THANK YOU ALL FOR BEING HERE, IT'S MY GREAT PLEASURE TO INTRODUCE TODAY'S NEUROSCIENCE SPEAKER DR. VANESSA RUTA WHO IS THE GRABRIEL REEM, AND GABRIEL CADENT, PROFESSOR, AND HEAD OF LABORATORY AT NEUROLOGY PROFESSOR WHERE SHE IS STUDYING OLFACTION OR BASED BEHAVIORS IN DROSOPHILA MALOGHASTOR. NOW SHE'S HAD A VERY INTERESTING PATH THAT BROUGHT HER TO NEUROSCIENCE. WHEN SHE FIRST GRADUATED HIGH SCHOOL, SHE ASPIRED TO BE A BALLET DANCER. AND DID SO VERY SUCCESSFULLY FOR A NUMBER OF YEARS IN NEW YORK CITY. AND THEN, I THINK IT WAS AN EXPERIENCE WHERE SHE TOOK A COURSE IN CHEMISTRY THAT SUDDENLY REVEALED TO HER THAT SCIENCE CAN BE VERY EXCITING AS WELL. AND SO THROUGH THIS CHEMISTRY COURSE SHE THEN ENROLLED AS AN UNDERGRADUATE AT HUNTER COLLEGE AND MAJORED IN CHEMISTRY AND THAT'S OUR GOOD FORTUNE THAT EVENTUALLY BROUGHT HER TO NEUROSCIENCE. FROM HUNTER SHE THEN JOINED THE LAB OF ROB Mc KINNON, AND SHE DID HER Ph.D. IN ROB'S LAB AT A TIME THAT WAS VERY EXCITING AND THIS WAS DURING THE PHASE WHERE A NUMBER OF THE CHANNELS WERE GOING CRYSTALLIZED IN ROD Mc KINNON'S LAB, THIS WORK WOULD LATER EARN HIM A NOBEL PRIZE. FROM HER Ph.D. WORK SHE DID IN ROD'S LAB, SHE THEN DECIDED TO MOVE UPTOWN, FURTHER UPTOWN AND OVER TO COLUMBIA UNIVERSITY WHERE SHE JOINED THE LABORATORY OF RICHARD AXLE AND IN RICHARD'S LAB SHE WAS INTRODUCED TO THE FIELD OF OLFACTION. AND SHE--HER WORK IN RICHARD'S LAB FOCUSED ON THE DROSOPHILA AND DEFINING THE NEUROPATHWAYS THATAR ASSOCIATED WITH FAIR MOAN RESPONSES AND I THINK THAT IT WAS THIS WORK THAT REALLY PROMPTED HER INTEREST IN BEHAVIOR. FORTUNATELY SHE WAS VERY SUCCESSFUL AND THIS TALENT WAS RECOGNIZED BY THE ROCKEFELLER UNIVERSITY. THEY OFFERED HER A POSITION TO RUN HER OWN LAB AND THAT'S WHERE SHE IS NOW. AND SHE IS. CURRENTLY FOCUSING ON WORK THAT'S TRYING TO UNDERSTAND THE CIRCUITRY THAT UNDERLIES INNATE VERSUS LEARNED BEHAVIORS AND I BELIEVE THAT THIS IS WHAT WE'LL HEAR ABOUT TODAY. THANK YOU VANESSA FOR BEING HERE. [ APPLAUSE ] >> CAN EVERYONE HEAR ME? THANKS FOR THE INTRODUCTION TO BE HERE. I'VE NEVER BEEN HERE BEFORE AND I AM EXCITED TO SPEND THE DAY HERE AND MEET WITH OLD COLLEAGUES AND SCIENTISTS WHOSE WORK I READ ABOUT BUT NEVER HAD A CHANCE TO INTERACT WITH SO TODAY I'M GOING TO TELL YOU ABOUT THE WORK THAT'S GOING ON IN OUR LAB AND REALLY IT STARTS WITH THINKING ABOUT THE FACT IS THAT ALL ANIMALS EXHIBIT DEHAIRIAL RESPONSES TO CERTAIN SENSORY ACUTES IN THE ENVIRONMENT BUT WE THINK ARE MEDIATED BY THE NEURAL CIRCUITS THAT ARE HARD WIRED INTO THE BRAIN AND IF YOU THINK ABOUT THE EVOLUTION OF THESE STEREOTYPES OF CIRCUITS INSURES ROBUST AND VARIANT RESPONSES TO SPECIES THAT STIMULI THAT ARE PREDICTABLE ACROSS MUTATIONS LIKE THE SWEET TASTE OF RASE MODELBY TO A FLY. BUT THE WIEW HAVE TO MAKE DEHAIRIAL DECISIONS IN THIS MOMENT BY MOMENT SCALE AND IT'S VERY RAPID AND UNPREDICTABLE WAYS AND THEN OF COURSE IN THE CONTEXT OF THIS REALLY KIND OF COMPLEX AND DYNAMIC ENVIRONMENT THAT WE LIVE IN, IT CAN RELY ON GENETICALLY HARD WIRED RESPONSES BUT BE ABLE TO MODIFY BEHAVIOR BASED ON THE PAST EXPERIENCE OR CURRENT CIRCUMSTANCES. SO FUNDAMENTALLY MY LAB IS INTERESTED IN HOW THE NEUROCIRCETS ARE ADAPTED OVER TIME SCALES AND HOW THE ETHICS ARE ABLE TO GIVE RISE TO SPECIES BEHAVIOR AND WHAT I WILL TELL YOU IS ABOUT OUR THINKING ABOUT HOW IT'S A MUCH MORE RAPID TIME SCALE IN THE MOMENT BY MOMENT BASIS, TO ALLOW FOR FLEXIBLE VARIATIONS THAT ARE REALLY INDICATIVE AND GIVE UNIQUE EXPERIENCES IN AN INDIVIDUAL. AND WE DO THIS LARGELY ON TAKING ADVANTAGE OF THE RELATIVE SIMPLICITY OF THE OLFACTORY SYSTEM IN THE FRUIT FLY. BECAUSE FRUIT FLIES OF COURSE RELY ON YOUR SENSE OF SMELL, IT'S A SENSORY MODALITY WE USE IN THEIR ENVIRONMENT. THEY PREDICTABLY TRIGGER CUES THAT DEVELOP HAIR, AND THEY MAKE SENSE OF COMPLEX AND CHEMICAL WORLD THAT THEY LIVE IN AND THEY DO ALL THIS USING THE OLFACTORY SYSTEM THAT IS SIMPLE BUT REMARKABLY ANALOGOUS SUGGESTING THESE ARE PRINCIPLES THAT ARE BEING EMPLOYED. SO, IT'S REALLY FROM CLASSICAL WORK THAT'S BEEN SUGGEST THAD FOR AN INDIVIDUAL ANIMAL FOR A SINGLE SLIDE, THE SAME STIMULUS CAN LEAD FOR AVIDDANCE BEHAVIOR, DIFFERENT RESPONSES DEPENDING ON THE CONTEXT AND CIRCUMSTANCES IN WHICH IT'S BEEN ENCOUNTERS SO IF WE THINK ABOUT IT IN THE FRAMEWORK OF THE CLASSIC OLFACTORY CONDITIONING, IT'S LONG BEEN USED TO PROBE LEARNING AND MEMORY ON THE FLY. IF AN O'DORSTIMULUS IS ENCOUNTERED AT THE SAME TIME OR IMMEDIATELY PRECEDING A REWARD LIKE SUGAR AND LEADS TO A POSITIVE ASSOCIATION IN WHICH THE ODOR STIMULUS PREDICTS THE WARD AND LEADS TO LEARNED TRACTION FOR THAT ODOR. BUT IF IT'S PAIRED WITH A PAINFUL AND PUNISHING REINFORCEMENT LIKE ELECTRICAL SHOCK, THIS ODOR IS ACTUALLY ENDOWED WITH AN AVERS VALENT AND LEADS TO AVOIDANCE AND SO THIS MEANS THAT THE SAME MOTOR STIMULUS CAN ILLICIT OPPOSING RESPONSES IN AN INDIVIDUAL AND THE QUESTION I WOULD LIKE TO BE ABLE TO ADDRESSED THIS IS HOW IT'S BEEN IN THE SAME SENSORY AND THE SAME ODOR STIMULUS CAN LEAD TO THESE OPPOSING BEHAVIORS AND IF YOU THINK ABOUT IT THEA THE NEURAL LEVEL, WHAT THIS IMPLY SYSTEM THAT THE OLFACTORY CIRCUIT IN THE BRAIN MUST CONVERGE WITH PATHWAYS THAT CONTRARY INFORMATION ABOUT THE CONTEXT OF THE FLY, EITHER IMMEDIATE CONTEXT OR THE STATE OR ENVIRONMENT OR PAST EXPERIENCE AND THE CONVERGENCE OF THESE 2 PATHWAYS CAN BASICALLY REROUTE THE SAME ODOR INFORMATION INTO ALTERNATIVE OUTPUT PATHWAYS, BEHAVIORIAL OUTPUT PATHWAYS TO TRIGGER BEHAVIORIAL RESPONSES AND SO TO BEGIN TO UNDERSTAND THE FLEXIBILITY HOW IT CAN BE IMPLEMENTED AT THE CIRCUIT LEVEL, THE LAB IS FOCUSING ON HOW THE INFORMATION IS PROCESSED WITHIN THE CENTER HERE CALLED THE MUSHROOM BODY WHICH WAS IDENTIFIED ACTUALLY OVER A HUNDRED AND 50 YEARS AGO BY THE FRESH ZOOLOGYST AND BECAUSE OF THE MUSHROOM LIKE SHAPE WHERE HERE'S THE CAP AND THE SOCK, AND THEY MADE TED INTERESTING SUGGESTION THAT MUSHROOM BODIES