I AM HARRY AND I AM A ZEBRAFISH GUY, AND IT'S MY PLEASURE TO INTRODUCE LISA STOWERS TO BE OUR SPEAKER TODAY. I ACTUALLY HEARD LISA SPEAK AT THE GLOBAL [INDISCERNIBLE] AND THIS WAS ONE OF THE MOST MEMORABLE MEETINGS I HAVE EVER BEEN TO IS ONE OF THE HIGHLIGHTS WAS LISA'S TALK AND I'M DELIGHTED SHE CAN BE WITHS TODAY. SHE DID HER BACHELOR DEGREE AT UC DAVIS AND WENT TO HARVARD WHERE SHE WORKED FOR HER Ph.D. SHE DID MOLECULAR SIGNALING, CONTROLLING, MECHANISMS OF CYTOSKELETON POLARITY. AT THE END OF HER Ph.D., SHE REALED HOW FASCINATING BEHAVIORIAL NEUROSCIENCE IS, SHE DIDN'T MOVE GEOGRAPHICALLY VERY FAR. SO SHE STAYED IN THE SAME DEPARTMENT BUT SHE COULD NOT HAVE MOVED INTO A AREA OF NEUROSCIENCE SHE SHE JOINED [INDISCERNIBLE] STUDYING SENSORRING MECHANISMS FOR GENETIC BEHAVIOR AND SHE DID SOME UNBELIEVABLE WORK IN THAT LABORATORY AND I THINK HER SCIENCE PAPER FROM HER Ph.D.--SORRY FROM HER POST DOC IS SOMETHING THAT MANY PEOPLE ARE FAMILIAR WITH, AMAZING PAPER WHERE SHE SHOWED THE SIGNALING [INDISCERNIBLE]--SHE THEN GOT FACULTY POSITION AT THE SCRIPS INSTEWS AND ASSOCIATE PROFESSOR IN THE DEPARTMENT OF MOLECULAR NEUROSCIENCE. SHE'S DONE REALLY BEAUTIFUL WORK OVER THE LAST DECADE OR SO LOOKING AT SIGNALING FROM THE NAISAL ORGANS, OLYMPIC FACTORY ORGAN CONTROLLING BEHAVIORS LIKE TUNNEL RECOGNITION, SPECIFIC RECOGNITION, AND SELF-VERSUSS OTHERS, AND ELEGANT, BEAUTIFUL WORK. SHE IS THE SKOALAR AND MAYBE AS IMPORTANTLY HER WORK JUST SPARKED THE IMAGINATION OF THE POPULAR SCIENTIFIC PRESS. SO AFTER A RECENT PAPER, WHERE SHE DEMONSTRATED THAT NAISAL SIGNALING IS ACTUALLY MODULATED DURING THE ESTRISK ASSESSMENTS CYCLE SO THAT FEMALES [INDISCERNIBLE] BY MALES THIS THERE WAS A GREAT ARTICLE THAT SUMMARIZED THE FINDING AS BOY MEETS GIRL, GIRL COMES TO KNOW BOY, BOY LOSES GIRL. SO I THINK IT'S IT IS FACT THAT THE WORK IS INTRINSICALLY SO INTERESTING THAT IT'S REALLY [INDISCERNIBLE]. WE'RE REALLY DELIGHTED TO HAVE HER TODAY. SO THANK YOU. [ APPLAUSE ] >> SO THANK YOU HARRY, THANK YOU FOR THE INVITATION TODAY. I'VE HAD A GREAT MORNING AND IT'S BEEN A PLEASURE AND THAT WAS QUITE AN INTRODUCTION AND WE'LL SEE WHAT I CAN DO TO LIVE UP TO IT. SO I STARTED WITH THIS SLIDE THAT WE STOLE OFF THE WEB BECAUSE IT CAPTURES EVERYTHING THAT INTERESTS ME. SO I'M INTERESTED IN HOW THE SENSORY ENVIRONMENT CAPTURING EVERYTHING, YOU CAN SEE THIS GUY CHASED BY THE CAT, HE'S MAKING A GREAT DECISION, HE'S RUNNING AWAY, SO THAT'S GREAT. BUT WHEN YOU LOOK AT BEHAVIOR AND INDIVIDUAL'S RESPONSE TO THE ENVIRONMENT, WHETHER IT'S MOUSE OR US, YOU FIND THAT NOT EVERYBODY RESPONDS THE SAME WAY TO A GIVEN ENVIRONMENT. THERE'S LOTS OF VARIAB, IT'S INTERESTING AND IT'S ALSO A PROBLEM FROM A NEUROSCIENCE POINT OF VIEW. YOU CAN SEE HERE THAT THIS LITTLE GUY HAS A PIECE OF FOOD IN HIS MOUTH RIGHT, AND IF I WAS THIS MOUSE OR IF YOU WERE TO LOOK AT OTHER MICE, PERHAPS ONCE THEY SENSE THE CAT, THEY WOULD DROP THE FOOD AND RUN BECAUSE ALL OF THEIR ENERGYOT REALLY IMPORTANT SAFETY BEHAVIOR, BUT INSTEAD THIS GUY HAS CHOSEN TO HOLD ON TO THIS, THAT WOULD BE A BEHAVIAL VARIABILITY, SO YOU CAN IMAGINE THAT THERE COULD BE TWO PRIMARY THINGS THAT WOULD MAKE HIM HAVE THIS RESPONSE, EHER HE'S EXPERIENCED THIS FOOD BEFORE AND HE KNOWS IT'S SUPER DELICIOUS, IT'S EXTREMELY HIGH VALUE. THIS FOOD IS SO AMAZING THAT IT'S WORTH GETTING EATEN FOR, RIGHT? SO THAT'S THE ONE THING. EXPERIENCE WILL CHANGE AN INDIVIDUAL'S BEHAVIOR IN A GIVEN ENVIRONMENT AND MAYBE THIS GUY IS JUST STARVING. MAYBE HE HASN'T EATEN IN FOREVER AND SO, THE POSSIBILITY OF NOT HAVING THIS FOOD IS REALLY AS BAD AS NOT BEING AS BEING ATTACKED BY THE CAT SO HE'S WILLING TO TAKE THE RISK AND KEEP THE FOOD, RIGHT? SO YOUR INTERNAL SPACE WILL CHANGE TO THE WAY YOU RESPOND TO A GIVEN ENVIRONMENT. SO WE'RE INTERESTED IN HOW SENSORY INFORMATION IS PROCESSED TO LEAD TO BEHAVIOR AND HOW THINGS LIKE EXPERIENCE AND INTERNAL STATE CAN ALTER THOSE BEHAVIORIAL RESPONSES. SO WE ARE LOOKING AT THOSE BASIC KIND OF MOTIVATED BEHAVIOR IN THE MOUSE AND WE'RE LOOKING AT THINGS LIKE RAGE AND FEAR AS WELL AS ATTRACTIVE BEHAVIOR AND YOU KNOW THESE ARE THE THINGS THAT IN HUGH MANS WE SAY ARE LINKED TO EMOTIONS IN IN THE MOUSE. I'M GOING TO SAY SO I DON'T USE THE WORD EMOTION, ALTHOUGH SOMETIMES I DO QUITE OFTEN, I WILL APOLOGIZE IF I DO, BUT WE'RE JUST--WE'RE REALLY INTERESTED IN THE COMMON ASPECTS OF THESE BEHAVIORS THAT LEAD TO AN INDIVIDUAL TO BE MOTIVATED TO GO TOWARDS SOMETHING OR OR AWAY FROM SOMETHING. HOW DOES IT ASSIGN VALUE AND WHAT THE NEURAL CODE THAT UNDERLIES THAT VALUE. AND SO THIS IS HAPPENING IN THESE--THESE ARE GRATUEITOUS PICTURES. BUT ANIMALS DO ALL OF THESE KINDS OF BEHAVIORS SO YOU MAY BE ABLE TO LOOK AT THESE PICTURES NOT ONLY FOR THE NEXT MOTOR PATTERN BUT THEIR INTERNAL STATE OF WHETHER THEY'RE LIKING SOMETHING, WHETHER IT'S POSITIVE VALENCE OR NEGATIVE VALENCE, RIGHT? SO BECAUSE OF THESE TYPES OF SIMPLE BEHAVIORS ARE HIGHLY CONSERVED ACROSS EVOLUTION, WE IMAGINE IF WE STUDY THEM IN THE MOUSE WE WILL LEARN SOMETHING ABOUT THESE SORTS OF NEURAL CIRCUITS IN GENERAL. NOW IN THE MOUSE ALL OF THESE BEHAVIORS ALTHOUGH THEY'RE INITIATED BY DIFFERENT THINGS IN THESE SORTS OF--SORTS OF IMAGES HERE IN THE MOUSE, WE CAN TRIGGER ALL THESE BEHAVIORS SIMPLY BY OLFACTORY CUES AND THIS WAS A REAL BONUS. SO WHEN WE FIRST STARTED THIS AND THE REASON IS BECAUSE, NORMALLY THESE BEHAVIORS HAVE TO BE TRIGGERED, THEY'RE SOCIAL BEHAVIORS TO A CERTAIN EXTENT BUT THEY HAVE TO BE TRIGGERED BY TWO INDIVIDUALS AND IF YOU TRY TO STUDY THE BRAIN OF THIS ANIMAL, BUT YET YOU HAVE ANOTHER UNPREDICTABLE ANIMAL IN THE ENVIRONMENT, YOU KNOW THAT'S LIKELY TO JUST CAUSE NOISE, IT WILL BE DIFFICULT TO INTERPRET, RIGHT. THIS GUY CAN BE EXTRA CRANKY, THIS GUY CAN BE EXTRA SLEEPY, MAYBE HIS SIGNALS ARE NOT SO GOOD, THAT WILL THROW OFF HOW THE STUDY THE RESPONSE FROM INDIVIDUAL TO INDIVIDUAL. SO THE IDEA OF USING THE MOUSE WITH THE OLFACTORY IS, ONCE LET'S REALLY SIMPLIFY THIS, SO THAT WE WOULD REDUCE THE NOISE AND BE ABLE TO UNDERSTAND JUST THE ASPECTS OF THE NEURAL CODE THAT WE'RE INTERESTED IN. AND SO THE IDEA IS THAT IN THE MOUSE, ALL THESE THINGS CAN BE TRIGGERED BY OLFACTORY CUES, WE CALL IT SPECIALIZED CUES THAT WE REFER TO THEM AS PHEROMONES AND IF WE USE THOSE, THE NEURAL ACTIVITY WOULD HAVE A HIGHER CHANCE OF