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.

项目概要 大脑节律协调多个大脑区域数千个神经元的活动，以实现复杂的认知 例如，海马 theta（4-12 Hz）节律不仅对于信息编码很重要。 在学习和记忆过程中，还与衰老和阿尔茨海默氏病的记忆功能障碍有关 (AD) 然而，控制θ节律的解剖学起源和相关电路仍然很大程度上未知。 在这个提议中，我试图确定乳头上核（SuM）的作用，这是一个尚未得到充分研究的 下丘脑结构作为海马θ振荡的关键调节器，阐明了之间的联系 SuM 电路的结构和生理变化以及记忆缺陷，并且发育程度最低 用于经颅 theta 夹带和认知储备的侵入式 SuM 刺激策略 我的初步数据表明，SuM 的光遗传学刺激具有显着的增强作用。 此外，引起的θ节律显着增强了动物的海马θ振荡。 这些结果表明 SuM 是一个依赖于海马的空间记忆任务的学习效率。 以前未知的下丘脑θ调节剂和预防或治疗策略的潜在靶点 该提案旨在获得对 SuM 及其机制的理解。 利用最近开发的转基因（SuM-Cre）小鼠的电路，提供遗传访问 在 K99 阶段，我将学习 SuM 和一系列现代神经记录和操作技术。 剖析 SuM-海马回路，探究它们在海马 theta 振荡中的生理作用，以及 阐明它们如何全局重塑海马编码以进行记忆处理（目标 1）。 衰老如何改变 SuM 电路的结构、生理和功能，从而导致振荡异常 和记忆功能障碍（目标 2）。为了实现这些目标，我将接受实验方面的免费培训。 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- György Buzsáki 博士实验室的体内记录和海马生理学以及神经数据分析和 陈哲博士实验室的神经系统建模 在R00阶段，我将开发微创SuM。 经颅θ夹带的刺激策略我将进一步应用该技术来测试SuM是否有效。 刺激可以增强 AD 小鼠模型的认知储备（目标 3）。 通过将 SuM 识别为先前未知的信号，为理解全脑 θ 电路奠定基础 下丘脑 θ 调制器，还提供了解开 θ 调制的直接切入点 衰老相关记忆功能障碍的机制和调节目标。