This is an application to establish a Silvio O. Conte Center for Neuroscience Research (CCNR) on GENETIC, PHYSIOLOGICAL, AND BEHAVIORAL STUDIES OF MEMORY. The long-term objective of the Center is to elucidate the molecular, cellular, and neuronal ensemble mechanisms of mammalian learning and memory. The CCNR attacks the problem at three levels. First, it seeks to understand the elementary mechanisms of synaptic plasticity in the hippocampus and neocortex, and how these are developmentally and regionally regulated. Second, the Center seeks to understand how neuronal activity in the hippocampus and neocortex represents information about the outside world, how this information is compared with previous experience, and how these representations are consolidated into long-term memory. Third, the Center seeks to connect the synaptic plasticity and the neuronal correlates of learning with behavioral measures of memory. The elementary mechanisms of synaptic plasticity will be studied by applying electrophysiological techniques to brain slices derived from the hippocampus and the visual and inferotemporal cortices of mice with several specific spatially targeted genetic lesions (knockout mice). A novel electrophysiological technique that permits the analysis of single visualized synapses of cultured neurons will also be used for the analysis of these mice. In order to understand how neuronal activity represents learned information, the Center will seek to identify alterations in the activity of neuronal ensembles in the hippocampus, inferotemporal cortex, and prefrontal cortex by applying the novel multiple tetrode recording techniques to monkeys or rodents that are undertaking various memory tasks. Finally, in order to connect synaptic plasticity and neuronal correlates of learning with behavioral measures of memory, the Center takes advantage of the new methods of regionally and temporally selective genetic disruptions in mice, some of which have already been developed in the Center (hippocampus CAI-selective) while others (neocortex and neocortical subregion-specific) are proposed to be developed as a core project. The proposed research is truly interdisciplinary covering molecular genetics of mice, electrophysiology of brain slices and cultured neurons from rats and mice, and multiple electrode recordings of monkeys, rats, and genetically engineered mice performing specific memory tasks. Six investigators from three institutions and the seventh investigator as a subcontractor, each possessing complimentary and well-recognized expertise and state of the art experimental technologies will join forces and collaborate extensively in the CCNR framework. The Center's research is highly relevant to mental health and illness because mnemonic impairments are a hallmark of aging and major neurological diseases such schizophrenia, Alzheimer's disease and Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH058880-05
Application #
6652460
Study Section
Special Emphasis Panel (ZMH1-BRB-I (03))
Program Officer
Nadler, Laurie S
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
5
Fiscal Year
2003
Total Cost
$1,356,836
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Redondo, Roger L; Kim, Joshua; Arons, Autumn L et al. (2014) Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513:426-30
Kohara, Keigo; Pignatelli, Michele; Rivest, Alexander J et al. (2014) Cell type-specific genetic and optogenetic tools reveal hippocampal CA2 circuits. Nat Neurosci 17:269-79
Liu, Xu; Ramirez, Steve; Tonegawa, Susumu (2014) Inception of a false memory by optogenetic manipulation of a hippocampal memory engram. Philos Trans R Soc Lond B Biol Sci 369:20130142
Dragoi, George; Tonegawa, Susumu (2013) Development of schemas revealed by prior experience and NMDA receptor knock-out. Elife 2:e01326
Dragoi, George; Tonegawa, Susumu (2013) Distinct preplay of multiple novel spatial experiences in the rat. Proc Natl Acad Sci U S A 110:9100-5
Dolan, Bridget M; Duron, Sergio G; Campbell, David A et al. (2013) Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc Natl Acad Sci U S A 110:5671-6
Suh, Junghyup; Foster, David J; Davoudi, Heydar et al. (2013) Impaired hippocampal ripple-associated replay in a mouse model of schizophrenia. Neuron 80:484-93
Buschman, Timothy J; Denovellis, Eric L; Diogo, Cinira et al. (2012) Synchronous oscillatory neural ensembles for rules in the prefrontal cortex. Neuron 76:838-846
Nakashiba, Toshiaki; Cushman, Jesse D; Pelkey, Kenneth A et al. (2012) Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149:188-201
Liu, Xu; Ramirez, Steve; Pang, Petti T et al. (2012) Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484:381-5

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