BEING MORE RELEVANT. SO THE OVERALL CODE THAT WE'RE TRYING TO SOLVE IS SORT OF SHOWN BY THIS SIMPLE CARTOON HERE, RIGHT? SO WE THINK THAT THE SENSORY INFORMATION THAT'S RELEVANT IS GOING GOING TO COME IN AT THE NOSE, SO THERE'S LIGANDS, OLFACTORY SENSORS, AND OLFACTORY SENSORY NEURONS AND AT THIS PART OF THE CODE, WE THINK THE NEURONS ACTIVATED ARE THERE TO TELL THE ANIMAL WHAT'S IN THE ENVIRONMENT. WHAT IS THE SENSORY CUE, WHAT'S THE IDENTITY OF THE CUES IN THE ENVIRONMENT. BUT AS THE INFORMATION MOVES THROUGH THE CIRCUIT, WE IMAGINE THAT THE ANIMAL HAS TO KNOW SEVERAL OTHER FEATURES ABOUT THE WORLD IN ORDER TO DETERMINE WHAT BRIE --BEHAVIOR IT'S GOING TO DO AND SOME OF THOSE INCLUDE THE VALANCE OF THE CUE, WHETHER IT'S THE ANIMAL, GOOD FOR THE ANIMAL OR BAD FOR THE ANIMAL, RIGHT? SO THAT'S SOMETHING THAT THE ANIMAL HAS KNOWN, NOT JUST WHAT IT IS BUT WHETHER IT'S GOOD FOR THEM OR BAD FOR THEM. WE IMAGINE IT'S WAYING ALL THE OTHER SENSORY INFORMATION THAT'S COMING IN, NOT JUST THE ODOR INFORMATION, SEEING IF THAT ALIGNS OR IS IN A DISCREPANCY SO IT'S GOT TO INTEGRATE OTHER SENSORY INFORMATION. WE HAVE TO--THE ANIMAL HAS TO DETERMINE WHAT IT'S INTERNAL STATE IS, WHETHER IT'S HUNGRY OR SCARED, IT'S GOING TO CHANGE ITS DECISION TO RESPOND. SO WHETHER IT'S TIRED, WHETHER IT'S STRESSED, ALL THESE THINGS HAVE TO ALSO BE INTEGRATED THROUGHOUT THE CODE, AND THEN AT SOME POINT WE IMAGINE THAT THERE'S A PLACE IN THE CIRCUIT CALLED A COMMAND CENTER THAT WILL WHALE IN INFORMATION AND DECIDE HOW TO TRIGGER THE APPROPRIATE MOTOR PATTERN TO DO THE RIGHT THING. SO ALL OF THESE THINGS, THE INFORMATION COMES IN AT THE SENSORY CUE, BEING INTEGRATED WITH A LOT OF OTHER OR MODIFIED BY A LOT OF OTHER INFORMATION AND THEN BEHAVIOR IS CHOSEN. SO, FOR MY LAB, WHAT WE'RE REALLY INTERESTED IN, IS SORT OF THIS QUESTION HERE. HOW DOES THE ANIMAL DECIDE WHETHER IT'S GOOD FOR YOU OR BAD FOR YOU AND ALL OF THESE BEHAVIORS THAT WE'VE CHOSEN ARE THINGS THAT ARE STRONGLY GOOD OR STRONGLY BAD FOR THEM AND THAT'S SORT OF THE RATIONAL BEHIND IT ALL. SO WE FIRST STARTED THERE WAS A PLAN, WE WERE GOING TO GET TO SORT OF INTERNAL VALANCE TYPE OF NEURAL CODING BUT THE PROBLEM WAS, WHEN I FIRST STARTED MY LAB, WE KNEW THAT ANIMALS MICE EMITTED QUEUES THAT MADE THEM DO THESE TYPES OF BEHAVIORS I'VE SHOWN YOU BUT NONE OF THEM HAD EVER BEEN PURIFIED OR IDENTIFIED AND SO, WE DIDN'T--WE HAD SPENT THE LAST MANY YEARS LOOKING FOR THESE CUES IN THE ENVIRONMENT IN ORDER TO DO THIS LITTLE TRICK AND SO WHAT I'M GOING TO FIRST SHOW SURVEYS JUST A COUPLE OF SHORT STORIES ABOUT WHAT THESE CUES ARE, HOW WE FOUND THEM, WHAT THEY CAN DO SO YOU CAN SEE THE POWER OF OLFACTORY SYSTEM TO DRIVE THESE SORTS OF BEHAVIORS. AND THE FIRST ONE I WILL TELL YOU ABOUT IS WORK WE DID TO FIND THE SORT OF INNATE FEAR CUE. AND LAB MICE ARE SUPER COOL SO EVEN THOUGH THEY'VE BEEN ISOLATED FROM PREDATORS FOR HUNDREDS OF GENERATIONS. WE GET OUR MICE FROM JACKSON LABS AND THEY HAVE BEEN THERE SINCE IT IS 1930S AND NONE OF THESE HAVE EXPERIENCED PREDATORS, THE GRAND PARENT VS TOLD THEM ABOUT PREDATOR YOU, THEY'RE NAIVE TO THIS BUT IF I PUT A COTTON BALL AND I ARE UBIQUITINNATION IT SO IT JUST HAS THE ODOR, OF A CAT OR A PREDATOR, THEY WILL AVOID THAT COTTON BOWL. SO THAT'S SHORT IN A CRUDE AVOIDANCE ASSAY. WE HAVE THEM IN A CAGE HERE, WE HAVE A COTTON BALL THAT'S NEUTRAL OR THE SMELL OF THE CAT ON IT AND IT'S ALL FILMED UNDER I. R. LIGHT SO IT'S IN THE DARK. WE WANT TO FIND IT. SO THERE'S AREA ONE, AND TWO, AND THESE MICE ARE IN THE CAGE ALL DAY LONG, THEY GET BORED SO IF YOU PUT ANYTHING IN THEIR CAGE THAT'S NOT SCARY, THEY'RE SUPER EXCITED ABOUT IT. SO IF WE PUT THIS GUY IN, IF WE PUT IN THE COTTON BALL, 20 OR 30 MINUTES OUT OF AN ASSAY, COTTON BALL, SUPER EXCITED BUT VERY LITTLE TIME IN AREA TWO, BUT IF WE PUT THE ODOR OF THE CAT ON THE COTTON BALL, IT DOESN'T CARE IT'S SOMETHING NEW, IT WILL AVOID IT THE WHOLE TIME, RIGHT? SO THIS TELLS US THAT THERE FROM'S AN INNATE RESPONSE TO THIS, THAT IT NEVER EXPERIENCED BEFORE, IT ALSO DOES A THING CALLED RISK ASSESSMENT AND IT GETS ON THE TIPY TOES AND SORT OF INVESTIGATES THE ENVIRONMENT CAUTIOUSLY, APPEARING AND THEN THE LEVELS IN THE STRESS HORMONE PRECURSOR, IT GOES WAY UP THROUGH THE ROOF, SO THESE THREE THINGS TOGETHER ARE SORT OF THIS RESPONSE THAT WE CAN SEE JUST THE ODOR OF CATS AND WE WERE VTED IN THIS. SO THE OLFACTORY SYSTEM IN THE MOUSE IS LOCATED HERE. AND GREAT PICTURE THAT I GOT FROM TOM BOZZA, THIS IS THE OLYMPIC PACT WE RECEPTORS AND THEY PROJECT INTO THE BRAIN, THIS IS THE FIRST RELAY INTO THE BRAIN, THE OLFACTORY BULB. IF WE TURN IT HERE, THIS IS THE RECEPTORS IN BLUE, THIS IS THE AREA BEFORE THE MAIN OLFACTORY SYSTEM DETECTING SMELL LIKE WE DO, SO THE SMELL OF COFFEE OR PIZZA, BUT THERE'S THESE SORT OF OTHER LITTLE ACCESSORY OLFACTORY ORGANS OR REGIONS IN THE MOUSE NODES THAT WE DON'T HAVE AND ONE OF THEM IS THE VOMERONAISAL ORGAN AND WE THOUGHT IT WAS DOING SOMETHING SPECIAL AND IT WAS LIKELY TO BE THE SAME THAT WAS HARD WIRED TO DETECT THESE PHEROMONE CUES. AND THIS IS LONG THOUGHT TO BE INVOLVED IN DETECTING PHEROMONES AND THIS IS THOUGHT TO BE DETECTING THE ODORS. WE KNOW THAT THESE PHEROMONES AS WELL BUT WE'RE INTERESTED WHEN WE WERE STARTING THIS WORK TO DETERMINE WHICH ORGAN, WHICH SENSORY NEURONS WAS THE STARTING POINT OF THE SENSORY INFORMATION WAS, THAT WE COULD DO. AND SO WE COULD DO THAT BY OBLATING THE FUNCTION OF THE VOMERONAISAL SENTENCE, AND THAT AND SO, WHETHER--SO WHAT WE USE, GAVE THAT TWO CHOICES, SO WE DID IT WITH THE COTTON BALLS AS I SHOWED YOU BEFORE, RATS ARE ALSO PREDATORS OF MICE AS WELL AS SNAKE SKIN. AND IN ALL THREE CASES, THE MICE AVOIDED THEM, THE WILD-TYPE MICE AVOIDED THEM AND PERFORMED RISK ASSESSMENT BUT ALL THESE OTHER SENSORY SYSTEMS WERE FUNCTIONING, THEY WERE UNABLE TO OVOID THESE ANIMALS AND THEN HERE, JUDGE OUST TO SHOW YOU, I DON'T HAVE THE MUTE ANT INFORMATION HERE BUT THE STRESS RESPONSE, YOU KNOW YOU HAVE VERY LITTLE ACTH HORMONE ACTIVITY IN THE CONTROL ODORIZED COTTON BALL, BUT THE CAT ODOR GIVES THAT VERY STRONG SURGE IN THE STRESS HORMONE, THAT'S LIKE A STRONG 30 MINUTE RESTRAINT. SO IT'S A VERY POWERFUL BEHAVIORIAL RESPONSE THAT WE'RE GETTING HERE AND IT ALL GOES AWAY IN THESE MUSEUM AT THAT POINT ANIMALS. AND WE COULD LOOK AT THE FIRST RELAY IN