GOOD AFTERNOON. WELCOME TO THE NEUROSCIENCE SEMINAR SERIES. OUR SPEAKER TODAY IS DR. SHERI MIZUMORI, SHE OBTAINED HER UNDERGRADUATE DEGREE FROM THE UNIVERSITY OF WASHINGTON AND RECEIVED HER Ph.D. AT BERKELEY, U. C. BERKELEY AND AFTER FACULTY STINTS AT THE UNIVERSITY OF COLORADO AT BOULDER AND THE UNIVERSITY OF UTAH SHERI WAS RECRUITED TO THE UNIVERSITY OF WASHINGTON WHERE SHE'S NOW PROFESSOR AND CHAIR OF THE DEPARTMENT OF PSYCHOLOGY. SHERI'S BEST KNOWN FOR EMPLOYING SINGEM IEWNLT RECORDING TECHNIQUES EELECTROPHYSIOLOGICAL TECHNIQUES TO STUDY SPATIAL COGNITION AND MEMORY. MATTER OF FACT THAT'S WHERE WE'VE KNOWN PEOPLE FOR MANY YEARS IS ACTUALLY IN MEMORY CIRCLES BUT SHE STUDIED MANY TOPICS IN BEHAVIORIAL NEUROSCIENCE INCLUDING HIPPOCAMPAL, TRI ADAL, MEDIAL FRONTAL CORTEX, SPATIAL COGNITION AND MEMORY. DOPA MEAN--DOPA MINE NEURONS AND SPATIAL LEARNING, THE LATERAL HABENULA MEASURES, NUCLEUS NEURONS, SO, SHE HAS ACTUALLY QUITE A BROAD BACKGROUND. RECENTLY SHE'S BEEN TRYING TO INTEGRATE HER STUDIES IN SPACIAL COGNITION AND SPATIAL MEMORY WITH DECISION MAKING AND THERE ARE DIFFERENT CAMPS OF PEOPLE THAT STUDY REWARD LEARNING AND DECISION MAKING ON THE ONE HAND AND MEMORYOT OTHER. TRADITIONALLY THEY'RE SORT OF SEPARATE DISCIPLINES. SO I'VE BEEN TRYING TO FOLLOW SHERI'S WORK WHERE SHE'S TRYING TO INTEGRATE THESE THINGS AND INDEED, EVEN THOUGH IT'S NOT USUALLY LOOKED AT THAT WAY IN DECISION MAKING, MANY OF THE ISSUES IN DECISION MAKING ARE DISTINCTLY MEMORY ISSUES. SO SHERI'S BEEN ATTACKING THAT. SHE HAS MANY AWARDS WHICH I WON'T READ NOW, BUT ONE OF HER MORE RECENT AWARDS I'LL MENTION IS THE NEAL MILLER DISTINGUISHED LECTURER AWARD FROM THE AMERICAN PSYCHOLOGICAL ASSOCIATION. SO I THINK WE'RE IN FOR A TREAT. SO THE TITLE OF SHERI'S TALK TODAY IS INTERACTION BETWEEN MEMORY AND DECISION SYSTEMS OF THE BRAIN. PLEASE JOIN ME IN WELCOMING SHEERI, MIZUMORI. [ APPLAUSE ] >> CAN YOU HEAR ME BACK THERE? AM I TURNED ON? THANK YOU BETSY FOR THE GREAT INTRODUCTION AND I WANT TO THANK THE ORGANIZERS OF THE SEMINAR SERIES FOR INVITING ME TO COME OUT HERE. I LOOK FORWARD TO SPEAKING A NUMBER OF YOU AND I LOOK FORWARD TO SPEAKING TO MORE OF YOU AFTER MY TALK TODAY. WELL, MAKING QUICK AND ACCURATE DECISIONS IS ACTUALLY ESSENTIAL IN THE EVERY DAY TASK, AND SOMETIMES IS VITAL. I THINK THIS DECISION MAKING PROCESS NECESSARILY INVOLVES INTERACTION BETWEEN MEMORY AND ECISION CIRCUITS OF THE BRAIN. CLEARLY IN ORDER TO MAKE ADAPTIVE GOOD DECISIONS, YOU NEED TO RELY ON YOUR MEMORY ABOUT PAST GOAL OUTCOMES AND WHEN YOU ARE TALKING ABOUT YOUR MEMORIES, YOUR MEMORIES ARE BASED ON ALL THE PAST ADAPTIVE DECISIONS THAT YOU'VE MADE. SO AGAIN, THE SYSTEMS I FEEL LIKELY HAVE TO BE INTERACTIVE. SO HOW DOES ONE GO ABOUT SETTING THESE KINDS OF INTERACTIONS. WELL WE BEGAN IN OUR LAB BY THINK BEING IT IN THE CONTEXT OF ADAPTABLE AND BROAD DECISION MAKING. I KNOW THAT SOUNDSA I BIT BROAD BUT I WILL EXPLAIN MORE ABOUT THAT. FIRST LET ME GIVE AN EXAMPLE. THOSE WHO DON'T KNOW SEATTLE, THIS IS A DOWN TOWN MAP OF SEATTLE AND THIS IS THE FREEWAY THAT GOES THROUGH FROM NORTHOT RIGHT SIDE TO SOUTH ON THE LEFT SIDE AND LET'S SAY YOU ARE LEAVING SEATTLE AND YOU WANT TO GO TO THE AIRPORT WHICH IS IN THE SOUTH PART OF SEATTLE SO YOU MIGHT NEED TO CATCH DINNER SO YOU MAKE PLANS TO GO TO THE INFAMOUS SPACE NEEDLE WHERE IF YOU GO UP TO THE TOP OF THE NEEDLE YOU GET THE GREAT VIEW OF SEATTLE. THE FOOD IS NOT THAT GOOD, SO YOU'RE MAKING A SACRIFICE. URE YOU'RE GOING FOR A GREAT VIEW, BUT THE FOOD IS OKAY ACCIDENT OR CAN YOU GO TO A HISTORIC SITE DOWN HERE IN THE HARBOR TO A PLACE CALLED TELECONVILLAGE WHERE YOU GET THESE REALLILY FABULOUS NATIVE AMERICAN SALMON BUT IT DOES TAKE MORE EFFORT AND EVEN THOUGH YOU MAKE A PLAN, ONCE YOU HIT ONE SPOT AS YOU GET CLOSER TO THE SPACE NEEDLE AREA, THAT GOSH, THE TRAFFIC IS HORRIBLE AS IT REALLY IS IN SEATTLE AND OFTEN TIMES YOU HAVE TO HAVE CONTINGENCY PLANS AND YOU HAVE TO FIGURE OUT ROUNDS TO GET TO YET ANOTHER PLACE. YOU MAY DECIDE THAT AFTER ALL THAT, I WILL PASS ON ALL THIS GREAT--THIS GREAT AMBIANCE AND I WILL HEAD TO THE AIRPORT AND TAKE ADVANTAGE OF THEIR FOOD COURT THERE. SO IN THIS KIND OF SIMPLE PROCESS, THERE'S LOTS OF DIFFERENT KINDS OF DECISIONS AND LOTS OF DIFFERENT KINDS OF INFORMATION THAT YOU HAVE TO CONSIDER. AND SO, I THINK A STRIKING FEATURE THOUGH ABOUT THE FACT THAT YOU ARE ABLE TO MAKE THESE PLANS IS THAT YOU CAN SWITCH, STRATEGY SWITCH GOALS VERY QUICKLY. OKAY? IN OTHER WORDS IT OCCURS FASTER THAN YOU WOULD EXPECT IF USE OF A DIFFERENT STRATEGY OR RESPONSE SYSTEM REFLECTS THE NEW ACQUISITION AND THE NEW MEMORY SYSTEM. SO WHEN YOU BRING--YOU CAN BRING NAVIGATIONAL PROBLEM INTO THE LAB IN A MORE SIMPLIFIED VERSION AS IN THIS CASE, A TWO-CHOICE POINT MAZE FOR THIS RAT AND WE CAN PRETTY MUCH EASILY SHOW THAT A NUMBER OF THESE DIFFERENT MEMORY SYSTEMS CAN BE BECOME ACTIVE DURING THE PERFORMANCE OF A SINGLE TRIAL. IN OTHER WORDS, THE ANIMALS MUST HAVE EXTERNAL SURROUND AND PUT THAT IN MEMORY WORKING FORMAT SO THEY CAN CONNECT WITH PAST MEMORY AND PAST INFORMATION. IT COULD BE THAT YOUR RAT'S EMOTIONAL STATE DETERMINES THE CHOICE THEY MAKE AS WELL AS MOTIVATIONAL CONDITION WHETHER IT'S SATED OR NOT. ANIMALS KNOW HOW TO MIKE--MAKE TURNS ON THE MAZE AND NOT FALL OFF AND THAT DEDERM WHAT IS KINDS OF CHOICES THE ANIMAL MAKES. SO IT'S REALLY MORE COMMON THESE DAYS THAT INSTEAD OF THINKING OF THESE DIFFERENT MEMORY SYSTEMS AS OPERATING SEPARATELY AND INDEPENDENTLY THAT THEY LIKELY OPERATE IN PARALLEL AND THAT AT ANY GIVEN TIME THEY ARE AS IF THEY ARE COMPETING FOR CONTROL FOR DIFFERENT YALE CONTROL OVER THE RESPONSE OUTPUT IN THE SYSTEMS. LONG STORY SHORT, WE RECORDED ACTUALLY IN OUR LAB FROM A NUMBER OF THESE DIFFERENT MULTIPLE MEMORY SYSTEMS AND IT ENDS UP THAT THEY ALL SHOW CORRELATES REGARDLESS OF THE NATURE OF THE TASK, SUGGESTING AGAIN THAT THESE ARE OPERATING IN PARALLEL AND THEY'RE ACTIVE PROCESSING THE RELEVANT INFORMATION. OKAY, NOW AS I SAID, THESE SYSTEMS MIGHT COMPETE FOR CONTROL OF RESPONSE OF OUTPUT SYSTEMS OR DECISIONS ABOUT THE KINDS OF RESPONSE YOU SHOULD MAKE. NOW HISTORICALLY THE PREFRONTAL CORTEX HAS RECEIVED SPECIAL ATTENTION IN THIS REGUARD IN THAT THE PREFRONTAL CORTEX IS THOUGHT TO BE PARTICULARLY IMPORTANT FOR DETERMINING WHETHER OR NOT THE CURRENT STRATEGY OR RESPONSE NEEDS TO CHANGE AS A FUNCTION OF YOUR RECENT OR EXPECTED GOAL OUTCOMES. ONE QUESTION I WOULD POSE IS, WHY IS THAT? AND I ASK THAT BECAUSE ANIMALS THAT DO NOT HAVE PREFRONTAL CORTEX, FOR EXAMPLE, FISH, THEY ARE QUITE CAPABLE OF EXHIBITING FLEXIBLE DECISIONS AND RESPONSES THAT DEPEND ON LEARNED GOAL OUTCOMES. SO WHAT'S GOING ON, WHAT'S DIFFERENT ABOUT THAT. WELL, THIS IS JUST AN EXAMPLE OF ONE OF THOSE FISH EXPERIMENTS WHERE IN THIS CASE, THERE'S TWO FISH HERE SEPARATED BY PARTITION AND IF YOU RAISE THE PARTITION, SO NOW THEY'RE ALLOWED TO INTERMINGLE. BUT THE ACTUAL BEHAVIORS THESE FISH WILL CHOOSE TO EXHIBIT DEPENDS ON A NUMBER OF FEATURES IN TERMS OF CONTEXT OR VISUAL IMAGE OF THE FISH THEY ARE WITH AND SO AS A RESULT, THEY CAN HAVE DISPLAY BEHAVIORS AS IN COURTING. THEY CAN EXHIBIT THESE CIRCLES, SORT OF BEHAVIORS. THEY CAN START BITING EACH OTHER, THEY CAN ENGAGE IN COMPETITION AND ESTABLISH A SOCIAL HIERARCHY. SO HOW DO THEY KNOW WHAT THEY WANT TO EXHIBIT. SO IT ENDS UP IN THIS PARTICULAR ND OF EXPERIMENT THAT THIS--RARE DISEASES OR ORPHAN DISEASES, SOME OF THESE ARE THINGS THAT CAME IN AS PART OF PEDUFA FIVE WITH PRIORITY REVIEW --IN CHANGING ENVIRONMENT SUCH AS SOMETHING LIKE THIS AND IN FACT THE DATA SUGGEST THAT A CORE STRUCTURE COULD BE A CORE CANDIDATE STRUCTURE COULD BE THE EPITHALAMUS STRUCTURE WITH THE HABENULA. AND IN FACT THAT IS