Application) Visual recognition memory engages the circuitry of the visual cortex, stretching from area 17 ventrally to area TE. Visual receptive fields of neurons in this pathway are increasingly complex as one moves from l7 to TE, and these responses are subject to experience-dependent modification. Robust plasticity is observed in area 17 only during a """"""""critical period"""""""" of postnatal life, whereas receptive field plasticity is observed in area TE throughout life. Nonetheless, formal similarities in the characteristics of plasticity across cortical areas suggests common underlying mechanisms, with different patterns of developmental regulation. Theoretical studies suggest that the experience-dependent changes in receptive fields reflect synaptic modifications that, distributed over many cortical cells, store information and serve visual recognition memory. Individual Project #6 contributes to the overall goal of the Center by examining the possible neural basis for, and developmental regulation of, visual recognition memory in the posterior neocortex of the mouse. This choice of species is important, because much of the research in Individual Project #6 lays the foundation for studies in which synaptic plasticity will be genetically disabled in the neocortex, thus enabling the hypothesis that neocortical plasticity is in fact related to long-term memory to be examined with behavioral tests. It is crucial that these studies be conducted in parallel with the development of neocortex-specific genetic knockouts so that the experimental models will be fully established when the genetic mutants become available. This project will be conducted in a laboratory that has great experience in the study of cortical synaptic plasticity, both in vitro and in vivo, and thus complements (without duplicating) the expertise in other labs of the center. The project is highly collaborative, taking advantage of mutant mice generated by the Tonegawa and Heinemann labs. A central goal of Individual Project #6 is to establish models for long-term synaptic plasticity in the visual neocortex of the mouse. Considerable progress has been made in primary visual cortex, area 17 (Oc1), and we propose to extend this work to include extrastriate (area 18 or Oc2) and temporal (TE) visual cortex, utilizing coronal slice preparations of posterior neocortex. There is considerable evidence that the stream of visual information from area 17 to 18 to TE in the rodent is analogous to the """"""""ventral stream"""""""" in the monkey, and is involved in object recognition. Long-term potentiation (LTP) and long-term depression (LTD) will be used as assays of synaptic plasticity in these cortical regions. The specific questions to be addressed are as follows. 1. Why is plasticity in primary sensory cortex restricted to a critical period of development? We will test the hypothesis that neurotrophins regulate developmental plasticity by studying LTP and LTD in animals in which the neurons of visual cortex are over-expressing brain-derived neurotrophic factor using mice supplied by Tonegawa. 2. How do LTP and LTD compare across cortical areas and across postnatal ages? We will test the hypothesis that plasticity in higher order visual cortex, believed to play an essential role in memory storage, is far less sensitive to age than plasticity in area 17. If correct, we will seek to understand the mechanisms that underlie the differences using genetic mutants supplied by Tonegawa and Heinemann. 3. Is there a protein-synthesis dependent """"""""late-phase"""""""" of LTP or LTD in the neocortex? We will use a genetically engineered CRE reporter to see what types of gene response are caused by different types of tetanic stimulation, both in vitro and in vivo. We will test the hypothesis that CREB is required for late-phase neocortical LTP by utilizing regionally specific CREB knockouts provided by the Tonegawa laboratory. The same animals will be studied in parallel experiments for deficits in visual recognition memory (see below). 4. What is the contribution of TE cortex to visual recognition memory in the mouse? We will develop a behavioral assay of TE-cortex-dependent visual recognition memory in the mouse, and will investigate the behavioral and electrophysiological consequences of genetic lesions that disrupt synaptic plasticity in TE (e.g. NR1 knockout). 5. How do specific genetic lesions of glutamate receptors affect LTP and LTD? Available data suggest that, to some extent, the molecular mechanisms of LTP and LTD are conserved across cortical areas; therefore, we will use hippocampal area CA1 as a model system to investigate the underlying mechanism of cortical synaptic plasticity. In collaboration with the Heinemann and Tonegawa laboratories, we will study CA 1-specific alterations of AMPA receptor subunits and mGluR5 (see description of Individual Project #5). Modification of AMPA receptors, either by phosphorylation or translocation, is believed to be one mechanism for the expression of LTP and LTD. Metabotropic glutamate receptors may be one means by which plasticity is triggered. We will test these hypotheses.
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