THE BRAIN, JUST BY CFOS, WHICH IS NEURONAL MARKER THAT AN INDICATOR OF THE NEURONAL ACTIVITY AND YOU CAN SEE HERE BY THE YELLOW CPH OS,--WHY DON'T WE JUST FOCUS ON THESE TWO LANES HERE BECAUSE THESE ARE LOWER MAGNIFICATION AND DIFFICULT TO SEE. SO IN THE CONTROL ANIMAL, WE HAVE VERY LITTLE NEURAL ACTIVATION BUT IF WE GIVE THEM ANYONE OF THESE PREDATOR ODORS WE SEE A STRONG INCREASE SUGGESTING THESE NEURONS WERE ACTIVE BUT IN THE SENSORY MUTE APTS THAT DON'T DO THE BEHAVIOR, WE DON'T SEE THAT INFORMATION BEING PASSED ON TO THE BRAIN. SO TOGETHER THAT TELLS US THAT THIS IS A SENSORY SYSTEM, DETECTING THEE PHEROMONES AND THIS IS A STARTING PLACE FOR OUR DOWN STREAM BEHAVIOR. AND JUST BEFORE I GO ON, WE WERE CURIOUS BECAUSE AS I TOLD YOU BEFORE, THE MICE IN THESE CAGES ARE BORED AND THEY'RE NOT DOING MEANINGFUL BEHAVIOR SO HERE WE ARE FORCING THEM TO INTERACT WITH THIS COTTON BALL AND WE'RE SEEING AN AVOIDANCE RESPONSE, SO IN THE WILD, WE'RE CURIOUS TO ASK WHETHER THE NOSE OR SENSE OF SMELL IS IMPORTANT IN GENERATING THESE BEHAVIORS BUT THE MOUSE HAS A LOT OF OTHER SENSORY INFORMATION TO BE WORKING WITH AND WHAT WAS THE RELATIVE OVERALL CONTRIBUTION OF THE OLFACTORY SYSTEM. SO WHAT WE DID WAS WE TOOK THIS--WE TOOK MICE IN A LARGER ARENA WITH THE PREDATOR THAT WAS ANESTHETIZED AND THE MOUSE COULD WALK IN AND OUT BETWEEN THE STATE'S HIDING BOX AND THE PREDATOR. AND SO WE ASKED HOW DOES THE BEHAVIOR DIFFER BETWEEN ANIMALS THAT ARE WILD-TYPE AND CAN USE ALL DIFFERENT INFORMATION INCLUDING THAT FROM THE DNL FROM THOSE THAT WERE MISSING THIS ACTIVITY, THOSE TRIPS THERE. SO--[INDISCERNIBLE]--SHOWN HERE, I APOLOGIZE, THIS SLIDE WAS--WE SET IT UP FAST SO YOU COULD GET A LONGER SENSE OF THE BEHAVIOR BUT WE MISSED SOME DETAILS. THIS IS ALL DONE IN I. R. IN THIS THE DARK, THIS IS A LITTLE DOOR, THE RAT, THE TAIL IS HERE AND THE WILD-TYPE ANIMAL IS DARTING IN AND OUT, HE'S SPEPPEDDING MORE TIME SORT OF THAL SIDE OF THE ARENA AND ESPECIALENTIALLY IN THE BOX AND CLOSE TO THIS BIG SCARY RAT. AND IF I WAS TO SLOW IT DOWN, WHAT YOU'RE MISSING IN THE SPED UP VIDEO IS THE RISK ASSESSMENT BEHAVIOR, WHEN HE GOES OUT, HE'S ON TIPY TOE AND HE'S UNDER HIGH ALERT. BUT IF YOU LOOK AT CONTRAST TO THE MUTANT ANIMALS. THIS RAT IS BREATHING, HE'S SNEAKY, SO GUY'S MAININOSE IS WORKING BUT THIS GUY IS MUCH MORE CURIOUS, IF I WAS JUST TO LOOK DOWN, YOU WOULD SEE HE'S REALLY RELAXED AND SPEPPEDDINGAIT GREAT AMOUNT OF TIME WITH THIS ANIMAL. THIS ANIMAL WAS WARM AND THIS ROOM WAS COLD AND WE ACTUALLY HAD AN ANIMAL THAT COZIED UP AND FELL ASLEEP NEXT TO THE RAT. [LAUGHTER] SO OVERALL IT TELLS US THAT THIS SENSORY ACTION IS IMPORTANT, IT'S THE INFORMATION THAT'S TRIGGERS INNATE BEHAVIOR, IF THE ANIMAL WAS TO WAKE UP EVEN THE MUTANT ANIMAL WOULD RUN AWAY AND SHE WOULD WOULD HAVE THE ASSOCIATED RESPONSE LATER. BUT FOR THIS INNATE BEHAVIOR WE THINK THIS CUE IS CRITICALLY IMPORTANT. WE DID QUANTIFY THE DATA HERE. OKAY, SO, WE WENT TO FIND THE CUE THAT WAS IN THE ODOR, SO WE COULD GO AHEAD AND HAVE OUR LIMPLIFED ENVIRONMENT AND IT TURNS OUT IT'S HARD TO FRACTIONATE STUFF FROM THE COTTON SWAP OF THE CAT SO WE STARTED WITH THE RAT URINE BECAUSE WE COULD GET A LOT OF RAT URINE NASALLY AND WE BROKE IT UP INTO THINGS THAT ARE BIG, HIGH WEIGHT MOLECULAR FRACTION AND THINGS THAT ARE SMALLER BI THE BIOCHEMICAL FACTION AND ALL OF THE BEHAVIOR GENERATING INFORMATION WAS IN THE HIGH MOLECULAR WEIGHT FRACTION BOTH HERE FOR AVOIDANCE AND THE RISK ASSESSMENT. IF YOU WERE TO COME UP CLOSE, I DON'T KNOW IF YOU CAN SEE, THERE'S STILL NEUROACTIVITY THAT'S BEING GENERATED IN THE ORGAN BY THE MOLECULAR WEIGHT AND THAT'S NOT WHAT'S INTERESTING, WE KNOW IT'S ACTIVATING THOSE NEURONS IN THE MAIN OLFACTORY SYSTEM. THAT'S THE WHOLE POINT OF THIS, WE WANT TO GET RID OF THIS BACKGROUND INFORMATION, AND YOU CAN SEE THAT THE ACTIVITY REAL LIE NICELY ACTIVATES THESE CIRCUITS SO THERE'S STUFF IN THERE BY THE SENSORY NODES SO WE COULD GO,A HEAD AND FRACTIONATE THAT BY IT AND WHETHER WE USE THE FPLC FRACTION, WE SAW THE PEAKS IN THERE AND ONE OF THEM IS THE SMALL NEUROPROTEIN, PROTEIN, THAT'S CALLED MUP IN THE RAT. WE MADE IT BIOCHEMICALLY, IT'S NEVER SEEN A RAT OR ANY OTHER PREDATOR BEFORE, SO WHETHER WE USE THAT INNATE FRACTION OR THE SYNTHETIC PROTEIN WE FIND IT'S SUFFICIENT TO GENERATE THE BEHAVIOR WE SEE. THE AVOIDANCE, RISK ASSESSMENT AND STRONG INCREASE IN THE STRESS PHEROMONE. SO IN OUR MINDS THERE MAY BE OTHER CUES BUT THIS IS DEFINITELY A RELATIVE, THIS IS THE CHI RAMOAN, THIS IS THE SPECIAL UIT'S FRACTIONATED AND WE ACTIVATE THE NEUROCIRCUIT AND WE GET THE BEHAVIOR THAT'S ALWAYS PREDICTABLE. OKAY, SO, FOR THE INTEREST OF SOME INFORMATION I'M GOING TO TELL YOU LATER, I WILL TELL YOU ONE MORE STORY SORT OF LIKE THIS BUT WE FOUND A DIFFERENT KIND OF LIGAND EARLIER. AND THIS WAS OUR SEARCH FOR THE RAGE CUE. SO WE THINK IT'S VERY SIMILAR AND IT'S ACTIVATING A NEGATIVE VALENT CIRCUIT BUT YET IT'S A WHOLE DIFFERENT SENSORY DETECTION, SO WAGE BEHAVIOR IS VERY COMMON AMONGST--ACROSS EVOLUTION. THIS BEHAVIOR WE'RE LOOKING AT IN PARTICULAR IS A MALE-MALE TERRITORIAL RAGE, SO MALES WILL FIGHT EACH OTHER TO KEEP TERRITORY OR GAIN RESOURCES SUCH AS FEMALES AND WE KNOW FOR THIS SORTS OF BEHAVIOR, IT'S PRIMARILY IN THE MALES AND FEMALES DON'T DO IT AND IT'S MOSTLY ON THE PRODUCTION OF TESTOSTERONE. SO FOR THIS WE WILL TAKE A RESIDENT AND PUT THEM THEM IN THE CAGE FOR THEMSELVES AND WE THINK OF THAT AS IT'S TERRITORY AND IF WE PUT ANOTHER ADULT MALE INTRUDER INTO THE CAGE. HE WILL BITE HIM AND IF WE PUT A FEMALE IN HE WON'T FIGHT HER, AND IT WE PUT A JUVENILE IN, IT WON'T FIGHT IT AND THE DIFFERENT BETWEEN THE ADULT AND THE JUVENILE IS THE ABILITY TO MAKE TESTOSTERONE, SO CASTRATED MAILS WON'T MAKE IT. SO IT'S IMPORTANT FOR MAKING THOSE CUES THAT ARE COMING OUT IN THE ENVIRONMENT BUT THEY'RE ALSO IMPORTANT NOT JUST FOR MAKING THOSE PHEROMONES BUT FOR BEING ABLE TO RESPOND TO THEM BECAUSE THIS CASTRATED MALE IS NONAGGRESSIVE EVEN IF HE'S ATTACKED HE WON'T FIGHT BACK, THIS--UNLIKE THE SIMPLIFICATION THAT WE WERE ABLE TO ACHIEVE, IT TURNS OUT WITH RAGE BEHAVIOR, THE MICE WON'T FIGHT THE COTTON BALL. THEY REALLY NEED ANOTHER MOUSE TO DETRACT THE TARGETS TOO. SO THERE'S ANOTHER SENSORS THAT ARE IMPORTANT TO THE OLFACTORY CUE. BUT WE CAN TAKE THE CASTRATED MALE AS