WHAT A LOT OF RESEARCHERS, INCLUDING THE RESEARCHERS OF THIS ONE RECENT SCIENCE PAPER SUGGEST IS THAT THE HABENULA, ALLOW THESE FISH TO ENGAGE IN FLEXIBILITY RESPONSES BASED ON LEARNED INFORMATION. THIS HAS ALSO BEEN A CONCLUSION BASED ON WORK WITH BIRD EXPWS ALSO IN REP--REPTILES. SO THIS EXPLAINS AGAIN IT DEPENDS ON THE FISH AND THE HABENLUA, THIS IS A HABENULA FROM A ZEBRA FISH THIS, IS THE LEFT AND WRITE SIDES AND YOU CAN SEE--RIGHT SIDES AND YOU CAN SEE THEY'RE HOMOGEANIOUS AND THE RIGHT SIDE LOOK LIKE THE LEFT BUT IF YOU MEASURED IT, YOU WILL SEE STRUCTURAL ASYMMETRY, THAT IS ONE IS TYPICALLY LARGER AT LEAST IN FISH AND PEOPLE ARE TRYING TO UNDERSTAND WHAT THAT MEANS AND IT HAS SOMETHING TO DO WITH MAKING IT MORE EFFICIENT FOR THE FISH TO PROCESS THE INFORMATION NEEDED FOR THESE SOCIAL INTERACTIONS. IF YOU LOOK AT THE INPUTS TO THE HABENULA IN FISH, YOU SEE THEY COME FROM THE SEPTUM, THE DIAGONAL AS WELL AS ON SENSORY STRUCTURES SUCH AS OLFACTORY BULB, THE PINEAL, AND THE LATERAL LINE. SO THE CONCLUSION HAS BEEN THAT THE HABENULA IS A HIGHLY CONSERVED STRUCTURE THAT INTEGRATES EXTERNAL SENSORY INFORMATION TO THEN BE USED TO GUIDE BEHAVIORIAL CHOICES. NOW WHAT'S INTERESTING IS THAT IF YOU LOOK AT THE HABENULA, AS ONE MOVES THE MORE COMPLEX BRAINS FOR EXAMPLE IN THE MOUSE HERE AND MONKEY AND PATIENTS IN THE CLINIC--PICTURE IN HUMANS TO SHOW YOU HOW TINY IT IS IF YOU LOOK HERE, JUST BASED ON SIMILAR OR COMPARISON OF THE CHEMICAL CHARACTERISTICS, YOU SEE THAT THIS PART--THIS PART HABENULA BECOMES THE MEDIAL HEALTH BENEFITS AND HEALTH BENEFITS AND--HABEIN, ULA, AND SEEMS LIKE A LATERAL WING EVOLVES AND IT EVOLVES GREATER AS IT GOES THROUGH THE MONKEYS. IT'S A LARGER COMPONENT OF THE HABENULA ITSELF. AND THEN ALSO IF YOU LOOK CLOSELY AT IT, YOU FIND THAT UNLIKE IN FISH, THE HABENULA IN MICE AND MONKEYS SHOW LESS STRUCTURAL ASSEMETRY BUT BASED ON GENETIC IDENTIFICATION OF CELLS IN THE RIGHT AND LEFT SIDES, THERE MAY BE SOME FUNCTIONAL ASYMMETRY. I THINK WE DON'T KNOW WHAT THE SIGNIFICANCE IS, BUT THERE'S FURTHER EVOLUTION ESPECIALLY THE LATERAL HABENULA, NOW GIVEN IT HAS ENLARGED, PERHAPS CO-EVOLVED WITH THE GROWING CORTEX, SUGGEST TO SOME FOLKS THAT PERHAPS THE HABENULA HAS EVOLVED TO,A LOW MORE COMPLEX SENSORY PROCESS SAYS TO GUIDE CHOICES OF ANIMALS. OKAY, SO THAT'S A THEME I WILL COME BACK TO HERE. OKAY. NOW THIS IS AN EXAMPLE OF A FIGURE THAT CAME FROM A LAB THAT ILLUSTRATES THAT NOT ONLY IS THE MEDIAL HABENULA, NOW AT LEAST IN MICE AND MONKEYS, THE LATERAL HABENULA HAS BEEN SUBDIVIDED INTO THE MEDIAL COMPONENT AS WELL AS LATERAL COMPONENT. AND I WANT TO POINT THIS OUT TO SHOW THAT IT SEEMS TO BE CHANGING AGAIN AS BRAINS GET MORE COMPLEX AND THIS IS JUST AN EXAMPLE OF THE DIFFERENT KINDS OF INPUTS, LIMPIC INPUTS THAT COME INTO THE ESPECIALLY THE MEDIAL HABENULA, AND THERE ARE SOME THAT GO INTO THE LATERAL HABENULA, THAT COULD SEND MESSAGES OUT TO STRUCTURES THOUGHT TO CONTROL BEHAVIOR. NOW THIS HERE IS SORT OF A RAT VERSION OF THAT SLIDE WHERE AGAIN, THIS IS--IN THIS CASE, THIS IS THE HABENULA, THESE REPRESENT THE LOWER BRAIN STRUCTURES, FOR EXAMPLE INFORMATION ABOUT TENSION, EMOTIONAL STATE, MOTIVATION, AROUSAL AND THAT'S LATERAL HYPOTHALAMUS, LATERAL AREA, THE NUCLEUS,--VENTRAL DIAGONAL BAND OF BROCA. NOW SHOWN HERE IS THE PREFRONTAL CORTEX HAS DIRECT INJECTIONS INTO THE HABENULA, THIS SHOWS IN RATS AND MICE THAT THE HABENULA CAN BE SEPARATED INTO MEDIAL AND LATERAL COMPONENTS AND IN THIS CASE, THE RED REPRESENTS THE MEDIAL AND BLUE IS THE LATERAL AND YOU CAN SEE A LOT OF THEEDZ INPUTS GO TO THE MEDIAL PART OF THE HABENULA AND BOTH MEDIAL, LATERAL OUTPUTS GO TO OVERLAPPING STRUCTURES, FOR EXAMPLE, THE VTA AND THIS SOME CASE THE MEDIAL HAS PREDOMINANT TO THE RAF-A AREA AND THAT MAY BE IMPORTANT IN A BIT AND I'LL COME BACK TO THAT POINT. NOW THE FEEL FOR THOSE WHO STUDY THE HABENULA KNOW THAT THE FIELD IS CONSTANTLY CHANGING. IN FACT, NOT TOO LONG AGO, WE DISCOVERED THAT THERE'S ALSO A DIRECT PROJECTION FROM THE SUPER CHIASMATIC NUCLEUS, SO INFORMATION ABOUT ONE CIRCADIAN STATE ARRIVES IN THE HABENULA PRESUMABLY TO GUIDE BEHAVIOR. ANOTHER PAPER CAME OUT RECENTLY THAT SHOWED IF YOU RECORD FROM THE NEURONS THERE IS INTRINSIC OF OSCILLATION OF NEURAL ACTIVITY, FOLLOWS THE DISCIPLINARY UNREGISTEREDDAL CYCLE. IT MUST MODIFY ITS ROLE IN NOW, OKAY, BASED ON REALLY AGAIN, THE ELEGANT WORK OF A NUMBER OF FOLKS AND ESPECIALLY THE LAB HERE HAS SHOWN OF WHICH THERE'S MANY REVIEWS OUT THERE. SO I WILL JUST SUMMARIZE THE--THOSE PAPERS RIGHT HERE AND THAT IS THAT REALLY THE LATERAL HABENULA SEEMS TO PROCESS EXTERNAL CONTEXT AND GOAL RELATED INFORMATION WHICH CAN THEN BE USE TO BE PASSED ON TO STRUCTURES TO CONTROL THIS HERE. AND THIS INCLUDES RESPONSES TO BOTH AVERSIVE AS WELLA AS APPETITIVE GOALS AND CUES. AND THIS HAS BEEN SHOWN IN PRIMATES MORE RECENTLY SHOWN IN RODENTS. NOW JUST TO SUMMARIZE THOSE DATA, THIS IS A FIGURE THAT SUMMARIZES REALLY THE SEQUENCE OF EVENTS AND DIFFERENT STRUCTURES THAT HAPPENS WHEN ANIMALS ARE EITHER PUNISHED OR EXPOSED TO NEGATIVE REWARD PREDICTION SICKINALS, YOU SEE GENERALLY THERE'S INCREASE IN ACTIVITY IN THE GLOBEUS PALLETUS, AND THIS RESULTS IN A DECREASE OF THE DOPA MINE NEURONS WHICH BEHAVIORIALLY ENDS UP DISCOURAGING ACTIONS THAT RESULTED IN THAT CONFENCE AND THEN THE FLIP SIDE OF THAT IS IF THERE'S REWARD OR POSITIVE PREDICTION SIGNALS WHAT YOU SEE IS A REDUCTION IN ACTIVITY IN THESE FIRST THREE STRUCTURES OF THE HABENULA, FOLLOWED BY ACTIVITY IN THE DOPA MINE NEURONS AND THAT LED TO THIS PARTICULAR OUT COME. --THIS SUGGESTED MAYBE THERE IS DIRECT HIGH TO MEMORY SYSTEMS SUCH AS PREFRONTAL SYSTEM AND THE HIPPOCAMPAL SYSTEM THAN I HAD ORIGINALLY THOUGHT. AND ONE THING TO NOTE, FIRST OF ALL IS THAT THAT SEQUENCE OF STRUCTURES THAT I DESCRIBED IN THE PREVIOUS SLIDE IS NOT ABSOLUTE. THAT IS THAT ONE CAN HAVE THE LESION, OR THE LATERAL HABENULA AND THIS REPRESENTS, FREEZING FOLLOWING FEAR CONDITIONING, CONTROL DATA SHOWING INCREASED FREEZING OVER A NUMBER OF TRIALS AND THE RMTG LESION AND YOU SEE THAT THE FREEZING IS IMPAIRED IN THE SAME TASK WITH THE HABENULA LESION, THERE'S NORMAL ACQUISITION AND NORMAL RETENTION OF THE FREEZING RESPONSE. SO THIS SUGGESTS THAT THESE TWO STRUCTURES REALLY THEY HAVE DIFFERENT INFLUENCES ON TO THEMSELVES THAT DETERMINE THEIR ROLE INY ABOUT HAIEVER. IT'S ALSO THE CASE THAT LATERAL HABENULA LESIONS, THAT BLOCK THOSE IN STRESS AND THAT'S REPEAT COMMON PHENOMENON THAT'S REPEATE MANY TIMES AND LATERAL LESIONS DO NOT IMPAIR FEAR LEARNING ITSELF AND SO THAT HAS SUGGESTED THE TO SOME THAT THE HABENULA HAS A GENERAL ROLE IN ADAPTATION OF LEARNED RESPONSES AS OPPOSE TO LEARNING THE RESPONSE ININITIALLY AND BEYOND CONTROL OF EXPLICIT RESPONSES. ALSO I WANT TO JUST POINT OUT THAT THE CIRCUIT IS MORE COMPLEX THAN THE PREVIOUS SLIDES SUGGESTED AND THAT IS THAT THE HABENULA LESIONS ONLY PARTIALLY ALTER THE REWARDS BY DOPAMINE NEURONS THAT IS OTHER FACTORS THAT CONTROL DOPAMINE CELLS TO RESPONSES TO REWARDS. OKAY, NOW, THESE ARE OTHER DATA& THAT CAME OUT OF STAN FLORESCO'S LAB, AND HE SHOWED THAT THE PROBABILITY AND DELAYED DISCOUNTING FUNCTIONS AND HE SUGGESTED THAT THE HABENULA IS IMPORTANT WHEN ONE NEEDS TO DETERMINE CHOICES AND WHETHER BEHAVIOR CHANGE IS NEEDED. SO IN THIS CASE, HERE, THIS IS PROBABLYITY DISCOUNTING TASK AND THIS IS THE PROBABILITY OF WHAT WE CALL THE LARGE REWARD BUT VARYING PROBABILITY LEVER OF RAT WHEN IS THEY'RE PERFORM NOTHING A TWO CHOICE LEVER PRESSING BOX. SO THIS CASE IS A PROBABILITY HUNDRED PERCENT THAT THEY GET THE LARGE REWARD, AND CONTROL ANIMALS SELECT THAT LEVER ALL THE TIME BUT AS A PROBABILITY GOES DOWN YOU SEE THIS NICE DISCOUNTING FUNCTION SO