Elucidating circuit mechanisms of brain rhythms in the aging brain

阐明衰老大脑中脑节律的回路机制

• 批准号: 10646164
• 负责人: Shuo Chen
• 金额: $ 13.59万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646164
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Anatomy; Animal Diseases; Animals; Area; Attenuated; Biological Models; Brain; Cell Nucleus; Cells; Cephalic; Chronology; Code; Cognition; Cognitive; Complex; Data; Data Analyses; Deep Brain Stimulation; Dentate nucleus; Electrophysiology (science); Episodic memory; Genetic; Goals; Hippocampus; Histologic; Hypothalamic structure; Impaired cognition; Individual; Learning; Link; Maps; Medial; Memory; Memory impairment; Mentors; Modeling; Modernization; Mus; Nature; Neurobiology; Neurodegenerative Disorders; Neurons; Pathway interactions; Performance; Phase; Physiological; Physiology; Play; Population; Risk; Role; Route; Science; Scientist; Shapes; Signal Transduction; Structure; Techniques; Technology; Testing; Theta Rhythm; Training; Transgenic Organisms; Work; aging brain; cognitive enhancement; cognitive function; cognitive reserve; computational neuroscience; dentate gyrus; frontier; improved; in vivo; insight; memory process; minimally invasive; molecular pathology; mouse model; neural; neuroregulation; optogenetics; prevent; resilience; spatial memory; success; targeted treatment; translational impact; young adult

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.

项目摘要 脑节律协调了多个大脑区域的数千个神经元的活性，以进行复杂的认知 功能。例如，海马theta（4-12 Hz）节奏不仅对信息编码很重要 在学习和记忆期间，但也与老化和阿尔茨海默氏病的记忆功能障碍有关 （广告）。但是，控制theta节奏的解剖学起源和相关电路在很大程度上仍然未知。在 这项建议，我试图确定超木核的作用（sum），一个理解的 下丘脑结构，作为海马theta振荡的关键调节剂，阐明 总和电路和内存不足的结构和物理变化，并最小开发 trancranial theta入口和认知储备的侵入性和刺激策略 广告动物的增强。我的初步数据表明，稳健的总和刺激 诱导海马theta振荡。此外，富含的theta节奏显着增强了动物的 海马依赖性空间内存任务中的学习效率。这些结果表明总和是 以前未知的下丘脑theta调节剂，也是预防或 反向内存障碍。该提议的目的是获得对总和及其的机械理解 通过利用最近开发的转基因（SUM-CRE）小鼠的电路 以现代神经元记录和操纵技术为总和。在K99阶段，我会 剖析总和 - 海马电路，探测其在海马theta振荡中的身体作用，并 阐明它们如何重塑海马编码以进行内存处理（AIM 1）。我将进一步识别 衰老如何修饰总和电路的结构，生理和功能，导致振荡异常 和内存功能障碍（AIM 2）。为了实现这些目标，我将获得实验中的免费培训 和计算神经科学，包括衰老的神经生物学和托马斯·韦斯尼维斯基博士实验室的AD 在GyörgyBuzsáki博士实验室和神经数据分析中，体内记录和海马生理学的规模 Zhe Sage Chen博士实验室中的神经系统建模。在R00阶段，我将开发最小的侵入性总和 刺激性theta入口的刺激策略。我将进一步应用这项技术来测试是否汇总 刺激可以增强AD小鼠模型中的认知储备（AIM 3）。这个项目不仅会放置 通过将总和识别为先前未知的基本，以理解整个脑部theta电路的基础 下丘脑theta调节剂，但也提供了直接切入点，以将theta调制作为一个 与衰老相关的记忆功能障碍的机理和调制目标。