ENCOW INSECTS WITH A DEGREE OF FREE WILL OR INTELLIGENT CONTROL OVER THEIR INSTINCTIVE ACTIONS AND HE DREW THIS FROM COMPARATIVE ANATOMY WHERE HE LOOKED AT THE SIZE OF THE MUSHROOM BODY AND SORT OF A SOPHISTICATION OF THE BEHAVIORIAL REPERTOIRE. BUT WHAT I'LL SHOW IS OF COURSE THIS IS A REALLY INTUITIVE AND PRESSING STATEMENT BECAUSE WE NOW KNOW THAT THE MUSHROOM BODY IS REALLY CENTRAL FOR LEARNING AND MEMORY IN THE FLY. AND SO IF YOU BELIEVE THAT SECTIONAL ANALYSISS HAVE A DEGREE OF FREE WILL, THE MUSHROOM BODY WILL MODIFY THE BEHAVIOR BASED ON THEIR KIND OF UNIQUE EXPERIENCE OF THE WORLD. SO IN DO SOV ILLEGALS ATHE MUSHROOM BODY IS LARGELY OLFACTORY INFORMATION AND IT'S COMPRISED OF ABOUT 2000 INTRINSIC NEWSPAPERONS CALLED KENYAN CELLS WHICH ARE SHOWN IN BLUE, AND THEY RECEIVE INPUT THROUGH A CONCISE CIRCUIT WHERE THERE ARE ONLY 2 SYNAPSES WHICH SEPARATE THE OLFACTORY SENSORY NEURONS AND DETECT VOLATILE CHEMICALS IN THE ENVIRONMENT FROM THE KENYAN CELL POPULATION ITSELF WHICH UNDERLIES THE LUNG AND DISCRIMINATION AND SO WE CAN TAKE ADVANTAGE OF THE SIMPLE ARCHITECTURE TO THINK ABOUT HOW IS IT THAT THE INDIVIDUAL CELLS INTEGRATE DIFFERENT OLFACTORY CHANNELS TO REPRESENT THE KIND OF VERY DIVERSE CHEMICAL WORLD THAT THE FLY LIVES IN. SO WE FOUND THAT A GIVEN CELL HAS ACTUALLY A LIMITED NUMBER OF INPUTS, ABOUT 7 ON AVERAGE AND WE USE THE APPROACHES TO SHOW THAT THE INPUT TO THE INDIVIDUAL CELL GUESTS TO THE CHEMICAL THAT INTEGRATE ARE REALLY THIS [INDISCERNIBLE] INDIVIDUAL CELLS INTEGRATE IS BASICALLY DONE IN A COMPLETELY UNBIASED MANNER AND CORE WITH RANDOM STATISTICS AND AS A CONSEQUENCE, THESE CELLS WITHIN THE MUSHROOM BODY CAN INTEGRATE REALLY VERY DIVERSE COMBINATIONS OF CHEMICAL CHANNELS COMBINING INFORMATION ABOUT FAIR MOANS, FRUITS AND FUNNING I IN THE SAME NEURAL POPULATION AND THIS KIND OF WIRING STRATEGY, THIS HIGHLY DISTRIBUTED WIRING OF MUSHROOM BODY IS UNBIASED STRATEGY, RENDERS THE MUSHROOM BODY BEST ABLE TO REPRESENT IN A COMPLETELY UNBIASED WAY AND THE FACTORY EXPERIENCE OF THE INDIVIDUAL FLY. AS A CONSEQUENCE, A GIVEN ODOR, FUNCTIONAL CALCIUM IMAGING EXPERIMENT CANS SHOW THAT AN ODOR ACTIVATES A ENSEMBLE THAT'S DISTRIBUTED THROUGHOUT THE MUSHROOM BODY POPULATIONS AND WE REALLY THINK THAT THAT KIND OF ODOR IDENTILITY IS ENCODED IN THE POPULATION OF KENYON CELLS THAT ARE ACTIVATED. THESE ARE THEN PROPAGATED AMONG THE MUSHROOM BODY OF THE KENYON CELL INTO THESE LOBE STRUCTURES. WHERE THE THEY CONVERGE ON A LIMITED NUMBER OF MUSHROOM BODY OUTPUT NEURONS HERE IN GREEN. SO THERE ARE ACTUALLY WORKING FROM THE FARM FROM THE GROUP SUGGESTED THAT THERE ARE ONLY 34 TOTAL MUSHROOM BODY OUTPUT NEURONS WHICH CARRY INFORMATION FROM THE MUSHROOM BODY, AND THESE 34 NEURONS ACTUALLY SEND PROJECTIONS TO A SMALL NUMBER OF TARGET NEURONS WHERE A RESULT OF THIS POPULATION WORKS IN CONCERT TO THE FACTORY, PREFERENCES OF AN ANIMAL SUCH AS DIFFERENT PATTERNS OF ACTIVITY AND THE POPULATION, COULD RELEASE EITHER ATTRACTION OR AVOIDANCE BEHAVIOR. AND SO YOU CAN SEE, IN ACARD OR SUGGESTION, THE MUSHROOM BODY REALLY STARTS AT A CRITICAL NODE IN THE OLFACTORY CIRCUIT THAT CAN TRANSLATE DIFFERENT OLFACTORY INPUT INTO DIFFERENT BEHAVIORIAL OUTPUT. BUT TO REALLY BEGIN TO UNDERSTAND HOW THIS FLEXIBILITY UNDERSTANDS, WE REALLY TOOK ADVANTAGE OFLET FACT THAT THE WIRING OFLET UNIQUE ARCHITECTURE OF THE MUSHROOM BODY LOBE AND IF YOU ZOOM INTO 1 OF THESE LOBE STRUCTURES, CAN YOU SEE THIS IS THE GAMMA LOBE, HERE AT THE CELL ACTS ON THAT'S PHOTOACTIVATABLE GFP. SO ALL THESE VARMIS VERSE THE ENTIRE LENGTH OF THE LOBE AND ALONG THE WAY, MAKE THE SYNAPSES OF A SMALL NUMBER OF MUSH ROOT BODY OUTPUT NEURONS, SHOWN HERE, EACH MUSHROOM BY THE OUTPUT NEURON HAS A DENDRITIC CELL RIDDIC INNERIVATION THROUGHOUT THE LOBE AND COLLECTS INFORMATION BASICALLY FROM A SMALL COMPARTMENT WITHIN THE MUSHROOM BODY. LIKEWISE THE AXONS AND THE DOPA MINERGIC NEURONS WHICH ARE THOUGHT TO CONVEY THE INFORMATION TO THE MUSHROOM BODY, THEY HAVE A RESTRICTED INNOVATION PATTERN WITHIN THE LOBE AND - IS REALLY THE CO-INNERIVATION OF THE AXONS OF A SUBSET OF DOPA MINERGIC NEURONS THAT FORM KIND OF THE DISCREET ANATOMIC COMPARTMENT. SO THERE ARE MULTIPLE ANATOMIC COMPARTMENTS WHICH TELL THE COMPLETE LENGTH OF THE MUSHROOM BODY LOBE, BUT FOR THE PURPOSE TODAY, ON THE 4, THE GAMMA 2, 3, 4, AND 5 COMPARTMENTS WHICH HAVE THE LENGTH OF THE GAMMA LOBE, AND SO WHAT THIS REALLY BEAUTIFUL KIND OF ORDILY ARCHITECTURE IN THE MUSHROOM BODY SUGJESTS IS THAT INTERESTING POSSIBILITY THAT EVEN THOUGH KENYON CELLS HAVE THE ANATOMIC CAPACITY TO TRANSPOLIT OLFACTORY SIGNALS TO EACH OF THE MUSHROOM BODY OUTPUT NEURONS WITHIN A LOBE BUT THE LOCAL MODULATION OF SYNAPTIC SIGNALING WITHIN A COMPARTMENT BY THE DOPA MINERGIC NEURONS AND IT'S A DIFFERENTIAL TUNING OF OLYMPIC FACTORY SIGNALS FROM THE SAME POPULATION, TO THE OUTPUT NEURONS, SUCH THAT BASICALLY AN ODOR REPRESENTATION SOAXONS CAN NOW ACTIVATE DIFFERENT OUTPUTS REALLY DEPENDING ON THE MODLATTORY NEURONS OR THE EXPERIENCES OF THE ANIMAL. SO WE'RE--WE'RE QUITE INTERESTED TO BEGIN TO TEST THIS MODEL AND SO WE DECIDED TO START BY LOOKING AT HOW THE NEURONS THEMSELVES REPRESENT CONTEXTURAL INFORMATION TO THE MUSHROOM BODY. SO REALLY, VERY NICE NEUROGENETIC APPROACHES HAVE ACTUALLY SUGGEST SAID THESE DOPA MINERGIC NEURONS WHICH INNERIVATE ARE SUFFICIENT TO INSTRUCT THE FACTORY ASSOCIATIONS. AND SO, WHAT THEY SUGGESTED IS THAT IF YOU PRESENT THE ODOR STIMULUS AND YOU ACTIVATE THIS SUBSET, IT ACTUALLY LISTENS TO LEARNED ATTRACTION TO THIS PARTICULAR ODOR. AND IF YOU TAKE THE SAME ODOR STIMULUS AND PAIR IT WITH THE ACTIVATION, THE ARTIFICIAL ACTIVATION WITH A DISTINCT VERSION OF THE MUSHROOM BODY IS TO LEARN AVOIDANCE. AND SO, THIS TYPE OF BEHAVIORIAL EXPERIMENT HAS SUGGESTED THE INTERESTING POSSIBILITY THAT YOU KNOW, POSITIVE AND NEGATIVE CONTEXTURAL CUES COULD BE ATON MOUSILY REPRESENTED