I AM TERRIBLY EXCITED TO BE HOSTING DR. HELEN BARBAS, SHE IS THE LEADING EXPERT OF THE CEREBRAL CORTEX AND SPECIFICALLYOT PATTERN AND SIN APTOLOGY OF PREFRONTAL PATHWAYS. HELEN GRADUATED AT Mc GILL UNIVERSITY WITH A Ph.D. AND POST DOC AT HARVARD MEDICAL SCHOOL. AND SHE'S STAYED IN BOSTON SINCE, I BELIEVE, CURRENTLY FULL PROFESSOR AT BOSTON UNIVERSITY AND THE BOSTON UNIVERSITY SCHOOL OF MEDICINE WHERE SHE RUNS HER NEURAL SYSTEMS LABORATORY. I'VE BEEN FOLLOWING HELEN'S WORK SINCE ABOUT 2003 WHEN I FIRST MET HER AT AN EXECUTIVE FUNCTIONAL WORKSHOP OR PREFRONTAL WORKSHOP, I THINK IT WAS HOSTED OR SPONSORED BY NIMH AND AT THE TIME HER WORK ON THE CONNECTION UNDERLYING SENSES OF COGNITION AND EMOTION WERE A REAL TAKE ON AN OLD HAT IDEA THAT PROCESSES ALL THE STRUCTURES THAT REVOLVED IN THESE FUNCTIONS BUT WERE SEPARATE ENTITIES IN THE BRAIN BUT INSTEAD HER EXPERTISE WHICH REALLY STEMS FROM HER ABILITY TO CONDUCT FUN ANALYSIS OF THE ULTRA STRUCTURE OF AXONS, LAYER SPECIFIC SITES TO TECTONICS AND STRUCTURAL CONNECTIVITY IN THE MACAQUE BRAIN SHOWED DISCONNECTION OR NORMAL COMMUNICATION BETWEEN THESE STRUCTURES, INTERTWINED& INTERCONNECIONS IS PROBABLY WHAT ACCOUNTS FOR MANY OF THE SYMPTOMS THAT WE SEE OR UNDERLIE THE SYMPTOMS AND PSYCHIATRIC NEUROLOGICAL DISORDERS. SHE HAS SINCE NOURISHED AND EXTENDED THESE IDEAS AND HER RECENT WO, IS FOCUSED ON THE CIRCUIT MECHANISMS THROUGH WHICH PREFRONTAL PATHWAYS INTERFACE WITH THE SUBCORTICAL STRUCTURES IN THE THALAMUS AND THE AMYGDALA AND WE HELPED THIS DATA FOR THIS IS REALLY LENDED ITSELF TO DESIGN COMPUTATIONAL MODELS AND/OR SIMULATE BOTH MORM NORMAL AND PATHOLOGICAL CONDITIONS, SO THAT'S PRETTY EXCITING. NOW VERY IMPRESSIVE IS THE FACT THAT--NOW IN ADDITION TO ALL HER OTHER FUNDING THAT SHE HAS, SHE'S 1 OF THE FEW IN NOT THE ONLY NEUROANATOMIST WHO HAS BEEN FUNDED BY NIH RO1s FOR HER ENTIRE CAREER IN THIS ANATOMY. I THINK THIS SPEAKS VOLUMES FOR THE CONSIDERABLY IMPORTANCE AND IMPLICATIONS OF HER WORK IN UNDERSTANDING THE ORGANIZATION OF THE BRAIN. SO I'LL STOP HARPING ON ABOUT HOW WONDERFUL HELEN IS, TODAY SHE WILL TALK ABOUT WHAT BRINGS ABOUT BRAIN DISORDER DYSFUNCTION AND DISDISORDERS. PLEASE WELCOME HELEN. >> THANK YOU FOR THIS NICE INTRODUCTION. IT IS VERY NICE TO BE TALKING TO A GROUP OF COLLEAGUES AND FRIENDS WHEN I'M IN THESE MEETINGS ALL THE TIME. SO I WOULD WOULD LOVE TALKING ABOUT THE CIRCUITS THAT WE HAVE IDENTIFIED THAT SEEM TO BE--TO FORM THE BASIS FOR FUNCTION AND ALSO DYSFUNCTION IN THE DISEASE AND THE MORE WE LOOK AT IT, THE MORE WE GET CONVINCED THAT THERE ARE REGULARITYS IN THESE FUNCTIONS. SO I WOULD START BY FLASHING SOME OF THE NAMES OF THE PEOPLE WHO HAVE PARTICIPATED IN THIS ENDEAVOR ON THE WAY BACK AND I WILL BE REFERRING TO THEIR SPECIFIC WORK AS WE GO ON. SO, WE START WITH DARWIN WHO SAID THAT LITTLE IS KNOWN ABOUT THE FUNCTIONS OF THE BRAIN BUT WE CAN PERCEIVE THE BEST INTELLECTUAL POWERS BECOME HIGHLY DEVELOPED, THE VARIOUS PARTS OF THE BRAIN MUST BE CONNECTED BY THE MOST INTRICATE CHANNELS OF INTERCOMMUNICATION AND FOR 1871 THAT WAS PLACED HERE BECAUSE THEY KNEW VERY, VERY LITTLE ABOUT THE TIME OF ANYTHING. SO I WILL BE TALKING ABOUT THE CIRCUITS IN THE RECESS MORVEGY THAT YOU SEE THERE ON THE LEFT IN BLUE, SO YOU SEE THE MEDIAL SURFACE WHICH IS UPSIDE DOWN BECAUSE THOSE SURFACES BECOME CONTINUOUS WITH THE LATERAL SURFACE THERE. AND THE LATERAL SURFACE AND THE BASAL SURFACE OR THE BOTTOM OF THE BRAIN. AND THESE ARE ALL THE PREFRONTAL REGIONS, THEY RECEIVE INPUT FROM JUST ABOUT EVERYWHERE WITHIN THE CORTEX BUT ALSO SUBCORTICAL STRUCTURES BUT IN AN ORGANIZED WAY AND THEY RECEIVE THAT INFORMATION AND USE IT FOR ACTION. SO THIS IS AN AREA THAT IS ACTION ORIENTED AND THIS IS--YOU CAN SEE THE SAME RELATIONSHIP IN THE HUMAN AND THIS IS WHAT MAKES IT SO EXCITING AND SO TELLING FOR PSYCHIATRIC AND NEUROLOGICAL DISEASES. SO NOW I GIVE A VERY SIMPLE SUMMARY OF WHAT THIS AREA MAY BE DOING AND WE KNOW THAT THE FUNCTIONAL SPECIALIZATION OF AREAS IS DEPENDENT ON THEIR CONNECTIONS SO IF WE TAKE A VERY SIMPLE VIEW, WE KNOW THAT THE LATERAL PREFRONTAL CORTEXS, RECEIVE RATHER DETAIL SENSORY INPUT FROM EARLY PROCESSING SENSORY AREAS, NOT THE PRIMATE AREAS BUT JUST ABOUT EVERYTHING ELSE AFTER THAT. AND THEY HAVE A ROLE IN COGNITIVE PROCESSES SUCH AS ORKING MEMORY AND A LOT OF PEOPLE ARE WORKING ON THAT. THE MEDIAL PREFRONTAL AREAS SHARE VERY LONG-TERM MEMORY FUNCTIONS WITH THE HIPPOCAMPUS AND THE SENSORY IPT GREATER PUT IS MOSTLY PROMOTED IN AREAS WHICH IS INTERESTING, BUT THEY HAVE A VERY STRONG CONNECTION WITH EMOTIONAL MODEL SYSTEM IN THE ROLE IN ATTENTION AND THE FRONTAL CORTEX AND I WILL BE TALKING ABOUT THIS AREA MORE LATER ON, ARE LARGELY MULTIMODAL. THEY SHARE UNDERLYING FUNCTIONS IN ECERTAINLY--CERTAINLY MOTIONAL MEMORY WITH THE AMYGDALA BUT THESE AREAS INTERACT AS YOU GET SUMMARIZED VERY MICELY, THEY INTERACT WITH EACH OTHER WHICH MEANS THE AREAS THAT ARE ASSOCIATED WITH COGNITION ARE ALSO LINKED TO AREAS ASSOCIATED WITH EMOTION AND THIS IS THE DISRUPTION IS WHAT UPDATER LIES A LOT OF THE PSYCHIATRIC DISEASES. SO I WILL FOCUS ON 2 PRINCIPALS THAT DEFINE DISRUPTION IN THE DISEASE. ONE OF THEM IS A CLASSICAL IDEA OF SYSTEMATIC CORTICAL VARIATION FROM THE WORK OF AN [INDISCERNIBLE] AND LATER ONAD [INDISCERNIBLE] AND COLLEAGUES BECAUSE THIS PROVIDES THE FRAMEWORK TO ORGANIZED CONNECTIONS AND THAT'S I WILL SHOW YOU IT ALLOWS US TO DEVELOP A MODEL THAT WE UNDERSTAND CONNECTIONS, AND THE OTHER PART OF THIS VERY IMPORTANT, THIS INHIBITORY CONTROL WHICH WE KNOW IS EFFECTED IN A LOT OF PSYCHIATRIC DISEASES AND NEUROLOGIC DISEASES AS WELL. SO WHAT DO WE MEAN BY THE CORTEX SYSTEMATIC VARIATION? WE KNOW THAT THE CORTEX, WE CAN DO A