PROJECT SUMMARY Brain rhythms coordinate the activities of thousands of neurons across multiple brain areas for complex cognitive functions. The hippocampal theta (4-12 Hz) rhythm, for instance, is not only important for information coding during learning and memory, but also associated with memory dysfunctions in aging and Alzheimer's disease (AD). However, the anatomical origin and related circuitry that control theta rhythms remain largely unknown. In this proposal, I seek to establish the role of the supramammillary nucleus (SuM), an understudied hypothalamic structure, as a key modulator of hippocampal theta oscillations, elucidate the link between structural and physiological changes of the SuM circuitry and memory deficiency, and develop minimally invasive SuM stimulation strategies for transcranial theta entrainment and cognitive reserve enhancement in AD animals. My preliminary data have shown that optogenetic stimulation of the SuM robustly induces hippocampal theta oscillations. Furthermore, the entrained theta rhythm significantly enhances animals’ learning efficiency in a hippocampal-dependent spatial memory task. These results suggest the SuM to be a previously unknown hypothalamic theta modulator and a potential target for therapeutic strategies to prevent or reverse memory impairment. This proposal is aimed to gain a mechanistic understanding of the SuM and its circuitry by taking advantage of a recently developed transgenic (SuM-Cre) mouse that provides genetic access to the SuM and an array of modern neuronal recording and manipulation techniques. In the K99 phase, I will dissect the SuM-hippocampal circuits, probe their physiological roles in hippocampal theta oscillation, and elucidate how they globally reshape hippocampal coding for memory processing (Aim 1). I will further identify how aging modifies the structure, physiology and function of the SuM circuitry, leading to oscillation abnormalities and memory dysfunctions (Aim 2). To achieve these goals, I will receive complimentary training in experimental and computational neuroscience, including aging neurobiology and AD in Dr. Thomas Wisniewski’s lab, large- scale in vivo recordings and hippocampal physiology in Dr. György Buzsáki‘s lab and neural data analysis and neural systems modeling in Dr. Zhe Sage Chen’s lab. In the R00 phase, I will develop minimally invasive SuM stimulation strategies for transcranial theta entrainment. I will further apply this technology to test whether SuM stimulation could enhance cognitive reserve in a mouse model of AD (Aim 3). This project will not only lay the groundwork for understanding a brain-wide theta circuitry by identifying the SuM as a previously unknown hypothalamic theta modulator, but also provide a direct entry point into disentangling theta modulation as a mechanism and modulation target for aging-associated memory dysfunctions.

PROJECT NARRATIVE Brain rhythms coordinate the activities of millions of neurons for complex cognitive functions, such as learning and memory. We will dissect the circuit mechanisms that generate and route the theta rhythm (4-12 Hz) – one specific brain rhythm critical for memory processing. Our systematic functional mapping of theta-related circuits connecting the hypothalamus and the hippocampus will provide insights into how aging affects brain rhythm coordination and have translational implications for improving memory function in Alzheimer’s disease.