BY DISTINCT SUBSETS OF DOPA MINERGIC NEURONS WITHIN THE BODY. SO TO BEGIN TO EXAMINE THESE TYPES OF CONTEXTURAL CUES ARE REPRESENTED BY THE DOPA MINERGIC POPULATION, CO HEN A STUDENT IN MY LAB ACTUALLY TOOK ADVANTAGE OF USING BIOGENETIC DRIVERS TO EXPRESS THE GENETICALLY ENCODED CALCIUM INDICATOR, IN EACH OF THE DOPA MINERGIC NEURONS WHICH INNERIVATE THE COMPARTMENTS OF HOW THE GABA LOBE. SO I WILL SHOW YOU THE MOVIE OF A FLY THAT'S BEEN FASTED OVER NIGHT AND WILL GET A SUGAR REWARD TO THE MOUTH OF THE FLY ON A PAPER WICK AS WE IMAGE THE DOPA MINERGIC NEURONS AND WHAT I HOPE CAN YOU APPRECIATE IS THAT AS SOON AS THE FLY BEGINS TO INGEST THE SUGAR REWARD THERE'S STRONG ACTIVATION OF THE GAMMA 4 AND 5 DOPA MINERGIC NEURONS AND A COORDINATED INHIBITION OF THE GAMMA 2 AND 3 DOPA MINERGIC, AND THE RED INCREASES AND BLUE IS DECREASE AND BELOW IS A TRIGGERED AVERAGE FOR DEEP OF THE NEURONS IN EACH COMPARTMENT. SO SUGAR ILLICITS THIS BI-DIRECTIONAL ACTIVITY ACROSS THE DOPA MINERGIC POPULATION. INTERESTINGLY ELECTRICAL SHOCK, COME IS A STIMULUS TO THE FLY, IT ILLICITS AND YOU DOPA MINERGIC NEURONS SO POSITIVE AND NEGATIVE HUGHES ILLICIT PATTERNS OF ACTIVITY ACROSS THE COMPLETE POPULATION, THIS KIND OF PARTIALLY ANTAGONISTIC NEURONS ARE INCREASED IN ACTIVITY AND SOME ARE DECREASED. SO WHAT I'VE SEWN YOU IS THAT ACTUALLY INTERESTINGLY, SUGAR REWARDS, ACTUALLY THE SAME DOPA MINERGIC NEUROONS THAT ARE ABLE TO DRIVE LEARNED ATTRACTION WAS ELECTRICAL SHOCK ACTIVATES SOME SUBSET OF THE DOPA MINERGIC NEURONS ARE ABLE TO DRIVE LEARNED AVOIDANCE SO WE WERE REALLY INTERESTED THEN TO ASK HOW IS IT THAT THE DOPA MINERGIC ACTIVITY, HOW DOES IT SHAPE THE OLFACTORY RESPONSES OF THE MUSHROOM BODY OUTPUT NEURONS AND IS ABLE TO IMPART MEANING TO AN ODOR STIMULUS DURING THE LEARNING PROCESS. AND SO, TO ADDRESS THIS, WE BASICALLY REP LITICATED THE CONDITIONING PARADIGM AT THE NEURAL LEVEL BY PRE'S SENTING A FLY UNDER THE MICROSCOPE WITH THE ODORS WITH ART FACIAL ACTIVATION OF THE GAMMA 4 AND 5 DOPA MINERGIC NEURONS USING A CHEM CHEMO GENETIC APPROACH, WITH THE TUNNEL. AND THEN WE MONITOR THE ACCYST OF THE GAMMA 4 MUSHROOM BODY OUTPUT NEURON USING THE DENDRITIC CALCIUM SIGNAL WHO MONITORING THE GCAMP EXPRESS INDEED THE PARTICULAR OUTPUT NEURON. AND SO WHAT WE FOUND IS THAT AFTER BASICALLY THE KIND OF PAIRED ACTIVATION OF OLFACTORY ASK DOPA MINERGIC REINFORCEMENT PATHWAYS THAT THERE'S ACTUALLY A STRIKING DEPRESSION IN THE MUSHROOM BODY OUTPUT NEURON RESPONSE TOTS PAIRED ODOR STIMULUS AND THIS IS SIMILAR TAKEN--THEY TO BEAUTIFUL WORK THAT WAS CARRIED OUT BY THE SAME TIME, THAT BASICALLY CARED OUT A VERY SIMILAR EXPERIMENT TO USE ELECTROPHYSIOLOGY AS A DIFFERENT READ OUT AND A DIFFERENT POPULATION, WHERE THEY FOUND THAT BASICALLY THE PAIRING OF THE OLFACTORY AND THE REINFORCEMENT PAPGHT WAYS LED TO DEPRESSION OF THE OUTPUT NEURON RESPONSE TO THE PAIRED OLFACTORY STIMULUS. BUT IN BOTH CASES WHAT WAS REALLY INTERESTING IS THAT THIS KIND OF DEPRESSION THAT WE OBSERVED IS REALLY SPECIFIC ONLY TO THE PAIRED ODOR AND NOT PARENT ANY UNPAIRED ODOR. SO THIS REALLY KIND OF REPLICATES THIS SORT OF TEMPORAL CONTINGENCY THAT'S REQUIRE REQUIRED FOR ASSOCIATIAATIVE LEARNING WHERE THE OLYMPIC FACTUALLY STIMULUS HAS TO BE TIGHTLY TEMPORALLY PAIRED SO FOR THE REINFORCEMENT TO ALLOW FOR SPECIFIC ASSOCIATION TO BE FORMED AND BASIC THAT THE O'DORS ARE UNPAIRED, THEIR RESPONSES SHOULD NOT BE CHANGED. AND SO, WHAT THIS SUGGESTS THEN IS THAT REALLY THE CONVERGENCE OF OLFACTORY AND CONTEXTURAL INFORMATION WITHIN THE MUSHROOM BODY LOBE PROVIDES A MECHANISM FOR ODOR SPECIFIC MODULATION OF THE MUSHROOM BODY OUTPUT NEURON DURING LEARNING, REALLY ALLOWING OR WEIGHTING FOR THE MUSHROOM BODY OUTPUT POPULATION DEPENDING ON LEARNING TO ALLOW AN ANIMAL BASICALLY TO ALTER BEHAVIORIAL RESPONSE AND OLFACTORY STIMULUS BASED ON PAST EXPERIENCE, BASED ON THE SOCIAATIVE EXPERIENCE THAT IT HAS. AND SO THIS IS OF COURSE VERY MUCH CONSISTENT WITH THE IDEA OF HOW MUSHROOM BODY WHICH HAS LONG BEEN STUDIED AS A SITE DEDICATED TO ASSISTED LEARNING HOW MODULATION OF OLFACTORY RESPONSES COULD LEAD TO CHANGES IN BEHAVIOR THROUGH THE ASSOCIATIAATIVE LEARNING PROCESS, BUT OF COURSE, ANIMALS HAVE TO MODIFY THE BEHAVIOR BASED ON PAST EXPERIENCE, BUT ALSO DUE TO ONGOING CHANGES TO THEIR EXTERNAL ENVIRONMENT OR THEIR INTERNAL STATE AND 1 THING WE STARTED TO THINK ABOUT IS THE SAME SORT OF CONVERGENCE AND CONTEXTURAL INFORMATION AND WOULD ALLOW FOR MUCH MORE RAPID OLFACTORY ADAPTATION PROCESSING TO ACCOMMODATE THE ACUTE NEEDS AND MOTIVATIONS OF AN ANIMAL AND WE'RE INTERESTED TO ASK WHETHER THE MUSHROOM BODY COULD SERVE THE MODULATION OF BEHAVIOR. AND IN PART WE'RE INTERESTED TO ASK THIS QUESTION BECAUSE WHEN WE--1 OF THE--CONTEXT OF THESE EXPERIMENTS, 1 THING WE NOTICE IS THAT THEY'RE REALLY ROBUST FLUCT WOGSS IN THE BASE AT ACTIVITY WITHIN THE MUSHROOM BODY. BUT ACTUALLY CORRELATED WITH THE MOTOR ACTIVITY OF THE ANIMAL. AND I THINK THIS IS MOST APPARENT IF YOU SIMPLY LOOK AT THE ACTIVITY OF THE DOPA MINERGIC FLUOROONS IN THE TETHERED FLY IN THE ABSENCE OF ANY OVERT EXPERIENCE THAT WE'RE PROVIDING AND WHAT YOU CAN SEE IS THAT IF A TETHERED SLIDE PREPARATION THAT WE TRADITIONALLY HAD BEEN USING WHERE WE CAN FIX THE BRAIN, THE ANIMAL ALTERNATES BETWEEN 2 DISTINCT BEHAVIORIAL STATE, 1 WHERE IT'S PAUSED AND STILL, AS YOU SEE HERE, AND 1 WHERE IT'S KIND OF RAPIDLY FLAILING ITS LEGS ALMOST LIKE AN ESCAPE REFLEX AND WHAT I HOPE YOU CAN APPRECIATE IS THE ACTIVITY OF THE DOPA MINERGIC NEURONS ALMOST PERFECTLY CORRELATE WITH THE DISTINCT BEHAVIORIAL STATES. OF COURSE WHEN THE ANIMAL IS RAPIDLY FLAILING, GAMMA 4 OR 5 DOPA MINERGIC NEURONS BUT WHEN THE FLY IS STILL, RECIPROCAL PATTERNS. SO THIS FLAILING BEHAVIOR IS QUITE INTERESTING AND WE THOUGHT, SPECULATED ITSELF WAS AN AVERSIVE STATE ASSOCIATE WIDE ANIMAL'S DESIRE TO [INDISCERNIBLE] AND IT PROMPTED