SIMPLE STAIN AND WE SEE THAT THERE ARE CHANGES AS WE GO FROM 1 AREA TO ANOTHER AND A LOT OF PEOPLE HAVE PROBLEMS SEEING THAT BUT WE CAN USE VARIOUS MARKERS AND HERE FOR EXAMPLE IS THE MARKER THAT LABELS PRIMARILY PROJECTION NEURONS SO WHAT WE DO SO IS NOT THE PREP CHANGES BUT SYSTEMATIC VARIATIONS. SO WE MADE THIS CARTOON TO SHOW YOU WHAT IS MEANT. SO BASICALLY WE CAN TAKE A LOT OF FEATURES, [INDISCERNIBLE] FEATURES OF THE BREAN AND ANALYZE THEM QUANTITATIVELY SUCH AS THE DENSITY OF NEURONS IN DIFFERENT LAYERS AND DIFFERENT TYPES OF INHIBITORY NEURONS AND A LOT OF OTHER VARIABLES AND THEN DO AN ANALYSIS AND SO WE SEE THAT SOME AREAS FOR EXAMPLE HERE THEY DON'T HAVE LAYER 4 SO THEY'RE TRULY GRANULAR AND THEN IN SOME AREAS NEXT TO THEM, HAVE A SMALL LAYER 4, THIS GRANULAR AND THEN AS WE GO ON YOU SEE BETTER DIFFERENTIATION, SO WHAT WE SEE, WE CAN DO IN THE QUANTITATIVE ANALYSIS, WE SEE THAT THESE AREAS THEY ARE GRANULAR AND DISGRANULAR, I WILL REFER TO THEM AS EMILY CIBOL AND I WILL SHOW YOU BY THE POSITION AND THEY CLUSTER ALL THE WAI TO THE LEFT HERE, SO THIS INVOLVES 17 PARAMETER DIMENSIONS SO THE CLOSER THEY ARE, THE MORE SIMILAR THEY ARE. AND THE OTHER LAMINAR AREAS WHICH HAVE 6 LAYERS THEY CLUSTER TO THE RIGHT AND THEN WE CAN DO A CLUSTER ANALYSIS WHICH IS INDEPENDENT AND WE SEE THE RELATIONSHIP OF THESE AREA SYSTEM VERY MUCH THE SAME. SO THERE IS SOMETHING THAT IS SYSTEMATIC AND CAN BE FAWNTIFIED AND THAT REMINDS ME THAT I WOULD LIKE TO SAY THAT EVERYTHING THAT I WILL SHOW YOU IS BASED ON QUANTITATIVE ANALYSIS. SO HOW ARE CONNECTIONS ORGANIZED? WELL CORTICAL CONNECTIONS WE KNOW ARE BI-DIRECTIONAL BUT THEY'RE UNEQUAL AND THEY'RE UNEQUAL IN STRENGTH AND LAMINA DISTRIBUTION AND THESE BECOME EVIDENT WHEN PEOPLE STARTED LOOKING USING TRACERS TO LABEL NEURONS AND FOR EXAMPLE, IN THE SENSORY SYSTEMS WHERE THEY HAD THE GOOD HANDLE OF THE INPUT, PEOPLE IN THE 70S SAW THAT NEURONS IN LAYER 3 FROM THE PRIMATE AREA, PRIMARY VISUAL PROJECT TO THE SECONDARY AREA, THEY DO SO FROM LAYER 3 AND THEIR ACCESS TERMINATE HERE AROUND LAYER 4. BUT THE CONNECTIONS GOING IN THE OPPOSITE DIRECTION ORIGINATE FROM THE DEEP LAYERS AND THE AXONS DIFFUSELY TERMINATE MOST IN LAYERED 1. SO THIS WAS THE FIRST TIME THAT PEOPLE APPRECIATED THAT. SO WHAT IS THIS DEPENDENT ON AND IF WE GO TO THE PREVIOUS VISUAL SLIDE I JUST SHOWED YOU, PEOPLE THOUGHT IT HAS SOMETHING TO DO WITH THE SEQUENCE OF INFORMATION PROCESSING, AND INDEED IT MAY BUT THEY THOUGHT ACTUALLY THAT IT MAY BE SPECIFIC TO THE SENSORY AREAS BUT WE'RE LOOKING AT THE PREFRONTAL AREAS, WORKING ON THE OTHER SIDE, WE SAW VERY SIMILAR PATTERNS AND MORE OVER, IT SEEMED TO BE THE LAMINA DISTRIBUTION OF PROJECTIONS SEEM TO BE REALLY DEPENDING ON THE RELATIONSHIP, THE STRUCTURAL RELATIONSHIP OF THE LINKED AREAS. SO HERE IS AN INJECTION IN AREA 9 THAT YOU SEE HERE AND WE SEE A PROJECTION NEURONS IN AREA 32 HERE, THEY MOSTLY ORIGINATED IN THE DEEP LAYERS. AND THIS RESEMBLE THE FEEDBACK CONNECTIONS IN THE SENSORY AREAS THAT I JUST SHOWED YOU. SO THIS IS HOW 32 WHICH HAS AICISMULAR ARCHITECTURE THAN AREA 9 TALKS TO IT. FOR THE 6 WHICH HAS A MUCH MORE ELABORATE ARCHITECTURE THAN AREA 9 THATY A PROJECT IN A FEET FORWARD PROJECTION FROM THE UPPER LAYERS AND THEN WE HAVE AREAS 11 AND 14 IN THE MIDDLE HERE AND THEY ARE VERY SIMILAR IN STRUCTURE WITH AREA 9. AND WHEN I SAY SIMILAR INSTRUCTIONURE, I DON'T--IN STRUCTURE, I DON'T MEAN WE CAN'T TELL THEM APART, IT'S ALMOST LIKE PUTTING PEOPLE IN GROUPS BY HEIGHT AND WEIGHT AND WHEY PUT THEM IN A PARTICULAR GROUP, WE DON'T CONFUSE THE PEOPLE BY THEIR FACES, WHICH WOULD REALLY GIVE AN IDENTITY TO THE INDIVIDUAL, BUT THERE ARE--THERE ARE ON THIS OBSTRUCTION OF HEIGHT AND WEIGHT THEY ARE SIMILAR. SO THIS IS WHAT IT SHOWS YOU HERE. SO IT SEEMS TO LOSE THE RELATIONSHIP BETWEEN THE LINKED AREAS THAT DETERMINES WHAT IS GOING ON. SO WE DISTILL THIS INTO A MODEL WHICH WE NOW CALL THE STRUCTURE MODEL AND IT STARTED ALL THE WAY THERE, THE INITIAL DESCRIPTION WAS IN 86 AND THE FORMALIZATION WAS IN 97 AND BASICALLY 1 IS SIMPLE AREA LIKE THIS PROJECTS TO AN AREA LIKE THAT, IT'S A FEEDBACK PROJECTION, WHEN IT GOES THE OTHER WAY FROM THIS TYPE OF CORTEX TO THAT, IT'S IN THE UPPER LAYERS AND TERMINATES IN THE MIDDLE LAYERS, FEET FORWARD. BUT THE MODEL ALSO PREDICTS WHAT WILL HAPPEN IF YOU HAVE VERY SMALL DIFFERENCES IN LAMINATION AND IS GOING FROM LOW TO HIGH OR FROM HIGH TO LOW, OR AS I SHOWED YOU EARLIER, YOU GET ABOUT THE SAME LEVEL THAT'S GOING TO INVOLVE ALL LAYERS EXCEPT THE LAYER 4 AND SO THE SYSTEMATIC VARIATION IS SEEN IN ALL CORTICAL SYSTEMS SURVEYING AT THE BASE OF THE BRAIN, THIS IS TENDED TO BIT TO SHOW YOU THE CONTINUITY, THE GRANULAR IN BLACK AND THIS GRANULAR IN GRAY HERE AND WE SEE A DIFFERENTIATION ALL OVER SO WE CAN TALK ABOUT THIS GRAD Y'ALL DIFFERENTIATION WITH THE PREFRONTAL SYSTEM, THE MODEL SYSTEM, PARIETAL, THE OCCIPITAL AND TEMPORAL AND SO FORTH SO IT APPLIES TO THE ENTIRE CORTEX AND IT BECOMES VERY EASY TO SEE THAT. NOW SOW I WILL GO TO THE SUBCORTICAL STRUCTURES BUT I WANTED YOU TO SEE SOME OF THESE PRINCIPLES THAT HELP US UNDERSTAND WHAT GOES ON IN THE SUBCORTICAL STRUCTURE WHICH IS ARE MORE DIFFICULT TO STUDY. SO, THE AREAS WITH THE SIMPLEST LAMINAR STRUCTURE WHICH IS THE ANTERIOR SINGULATE, ACC FOR SHORT, IN THE POSTERIOR OR FRONTAL CORTEX, POFC FOR SHORT, HAVE THE STRONGEST CONNECTIONS WITH THE AMYGDALA, MY STUDENT WHEN HE WAS A GRADUATE STUDENT MAPPED THESE, THIS IS NOT FUNCTIONAL IMAGING, THIS IS SECTION BY SECTION ANALYSIS THAT IS AT THE QUANTITATIVE LEVEL, WE WANTED TO DO IT THIS WAY BECAUSE THE POOEM WHO DO FUNCTIONAL IMAGE WILL FUNCTIONALLY UNDERSTAND AND I THINK IT WORKED. SO THIS IS AN INPUT AND