OUR TARGET AND HE WON'T EVOKE ANY AGGRESSION SO ANY AGGRESSION COMES FROM OUR INTRUDER AND WE CAN PAINT URINE ON HIS BACK AND NOW HE'LL FIGHT HIM AND WHEN WE DO THAT, THIS IS THE BEHAVIOR, SO OVER 10 MINUTES INTO THE BEHAVIOR, AND I DON'T KNOW 38 MICE HERE, WE PUT A LITTLE MARK ANYTIME THERE'S AGGRESSION WHETHER THEY'RE KICKING OR BITING AND YOU CAN SEE WITH THE CONTROL, THERE'S VERY LITTLE BACKGROUND. SOME OF THEM ARE MORE CRANKY BUT THERE'S SOME AGGRESSION, BUT IF WE PARTICIPATE IN A TRIAL THEM IT GOES WAY UP BUT ALL THE OTHER SENSORY SYSTEMS ARE INTACT, THAT BEHAVIOR COMPLETELY GOES AWAY. THIS IS LIKE THE CRAZIEST THING EVER. THESE GUYS DON'T FIGHT AT ALL. THEY'RE NOT FIGHTING OCCASIONAMY, THEY'RE NOT KINDA CRANKY, THEY JUST DON'T FIGHT. SO WE DID THE SAME THING WHERE WE BIOCHEMICALLY FRACTIONATED AND WE LOOK FOR THINGS THAT ACTIVATED THAT INITIATED THE BEHAVIOR AND WERE DETECTED BY SENSORY NEURONS AND WE WERE ABLE TO P AS WELL. AND SO THAT'S SHOWN HERE. SO ON THE LEFT IS A--IS A RESIDENT MOUSE AND THIS IS THE INTRUDER AND YOU CAN SEE HE DOESN'T CARE. SO HE'S RELAXED, TAIL'S RELAXED AND IN THIS ENVIRONMENT AND COULD CARELESS. BUT IF WE TAKE THESE SAME TWO ANIMALS AND PAINT URINE ON THIS ONE, A FEW MINUTES LATER YOU CAN SEE THIS IS FIVE OR 10 MINUTES ASSAY FOR BOTH, YOU CAN SEE HE'S UPSITE ABOUT THIS MOUSE IN HERE AND THE REAL DIFFERENCE IS JUST THE OLFACTORY CUE, SO HE'S--YOU KNOW YOU CAN SEE HE'S STALE RATTLING AND FIGHTING AND IT'S A REALLY STRONG AGGRESSION AND THIS GUY, HE'S JUST DEFENSIVE, HE DOES NOT--HE'S NOT INITIATING ANY OF THIS TO ESCALATE IT. SO THAT'S THE POWER OF THESE TWO CUES THAT WE FOUND. WE'VE BEEN ABLE TO FIND THESE CUES AND THE IDEA IS NOW TO WORK WITH THEM FROM THE PERIPHERY INTO THE BRAIN TO BE ABLE TO FIND THE NEUROCOMPUTATIONS TO GENERATE THE MOTIVATIONAL BEHAVIOR. SO WE'VE BEEN GEARING UP TO DO THIS, GENERATING MICE AND STARTING THIS STUDY AND IT TURNS OUT THAT THE THINGS ON THE BRAIN ARE GOING TO BE A LITTLE MORE COMPLICATED THAN I WAS HOPING FOR AND ONE OF THE PROBLEMS THAT I SHOWED YOU IS THE CARTOON AT THE BEGINNING ISN'T THE WHOLE PUZZLE. ONCE WE GET INTO THE BRAIN AND THE AMYGDALA, IT'S 6-DEGREES OF SEPARATION TO THE REST OF THE BRAIN. EVERYBODY'S TALKIN EACH OTHER. AND THIS CARTOON, THIS IS SORT OF WHAT EVERYBODY IN THE OLFACTORY FEELS IS WORKING OFF AND EVERYBODY'S FOCUSING HERE BUT THESE PARTS ARE REALLY NOT BEING APPRECIATED. WHAT'S HAPPENING IN THE AREAS THAT WE'RE NOT LOOKING AT. AND WHAT WE WOULD REALLY LIKE TO DO EVEN THOUGH WE THINK THE MOUSE IS A PRETTY SIMPLE SYSTEM, WE LIKE TO HAVE AN EVEN SIMPLER SYSTEM BECAUSE WORKING THE FLY LATELY HAS BEEN REMARKABLE IN FINDING COMPLETE CIRCUITS ONCE THEY HAVE THE COMPLETE CIRCUITS IT'S BEEN INFORMATIVE TO ASSIGN FUNCTION TO PARTICULARLY PIECES TO THE BRAIN IN A LOGICAL MANNER. WE'RE VERY JEALOUS OF THIS SO WE WOULD LIKE TO TURN THE MOUSE INTO A FLY AND HAVE THE WHOLE CIRCUIT, THE WHOLE PIECE SO WE'RE NOT BLINDLY TOUCHING A PIECE OF THE ELEPHANT, WE WANT TO KNOW THE WHOLE THING SO WE CAN START TO UNDERSTAND THE INDIVIDUAL FUNCTIONS. AND WE'RE GRABBLING WITH THIS A FEW YEARS AGO, I HAD A STUDENT IN MY LAB AND HE'S LIKE, WE CAN DO THIS, WE NEED A MORE SIMPLE BEHAVIOR, MORE SIMPLE OUTPUT BEHAVIOR AND SO, JASON'S IDEA IS--IT WAS A LITTLE DISTURBING TO ME AT FIRST IN ITS SIMPLICITY BUT IT'S VERY ELEGANT AND I WANT TO SHARE WITH YOU. SO MICE USE OLFACTORY CUES TO INITIATE A MOTIVATED PATTERN OF URINE MARKINGS. SO IF THEY SMELL CERTAIN CUES AND MOSTLY IF THEY SMELL A CUE FROM A FEMALE, THEY WANT TO ADVERTISE THAT THEY'RE STRONG ENOUGH AND THEY'RE NOT WORRY BODY OTHER MALES OR PREDATORS FINDING THEM AND THEY JUST COVER THE GROUND WITH URINE SPOTS, THEY MARK, THE URINE SPOTS ARE ATTRACTED TO FEMALES, THE FEMALES COME. SO THIS IS BEHAVIOR THAT JASON WANTED TO USE. SO WE DID THIS UNDER UV BECAUSE THE URINE WILL BE FLUORESCENT. YOU CAN SEE HE STARTS PEEING, HE'S WALKING AROUND, HE WILL SMELL IT AGAIN AND RELOAD AND NOW HE'S DRIBBLING MORE. SO THIS ONE IS IN REALTIME, THIS IS NOT SPED UP AND OVER THE COURSE OF 10 MINUTES WE CAN GET TWO HELPED LITTLE DOTS BASICALLY, SO THIS IS BEHAVIOR. HE IS ROUGH ATOM LOADING AGAIN. WE LOVE THIS. AND THE COOL THING ABOUT THIS IS THE TARGET ISN'T SOMETHING COMPLEX, LIKE RAGE BEHAVIOR WHICH HAS A COMPLICATED MUSCLE OUTPUT THAT'S VARIABLE, THIS IS JUST THE BLADDER SO WE WANT TO SEE, CAN WE FIND A CIRCUIT THAT GOES FROM THE ODOR TO THE NOSE FROM THE BEHAVIOR, THE BLADDER, THE MUSCLE OUTFIT, RIGHT? SO, JASON STARTED DOING BASIC TRACING STUDIES BECAUSE THIS CIRCUIT ALTHOUGH IT'S BEEN WELL STUDIED IN THE RAT AND THE CAT BECAUSE OF MALE INCONTINENCE SO WE KNOW A BIT ABOUT THE CIRCUIT IN THOSE MODEL SYSTEMS WE BEDN'T FIND IT DESCRIBED AT ALL IN THE MOUSE SO WE WANTED TO SEE IF WE CAN TRACE THE CIRCUIT AND THEN STUDY IT. SO JASON DID SOME RETROGRADE LABELING FROM THE BLADDER, WENT THROUGH THE SPINAL CORD AND INTO THE BRAIN SYSTEM AND ENDED UP BEING INTO THIS REGION THAT HAD BEEN DESCRIBED IN THE RAT AND THE CAT CALLED THE PONTINE [INDISCERNIBLE]. AND SO SHE WANTED TO KNOW IF SHE WAS ON THE RIGHT TRACK, WHETHER THAT HAD ANYTHING TO DO WITH PEEING AND HE PUT ARCH T LIGHT SENSITIVE CHANNEL THAT'S GOING TO SILENCE, NEURONAL ACTIVITY BILATERALLY INTO THE PMC. SO WE WILL START WITH OUR CONTROL SPOT, FLUORESCES, THE MICE DON'T PEE, WITH THE LIGHT ON SO THAT THE PMC IS NOT ACTIVE. AND WHEN WE DO THAT, SO THE MOUSE--THE LIGHT'S ON, NOTHING'S HAPPENING. NOT REALLY MOVING MUCH YET BUT HE WILL GET GOING IN A MINUTE. SO WE PUT DOWN THE FEMALE URINE AND NOW HE'S COMING OUT AND GETTING A BIG NOSE FULL OF IT AND UNLIKE BEFORE, WE HAVE TWO LITTLE TINY SPRITSS THERE, HE'S REALLY GETTING--SMELLING MORE, SRITS THERE, BUT NOT MUCH, RIGHT? SHOW THEN HE GOES BACK. THE TURN OFF THE LIGHT AND WHAT YOU CAN'T SEE IS THERE'S A BIG POOL OF URINE AND HE'S PEEING ALL OVER THE PLACE NOW AND NOW, MAYBE HE HASN'T REALLY RELOADED YET, RIGHT? SO THIS IS EXCITING TO US, THAT TRACING IS RIGHT, WE'RE ON THE RIGHT TRACK FOR THE SENSORY CIRCUIT. THAT THE PMC IS INVOLVED AND THAT IT SEEMS LIKE THE SENSORY INFORMATION WAS KIND OF GETTING IN BECAUSE THE LATENCY TO PEE WITHOUT SMELLING WAS REALLY FAST SO MAYBE [INDISCERNIBLE]. SO HE DID SOME LABELS FROM THAT AND IF HE BACK LABELS HE GETS THE BMFT AND THE P. O. A. AND INTERIOR