TO THINK THIS BECAUSE OF THE PATTERN OF ACTIVITY IN THE DOPA MINERGIC POPULATION, IT IS STRONGLY RESEMBLES THAT WHICH WAS ILLICITTED BY THE PAINFUL SHOCK. SO WHEN THE FLY IS POSITIVE WE SEE AN ACTIVITY PATTERN IN THE DOPA MINERGIC NEURONS BECAUSE IT'S TO WHEN THE FLY GETS A SUGAR REWARD. AND SIMILAR RITE PATTERNS SUGGESTED TO US THE POSSIBILITY OF THE BEHAVIORIAL STATE OF ANAANIMAL AND COULD SHAME THE WAY IT'S COMPOUNDED IN THE MUSHROOM BODY. SO WE'RE INTERESTED TO ASK ARE THESE ASSOCIATED FLUCTUATIONS ARE THEY SUFFICIENT TO DRIVE DOPA MINE RELEASE WITHIN THE MUSHROOM BODY AND IN ORDER TO ALLOW FOR A KIND OF MODULATION OLFACTORY PROCESSING. AND SO, IN THE ABSENCE OF A DIRECT METHOD TO ACTUALLY MONITOR DOPA MINE RELEASE IN THE FLY, WE TOOK ADVANTAGE OF THE FACT, OF THE FACT THAT THE DOPA MIN RECEPT ORS THAT ARE HIGHLY EXPRESSED WITHIN THE MUSHROOM BODY, DOPE R1 AND DOPR2, THEY ARE COUPLED TO THE INTRA CELLULAR AMP. SO, AND AN ANNIE EXPRESSED A GMP REPORTER WITHIN THE GAMMA CELL POPULATION, THIS A REPORT THEY'RE TAKES ADVABTAGE OF THE BINDING MODULE AND SHE ASKED BASICALLY, SHE SAID TO USE THIS AS A METRIC TO LOOK AT DOPA MINE RELEASE ALONG THE LENGTH OF THE LOBE. SO DESPITELET FACT THAT THE RESPORTER IS ALONG THE LENGTH, WHAT SHE FOUND IS THAT ACTUALLY THERE REALLY IS A STRIKING ASSEMETRY AND CONCENTRATIONS OF CYCLIC AMP ALONG THE LENGTH OF THE LOBE. THAT SEEMS TO ADHERE OF THE COMPORTMENTAL MUSHROOM BODY, AND THOSE DEPEND OFFICE OF DIVERSITY THE BEHAVIORIAL STATE OF THE ANIMAL. AND SUCH THAT WHEN THE ANIMAL WAS FLAILING, YOU CAN SEE ELEVATIONS OF CYCLIC AMP AND THE GAMMA TABOO AND 3 COMPARTMENT AND WHEN THE ANIMAL WAS PAUSED AND STILL, SHE WOULD SEE INCREASES IN CYCLIC AMP IN THE GAMMA 4 AND 5 COMPARTMENT. SO THESE MODULATIONS, IS SICK LIKE AMP IN THE KENYON CELL AXONS ARE DUE TO DOPA MINE SIGNALING BECAUSE WE LOOK IN ANIMALS THAT ARE MUTE ABTS FOR THESE DOPA MINE RECEPTORS AND THIS IS THE DOUBLE MUTE ANT AND YOU SEE THAT THESE FLUCTUATIONS IN THE AMP LEVELS WITH BEHAVIORIAL STATE BASICALLY ARE STRONGLY ATTENUATE. AND SO WHAT THIS SUGGEST SYSTEM THAT ACTUALLY, THERE'S--KIND OF AN ONGOING REPRESENTATION OF THE BEHAVIORIAL PHASE OF THE ANIMAL THAT, IS ENCODED IN THE ACTIVITY OF THE DOPA MIN ERNLGIC NEURONS AND THIS IS TELEVISION TO DRIVE DOPA MINE RELEASE AND ENGAGE SIGNALING PATHWAYS IN THE KENYON CELL AXON. IT SUGGESTS TO US BASICALLY THAT THE MUREONS WITHIN THE MUSHROOM BODY, PROVIDES ONGOING REPRESENTATION OF THE EXPERIENCE OF THE ANIMAL THROUGH THESE COORDINATED AND ANTAGONISTIC PATTERNS OF ACTIVITY ACROSS THE POPULATION THAT REPRESENT NOT ONLY CLASSICAL REINFORCEMENT FOR ELECTRICAL SHOCK AND SUGAR BUT THE INTERNAL STATE OF THE ANIMAL. SO OUR NEXT INTERESTED TO ASK, HOW IS IT THAT THIS COMPARTMENTALIZED PATTERNS OF MODULATION IN THE BODY, HOW DO THEY SHAPE THE OLFACTORY INFLAMMATION THROUGH THE LOBE AND HOW DO THEY SHAPE THE WAY ODORS ARE REPRESENTED ALONG THE AXONS, AS THEY TRAVERSE THROUGH THE MULTIPLE COMPARTMENTS OF THE LOBE. AND SO, TO ADDRESS THIS, WE GENERATED THE SYNAPTICALLY LOCALIZED VARIANT OF THE CALCIUM SENSOR, SIMPLY BY TETHERING IT TO THE SYNAPTIC PROTEIN AND THE LIGANDS AND HERE YOU CAN SEE A MOVIE WHICH IS BASICALLY WE HAVE EXPRESSED THE SYNAPTIC CALCIUM SENSOR IN ALL KENYAN CELLS AND ACTIVATED THE FAR SUBSET OF THEM AND THIS ALLOWS US TO REVEAL THE INFLUX WHICH IS DISTINCT FOR THE LOCI. SO WE THEN EXPRESS THE INAPTIC GCAMP IN ALL THE DENNION CELLS OF THE GAMMA LOBE, TO MONITOR SYNAPTIC RESPONSES TO ODOR STIMULI IN THE ODOR COMPARTMENT. AND WHAT WE FOUND IS THAT ODOR WAS STRIKINGLY ASYNAPTIC PATTERN ALONG THE LENGTH OF THE LOBE WITH MUCH MORE ROBUST ROUGH ATOM SPONSES TO ODOR STIMULI WITH THE GAMMA 2 AND 3 COMPARTMENTS COMPARED TO 4 AND 5 COMPARTMENTS. SO THESE REALLY PRECISE FUNCTIONAL SYNAPTIC DOME MAINES THAT ARE BOUNDARIES THAT ARE ONLY A FEW MICRONS IN WIDTH, WE CAN DEMONSTRATE FROM ANATOMIC EXPERIMENTS ARE NOT DUE TO DIFFERENCES IN THE INNOVATION LONG THE KENYAN CELLS WHICH ARE ALL CELLS TRANSLATIONAL RESEARCH VERSING THE ENTIRE LENGTH OF THE NOR ARE THEY DUE TO DENSITY IN THE COMPARTMENTS SO THESE ARE DUE TO FUNCTIONAL HETEROGENEITY OF THE INDIVIDUAL AXONS AND THIS IS APPARENT IF YOU IMCANCER CENTER THE SUBSETS OF GAMMA 10ION CELLS THAT COCO-EXPRESS THE MARKER SO THAT WE CAN VISUALIZE THE LENGTH OF THE PROJECTION ALONG WITH THE SYNAPTIC CALCIUM SENSOR. SO I HOPE YOU CAN APPRECIATE THAT THE INDIVIDUAL FOCUSED ON TANS OF THE SAME SET OF AXONS HAVE STRONGER ROBUST STIMULI WHEN THEY TRAVERSE THROUGH THE COMPARTMENTS THAN WHEN THEY PROJECT TO THE DISTAL COMPARTMENTS OF THE LOBE. SO THE IDEA OF A FUNCTIONAL HETEROGENEITY, OF INDIVIDUALAXONS OF COURSE, IT'S BEEN OBSERVED IN MANY MAMMALIAN NEURONS WITHIN THE BRAIN AND IT'S REALLY TO UNDERLIE THE INDIVIDUAL NEURONS TO DIFFERENTIALLY COMMUNICATE THE MYRIAD OF SYNAPTIC PARTNERS AND WITHIN THE COMPLEXITY OF THE BRAIN IT'S BEEN DIFFICULT TO REALLY UNDERSTAND HOW THIS KIND OF FUNCTIONAL HETEROGENEITY ARISES, AND ULTIMATELY WHAT IS THE FUTILITY OF THE PROCESSING SO THIS IS SOMETHING WHERE WE TAKE ADVANTAGE OF THE COMPARTMENTAL ORGANIZATION OF THE MUSHROOM BODY IF YOU THINK ABOUT THIS. SO WHAT I SHOWED YOU THEN IS THAT ACTUALLY KENYON CELLS DIFFERENTIALLY REPRESENT THE SAME OLFACTORY STIMULUS ALONG THE LENGTH OF THE AXONS AS THEY TRAVERSE THROUGH THE DIFFERENT COMPARTMENTS OF THE LOBE AND I SHOULD SAY THAT WE SEE THIS IN EVERY TETHERED FLY SO ALMOST ANY OLFACTORY FLY WE PRESENT TO THE ANIMAL AND ABSENCE OF ANY EXPERIENCE THAT WE'RE PROVIDING THE ANIMAL WITH. BUT OF COURSE SOME OF YOU HAVE ALREADY APPRECIATE HAVE HAD AND I'LL JUST REMIND YOU THAT IN THIS TETHERED FLY PREPARATION, THE MOST PREVALENT BELAIEVERRIAL STATE OF THE ANIMAL IS IN THE PERIOD WHERE BASICALLY IT'S RAPIDLY FLAILING ITS LEGS AND ALMOST LOOKING LIKE A SAFE REFLEX TRYING TO ESCAPE FROM THE TETHER. AND THIS IS A PATTERN OF