AS YOU SEE THIS BIT OF FRONTAL CORTEX IS STRONG RECIPIENT FROM INPUT FROM THE AMYGDALA AS THE SINGULATE AND THIS IS THE OUTPUT. SO THE ORBITAL CORTEX AS I SHOWED MULTIMODAL AND INPUT IS STRONG WITH THE SENSOR MORDALLASCOWBOYS.COMITY WITHIN THE CORTEX FROM HIGH ORDER ASSOCIATION AREAS IN THE SAME AREAS PROJECT TO THE AMYGDALA, IN THE SAME SIDES IN THE AMYGDALA IN THE PREFRONTAL CORTEX, SO WE THOUGHT THAT THIS INDIRECT PROJECTION FROM SENSORY AREA ITS THE AMYGDALA MAY BE AND THEN TO THE ORBITAL FRONTAL CORTEX MAY BE WHAT GIVES THE ORBITAL FRONTAL CORTEX A SENSE OF THE EFFECT OF SIGNIFICANCE OF THE ENVIRONMENT BUT WE DIDN'T KNOW THIS IS REALLY WHAT HAPPENS SO CAN WE USE SOME OF THIS INFORMATION I SHOWED YOU TO UNDERSTAND WHAT MAY BE HAPPENING IN THIS SYSTEM THAT IS THE NUCLEAR LEVEL. SO WE'LL KNOW THAT THE PREFRONTAL PROJECTIONS TO THE AMYGDALA REGIONS MOSTLY FROM LAYER 5 RESEMBLING FEEDBACK CONNECTIONS BUT IF PATHWAYS FROM SENSORY AREAS TO THE AMYGDALA CONVEY, SOME INFORMATION ABOUT THE EMOTIONAL SIGNIFICANCE OF THE ENVIRONMENT, THEY WOULD BE FEET FORWARD JUST LIKE THE INFORMATION PROCESSING FROM V1, TO V-2 AND FROM THERE AND BEYOND. SO WHAT ARE ALL THESE LIKE? SO IN THE SAME EXPERIMENTS THAT WE USE TO MAP THE PREFRONTAL CONNECTIONS, WE WENT TO THE TEMPORAL AREAS TO SEE WHAT IT LOOKS LIKE, SO THIS IS THE [INDISCERNIBLE] HERE. A LOT OF PEOPLE WORKING IN THIS ROOM UNDERSTAND THIS RIGHT AWAY, THIS IS THE INTERRHINAL CORTEX HERE AND YOU SEE THE PROJECTION NEURONS JUST LIKE PREFRONTAL ARE IN THE DEEP LAYERS, AND HERE I DON'T KNOW IF YOU CAN SEE THE LABEL NEURONS FROM WHERE YOU ARE. THP WE COME AROUND THE CORNER AND IN IS AREA 36 WHICH IS A PERIMODAL AREA AND [INDISCERNIBLE] AREA WHICH IS VISUAL ASSOCIATION AREA AND THERE IS A DRAMATIC SHIFT OF THE LABELED NEURONS AND THEY'RE NOW FEET FORWARD TYPE FROM LAYER 3 AND THIS IS REALLY AS CLOSE TO PROOF THAT WE GET IN ANATOMY AS WE COULD AND YOU SEE IT ALL IN FRONT OF YOU SHIFTING RIGHT AWAY. SO, IT REINFORCES THE HYPOTHESIS THAT I TOLD YOU BEFORE THAT THERE IS SOMETHING ABOUT THIS INFORMATION FROM THE AMYGDALA FROM THE SENSORY AREAS TO THE AMYGDALA AND FROM THERE TO THE PREFRONTAL CORTEX. SO WE HAVE SEEN THE SIGNALS FROM THE INTERNAL ENVIRONMENT ARE PROPAGATED THROUGH THE LAT RAT CORTEX THROUGH THE SEQUENTIAL FEEDBACK PATHWAYS SO THESE HAVE THE STRONGEST RECIPIENTS OF INPUT FROM SUBCORTICAL EMILY CIBOL STRUCTURE WHICH IS INCLUDES THE HYPOTHALAMUS AND OTHERS AND IT GOES TO AREAS THAT ARE CLOSER TO IT AND FROM THERE, TO AREAS BEYOND THAT AND SO THIS IS JUST THE OPPOSITE OF WHAT PEOPLE HAVE SEEN IN THE SENSORY SYSTEMS. SO SOMETHING THAT COMES FROM THE INTERNAL ENVIRONMENT IS CONNECTIONS AND NOW WE HAVE SEEN, OTHERS HAVE SEEN THAT THIS IS THE PATHWAY ALSO FOR PROPAGATION IN THE MOTOR SYSTEM, SO THE EMOTIONAL SYSTEM IS ESSENTIALLY ANOTHER MODAL SYSTEM, AFTERALL EMOTION IS E-EMOTION AND IT COMES FROM THAT. SO NOW THE OTHER PART I WAS GOING TO TALK TO YOU ABOUT WAS THE ROLL OF THE PREFRONTAL CORTEX AND INHIBITORY CONTROL, AND I'M GOING TO FOCUS ON 2 SUBCORTICAL INTERACTIONS BETWEEN PREFRONTAL AREAS WITH 2 INHIBITORY SYSTEMS. ONE IS IN THE AMYGDALA AND THE OTHER IN THE HAL MUS, SO AGAIN, THE POSTERIOR ORBITAL FRONTAL CORTEX PROJECTS STRONGLY TO THIS INTERPOLATED NEURONS IN THE AMYGDALA, THIS IS SMALL NEURONS THAT ARE FOUND BETWEEN THE NUCLEI OF THE AMYGDALA AND THEY'RE ALL GABAERGIC, THEY RESEMBLE SORT OF NEURONS BUT NOT ALL OF THEM EXACTLY BUT MOST OF THEM DO. AND WE--MY STUDENT [INDISCERNIBLE] SAW THESE VERY DRAMATIC TERMINATION, IT WASN'T EXCLUSIVE TO THOSE BUT IT WAS THE STRONGEST AND SO, WE DIDN'T REALLY KNOW WHAT IT MEANT. WE KNEW THAT IT MUST BE IMPORTANT BECAUSE OF THE DENSITY OF THESE PROJECTION AND SO, IT WASN'T UNTIL VERY RECENTLY THAT WE BEGAN TO TEASE A PART THESE PATHWAYS TO REALLY UNDERSTAND WHAT WAS GOING ON AND RECENTLY AND THIS WAS FROM 2016 AND 2017, WE FOUND THE [INDISCERNIBLE] AND OTHER PEOPLE IN THE LAB FOUND THAT ABOUT 10--THERE WERE 3 CLASSES OF INHIBITORY NEURONS, 1 OF THEMSELVES WAS NOS, NITRIC OXIDE SYNTHASE, THE NEXT 20% WERE ABOUT NEURONS WERE POSITIVE FOR THE CALCIUM BINDING PROTEIN [INDISCERNIBLE] AND THEY WERE INHIBITORY ALSO. AND THE VAST MAJORITY WERE POSITIVE FOR DARK 32 WHICH IS THE FOSTER NURSED FOCUSED ON PROTEIN THAT WAS ISOLATED IN THE STRIATUM BY PAUL AND HIS CREEING COLLEAGUES. SO ALL 3, INTERPRETED NEURONS, IM, RECEIVE INPUT FROM THE PREFRONTAL CORTEX, OVER THE FRONTAL CORTEX IN THIS CASE THAT I SHOWED YOU IN ABOUT THE SAME PROPORTION AS WE FIND THEM. SO THE OTHER PART OF WHAT WOULD BECOME CRITICAL IN THIS PATHWAY IS SEEING HOW THEY INTERACT WITH EACH OTHER. YOU HAD TO GO TO THE E. M. ON TO SEE WHAT KIND OF INTERACTIONS THEY HAD, SO WHAT IS THE INTRINSIC [INDISCERNIBLE] AND WE FOUND THIS DARK 30 NEURONS INNERIVATE AND INHIBIT NOS NEURON SAYS WHICH INNERIVATE AND INHIBIT CB [INDISCERNIBLE] NEURONS AND EACH OF THESE 2 CLASSES INHIBITS ITS OWN, THE CB AND THE PV BUT NOBODY ISHED ACT WITH THE DARK 32 NEURONS. SO KNOWING THIS, WE TRY TO FIGURE OUT WHAT WAS HAPPENING IN THIS PATHWAY. SO I TOLD YOU THAT THE BIGGEST CLASS, MORE THAN 60%, THEY WERE THIS IM INTERPOLATED NEURONS WERE DARPP-32 POSITIVE AND BASED ON THE CIRCUITRY AND BY THE MANAGEMENT WE WORK IN THE TRIAT UMKC, WE PUT A FEW THINGS TOGETHER SO ESSENTIALLY ALL THE WORK THAT WAS DONE IN THE STRIATUM TO SEE UNDER WHAT CONDITIONS THESE STRIATUM NEURONS GET PHOSPHORALATED, [INDISCERNIBLE] AND HIS COLLEAGUES FOUND THAT WHEN THE& DOPAMINE LEVELS ARE LOW OR AMBIENT, DARPP-32 IS PHOSPHORALATED MOSTLY AT 375 AND THE NEURONS CAN BECOME POLARIZED BUT WHEN THE LEVELS ARE HIGH, THE DARPP-32 NEURONS ARE PHOSPHORALATED AT THR32 ON THE OTHER SIDE OF THE PROTEIN AND