GRADE, AND VERY LITTLE LABELING OTHER PLACES AND THERE ARE SOME AREAS THAT HAVE MORE THAT WE'RE INTERESTED IN BUT MOSTLY WE'RE GETTING STRONG ONES THERE AND WE CAN RECIPROCALLY AND LOCATE IT BACK TO THE PMCs AND WE'RE CONFIDENT FOR THE APPROACH FROM THAT HE'S BEEN ABLE TO GET THIS MUCH OF THE UTR IN A SHORT PERIOD OF TIME REALLY AND WE KNOW THAT THE SENSORY INFORMATION IS COMING IN HERE AND IT'S OLFACTORY INFORMATION AND IT'S REALLY ONLY A COUPLE WAYS TO GET FROM HERE TO HERE SO WE THINK WE'RE VERY CLOSE TO GETTING THE WHOLE PARTS LIST. AND WE'RE SUPER EXCITED ABOUT THIS BECAUSE THIS BEHAVIOR NOT ONLY ARE THE MICE SO WE THINK WE CAN GET THE PARTS LIST AND BE LIKE THE FLY, SO STUDYING IT WILL BE HARDER BUT AT LEAST WE WILL HAVE IT SO WE CAN START TO TEST THE MODEL. IS THE INFORMATION COME BEING IN AS A SENSORY CUE, CAN WE MANIPULATE IT. THE THIS BEHAVIOR WE CAN ADD A PREDATOR ODOR TO IT AND THE MOUSE WON'T PEE TO THE FEMALE URINE, HE WON'T MARK ANYMORE, SO THERE'S DECISION MAKING IN THE CIRCUITS AND THIS IS DISTRACTING FROM THE SIMPLE CIRCUIT AND SORT OF LEARN THE RULES OF THIS OVERALL INFORMATION PROCESSING AND THEN APPLY IT TO MORE COMPLEX CIRCUIT. SO IN THE LAST BIT OF MY TALK, I WILL TELL YOU ABOUT A PROBLEM WE'VE BEEN THINKING ABOUT FOR A REALLY LONG TIME. IT STARTED WITH THAT RAGE CUE I SHOWED YOU A FEW MINUTES AGO, WHERE THE TWO MICE FIGHT AND THAT IS IN ALL THESE SYSTEMS, AND IN THE MOUSE SYSTEM, THAT CUE THAT WE PURIFIED, WE PURIFIED FROM OTHER MALES URINE. SO MAILS ARE MAKING A CUE THAT MAKES OTHER GUYS FIGHT THEM WHICH, YOU I'M A FEMALE BUT I THINK THAT'S RIDICULOUS, WHY WOULD YOU MAKE--IT'S GREAT TO FIGHT, I'M NOT AGAINST VIOLENCE BUT I'M--I'M ALL FOR--WHY NOT DO IT STEALTHILY, WHY MAKE THE CUE THAT SAYS COME FIGHT ME. FIGHT ME, RIGHT? SO THIS HAS PUZZLED US FOR A LONG TIME AND IT TURNS OUT IN THE LAB, WAS LOOKING AT THESE CUES FROM A DIFFERENT ANGLE AND SHE GOT TO THE REAL HEART OF IT. THIS SAME CUE IS NOT TO MAKE GUYS FIGHT THEM, IT'S REAL PURPOSE IS TO ATTRACT FEMALES. FEMALES LOVE THIS CUE. OKAY? SO THE MALES MAKE THIS CUE, AND THE FEMALES LOVE IT AND THAT BENEFIT FAR OUTWEIGHS THAT THE FEW GUYS ARE GOING TO BOTHER YOU AND FIGHT YOU. THESE ARE CONFIDENT EMITTERS SO WE LOVE THIS PROBLEM BECAUSE THIS IS THE SAME SENSORY AND IT'S GOING IN ONE BRAIN AND MAKING NEGATIVE VALANCE AND GOING IN THIS OTHER BRAIN AND GOING IN THE POSITIVE VALENCE AND THESE ARE WHAT WE'VE BEEN SET UP TO USE AND NOW WE HAVE IT IN ONE MOLECULE AND WE'RE SUPER HAPPY ABOUT THAT AND WE WANT TO--WE IMAGINE NATHE INFORMATION WILL BE PROCESSED VERY SIMILARLY AT THE PERIPHERY AND AS IT GOES THROUGH THE BRAIN, AT SOME PLACE THAT THE ACTIVITY THAT ENCODING THE EMOTION OR THE VALENCE WILL BE DIVERTED BETWEEN THE MALE AND FEMALE BRAIN AND THAT'S WHAT WE'RE INTERESTED IN FINDING. WHERE DOES THAT PATTERN OF NEURAL ACTIVITY DIVERGE AND WE'RE STARTING TO GET INTO THIS AND TURNS OUT THERE'S DIFFERENCES BETWEEN THE MALES AND FEMALESICIDES THE IMMEDIATE BEHAVIOR, AND YOU KNOW THESE GUYS GROW UP IN CAGES, YOU KNOW THEY'RE ISOLATED FROM FEMALES AND THEY'RE DEVELOPMENTALLY DIFFERENT AND SO BEING ABLE TO SAY THAT AND THEY'RE ALL--THIS SENSORY--THIS SENSORY ACTIVITY DOES SOAK ALL THE WAY THROUGH ON BOTH MALES AND FEMALES SO THESE TO SAY THESE ARE THE NEURONS THAT ARE CONTRIBUTING TO VALENCE, VERSES OTHER DIFFERENCES IN THE FEMALES IS ACTUALLY, IT'S QUITE DIFFICULT. OKAY? SO I'LL JUST--I'LL JUST GO WITH THAT AND SO, ANOTHER FABULOUS POST DOC JOIN THE LAB AND THEY SAID, WELL, THIS WOULD BE EASIER IF WE COULD LOOK AT IT IN THE SAME BRAIN WITHOUT LOOKING AT THIS DISCIPLINARY MORPHISM PROBLEM, IN DIFFERENT BRAINS AND DEVELOPMENTAL HISTORY AND SO SHE DECIDED TO ASK THE SAME QUESTION AND TWEAK IT AND INSTEAD OF LOOKING AT DEFENSES BETWEEN MALES AND FEMALES IN BEHAVIOR, SHE WANTED TO LOOK AT THE DIFFERENCES IN FEMALES. SO FEMALES, FEMALE MICE, NOBODY USES THEM IN MY FIELD BECAUSE THEY'RE CONFUSING. FIELD FUNCTIONS MALE MICE, YOU PUT THEM AND ONE DAY THEY'LL DO A BEHAVIOR AND THE NEXT DAY THEY WON'T AND WE THINK IT'S ALL ATTRIBUTED TO THE OFULATIONATION CYCLE AND THAT'S USUALLY A BIG PROBLEM BUT IN THIS SANDIPPA'S MIND THIS WAS A BEHAVIOR BASED ON THE CHANGES IN THE DIFFERENT FEMALE SEX HORMONES. SO AS MOST OF YOU KNOW, THE OVULATION CYCLE IN MICE IS ESTRICE, AND THERE'S PHYSIOLOGY CHANGES AND CHANGES IN BEHAVIOR IN THE FEMALE SO WE WANT TO ASK DOES THIS OLFACTORY CUE THAT PROMOTES ATTRACTION, DOES IT CHANGE--IS THIS A CUE WE COULD USE TO STUDY THESE DIFFERENT CHANGES AND BEHAVIORS. AND SO, WHEN JANE'S GROUP FOUND THIS ATTRACTION CUE, THEY WERE A GOOD LAB AND THEY ONLY STUDIED IN THIS FEMALES IN ESTRICE, AND WE ALSO LOOKED TO SEE IF EVOKES ATTRACTION DURING DISCIPLINARY-ESTRISE, ANYTHING ABOVE THE ZERO IS ATTRACTION TOWARD THE CUE, WHETHER WE USE THE NATIVE OR THE RECOMBINANT VERSION WE MAKE IN THE TEST TUBE, YOU CAN SEE, THE PINK CYCLE HERE, IT'S--IT'S ABOVE THE LINE SO SHE'S ATTRACTED TO IT. UPON AND DURING THIS, SHE'S INDIFFERENT, SHE DOESN'T REALLY CARE ABOUT IT AT ALL. SO THIS ISN'T NEARLY AS COOL AS GOING FROM ATTRACTION TO RAGE BUT IT'S STILL KIND OF COOL. RIGHT? SHE'S CHANGING BEHAVIOR EVERY FOUR DAYS AND WE WANTED TO KNOW WHY. SO SANDEPA, WANTED TO DO THE CONTROL AND SHE WAS EXCITED, GO IN THE BRAIN AND FIND OUT WHAT'S GOING. AND SHE WAS LIKE WAIT, WAIT, WAIT, LET'S SEE IF THE NOSE NEURONS ARE EQUALLY AS RESPONSIVE AND THIS IS A RIDICULOUS QUESTION, IT MAKES NO SENSE BECAUSE WE ALL KNOW THAT THE FUNCTION OF THE SENSORY SYSTEM IS TO VACUUM UP ALL THE INFORMATION THAT YOU'RE CAPABLE OF AND PASS IT LONG TO THE BRAIN AND THE BRAIN SHOULD MAKE THE DECISION ABOUT HOW TO ACT ON IT, AND IT SHOULD NOT--IT SHOULD NOT, IT SHOULD GET EVERYTHING AND WE KNOW THIS IS LIKELY TO BE TRUE BECAUSE OF THE COCKTAIL PARTY PHENOMENON IN IF THE AUDITORY SYSTEM. RIGHT, SO YOU'RE IN A CROWDED ROOM AND IT'S NOISY, THERE'S LOTS OF CONVERSATIONS GOING ON BUT YOU CAN FOCUS ON THE PERSON IN FRONT OF YOU BECAUSE OF YOUR ATTENTION. BUT IF SOMEBODY ACROSS THE ROOM YELLS YOUR NAME, YOU HEAR IT AND YOU TURN AND YOU NOTICE IT, YOU'RE AWARE OF IT. AND THAT TELLS YOU YOU'VE BEEN GETTING ALL THE SENSORY INFORMATION IN BUT SOME PLACE IN YOUR BRAIN, YOUR BRAIN DECIDED NOT TO ATTEND ON IT SO THAT'S A GOOD SENSORY SYSTEM, IT'S GIVING YOU EVERYTHING AND LETTING