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.