THE NEURONS ARE HYPER POLARIZED. AND SO WE KNOW THAT WHEN DOPAMINE LEVELS ARE VERY HIGH, THE DOPAMINE LEVELS ARE VERY HIGH IN ANXIETY DISORDERS AND THIS IS SOMETHING WE SEE, SO LET'S SEE WHAT MAYBE HAPPENED IN VIEW OF WHAT WE SEE HERE. SO I SHOWED YOU THE ORBITAL FRONTAL PROJECTS TOWARD THE CLASSES, THIS DARPP-32, AND THEREFORE WHEN YOU HAVE A LITTLE BIT OF DOPAMINE AND THAT IS SHOWN HERE BY THESE BLUE MARKER HERE, AND THE NOS NEURONS ARE GOING TO BE INHIBITED, NOS NEURONS WILL NOT BE ABLE TO INHIBIT CB-NEURONS IN BOTH OF THESE THE DARPP-32 NEURONS AND THE PROJECT TO THE SEBTERAL PROVIDES THE OUTPUT OF THEICH IS- AMYGDALA TO AUTONOMIC STRUCTURES. SO BANKLY IF CONDITIONS WHERE THE A--BITS MALIS CALM FOR A HUMAN BEING HERE YOU CAN SEE THERE'S A STRONG INHIBITION BY THESE 2 CLASSES OF INHIBITORY NEURONS ON TO THE CENTRAL NUCLEUS OF THE AMYGDALA BUT LET'S SLEEP APNEA AND OBESITYY WHAT HAPPENS WHEN WE HAVE A LOT OF DOPAMINE HERE LIKE AN ANXIETY, OR YOU SEE THIS, BASICALLY THE DARPP-32 NEURONS ARE HYPER POLARIZED THEY CANNOT VERY MUCH INHIBIT THE NOS, AND NOS IS LEFT TO ITS OWN DEVICES TO INHIBIT THE BENDING NEURONS SO OVER 90% OF THE NEURONS IN THE INTERPROUGH ATOMALATED MASSES ARE PRETTY MUCH OUT OF COMMISSION AND THEREFORE THE CENTRAL NUCLEUS OF THE AMYGDALA PROJECTS VERY STRONGLY TO THE AUTONOMIC STRUCTURE SAYS AS WE SEE AN EMOTIONAL AROUSAL. SO THIS IS THE PATHWAY THAT WE THINK IS HAPPENING TO EXPLAIN THE SYNAPTIC LEVEL WHAT MAY BE HAPPEN WHG YOU HAVE DOPAMINE LEVELS AND WHAT HAPPENS TO THE OUTPUT OF THE AMYGDALA. NOW, THE ACC AND THE PUC INNERIVATE THE AMYGDALA DIFREPRESENTIALLY AND WE THINK IT DOES SO IN ALSO IN OTHER--IT HAS VERY DIFFERENT FUNCTIONS, THESE 2 PATHWAYS THAT CAN--I WANT TO SKIP IT TO GET TO SOME OTHER AREAS THAT WE CAN HAVE A DISCUSSION IN THE END PERHAPS. SO THE IN ACCIDENT MAJOR PREFRONTAL TARGETING OF SUBCORTICAL INHIBITORY SYSTEM IS THE THALAMIC RIDICULAR NUCLEUS WHICH IS INTERPOSED BETWEEN THE CORTEX AND THE MAIN THALAMUS, THE DORSAL THALAMUS, SO, A CORTICAL NEURON ON ITS WAY TO THE THALAMUS SENDS THE BRANCH TO TRM, I WILL USE TRM FOR SHORT, AND THE THALAMIC NEURON ON ITS WAY TO THE CORTEX SENDS A BRANCH TO TRN. SO I VIEW THIS AS THE PASS PORT CONTROL CENTER FOR THE BRAIN. SO IF YOU GO IN A COUNTRY, YOU SHOW YOUR PASS PORT, YOU LEAVE THE COUNTRY, YOU HAVE TO SHOW YOUR PASS PORT. THE TRN IS TAUGHT, IT FILTERS INFORMATION THROUGH THE THALAMUS SO NOT EVERYTHING THAT HITS THE THALAMUS, NOT EVEN IN THE SENSORY REALM GOES TO THE CORTEX AND HAD IS 1 OF THE FILTER EXISTENCE, SO THE COPOLUS WHEN HE CAME TO THE LAB, I GAVE HIM THIS PROBLEM TO SEE MOST OF THE WORK WAS DONE IN RATS ASK THROUGH THE WORK OF OTHER PEOPLE, WE SAW--WE MIGHT PUT THE TRN IN 3D AND THE AUDITORY PART BECAUSE THERE IS A TOPOGRAPHIC ORGANIZATION IS OCCUPIES THIS POSTERIOR PART AND DIVISION 1 AND SOMATOSENSORY MODEL AND OKAY, THE PRENONTAL HAS TO BE THERE, WHERE ELSE? AND FOR THE MOST PART IT WAS BUT WE GOT SOME SURPRISES AND BASICALLY WHAT HAPPENED IS WHAT IS MOST OF THE PROJECTIONS TERMINATE ON THE ANTERIOR PART OF TRN, THERE ARE SOME THAT EXTEND WAY THROUGHOUT THE TRN. IT GOES TO THE AUDITORY VISUAL SOMATOSENSORY AND SO FORTH. SO THE PRESENCERY AREAS THAT ARE ASSOCIATE WIDE WORKING MEMORY IN THE POFC PROJECT VERY REQUESTEDLY TO TRN. AND HERE IS THE MEDIAL DORSAL NUCLEUS OF THE THALAMUS WHICH IS CONNECKED WITH THE PREFRONTAL CORTEX, IT ALSO HAS A BIG EXTENT ON THE NUCLEUS, SO IT'S ALMOST LIKE SOME OF THIS PREFRONTAL AREAS AND IT'S NOT ALL OF THEM, MAY HAVE A LITTLE POWER AS TO WHAT GOES IN AND OUT OF THE THALAMUS THAT HAPPENS VERY EARLY ON IN PROCESSING. AND WILL COME BACK TO IT IN LATER ON, SO, THE QUESTION WAS WHAT ABOUT THE AMYGDALA, WE UPON THESE 2--MEDIAL DORSAL AND THE PUFC, THEY ARE CONNECT WIDE THE AMYGDALA, IS THE AMYGDALA ALSO CONNECT WIDE TRN, NOBODY LOOKS AT IT IN ANY SPECIES AND THIS PAPER CAME OUT IN 2012 AGAIN, LOOKED INTO IT, AND THIS IS A VERY STRONG PROJECTION FROM THE AMYGDALA TO THE TRN AND HERE IS A SMALL PART OF THE DENDRITE OF A TRN NEURON, YOU SEE HERE IN GRAY, AND ALL OF THESE BLUER TERMINALS FROM THE AMYGDALA AND YOU CAN SEE IT'S STUDIED WITH THE TERMINALS FROM THE AMYGDALA AND INCLUDING THIS 1 WHICH IS OPENED UP TO SHOW YOU THE SYNAPTIC VESICLES INSIDE AND THE MIGHT O CHND RIA SUGGESTING A PATHWAY, SO THE AMYGDALA HAS A LOT OF INPUT TO THIS REGION AS WELL. SO THE--THE AMYGDALA INDEED HAS A BIG RIDGE IN A LOT OF THESE CORTICAL AND SUBCORTICAL STRUCTURES AND WE NEXT TRY TO SEE HOW IT INTERFACES WITH THE HIPPOCAMPUS. A LOT OF PEOPLE HERE WORK WITH THE HIPPOCAMPUS, THIS IS SCRUOF THE A SUMMARY OF THE WHAT I JUST TOLD YOU FROM FRONT TO BACK, THE TRN, AND SO FORTH AND YOU CAN SEE THE OVA LAB. SO NOW THE PATHWAYS FROM THE AMYGDALA TO HIPPOCAMPUS, THEY INNERIVATE MOSTLY EXCITATORY NEURONS LIKE CORTICAL, CORTICAL PATHWAYS, BUT THE SMALL PART OF THE SYNAPSES ARE WITH INHIBITORY NEURONS AND WE SEE THAT THE CONFOCAL MICROSCOPE HERE AND YOU SLEEP APNEA AND OBESITYY THE SYNAPTIC LEVEL AS WELL SO THE INTERESTING PART WAS IN C. A. 1 WHICH YOU SEE OVER HERE IS AMYGDALA INNERIVATES THE INHIBITORY NEURONS THE [INDISCERNIBLE] IN THE LAB ANALYZED 2 CLASSES, [INDISCERNIBLE] CR, AND [INDISCERNIBLE] PB, AND THAT'S WHAT SHE FOUND. BUT IN CA3 SHE FOUND THAT ABOUT 3-4% INNERIVATE [INDISCERNIBLE] AND PV AS WELL SO IN CA 3 THE AMYGDALA INNERIVATE BOTH OF THESE STRUCTURES SO THE QUESTION IS, AND THIS IS THE CONFOCAL LEVEL AND THE SYNAPTIC LEVEL AND WE GET THE SAME ANSWER, THESE ARE NO DIFFERENCE STATISTICALLY. SO YOU MIGHT SAY, WELL, 3 OR 4%, IS A LOT OF WORK AND WHAT IT COULD BE DOING THERE AND LET'S TAKE A LOOK AT IT, THIS IS [INDISCERNIBLE] LABELING OF THE [INDISCERNIBLE] AT THE LEVEL THROUGH