ACTIVITY OF STRONG ACTIVATION OF THE GAMMA 2 AND 3 DOPA MINERGIC NEURONS AND ELEVATES CYCLIC A&M IN THE GAMMA 2 AND 3 COMPARTMENT SO THE STRIKING SIMILARITY OF THE SPACIAL PATTERNING OF THE LEVEL OF THE DOPA MINERGIC NEURONS AND EITHER CYCLIC AMP OR CALCIUM IN THE CANYON CELLS SUGGESTED TO US THE POSSIBILITY THEN OF ACTUALLY THE BEHAVIOR STATE OF THE ANIMAL IS THE DOPA MINE RELEASE THAT HAVE SHAPED THE SIGNALING IN THE KENYON CELL AXON. SO I'LL SHOW YOU A LINES OF EVIDENCE THAT IT IS DOPA MINE THAT'S SENDING THIS IN THE AXON. SO IF WE IMAGE ACTUALLY THE DENNION CELLS, WHERE BASICALLY THE DOPE R2, DOPA MINE RECEPTOR HAD BEEN SPECIFICALLY KNOCKED DOWN USING RNAI, THE OLFACTORY RESPONSE OF THE CELL SYSTEM ACTUALLY NOW RELATIVELY HOMOGENIUS ALONG THE LENGTH OF THE LOBE, LIKEWISE IF WE IMAGE OLFACTORY RESPONSES IN THE CELLS WITH THE DOPA MINE REUPTAKE TRANSPORTER IS MUTANT FOR THE TRANSPORTER AND DOPA MINE HANDLING IS AUTHORED, WE LIKEWISE SEE UNIFORM RESPONSES. AND FINALLY, ACTUALLY IF WE BASICALLY LOOK AT KIND OF THE DIRECT ACTIVATION OF KENYON CELLS AND A BRAIN EXPLANT WHERE WE TAKE THE BRAIN OUT OF THE ANIMAL AND COVERED BASICALLY ANY KIND OF SENSORY OR MOTOR INPUT TO THE BRAIN AND WE'RE DOPA MINE SIGNAL SUGGEST VERY, VERY LOW. WE ALSO SEE UNIFORM AND RESPONSES ALONG THE KENYON CELL AXON. SO WHAT THIS SUGGEST SYSTEM THAT THE CELLS HAVE THE ANATOMIC CAPACITY TO PROPAGATE REALLY EQUIVALENT OLFACTORY OR NEURAL SIGNALINGS ALONG IT IS LENGTH OF THEIR AXONS BUT THERE REALLY MUST BE THIS ACTIVE MODULATION THAT OCCURS BY DOPA MINE SIGNALING, THE SHAPA'S SPACIAL OF TOPOGRAPHY AND CALCIUM IN THE FUNCTIONAL ASYMMETRY. SO DOPA MEAN IS NECESSARY FOR SETTING UP THE FUNCTIONAL ASYMMETRY, AND IF WE ARTIFICIALLY ACTIVATE THE GAMMA 4 AND 5 NEURONS USING THE GENETIC APPROACH WILL FEED THE FLY TO ACTIVATE THEM PHYSIOLOGICALLY WE CAN SEE HOW THEY INJECT THE AXONS BY MONITORING THE OLFACTORY RESPONSES USING THE CALCIUM SINATTIC SINCOR AND I HOPE CAN YOU APPRECIATE IS THAT AFTER THE DOPA MIN ERNLGIC VACIVATION OF THESE DOPA MINERGIC ACTIVATIONS WOO SEE ENHANCEMENT OF OLFACTORY RESPONSES IN THE GAMMA 4 AND 5 COMPARTMENT AND A RELATIVE DECREASE IN THE RESPONSES OF THE GAMMA 2 AND 3 COMPARTMENTS. AND SO WHAT THESE EXPERIMENTS SUGGEST THEN IS THAT REALLY DOPA MEAN HAS THE CAPACITY TO ACTIVATE SIN APTIC SIGNALING IN THIS SPECIFICITY IN THE SUBCELLULAR COMPARTMENT ALONG THE LENGTH OF INDIVIDUAL KENYON CELL AXON. SO THIS REALLY SHOULD HAVE BEEN ALLOWED FOR DIFFERENTIAL COMMUNICATION OF EVERY KENYON CELL TO EACH POST SYNAPTIC PARTNER FOR EACH OF THESE OUTPUT NEURON RESPONSE PARTNERS AND IN THIS WAY, COULD--AND THESE OUTPUT NEURONS OF COURSE HAVE THE IMPACT IN BEHAVIOR. AND SO IT'S REALLY TO LOOK AT HOW THESE RESPONSES AND FUNCTIONAL ASSEM SITRY OF THE KINNION CELL LEVEL ARE TRANSLATED INTO THE MUSHROOM BODY OUTPUT NEURONS WE PERFORM THE FUNCTIONAL CALCIUM OUTPUT NEUROIMAGES AND WE FIND OUT THAT DOES INDEED PROVOKE A DIFFERENTIALLY ACTIVATE THE OUTPUT POPULATIONS. SO, THE ODOR IS MORE ROBUST RESPONSES IN THIS TETHERED SLIDE PREPARATION IN THE GAMMA 2 AND 3 COMPARTMENT RELATIVE TO THE GAMMA 4 AND 5 COMPARTMENT THAT YOU SEE HERE. SO THE FUNCTIONAL ASSEMIT REOF THE LEVEL NEURONS BEAUTIFULLY PARALENS LENS LENS LENSS THE FUNCTIONAL ASSEM RETINAL LOCATIONRY OF THE PARTNERS, THE KENYON CELLS AND OF COURSE, THE DOPA MINERGIC NEURONS WITHIN THIS PREPARATION. SO WHAT IT WOULD THEN SUGGEST TO US IS THAT IT WILL BE DOPA MINE RELEASED IN THESE COMPARTMENTS, POTENTIALLY WITHIN THE CELLS THAT IT'S TRANSALATES INTOED ENHANCED OLFACTORY RESPONSES IN THE OUTPUT POPULATION, AND SO THIS ACTUALLY WAS SUGGESTED, THIS DOPA MINE THROUGH THE EXPERIENCE OF THE ANIMAL MAY NOT LEAD TO SYNAPTIC DEPRESSION LIKE I SHOWED YOU IN THE CONTEXT OF LEARNING PARADIGM BUT LEAD TO INAPTIC IN'RE ENHANCEMENT AND MORE DIRECTLY PROBE THIS POSSIBILITY WE PROP VIED THESE RECORDINGS FROM THE OUTPUT NEURON TO LOOK AT SYNAPTIC RESPONSES DIRECTLY AND HERE YOU CAN SEE, WE ACTUALLY RECORDED FROM THE OUTPUT NEURON AND DIRECTLY STIMULATED THE KENYON CELLS TO ILLICIT A MODEST INWART EXCITEATORY CURRENT IN THE NEURON. AND WE THEN ACTIVATED THE GAMMA 4 AND 5 DOPA MINERGIC NEURONS USING THE APPROACH TO BASICALLY ON THEIR OWN, BASICALLY TO MIMIC THE NEUROMODLATTORY SPACE TO THE ONGOING ACTIVITY OF THE ANIMAL. AND THEN WE STIMULATED THE KENYON CELLS AGAIN AND LOOK AT THE CHANGE IN THE NEURON AND AS YOU MIGHT HAVE EXPECTED FROM THE PREVIOUS SLIDE, WE SEE A STRIKING POTENTIATION BETWEEN THE KENYON CELLS AND THE MUSHROOM BODY OUTPUT NEURONS BY JUST THE RELEASE OF DOPA MINE ON ITS OWN. AND SO WHAT THIS SUGGESTS THAT IS THAT DOPA MINE WITHIN THE MUSHROOM BODY COMPARTMENT IS ABLE TOW ILLICKITY MULTIPLE FORMS, THAT DEPEND NOT ONLY--DEPENTINE REGIMEN REALLY ON THE TEMPORAL ORGANIZATION OF THE DIFFERENT STIMULATION, SO WHAT I SHOWED YOU INITIALLY IS THAT IN KIND OF THE CONTEXT OF THE SOCIAATIVE PATHWAYS WHERE THE KENYON CELLS ARE TEMPORALLY ACTIVATED THE SAME TIME AS A DOPA MINERGIC REINFORCEMENT PAPGHT WAY, THIS LEADS TO STRIKING DEPRESSION IN THE MUSHROOM BODY OUTPUT NEURON RESPONSE. BUT IF INSTEAD RATHER THAN HAVING THIS PAIRED ACTIVATION, WE SIMPLY ACTIVATE THE DOPA MINERGIC NEURONS ON THEIR OWN RATHER THAN SEEING DEPRESSION, WE ACTUALLY SEE AN ENHANCEMENT OF OLFACTORY SIGNAL IS SO WE'RE REALLY INTERESTED TO UNDERSTAND HOW IS IT THAT THE SAME DOPA MINE RELEASED AND HOW IS IT THE SAME DOPA MINE SIGNAL CAN ILLICIT THESE MODULATION BETWEEN KENYON CELLS AND THE OUTPUT NEURON AND WE THINK THIS MAY DEPENDOT ENGAGEMENT OF DIFFERENT DOPA MIN RECEPTORS OR THE ACTUALLY RECRUITMENT OF THE DETECTION PATHWAY, DETECTORS FROM THE MOLECULES ACTS AS THE DETECTORS AND THEY ARE SPECIFICALLY ENGAGED IN 1 REGIME VERSUS ANOTHER. BUT THIS IS KIND OF A REALLY ROBUST BI-DIRECTIONAL MODULATION THAT CAN OCCUR WITHIN A COMPARTMENT HAS A REALLY IMPLICATION, SO 1 THING THAT SUGGESTS