RF1MH139176

SYNAPTIC PLASTICITY MECHANISMS THAT PROTECT AND REFINE LOCAL CIRCUITS - ABSTRACT SYNAPSES FORM TRILLIONS OF CONNECTIONS BETWEEN BILLIONS OF NEURONS IN THE BRAIN TO ESTABLISH NEURAL CIRCUITS THAT ALLOW US TO SENSE, THINK, ACT, LEARN, AND REMEMBER. OUR GOAL IS TO UNDERSTAND HOW SYNAPSE STRUCTURE SUPPORTS LEARNING AND MEMORY WITH A FOCUS ON DENDRITIC SPINES, THE TINY PROTRUSIONS THAT HOST MOST OF THE EXCITATORY SYNAPSES IN THE BRAIN. WHILE MOST NEUROSCIENTISTS AGREE THAT SYNAPTIC STRUCTURAL CHANGES ARE VITAL FOR LEARNING AND MEMORY, THE CELLULAR AND MOLECULAR MECHANISMS THAT PROTECT RECENT SYNAPTIC CHANGES FROM BEING OVERWRITTEN BY ONGOING PLASTICITY REMAIN ILL-DEFINED. OUR THREE-DIMENSIONAL RECONSTRUCTIONS FROM SERIAL SECTION ELECTRON MICROSCOPY (3DEM) REVEAL DISTINCT SUBREGIONS OF THE POSTSYNAPTIC DENSITY (PSD) WHERE ACTIVE ZONES (AZS) ARE ASSOCIATED WITH PRESYNAPTIC VESICLES AND NASCENT ZONES (NZS) HAVE NO PRESYNAPTIC VESICLES. AT THE ONSET OF LONG-TERM POTENTIATION (LTP), PRESYNAPTIC VESICLES ARE RAPIDLY RECRUITED TO THE NZS, CONVERTING THEM TO AZS. PROTEIN FILAMENTS SHORTEN AND DRAW DOCKED PRESYNAPTIC VESICLES CLOSER TO THE ENLARGED AZS, AND RECRUIT VESICLES TO DOCK AT WEAK AZS. THIS EVIDENCE OF PRESYNAPTIC PLASTICITY WOULD INCREASE THE AREA OF RELEASE AND PROBABILITY OF POSTSYNAPTIC RECEPTOR RESPONSE. THE RECOVERY INTERVAL FOLLOWING SATURATION OF LTP IS 1-4 HOURS DEPENDING ON THE PREPARATION. DURING THIS INTERVAL, NEW NZS FORM, PRIMARILY ON SPINES CONTAINING SMOOTH ENDOPLASMIC RETICULUM, A LOCAL RESOURCE FOR REGULATING CALCIUM AND TRAFFICKING OF LIPIDS, PROTEINS, AND ORGANELLES. CLUSTERS OF SPINES FORM IN THE VICINITY OF THESE ENLARGED SPINES. WE HYPOTHESIZE THAT SYNAPSE-SPECIFIC EXPANSION OF NZS DURING LTP PROVIDES A BASIS FOR LEARNING AND THE ADVANTAGE OF SPACED OVER MASSED LEARNING TO ESTABLISH LONG- LASTING MEMORIES. FURTHERMORE, WE HYPOTHESIZE THAT LTD IS DRIVEN BY THE CONVERSION OF AZS TO NZS AND ULTIMATELY ELIMINATION OF SPINES WITHOUT AZS. TO ADDRESS THESE HYPOTHESES, WE PROPOSE MULTIDISCIPLINARY APPROACHES TO INVESTIGATE THE CELLULAR AND MOLECULAR MECHANISMS THAT DRIVE THE CONVERSION OF NZ TO AZ AND LIMIT PLASTICITY AT SYNAPSES—INCLUDING SLICE PHYSIOLOGY, OPTOGENETICS, MOLECULAR GENETICS AND PHARMACOLOGY, GLUTAMATE UNCAGING, AND TOMOGRAPHIC 3DEM OF SYNAPSES ALONG ACTIVATED AXONS LABELED WITH APEX. OUR SPECIFIC AIMS ARE: AIM 1) DETERMINE THE SPECIFICITY OF NZ TO AZ CONVERSION DURING SYNAPSE ENLARGEMENT, RESOURCE UTILIZATION, AND SPINE CLUSTERING UNDERLYING THE SATURATION, RECOVERY, AND ENHANCEMENT OF LTP. AIM 2) TEST WHETHER SATURATING LTP AT AN ISOLATED DENDRITIC SPINE IS SUFFICIENT TO FILL NZS AND DETERMINE THE ROLE OF PSD-MAGUK PROTEINS AND THEIR INTERACTING PARTNERS IN RECOVERY OF LTP FROM SATURATION. AIM 3) DETERMINE HOW THE SATURATION AND RECOVERY OF LONG-TERM DEPRESSION (LTD) ALTERS THE STRUCTURE OF AZS, NZS, AND SPINES, AND INFLUENCES THE SUBSEQUENT CAPACITY FOR LTP. OUTCOMES PROMISE NEW INSIGHTS ABOUT SYNAPTIC MECHANISMS OF LEARNING AND MEMORY AND NEW TARGETS FOR UNDERSTANDING AND TREATING LEARNING DISABILITIES.

University Of Texas At Austin

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Austin, Texas 787121507 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)