Elucidating circuit mechanisms of brain rhythms in the aging brain

项目摘要 大脑节律协调了数千个神经元在多个大脑区域的活动，以实现复杂的认知功能。 功能协调发展的例如，海马体θ（4-12 Hz）节律不仅对信息编码很重要， 在学习和记忆过程中，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θ节律的解剖学起源和相关电路在很大程度上仍然未知。在 在这个提议中，我试图建立乳头体上核（SuM）的作用，这是一个研究不足的核。 下丘脑结构，作为海马theta振荡的关键调制器，阐明了 SuM电路的结构和生理变化和记忆缺陷，并最小限度地发展 有创性SuM刺激策略对经颅Theta夹带和认知储备的影响 在AD动物中增强。我的初步数据表明，对SuM的光遗传学刺激 诱导海马体θ振荡。此外，夹带θ节律显着提高动物的 学习效率在一个依赖于营地的空间记忆任务。这些结果表明，SuM是一个 以前未知的下丘脑θ调节剂和治疗策略的潜在靶点，以预防或 逆转记忆障碍这项建议的目的是从机制上了解苏丹及其 利用最近开发的转基因（SuM-Cre）小鼠， 以及一系列现代神经元记录和操作技术。在K99阶段，我将 解剖SuM-海马回路，探索它们在海马θ振荡中的生理作用， 阐明他们如何全面重塑海马编码记忆处理（目标1）。我会进一步确认 衰老如何改变SuM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，包括老化神经生物学和AD在博士托马斯Wisniewski的实验室，大- 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， 在Zhe Sage Chen博士的实验室进行神经系统建模。在R 00阶段，我将开发微创SuM 经颅θ波夹带的刺激策略。我将进一步应用这项技术来测试SuM是否 刺激可以增强AD小鼠模型的认知储备（目的3）。该项目不仅将奠定 通过将SuM识别为以前未知的， 下丘脑θ调制器，而且还提供了一个直接进入解开θ调制点， 衰老相关记忆功能障碍的机制和调节目标。

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.