THE HIPPOCAMPUS IN THE RHESUS MONKEY AS YOU CAN SEE, IT INNERIVATES DIFFERENT PARTS OF THE HIPPOCAMPUS COMPARED TO [INDISCERNIBLE] WHICH IS IN THE GREEN HERE, SO THESE NEURONS OCCUPY IN THE MINORITY JUST LIKE IN THE CORTEX BUT THEY HAVE A WIG RIDGE AROUND THEM, SO CAN YOU SEE THEY HAVE A LOT OF REACH OF WHAT IS GOING ON IN THE HIPPOCAMPUS. SO I WANT TO GIVE YOU A TIDBIT ABOUT WHAT WE THINK MAY BE HAPPENING HERE BASED ON THE CONNECTIONS AND SO WHAT COULD THE AMYGDALA BE DOING IN THE HIPPOCAMPUS? SO WE HAVE CA3 ON THE LEFT HERE AND CA-1, SO CA3 PROJECTION GOES TO C,A 1 AND OUT OF THE HIPPOCAMPUS SO IF YOU HAVE MORE ACTIVITY IN THE AMYGDALA, THE INPUT, THAT MEANS THIS NEURON THAT GETS INPUT FROM THE AMYGDALA IS THAT IT MAY BE ACTIVATED THIS NEURON DOES NOT GET INPUT FROM THE AMYGDALA AND HAS A CHANCE OF BEING ACTIVATED SO THERE ARE DIFFERENT TYPES OF INFORMATION PROCESSING. BUT WHAT HAPPENS WHEN YOU HAVE VERY STRONG INPUT FROM THE AMYGDALA SUCH AS WHEN YOU SEE VERY HIGH EMOTIONAL AROUSAL. SO THIS IS SOME DETAIL SHOWN HERE, AND THIS I COULD TALK ABOUT LATER ON IF YOU WANT, BUT AS I TOLD YOU IN CA3, IT INNERIVATES THE NEURONS WHICH DISINHIBIT EXCITATORY NEURONS AND DOES TO THE NEURON AND TO ITS NEIGHBOR. PV NEURONS ARE VERY STRONG BECAUSE THEY HAVE SOMATIC ININCREASE IN BODYITION AND JUST LIKE THEY DO IN THE CORTEX SO THEY'RE VERY STRONG INHIBITORS OF PARAMETER NEURONS, SO, THIS NEURON IS VERY ACTIVATED SO INHIBITION IS LESS LIKELY TO SILENCE IT BECAUSE OF THE STRONG EXCITATION, BUT THE POOR NEIGHBOR HERE THAT DOES NOT GET STRONG PRACTICES THE AMYGDALA FOR SILENCE SO IT DOESN'T USE THE NEURONS ACTING AS A FILTER SO THAT IN CONDITIONS OF HEIGHTEN ANXIETY, ONLY INPUT THAT GOES THROUGH FROM THE AMYGDALA TO HIPPOCAMPUS, GOES THROUGH AND THIS IS ESSENTIALLY THE PATHWAY THAT IS ACTIVATED THAT GOES WRONG IN PTSD SO WE THINK THIS IS A HYPOTHESIS THAT CAN BE TESTED IN THE FUTURE BASED ON THE SYNAPTIC CONNECTIVITY THAT WE HAVE SEEN. SO MOVING ON TO THE CORTEX, IN THE CORTEX IT'S--THE CORTEX IS ALWAYS MORE SUBTLE BUT IT'S VERY INTERESTING BECAUSE IN THE PRIMATE CORTEX INHIBITORY NEURONS CAN BE LABELED BY 3 NORMAL OVERLAPPING NEUROCHEMICAL CLASSES FOR CALCIUM BINDING PROTEINS, SO BASICALLY THE NEURONS INHIBIT OTHER NEURONS AND [INDISCERNIBLE] NEURONS INNERIVATE THE PARAMETRAL NEURONS SHOWN HERE IN GREEN. I TOLD YOU PV INNERIVATE PERISOMATTIC SIDES OF CORTICAL NEURONS AND EXHIBITION, THEY ALSO ARE A DIFFERENCE IN THE DISTRIBUTION IN TERMS OF THE LAMINA DISTRIBUTION, SO NEURONS SHOWN HERE IN GREEN ARE IN LAYER 1 AND NUMBER 2 FOR THE MOST PART, NOT EXCLUSIVELY, [INDISCERNIBLE] NEURONS IN 2 AND 3 NOT EXCLUSIVELY AND PV NEURONS UPON LIMITED TO DEEP LAYERS. SO I WOULD LIKE TO USE THIS TO REALLY PUT INFORMATION TOGETHER FROM WHAT WE KNOW ABOUT THE CONNECTIONS WITHIN THE CORTEX AND WHAT I SHOWED YOU WITH SUBCORTICAL STRUCTURES TO TRY TO FIGURE OUT WHAT MAY BE HAPPENING IN DISEASES SUCH AS SCHIZOPHRENIA BECAUSE WE KNOW THAT SUCH DISEASES, PEOPLE SAY, [INDISCERNIBLE] ARE BORN AND OTHER PEOPLE SAY WELL IT'S PV THAT ARE INVOLVED AND SOME PEOPLE STILL SAY PRN NEURONS IN THE THALAMUS ARE INVOLVED. SO WE USE THE INFORMATION THAT WAS AVAILABLE FROM THE BEHAVIORIAL STUDIES AND THE CLINICAL LITERATURE, AND WHAT WE KNOW FROM THIS TO COME UP WITH A COMPUTATIONAL MODEL THAT WOULD COMBINE ALL 3 TO SEE WHAT MAYBE HAPPENING AND THIS IS WHAT JOHAN AND JOHN COMPUTATIONAL NEUROSCIENTIST IN THE LAB DID. SO WE KNOW THAT THE DEFICITS IN INHIBITORY NEURONS IN SCHIZOPHRENIA, SOME PEOPLE YOU SEE CB, OTHER SAY PV NEURONS, TBRN NEURONS AND HERE IS THE LAMINA CORTICAL LOOP THAT CAN INCORPORATE ALL OF THIS AND SO WHAT HE DID WAS TO MODEL [INDISCERNIBLE] TASK AND THIS, I WOULD SHOW YOU IN THE NEXT SLIDE SO ESSENTIALLY THE CORTICAL THALAMIC MOTIF THAT I SHOW YOU IT GOES FROM THE DEEP LAYERS OF THE CORTEX TO TRN IN THE THALAMUS AND BACK AS I SHOWED YOU BEFORE AND YOU CAN INTORPERATE ALL OF THAT AND WITHIN THE COLUMN, WE HAVE NOW THIS CBM PV AND CRN NEURONS. AND WHAT HIS--SO THE MOTOR LINE MOVEMENT, I WILL SHOW YOU A NIGHT TRACKING TASK IN THE PRESENCE OF A DESTRUCTOR IN THE FIXATION TASK AND HE FOUND THAT IF THERE IS INTERMITTENT CORTICAL THALAMIC ACTIVITY AS YOU SEE HERE, NO 1--NO NEURON IN THE THALAMUS GAINS FAVOR FOR BEING TRANSMITTED TO THE CORTEX BUT IF THERE IS PERSISTENT CORTICAL THALAMIC ACTIVITY IN 1 COLUMN, WHAT HAPPENS, THE TRN NEURON UNDERGOES THE SYNAPSE BETWEEN THE TRN NEURON AND THE THALAMIC NEURON AND THERE GOES TEMPORARY PLASTICITY AND THIS WAS DONE IN PHYSIOLOGICAL STUDIES MICE, IN RATS BY [INDISCERNIBLE] AND THEIR COLLEAGUES SO THAT THE PHYSIOLOGICAL LEVEL, SO WELL IS SOMETHING THAT IS HAPPENING THAT IS FAVORING ACTIVITY HERE BUT THE NEIGHBORS ARE SUPPRESSED AS YOU SEE HERE, SO THIS IS HOW THE SYSTEM BECOMES SELECTIVE SO IF YOU HAVE SOMEBODY FOCUSING ON SOMETHING, THE SYSTEM CAN BECOME SELECTIVE AND WHAT GOES IN THROUGH THE THALAMUS, LET'S LOOK AT THE TASK HERE, HERE IS THE MODEL, THE CORTICAL THALAMIC MOTIF THAT HAPPENS THROUGHOUT THE CORTEX. SO WE SEE THE INTENSERY SYSTEMS AND HIGH ORDER ASSOCIATION, AND EMILY CIBOL SYSTEMS, WE SEE VARIATIONS OF THIS, SO WHAT WE FOUND WAS THAT I-TRACK, THE STIMULUS IS SHOWN IN BLUE HERE AND THEN WHAT HE DID, HERE WAS TO PERTURB ON THE TOP IS THE P A RVO-ALBUMIN NEURONS AND YOU CAN SEE PERTERBS THIS SMALL MOVEMENT OF A STIMULUS IN THE PLACE--IN THE PRESENCE OF A DISTRACTER. AND THEN OVER HERE IS THE BENDING NEURONS AND YOU SEE THAT ALSO DISTURBS WHAT IS HAPPENING HERE AND THEN P THIS IS THE TRN NEURON AND THE TRN NEURON IS NOT VERY MUCH PERTURBED, THIS IS THE--THIS IS THE SHORT-TERM PLASTICITY THAT CONNORS AND HIS COLLEAGUES HAVE SHOWN. AND THE FIXATION TASK IS ALSO AFFECTED