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. This project aims to discover which components of the neural circuitry are involved in the generation of the theta rhythm. There are at least two major components of theta rhythm. One of these occurs in isolation during motionless behaviors and during urethane anesthesia, and is abolished by atropine, hence is considered to be cholinergically mediated. The second component may be induced by serotonergic systems, since it is abolished by serotonergic neurotoxins. In freely-moving rats it combines with the cholinergic component during walking. 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 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. The project proposes studies designed to contribute to our understanding of the theta rhythm with experiments designed to determine the afferents responsible for the synaptic conductance changes generating the theta rhythm in rats. These experiments involve several sets of methods and several regions of the brain. First, extracellular investigations of the contributions of the retrohippocampal areas to the hippocampal theta rhythm will be carried out. The largest phasic current sink generating the theta rhythm in the hippocampus is probably caused by phasically modulated firing of retrohippocampal afferents. Secondly, current source density (CSD) measurements will be made in the hippocampus before and after a) lesioning anatomical sources of afferents, b) cooling afferent tracks and c) administration of drugs. These manipulations will interfere with appearance of particular peaks in the CSD profiles, thereby implicating activity in specific sets of afferents as generators of the theta rhythm. Third, intracellular and extracellular recordings will be made from the rhythmically bursting septal neurons presumed to be the """"""""pacemakers' for the hippocampal theta rhythm. These experiments are proposed to identify the classes of """"""""pacemaker"""""""" cells responsible for the two naturally occurring components of the theta rhythm. Fourth, intracellular recording and AC impedance analysis will be performed on hippocampal pyramidal cells in urethane anesthetized rats after treatment with atropine. These experiments in conjunction with CSD will locate the terminals of one subset of the """"""""pacemaker"""""""" cells.
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