YOU MAKE THE CHOICE AND THE ONLY REASON WE DID THIS EXPERIMENT IS BECAUSE IT WAS SIMPLE SO WE CAN SEPARATE THE NOSE FROM THE BRAIN VERY EASILY AND IN THIS CASE, THE NAISAL ORGAN SO WE PULL IT OUT AND THIS IS A PICTURE FROM THE LAB, AND DIFFERENT SENSORY NEURONS HAVE BEEN LABELED IN DIFFERENT COLORS AND YOU CAN SEE THERE'S DIFFERENT KIND OF SENSORY NEURONS HERE THAT ARE ALL DETECTING DIFFERENT ODORRENS AND THEY'RE TO PROTECT DIFFERENT OORIN AND IF WE RUN THIS, ONLY A FRACTION RESPOND. SO WE CAN DO THIS. WE CAN TAKE THE ORGAN OUT AND DO CALCIUM IMAGING AND WE CAN ASK ARE THE SENSORY NEURONS RESPONDING THE NAME BETWEEN ESTRICEEAND TED BEHAVIOR. SO THIS IS BETWEEN THE DISCIPLINARY-ESTRICE, AND THE RESPONSE DOES CHANGE. SO THERE'S FIVE% OF THE NEURONS ARE ACTIVATED DURING ESTRISE, THAT'S WHAT WE COULD EXPECT AND THAT'S WHAT IS ATTENUATE. OKAY, THE DIFFERENCE BETWEEN ESTRISEAND DISCIPLINARY ESTRISE, IS THE OVARIES WE COULD REMOVE THE ORVARIES AND PREVENT THESE HORMONES. LET IF WE TAKE THE OVARIES OUT THERE'S A HIGH RESPONSE. SO THE BASAL BACKGROUND ACTIVITY WITHOUT HORMONES IS TO RESPON AND THAT'S SHOWN HERE. SO THE HORMONES ARE PREVENTING THE RESPONSE SOMEHOW. AND DURING ESTRISE, DURING THE OVULATION CYCLE THE OVARIES PRODUCING TWO FEMALE HORMONES SO IT'S ESTROGEN AND THEN DURING DI-ESTRISE, THERE'S PROGESTERONE. SO WE COULD DO THIS EXVIVO. SO IN OUR OVARY OPTIMIZED ANIMALS WE COULD RESPOND AND WE COULD ADD ONE OF THESE AND ASK DOES IT MAKE A DIFFERENCE, DOES IT CHANGE THE RESPONSE OF THE NEURONS SO IF WE JUST ADD EXOGENOUS ESTROGEN BEFORE WE ADD THE FARRA MOANS, HERE AT THE ESTRISE PHYSIOLOGICAL CONCENTRATION, NOTHING HAPPENS. IF WE ADD BACKGROUND LEVEL OF PROGESTERONE, NOTHING HAPPENS, THERE'S STILL A ROBUST RESPONSE BUT IF WE ADD THE PROGESTERONE IT'S ATTENUATE. OKAY? AND THIS TURNED OUT TO BE AN AMAZING RESPONSE TO ME. SO I WILL SHOW YOU THE RAW DATA SO WHAT HAPPENS IS THESE ARE INDIVIDUAL TRACES OF THE CALCIUM IMAGING, WE CAN SEE THE PHEROMONE, AND THEY RESPOND. WE ADD THE PHEROMONE AND THEY IT'S JUST A SHORT PERIOD OF TIME. 10-15 MINUTES NOW WE ADD THEM AND WE DON'T RESPOND. NOW WE ADD A DRUG, AND THESE NEURONS ARE IN A DISH NOW, MAYBE THEY'RE JUST ALL DEAD AND WE CAN ADD AN AGONIST THAT BYPASSES THE RESUPPORTOR AND ALL THESE NEURONS ARE ALIFELIVE AND THEY CAN RESPOND. SO THIS EXPERIMENT TELLS US TWO THINGS. FIRST OF ALL IT TELLS US THAT SOMETHING IS HAPPENING RIGHT AT THE PERIPHERY. THAT THESE NEURONS, THESE NEURONS ARE SEVERED FROM THE BRAIN, THEY'RE NOT GETTING SIGNALS BACK FROM THE BRAIN THAT SAID WE'VE SEEN THIS INFORMATION AND THEY DON'T RESPOND AND THIS IS HAPPENING DIRECTLY TO THE SENSORY NEURONS THEMSELVES AND IT'S HAPPENING REALLY QUICKLY WHICH IS NOT CONSISENT WITH WHAT HOW THE HORMONES NORMALLY RESPOND. SO PEOPLE HAVE LOOKED IN THE VNO FOR INTERESTING STEROID RECEPTORS AND WE WERE INTERESTED IN UNDERSTANDING THIS BECAUSE THIS WAS SOMETHING I HUNDRED HEARD OF BEFORE, SENSORY SYSTEM BASED ON RESPONSE BASED ON INTERNAL STUDY AND PEOPLE LOOKED FOR STEROID RECEPTORS AND HAVEN'T FOUND THEM AND WE DID RNA-SEQ AND WE DIDN'T FIND THEM EITHER UPON BUT WE DID FIND A NONCONONICLE SINGLE MEMBRANE PATH RECEPTOR, CALLED THAT DETECTS AND RESPONDS TO PHEROMONE. I MEAN--SORRY TO PROGESTERONE. FELT AND SO THE PGRMC ONE IF WE TAKE THE ORGAN HERE AND HERE IT'S IN THIS CORONAL SECTION HERE SO THIS IS THE AREA WHERE THE LIGANDS COME IN, THE LUMEN AND THERE'S DENDRITES THAT AND THE SENSORY NEURONS ARE HERE AND THESE PRESENT AND THEY PROJECT THIS WAY TOWARDS THE LUMEN AND YOU CAN SEE THE READ AND ANTIBODY STAINING IS WITH ALL OF THESE DENDRITES HERE AND WE THINK IT'S REAL BECAUSE WE HAVE A PHLOX VERSION AND DID THE KNOCK OUT IN THE NOSE AND FOUND THAT THAT STAINING WENT AWAY, SO WE THINK IT'S DEFINITELY THERE, IT'S EXPRESSED AND THE COOL THING ABOUT THIS PHLOX VERSION WE GOT IS THAT PGRMC-ONE IS USUALLY KNOCKED OUT BUT THESE FEMALES WERE STILL FETTERILE AND GOING THROUGH THE OFULATION CYCLE AND WE COULD--OVULATION AND WE COULD ASK THESE QUESTIONS ABOUT THE MICE. SO WE TOOK THE MICE EXVIVO, DID THE SENSORY NEURONS STILL RESPROND TO PROJECT ROAN WITHOUT THE RECEPTOR? SO BEFORE I SHOWED YOU THE WILD-TYPE ANIMAL, AND THIS IS ATTENUATED AND IN THE MUTE ANT ANIMALS THEY'RE STILL RESPONDING SO THEY'RE NOT ABLE TO PROTECT THE PROGESTERONE AND WE COULD DO THIS, ALSO EXVIVO WITHOUT THE OVAFY ETC. MYSELF AND CYCLING FEMALES, SO ESTRISE THEY RESPOND AND ATTENUATE AND HERE THEY STILL RESPOND AND WE COULD ASK THE BEHAVIOR OF THESE ANIMALS AND IN DI-ESTRISE, THEY'RE ATTRACTED TO IT SO THAT TELLS US THAT THIS IS THE MOLECULE THAT'S LINKING THE STATE OF THE FEMALE TO THE SENSORY NEURON SO IN ESTRI SE AND THEY ARE ACTIVATED AND GET ATTRACTION AND IN DISCIPLINARY-ESTRISE, THEY'RE NOT WELL ACTIVATED AND WE GET INDIFFERENT. SO THIS SEEMS GREAT BUT I'VE TOLD YOU @ VERY BEGINNING OF MY TALK THAT ONE OF THE FUNCTIONS OF THE SENSORY SYSTEM IS TO DETECT PREDATORS. SO I CONCERNED OF THE WEALTH OF THE FEMALES HOW DO WE HAVE SO MANY FEMALES IF THEY CAN'T DETECT PREDATORS EVERY TWO DAYS OF THEIR LIFE. AND THIS PGRMC-ONE IS ON 80% OF THE NEURONS SO IT'S REASONABLE THAT IT WAS ON THE PREDATOR EXPRESSING NEURONS SO WE WANTED TO ASK, IS THE FEMALE DETECTING PREDATORS EVERY FEW DAYS AND IT TURNS OUT SHE IS, SO WE HAD THAT CAT CUE, WE ALSO ISOLATED A CUE CUE AND HERE IT ACTIVATES LESS OF THE NEURONS BUT WE KNOW IT ROUTINELY ACTIVATES 2 PERCENT PF THE NEURONS AND DOES SO WHETHER SHE'S IN ESTRUS, OR DISCIPLINARY-ESTRUS, SO SHE'S AVOIDING IT ANY SHE'S IN ESTEROUS OR DISCIPLINARY-ESTRUS. SO WHAT'S THE DIFFERENCE? WHY ARE THEY ESCAPING THE SUPPRESSION ACTIVITY BUT THE ONES THAT ARE DETECTING THE MALE CUE ARE NOT? SO IT TURNS OUT THAT SANDIP A'S MODEL WAS SOMETHING DIFFERENT DOWN STREAM FROM THE PROGESTERONE RECEPTOR, SO THE RECOAPTOR IS JUST EVERYWHERE SO THE DOWN STREAM RECEPTOR, SORT OF PARALLEL WITH IT IS THE PHEROMONE AND COUPLED RECEPTOR IS ACTIVATING PROTEINS IT WAS KNOWN TO ACTIVATE ACT C AND THEN THE DIGLYCERIDE THIS TRIP CHANNEL WHICH IS THE THING WE MANIPULATED BEFORE TO GET THE LACK OF BEHAVIOR. RIGHT? SO WE KNEW FROM OUR RNASEQ THAT THE RECEPTOR EXPRESSION DIDN'T CHANGE BETWEEN ESTRUS, AND MAYBE THERE'S SOMETHING GOING ON HERE BUT THAT HAD BEEN DESCRIBED BEFORE, I MEAN WHAT'S REALLY FUN IS THAT WITH THE OLFACTORY