AND THIS IS THE PV, AND BY THE WAY, HE DIDN'T TAKE ALL OF PB NEURONS OUT, JUST THE NMBA RECEPTORS AND SOME PV NEURONS WHICH IS WHAT PEOPLE REPORT HAPPENS IN SCHIZOPHRENIA. AND SO HE FOUND ALSO THIS FIXATION TASK WAS EFFECTED IN ALL CASES. BUT WHAT IS MOST INTERESTING ABOUT THIS, IS THAT EVEN THOUGH THIS PERTERBATION AT DIFFERENT PARTS OF THE CORTICAL THALAMIC LOOP PERTURBED BY MOVEMENTS AND PAYING ATTENTION TO THE STIMULUS, QUALITATIVELY, THEY'RE DIFFERENT AND SO WHAT WE HOPE IS THAT PEOPLE CAN GO BACK IN THE DATABASES WE HAVE MOVEMENTS WHICH WE KNOW ARE DISTURBED IN SCHIZOPHRENIA AND THIS IS WHY THE STASK WAS CHOSEN BECAUSE YOU CAN SEE THE ABNORMAL LINE MOVEMENTS AND THEY HAVE THIS PREDICTION ABOUT YOU CAN PREDICT SCHIZOPHRENIA BY RECORDING EYE MOVE UPONS AND PSYCHIATRYS KNOW MORE ABOUT THAT. SO THE THALAMIC SYSTEM IS ALSO VARIABLE, SO IT'S NOT REALLY ALL PROJECTIONS FROM THE CORTEX TO THOSE AND EQUIVALENT, THERE'S SYSTEMATIC VARIATION IN THE PROPORTION OF NEURONS FROM LAYER 5 THAT PROJECT TO THE THALAMUS AMONG PREFRONTAL AREAS AND SO, WHAT I WANTED TO TELL YOU NOW IS THAT THERE'S A SPECIAL RELATIONSHIP OF THE PREFRONTAL CORTEX WITH 2 LARGE STRUCTURES, THE BASAL GANGLIA AND THE CORTEX, SO THESE SPEAK TO THE STRUCTURES THROUGH THEIR INPUT STAGES BUT THROUGH SEVERAL STAGES TO THE THALAMUS, ONLY THE FRONTAL LOBE GETS ACCESS FOR THE FEEDBACK INFORMATION FROM THE BASAL CELL GANGLIA, SO THESE HAVE BEEN SPOILED FOR THE BASAL GANGLIA AND THE FRONT. SO WHAT I MEAN BY THAT IS THE PRIMARY MODEL. PREMODEL AND FRONTAL. SO THAT CONITUTES THE FRONTAL. SO THE AREAS THAT MAKE DECISIONS IN THE ACTIONS, ARE THE 1S THAT ARE ACTUALLY DO THAT. SO THE THALAMIC NUCLEI, THAT CONNECTED WITH THE FRONTAL CORTEX OF A HUB FOR THE OUTPUT OF THE BASAL GANGLIA AND SO, I'M BRINGING THIS UP BECAUSE WE REALLY DON'T KNOW HOW NOT ONLY MOTOR ACTIVITY BUT COGNITIVE ACTIVITY SUCH AS WHEN PEOPLE IS THINKING, THINKING WORDS AND SENTENCES TOGETHER FOR FLUENT SPEECH, HOW DO THEY REALLY COME ABOUT. NOW THE BASAL GANGLIA IS INVOLVED IN THIS HABIT FORMATION, YOU SEE THE CHART, THEY LEARN TO WALK AND TALK AND THEY DO IT ACCORDINGLY AND IT BECOMES A HABIT AND THE CEREBELLUM IS A VERY--IT'S A 3 LAYER CORTEX AND PERHAPS IT DOES SOMETHING VERY WELL AND IT'S ALMOST LIKE IT GET THIS IS INFORMATION AND MAYBE KIND OF PACKAGES IT, SENDS IT TO THE THALAMUS AND MAKES IT READILY AVAILABLE TO THE FRONTAL CORTEX AND FREE RADICALS FRONTAL AND MODAL, AND PREMOTOR AREAS AND THIS IS JUST SOMETHING TO THINK ABOUT IN THIS SENSE. SO NOW, YOU SAY, WELL THIS IS WELL AND GOOD FOR MONKEYS, WHAT ABOUT HUMANS THAT DO ALL OF THESE PATTERNS OF CONNECTIONS APPLY AND WE'RE STARTING TO ELECTRIC AT THE RELATIONSHIP AND IN THIS CASE, THE [INDISCERNIBLE] DENSITY IN THE WHITE MATTER AND DIEWRON DENSITY IN MONKEYS AND IN HUMANS IN 3 AREAS, THE ACCO, THE LATERAL PREFRONTAL AREA AND VERY NICE PARALLELS ACROSS THIS AREA. SO YOU CAN SEE IT'S VERY HIGH CORRELATION THIS, IS FROM RECENT PAPER IN [INDISCERNIBLE] BIOLOGY. SO WE CAN USE WHAT WE KNOW IN MONKEYS IN THE EXPECTED CONNECTIONS TO PREDICT WHAT MAY BE HAPPENING IN HUMANS BECAUSE WE CAN DO THIS AT HIGH RESOLUTION. SO THE QUESTION IS, IF THESE AREAS TALK TO EACH OTHER IN A VERY ORGANIZED WAY IN THE RELATIONSHIP OF THEIR STRUCTURE MATTERS, THE QUESTION IS HOW DO THESE DIFFERENCES IN CORTICAL ARCHITECTURE ARISE? HOW CAN WE EXPLAIN THIS REGULARITY IN THESE CONNECTIONS FOR THE AVAILABILITY BUT THEN IN A SYSTEMATIC WAY. AND WE THOUGHT THAT, YOU KNOW YOU HAVE THIS GRANULAR AREA, LOOKS LOAMACYIC THIS IN THE ADULT, AND THIS IS THIS NICE 6 LAYER CORTEX AND HOW CAN YOU EXPLAIN THAT. WITH WHAT THEY HAD TO DO WITH DEVELOPMENT? SO WE KNOW THAT THE CORTEX DEVELOPS FROM INSIDE OUT HERE AND SO WE THOUGHT THAT THE ONLY WAY WE COULD EXPLAIN THIS DIFFERENCES IN THE ADULT IS IF THEY--THIS CORTEX CONTINUES TO DEVELOP BUT THIS 1 STOPS EARLIER. SO THAT WAS THE OHM WAY I COULD EXPLAIN WHAT IS HAPPENING WITH THAT BUT WE DIDN'T LEGALLY HAVE A LOT OF DATA, THIS WAS PREDICTED IN AN EARLY PAPER AND THERE WAS A STUDY BY [INDISCERNIBLE] IN 2002 IN A REVIEW OF ALL PLACES AND HE HAD 3 AREAS AND THIS IS THE DEVELOPMENT EMBRYONIC [INDISCERNIBLE] GO FROM HERE, THE BEGINNING OF THE EMBRYONIC DAY 40, ALL THE WAY DOWN HERE AND THIS IS LAYER 6 TO LAYER 2 WHICH IS AT THE CELLULAR LAYERS. AND WE SEE THAT IN THIS AREA STOPS DEVELOPING AND IT'S THE E70, THE BLUE TRACE AND THEN IN THE GREEN TRACE, IS AREA 11 LIKE AN INTERMEDIATE AREA AND BECAUSE ALL THE WAY TO E80 AND 46 CONTINUES ALL THE WAY TO EMBRYONIC DAY 90 AND I SHOW YOU THE STRUCTURE WHERE IT'S VERY DIFFERENT AND THIS RED LINE HERE THAT GOES AND GOES, IS V1 WHICH HAS MORE NEURONS THAN ANY OTHER CORTICAL AREA IN PRIMATES, SO MORE RECENTLY A COLLEAGUE OF MINE, WHO IS A NAWR O SCIENTIST BUT ALSO A PATHOLOGIST, HE WAS HELPING SOME OF HIS COLLEAGUES WITH SOME STUDIES WHEN HE WAS IN SPAIN AND HE SAYS, YOU KNOW I HAVE THE SLIDES FROM FETAL HUMAN TISSUE THAT WE HAVE, WE HAVE GOTTEN FROM SPONTANEOUS ABORTIONS BECAUSE THERE WAS SOMETHING IN THE PLACENTA AND HE--THEY LOOKED AT IT AND HERE THIS PROSPECTIVE EMILY CIBOL AREA, BECOME MORE LAMINATE AS YOU GO THIS WAY, AND HERE IS THE CROSS SECTION, I THINK THAT EVEN AT THIS LEVEL, YOU CAN SEE THAT THE PERSPECTIVE AREAS HAVE FEWER NEURONS THAT THEY PROSPECTIVELY LAMINATE AND THE EMBRYONIC DAY 20 WHICH YOU ALSO HAD SOME TISSUE, YOU SEE THIS EMILY CIBOL PERSPECTIVE EMILY CIBOL AREA HERE ABOVE THE CORPUS CO LOSS UMKC, THESE LOOK LIKE THEY'RE ALREADY MATURE AND THESE NEWSPAPERONS DOWN HERE IN PERSPECTIVE, LAMINATE 6 LAYER CORTICES, SUGGEST THEY'RE NOT MATURE YET. SO THIS LINK WHAT IS WE JUST TOLD YOU TO THE DEVELOPMENT. AND LET ME QUICKLY SUMMARIZE THAT THIS VERY ABILITY