Long term potentiation (LTP), a long lasting enhancement of synaptic efficacy in the hippocampus, a brain structure, is considered a model for memory and learning. However, the stimuli used for its induction, typically 50-400 pulses delivered at frequencies of 100-400 Hz, are distinctly above physiological levels. Long term potentiation (LTP) of principal cell groups of the hippocampal formation may play an important role in learning and memory. The precise role that LTP might fulfill is unknown, but possible models of neocortical-hippocampal interaction are currently under consideration. Whatever the circuitry underlying learning and memory, and whatever the role of LTP may be, it is clearly of interest to determine the physiological conditions under which LTP is actually induced in the normal, unanesthetized animal. Dr. Jonathan Winson proposes here to carry out a series of experiments, first in anesthetized and then in freely moving rats, to investigate the phenomenon that may be present and physiologically relevant to the induction of LTP. Assuming that LTP proves to be a physiologically relevant aspect of hippocampal function, it will be of considerable importance to determine the conditions underlying its induction in the normal animal. This will have a two-fold benefit. First, it will further our understanding of the function of LTP and its possible role in memory. Second, it will provide a knowledge of physiologically relevant stimuli to serve as a basis for the investigation of the pre- and/or post-synaptic mechanisms, at the cellular level, responsible for LTP. Dr. Jonathan Winson proposes to study particular conditions by which LTP may be induced in normally behaving rats. The proposed experiments are based on the following. 1) He has recently shown that LTP is preferentially induced in the rat at 400 Hz compared to lower frequencies. The same effect is achieved when lower frequency input volleys are applied to the medial and lateral perforant pathways asynchronously such that the composite stimulus seen by granule cell dendrite is 400 Hz. Such asynchronous inputs may reflect the manner in which LTP is induced physiologically. 2) In preliminary studies he has found that LTP is preferentially induced on one phase of the theta rhythm. 3) Studies in the hippocampal slice in other laboratories have demonstrated a "priming" effect on the CA 1 field, i.e., bursts applied to CA 1 afferents separated by 170-200 ms, the periodicity of theta rhythm, preferentially induced LTP. Dr. Winson proposes to study these newly revealed phenomena in the dentate gyrus, first in anesthetized and then in freely moving rats during several behaviors. Time permitting, similar studies will be performed in the CA 1 field.