OF COURSE IS THAT THE CONTEXT OF THE INDEPENDENT MODULATION THAT WE OBSERVE THAT ACTUALLY CAN OCCUR JUST DUE TO DOPA MINE RELEASE ON ITS OWN, MAY BE ABLE TO ERODE ODOR SPECIFIC LEARNED ASSOCIATIONS BY BASICALLY ALTERING THE SYNAPTIC DEPRESSION THAT OCCURRED DURING LEARNING AND THIS WAY THE IMMEDIATE AND ACUTE CIRCUMSTANCE OF THE ANIMAL MAY BE ABLE TO DOMINATE OVER PAST LEARNED ASSOCIATIONS THAT ARE NO LONGER RELEVANT OR PRO DICKIVE AND IN FACT, THERE'S ACTUALLY REAMLY NICE BEHAVIORIAL EXPERIMENTS TO SHOW THAT--TO SUPPORT THIS IDEA, TO WORK FROM BOTH JERRY RUBEN AND RON DAVIS' LAB HAVE SUGGEST THAD AFTER A LEARNED ASSOCIATION IS FORMED AND KIND OF IN THE CLASSICAL PAIRING OF OLFACTORY AND REINFORCEMENT THROUGH ELECTRICAL SHOCK, AFTER THERE'S A SPECIFIC LEARNED ASSOCIATION THAT WAS GENERATED, ACTUALLY CAN YOU COMPLETELY OVERRIDE THAT ASSOCIATION SIMPLY BY STRONG ACTIVATION OF THE DOPA MINERGIC NEURONS SO WHAT THIS SUGGEST SYSTEM THAT DOPA MINE IS ABLE TO CAUSE THOSE SYNAPTIC STRENGTHS LIKE A SWITCH IN BOTH DIRECTIONS AND ACTUALLY BOTH SYNAPTIC FUNCTIONS TO ALLOW IN A WAY THAT REFLECTS LEARNED ASSOCIATION BUT ALSO RELATE TO KIND OF ACUTE STATE OF THE ANIMAL. AND SO THERE'S A REALLY KIND OF VARIED DYNAMIC PROCESS THAT'S CONSIDERING WITHIN THE MUSHROOM BODY TO SHAPE THE OUTPUT OF THE MUSHROOM BODY OUTPUT PATHWAYS AND THESE EXPERIMENTS THEN SUGGEST TO US BASICALLY THAT THE MUSHROOM BODY COULD ACT SOMETHING LIKE A SWITCH BOARD AND IT CAN BE REROUTED INTO ALTERNATIVE OUTPUT PATHWAYS DEPENDING ON THE STATE OF AND INNEREXPERIENCE OF THE ANIMAL AND THE DOPA MINERGIC SIGNALS PROVIDED HAVE THE CAPACITY TO ACUTELY MODULATE SIGNALING BETWEEN KENYON CELLS AND OUTPUT NEURONS BUT ALSO SHAPE MUCH LONGER TERM SYNAPTIC PLASTICITY THROUGH LURING THAT MAY BE MAINTAINED THROUGH A LONGER PERIOD OF TIME AND THAT DOPA MEAN HAS THE CAPACITY TO KIND OF BE ACTIVE AND THE DOPA MINERGIC SIGNALS THAT ARE CONVEYED BY THE NEURONS, SO THEY CAN ALLOW AN ANIMAL TO ACUTELY MODULATE BEHAVIOR BUT ALLOW THEM TO TAKE ADVANTAGE OF THE PREDICTIVE VALUE OF CURRENT CIRCUMSTANCES TO SHAPE FUTURE BEHAVIOR. SO, THIS ACTUALLY WE THOUGHT WAS REALLY QUITE INTERESTING, 1 THING I WOULD LIKE TO ACTUALLY EXTEND UPON THOUGH, TO THINK ABOUT IS WHAT I SHOWED YOU, IS THAT THERE ACTUALLY IN THE CONTEXT OF THINKING ABOUT CONTEXT DEPENDENT MODULATIONS AND WHAT I SHOWED YOU IS THAT WE SEE THESE ROBUST FLUCTUATIONS IN THE DOPA MINERGIC NEURONS IN THIS ANIMAL TETHERED STATE, AND RIGHT? AS I SUGGESTED THIS CAN BE A EXTREME SALIENT STATE, LIKE REFLECTING TOWARDS EXAMPLES THE POSSIBILITY OF ANIMAL WANTS TO ESCAPE AND SO IT'S INTERESTED TO KNOW WHETHER THE ACTIVITY WAS ONLY PROVIDING SORT OF A CONTEXTURAL SIGNAL THAT OCCURRED ONLY EXTREME BEHAVIORIAL STATES OR WHAT HAPPEN FIST WE THINK ABOUT WHEN THE ANIMAL IS ACTUALLY NAVIGATING INTO A MUCH MORE NATURAL ENVIRONMENT, BASICALLY WALKING THROUGHOUT ITS WORLD OUR DOPA MINERGIC NEURONS ALSO BEING PROVIDING AN ONGOING REPRESENTATION OF THE STATE OF THE ANIMAL AND THE EXPERIENCE OF THE AN MA NOT EVEN IN EXTREME STATES BUT A MORE NATURAL PHYSIOLOGICAL STATE. AND SO TO ADDRESS THIS, IN THE LAB, WE START TO LOOK AT THE DOPA MINERGIC NEURON ACTIVITY WITHIN THE MUSHROOM BODY AS AN ANIMAL IS WALKING ON A FREELYY ROTATING BALL WHICH IS SUPPORTED BY A LITTLE--SUPPORTED BY AIR, SO IT ROTATES AROUND LIKE A LITTLE FLY TYPE TREADMILL AND HERE CAN YOU SEE THE ACTIVITY IN THE DOPA MINERGIC NEURONS AND IT'S PLOTTED BELOW THE COMPARTMENTS AS THE ANIMAL WALKS ON THE BALL AND SO EVEN IN THIS LESS EXTREME BEHAVIORIAL STATE THERE'S STILL STRIKING MODULATION OF THE DOPA MINERGIC NEURONS, SO CAN YOU SEE THE RED BY THE POLEAR VELOCITY OF THE BALL. SO IF WE ALINE THESE MOTIONS FROM 25 DIFFERENT ANIMALS CAN YOU SEE THAT BASICALLY ALL THE DOPA MINERGIC NEURONS, ALL THE DIFFERENT DOPA MINERGIC NEURONS, THE ACTIVITY IS MODULATED BY LOCOMOTION. BUT 1 THING WE FOUND THAT WAS INTERESTING IS THAT THE DOPA MINERGIC NEURONS WITHIN THE GAMMA LOBE ARE NO LONGER REPRESENTING DIFFERENT FACETS OF LOCALLAL MOTOR ACTIVITY. FOR EXAMPLE, THE GAMMA 3 COMPARTMENT PROVIDES A HIGH FIDELITY REP REPRESENTATION OF WHETHER THE ANIMAL IS WALKING OR NOT SO CAN YOU APPRECIATE THIS FROM LOOKING AT THE RAW DATA, THAT ARE BASICALLY PLOTTING THE ACTIVITY OF THE GAMMA 3 NEURONS FROM THE SIGNAL OVER THE NET ROUGH ATOMERATIONAL VELOCITY OF THE BALL IN WHITE. THE 7 SNAPSHOTS FROM 7 DIFFERENT ANIMALS AND YOU CAN SEE THAT BASICALLY ALMOST PERFECTLY MATCHES THESE 2 AND USING A LYNNIAN CLASSIFIER MODEL WITH 90% ACCURACY, WE CAN PREDICT WHETHER THE ANIMAL IS WALKING OR NOT JUST FROM LOOKING AT THE ACTIVITY OF THE 1 DOPA MINERGIC COMPARTMENT BUT GOINGLY OTHER COMPARTMENTS WITHIN THE GAMMA LOBE ARE NOT SO HIGH FIDELITY IN THE REPRESENTATION AND HAVE MORE VARIABILITY BOTH WITHIN AND ACROSS ANIMALS. AND SO HERE YOU CAN SEE THE ACTIVITY OF THE GAMMA 2 DOPA MINERGIC NEURONS AND HERE YOU CAN SEE THE ACTIVITY OF THE GAMMA 4 DOPA MINERGIC NEURONS AND YOU CAN SEE THEY ARE MUCH MORE VARIABLE IN HOW, SOMETIMES THEY PROVIDE A VERY GOOD REPRESENTATION WHETHER THE ANIMAL WALKING AROUND AND THE TIME THAT REPRESENTATION IS MUCH MORE DIFFICULT TO SEE. AND THE GREATER VARIABILITY AND THIS IS SHOWING A SUMMARY WHICH SHOWS A CROSS CORRELATION FOR ALL THE STARTING ACTIVITY BETWEEN THE DOPA MINERGIC NEURONS, THE DIFFERENT COMPARTMENTS FOR BASICALLY 21 DIFFERENT ANIMALS. AND 1 STRIKING THING YOU SEE IS AS I SHOWED YOU THE GAMMA 3 NEUROWNS PROVIDE THE NEURONS ACROSS TED INDIVIDUALS, BUT THERE'S MUCH MORE VARIABILITY ACROSS THE OTHER INDIVIDUALS IN THE OTHER COMPARTMENT AND SO WE'RE CURRENTLY EXPLORING WHAT IS THE SOUTHERLIES OF THIS VARIABILITY, IS IT DUE TO BASICALLY KIND OF IDIO SYNCRATTIC PREFERENCES OF THE ANIMAL IN TERMINGS OF BEHAVIORIAL ACTIVITY SO DOES IT REFLECT OTHER ADDITIONAL ASPECTS FROM HIDDEN ASPECT OF THEIR INTERNAL BEHAVIORIAL STATE. WE'RE INTERESTED