THEY SELECT THAT LARGE LEVER LOSS. ON THE OTHER HAND THEY SHOW NO LESION AT ALL. THEY'RE AT CHANCE. NOW TO MAKE MORE DIRECT CONNECTION OF THE HIPPOCAMPAL BASE LEARNING SYSTEM, IT'S--ALSO BEEN A FEW STUDIES NONAPOPTOTIC YOU THAT HAS SHOWN THERE SEEMS TO BE STRONG FUNCTIONAL TILES BETWEEN HABENULA AND HIPPO CAMPUS. SO IN THIS CASE, THAT THIS IS AN EXAMPLE OF A WATER MAZE TASK WHERE ANIMALS SWIM AROUND AND FIND THE LOCATION OF AN ESCAPE PLATFORM AND THEN YOU CAN MOVE THAT FLAT FORM AND YOU LOOK TO SEE WHERE THEY SPEND MOST OF THEIR TIME. CONTROL ANIMALS WILL SPEND THE TIME AROUND THE AREA WHERE THE PLATFORM USED TO BE BUT THE HABENULA IN ACTIVATION, YOU FIND THAT THE ANIMALS BECOME TOXIC, THEY TEND TO HUG THE WALLS WHEN THEY'RE INFUSED INTO THE HABENULA, OR THE LATERAL HABENULA, AND YOU ALSO SEE A SIMILAR KIND OF PATTERN THAT IS KIND OF IMPAIRS THEIR ABILITY TO REMEMBER WHERE THAT SPATIAL LOCATION IS. THESE HERE ARE NOW A SUMMARY OF DATA SHOWING THAT THE AMOUNT OF TIME THAT ANIMALS SPEND IN THE CORRECT QUADRANT IS PRETTY HIGH FOR CONTROL BUT IS IMPAIR INDEED ENACTIVATED--ENACTIVATED ANIMALS. NOW SHORTLY JUST AGAIN, A FEW YEARS AGO, THERE WAS A STUDY THAT CAME OUT OF Mc CORDY'S LAB, THAT WHEN YOU RECORD THE THETA IN THE HAIP O CAMPUS, SIMULTANEOUSLY THAT YOU FIND IN ANIMALS THAT ARE EXPLORING AROUND AND IN AN OPEN AREA THAT--AND THIS IS THE RAW SIGNAL, THIS IS THE FILTER SIGNAL, SO YOU CAN SEE THE OSCILLATIONS MORE CLEARLY AND THESE RED LINES ILTRAIT TO YOU THAT THEY ARE ACTUALLY IN SYNCH, THEY ARE FIRING WHEN THE ANIMALS ARE EXPLORING. ONE WAY TO SHOW THIS IS AT A POPULATION LEVEL, AS A FUNCTION OF TIME IN THIS HERE ASK IS DIFFERENT FREQUENCIES IN THE LFP THAT WERE RECORDED BUT THIS RED BAND OCCURS AT ABOUT THE THREATA FREQUENCY. IT'S IT'S PRETTY CONSISTENT BUT UNIQUE. THERE'S A GAMMA FREQUENCY BUT THE PREDOMINANT PATTERN IS THE THETA FREQUENCY. SO IF YOU RECORD AND PLOT AS A FUNCTION OF TIME AND SLEEP THAT DURING REMETABOLISM SLEEP SHOWN BY THE BLACK BOX HERE THERE'S THETA COHERENCE AS WELL. THAT HAS IMPORTANT IMP LIAISON KAIGDZS PERHAPS FOR DURING MEMORY AND MEMORY CONSOLIDATION. SO THESE ARE JUST QUANTITATIVE DATA THAT SHOW THAT USING A COHERENCE INDEX SCORE IN THE COUPLE VARIATIONS OF THE SAME THEME AND THAT IS THAT DURING SLEEM OR DURING EXPLORATION, THE CO HERENT SCORES GREATER FOR THETA THAN IT IS FOR GAMMA BUT BOTH ARE SIGNIFICANTLY HIGHER THAN CHANCE. NOW IF YOU LOOK DOWN HERE IN THIS BOX, WHAT YOU SEE, WHAT THIS DOES IS IT PLOTS THE PHASE LEG BETWEEN THETA RECORDED IN THE HABENULA AND THE HIPPO CAMPUS. AND YOU CAN SEE THAT THE HIPPOCAMPAL PEAKS OCCUR BEFORE THAT WAS THE HABENULA, IT'S AS IF THE THETA LEADS THE THETA IN THE HABENULA. AND THIS IS TRUE REGARDLESS OF WHETHER THE ANIMAL IS SLEEPING OR IN REMETABOLISM SLEEP OR DURING EXPLORATION. THIS IS AN EXAMPLE OF THE OPEN FIELD THEY WAS JUST TALKING ABOUT, IN WHICH THOSE NEURDATA ARE RECORDED IN THIS SPLAYS, THERE ARE OBJECTED PLACED IN THE FIELD, AND SOMETIMES OBJECTS ARE IN THE SAME PLACE FOR EXAMPLE, HERE, SOMETIMES YOU'LL HAVE OBJECTS PUT IN A NEW LOCATION AND SOMETIMES THE EXPERIMENT WOULD PUT IN A NEW OBJECT, OKAY? SO WHAT THEY DID WAS LOOK AT SNIFFING TIME, RELATIVE TO EACH OF THESE OBJECTS AND CONTROL ANIMAL VS A BASE LINE OF SNIFFING OF FAMILIAR OBJECTS BUT IF A FAMILIAR OBJECT IS PUT INTO A NOVEL LOCATION, YOU CAN SEE THAT THE INCREASED SNIFFING TIME IS QUITE LARGE. THIS MIDDLE BAR HAS TO DO WITH A NOVEL OBJECTS, THEY INCREASE SNIFFING FOR THAT NOVEL OBJECT AS WELL, BUT AGAIN, THE BIG INCREASE HAS TO DO WITH NEW LOCATIONS OF FAMILIAR OBJECTS. WITH HABENULA IN ACTIVATION, YOU SEE THAT THIS COMES DOWN. THERE'S NO DIFFERENCE IN SNIFFING TIME ACROSS THESE DIFFERENT OBJECTS. SO AGAIN THIS IS ANOTHER EXAMPLE OF WHERE THE LESIONS PRODUCE A HIPPOCAMPAL LIKE MEMORY DEFICIT. THIS HERE THEN REPRESENTS WE HAVE A MORE OF A COMPLEX, OR INDEX OF RECOGNITION MEMORY AND THIS IS AGAIN ILLUSTRATES THAT WITH THE HABENULA ACTIVATION, THE ANIMALS ARE ABOUT CHANCE PERFORMANCE COMPARED TO CONTROLS. IN THIS LAST FIGURE HERE, THAL PLOTS THE--THIS PLOTS THE INDEXES ACCORDING TO THE DEGREE OF COHERENCE BETWEEN THE HABENULA AND HIPPOCAMPAL DORSAL THETA AND YOU SEE THE STRIKING CORRELATION. SO THE MORE COHERENCE THERE IS, THE BETTER THE ANIMALS REMEMBER THESE OBJECTS. SO NOW, I'VE MODIFIED MY MAP A LITTLE BIT AND I ADDED, YOU KNOW HIPPO CAMPUS AND IT'S POSSIBLE CONNECTIONS BECAUSE WE STARTED WONDERING, WELL WHAT ARE THE CONNECTIONS FOR THE STATE OF COHERENCE AND FUNCTIONAL CONNECTIVITY IN TERMS OF PERFORMANCE AND THIS IS OF COURSE NOT A STRAIGHT FORWARD ANSWER BECAUSE AS FAR AS WE KNOW NOW WITH CURRENT TECHNIQUES, DOESN'T MEAN IT CAN'T CHANGE THAT WE DON'T KNOW OF ANY DIRECT CONNECTION BETWEEN THE LATERAL HABENULA AND THE HYPOCAMPUS. SO WHAT I SHOW HERE IS, THIS IS WHAT I SHOWED YOU BEFORE THAT THE OUTPUT OF THE LATERAL HABENULA, IS SUCH THAT IT'S REALLY THE MEDIUM RFA, WHICH PROJECTS UP TO HIPPO CAMPUS, THIS IS THE MOST DIRECT ROUTE BACK TO THE HIPPO CAMPUS FROM HABENULA, LIKEWISE, THERE IS NO DIRECT PATTERN OR CONNECTION BUT IF INFORMATION GOES THROUGH THE PREFRONTAL CORTEX, WHICH GOES TO THE HABENULA, THAT IS SOMETHING OF INTEREST TO US BECAUSE THAT ENDS UP BEING A DIRECT CONNECTION. NOW AS I SAID, THE LITERATURE CONTINUES TO CHANGE PRETTY QUICKLY SO I NOW ADD THIS ONE STRUCTURE, THE IN YOU CLEUS, WHICH IS INTERESTING BECAUSE THE LATERAL HABENULA, OF THE NUCLEUS BUT THIS ALSO PROJECTS BACK TO THE CAMPUS, BUT THIS ALSO HAS TIES TO STRUCTURES LIKE THE SUPO MAMMARY NUCLEUS AND THE SEPTUM IN THE BRAIN'S GENERATION OF THE THETA. AND THESE ARE RECIPROCAL CONNECTIONS SUGGESTING THAT THE IPN MAY PROVOID A LINK THAT MAY HELP IN THE SYNCHRONIZATION OF THETA AND THESE TWO STRUCTURES AND AGAIN, THIS IS JUST ONE MY GUESS IS THAT THERE WILL BE MORE. SO PROBABLY THE STORY WILL BE MUCH MORE COMPLICATED THAN BEFORE BEFORE IT BECOMES MORE SIMPLE. OKAY. OKAY. SO, SINCE WE DON'T KNOW THAT THERE'S--ABOUT DIRECT CONNECTIONS, WE KIND OF TOOK THE PROBLEM OF TRYING TO UNDERSTAND THE RELATIONSHIP BETWEEN HIPPO CAMPUS AND HABENULA AND TURNED IT OVER AND LOOKED AT IT FROM A DIFFERENT ANGLE. BUT WE ASKED IS NOT THE HABENULA IS IMPORTANT FOR ADAPTIVE NAVIGATION, A FUNCTION WE KNOW HIPPO CAMPUS IS CRITICAL FOR. IT'S A MORE SIMPLE QUESTION, WHETHER OR NOT THE HIPPO CAMPUS IN THE COMPLEX, WHETHER THEY SPEAK THE SAME LANGUAGE? DO THEY ENCODE SIMILAR KINDS OF INFORMATION? WELL I WILL TELL YOU RIGHT NOW THAT WE HAVE GONE AND RECORDED AND BOALGT THOSE STRUCTURES THE VTA AND THE HABENULA, IN ANIMALS THAT ARE PERFORMING A HIPPOCAMPAL DEPENDENT TASK. THERE'S NO PLACE FIELDS IN THE VTA, NO PLACE FIELDS IN THE HABENULA, PERHAPS NONAPOPTOTIC THE SURPRISING BUT WE HAD TO MAKE SURE THIS IS NOT THE CASE. BUT I SHOW THIS TO SHOW THAT IN ANIMALS THAT ARE PERFORMING A HIPPO CAMPAAL TASK, WHERE WE PRESENT FOUR ARMS FITTER AND THE ANIMAL MUST GO DOWN TO THE END OF THE ARM WHERE THEY GET FOOD AND FOR THESE EIGHT ARMS EVERY OTHER ARM IS BAITED WITH EITHER A LARGE REWARD WHICH IS FOUR SUGAR PELLETS AS OPPOSE TO A SMALL REWARD WHICH IS A ONE SUGAR PELLET. SO WHEN THE ANIMAL ENTERS, THEY HAVE EIGHT CHOICES WHEN THEY COME TO THE CENTER AND THE GOAL IS TO SELECT THOSE ARMS THEY HAVEN'T VISITS TO SECURE THE REWARDS AND WE CAN SHOW THAT THE ANIMAL UNDERSTANDS THAT THOSE FOUR ARMS BECAUSE THEY HAVE A BIAS, THEY GO TO A LARGE REWARD ARMS BELOW THE REWARD ARMS AS THEY SHOVEL--SOLVE THE TASK. AND I WANT TO SHOW THAT WHEN YOU RECORD FROM THE VTA, THE LARGE WARDS, WE SEE THIS NICE HIGH FREQUENCY PHASIC RESPONSE OF THE DOPAMINE NEURONS FOR WHAT HAS BEEN REPORTED FOR PRIMATES, AND THE ANIMALS ENCOUNTER LARGE REWARDS AND SMALL REWARDS AND MORE IMPORTANTLY