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

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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.