TO TRY TO THINK ABOUT BASICALLY AND WHAT WE SEE FROM 1 INDIVIDUAL ANIMAL TO THE NEXT. AND I WOULD JUST LIKE TO TELL YOU 1 DIRECTION THAT WE'RE TRYING TO GO TO THINK ABOUT HOW THAT VARIABILITY IS GENERATED AND TRY TO THINK ABOUT BASICALLY WHAT TYPES OF SIGNALS THESE NEURONS CARRY THAT COULD SHAPE OLFACTORY BEHAVIORIAL RESPONSES. START TO THINK ABOUT THE FACT THAT WHEN ANIMALS ARE WALKING IN THE TETHERED SYSTEM, IN AN A-SENSORY ENVIRONMENT WITH NO PUTATIVE SENSORY INFORMATION, THEY'RE WALKING IN THE DARK WITH NO BASICALLY KIND OF OTHER ADDITIONAL SENSORY FEEDBACK. IT'S POSSIBLE THAT SOME FORM OF THE VARIABILITY IS ACTUALLY INDICATIVE OF ANIMALS THAT ARE NOT COMPLETELY IDENTICAL STATE. FROM 1 ANIMAL TO THE NEXT, THERE ARE LITTLE DIFFERENCES THAT WE'RE BASICALLY NOT AWARE OF. ONE IDEA WE HAD WAS TO MAKE ANIMALS MORE UNIFORM AS WE START TO LOOK AT THE DOPA MINERGIC ACTIVITY IN THE MUSHROOM BODY HAS THE DOPA MINERGIC NEURONS REPRESENT ANIMAL BEHAVIOR WHEN THE ANIMAL IS TRACKING ON OLFACTORY STIMULUS. AND THAT WE WOULD ALSO LIKE TO BE ABLE TO UNDERSTAND ACTUALLY GIVEN THE IDEA OF THE DOPA MINERGIC NEURONS PLAY AN IMPORTANT ROLE IN THE BEHAVIORS BUT THE ACTIVITY OF THESE NEURONS LOOK DIFFERENT WHEN ANIMALS WALKING IN AN ASENSORY ENVIRONMENT COMPARED TO WHEN THEY'RE WALKING SORT OF TOWARDS AN OLFACTORY STIMULUS, SO RECENTLY WE START TO DEVELOP DIFFERENT BEHAVIORIAL PARADIGMS THAT MIGHT ALLOW US TO DO THIS. AND IN PART, PART OF WHAT WE THEN TRADITIONALLY AND I THINK MOST PEOPLE HAVE THIS IN THIS KIND OF OLFACTORY WORLD AND TO PRESENT THE STIMULUS FIXED RELATIVE TO THE POSITION OF THE ANIMAL SO IF THE SLIDE IS WALKING ON A BALL AND IT ROTATES IN RESPONSE TO THE OLFACTORY STIMULUS, IT CANNOT ACTUALLY HAVE NO CONTROL OVER--INFAR VAUNT POSITION AND CONTROL THE ORIENTATION OF THE ANIMAL ITSELF RELATIVE TO THE OLFACTORY ODOR. SO THIS IS A CLOSED SYSTEM WHERE THE HEADING DIRECTION OF THE ANIMAL IS FED BACK TO THE STIMULUS AND DICTATES THROUGH THE ANGLE OF THE ODOR STREAM RELATIVE TO THE FLY. AND IN THIS WAY, THE ANIMAL CAN NOW CONTROL IT'S OLFACTORY IN THE PLUME, AND I THINK THE BEST WAY TO APPRECIATE THIS IS TO SHOW YOU AN EXAMPLE. SO HERE YOU SEE A FLY THAT'S TETHERED TO A PIN AND IT'S WALKING AROUND ON THE ROTATING BALL AND IT IS CONTROLLING THE POSITION OF AN AIR STREAM WHERE THERE'S CLEAN AIR BEING BLOWN THROUGH AND WHAT I HOPE CAN YOU SEE IS THAT BASICALLY PRIOR TO AN OLFACTORY STIMULUS BEHAVIOR, IT DOESN'T AIRY CARE WHERE THE AIR STREAM IS, BUT AS SOON AS IT IT'S INTRODUCED VINEGAR, THE FLY WALKS STRAIGHT UPWIND AND YOU CAN SEE IT'S MORE EFFECTIVE WHEN YOU PLOT OUT THE HEADING OF THE DIRECTION OF THE ANIMAL OVER TIME. AND YOU CAN SEE THAT ONCE THE OLFACTORY STIMULUS PROVIDED TO THE FLY THAT IT WALKS IN A MUCH MORE STRAIGHT MANNER AND ACTUALLY THIS IS QUITE CONTRAST THAT EVEN IF YOU HAVE THE AIR STREAM FLYING DIRECTLY AT THE ANIMAL, AND THERE'S NO SENTENCERY FEEDBACK, THERE'S NO COHERENT BEHAVIORIAL RESPONSE. THE CASE WHERE THE STREAM IS BASICALLY FIXED RELATIVE TO THE POSITION OF THE ANIMAL AND YOU CAN SEE THAT IT CONTINUES TO WALK BASICALLY IN CIRCLES IN THE OLFACTORY STIMULUS. SO WE THINK THAT THIS NOW, THIS TYPE OF PARADIGM ALLOWS TO BE INSIGHT INTO HOW THE POPULATION OF THE NEURONS AND HOW THE WHOLE MUSHROOM BODY ITSELF INVOLVED IN SHAPING OLFACTORY BEHAVIOR, SO GOING FORWARD, WE'RE INTERESTED TO LOOK AT THE DOPA MINERGIC ACTIVITY, DOPA MINERGIC NEURONS HOW THEIR ACTIVITY TRACKS WITH KIND OF SENSORY DRIVEN AND MOTIVATED BEHAVIOR. SO JUST TO CONCLUDE, I WOULD LIKE TO REMIND YOU THAT 1 OF THE THINGS WE START TO THINK ABOUT IS THAT IF YOU THINK INTUITIVELY ABOUT IT, AN ANIMAL'S ABILITY TO RESPOND TO THE SENSORY CUES IN THE ENVIRONMENT, BASED ON SORT OF PAST EXPERIENCE OR EVEN ON CURRENT CONTEXT, WE THINK REALLY HAS FUNDAMENTALLY RELY OFFICE OF DIVERSITY CIRCUIT ARCHITECTURE, 1 IN WHICH THE SAME SENSORY STIMULUS CAN BE PLOTTED INTO ALTERNATIVE STATE AND CONTEXT OF AN ANIMAL. AND WHILE THE MUSHROOM BODY HAS BEEN KNOWN TO BE A NEURAL CENTRAL LOCUST FOR LEARNING IN THE FLY, WE THINK THERE'S INCREASING EVIDENCE OF SUPPORT FROM WORK AND WORK THROUGH OTHER LABS FROM BEHAVIORIAL DATAS, THAT THE MUSHROOM BODY AND THE BEHAVIOR. SO WE THINK THAT DOPA MEAN HAS A ROLE IN THE BODY AND SHAPING LONG-TERM CHANGES IN BEHAVIOR THROUGH LEARNING AND THIS DUAL ROLE PROVIDES A STRIKING PARALYLE TO THE REEL THAT DOPA MEAN PLAYS IN THE MAMMALIAN CENTERS IN THE STRAYAT UMKC WHERE DOPA MINERGIC NEURONS WITHIN THE MAMMALIAN STRIATUM ARE EXPECTED TO ENFORCE LEARNING AND REPRESENTING POSITIVE AND NEGATIVE CUES AND DIRECTIONAL PATTERNS OF ACTIVITY AND REALLY THERE'S AN EMERGING APPRECIATION FOR THE FACT THAT THESE NEURONS ALSO PROVIDE AN ONGOING REPRESENTATION OF KIND OF THE BEHAVIORIAL STATE OF THE ANIMAL AND REALLY VERY NICE WORK FROM DANIEL DON BECK AND MARIE AS WELL AS OTHERS SUGJUDGESTED THAT THE NEURONS IN THE STRIATUM ARE ACTUALLY ACUTELY ACTIVATED BY LOCOMOTION AND RATHER REPRESENTATION OF THE ANIMAL TO MORE DIRECTLY EFFECT MOTOR ACTION. AND SO WE THINK THAT THERE MIGHT BE THIS KIND OF DUAL ROLE FOR DOPA MEAN MAY BE PRESENT--PRESENT SORT OF A CONSERVED FORM OF FLEXIBILITY THAT IS ALLOWED WHERE IT CAN ACTUALLY ACT AT DIFFERENT TIME SCALES TO SHAPE BEHAVIORIAL OUTPUTS SO WITH THAT I WOULD JUST LIKE TO ACKNOWLEDGE AND THANK THE PEOPLE IN MY LAB WHO CARRIED OUT THIS WORK. MUCH OF THE DOPA MINERGIC MODULATION THAT I DESCRIBED TO YOU AND THE CLOSED LOOP BEHAVIOR WAS CARRIED OUT BY MY FIRST STUDENT RAFFI KOHN, AND HE'S DONE A LOT OF WORK LOOKING AT DOMA MINERGIC ACTIVITY IN ANIMALS THAT ARE WALKING ON A TETHERED BALL. AND AN ANNIE HANDLER AND IANESSA AND ANDROGEN RUE ARE LOOKING AT THE CHEMICAL PATHWAYS THAT UNDERLIE DIFFERENT FORMS OF DOPA MINERGIC PLASTICITY AND WE ARE DEDICATED TO OTHER LABS FOR FLY STRAINS AND I WANT TO THANK MY FORCES OF SUPPORT AND THANK YOU FOR THE INI HAVEITATION TO