GENETIC ANALYSIS OF PLACE CELL STABILITY AND FUNCTION

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DESCRIPTION (Adapted from applicant's abstract): The overall goal of the proposed research is to understand explicit memory, memory for places and events. The form of memory is subserved by a brain structure called the hippocampus. People with severe hippocampal damage often show "retrograde amnesia", they lose memories about events before the damage occurred with the worst losses being for the most recent events. Such individuals also show "anterograd amnesia", they are unable to learn events that happen after the damage. To study explicit memory, spatial memory in rodents will be used as a model. Rats and mice with hippocampal damage are often unable to remember how to solve spatial problems learned before the damage, and are impaired in solving new spatial problems presented after the damage. The goal is to understand the molecular, cellular and network mechanisms that underlie spatial memory. To this end, hippocampal "place cells" will be recorded in genetically modified freely moving mice. Place cells signal the animal's location and are thought to be essential units of a neural map of the environment used in spatial problem solving. A major aim is to determine if the synaptic plasticity mechanism called long-term potentiation (LTP) participates in the formation and stabilization of place cells. Thus, different molecular mechanisms of LTP will be genetically altered and the effects of these alterations on place cell properties will be determined. It is expected that place cell defects of different kinds will be caused by genetic alterations of different kinds. Moreover, knowledge of place cell defects will allow predictions of the nature of the defect of spatial memory in each mouse strain. An important part of the plan to test these predictions with behavioral studies is to record place cells as mice perform a spatial task, allowing our predictions to be tested. One hope for the research is that understanding the coupling of LTP to explicit memory via place cells will provide a firm basis on which to design pharmacological agents that affect specific aspects of memory. It has been the common experience of biologists that understanding at the molecular level allows systems to be controlled with great precision. Perhaps this end can be achieved for memory, the most delicate of all biological processes.