WE'RE INTERESTED TO SEE WHETHER OR NOT WE SEE EVIDENCE OF REWARD PREDICTION DURING SPATIAL NAVIGATION WHICH IS WHEN WE REMOVE REWARD THAT IS WHEN AN ANIMAL GOES TO THE END OF THE ARM AND EXPECTING A REWARD AND IT'S NOT THERE. SO WE SEE NEGATIVE PREDICTION THERE SIGNALS. NOW THESE ARE DATA TAKEN FROM SCAN SICKLICAL DATA I COLLECTED WITH IN COLLABORATION WITH PAUL PHILLIPS AT THE UNIVERSITY OF WASHINGTON. WE WERE MONITORING THE RELEASE AS A FUNCTION OF SPATIAL MEMORY TASK AND WE SEE LARGER INCREASE OF DOPAMINE WHEN THE LARGER RELATIVE TO SMALL REWARDS AS WOULD HAVE BEEN PREDICTED BASED ON THE PRIMATE LITERATURE. THIS IS JUST AN OVERALL SUMMARY, POPULATION SUMMARY OF DOPAMINE REWARDS SHOWN IN RED, BLUE IT'S HARD TO SEE BECAUSE THEY OVERLAP, YOU SEE THIS A POPULATION RESPONSE TO LARGER AWARD AND IN THIS BAR GRAPH, CAN YOU SEE THAT THE RESPONSE TO THE LARGER REWARD IS PART OF A RESPONSE TO THE SMALL REWARD AND DURING CHOICES WHERE THE REWARD HAS BEEN UNEXPECTEDLY REMOVED, YOU SEE THAT AGAIN AS A GROUP, THAT THEY'RE SHOWING THIS NEGATIVE PREDICTION AND A SIGNAL. WELL WHAT ABOUT THE HABENULA, WELL, WE HAD ANIMALS TRAINED ON THE SAME TASK AND WE SEE SLIGHT DIFFERENCES AND WE SEE THE ANIMALS MOVING ALONG TIME AND THE TIME ZERO IS THE TIME WHEN THEY ENCOUNTER THIS LARGE REWARD OR SMALL REWARD AND YOU CAN SEE THEN THAT THERE IS A RESPONSE TO REWARD IN THE TWO CASES, IT'S NOT AS SHARP AS WAWE HAD SEEN WITH THE DOPAMINE NEURONS. OKAY. THE OTHER THING TO NOTICE IS THAT WHILE THE ANIMALS MOVING AROUND THE MAZE ON THE WAY TO REWARD. THAT WOULD REFLECT THIS TIME PERIOD HERE, YOU SEE THAT THERE'S ACTUALLY EVEN A LARGER INCREASE IN FIRING. THE RED LINE IF YOU CAN SEE IT AROUND THE BLACK, THAT REPRESENTS THE VELOCITY OF THE ANIMALS. IT'S HIGH HERE AND BECOMES VERY LOW AS THE ANIMAL ENCOUNTERS A REWARD AND YOU CAN SEE THAT AS THE VELOCITY GOES DOWN, SO DOES THE RATE. NOW YOU CAN ALSO SEE THAT IN TIME WHEN IS WE EXPLICITLY REMOVE THE REWARD SO THAT THE ANIMAL NOW ENCOUNTERS A LOCATION WITH UNEXPECTED REWARD OMISSION, WE SEE EVIDENCE OF NEGATIVE PREDICTIONARY SIGNALS WE ALSO SEE EVIDENCE OF POSITIVE REDICTION SIGNALS. WE HAVEN'T RECORDED ENOUGH CELLS TO MAKE ANY MAJOR CONCLUSIONS ABOUT THAT BUT I WANT TO POINT OUT THAT BASICALLY WE'RE SEEING SIMILAR KINDS OF RESULTS AS BEEN REPORTED FOR PRIMATES BUT SIMILAR TO WHAT WE HAD SEEN IN THE VTA. SO NOW WE SPLIPPED A QUESTION AND WE KNOW THERE'S NO SPATIAL CODING IN THE VTA AND THE HABENULA, IS THERE REWARD CODING IN THE HIPPO CAMPUS. SO WE SET OUT TO ANSWER THAT QUESTION. WELL, FIRST I WANT TO SAY AGAIN IS TO SHAY THAT WE AND LITTLERS WHO HAVE LOOKED FOR THIS, HAVE NOT BEEN ABLE TO FIND PHASIC RESPONSES TO HIPPOCAMPAL NEURONS TO REWARD ENCOUNTERS THAT WOULD LIKE LIKE WHAT WE SEE IN THE VTA ORIGINAL HPV-OR LATERAL HABENULA. DOESN'T MEAN IT'S NOT SENSITIVE TO REWARD INFORMATION SO IN THIS CASE AS YOU KNOW WHEN YOU RECORD HIPPO CAMPUS, THESE ARE PLACE FIELDS SO THESE ARE LOCATIONS SELECTED BY PARAMETER NEURONS AND THIS REPRESENTS THE ANIMAL TOOK IN WHITE AS THEY'RE PERFORMING THE PLUS MAZE TASK AND THE HEAT MAP SHOWS THE LOCATION OF THE FIRING OF THE CELL BEING RECORDED. NOW IN THIS TASK, THIS DIVIDED INTO TWO PHASES SO HERE THE ANIMAL CAN START FROM EITHER THE NORTH, WEST, OR SOUTH ARMS TO FIND FOOD IN THE EAST ARM. AND SO AT THE START OF THE TRIAL, WE WILL PUT HIM IN AN ARM AND THE GOAL IS SIMPLY JUST TO MOVE TO THE EAST ARM TO FIND FOOD. THEN WE HAVE THE ROOM LIGHTS GO OFF AND ON AS A CUE THAT THE REWARD LOCATION HAS NOW SWITCHED TO THE OPPOSITE ARM. SO FOR THESE TRIALS THE REWARD IS FOUND ON THE OPPOSITE SIDE ON THE WEST SIDE BUT THEY START FROM THESE ARMS HERE. SO THIS REPRESENTS CONTEXT A, THIS REPRESENTS CONTEXT B. NOW IN THE VERY BEGINNING OF TRAINING FOR A GIVEN RAT, WE HAVE FOOD PELLETS RANDOMLY SCATTERED THROUGHOUT THE MAZE FOR THE FULL DURATION OF THE TRIALS, JUST TO SHOW THAT THEY'RE RABLY AND CONSISTENT THROUGHOUT OUR RECORDING SESSION. HOWEVER ONCE YOU START TRAINING ANIMALS TO EXPECT REWARDS IN DIFFERENT LOCATIONS DEPENDING ON CONTEXT A OR B, WHAT YOU SEE IS SOMETHING VERY INTERESTING. SO IN THIS CASE, HERE THE ANIMAL IS MOVING TO THE EAST ARM TO FIND FOOD IF YOU JUST RECORDED IN THIS CASE, YOU WOULD SAY THAT'S NOT IMPRESSIVE, THE CELLS ARE NOT FIRING, THERE'S NO PLACE FIELD. BUT A FIELD EMERGES WHEN THE ANIMALS FORM A REWARD LOCATION CONDITIONS EACH THOUGH THEY'RE PASSING THROUGH THE CENTER AREA IN BOTH CASES. THE PASSING THROUGH THE SPACES IN BOTH CASES, THE DIFFERENCE IS THE EXPECTATION OF WHERE TO FIND REWARDS AND YOU CAN SEE THERE'S A NICE FIELD HERE. THIS REPRESENTS THE COMPARISONS OF THE PLACE FIELDS OF ANOTHER CELL IN CONTEXT A, B, AND YET ANOTHER CELL CONTEXT A, CONTEXT B. SO THIS SUGGESTS THAT KNOWLEDGE ABOUT THE EXPECTED LOCATIONS OF REWARDS DIRECTS THE HYPOCAMPAL PLACE CELLS TO EXHIBIT FIELDS IN PARTICULAR CONTEXT FIELDS LOCATIONS. NOW IN THIS TASK, WHEN ANIMALS ARE PERFORMING THIS TASK, IT'S CASE OF WHEN THEY FIND THEIR FOOD, THE EXPERIMENTER, LITERALLY THIS, IS ON AN AUTOMATED VERSION SO WE PICK UP THE RAT AND PLACE THEM OVER HERE ON THE PLATFORM FOR THE INTERVAL AND WHILE THE EXPERIMENT REBATES IN THE ARM AND THEN WE PICK THEM UP AND PUT THEM ON ONE OF THESE THETA LOCATIONS, WELL WHEN THE ANIMAL WAS HERE, WE ARE RECORDING THE NEURAL ACTIVITY. THIS IS SHOWN IN THE HISTOGRAM HERE EACH BOX IS DATA FROM ONE CELL. THIS IS TIME ON THE X AXIS AND EACH OF ROWS REPRESENTS A SINGLE TRIAL INTERVAL AND THIS IS A THE CELL.SHOWING THE FIRING OF YOU CAN SEE ESPECIALLY IN THIS ONE THAT WHEN ANIMALS ARE MOVING TO THE EAST VERSUS MOVING TO THE WEST, THIS IS CONFIXTURE A, CONTEXT B THAT THIS CELL FIRES AT THE BEGINNING OF THE INTERTRIAL INTERVAL MORE SO IN A THAN IN CONTEXT B. IF YOU LOOK AT THE DIFFERENCE BETWEEN THE FIRING PATTERNS AND THE TOP OF THE BOTTOM FOR ALL OF THESE DIFFERENT PLOTS, CAN YOU SEE LOTS OF EVIDENCE FOR DIFFERENTIAL FIRING. FOR EXAMPLE HERE'S ANOTHER ONE. DOESN'T FIRE SO MUCH IN CONTEXT WHEN THE ANIMALS ARE WAITING DURING CONTEXT A TRAINING, VERSUS CONTEXT B TRAINING. SO THIS SUGGESTS THAT HIPPO CAMPUS, IT EITHER RETAINS THE INFORMATION OR SOMEHOW IT HAS ACCESS TO LONG-TERM--LONGER TERM MEMORIES, NOT IMMEDIATE MEMORIES THAT REPRESENT THE REWARD INFORMATION AND IN THIS CASE, REWARD LOCATION AND THAT SEEMS TO DRIVE AND DETERMINE PATTERNS OF CELL FIRING. AND THIS DOWN HERE ILLUSTRATE FIST YOU COMBINE ALL THE CELLS TOGETHER, WE HAVE ALL THE DIFFERENT TIME PERIODS REPRESENTED SO PERHAP THIS IS IS REPRESENTING TIME LIKE FUNCTIONS. THAT'S ANALOGOUS TO THE CELLS THAT HOWARD HAS DESCRIBED IN HIPPO CAMPUS. SO AGAIN, ARE SENSITIVE TO REWARD LOCATIONS AND THEY DON'T SHOW THE PHASIC RESPONSES TO REWARDS. WHAT ABOUT OTHER ASPECTS OF REWARD CODING? --AND THIS IS SHOWN HERE IN THIS PARTICULAR EXAMPLE THAT WHEN THE REPORT PROBABILITY WAS ABOUT 50% THAT'S WHEN YOU SAW THE LARGEST OR LARGE RESPONSE TO THE CUES THAT PREDICT REWARDS THAT HAPPEN AT THE SECOND ARROW HERE, OKAY? AND THIS IS CONNIVITIENT AS YOU INCREASE THE PROBABILITIES. SO WHAT WE DID WAS WE DEVELOPED A MAZE BASED VERSION OF A PROBABILITY TASK AND SO THAT WE CAN ASSESS HIPPOCAMPAL NEURON RESPONSES TO PROBABILITY CHANGES IN EXPECTATIONS OF REWARD. SO LET ME JUST EXPLAIN THE MAZE FIRST AND THEN, IF YOU WANT MORE DETAILS ARE HERE, BUT I'M JUST GOING TO EXPLAIN IT FIRST AND SO THE ANIMAL MOVES AROUND THIS LOOP MAZE IN THIS DIRECTION LIKE SO. AND WHEN THEY START ON THIS ONE CORNER HERE, THEY CAN HAVE A CHOICE OF GOING THROUGH ONE OF TWO DOORS. IF THEY GO THROUGH ONE DOOR, LET'S SAY IT'S A TOP ONE, THAT MEANS WHEN THEY COME AROUND THE MAZE AND GET FOOD AT THIS FEEDER THAT THEY CAN EXPECT A LARGE REWARD, AGAIN FOUR PELLETS BUT ON A