BE HERE AND I WILL BE HAPPY TO ADDRESS ANY QUESTIONS. [ APPLAUSE ] >> THIS IS GREAT, I LIKE THE VIRTUAL REALITY FOR [INDISCERNIBLE]. BUT I'M GLAD YOU BROUGHT UP THE [INDISCERNIBLE]. IS THERE ANY SENSE OF WHETHER THERE ARE THOSE THAT ACTUALLY HAVE SENSORY RESPONSE OR THE SAME 1S THAT ARE ACTIVATED OR THEY SULLY SHOWED SOME [INDISCERNIBLE] DEGREE? >> YOU BRING UP AN INTERESTING SYSTEM THERE THAT THERE MAY BE DIFFERENT POPULATIONS OF DOPA MINERGIC NEURONS THAT ARE ACTIVATED BY REINFORCEMENT EXPERIENCES LIKE SUGAR REWARDS VERSUS MOTION AND 1 THING WE CAN SAY IN THE MUSHROOM BODY IS THESE ARE THE SAME NEURONS THESE ARE THE SAME NEURONS THAT PROVIDE POSITIVE AND NEGATIVE REINFORCEMENT ARE THE NEURONS THAT ARE PROVIDING THIS ONGOING REPRESENTATION OF THE ANIMAL. SO IT'S INTERESTING TO THINK ABOUT HOW THIS MIGHT BE USED EITHER AT DIFFERENT TIME SCALES OR DIFFERENT REGIMES TO EFFECT BEHAVIOR. BUT IT ALSO SUGGESTS THAT THE TRIAT UMKC AND THE MUSHROOM BODIES THERE MAY BE DIFFERENT COMPUTATIONS THAT ARE CARRIED OUT. . >> [INAUDIBLE QUESTION FROM AUDIENCE ] >> GREAT QUESTION ABOUT THE NUMBER OF COMPARTMENTS SO IN THE MUSHROOM BODY THERE ARE 16 COMPARTMENTS TOTAL AND I'VE CHAUFFEUR SHOWN YOU TO LOOK AT 4 OF THEM. ALL OF WHICH ARE INNERIVATED IN THE SIMILAR MANNER BY UNIQUE POPULATIONS OF DOPA MINERGIC NEURONS AND HAVING 1 OR MUSH ROPE BODY OUTPUT NEURONS SO 1 QUESTION WE HAD IS ACTUALLY REALLY WHAT DOES IT MEAN TO HAVE 15 COMPARTMENTS, WHY DO YOU 15 AND NOT 2, YOU HAVE 1 THAT LEADS TO APPROACH AND 1 THAT LEADS TO AVOIDANCE AND 1 IS THAT WE DON'T KNOW. WE DON'T KNOW HOW THE MUSHROOM BODY OUTPUT POPULATION, AS A POPULATION IS REALLY BIASING OLFACTORY BEHAVIOR AND I THINK THAT'S 1 OF THE REASONS WHY WE ARE EXCITED TO ALSO DEVELOP METHODS LIKE A CLOSED SYSTEM WHERE WE CAN LOOK AT THE POPULATION ACTIVITY AND START TO THINK ABOUT HOW THEY ENCODE KIND OF DIFFERENT FACETS OF BEHAVIOR. BUT IT'S TRUE. WE DON'T KNOW--MOST OF THE BODY NEURONS HAVE BEEN LOOKED AT IN THE CONTEXT OF BIASING, ANIMALS TO MOVE FORWARDS AN ODOR OR AWAY FROM IT. ONE POSSIBILITY I COULD IMAGINE, YOU COULD SAY THERE MIGHT BE 15 COMPARTMENTS NOT ONLY BECAUSE YOU WANT MAYBE ONLY 2 TYPES OF BEHAVIORIAL OUTPUT BUT THERE COULD BE MANY DIFFERENT FORMS OF CONTEXT THAT NEED TO BE REPRESENTED AND THAT'S 1 IDEA AND ALL THOSE COMPARTMENTS ARE ACTUALLY FUNCTIONALLY COORDINATED AND THEY MAY REFLECT THE DIFFERENT PATTERNS OF ACTIVITY, UNDER THE DIFFERENT CONTEXTURAL EXPERIENCES. >> [INDISCERNIBLE]. >> YOU RAISE AN INTERESTING POINT WHICH IS INTERESTING DUE TO THE SAME DOPA MINERGIC NEURONS PROVIDE ABOUT INFORMATION ABOUT SUGAR AND CHALK AND REINFORCERS AS WELL AS BEHAVIORIAL STATE OF THE ANIMAL SO SOPHISTICATED I SHOWED THAT WHEN THE ANIMAL IS FLAILING, YOU HAVE TO SEE SIMILAR PATTERNS THAT IS ILLICITTED BY THE SHOCK AND WHEN THE ANIMALS PAUSE, YOU SEE THE PATTERN SIMILAR TOW A SUGAR REWARD AND 1 THING YOU COULD IMAGINE IS ACTUALLY WHEN YOU SHOCK AN ANIMAL IF FLAIL ASKS AND WHEN THE ANIMAL STOPS TO USE ITS PROBUS KUS AND--IT'S SOMETHING WE CAPTAIN ADDRESS BUT BASED ON QUANTITATIVE DIFFERENCES THERE'S AN IMPORTANT CONTRIBUTION OF BOTH BUT THE 1 THING I THINK THE MORE WE LOOK THE MORE WE APPRECIATE IS THAT THE MOTEAR ACTIVITY OF THE ANIMAL AND THE BEHAVIORIAL STATE OF ANIMAL IS A VERY PROMINENT COMPOSSIBLIENT OF HOW THE ACTIVITY OF THE DOPA MINERGIC NEURON SYSTEM SHAPED. >> [INDISCERNIBLE]. >> SO THERE ARE 2 QUESTIONS THERE. ONE IS ABOUT THE QUAWBTITATIVE DIFFERENCES MAYBE IN THE PATTERN OF ACTIVITY ARE SIMILAR UNDER THESE DIFFERENT CIRCUMSTANCES ABOUT SENSORY INFORMATION AND MOTOR? BUT MAYBE THEY'RE QUANTITATIVE DIFFERENCES AND I THINK THERE ARE. IN ORDER TO INDUCE THE MODULATION YOU SEE THAT CHAIRVELGS THE SYNAPTIC SIGNALING BETWEEN THE NEURONS, IT NEEDS TO BE RELATIVELY STRONG SIMULATION AND IT'S NOT COMPLETELY CLEAR, YOU KNOW WHETHER ALL BEHAVIORIAL CHANGES ALL LOCOMOTOR PATTERNING WILL ILLICKITY THE SAME LEVEL OF ACTIVATION AS A SUGAR REWARD, SO IT'S AN INTERESTING DIFFERENCE AND HOW THE MUSHROOM BODY FUNCTIONS AND THE STRENGTH OF DOPA MIN ACTIVATION AND WITHIN THE MUSHROOM BODY, WE SEE THE BEAUTIFUL VERY DISCREET SYNAPTIC DOMAINS THAT ARE DEPENDENCE ON DOMA MEAN AND THEY CORRELATE TO THE ANATOMIC CORRELATION OF THE DOPA MINERGIC NEURONS AND THERE'S BEEN SUGGESTION BY STUDIES THAT THERE ARE SYNAPSES THAT THERE ARE A NUMBER OF KENYON CELL MUSHROOM BODY SYNAPSES THAT ARE ALSO TRIADIC WHERE'S DOPA MEAN ON THIS SAME REGION BUT WE THINK THAT BASICALLY WHETHER'S A SUGGESTION IN THE BRAIN THAT THE DOPA MINE MIGHT HAVE A SPACIALLY DIFFUSE ROLE. AND HERE WE SEE THAT THE VERY, VERY SPACIALLY PRECISE AND PART OF IT IS DUE TO THE KIND OF NATURE OF THE INNOVATION PATTERN WHERE THE DOPA MINE NEURONS HAVE THE RESTRICTED INNOVATION PATTERN BUT WHATEVER HAPPENS, YOU SEE THE FUNCTIONAL MODULATION IS OCCURRING ONLY WITHIN THAT 1 DOMAIN. >> YEAH, I THINK THAT'S A VERY, VERY GOOD QUESTION. IT'S WHAT WE'RE GRAPPLING WITH NOW. WHAT'S THE SIGNAL THAT'S REPRESENTED AND WHAT IS THE UTILITY OF THE ANIMAL IN TERMS OF NAVIGATION AND I CAN TELL YOU WE THINK THAT COULD BE INDEED THE CASE THAT IT MIGHT BE PROVIDING THIS KIND OF ONGOING REPRESENTATION OF WHAT THE ANIMAL IS DOING AND MAYBE, ALLOW THE AN MA THE MUSHROOM BODY TO MAKE THE COMPARISON OF THE ERROR SIGNAL ABOUT WHETHER, YOU KNOW IT'S EXPECTATION OF WHAT IT'S RECEIVING IN TERMS OF SENSORY INFORMATION IS WHAT IT SHOULD HAVE PREDICTED AND THESE ARE SORT OF EXPERIMENTS THAT ARE KIND OF--THEY'RE COMPLEX AND TANGLE BUT IT'S SOMETHING THAT WE'RE INTERESTED IN TRYING TO GO TO AND I THINK IT ALSO HIGHLIGHTS THE IMPORTANCE OF LOOKING AT THIS BRAIN CENTER IN THE CONTEXT OF A STIMULUS NA BEHAVIORIAL PATHWAY GIVES AREA DIME WHERE YOU HAVE BOTH SENSORY AND BEHAVIORIAL SYSTEMS IN FACT, WHERE YOU HAVE BASICALLY THIS IS WHY I THINK THE SYSTEM MUST ALSO BE VERY VALUABLE TO THINK ABOUT THAT. >> [APPLAUSE ]