SEVERAL TOOLS WERE DEVELOPED BY (INDISCERNIBLE) A POST-DOC IN THE LAB WHO IS OUR BASEMENT TINKERER WHO MAKES COOL MOLECULAR TOOLS FOR MONITORING NEURAL ACTIVITY. DURK ALBRECHT AND (INDISCERNIBLE) HERE ENGINEERED THE IMAGING SYSTEM FOR DOING REAL TIME IMAGING OF NEURAL ACTIVITY AND BEHAVIOR. JENNIFER GARRISON'S WORK ON OXYTOCIN I TALKED AT THE BEGINNING OF THE TALK. THANK YOU VERY MUCH. [APPLAUSE] >> THANKS FOR A VERY INTERESTING AND SOMEWHAT SURPRISING TALK IN TERMS OF SOME OF THE CONNECTIONS UNHEARTED. WE HAVE TIME FOR QUESTIONS SO THOSE WATCHING ON VIDEO CAN HEAR THE QUESTIONS AND WE CAN START OVER HERE. >> ONEth MOST IMPORTANT SOURCES OF NEUROMODULATORS IN THE VERTEBRATE NERVOUS SYSTEM ARE GLIAL CELLS. THE MORPHOLOGICAL CHANGES IN ASTROCYTES REGULATE OXYTOCIN AND PAIN AND SLEEP ET CETERA, HOW IMPORTANT DO YOU THINK GLIAL CELLS ARE IN MODULATING NEURAL CIRCUITS AND WONDERING WHY THEY'RE NOT MENTIONED IN C ELEGANS WORK. >> ONE THING ABOUT BEING A GENETICIST IS THEY'RE AGNOSTIC TO WHERE YOU'RE LOOKING. THESE PARTICULAR MOLECULES WERE NOT EXPRESSED IN GLIAL CELLS BUT IF THEY HAD BEEN WE WOULD HAVE FOLLOWED THAT UP. MY NOT MUCH IS DONE ON C ELEGANS NEAL CELLS, MY COLLEAGUE AT ROCKEFELLER HAS BEEN THE GROUP THAT'S DONE THE MOST AND IDENTIFIED A VARIETY OF FUNCTIONS AND DEVELOPMENT SOME WHICH ARE SIMILAR TO THOSE THAT ARE KNOWN IN VERTEBRATE SYSTEMS. I THINK HE'S TRYING -- HE HAS SHOWN THEY HAVE ROLES IN ENHANCING NEURAL ACTIVITY, WHAT THOSE ARE, RIGHT NOW DON'T INVOLVE THESE PARTICULAR MODULATORS AND THESE PARTICULAR BEHAVIORS BUT I WAS -- I WOULD STAY TUNED. >> YOU MENTIONED SIGNALS ARE GOING TO A C ELEGANS PERSON IN THE WRONG DIRECTION FROM MOTOR NEURONS BACK UP THE INNER NEURONS SUCH. DOES THAT MATTER? IS THERE A LOGIC FOR WHY THOSE ARE THE CELLS THAT ARE PROVIDING THE SEROTONIN? OR IS IT JUST ANATOMIC LOGIC CELLS USED BECAUSE THEY'RE IN THE RIGHT PLACE? >> I DON'T HAVE -- I DON'T THINK WE UNDERSTAND THE LOGIC WHERE THESE GUYS ARE BEING MADE AT THIS POINT. I THINK WE HAVE TO THINK ABOUT THAT MORE CAREFULLY THESE MOLECULES HAVE OTHER FUNCTION WHEN EXPRESSED FROM OTHER NEURONS IN OTHER BEHAVIORS, PBS IS SHOWN BY MAUREEN BAR'S LAB TO AFFECT MALE MATING BEHAVIORS THAT USES A DIFFERENT NEURON FROM SOURCE OF PDF AND NEURONS EXPRESSING THE RECEPTORS FROM THE ONES STEVE DEFINED HERE. SEROTONIN AFFECTS A VARIETY OF OTHER BEHAVIORS, AGAIN, OFTEN THROUGH SOURCES OF OTHER NEURONS AN RECEPTORS ON DIFFERENT NEURONS. THESE ARE NEITHER ACTING AT A COMPLETE POINT TO