NEURONS WHETHER IT'S IN THE MAIN OLFACTORY SYSTEM, WHAT MAKES THEM UNIQUE IS THIS SENSORY RECEPTOR AND THAT IT'S JUST PLUGGING IN TO A MODULE OF SIGNALING THAT'S THE SAME IN ALL OF THE DIFFERENT SENSORY NEURONS. BUT IT TURNS OUT THAT WHO KNEW, THERE'S 14 PLC VARIANTS IN THE MOUSE, NOT JUST ONE. THERE ISN'T JUST PLC, THERE'S 14 OF THEM. AND IF WE DO, RNA-SEQ ON THE TOTAL, WE FIND THAL ONE IS HIGHLY EXPRESSED FOLLOWED BY BETA THREE, SO THERE'S A LOT GOING ON, BUT IF WE TAKE--IF WE CALCIUM IMAGE AND LOOK FOR THE ONES RESPONDING TO THE MALE PHEROMONES AND THEN WE DO RNA-SEQ JUST ON THOSE, WE PULLED THE CELLS TOGETHER AND DID RNA-SEQ ON THOSE, THIS IS IN RED, BETA TWO. OKAY AND WHEN WE SCAN THE BETA TWO, IT'S NOT EVERYWHERE AS WE WOULD WOULD EXPECT FROM A SIGNALING UNIT THAT'S USED EVERYWHERE BUT IT'S IN THE REALLY SPARSE AND PATTERN THAT'S REMINISCENT OF A RECEPTOR BUT IT COULD BE JUST BE IN THESE TWO CELLS IT'S BEAUTIFUL, LITTLE EXCITING PATTERN TO ME BUT IT COULD BE THERE FOR DECORATION OR DOING SOMETHING ELSE, RIGHT? SO THE QUESTION IS, IS IT ESSENTIAL FOR SIGNALING IN THESE CELLS? SO WE GOT A MUTE ANT OF IT, STAINING THOSE AWAY, WE THINK THIS IS ALL REAL. SO, IN THOSE CELLS, WE COULD ASK, BY CALCIUM IMAGING AND THE WILD-TYPE ANIMALS THEY RESPOND TO THE PHEROMONE AND WITHOUT PLC BETA TWO, THEY DON'T RESPOND. SO IT'S NOT JUST THERE FOR DECORATION, IT'S NONAPOPTOTIC THE DOING SOME OTHER THING, IT'S THERE FOR PRIMARY SENSORY SIGNALING. SO THE BEHAVIOR, THE PREFERENCE IS THEY GO DOWN TO BEING INDIFFERENT DURING ESTURUS, BECAUSE THESE ARE CYCLING JUST FINE AND WE KNOW THAT IS NOT EFFECTING, THEY'RE NOT THIS MOLECULE IS NOT BEING USED FOR THE SIGNAL TRANSDUCTION IN THE CAT ODOR, SO THEY CAN DETECT THIS JUST FINE IN THE MUTE ANT ANIMAL AND THEY CAN STILL AVOID IT IN THE MUTANT ANIMAL. SO OVER ALL. TELLS US THAT THESE ARE OVERALL DIFFERENT THAT YOU CAN SEE HERE BUT THERE'S THIS SIGNALING MOLECULE THAT'S VARIABLE, WE PUT THESE IN SITUs AND THEY'RE ALL A DIFFERENT PATTERN. SO WE THINK THEY'RE ALL LIKELY FUNCTIONAL ALTHOUGH IT WILL TAKE US A WHILE TO FIGURE OUT AND THESE THINGS NOW ARE THE FIXED THINGS AND WE'RE PRETTY SURE THESE ARE FIXED. OKAY, BUT WHY GO THROUGH ALL THE BOTHER, WHAT WHAT SEA SO SPECIAL ABOUT PLC BETA TWO THAT WE WOULD NEED THE CELL SO THAT THE CELLS DON'T RESPOND TO THE MALES AND SO, IT TURNS OUT THAT ALL OF THESE PLCs CAN BE MODULATED BASED ON PHOSPHTION, WHEN THEY'RE PHOSPHORYLATED SOME OF THEM BECOME MUCH MORE ACTIVE AND GO TO BEING ACTIVE AND SOME OF THEM BECOME ENZYMATICALLY DEAD AND IT TURNS OUT THAT PLC BETA TWO BECOMES COMPLETELY DEAD IF IT'S PHOSPHORYLATED AND IT TURNS OUT THAT THAT PGRMC ONE THAT'S DETECTING THE PROGESTERONE, IT INITIATES THE MAP KINASE KASP A RICATE SO IT'S CAPABLE OF INITIATING PHOSPHORYLATION SO WE ASK, IS THIS TWO SILENT BY PHOSPHORYLATION IN THE PRESENCE OF PROGESTERONE. AND SO, HERE IS AN IP, WE IP DOWN, PLC BETA TWO AND DID WESTERN SERINE SO IF WE TAKE THE WILD-TYPE FEMALE, AND THESE ARE OVERECTOMYSELFED SO THERE'S NO HORMONE GOING AROUND AND WE DON'T ADD HORMONE, BUT IF WE ADD PROGESTERONE IT BECOMES NICE LOW PHOSPHORYLATED SO THAT'S THE NONAPOPTOTIC REMEMBERRAL CASE OF WHAT'S HAPPENING DURING DISCIPLINARY-ESTRUS, BUT HERE IF WE TAKE AWAY IT, THIS IS THE PROGESTERONE. SO THIS CORRELATES NICELY AND IF WE LOOK IN THE BRAIN OF THE ANIMALS AND WE SAY DOES THE PATTERN OF THIS ACTIVITY BECAUSE OF THE ATTENUATION THAT WE'RE SEEING IN CALCIUM IMAGING DOES THAT TRANSLATE TO ANYTHING IN THE BRAIN? WE CAN SAY THAT DURING ESTRISK ASSESSMENTS WE GET THE LINE OF C-FOS ACTIVITY AND THIS IS WHAT WE WOULD EXPECT FROM INITIATING WITH THE PURIFIED SINGLE HUGH AND WE FIND THAT THAT'S GREATLY ATTENUATE SO WE'RE IMAGINING THIS PATTERN OF ACTIVITY IS INITIATING PATTERN BEHAVIOR AND THIS PATTERN IS NOT SUFFICIENT. SO WHAT WE'RE SEEING AT THE PERIPHERY IS CHANGING THE ACTIVATION OF THE SENSORY CIRCUIT. SO JUST TO SUMMARIZE, WE FOUND OUT THINGS I DID NOT EXPECT TO FIND AND I THINK THAT'S REALLY FUN. SO WE HAD THIS CHANGE IN BEHAVIOR FROM ATTRACTION TO INDIFFERENCE BUT IT'S NOT BECAUSE THE FEMALE'S GETTING THE INFORMATION IN DURING DISCIPLINARY ESTRUS, SAYING NO THANK YOU I'M IN DIESTRUS, I'M NOT INTERESTED. SHE IS ACTUALLY BLIND TO IT. SHE HAS NO WAY THAT IT IS THE MALE IS OUT THERE, SHE HAS NO WAY TO BE ATTRACTED TO IT BECAUSE SHE CAN'T SMELL IT. SO INSTEAD OF THE SENSORY SYSTEM PASSING THE INFORMATION ON TO THE BRAIN, THE SENSORY IS DATING IT ON THE PERIPHERY AND IT'S MAKING EXECUTIVE DECISION, IT'S DOING THE JOB OF THE BRAIN. OKAY SO IN ADDITION THIS ISN'T JUST--WE DON'T THINK THIS IS JUST SOME WEIRD THING THAT THE FEMALE VNO IS DOING, WE CAN ALSO IGF NORTHE FEMALE VNO BUT OUR RNA-SEQ HAS REALLY COOL RECEPTOR SO IN THAT WE HAVE FOUND ALL OF THE AGGINERGIC RECEPTORS AND SUGGESTING MAYBE THE SYSTEM COULD BE RESPONSIVE TO THE STATE OF STRESS AND WE FOUND SOME REALLY INTERESTING RECEPTORS THAT ALSO MAKE US THINK COULD COULD BE RESPONSES TO THE HUNGER AND SATY ETICSY, AND WE ON ALMS FOUND THESE IN M. O. E. OF THE MOUSE AND WHEN YOU TAKE HUMAN OLFACTORY NEURONS AND DO RNA SEQ ON THOSE WE FIND ALL OF THESE THERE AS WELL. SO WE THINK EVEN THOUGH WE FOUND THIS IN THIS WEIRD LITTLE BEHAVIORIAL EXCEPTION THAT TIARAS MAY BE MORE OF A GENTLEMEN PROPERTY, AND WHAT THAT S&P THE ABILITY, THESE ARE CHEMO DETECTING CELLS THE THINGS THAT--AND THE THINGS THAT SIGNIFY INTERNAL ESTATES THAT ARE PERFECT FOR THESE CELLS AND RESPOND TO SO WE THINK THESE CHEMO CELLS AND OLFACTION IS ONE OF THE ANCIENT SENSORY SYSTEM. IT DOESN'T PROJECT THROUGH THE THALAMUS WHERE THE GATING IS THOUGHT TO OCCUR AND WE THINK THIS THING EVOLVED BEFORE HAND AND IS ACTING LIKE AN EXECUTIVE COMMAND AND IT'S POSSIBLE IT'S DETECTING OTHER EXTERNAL STAKE CUES AS WELL AS INTERNAL STAKE CUES. AND FINALLY WE THINK THAT THIS HAS THROWN OFF OUR WHOLE ROADMAP FOR HOW WE STUDY THE INFORMATION CODING BECAUSE ONE OF THE PROPERTIES WE THOUGHT WAS A KEY FEATURE OF WHAT THE BRAIN IS DOING, WAS FINDING IN THIS SITUATION, IT'S HAPPENING RIGHT OUT HERE WHERE WE THOUGHT THE ONLY INFORMATION PASSED ON WAS WHAT'S IN THE ENVIRONMENT INSTEAD IT'S ABLE TO MAKE AN IF-THEN DECISION ABOUT WHETHER THE NEURON SHOULD FIRE BASED ON WHETHER THE ANIMAL IS IN ONE INTERNAL STATE OR ANOTHER. SO WE'RE VERY INTERESTED IN THIS NOW RETHINKING