PROBABLISTIC SCALE, HUNDRED PERCENT OF THE TIME, 50 PERCENT OF THE IF I'M OR 25 PERCENT OF THE TIME OR 12 EXPW HALF PERCENT OF THE TIME. IF THEY GO THROUGH THE BOTTOM DOOR, THAT'S A CERTAIN DOOR AND WHEN THEY GO THROUGH THERE, THEY COME AROUND TO THE SAME FEEDER, THEY EXHIBIT THE SAME BEHAVIORS BUT THEY CAN EXPECT TO FIND ONLY ONE PELLET, A HUNDRED PERCENT OF THE TIME. SO THIS IS MEANT TO PARALLEL THE KINDS OF PROBABILITY TASKS THAT ARE CONDUCTED IN CHAMBERS. NO IMPORTANTLY WHEN THE ANIMAL COMES THROUGH, LET'S SAY A IT'S A 50% TRIAL, WHEN THEY COME THROUGH HERE, THE RISKY DOOR, THEY DONE KNOW FOR SURE WHETHER OR NOT THEY'RE GOING TO GET THE FOOD BECAUSE IT'S A 50% PROBABILITY BUT WE HAVE HERE WHAT'S CALLED A FEEDER TRIGGER THAT THERE'S ACTUALLY A SOUND, AUDITORY CUE THAT TELLS THE RAT THAT OH, FOOD IS NOW DISPENSIONED IN THE FEEDER SO THAT BECOMES THE CUE THAT PREDICTS REWARD ON THAT PARTICULAR TRIAL. IF IT'S A LOOSE TRIAL, IF IT'S ONE OF THOSE TRIALS WHERE THEY WILL NOT GET REWARD, THEN THE ANIMAL COMES OROUND HERE AND DOESN'T HERE THE TRIGGER AND YOU CAN TELL THEY KNOW THAT BECAUSE THEY WILL BYPASS THE FEEDER AND THEY WILL COME TO A START PLACE RIGHT HERE AND I WILL SHOW YOU A MOVIE ABOUT THIS IN A SECOND. OKAY? SO THIS REPRESENTS THE FACT THAT WE HAVE SEVERAL BLOCKS OF TRIALS IN A GIVEN SESSION AND WE FORCE CHOICE THEM THROUGH THESE& DIFFERENT DOORS SO THEY UNDERSTAND THE PROBABILITY SESSION FOR THAT SET OF TRIALS AND THAT'S FOLLOWED BY A SERIES OF FREE CHOICES. AND THEN WHEN THE NEXT PROBABILITY WILL BE TESTED, AGAIN WE HAVE FORCED CHOICES FOLLOWED BY FREE CHOICES AND SO ON. SO LET'S FIGURE HERE ILLUSTRATINGS THAT--ILLUSTRATES THAT ANIMALS UNDERSTAND THESE PROBABILITY CHANGES AND THEY ADJUST ACCORDINGLY SHOWING A NICE DISCOUNTING CURVE AND THIS IS EXAMPLES WHERE WE RECORD IN HIPPOCAMPUS. SO THIS IS NOW JUST THE MOVIE OF THE RAT GOING AROUND. IT'S KIND OF--THERE HE IS GOING THROUGH ONE OF THE DOORS AND THEN HE--DIDN'T GET FOOD BECAUSE HE DIDN'T HEAR THE TRIGGER. HE GOES THROUGH THE OTHER DOOR, HE HEARS A TRIGGER, PAUSES GETS HIS FOOD, COME, AROUND AND WAITS AND THE DOOR OPENS AGAIN AND HE GOES THROUGH--YOU CAN IMAGINE HIM, DARN IT, I KNOW I'M NOT GETTING ANY FOOD AND HE COMES RIGHT AROUND. THEY SHOW A LOT OF BODY LANGUAGE WHEN THEY DO THIS TASK, IT'S KIND OF INTERESTING. THEY LEARN IT QUICKLY AND THEY PERFORM 70-80 TRIALS IN LESS THAN AN HOUR. IT'S COMPLETELY NICE AND AUTOMATED. SO WHAT WE'RE INTERESTED IN IS HOW PLACE FIELDS RESPONDED IN THIS SITUATION. SO I WILL JUST GIVE YOU ONE OF OUR EXAMPLES WHICH ILLUSTRATES REALLY THE MAIN EFFECT. SO I JUST--WE TOOK THIS MAZE AND LINEARIZED IT HERE SO THIS TIME PERIOD IS A START DOOR, CHOIZ DOOR, THIS IS THE FEEDER TRIGGER AND THIS IS ABOUT THE TIME THE AN HAL ARRIVES AT THE FEEDER ITSELF AND WHAT'S SHOWNOT BOTTOM, WHAT WE HAVE SEPARATED HERE IS THE DISTRIBUTION OF THE PLACE FIELDINGS AS A FUNCTION OF PROBABILITY OF GETTING THE FOOD. SO THE LOWER BAR HERE, THIS IS ONE THAT'S HUNDRED PERCENT PROBABILITY WHEN THEY COME THROUGH THAT LARGE RISKY DOOR, THE NICK ONE IS 50% PROBABILITY TRIALS AND 12 AND HALF PERCENT PROBABILITY TRIALS. IN THIS CASE, THIS IS ALL WHAT I CALL WIN TRIALS. THEY CAME THROUGH HERE, THEY HEARD THE TRIGGER AND THEY WERE ABLE TO RECEIVE THE FOOD. IN THIS CASE, THESE ARE ALSO FOR THESE DIFFERENT PROBABILITY CONDITIONS BUT ON TRIALS WHERE THE ANIMAL LOSES, THAT IS THEY GO,A ROUND AND THEY DON'T GET THE FOOD. AND I THINK THERE'S COUPLE THINGS THAT ARE INTERESTING VISUALLY THAT IS THAT, IN THE HUNDRED% CONDITION, YOU SEE THERE'S PRETTY EVEN INTRIEWKS OF THESE PLACE FIELDS. OKAY? DOESN'T MATTER IF YOU WIN OR LOSE BUT AS THE PROBABILITY BECOMES MORE UNCERTAIN, WHAT YOU SEE IS THAT AFTER THE FEEDER TRIGGER YOU GET THIS REMAPPING OR REDISTRIBUTION OF PLACE FIELDS AND THEY TEND TO COALESCE AROUND THE LOCATION, AND THE DEGREE TO WHICH THIS HAPPENS SCALES WITH THE PROBABILITY OF THE TRIAL. SO THE LOWER PROBABILITY OF THAT TRIAL, YOU SEE THIS GREATER MORE ENHANCED TYPE OF REMAPPING THAT OCCURS. AGAIN, YOU SEE NO EVIDENCE OF THIS IN THE LOOSE TRIALS. SO THIS REPRESENTS AGAIN, THE SAME KIND OF DATA BUT NOW DIVIDED OUT MORE INTO THE WIN TRIALS, CERTAIN TRIALS WHERE THEY GO THROUGH THE DOOR WITH A CERTAIN REWARD BUT THEY ALWAYS HAVE HUNDRED PERCENT LIKELIHOOD OF GETTING THE REWARD. THESE ARE THE LOOSE TRIALS. AND I WANT TO SHOW AGAIN, THIS IS THE FORGS CHOICE VERSUS FREE CHOICE PHASES, SO BASICALLY IF ANIMAL'S GOING TO WIN, THEY WILL GET FOOD. YOU SEE THE SIMILAR KIND OF REMAPPING THAT APPEARS. AND CERTAINLY TRIALS, YOU SEE THAT THERE'S NOT SO MUCH IN THE FORCED CHOICE, YOU SEE IT DURING FREE CHOICE. SO THERE SEEMS TO BE AGENCY EFFECTS ON PLACE FIELDS AND OF COURSE IN LOSE TRIALS YOU SEE NO DIFFERENCE AT ALL. SO THIS SUGGESTED TO US THAT AT LEAST, IN HIPPOCAMPUS, WHILE THESE INDIVIDUAL CELLS ARE NOT RESPONDING TO REWARDS, IT'S VERY CLEAR THAT THESE CELLS INDIVIDUALLY ARE RESPONDING TO INFORMATION ECONOMIC INFORMATION ABOUT THE REWARDS. AGAIN THIS KIND OF ECONOMIC INFORMATION THAT STRUCTURES LIKE DOPAMINE NEURONS AND VTA DOPAMINE NEURON VS KNOWN TO BE RESPONSIVE TOO AND WE ALSO KNOW THERE'S THETA IN THE HIPPOCAMPUS AND WHAT WE WERE INTERESTED IN LOOKING AT AS A FUNCTION OF AGAIN, THESE LINEARIZED VERSION OF THE MAZE, WE WANTED TO KNOW WHAT THETA POWER LOOKED LIKE AS A FUNCTION OF AN ANIMAL MOVING AROUND THIS MAZE. CAN YOU SEE THERE'S A LOT OF VARIATION HERE BUT WE'RE INTERESTED IN WHAT'S HAPPENING AT THE FEEDER BECAUSE WE SAW THE LARGEST EFFECT ON THE PLACE FIELDS AND I DON'T KNOW IF YOU CAN SEE IT, THE BLUE AND THE GREEN ACTUALLY ARE OVERLAPPING SO ALMOST COMPLETELY THEY LOOK LIKE A SINGLE LINE BUT YOU SEE THE THETA POWER INCREASES BEFORE THE ANIMAL GETS TO THE FEEDER BUT AFTER THE FEEDER TRIGGER AND IT'S MUCH HIGHER THAN THE THETA POWER YOU SEE INCREASE DURING LOSE TRIALS AND WE CAN DIVIDE IT UP ACCORDING TO FORCED CHOICE OR FREE CHOICE TRIALS AND THEN COMPARE WIN, CERTAIN AND LOSS CONDITIONS AND AGAIN THE MAIN THING HERE IS THAT DURING WIN TRIALS YOU SEE SIMILAR RESPONSES WHETHER THEY'RE FORCED OR FREE AND I DON'T KNOW IF YOU CAN SEE THE DETAILS HERE BUT THE INCREASE IN THE AMPLITUDE OF THE THETA POWER SCALES WITH THE PROBABILITY. SO IN OTHER WORDS, THE LOWER THE PROBABILITY, THEY'RE EXPECTING THE REWARD, THE HIGHER THE AMPLITUDE OF THE THETA POWER IS AT THE GOAL LOCATION. YOU CAN ALMOST SEE THIS MORE CLEARLY. THIS IS AN INDIVIDUAL EXAMPLE OF THIS WHERE THE ANIMAL'S MOVING ALONG AND YOU CAN SEE THE FOUR DIFFERENT LINES HERE THAT CORRESPOND TO THE DESCENDING PROBABILITY OF THE REWARDS. NOW THOSE VARIATIONS IN THETA SUGGESTED TO US THAT THETA MIGHT BE ENCODING DIFFERENT ASPECTS OF REWARD OR DIFFERENT ASPECTS OF AT LEAST A TASK CONDITION AS A FUNCTION, AS ANIMALS MOVED AROUND THE MAZE, AND WE CALCULATED THETA POWER FOR DIFFERENT SEGMENTS OF THE MAZE THAT ARE NUMBERED HERE AND THIS IS LINEARIZED REPRESENTATION OF THE DIFFERENT REGIONS AND THEN WHAT WE DID IS WE CONDUCTED A MULTIPLE REGRESSION ANALYSIS AT EACH AREA WITH AGENCY, PROBABILITY OUTCOME AND VELOCITY AS POSSIBLE PREDICTERS SO WE CAN UNDERSTAND WHICH FEATURES OF THE TASK FOR THE ANIMALS BEHAVIOR MIGHT BETTER PREDICT THETA POWER IN THOSE SECTIONS. THERE'S ACTUALLY A LOT GOING ON HERE BUT THE MAIN THING I WANT TO POINT OUT AT THIS TALK IS THESE INCREASES HERE. THAT IS THAT, AT THIS RED ARROW HERE, THIS A TIME WHEN THE ANIMAL RECEIVES INFORMATION CUE THAT THEY'RE GOING TO BE GETTING THAT REWARD AND THAT CORRESPONDS TO THIS RED ARROW HERE AND IT'S THOSE FIRST, NEXT FEW SECTIONS, THESE FIVE, SIX, SEVEN HERE THAT YOU SEE THE OUTCOME IS THE STRONGEST PREDICTER OF THETA POWER, RELATIVE TO BEFORE, BUT AFTER THE ANIMAL RECEIVES THE