POINT LEVEL NOR ACTING AS A GLOBAL SPRINKLER SYSTEM TO USE ONE OF THE OLD TERMS FROM NEUROMODULATION. THERE IS A SELECTIVITY IN THE WAY THEY'RE PUT TOGETHER. AND HOW THAT WHAT THAT REPRESENTS IN SPACE AND LEVEL IS AN IMPORTANT QUESTION TO BE WORKED OUT. IT WILL HAVE TO DO WITH SOURCE, HOW MUCH IS RELEASED, HOW FAR THE RECEPTOR S EFFICACY OF THAT RECEPTOR AND THAT REPRESENT AS DECODING OF THESE SIGNALS. WE DON'T HAVE INSIGHT INTO THAT YET. >> WE DON'T KNOW HOW MUCH REGULATION IS IN TERMS OF THE DISTANCE SPREAD OR IS IT A GATING AS FAR AS WHEN THE NEURON IS -- THE RECEIVING NEURON IS READY TO RECEIVE THE SIGNAL. TEMPORAL OR SPATIAL CODING. YOU DON'T HAVE A SENSE OF THAT YET? >> WE DONE. WE HAVEN'T DONE COMPARATIVE BEHAVIOR. >> BEHAVIORAL STATES IN ANIMALS ARE A MIXTURE OF CHANGES IN ACTIVITY AND CHANGES IN TENSE RESPONSIVENESS SO THIS BACKWARDS FLOW MAKES SENSE IN TERMS OF MODULATING SENSORY RESPONSES DO YOU THINK IT'S POSSIBLE THAT DRIVE IT IS CHANGE IN ACTIVITY? THE STATES THEMSELVES ARE DRIVEN BY PARTICULAR ENVIRONMENTAL SIGNALS CHANGING SENSITIVITY OF THE NEURONS THAT ARE SENSING ENVIRONMENTAL SIGNALS. >> THERE'S NICE WORK COMING UP WITH AN EXAMPLE FROM DAVID ANDERSON'S LAB, RESULTS FROM OTHER SYSTEMS AS WELL. SHOWING THAT NEUROMODULATORS CAN IN FACT CHANGE THE SENSITIVITY OF SENSORY NEURONS OR ABILITY TO COUPLE I WOULD SAY MORE THE DOWNSTREAM CIRCUITS. WHAT DAVID SAID IS HUNGRY FLIES DOPAMINE IS PRODUCED AND THAT DOPAMINE ACTS ON TERMINALS OF THE SWEET SENSING NEURON TO ENHANCE SYNAPTIC TRANSMISSION AND MAKE THE SLIDE MORE SENSITIVE TO FOOD WHEN THEY'RE HUNGRY. SO IT'S NOT IN THE PERIPHERY BUT AT FIRST SYNAPTIC INPUT. THAT'S AN EXCELLENT EXAMPLE. WE HAVE OTHER EXAMPLES I THINK THAT WE DON'T UNDERSTAND AS WELL AND THERE ARE EXAMPLES IN OTHER SYSTEMS SO YES, I DON'T -- I THINK THE PRINCIPLE ISES OF HOW THESE SYSTEMS ARE CHANGES WILL INVOLVE CHANGES IN THE PERIPHERAL DETECTION OF QUEUES AND OTHER PLACES CHANGES IN THE DYNAMICS OF THE SPECIAL CIRCUITS THAT ARE RELEVANT TO THE BEHAVIOR. WE HAVE TO INTERPRET THOSE WITH THEY ARRIVE. >> THIS IS SLIGHTLY RELATED. IN YOUR OPTO GENETIC EXPERIMENTS WHERE YOU STIMULATED SEROTONIN NEURONS OR INHIBITED RECERTAINTOR NEURONS HAVE YOU PLAYEDED WITH THE ENVIRONMENTAL CONDITIONS SO WHEN YOU INDUCE THE ROAMING DWELLING TO ROAMING IF YOU DO IT IN TAINTED FOOD DO YOU HAVE A HARDER TIME MAKING THAT SWITCH? >> THOSE ARE GOOD EXPERIMENTS. WE HAVEN'T DONE THAT, WE HAVEN'T STARTED PLAYING WITH THE INTERSECTION BETWEEN OTHER