The long-term objective of the proposed CCNR is to elucidate the molecular, cellular, neuronal ensemble, and neuron circuitry mechanisms of mammalian learning and memory. The CCNR attacks the problem at three levels of complexity: First, to understand the elementary mechanisms of synaptic plasticity and its regulation. Second, to understand how synaptic plasticity subserves single or ensemble neuron activities in the hippocampus and neocortex. Third, to understand how single and ensemble neuron activities represent specific aspects of learning and memory. Further, the Center seeks to integrate findings made at these multiple levels of complexity to reach a comprehensive and coherent understanding of memory. To accomplish these objectives, six investigators from MIT and one from the Salk Institute, who share common intellectual interests and yet come from different fields with complementary expertise ranging from molecular, cellular, and genetic neurobiology to electrophysiology and computational and behavioral neurosciences, will join forces to pursue 30 Specific Aims, many of which are to be carried out in synergistic collaborations. For the elementary mechanisms of plasticity, the Center proposes to apply in vitro electrophysiological recording and fluorescence-mediated imaging techniques to cell-culture and brain slice preparations treated with pharmacological agents or derived from genetically engineered rodents. To understand how synaptic plasticity subserves single neuron or ensemble neuron activities, the Center proposes to use multi-electrode recording techniques in freely behaving rodents. In order to understand how neuronal activities represent encoded, consolidated or retrieved memory information, the Center proposes to study populations of neurons in monkeys and rodents undergoing a specific goal-oriented task. Many projects at the Center use rodents, but monkeys are also used for the study of complex phenomena such as the identification of the neuronal correlates of "executive control" of memory recall. Finally, in order to correlate neural events or processes occurring at multiple levels of complexity with behaviorally manifested memory, the Center proposes to generate mouse strains in which a specific genetic disruption of neural function is spatially and/or temporally selective, and subject them to all the analytical methods described above. Seven Individual Projects are to be supported by three Cores which provide production and maintenance of key mouse mutant strains and administrative services. The Center's basic research is relevant to mental health and illness because mnemonic decline and impairments are a hallmark of aging and neurodegenerative disease.