REWARD, YOU SEE THAT THAT COMES DOWN UNDRAMATICALLY. SO THAT WOULD SUGGEST THAT AS ANIMALS ARE MOVING ACROSS THE MAZE, THESE DIFFERENT ASPECTS OF REWARD OR BEHAVIOR ARE BIASING THE AMPLITUDE OF THETA. THETA IS NOT PROCESSING ONLY A SINGLE TYPE OF INFORMATION. FOW ONE THING WE'RE LOOKING FOR BECAUSE WE KNOW THAT DOPAMINE NEURONS RESPOND TO CUES THAT PREDICT REWARD, IF PLACE CELLS THAT RESPOND TO THE PREDICTEDY REWARDS AND THE SHORT ANSWER IS NO, NOT AT ALL. THERE'S NO CORRELATION OR INCREASED FIRING. SO WE DID IMPLANT A COUPLE OF ANIMALS USING THE SAME TASK AND RECORDED FROM VTA DOPAMINE NEURONS AND THIS SHOWED HOW WE SORTED OUT OUR RECORDS ACCORDING TO STANDARD METHODS. AND THIS FIGURE HERE IS TIME, AND THIS IS A FIRING RATE OF THE DOPAMINE CELL THAT'S RECORDED AND YOU CAN SEE THERE ARE THESE PEEKS HERE AND IT JUST SO HAPPENS THAT THOSE PEEK CORRESPOND TO THE DELIVERY OF THE FOUR PELLETS AND THE DELIVERED SEQUENCE. IN OTHER WORDS THE DOPAMINE CELL WAS RESPONDING TO EACH OF THE FOUR PELLETS DURING THOSE RISKY WIN TRIAL BUT WHEN THE ANIMAL WENT THROUGH THE CERTAIN DOOR, THEY CAME AROUND AND THERE WAS ONE PELLET DIGS PENS AND YOU SAW THERE WAS ONE PEAK IN THE DOPAMINE CELLS. SO THIS HELPS TO GAIN CONFIDENCE THAT BOTH THE DOPAMINE--WE HAVEN'T TESTED THE HABENUWELL,A, BUT THAT SYSTEM IS ACTIVE AND PROCESSING REWARD INFORMATION DESCRIBING THIS TASK AND ALSO IN THE NAVIGATION BASED TASK WHERE WE RECEIVE THE HIPPOCAMPAL RESPONSES. OKAY. OKAY, SO, IN TERMS--JUST A SHORT INTERIM SUMMARY, WE FIND THAT THE THETA POWER IS REGULATED BY THE SPECIFIC ECONOMIC INFORMATION, NOT JUST SENSORY OR BEHAVIORIAL INFORMATION WHICH IS HOW IT'S TYPICALLY DESCRIBED AND THAT THIS INFORMATION SEEMS TO BE DYNAMIC THAT IT WILL ADJUST AND PAY ATTENTION, YOU MIGHT SAY TO DIFFERENT KINDS OF INFORMATION AS NEEDED AS ANIMAL TRAVERSE THIS MAZE. THE SIGNIFICANCE IN ELEVATION AND THETA POWER OBSERVED IF ANTICIPATION OF THE REWARD AND ENCOUNTERS THEMSELVES SO THEY CAN'T BE STRIGGERRED--TRIGGERED BY THE ACTUAL FOOD. AND THE INCREASE IN POWER, SCALED WITH THE PROBABILITY CONDITION OF THE TRIALS. OKAY? ALSO, IT'S--WE FOUND, OF COURSE THE VTA DOPAMINE NEURONS, CODE THE CUES THAT PREDICT REWARD ENCOUNTERS. SO THIS IS HOW WE'VE BEEN--FIRST APPROACHING THIS UNDERSTANDING OF MAYBE THE CONNECTION BETWEEN HIPPOCAMPAL MEMORY SYSTEMS AND THE VTA HABENULA SYSTEM; AGAIN COMPARING SIMILAR KINDS OF INFORMATION. WE CONCLUDE THAT THEY DO BOTH ENCODE REWARD INFORMATION ALTHOUGH IN DIFFERENT WAYS. OKAY? SO, ANOTHER QUESTION THAT WE ASKED IS--WE'RE CONCERNED ABOUT IS THINKING ABOUT WHAT INFORMATION HYPOCAMPUS MIGHT PASS ON TO THE HABENULA EVENTUALLY? SO WHEN THE INFORMATION IS PASS SAIDED ON TO PREFRONTAL AND WE KNOW WHAT'S PASSING ON TO THE HABENULA, AND OTHER VS DONE, AND OTHERS HAVE SHOWN THAT INDEED THE HIPPOCAMPUS AND PREFRONTAL CORTEX, THETA ENDS UP BEING CO- MODULATED AND THE CO-MODULATION IS RELATED TO THE CHOICES ANIMALS MAKE IN THE HIPPOCAMPAL RELATED TASK. THIS REPRESENTS THE CORRELATION BETWEEN THE COHERENCE BETWEEN HIPPOCAMPAL AND PREFRONTAL THETA AND YOU CAN SEE THAT HERE WHAT YOU--DURING--THIS IS DURING FORCE CHOICE TRIALS, DURING CHOICE TRIALS AND YOU CAN SEE IT'S GREATER DURING CHOICE TRIALS. WHEN THEY PLOT THE LAG TIME AND THAT IS THEY WANT TO KNOW IF HIPPOCAMPAL LEADS THE FREE RADICALS FRONTAL OR VICE VERSA, THEY SHOW THAT IT ACTUALING FOLLOWS THE FRONTAL. SO THE HIPPOCAMPUS IS LEADING THE FRONTAL SUGGESTING THAT THE INFORMATION IS MOVE NOTHING THAT DIRECTION. THIS IS JUST A BAR GRAPH SHOWING THAT THE PEAKS ARE GREATEST DURING CORRECT CHOICE TRIALS AND DURING ERROR TRIALS AND BOTH OF THOSE ARE GREAT DURING THE CHOICE TRIALS. SO WHAT INFORMATION IS PASSED ON TO THE FREE RADICALS PRONTAL CORTEX? --FRONTAL CORTEX? SO IN ORDER TO ANSWER THIS QUESTION, WE THOUGHT OF ANOTHER AREA OF RESEARCH THAT YOU MIGHT BE AWARE OF AND THAT IS WITH THE EXPERIENCE, THE HIPPOCAMPUS TENDS TO TEMPORAL LYE ORGANIZE THE PLACE FOR FIRING, NOT ONLY DURING PERFORMANCE BUT WHEN THE ANIMALS OUT--ASLEEP AFTER PERFORMANCE OR JUST ABOUT TO PERFORM A TASK AND THIS IS JUST AN EXAMPLE HERE. THIS IS THE CASE OF ANIMAL'S ASLEEP AND RECORDING FROM THESE DIFFERENT NEURONS, THEY WERE CELLS THAT WERE PLAS THESE ON MAZES AND THEN YOU JUST PLOTTED WHEN THE CELLS FIRING AS A FUNCTION OF TIME BUT THEY SHOULD BE RELATIVELY RANDOM IN A NAIVE ANIMAL. HOWEVER IF WHEN THE ANIMAL AWAKES AND YOU ASK THEM TO PASS THROUGH A PARTICULAR PLACE IN THE ENVIRONMENT WHERE THESE CELLS ARE ACTIVATED IN SEQUENCE, WHAT YOU SEE IS THAT IN THE FOLLOWING SLEEP PERIODS, THE SAME BEHAVIOR, THE FIRING OF THESE CELLS HAVE BEEN TEMPORALLY REORGANIZED THE MATCH, THAT THE ANIMAL'S EXPERIENCE DURING THE PERIOD, ALBEIT IN A SLIGHTLY COMPRESSED FASHION. SO THIS IS ONE OF THE INITIAL RESULTS THAT WAS DESCRIBED EARLIER, OF COURSE,--WHICH HAS LOTS OF IMPLICATIONS FOR MEMORY, CONSOLIDATION AND SO ON. SO THIS HERE JUST REPRESENTS A SUMMARY OF THIS PHENOMENON. AND NOW IT INCLUDES THE VENTRAL STRIATUM. THIS IS A CASE WHERE AN ANIMAL IS MOVING THROUGH THE PLATFORM HERE TO GET THE FOOD AT THE END. THESE ARE DIFFERENT--EACH ROW REPRESENTS THE HYPOTHETICAL FIRING OF HIPPOCAMPAL NEURON AND THE BOTTOM ROW IS THE FIRING OF THE VENTRAL STRIATAL NEURON. YOU CAN SEE THE CELLS SEQUENTIALLY ACTIVATED, NOT TOO SURPRISING AND THEN WHEN THE ANIMAL GETS THE REWARD, YOU SEE ACTIVATION OF A VENTRAL STRIATUM. AND AFTER THAT, THE ANIMAL IS PUT IN ANOTHER PLACE WHERE THEY'RE ALLOWED TO GO TO SLEEP, YOU SEE THE SAME TEMPORAL ORGANIZED SEQUENCE HAPPENING INCLUDING VENTRAL STRIATAL FIRING. IF AN ANIMAL IS AGAIN ALLOWED TO GO DOWN TO THE ARM, THEY HANG OUT IN THE BEGINNING FOR A BIT, THEY HANG OUT IN PLACE FIELDS, COME HERE, EATING THEIR FOOD, HANG OUT. YOU FIND SOMETHING INTERESTING. WHEN THE ANIMAL'S DONE WAITING AND THIS IS A TRAINED ANIMAL THAT'S BEEN ON THIS ARM BEFORE, WHAT YOU FIND IS THAT DURING THE SHOCK WAVE RIPPLES, THESE ARE LIE FREQUENCY OSCILLATIONS, YOU CAN SEE THAT THE SEQUENCE OF FIRING, OF THESE PARTICULAR CELLS MATCHES THE SEQUENCE, THAT THE ANIMAL EXPECTS TO EXPERIENCE WHEN THE ANIMAL GOES THROUGH THE ACTUAL PLACE FIELDS. AND THAT'S JUST SHOWN AS THESE COLORS MATCH THIS PROGRESSION RIGHT HERE. WHAT WAS ALSO INTERESTING IS THAT'S RECENTLY DISCOVERED ISA AFTER THE ANIMAL GETS TO THE END OF THE ARM AND THEY'RE LOOKING AROUND, WHAT YOU FIND IS THAT WHEN THESE SHOCK WAVE RIPPLES HAPPEN AGAIN, YOU WILL ALSO SEE THESE REPLAY EVENT BUT INSTEAD OF GOING TO THE FORWARD SEQUENCE, YOU SEE IT GOING REVERSE SEQUENCE. THESE ARE SOMETIMES CALLED REVERSE REPLAY AND THESE ARE SOMETIMES CALLED FORWARD REPLAY. AGAIN WE'RE TRYING TO UNDERSTAND THE SIGNIFICANCE OF THESE TWO BUT THE IMPORTANT POINT IS THAT EXPERIENCE ALTERS TEMPORAL FIRING PATTERNS OF THESE CELLS IN VERY INTERESTING WAYS AND EXPERIENCE DEPENDENT CONTEXT DEPENDENT WAYS. NOW THIS HERE JUST ILLUSTRATES AGAIN THE POWER OF THE METHOD AND WHEN THE ANIMAL GOES DOWN TO THE TEAMMATES AGAIN THIS IS A TRAINED ANIMAL SO WHEN THEY LOOK DOWN ONE SIDE, THEY HAVE EXPECTATIONS AND PLACES THEY WILL VISIT AND LOOK TO REWARD. WHEN THEY LOOK TO THE RIGHT, THEY HAVE EXPECT OF PLACES THEY WILL VISIT AND THIS CAN BE REFLECTED IN THE SEQUENTIAL FIRING PATTERNS THAT YOU OBSERVE WHEN ANIMALS EITHER LOOK TO THE LEFT OR THE RIGHT. YOU WILL SEE PRE-PLAY OF POSSIBLE PATHS. AND THEN THIS WILL MATCH WHATEVER THE ANIMAL HAPPENS TO PICK. OKAY? AND THEN AGAIN, THIS ONE LAST POINT WHICH I THOUGHT WAS THE MOST AMAZING ONE, IS WHEN AN ANIMAL GOES IN A NOVEL ENVIRONMENT, LET'S SAY THEY GO THRU THIS PATH, AS SHOWN BY THE DOTTED LINE AND WHEN THEY'RE UPHERE IN THE CORNER YOU ASK THE ANIMAL TO COME DOWN HERE AND GET THE REWARD. THEY WILL MAKE A STRAIGHT