IN CORTICAL STRUCTURE PROVIDES THE BASES TO FORMULATE WHAT WE CALL A STRUCTURAL MODEL THAT DESCRIBES AND PREDICTS THE STRENGTH, PATTERN, PRESENCE AND EVEN ABSENCE OF CONNECTIONS WITHIN THE CORTEX, THE VARIABLE RECRUITMENT OF AREAS OF THE LAYERS, THE ONLY WAY THIS CAN HAPPEN, AND THROUGH THE CORTEX, THROUGH THE THALAMUS THAT IS LINKED WITH IT, THE BASAL GANGLIA AND THE CEREBELLUM THAT HAS ARRIVED THROUGH THE THALAMUS AND THE RECRUITMENT OF PATHWAYS LINKS THESE DISTRIBUTED PATHWAYS TO EFFECTOR SYSTEM FOR SMOOTH SEQUENCING OF ACTIONS THAT WE THINK ARE CRUCIAL FOR NORMAL BEHAVIOR AND THEY FALL APART IN DISEASES. WE KNOW THAT CORTICAL REGIONS CRITICALLY DEPEND ON THE INTERFACE OF EXCITATORY PATHWAYS WITHS DISTINCT CLASSES OF INHIBITORY NEURONS FOR SHIFTING OF LAYER AND THIS IS AN AREA THAT I HOPE MORE PEOPLE WOULD TAKE UP ON BECAUSE I THINK THIS WOULD TELL US A LOT ABOUT COGNITIVE PROCESSES AND HOW THESE SYSTEMS ARE RECRUITED. IN THE PATTERN OF CONNECTIONS IT'S PERTERBED IN THE DISEASES OF DEVELOPMENTAL ORIGIN, THAT INCLUDES SCHIZOPHRENIA, AUTISM, BUT THERE'S OTHER DISEASES THAT HAVE NOT SPOKEN ABOUT. SO THE STRUCTURAL MODEL WE'VE BEEN ABLE TO FORMULATE BASED ON THIS PRINCIPLE OF SYSTEMATIC VARIATION EXPLAINS CONNECTIONS BUT ALSO THE PLASTICITY'S ABILITY IN THE CORTEX AND WE HAVE THE PAPER IN 2017 THAT TALKS ABOUT IT BUT ALSO THE PREFERENTIAL VULNERABILITY TO PATHOLOGY, BOTH IN PSYCHIATRIC AND NEUROLOGICAL DISEASES. AND THE AREAS WITH THE SIMPLEST ARCHITECTURE ARE THE MOST PLASTIC AND THE MOST VULNERABLE TOOL OF THESE DISEASES AND THESE ARE THE AREAS THAT PERHAPS WE SHOULD PAY MORE ATTENTION TO TO UNDERSTAND PSYCHIATRIC DISEASES AND WE KNOW THAT THE MODEL IS NOW LINKED TO DEVELOPMENT AND WE HAVE PROOF FROM BOTH MONKEYS AND HUMANS FETAL TISSUE AND WE THINK THAT IT ALSO TELLS US A LOT ABOUT THE EVOLUTION OF THESE AREAS, THE DEVELOPMENT OF THESE AREAS IN EVOLUTION AND THAT WE HAVE A PAPER HERE THAT SUMMARIZES ALL OF THESE PRINCIPLES AND I WOULD LIKE TO STOP HERE AND GET SOME OF YOU QUESTIONS IF YOU HAVE ANY. [APPLAUSE ] >> THAT WAS MARVELOUS, I WONDER IF YOU COULD SPECULATE ABOUT THE FIRST PART OFIOURE TALK WHICH WAS RELATED TO THE FEED FORWARD AND FEEDBACK AND HOW THAT RELATES TO MAYBE EVEN GRANULAR AND DISGRANULAR TRAJECTORIES AND THE LAST PART OF TALK THAT LINKS TO DEVELOPMENT AND SINCE SOMETIMES AS CELLS ARE SAY GOING TO THE UPPER LAYERS, THEY CARRY EXCELLENCE WITH THEM, DURING THAT FACE OF DEVELOPMENT, CAN THAT ASYNCHRONY ACROSS THE CORTEX HAVE SOMETHING TO DO WITH THE ESTABLISHMENT OF THE PATTERN THAT DEFINES OUR CORTICAL HIERARCHY. >> THAT'S EXACTLY WHAT WE THINK AND WE DON'T HAVE DIRECT PROOF. IT'S AN EXCELLENT POINT AND WE WOULD LIKE TO NAIL THAT AND UNFORTUNATELY, THERE'S VERY LITTLE IN THE WAY OF DEVELOPMENTAL STUDIES AT THIS CLASSICAL LEVEL BECAUSE PEOPLE ARE REALLY ENAMORED OF OTHER PARTS OF DEVELOPMENT NOW AND GENE EXPRESSION SO IT'S ALSO VERY IMPORTANT BUT THIS CLASSICAL PART REALLY SEE WHAT IS HAPPENING IN BETWEEN WE HAVE VERY LITTLE, YOU KNOW? IT WAS JUST THAT, BUT WE THINK THAT THE TIMING IS WHAT GIVES THIS KIND OF GRADED PATTERN IN THE COP NEKSS OTHERWISE, I COULD NOT REALLY EXPLAIN THAT IN ANY OTHER WAYS AND THESE--THE SIMILARITY IN OTHER AREAS, IT ALSO EXPLAINS WHY SOME OF THESE AREAS ARE CONNEBTED, YOU KNOW SOME FREE RADICALS FRONTAL AREAS IN THE FRONTAL FIELDS AND THEREFORE THE 6 ARE CONNECTED WITH PARIETAL AREAS, THEY'RE VERY FAR FROM EACH OTHER, SO WHEN PEOPLE SAY, IT'S BASED ON DISTANCE, IT CO INSIDES WITH DISTANCE BUT DISTANCE IN SOME AREAS ESPECIALLY IN THE VISUAL SYSTEM AS YOU KNOW CHANGES WITH THE ARCHITECTURE SO HAVE YOU THE BEST ARCHITECTURE IN V1 AND BY THE TIME YOU GET TO THE TEMPORAL POLE IS THE EMILY CIBOL PART OF THE VISUAL SYSTEM AND YOU SEE THE SAME PART ON THERE. SO I THINK THAT YES, THAT'S WHAT MY HIGHWAY POGHT SIS WOULD BE THAT THIS IS WHAT HAPPENS. AND I WILL HAVE PEOPLE IN THE LAB NOW TRYING TO DO IT USING COMPUTATIONAL METHODS AND THE REST I'M KIND OF CLEVER WAYS 1 CAN GO ABOUT IT TO FILL IN THE GAPS BUT WE DO HAVE A LOT OF MISSING LINKS IN THAT. >> HI, HELEN, THANK YOU FOR THE TALK. IT'S ALWAYS NICE TO HEAR THE GROUND TRUTH, I FEEL THAT NEUROANATOMY IS SORT OF THE GROUND TRUTH FOR MAIN OF THE THINGS WE'RE DOING. SO MY QUESTION IS ABOUT THE INTERKOLATED MASSES. >> YES? >> BUT IS THE OUTPUT OF THE INTERKOLATED MASSES WHICH IS ALL THIS INHIBITORY-- >> IN THE AMYGDALA. >> YES? IS IT ALL IN THE CENTRAL NUCLEUS OF THE AMYGDALA? >> IT GOES TO SOME OF THE OTHER NUCLEAR OF THE AMYGDALA ALSO, IT GOES TO SOME EXTENT TO THE BASAL NUCLEAR FOR EXAMPLE, SOME PEOPLE HAVE SHOWN AT LEAST IN MICE AND RATS. BUT THE INTERPOLATED NEUROSTRUCTURE TO THE CORTEX, SO ALL--ONLY WITHIN THE AMYGDALA, AND THOSE EXPERIMENTS ARE VERY HARD TO DO. I WOULD LOVE TO REALLY KNOW DEFINITIVELY WHERE THEY GO BUT HOW DO YOU GET THEM, THEY ARE JUST IN BETWEEN IN THE MONKEY, THEY'RE IN BETWEEN THE NUCLEAR OF THE AMYGDALA, LITTLE HALLWAYS AND IF YOU LOOK AT A LOT OF ATLASS THEY COMPLETELY IGNORED THEM SO THEY MAKE THE NUCLEI CONTINUOUS WITH EACH OTHER WITH NO HALLWAY. BUT THEY'RE VERY, VERY IMPORTANT WITH THAT. WE TRIED A LOT OF DIFFERENT WAYS, I WAS TELLING THEM, THESE PEOPLE THIS MORNING WE TRY TO DO SLICE IT AND TRY TO USE POSTMORTEM DICE AND UNFORTUNATELY IT DON'T WORK VERY WELL BUT WE DO HAVE SOME CONNECTIONS. YES? >> I HAVE 2 QUESTIONS. FIRST 1 IS ABOUT TIMING SO IN ONSET SCHIZOPHRENIA, LET'S SAY IN HUMANS IN THE 20S AND 30S, IS THERE ANY EVIDENCE FOR A SELECTIVE TIMING FOR LOSS OF INHIBITORY NEURONS DURING THAT TIME PERIOD OR CAN YOU SPECULATE A LITTLE BIT ABOUT WHAT WOULD BE THE TRIGGER. SECOND QUESTION IS MORE GENERAL QUESTION ABOUT THE ROLE OF TOP DOWN PROJECTIONS FROM