Interdisciplinary Studies for Mechanisms Underlying Social Isolation-Induced Health Critical Behavior Changes

项目摘要 社会互动对动物健康至关重要。长期与社会环境隔绝， 影响动物行为、生理和健康，在COVID-19大流行期间表现为增加 睡眠中断和饮食失调的水平，以及其他人口行为问题。的 慢性社会隔离的处理和影响健康的根本机制 行为不明。与社会环境短暂的脱节并不是有害的。社会隔离， 它的本质是一个持续和长期的过程，但动物大脑如何构建一个进化的状态， 记录这一过程仍然是从生物学角度理解社会隔离的一个突出问题。到 为了应对这一挑战，我建立了黑腹果蝇模型并发现了分子 与急性和慢性社会隔离相关的生理状态之间的差异。这本小说 这种方法已经能够通过使用“隔离时间”作为参数来剖析潜在的机制， 从而允许识别细胞的信号的慢性状态的社会孤立的第一次在任何 模型系统我之前的研究表明，操纵识别出的细胞会改变对 社会隔离持续时间和社会隔离引起的行为结果，包括睡眠不足， 食欲过盛在本提案中，我们计划实施三个互补项目，以利用我们最近的 结果，以进一步揭示在慢性社会过程中调节生理效应的计时机制， 隔离首先，我们将阐明有助于计时的遗传和分子途径， 介导慢性社会隔离引起的健康关键行为改变，特别关注 与生物钟的交互作用。其次，我们将确定“隔离”背后的分子底物 并询问“隔离计时器”如何发出睡眠/觉醒调节信号。 网络第三，我们将研究长期的社会孤立如何驱动永不满足的饥饿和影响。 新陈代谢.为了实现这些目标，我们将采用多学科的方法，包括神经遗传学，高 通量和高分辨率行为测量，转录组分析，功能成像， 代谢组学分析拟议的研究，使用一个创新的框架，调查的机制， 这种慢性社会隔离是在长时间范围内进行的，并影响了健康关键行为。 分子和细胞水平，最终将导致更深入地了解社会隔离的生物学 和潜在的干预/治疗，以减轻长期社会隔离造成的痛苦和疾病。

Project Summary Social interactions are essential for animal health. Prolonged isolation from social environments profoundly affects animal behavior, physiology, and wellness, expressed during the COVID-19 pandemic as increased levels of sleep disruption and eating disorders, among other population-wide behavioral problems. The underlying mechanisms through which chronic social isolation is processed and impacts health-critical behavior are unknown. A brief disconnection from the social environment is not detrimental. Social isolation, by its very nature, is a continuous and prolonged process, yet how animal brain constructs an evolving state recording this process remains an outstanding problem in understanding social isolation biologically. To address this challenge, I established a Drosophila melanogaster model and discovered the molecular differences between physiological states associated with acute and chronic social isolation. This novel approach has enabled the dissection of underlying mechanisms by using “isolation timing” as a parameter, thereby allowing the identification of cells that signal the chronic status of social isolation for the first time in any model system. My previous research has shown that manipulating the identified cells alters the perception of social isolation duration and social isolation-induced behavioral outcomes, including sleep loss and hyperphagia. In this proposal, we plan to carry out three complimentary projects that capitalize on our recent results to further uncover the timekeeping mechanism modulating physiological effects during chronic social isolation. First, we will elucidate the genetic and molecular pathways that contribute to timekeeping and mediate health-critical behavioral alterations induced by chronic social isolation, with a special focus on the cross talk with the circadian clock. Second, we will identify the molecular substrates underlying “isolation timing” during chronic social isolation and interrogate how an “isolation timer” signals the sleep/wake regulatory network. Third, we will investigate how chronic social isolation drives insatiable hunger and impacts metabolism. To achieve these goals, we will employ a multidisciplinary approach including neurogenetics, high throughput and high-resolution behavioral measurements, transcriptome profiling, functional imaging, and metabolomic analysis. The proposed study, using an innovative framework to investigate the mechanisms by which chronic social isolation is processed on long-time scales and impacts health-critical behaviors at the molecular and cellular levels, will ultimately lead to a deeper understanding of the biology of social isolation and potential interventions/treatments to alleviate the suffering and diseases caused by chronic social isolation.