LINE DOWN HERE TO THE REWARD. THE QUESTION IS WHAT KINDS OF SEQUENCE PATTERN WILL YOU OBSERVE? WELL WHEN THE ANIMAL IS MOVING AROUND IN THE SPACE, IN A SECUREITOUS FASHION, YOU WILL SEE THAT THE PATTERN OF ACTIVITY WILL REFLECT THE FIELDS THAT I GO INTO. AND WHILE THE ANIMAL IS OUT HERE, THERE IS PREPLAY OF FIELDS THAT THE ANIMAL EXPECTS TO GET TOO EVEN THOUGH THEY'VE NEVER BEEN THROUGH THIS PARTICULAR PATH TO GET TO THE REWARD AND THAT IS SHOWN RIGHT HERE. OKAY. SO, IT'S NOW GENERALLY ACCEPTED THEN, THAT DURING SHOCK WAVE RIFFLE EVENTS AND--RIPPLE EVENTS AND NOW WE KNOW ALSO THAT THESE SEQUENTIAL EVENTS OCCUR DURING THETA. THESE EVENTS THAT ARE PARTICULARLY CONNECTED WITH THESE SEQUENCE EXHIBITIONS AND SO THAT SUGGESTS TO US THAT IF YOU'RE THINKING ABOUT, TRYING TO ANSWER THE QUESTION, OF WHAT INFORMATION HIPPOCAMPUS IS TRANSMITTING TO THE PREFRONTAL CORTEX THAT IT COULD BE THAT AND REMEMBER THIS HAPPENS WHEN THETA IS CO-MODULATED AND WE KNOW THAT THE SEQUENCES OCCUR WHEN THETA IS OCCURRING. AND SO, THAT SUGGESTS THAT HIPPOCAMPAL PLACE SEQUENCE MAY BE PART OF THE INFORMATION THAT'S TRANSMITTED TO THE PREFRONTAL CORTEX AND IF YOU THINK ABOUT, THE POTENTIAL IMPACT ON RESPONSE SELECTION, IT COULD BE THAT THAT HELPS THE PREFRONTAL CORTEX TO KNOW WHAT TO EXPECT IN THE FUTURE AND THAT MAY HELP GUIDE THE SELECTION OF BEHAVIORIAL RESPONSES. OKAY? SO THIS PRETTY MUCH SAYS WHAT I HAD SAID THAT HIPPOCAMPUS MAY PASS ON EXPECTED SPATIAL SEQUENCE INFORMATION TO THE PREFRONTAL CORTEX. OKAY, SO, BUT WHAT IS THE EVIDENCE THEN THAT THE LATERAL HABENULA IS REALLY IMPORTANT FOR FLEXIBILITY RESPONDING? OKAY THIS IS WHERE I STARTED OFF IN THE BEGINNING OF MY TALK.& SO FAR I TALKED ABOUT POSSIBLE PATHWAYS AND KINDS OF INFORMATION THAT MIGHT INFLUENCE THE LATERAL HABENULA, BUT THE QUESTION IS IS IT IMPORTANT FOR THESE COMPLEX DECISIONS THAT HAVE TO BE MADE WHEN ANIMALS HAVE TO RESPOND TO CHANGING ENVIRONMENTS IS IT IT--ENVIRONMENTS? SO WHAT WE DID IS RECORD THE NEURONS AND AS RATS ARE PERFORMING THE SAME HIPPOCAMPAL TASKS WE ACTUALLY FIND THERE ARE A GOOD NUMBER OF RESPONSE TO REWARDS AND ONLY THE VELOCITY OF THE ANIMAL AND SOME THAT ARE RESPONSIVE TO BOTH. THIS IS THE FIGURE I SHOULD SHOWED YOU EARLIER, SHOWING REWARD RESPONSIVENESS OF NEURONS AND THIS FIGURE, I WANTED TO SHOW IF YOU TAKE A TRAINING TRIAL, LET'S SAY 10 TRIALS AND BLOCK ONE, REPRESENTS THE FIRST FIVE TRIALS, BLOCK TWO IS SECOND FIVE TRIALS AND WE COMPARED THE CORRELATION BETWEEN THE FIRING RATE OF THE CELL AND THE VELOCITY OF THE ANIMAL AND WHAT YOU CAN SEE IS THAT THERE'S A LOT OF DOTS UP HERE IN THE UPPER RIGHT CORNER AND THEY ARE VERY HIGH SO THAT SUGGESTS THAT THE UNIT FIRING IS HIGHLY CORRELATED WITH THE VELOCITY OF THE ANIMAL, IN SOME CASES VERY STRONG NEGATIVE CORRELATIONS AND OF COURSE THERE'S SOME THAT ARE NOT CORRELATED SO IF WE LOOK AT THETA POIR AND CORRELATE IT WITH VELOCITY WE SEE A SIMILAR DISTRIBUTION THIS IS CLUMPING AND A LOT OF THEM TEND TO BE STRONGLY, OR POSITIVE NEGATIVELY CORRELATED SO IT'S AS IF THE HABENULA MUST BE RETAINING INFORMATION ABOUT THE BEHAVIORIAL STATE OF THE ANIMAL WHETHER THAT REFLECTS ACTUAL MOTOR ACTIONS OR INTERNAL STATE INFORMATION IS NOT CLEAR. THIS IS JUST SHOWING WE TRIED MANIPULATIONS OF REWARD OMISSIONS AND SO ON. AND WE DIDN'T SEE VERY MANY RESPONSES OF THESE VELOCITY CORRELATED NEURONS. SO, AGAIN, IS THIS REALLY EVIDENCE THAT THE LATERAL HABENULA DRIVES RESPONSES DURING NAVIGATION? THAT'S KIND OF CORRECT BUT THERE ARE OLDER DATA THAT SUGGEST AND I WILL SHOW YOU NEW DATA FROM OUR LAB THAT SUGGESTS THAT INDEED THIS IS POSSIBLY THE CASE. SO FROM THE 1980S, THEY ACTUALLY HAD ANIMALS THAT HAD LATERAL HABENULA LESIONS AND THEY FOUND RESPONSES WHEN THE PLATFORM OR A WATER MAZE WAS SWITCHED PERIODICALLY. SO CONTROL ANIMALS CAN LEARN THIS QUICKLY. THEY WILL LEARN THAT A SWITCH WILL HAPPEN BUT THEY ONLY TAKE A FEW TRIALS TO FIND THE NEW LOCATION AND THEY START GOING THERE. BUT THE ANIMAL VS A DIFFICULT TIME WITH THIS. AND THESE EARLY PAPERS THEY SHOWED THAT THE IMPAIRMENT AND THE ABILITY TO FLEXIBILITY RESPOND THEN WAS NOT DUE TO POOR ATTENTION, PROMOTER ABILITIES AS WELL AS SEPARATION AND THEY COULDN'T--THEY DIDN'T FIND ANY CHANGES, OKAY? SO THE QUESTION IS REALLY A DEFICIT DUE TO IMPAIRED RESPONSE FLEXIBILITY? AND SO THIS NOW THEN LEADS TO SOME OF THE MORE RECENT WORK& WE'VE DONE IN OUR LAB WHERE WE ARE TRYING TO ADDRESS THIS QUESTION. IN THIS CASE, WE HAD ANIMALS TRAINEDOT SIMPLE TASK WHERE THE ANIMAL COMES OUT HERE TO THE STEM, MAKES A LEFT OR RIGHT TURN AND GOES TO FIND FOOD WHERE THESE RED AREAS ARE. ONE CASE, THE FOOD IS FOUND THERE 80% OF THE TIME AND ON THE OTHER SLIDE 20% OF THE TIME AND LIKE MOST RATS IT WILL LEARN TO GO TO THE 80% SLIDE VERY QUICKLY. BUT WHAT WE DID WAS WE SAID ONCE THE ANIMALS LEARNED THIS TASK, WE SWITCHED IT SO NOW 80% IS ON THIS SLIDE AND 20% IS ON THE OTHER SLIDE AND THEN WHY WOULD SWITCH IT AGAIN AND WE KEPT SWITCHING ASK BACK AND FORTH UNTIL THE TRIALS WERE UP AND THEN WE COUNT TO THE NUMBER OF TRIALS TO CRITERION AND THE NUMBER OF TOTAL REVERSALS THAT WERE ACCOMPLISHED BY A CONTROL RATS AS WELL AS LATERAL HABENULA ACTIVATED RATS. SO CAN YOU SEE THE ENACTIVATED RATS REQUIRE MORE CRITERION AND HAD FEWER TOTAL REVERSALS. IF WE LOOK AND PERFORM A SHIFT ANALYSIS, WE LOOK AT THE LIKELIHOOD THAT THE ANIMALS WILL STAY WHEN THEY GET THE WIN, WHEN THEY FIND THE FOOD OR THE LIKELIHOOD THEY WILL SWITCH, YOU FIND THAT CONTROL RATS ARE KEENLY SENSITIVE TO THE OUTCOMES OF THE CHOICES BUT YOU SEE THAT THESE HABENULA ARE NOT. THERE'S NO DIFFERENCE THERE. NOW WE SHOW THAT THESE ARE ANIMALS CANNOT LEARN THE TASK BECAUSE THE LATERAL ANIMALS AND CONTROL ANIMALS LEARN EQUALLY WELL AND NOT ONLY THAT WHEN YOU BRING THEM BACK, THE NEXT DAY, THEY SHOW THE SAME AMOUNT OF RETENTION THE NEXT DAY. LONG-TERM MEMORY. THE LAST TEST I WILL TALK ABOUT IS ONE WHERE WE HAD ANIMALS IN A TWO CHOICE TASK THAT GO TO THE LEFT OR RIGHT, AND WHAT WE DO DO--TO TELL IT WHERE THE FOOD WILL BE SO IF IT'S A LOW TONE THE ANIMAL SHOULD GO LEFT, IF IT'S HIGH THE ANIMAL SHOULD GO RIGHT. SOPHISTICATEDY WE PRESENT THE TONE OVER AND OVER AGAIN AS SHOWN HERE IN THE DIFFERENT TRIALS ANDLET ANIMAL GOES THROUGH ALL THE TIME AND ONCE THEY REACH CRITERION, WE TURN ON THE OTHER TONE AND SEE HOW LONG IT TAKES THEM TO SWITCH. SO THIS IS JUST ANOTHER EXAMPLE, OF THESE ARROWS FOR THE ANIMALS ARE FIRST GOING LEFT, OF COURSE IT WAS RANDOM IN THE REAL EXPERIENCE, AND THEN, THE OTHER TONE COMES ON AND IF THE ANIMAL GOES LEFTOT FIRST TRIAL, WE SAY THAT'S A SWITCH ERROR AND A CONTROL ANIMAL WILL GO LEFTOT FIRST TRIAL AND MAYBE AFTER THAT THEY WILL GO TO THE RIGHT BECAUSE THEY KNOW WE'RE SUPPOSED TO SWITCH. BUT IT'S ALSO POSSIBLE THAT THE ANIMALS CONTINUE TO GO TO THE LEFT, WHICH WE CONSIDER THEN AN ERROR BUT IT'S ALSO POSITIVE THE ANIMALS WILL SWITCH, THEY WILL HEAR THE TONE, THEY WILL SWITCH AND THEN THEY MAKE ERRORS OUT HERE. THEY CAN CALL THOSE MAINTENANCE, THEY ARE NOT ABLE TO RETAIN THE SWITCH STRATEGY. IF YOU LOOK AT THE EFFECTS OF THE HABENULA LESIONS, YOU SLEEP APNEA AND OBESITYY - IT HAS A DEVASTATING EFFECT ON THESE ANIMALS, IT HAS FEWER TRIALS CORRECT AND IF YOU LOOK AT ERROR ANALYSIS, WE SEE THAT IN TERMS OF THE SWITCH'RORS THAT THE ANIMALS ARE MAKING MORE ERRORS AND OF COURSE, THEN THAT'S ALSO REFLECT INDEED WHAT APPEARS TO BE MORE ERRORS BUT IF YOU LOOK AT MAINTENANCE ERRORS THAT IS THE SAME, THAT IS ONCE ANIMALS QUIT, THEY'RE FINE, THEY'RE GOOD, THEY KNOW THE TASK TASK. SO THEY'RE NOT PERFORM THAG AT HAND ORDER OF MICRONS. WE PERFORM THE CONTROL WHERE WE JUST TALK TO THEM, CUE AND FOOD ASSOCIATIONS THAT--AND THEY FIND THAT WITHOUT SWITCHING AND YOU FIND THAT