Elucidating circuit mechanisms of brain rhythms in the aging brain

项目总结 大脑节律协调数千个神经元在多个大脑区域的活动，以进行复杂的认知 功能。例如，海马theta(4-12赫兹)节律不仅对信息编码很重要 在学习和记忆过程中，但也与衰老和阿尔茨海默病的记忆功能障碍有关 (Ad)。然而，控制theta节律的解剖起源和相关回路在很大程度上仍不清楚。在……里面 这一建议，我试图确定乳头上核(SUM)的作用，这是一个未被研究的 下丘脑结构作为海马Theta振荡的关键调节器，阐明了两者之间的联系 和电路的结构和生理变化与记忆缺陷，并发展到最低限度 侵入性总和刺激策略对经颅theta夹带和认知储备的影响 对阿尔茨海默病动物的增强。我的初步数据显示，光遗传刺激对总和的强健 诱导了海马塞塔的振荡。此外，夹带的theta节奏显著增强了动物的 海马区依赖的空间记忆任务中的学习效率。这些结果表明，总和是 以前未知的下丘脑theta调节剂和潜在的治疗策略的靶点，以预防或 逆转记忆损伤。这一建议的目的是机械地理解和及其 利用最近开发的提供遗传通路的转基因(SUM-CRE)小鼠的电路 一系列现代神经元记录和操作技术的总和。在K99阶段，我将 解剖和-海马环路，探讨它们在海马theta振荡中的生理作用 阐明它们如何全局重塑记忆处理的海马体编码(目标1)。我会进一步确认 衰老如何改变和电路的结构、生理和功能，导致振荡异常 和记忆功能障碍(目标2)。为了实现这些目标，我将接受免费的实验培训 和计算神经科学，包括Thomas Wisniewski博士实验室的衰老神经生物学和AD，大型- 格奥尔基·布兹萨基博士的实验室中的活体记录和海马体生理学以及神经数据分析和 陈哲圣博士实验室中的神经系统建模。在R00阶段，我将开发微创SUM 经颅theta夹带的刺激策略。我将进一步应用这项技术来测试SUM 刺激可增强阿尔茨海默病小鼠模型的认知储备(目标3)。这个项目不仅将为 通过将和识别为先前未知的和来理解全脑theta电路的基础 下丘脑theta调节器，但也提供了一个直接进入解开theta调制作为 衰老相关记忆功能障碍的机制和调控靶点。

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.