Project Grant R01EY035248

MECHANISMS OF NEURONAL ENSEMBLES IN VISUAL CORTEX - SINCE THE PIONEERING WORK OF HUBEL AND WIESEL, THE MAMMALIAN VISUAL CORTEX HAS BEEN USED AS A MODEL FOR THE REST OF THE CEREBRAL CORTEX. IN SPITE OF THIS, LITTLE IS KNOWN ABOUT THE DETAILED OPERATIONS OF ITS MICROCIRCUITS. IN FACT, THE CORTEX IS COMPOSED OF MORE THAN A HUNDRED CELL TYPES, AND IT IS LIKELY THAT EACH CELL TYPE HAS A PARTICULAR CIRCUIT FUNCTION. IN A RECENTLY ENDED NEI AWARD WE STUDIED THE FUNCTIONAL PROPERTIES OF THE MICROCIRCUITS OF MOUSE PRIMARY VISUAL CORTEX AND DISCOVERED THAT GROUPS OF COACTIVE NEURONS, TERMED "NEURONAL ENSEMBLES", ACCOUNT FOR THE MAJORITY OF CORTICAL RESPONSES TO VISUAL STIMULI AND ALSO DOMINATE SPONTANEOUS ACTIVITY. FURTHER, USING TWO-PHOTON OPTOGENETICS, WE FOUND THAT ENSEMBLES CAN BE ARTIFICIALLY IMPRINTED INTO THE CORTEX AND THEY CAN BE RECALLED BY STIMULATING INDIVIDUAL NEURONS (PATTERN COMPLETION), EVEN DAYS AFTER IMPRINTING. CONFIRMING THEIR FUNCTIONAL ROLE, ACTIVATING ENSEMBLES WITH HOLOGRAPHIC OPTOGENETICS LED TO PREDICTABLE CHANGES IN VISUAL DISCRIMINATION IN A GO/NOGO BEHAVIORAL TASK. THESE DATA, CONFIRMED BY OTHERS, AND THE WIDESPREAD ALTERATION OF ENSEMBLES IN MOUSE MODELS OF DISEASE, SUGGEST THAT ENSEMBLES ARE MICROCIRCUIT BUILDING BLOCKS OF CORTICAL FUNCTION. TO BETTER UNDERSTAND ENSEMBLES WE NOW PROPOSE TO CHARACTERIZE THEIR BASIC PHENOMENOLOGY AND CELLULAR IDENTITY, UNDERSTAND THEIR BIOPHYSICAL, SYNAPTIC CIRCUIT MECHANISMS AND EXPLORE THE ROLE OF INHIBITORY INTERNEURONS. OUR PRELIMINARY DATA SUPPORT THE HYPOTHESIS THAT ENSEMBLES ARE DUE TO INCREASES IN EXCITABILITY AND ARE SCULPTED BY INHIBITION. TO TEST THIS, WE WILL STUDY PRIMARY VISUAL CORTEX OF AWAKE BEHAVING MICE AND USE A NOVEL TWO-PHOTON HOLOGRAPHIC MICROSCOPY METHOD TO IMAGE AND OPTICALLY MANIPULATE NEURONS IN DIFFERENT CORTICAL LAYERS SIMULTANEOUSLY. WE WILL ALSO USE IN VIVO PATCH CLAMPING OF ENSEMBLE CELLS AND NOVEL GRAPH THEORY MODELS TO MAP THE CIRCUIT, IDENTIFY KEY CELLS FOR MANIPULATION AND TEST THEIR ROLE IN ENSEMBLE ACTIVATION/SUPPRESSION. OUR WORK WILL PROVIDE A SYSTEMATIC DESCRIPTION OF ENSEMBLES IN PRIMARY VISUAL CORTEX, HOW THEY WORK, HOW THEY REGULATE THE ACTIVITY OF THE CORTEX AND HOW THEY CAN BE MANIPULATED AND RECONFIGURED. NEURONAL ENSEMBLES COULD CONSTITUTE FUNCTIONAL MODULES OF CORTICAL FUNCTION. UNDERSTANDING THE LINK BETWEEN ENSEMBLES AND CORTICAL PLASTICITY COULD HELP DESIGN NOVEL THERAPEUTIC STRATEGIES TO TREAT AMBLYOPIA OR CORTICAL CEREBRAL VISUAL IMPAIRMENT BY RECONFIGURING PATHOLOGICAL CIRCUITS.