THEY LEARN THAT OVERALL PRETTY QUICKLY, AND THAT THE NEXT DAY, THEY RETAIN THAT INFORMATION. SO WE--SO THIS SUGGESTS THAT REALLY, AGAIN, THE RESPONSE FLEXIBILITY AS OFTEN IS USED IN THE OTHER STUDIES BY OTHER FOLKS AS WELL AS THE PRIMATE FOLKS THAT IT SUGGESTS THAT THE HABENULA IS IMPORTANT. SO I JUST WANT TO ALSO SAY THAT THE ACTION BETWEEN THE HABENULA, THESE ARE DECISION MAKING TASKS SO HERE'S A STUDY THAT WAS--THIS IS NOW DELAYED DISCOUNTING WHERE THE ANIMALS CAN--THEY PICK A LARGE REWARD BUT THEY MIGHT HAVE TO WAY DIFFERENT DELAYS AND LONGER THEY WEIGHT, THE LESS LIKELY THEY WILL PICK THAT REWARD LEVER AND CONTROL ANIMALS THEY SHOW A NICE DISCOUNTING CURVE ASK AND WITH THE HABENULA THEY SHOW AN IMPAIRMENT BUT WHEN I DO A DISCONNECTION STUDY, THAT IS YOU ENACTIVATE, THE PREFRONTAL AND THE OTHER SIDE, THE LATERAL HABENULA, THEN YOU SLEEP APNEA AND OBESITYY A DRAMATIC EFFECT AND THE INTERPRETATION IS THAT THE ACTION BETWEEN THOSE ARE IMPORTANT FOR THIS KIND OF BEHAVIOR TO BE--KIND OF FLEXIBLE BEHAVIOR TO BE EXHIBITED. SO AGAIN THIS SUGGEST THERE IS IS A REALLY IMPORTANT SORT OF PNEUMONIC FUNCTION BETWEEN THESE TWO STRUCTURES. SO WHAT I WANT TO DO IS JUFULT----JUST THIS, IS NOW A SUMMARY OF WHERE WE'RE THINKING THESE DAYS AND THAT S&P REPRESENTS THE CIRCUIT BETWEEN HIPPOCAMPUS AND FREE RADICALS FRONTAL CORTEX AND HABENULA, THESE DARK LINES REP RESEBT THE FACT WE KNOW THESE ARE DIRECT CONNECTIONS THESE DOTTED LINES ARE INDIRECT CONNECTIONS AND WE'RE NOT SURE WHAT PATHWAYS ARE INVOLVED BUT THIS IS IDEAS ABOUT WHAT INFORMATION MIGHT BE PASSED DOWN THROUGH THERE. SO AS I SAID IN THE HIPPIE CAMPUS, IT MAY BE PASSING ON INFORMATION ABOUT THE BEHAVIOR SEQUENCE. IT COULD BE FUTURE, PAST, CURRENT BEHAVIORIAL SEQUENCES AND THAT IS INFORMATION THAT'S PASSED ON TO PREFRONTAL CORTEX, PRESUMABLY TO HELP PRECORTICAL COMPUTATIONS TO ESTABLISH WHETHER OR NOT RESPONSE NEEDS TO CHANGE. SOME OF THIS INFORMATION COULD COME FROM THE OFC, FROM THE STRIATUM AND ALL OF THIS MIGHT CONVERGE ON TO THE PREFRONTAL CORTEX WHICH HAS DIRECTION TO THE LATERAL HABEN, ULA, AND THE MESSAGE IS ABOUT THE NEXT RESPONSE WHETHER IT'S STAY OR ADJUST SIDE PASSED ON TO THE HABENULA, SO WHAT'S IT DOING? WELL, AGAIN, THERE'S A LOT OF INTERNAL STATE INFORMATION AND THAT'S COMING INTO THE SAME AREAS OF HABENULA AS IS COMING DOWN THE PREFRONTAL CORTEX, SO IT SEEMS LIKE IT'S IN A GOOD POSITION TO INTEGRATE AND GAIN THOSE MESSAGES COMING FROM THE CORTEX TO DECIDE WHETHER OR NOT THE CURRENT INTERNAL STATE MATCHES FOR THE RESPONSE A OR B AND IF IT DOES MATCH OR MISMATCH THAT WILL DETERMINE WHETHER A RESPONSE WILL BE EXHIBITED AND IF WANTS FOR HABENULA BECAUSE OF THE DOPAMINE AND SINNER GESTIC MECHANISMS THEY MAY MORE DIRECTLY GUIDE RESPONSES BUT THEN THE QUESTION IS, WELL, WHAT IS THIS INFORMATION THAT'S COMING BACK UP TO HIPPOCAMPUS. WELL IT COULD BE THAT THIS MISMATCH BETWEEN THE EXPECTED RESPONSES AND WHAT THE EXPECTED INTERNAL STATE, BUT THAT MAY ACTUALLY FEEDBACK SUCH THAT IF THERE'S A MATCH BAIRVEGLY THEN, THE SAME PATTERN, POPULATION OF PLACE FIELDS MIGHT BE ACTIVATED PRESUMABLY IT HELPS THE ANIMAL TO SOLVE THE TASK BECAUSE THE RESPONSE IS HAPPENING TO GET THE GOAL THAT YOU WANT AND THAT'S CONSISTENT WITH INTERNAL STATE. BUT IF THERE'S A MISMATCH, YOU'RE SATED AND YOU'RE NO LONGER MOTIVATED TO GET THE FOOD EVEN THOUGH YOU KNOW THE FOOD IS OUT WELL AND I SHOULD GO GET IT, YOU SAY WELL, I'M NO LONGER HUNGRY. WELL THAT MAY CHANGE THE REPRESENTATIONS HERE IN HIPPOCAMPUS. IT MAY BE A DIFFERENT PATTERN OF CELLS BEING ACTIVE AND SO IN OTHER WORDS A MESSAGE MIGHT GO BACK TO HIPPOCAMPUS THAT INCREASES THE PLASTICITY OF THE MAPPING AND REMAPPING HAPPENS. AND WE KNOW REMAPPING HAPPENS WHEN ANIMALS ARE SWITCHED FROM BEING HUNGRY TO BEING THUFORTY. SO THIS IS AGAIN VERY, VERY BROAD BUT THIS IS THE KIND OF CONCEPTUAL FRAMEWORK THAT WE'RE WORKING ON. OKAY? AND AS I MENTIONED BEFORE, THERE'S A LOT BEING DISCOVERED ABOUT HABENULA, AND AS NEW DISCOVERIES HAPPEN, WE WILL ALTER OR MAPS ARE ALTERING OUR THEORY AND THAT WILL DETERMINE WHAT KIND OF FUTURE EXPERIMENTS THAT NEED TO BE DONE SO THIS IS JUST AN EXAMPLE OF SOME OF THE KINDS OF THINGS AND I THINK NEED TO BE DONE. FOR EXAMPLE, WE HAVE TO HAVE A BETTER UNDERSTANDING OF THE PROCESSES THAT ARE INVOLVED IN FLEXIBILITY RESPONDING. YOU KNOW TO WHAT EXTENT DOES IT INVOLVE WORKING MEMORY AND SOME OF THIS HAVE TO CHANGE BEFORE YOU DECIDE THE RESPONSE IS NO LONGER WORKING AND NOW I NEED TO EXHIBIT A DIFFERENT RESPONSE. WE NEED TO HAVE A BETTER UNDERSTANDING OF WHAT ARE THE CONDITIONS THAT RECRUIT THE LATERAL HABENULA TO GUIDE RESPONSES AND WE KNOW IT SEEMS TO EFFECT ACQUISITION WHICH IS SURPRISING TO ME BUT IT'S CONSISTENT ACROSS TOWN BUT DOES REFLECT RESPONSE FLEXIBILITY AFTER LEARNING. WE KNOW, I THINK WE'RE JUST BEGINNING TO KNOW AND UNDERSTAND THE PATTERN OF CONNECTIONS WITH THE HABENULA AND I FORESEE THAT WITH THE NEW METHODS NOW, FOR ESTABLISHING CONNECTIVITY PATTERNS THAT WE WILL SEE AN EXPLOSION AND AN EXVIETING EXPLOSION OF IDEAS FOR HOW--EXPLEDDING IDEAS OF HOW THE INFORMATION IS GETTING INTO THE MEDIAL AND LATERAL HABENULA,Y SEE A HETEROGENEOUS ROW GENIUS COLLECTION OF CELLS AND THE COUPLE STUDIES THAT HAVE BEEN DONE LOOKING AT THIS HAVE NOT BEEN ABLE TO IDENTIFY A NEURAL SIGNATURE THAT MATCHES THE DIFFERENT CELL TYPES SO FOR PEOPLE LIKE ME WHO GO IN WITH AN EXTRA CELLULAR RECORDING THIS KIND OF NIGHTMARE, I HAVE NO KIND OF IDEA WHAT KIND I'M RECORDING FROM CAN IT WOULD BE NICE IF I COULD. AND ALSO, IT--I THINK THERE'S STILL AN ISSUE OF TRYING TO FIGURE OUT HOW THESE REPETITIVE FUNCTIONS OF HABENULA, INTERACT WITH THE MORE AVERSIVE FUNCTIONS OF HABENULA, AND A LOT OF PEOPLE THAT WORK HERE ARE THINK BEING THIS QUESTION. SO FINALLY I WANT TO THANK THE MANY SUPPORTEDDERS OF THIS WORK OVER THE YEARS HERE AND IN PARTICULAR, PHIL BAKER, A POST DOC IN MY LAB, CARRIED OUT A LOT OF THE WORK WITH SUE GENE AND RECENT STUDENT WHO IS CONDUCTED THE HIPPOCAMPAL DATA AS WELL AHABENULA WORK AND THESE ARE STUDENTS IN MY LAB WHO WERE SUPER STELLAR AND CONTRIBUTED SIGNIFICANTLY AS WELL. WITH THAT I WILL TAKE QUESTIONS. [ APPLAUSE ] >> WE HAVE TIME FOR A FEW QUESTIONS AND IF YOU DO HAVE A QUESTION, WOULD YOU PLEASE USE THE MICROPHONE? AND WHILE WE'RE WAITING MAYBE I CAN ASK A QUICK QUESTION. YOU KNOW IN THE LOOP MAZE EXPERIMENT WHERE YOU ARE TRYING TO UNDERSTAND THE INFLUENCE OF REWARD ON YOUR HIPPOCAMPAL NEURONS, YOU SHOWED IT KIND OF REMAPPING AND I GUESS I'M TRYING TO UNDERSTAND WHY YOU THINK IT'S REMAPPING INSTEAD OF SAY, RETRIEVAL. >> YEAH, I'M JUST SAYING OPERATIONALLY, SO A MAP IS A DISTRIBUTION OF FIELDS SO IN THAT SENSE IT'S CHANGING THE DISTRIBUTION OF FIELD SO I DID NOT MEAN TO IMPLAY THAT IT NECESSARILY INVOLVES ONE TYPE OF A PROCESS OR ANOTHER. >> I'M TRYING TO UNDERSTAND THE RELATIONSHIP BETWEEN THE HIPPOCAMPAL, PREFRONTAL CIRCUIT VERSUS HABENULA CIRCUIT. SO MY UNDERSTANDING SO FAR IS THAT HIPPOCAMPAL AREA ENCODES THE SPACIAL AND TEMPORAL ASPECTS FOR BEHAVIOR FOR OBJECTS BUT THAT CIRCUIT RECEIVESSISMS IMPS FROM THE REWARD OR PUNISHMENT BUT THE HIPPOCAMPAL AREA DOES THOT STABLY ENCODE THE REWARD VALUE WHEREAS THE LATTER HABENULA ENCODES REWARD PUNISHMENT VALUE BUT NOT A SPATIAL TEMPORAL-- >> EXACTLY. >> EXACTLY. THAT IS CORRECT, SO IT'S GOING TO BE REALLY IMPORTANT TO UNDERSTAND BECAUSE IT'S NOT A DIRECT CONNECTION BACK TO HIPPOCAMPUS AS WELL SO IT WILL BE IMPORTANT TO UNDERSTAND HOW THE INFORMATION GETS TRANSFORMED AS IT GOES THROUGH THE DIFFERENT STAGES AND MY HUNCH IS THAT THE THETA WILL BE IMPORTANT MECHANISM FOR INTEGRATING INFORMATION MAYBE NOT FROM THE HABENULA BUT MAYBE AS WELL AS IT GETS INTO THE HIPPOCAMPUS. [ APPLAUSE ] CLER CLEAR