Dynamic cholinergic regulation of hippocampal processing, learning, and memory

University Of California, San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): The hippocampus is a remarkable structure that supports multiple learning and memory behaviors. Recently, the Frank laboratory has examined how information processing in the hippocampus changes during different behavioral states associated with memory storage, memory consolidation, and memory retrieval. They found that that there is a smooth transition from greater CA3 to greater EC drive of hippocampal output area CA1 as animals move more quickly. These changes are rapid and are most pronounced in new environments. Further, the level of coordinated spiking activity in CA1 reflects that transition: cell pairs are highly correlated at low speeds and become progressively less correlated as animals move more quickly. These results suggest that behavior drives a dynamic balance between correlated activity representing stored associations and more independent sensory representations in the hippocampus. This dynamic balance is well suited to support the mnemonic functions of the hippocampal circuit, including the formation of reliable memories during exploration of new places. The goal of this grant is to investigate the mechanism that drives this dynamic balance and its role in learning and memory. Currently available results suggest that cholinergic modulation from the medial septum and the ventral diagonal band of Broca (MS/DB) is central to regulating hippocampal circuits. My hypothesis is that both low and high levels of cholinergic activity are important for spatial learning, with low levels allowing fo CA3-driven memory retrieval and consolidation during sharp wave ripple (SWR) events and high levels allowing EC-driven rapid learning of spatial relationships by promoting the formation of spatial representations. To test this hypothesis, I plan to take advantage of the recent availability of ChAT-Cre transgenic rats and the Frank lab's ability to combine multielectrode recording and optogenetic manipulations in awake, behaving animals. My Specific Aims are: 1: Test the hypothesis that modulation of MS/DB input populations is sufficient to control the dynamic balance of information processing in the hippocampus and 2: Test the hypothesis that dynamic levels of MS/DB cholinergic neuron activity are important for rapid learning. The experiments carried out to accomplish these aims have the potential to provide a fundamental new understanding of the regulation of the many functions of the hippocampal circuit, and how alterations in this regulation contribute to pathological states.