This competing continuation application focuses on understanding how changes in physiological properties at different phases of each cycle of the theta rhythm play a role in the functional dynamics necessary for memory guided behavior. Physiological experiments will test hypotheses from detailed network simulations of neurons in the hippocampal formation, which guide the movements of a virtual rat in a virtual environment performing memory-guided behavioral tasks. These models replicate electrophysiological recordings from awake behaving animals, including data from current source density analysis, and unit recording data showing phenomena such as theta phase precession and """"""""splitter cells"""""""". We will test two specific hypotheses about how memory-guided behavior is enhanced by specific features of theta rhythm: Hypothesis #1. Changes in LTP and synaptic input during theta rhythm provide separate phases of encoding and retrieval in hippocampal circuits. Hypothesis #2. Phasic timing of synaptic input provides the most effective episodic retrieval for memory-guided behavior. Tests of these hypotheses include measuring timing of units relative to theta rhythm during exposure to a novel environment, measuring theta phase reset and spike timing relative to theta rhythm in prefrontal cortex and hippocampus during performance of a delayed match to sample task, testing unit activity relative to theta rhythm during delayed spatial alternation with different path lengths, testing unit activity during random exploration and single sided reward in a linear track, testing time course of modulation of synaptic transmission mediated by activation of interneurons in stratum oriens projecting to stratum lacunosummolecutare (s. I-m), and testing time course of mGluR modulation of transmission in s. I-m. Understanding these mechanisms may assist in development of pharmacological treatments for Alzheimer's disease.
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