Cellular mechanisms of hippocampal theta oscillations

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PROJECT SUMMARY/ABSTRACT The mammalian brain has an incredible capacity to learn and store information that can be subsequently retrieved. A key brain structure that supports cognition and the formation of new memories is the hippocampus. Damage to the hippocampus impairs memory and results in debilitating maladies like Alzheimer's disease or epilepsy. Studies in primates and rodents have provided a rich systems-level understanding of hippocampal function and its interaction with other structures like neocortex. However, models that explain hippocampus physiology at the cellular and microcircuit level exclusively come from studies in rodents. Due in part to our limited understanding of the mechanisms that govern primate cellular physiology, treatments for complex neurological diseases have fared poorly when introduced in human clinical trials. Our long-range goal is to better understand how the primate hippocampus processes information in support of memory at the cellular and microcircuit level, thus connecting cellular physiology to network function in primates. Here we propose to develop a non-human primate model that allows the study of the cellular and microcircuit physiology of the primate hippocampus. We will combine whole-cell patch clamping and pharmacology in a novel in vitro approach to delineate the mechanisms that support theta oscillations in monkeys. Theta oscillations reflect temporally coordinated network activity in the hippocampus that occurs while attending to incoming stimuli and during successful memory encoding. They are present in both rodents and primates, but this activity only sparsely occurs in primates, suggesting that there are substantial differences in the neuronal circuits of the hippocampus and the properties of its neurons across species. To understand how cellular physiology shapes the theta oscillation in primates, we will both characterize the physiological properties of principal cells in the monkey hippocampus and the effect that the critical theta neuromodulator acetylcholine has in regulating the intrinsic properties of hippocampal neurons in vitro. The proposed experiments have the following potential outcomes: 1) establish whether the cellular physiology of pyramidal neurons in the hippocampus of monkeys differ from that of rodents, 2) identify mechanisms in monkeys at the cellular level that contribute to coordinated network activity. These experiments will provide species-specific evidence for a model that may translate better to human physiology.