ABOUT HOW--WHAT WE LOOK FOR AND HOW WE STUDY THE DOWN STREAM CIRCUIT AND MORE OVER WE WILL SPEND A BIT MORE TIME LOOKING AT THOSE OTHER RECEPTORS IN THE PERIPHERY AND BE ABLE TO UNDERSTAND IT BECAUSE WE THINK TO BE ABLE TO JUMP IN AND START TO STUDY, THESE NEURORESPONSES HERE IS VIRTUALLY IMPOSSIBLE IF YOU DON'T KNOW WHAT'S PASSED ON IN THE PERIPHERY. AND IF THIS CAN HAPPEN IN MALES OVERSTRESS, TWO DIFFERENT MALES THAT ARE AT A DOMINANT STATE AND YOU RESPOND TOTALLY DIFFERENTLY AND SO YOU CAN FIGURE OUT WHAT'S GOING ON HERE AND WE CAN CLAMP IT AND CONTROL IT SO WE CAN BETTER STUDY WHAT'S GOING ON HERE WITH MORE CLARITY. SO THIS WAS ALL LARGELY, EVERYTHING I TOLD YOU AT THE END WAS DONE BY A FABULOUS POST DOC IN THE LAB SANDEEPA, DEY, AND WE HAD HELP WITH THE SINGLE CELL OR THE SMALL POOL OF CELLS, RNA-SEQ, AND TURNING THE MOUSE INTO A SLIDE, GETTING THE SENSORY CIRCUIT FROM THE BLADDER IS DONE BY A GRADUATE STUDENT AND THEN ALL THE INITIAL HUNT FOR PHEROMONES WERE DONE BY THIS SORT OF TEAM OF PEOPLE THAT ARE OFF DOING WONDERFUL THINGS THEMSELVES. SO THANK YOU. [ APPLAUSE ] >> [INAUDIBLE QUESTION FROM AUDIENCE ] >> NO, RIGHT. SO IT'S REALLY THAT THING WE POINTED OUT EARLIER WE GET THEM TO FIGHT TO ANYTHING ON A COTTON BALL. SO THEY'RE INDIFFERENT TO COTTON BALL FROM OTHER GUYS AND IF WE TAKE THEIR OWN URINE AND PUT IT ON A CASTRATED ANIMAL THEY'LL FIGHT IT. SO THAT CUE IS INSTRUCTED TO FIGHT IRRESPECTIVE OF IT'S HIM OR SOMEBODY ELSE, THERE'S NOTHING ABOUT INDIVIDUAL IDENTITY IN THAT CUE AT ALL. IT JUST MAKES THEM CRANKY BUT IT HAS TO BE IN THE RIGHT CONTEXT. SO WHEN HE'S JUST HIMSELF AND THERE'S NO OTHER MALE OUT THERE, IT'S NOT SUFFICIENT, HE JUST DOESN'T WALK AROUND IN A CONSTANT STATE OF AG GRAVATION, SO THERE MUST BE SOMETHING ELSE ABOUT THE VISUAL CUES OR AN ADDITIONAL MALENESS CUE THAT THE CONCENTRATION OF THAT ADDITIONAL CUE WOULD OUTWEIGH IT WE DON'T KNOW. HARD TO STUDY. >> I HAVEN'T DONE THAT. THE OLD LITERATURE, I DON'T SEE THAT. THE IT REALLY--I MEAN WE THINK THAT THERE'S VISUAL CUES: DAVID APEDDERSON CAN GET A MOUSE TO FLIGHT, LOAMACY ACHE BLOWN UP GLOVE, GLOVE BALLOON THAT HE MOVES AROUND. HE HAS TO STIMULATE--YEAH, YEAH, SO THE MOVEMENT IS IMPORTANT. >> [INAUDIBLE RESPONSE FROM AUDIENCE ] >> SO THEY'RE ALWAYS FIGHTING THE MALES BECAUSE THE WAY IT WORKS THE MALE IS IN A TERRITORY AND HE DEFENDS HYSTERRATORY AND FROM WHAT I CAN TELL FROM PEOPLE THAT HAVE BEEN OUT WATCHING WILD ANIMALS OR SET UP SORT OF LARGE MORE ECOLOG RELEVANT SPACES, THEY WILL SPEPPED A LOT OF TIME AT THE PERIMETER DEFENDING THEIR TERRITOR SCHEIN THAT SITUATION, THESE LARGE TERRITORIES THEY DON'T MARK THE WHOLE THING, THEY MARK THE BOUNDARIES AND SO THEY SPEND A LOT OF TIME CHECKING THE MARKS IF ANOTHER MORE DOMINANT GUY WILL COME IN AND AND THEY WILL KNOW WHO TO FITTED AND THE THOUGHT IS TO STAY AWAY, SORT OF A SIGNAL OF, I'M DANGEROUS DON'T COME IN HERE SO WE DON'T THINK--WE THINK THAT THEY'RE KIND OF FIGHTING ALL THE TIME TO PROTECT THEIR TERRITORY, THE MATING THING IN THE LAB, THEY WILL TRY TO MATE WITH A FEMALE ANYTIME, WITH THE JACKSON MICE, REAL MALES MAYBE DON'T BUT IT'S REALLY THE FEMALE THAT MAKES THE DECISION TO GET HIM AWAY. >> [INAUDIBLE QUESTION FROM AUDIENCE ] >> SO THERE'S EVIDENCE TO SUGGEST THAT THE INDIVIDUAL IDENTITY CUES THAT THE FEMALE IS WEIGHING AND ESTABLISHING SOMEHOW WITH EXPERIENCE OR SOMETHING, AS WELL AS THERE'S ALL SORTS OF THEORIES ABOUT A MATE CHOICE WHETHER A FEMALE IS CHOOSING A MAIL WHETHER IT HAS A DIFFERENT GENETIC IDENTITY SO THAT SHE WOULD WOULD HAVE AN IMMUNO FITNESS, THE PUPS WOULD HAVE THE IMMUNO FITNESS AND SUCH LIKE THAT, I DON'T THINK WE KNOW THOSE CUES AT THIS POINT. THERE'S BEEN SPECULATION BUT I DON'T THINK ANY OF THEM WILL HOLD UP, THERE ARE 650 VOLATILE ODOR ANTS IN MOUSE-MALE URINE AND THEN THERE ARE OTHER SMELLS THAT ARE EMANATING FROM OTHER GUYS AND THERE'S 315,000 RECEPTORS IN THE VNO AND THEN THRESHOLD RECEPTORS IN THE M. O. E. SO THE MAIN NOSE IS DOING PHEROMONE PROCESSING SO THAT ODOR SPACE IS SO LARGE THAT WE--FOR ME WE HAVE ALL THE CUES WE NEED TO STUDY COOL QUESTIONS, SO I'M NOT DOING CUES ANYMORE BUT IT WOULD BE--YOU COULD GO FOREVER. >> YEAH. >> YEAH, WE THINK SO. THIS A HARD PROBLEM TO EVOLVE SO BEFORE IT WAS HARD NOT TO GET WOP OLFACTORY RECEPTOR, OF THE NAISAL RECEPTOR IN THE RIGHT NEURON THAT'S WIRED TO THE RIGHT PLACE, RIGHT BUT NOW YOU HAVE TO DO THAT WITH THE RIGHT HORMONE RECEPTOR WITH THE RIGHT SIGNALING MOLECULE, SO, I DON'T THINK THAT THE--FEMALES DOING IT JUST BECAUSE SHE CAN'T BE BOTHERED WITH THE MALE CUES DURING DISCIPLINARY ESTRUS, SHE'S STILL NOT GOING TO MATE WITH HIM WITHOUT ESTROGEN AND WE'RE ALLET GETTING CUES ALL THE TIME THAT DON'T MAKE OUR BRAIN OVERLOAD, SO IT'S PRETTY--SO WE THINK THERE'S FUNDAMENTEDDAL REASONS WHY THESE THINGS ARE TOGETHER AND THAT THEY'RE PROBABLY IMPORTANT. YOU KNOW WHAT WE'VE SEEN IS JUST AN ASSAY TO DETECT IT BUT PROBABLY NOT THE REAL THING. MENT SO THE--YOU WERE ASKING ABOUT WHETHER-- >> [INAUDIBLE RESPONSE FROM AUDIENCE ] >> YES, SO WE SEE A WHOLE OTHER SUBSET OF NEURONS THAT ARE MORE ACTIVE DURING DIEST RUS, SO WE THINK THESE ARE IN THE PLC VARIANTS THAT GET TURNED ON IN RESPONSE TO PHOSPHORYLATION AND THERE'S A BUNCH WE CAN'T TEST BECAUSE WE DON'T HAVE CUES FOR THEM. AND THEN WE HAVE NO IDEA IF FUNC, IF WE CAN GET THEM ACTIVATED SO,--BUT, SO WE THINK OF THE FEMALE, THERE MUST BE A REASON FOR IT ALL. IN THE MALE, THE PGRMC ONE IS THERE AS WELL. AND SO EITHER IT'S THERE JUST BECAUSE IT'S EASY AND THERE'S NO PROGESTERONE AND IT WILL BE FINE OR THIS THING COULD BE RESPONSIVE TO OTHER LIGANDS AS WELL IF THERE'S EVIDENCE THAT IT COULD BE RESPONSIVE TO ESTOFTROAN AND ESTROGEN AS WELL. --TESTOSTERONE AND ESTROGEN AS WELL. >> [INDISCERNIBLE] >> SO THE MOLECULE WE LED TO FEAR IS AN ORTHOLOG TO THE ATTRACTION CUE. AND I THINK IT'S LIKE 30 PERSON SIMILAR. IT'S PRETTY LOW. WHERE THE MOUSE CUES ARE ALL LIKE 99% IDENTICAL AND THE MICE CAN DETECT THE DIFFERENCE'RE DIFFERENCE. THERE'S 21 OF THEM. ONLY ONE OF THEM DOES THE RAGE, THE OTHER SPECIFIC DETAILS ON THE OTHER THINGS AND IT CAN DETECT THOSE IN THE INDIVIDUAL VARIANTS SO WE FIND THERE'S A SMALL. IT'S SORT OF A LITTLE BIT OF A COMBINATTORRIAL CODING THERE, WE SEE THERE'S A SMALL RAT OR ACTIVITY, BUT VERY LITTLE. [ APPLAUSE ] LITTLE. [ APPLAUSE ]