The hippocampal theta rhythm is an ideal model system for studying the generation of rhythmic slow waves in the brain. The mechanisms of naturally occurring slow waves are poorly understood at the present time, yet this information is crucial for understanding the generation of pathological slow waves. Knowledge of the mechanisms of theta rhythm may also suggest hypotheses about its function. The role of the hippocampus in mnemonic processes, the cholinergic nature of a component of the theta rhythm and the presence of theta rhythm in primates suggest that part of the symptomatology of Alzheimer's disease may be related to loss of the theta rhythm. Recordings from hippocampal pyramidal cells in freely-moving rats have shown that they fire most rapidly when the rat is in a particular part of its environment, as if they were extracting """"""""place"""""""" information from multimodal sensory cues. The regions where these units exhibit such high firing rate are termed """"""""place fields"""""""". The walking-induced theta rhythm occurs naturally as the rat moves from place to place and it represents oscillations of the membrane potentials of these same pyramidal cells, so it may be involved in this extraction process. There is an extensive literature on hippocampal place fields and an extensive literature on hippocampal theta rhythm, but little regarding their relationship to each other. Recent work has indicated that a) the place field is enhanced during theta rhythm by increased firing inside the field and decreased firing outside the field, and b) the timing of the relationship between the firing of the cells and the waveform of the theta rhythm changes as the rat passes through the place field. This project proposes studies designed to contribute to our understanding of the synaptic mechanisms of these two effects. First, further quantitative descriptive studies on the two effects are necessary to characterize them more completely. Secondly, the synaptic mechanisms leading to these two effects will be studied by administration of drugs that activate or interfere with specific neurotransmitter systems that are suspected sources of such changes. Initially, these studies will center around three important transmitters that are central to hippocampal function: acetylcholine, GABA and glutamate. We intend to study these systems by applying neurotransmitter specific drugs to the area surrounding our unit recording electrode and observing the effect on our recording. In this way the drug will influence the activity of only a small subset of hippocampal neurons, keeping behavior constant so the incoming activity is controlled. We should be able to mimic components of the changes in behaviors where they do not ordinarily occur and block them in the behaviors where they ordinarily would occur. These studies will provide critical tests of the specific features of our hypothetical model for the role of the theta state in hippocampal function.
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