FORMS OF REGULATION, YES. YES. >> CAN I ASK ONE MORE QUICK QUESTION? GIVEN CONFLICTING ROLES OFOXYTOCIN IN MAMMALS AN ROLE IN FEEDING BEHAVIOR DID YOU SEE ANYTHING? WHEN YOU WERE LOOKING AT YOUR MATING BEHAVIOR AND YOUR OXYTOCIN MUTANTS OR WHEN YOU MADE YOUR RESTING EXPERIMENT, QUARZAN CONSTITUTIVE ACTIVE OXYTOCIN RECEPTORS IN C ELEGANS AND SEEN DIFFERENCES IN FEEDING BEHAVIOR? >> WE HAVE NOT SEEN DIFFERENCES IN FEEDING BEHAVIOR, WE HAVE SEEN DIFFERENCES IN SOME THERMAL STRESS RELATED BEHAVIORS WHICH VASOPRESSIN PLAYS A ROLE IN MAMMALS BUT THAT'S UNPUBLISHED. (INDISCERNIBLE) LAB SHOWED A ROLE IN SOME LEARNING BEHAVIORS BUT AGAIN NOT EXPLICITLY FEEDING RELATED. SO IT MIGHT COME AROUND, YOU MAY HAVE TO ZOOM IN ON PARTICULAR ELEMENTS BUT THERE MAYBE PIECES THAT ARE CONSERVED AND PIECES THAT ARE NOT. EVOLUTION HA A MADDENING COMBINATION OF MAINTAINING FUNCTIONS AND THEN JUST OPPORTUNISTICALLY MAKING SOMETHING NEW THAT TENDS TO LAUGH IN THE FACE OF YOUR CONCEPTUAL DIVISION. THIS MAYBE ONE OF THOSE. >> THANK YOU. >> BESIDES ROAMING AND DOYLEING IS THERE ANY OTHER INTELLECTUAL ACTIVITY THESE GUYS COULD DO? >> IN TERMS OF BEHAVIOR STATES A SLEEP LIKE STATE, THEY HAVE DIFFERENT FORAGING BEHAVIORS OF FOOD WHERE THEY FORAGE SEARCH LO KALELY AND LONG LISTING DISPERSEAL STATES. THESE ARE LONG LASTING TEN MINUTE OR MORE OR LONGER BEHAVIORAL STATES. THE OTHER THING THAT C ELEGANS IS QUITE -- IS MOTIVATED ON SHORTER TIME SCALES TO DO A VARIETY OF SENSORY BEHAVIORS, IT DETECTS THOUSANDS OF ODORS CHEMO TAXES ODORS, IT LEARNS TO AVOID ODORS WHEN IT WAS STARVED, AVOID ODORS PAIRED WITH PATHOGENIC INTRODUCTION SO THERE ARE -- LEARNS TO TRACK TO A PREFERRED TEMPERATURE SO THERE ARE SETS OF BEHAVIORS, THERE ARE PHEROMONE RELATED BEHAVIORS AS WELL. IT'S COMPACT DIVERSITY OF BEHAVIOR. NOBODY WILL TEACH C ELEGANS TO SPEAK FRENCH OR PLAY THE PIANO BUT IN TERMS OF HAVING BASIC ELEMENTS YOU HI MIGHT THINK ABOUT THAT YOU MIGHT INTERESTED IN THE NERVOUS SYSTEM, JUST A BUILDING BLOCK OF BEHAVIOR SUCH AS SENSORY BEHAVIOR, SENSORY DISCRIMINATION, LEARNING ASSOCIATE AND NON-ASSOCIATIVE, OTHER FORMS OF PLASTICITY, MULTI-MODAL INTEGRATION DO EXIST IN THE SYSTEM. IT'S A PLACE TO THINK ABOUT MIX METAPHORS THE GRAMMAR AND SYNTAX BEHAVIORS. >> CONSIDERING IF NUMBER OF NEURONS 40,000 GENES SO EACH CELL HAVE MULTI-FUNCTION YOU THINK THEY COULD DEAL WITH EFFECTIVELY OR EVERYTHING DONE AT MUCH SLOWER LEVEL? >> I DO -- I SUSPECT ALL THE NEURONS ARE MULTI-FUNCTIONAL, BECAUSE ANY EAR FOESED INTO