The theta rhythm appears in the rat hippocampal electroencephalogram during exploration and shows phase locking to stimulus acquisition. Lesions that block theta rhythm impair performance in tasks requiring reversal of prior learning, including reversal in a T-maze, where associations between one arm location and food reward need to be extinguished in favor of associations between the opposite arm location and food reward. Here, a hippocampal model shows how theta rhythm could be important for reversal in this task by providing separate functional phases during each 100-300 msec cycle, consistent with physiological data. In the model, effective encoding of new associations occurs in the phase when synaptic input from entorhinal cortex is strong and long-term potentiation (LTP) of excitatory connections arising from hippocampal region CA3 is strong, but synaptic currents arising from region CA3 input are weak (to prevent interference from prior learned associations). Retrieval of old associations occurs in the phase when entorhinal input is weak and synaptic input from region CA3 is strong, but when depotentiation occurs at synapses from CA3 (to allow extinction of prior learned associations that do not match current input). These phasic changes require that LTP at synapses arising from region CA3 should be strongest at the phase when synaptic transmission at these synapses is weakest. Consistent with these requirements, our recent data show that synaptic transmission in stratum radiatum is weakest at the positive peak of local theta, which is when previous data show that induction of LTP is strongest in this layer.

Experimental evidence suggests that the hippocampal theta rhythm plays a critical role in learning. Previous studies have shown long-term potentiation (LTP) to be preferentially induced with stimulation on the peak of local theta rhythm in region CA1 in anesthetized rats and with stimulation of the perforant path at the peak of theta in both anesthetized and behaving animals. We set out to determine the effects of tetanic burst stimulation in stratum radiatum of region CA1 in awake behaving animals, delivered during either the peak or the trough of the theta rhythm in the EEG. Bursts delivered to the peak resulted in an increase of 17.9 +/- 0.94% in potential slope. When identical stimulation bursts were delivered to the trough of local theta waves, the potential slope decreased 12.9 +/- 1.03%. This is the first report of LTP being preferentially induced at the peak of local theta rhythm in behaving animals in region CA1 and that LTD was found in response to tetanic stimulation at the trough of the local theta wave. The results are discussed within the framework of a recent theory that proposes that the theta rhythm sets the dynamics for alternating phases of encoding and retrieval (Hasselmo et al., 20021).

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This research focuses on linking episodic memory function to the cellular physiology of hippocampal neurons, with a particular emphasis on modulatory effects at cholinergic and g g-aminobutyric acid B receptors. Drugs which block acetylcholine receptors (e.g., scopolamine) have been shown to impair encoding of new information in humans, nonhuman primates, and rodents. Extensive data have been gathered about the cellular effects of acetylcholine in the hippocampus. In this research, models of individual hippocampal subregions have been utilized to understand the significance of particular features of modulation, and these hippocampal subregions have been combined in a network simulation which can replicate the selective encoding impairment produced by scopolamine in human subjects.