FRONTAL CORTEX AND I GUESS THE QUESTION THAT I HAVE IS YOU SOMETIME VS A LOT OF FRONTAL CELLS THAT SHOW MULTIMODAL PROPERTIES SO HOW SPECIFIC ARE THE PROJECTIONS THAT ARE ACTUALLY SOME SURVEYING OR PROPOSED INTENTIONAL EFFECT FROM THE ANATNY? >> FROM THE PRN? >> FROM TRN. >> YEAH. >> WELL, THE FIRST PART ABOUT THE SCHIZOPHRENIA THERE ARE PEOPLE WHO LOOK AT THIS AND THE QUESTION IS, WHAT IS THE TRIGGER THAT THEY MAY BE LOSING THE NMDA RECEPTORS THAT PEOPLE THOUGHT ARE EFFECTED [INDISCERNIBLE] IN PITTSBURGH DID A LOT OF THESE STUDIES. WE DON'T REALLY KNOW, I MEAN THERE IS THE SYSTEM BECOMES MORE SPECIFIC DURING THE PUBERTY AND BEYOND IN ADOLESCENCE BUT THERE ARE A LOT OF OTHER THINGS THAT ARE HAPPENING AT THE SAME TIME THAT CONFOUND ANY KIND OF ANALYSIS FOR EXAMPLE, THE NEUROTRANSMITTER SPECIFIC SYSTEMS ARE ALSO CHANGING AT THAT TIME AND YOU KNOW FROM THE BASAL FOREBRAIN AND COLONERGIC, [INDISCERNIBLE] AND ALL OF THOSE ARE CHANGING AT THE SAME TIME SO WE REALLY DON'T KNOW BUT I THINK PEOPLE ARE FINDING THAT WHATEVER POSTMORTEM TISSUE THEY CAN GET, AND THAT THEY HAVE THAT REALLY IS THERE, YOU KNOW, YOU LOSE THE RECEPTORS IN SCHIZOPHRENIA WHICH IS WHY WE USED IT IN THE MODEL TO SEE WHAT HAPPENS WHEN EYE MOVEMENT. AND WITH RESPECT FOR THIS HAPPENING WITH PREFRONTAL TO OTHER AREAS WITH TRN, WE WERE VERY SURPRISED TO SEE THIS BIG OUTREACH OF SOME FRONTAL AREA ACCIDENT NOT ALL OF THEM ON TRN. AND FOR--FOR SOMETIME, HI--WE HAD NO IDEA HOW TO MAKE IT SPECIFIC, WHY IS THAT SPECIFIC? AND I HAD INTERACTIONS WITH COLLEAGUES AND SAYING YES BUT HOW DO YOU MAKE IT SPECIFIC? AND THEN, THIS PAPER CAME OUT WHICH WAS VERY RECENT ACTUALLY IN 2015 FROM CRANEDDAL [INDISCERNIBLE] AND COLLEAGUES IN 2015 AND THEY SHOWED THIS SPECIFIC TYPE OF PLASTICITY THAT WAS TRANSIENT SO IF SOMEBODY'S FOCUSING AND YOU'RE ASKING SOMEBODY TO FOCUS AND THEY'RE FOCUSING ON SOMETHING, THAT PART OF THE CORTICAL THALAMIC LOOP THAT IS PARTICIPATING IN FOCUSING CHANGES, IT CHANGES THE PROPERTIES OF THE TRN NEURON AND YOU GET THIS SHORT-TERM PLASTICITY THAT ALLOWS INPUT TO GO TO THE CORTEX. SO SUPPOSE YOU TELL A SUBJECT TO FOCUS ON THIS VISUAL STIMULUS, WHEN THERE IS INPUT THAT GOES FROM FOR EXAMPLE, FROM THE LIAISON FILLS AND AREA 46 BOTH OF WHICH GET INPUT FROM VISUAL AREAS AND SO, IT COULD GO DOWN TO THAT REGION THROUGH TRN AND SAY, LET THIS 1 IN AND SEPARATE ALL THE OTHERS. AND WHEN PEOPLE WERE STUDYING TRN, PHYSIOLOGICALLY THEY ARE VERY CHALLENGING NEURONS THEY HAVE EXTREMELY COMPLEX PROPERTIES AND IT WASN'T UNTIL VERY RECENTLY THAT PEOPLE STARTED TO ACTUALLY MAKE A LITTLE BIT OF SENSE ABOUT WHAT IS HAPPENING. SO THE SHORT-TERM PLASTICITYS ARE VERY IMPORTANT CONCEST. THERE'S PEOPLE SOMEBODY BY THE NAME OF [INDISCERNIBLE] WHO SHOWED THAT IN THE VISUAL SYSTEM, THE COLUMN THAT IS ACTIVATED BECOMES MORE ACTIVE BUT WE DIDN'T KNOW HOW. BUT THE SHORT-TERM PLASTICITY SEEMS TO BE WHAT ALLOWS THAT TO THE COLUMN TO WIN THE COMPETITION IN THE AREAS IN THE FLANKING REGIONS SORT OF LIKE LATERAL INHIBITION ARE ACTUALLY INHIBITED AND MAKES THE SYSTEM VERY FLEXIBILITY AND BECAUSE IT'S REALLY SOMETHING THAT WE SEE ACROSS THE CORTEX, COTTER CO THALAMIC GROUP, WE CAN EXTEND IT BEYOND THE SENSORY AREAS AND WE CAN EXTEND IT TO COGNITIVE PROCESSES AND WHAT MAY BE HAPPENING IN THESE PSYCHIATRIC DISEASES. YOU KNOW WHY IS THAT SCHIZOPHRENIC PATIENTS HAVE A PROBLEM WITH FOCUSING? AND THEY GET DISTRACTED VERYACILY AND IN FACT DESTRUCTION SEEMS TO BE WORSE THAN ALL THESE OTHER SYMPTOMOLOGYS SUCH AS HALLUCINATIONS FOR COGNITION AT THE LEAST. >> [INDISCERNIBLE]. --WHEN THEY ACTIVATED TRN OPTICAL IMAGES O GENETICALLY THEY INKRES THE THALAMIC INHIBITION AND THEY PRODUCE LOW CORTICAL SLOW WAVES IN AND THE ACEROUSAL WENT DOWN SO WHAT IS YOUR, I GUESS GUT FEELING? IN THIS CASE OR HIGH AROUSAL LIKE IN PTSD? DO YOU THINK IT'S MORE KIND OF A PROBLEMATIC INHIBITION THAT'S NOT WORKING OR [INDISCERNIBLE] PROPOSE IT JUST [INDISCERNIBLE] TONE COMING FROM THE STRIATUM TO THE AMYGDALA IN THE FIELD? >> YEAH, I THINK IT'S GREAT. I THINK A LOT OF THESE THINGS MAY BE HAPPENING AND I'M WONDERING IF THE AMYGDALA TAKES OVER, YOU KNOW WHEN YOU HAVE THIS HYBRID AROUSAL SYSTEM, WE PRODICKED IT SHOULD BE PROJECTED TO TRN AND THE FACT THAT NOBODY HAD LOOKED THROUGH THE AGES IN ANY SPECIES WAS KIND OF SURPRISING BUT THAT'S MAYBE BECAUSE PEOPLE DON'T REALLY DO A LOT OF ANATOMICAL STUDIES SO I'M WONDER WHAG REALLY HAPPENS AT THAT LEVEL, YOU KNOW? THE AMYGDALA TAKES OVER IN THE HYPER AROUSAL STATE SO ALLOWING ONLY THESE STIMULI WITH THAT SIGNAL EMOTIONAL AROUSAL TO GO& THROUGH FOR THIS SYSTEM AND THE HIPPOCAMPUS AS WE SHOWED, YOU KNOW? THAT SEEMS TO GO HAND IN HAND AND WE SAY THAT THE AMYGDALA FROM WHAT WE FIND, IT DOESN'T REALLY TALK TO AREAS, IT SHOUTS. THE SYNAPSES ARE LARGER AND IN [INDISCERNIBLE] STUDY, SHE FOUND THAT THE SYNAPSES BETWEEN THE AMYGDALA AND THE HIPPOCAMPUS ARE LARGER THAN IN THE SURROUNDING NEUROFILL AND IN FACT, SOME VERY SMALL PARTS OF THE DENDRITE HAVE DUAL SYNAPSES IN THE DENDRITE WHICH IS UNUSUAL YOU SEE THEM BUT IT'S NOT A VERY USUAL PHENOMENON AND SHE SAW IT IN LARGE NUMBER OF THE SYNAPSES SO WHEN YOU REALLY LOOK DOWN, YOU SEE THAT, SO HAVE YOU HYPER AROUSAL, ALL OF THESE WILL TAKE OVER AND KIND OF HIJACK THE SYSTEM, SO ONLY WHAT THE AMYGDALA WANTS TO SEE, GOES THROUGH AND I SHOWED YOU THIS LITTLE INHIBITION THROUGH PB NEURONS, SILENCES EVERYTHING ELSE BUT THAT GOES THROUGH AND MAYBE THAT'S WHY PEOPLE ARE MOTIVATED BY FEAR AND THEY CAN REALLY THINK LOGICALLY ABOUT ANYTHING ELSE THAT MAY BE HAPPENING WHETHER IT'S IN THEIR LIVES OR IN THEIR SURROUNDINGS AND SO FORTH. IT'S GOOD TO SPECULATE. >> WE WILL STOP THERE, THANKS SO MUCH, HELEN FOR A VERY GOOD TALK.