THAT BY SMALL NERVOUS SYSTEM, HOWEVER MULTI-FUNCTIONALITY IS SEEN IN A LOT OF NERVOUS SYSTEMS WITH MANY, MANY MORE NEURONS. THE LITTLE RETINAL SUBCIRCUIT I SHOWED THERE ACTUALLY THE CERTAIN ELEMENTS OF THAT CIRCUIT ARE SHARED BETWEEN AN CONE VISUAL SYSTEMS THEY WOULDN'T HAVE TO BE SO THOSE ELEMENTS ARE MULTI-FUNCTIONAL ELEMENTS. I SUSPECT THAT THAT IS A FEATURE OF OTHER NERVOUS SYSTEMS BUT A VERY PROMINENT FEATURE OF C ELEGANS NERVOUS SYSTEM. THEY ARE SLOW. NO ONE REALLY KNOWS WHY, MY THINKING IS THEY DO A LOT OF GRADED, THEY HAVE GRADED POTENTIAL TO DO LOCAL COMPUTATION. THAT KIND OF INFORMATION IS LOST IF YOU HAVE ACTION POTENTIALS. THEY MAY HAVE CHOSEN TO GO FOR HAVING THE LARGEST DIVERSITY OF COMPUTATIONS WITHIN THEIR NEURONS RATHER THAN HAVING THE TRANSMISSION OF INFORMATION. >> THANK YOU. >> LET ME ASK THE LAST QUESTION. OBVIOUSLY PEOPLE WILL ARGUE UNDERSTAND THE SYSTEM WHEN YOU CAN MODEL IT AND PREDICT BEHAVIOR BASED ON WHAT YOU KNOW AND OBVIOUSLY THOSE WHO WOULD LOVE TO BUILD A COMPUTATIONAL MODEL OF THE HUMAN BRAIN SHOULD BE SOBERED BY THE COMPLEXITY THEY'RE FACING. AND MAYBE ASK THE QUESTION HOW FAR AWAY ARE WE FROM HAVING AN EFFECTIVE DETAILED COMPUTATIONAL MODEL C ELEGANS THAT YOU COULD TRUST TO ACTUALLY PREDICT REAL BEHAVIOR MOST OF THE TIME? HOW ARE WE DO SOMETHING >> THAT IS A GREAT QUESTION. MITCHELL'S LAB HAS A GOOD MODEL FOR SINUSOIDAL LOCOMOTION. THAT'S THE MOTOR PATHWAYS. UP AND DOWN LIKE THAT PEOPLE ARE STARTING TO THINK ABOUT MODELS WHERE LITTLE CHUNKS MOTIFS WITHIN THE WIRING DIAGRAM WHAT THOSE ARE DOING, VERY MUCH ALONG THE SAME LINES PEOPLE DO IN SYSTEMS BIOLOGY AND SOME HAVE PREDICTIVE POWER, TEST WITH EXPERIENCE AND THINK THIS IS RIGHT. SO I THINK THE ABILITY TO COMBINE IS MOVING UP HERE. THE INITIAL MODEL I SHOULD SAY WHEN PEOPLE LOOK AT THE WIRING DIAGRAM, PEOPLE TRY TO MODEL BASED ON ANATOMY, THAT DIDN'T YIELD A LOT OF INSIGHT. EVERYWHERE TO EVERYWHERE, I THINK THE ANSWER TO THAT IS THE FUNCTIONAL, THEY OPERATE ON DIFFERENT TIME SCALES. THEY'RE REGULATED THE STRENGTH CHANGE DEPENDING ON MODULATORY STATES SO IT'S JUST A SET OF POSSIBILITIES. IT IS NOT A SINGLE ANSWER. THAT LED PEOPLE -- THAT PREVENTED PEOPLE FROM LOOKING AT THAT FIRST STEP. SOY THINK WE NEED TO IMPOSE ACTIVITY ON THAT CONNECTIVITY. >> GREAT. WELL, THERE WILL BE A RECEPTION IN THE LIBRARY AND YOU'LL HAVE A CHANCE TO SPEAK IN GREATER DETAIL TO THE SPEAKER IF YOU WOULD LIKE BUT PLEASE LET'S THANK DR. BARGMANN AGAIN FOR A VERY STIMULATING LECTURE. [APPLAUSE]