About

Amita Sehgal, Ph.D., is the John Herr Musser Professor, Investigator at the Howard Hughes Medical Institute, and Director of the Chronobiology and Sleep Institute at the University of Pennsylvania School of Medicine. Her research focuses on the molecular basis of behavior, with a major emphasis on the mechanisms underlying circadian rhythms of behavior and physiology. Her laboratory has made significant contributions in this area, including the isolation of the timeless clock gene, elucidating the function of timeless (tim) in an autoregulatory loop at the core of the endogenous clock, and uncovering mechanisms that synchronize the clock to light. Her work also involves identifying neural circuits that drive rest-activity rhythms and mapping molecules and peptides involved in these circuits, as well as investigating circadian control of physiological processes in both Drosophila and mammals. Additionally, her research addresses sleep regulation and function, utilizing a Drosophila model for sleep to explore the genetic and circuit mechanisms underlying sleep need and regulation. Her work extends to understanding the relevance of circadian and sleep systems to metabolism and healthy aging.

Research topics

• Neuroscience
• Computer Science
• Cell biology
• Biology
• Genetics
• Bioinformatics
• Physiology
• Physics

Selected publications

• Sleep in a mouse model of fragile X syndrome is resistant to metabolic manipulations

  Human Molecular Genetics · 2025-09-19

  articleOpen accessSenior author

  Fragile X Syndrome is the most prevalent known genetic cause of intellectual disability (ID), affecting around 1 in 4 000 individuals, and is also highly associated with autism spectrum disorder (ASD). Humans with the disorder and animal models display sleep and metabolic abnormalities. Given growing evidence of links between sleep and metabolism, we sought to determine if metabolic abnormalities underlie sleep deficits in mice lacking the Fragile X messenger ribonucleoprotein 1 (FMR1) gene. We found that metformin, a drug that targets metabolic pathways and has been shown to alleviate other symptoms in FXS, did not rescue sleep in mutant mice. Instead, metformin enhanced activity of Fmr1 knockout (KO) mice. As a way of exaggerating possible metabolic phenotypes, we treated mice with a high fat diet (HFD) and found that although this disrupted the sleep pattern in controls, it did not impact the sleep phenotype in Fmr1 KOs. Increased sleep during the dark phase, caused by HFD in wild type animals, was alleviated by metformin treatment. Metformin also decreased weight gain of wild type animals on a HFD, but the effect was delayed in Fmr1 KO mice. Fmr1 KO mice with or without metformin treatment displayed hyperphagia on a HFD, yet did not show higher weight gain than wild type. And, surprisingly, their glucose tolerance was equivalent to that of wild type mice on metformin. We suggest that Fmr1 KO mice are better able to metabolize fat and so are relatively resistant to its negative effects on sleep and metabolism.

  PublisherOA PDFDOI

• Neutral lipid processing in glia is sexually dimorphic and promotes sleep through diacylglycerol catabolism

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-12 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Sleep is thought to have a protective role in clearing toxic waste from the brain, which may include processing of damaged lipids. We recently showed that blocking endocytosis in glia increases sleep and report here that this block is associated with an increase in peroxidized lipids and glial lipid droplet accumulation, raising the possibility that accumulation of these lipids increases the need to sleep. Sleep gain induced by blocking glial transport is exaggerated by knockout of the lipid droplet coat protein, Lipid Storage Droplet 2 ( Lsd2 ), suggesting that sleep-promoting lipids are not contained in lipid droplets. To identify lipids regulated by sleep state, we performed global, targeted lipidomics analysis on Drosophila neurons and glia, screening nearly 3,000 lipids across 11 major classes. This revealed that sex influences lipid composition in both cell types and lipid homeostasis following extended wakefulness. Female neurons and glia are enriched in ultra-long chain fatty acids, triacylglycerols, and diacylglycerols, with glial diacylglycerol enrichment correlating with elevated sleep need. Based on manipulations of neutral lipid metabolic pathways, we propose that monoacylglycerols, products of glial diacylglycerol catabolism, promote sleep.

  PublisherOA PDFDOI

• Author response: The microbiome interacts with the circadian clock and dietary composition to regulate metabolite cycling in the Drosophila gut

  2025-06-04

  peer-reviewOpen accessSenior author

  The gut microbiome plays a key role in the maintenance of host metabolic homeostasis and health. Most metabolic processes cycle with a 24-hour rhythm, but the extent to which the microbiome influences metabolite cycling under different conditions, such as variations in dietary composition, remains largely unknown. In this study, we utilized high temporal resolution metabolite profiling of the Drosophila gut to investigate the role of the microbiome in metabolite cycling. We find that the microbiome increases the number of oscillating metabolites despite the previous finding that it dampens transcript cycling in the gut. Time restricted feeding (TF) also promotes metabolite cycling and does so to a larger extent in germ-free flies, thereby increasing cycling in these flies to levels comparable to those in microbiome containing flies. Enhancement of cycling by the microbiome depends upon a circadian clock, which also maintains phase in the face of changes in the microbiome. Interestingly, a high-protein diet increases microbiome- dependent metabolite cycling, while a high sugar diet suppresses it. Gene Ontology identifies amino acid metabolism as the metabolic pathway most affected by changes in the gut microbiome, the circadian clock and timed feeding, suggesting that it is subject to regulation by multiple inputs. Collectively, our observations highlight a key role of the gut microbiome in host metabolite cycling, and reveal a complex interaction with internal and external factors.

  PublisherDOI

• Author response: Integrated Respirometry and Metabolomics Unveil Circadian Metabolic Dynamics in Drosophila

  2025-11-04

  peer-reviewOpen access

  Precise temporal regulation of metabolism by sleep and circadian rhythms is essential for dynamic energy homeostasis, yet the link between systemic metabolism and respiratory demands remains poorly defined. We combined high-resolution respirometry with LC-MS-based metabolomics to characterize respiratory dynamics and metabolic states in Drosophila melanogaster to uncover genotype-specific impacts of sleep and circadian disruption. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. In contrast, short-sleep mutants (fmn, sss) exhibited elevated metabolic rates and reactive shifts of fuel preferences toward lipid and amino acid catabolism and displayed signs of mitochondrial stress. Circadian-clock disrupted flies (per01, WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems are essential for aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.

  PublisherDOI

• Integrated Respirometry and Metabolomics Unveil Circadian Metabolic Dynamics in Drosophila

  eLife · 2025-11-04

  articleOpen access

  Precise temporal regulation of metabolism by sleep and circadian rhythms is essential for dynamic energy homeostasis, yet the link between systemic metabolism and respiratory demands remains poorly defined. We combined high-resolution respirometry with LC-MS-based metabolomics to characterize respiratory dynamics and metabolic states in Drosophila melanogaster to uncover genotype-specific impacts of sleep and circadian disruption. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. In contrast, short-sleep mutants (fmn, sss) exhibited elevated metabolic rates and reactive shifts of fuel preferences toward lipid and amino acid catabolism and displayed signs of mitochondrial stress. Circadian-clock disrupted flies (per01, WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems are essential for aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.

  PublisherDOI

• Effect of external cues on clock-driven protection from influenza A infection

  Journal of Clinical Investigation · 2025-11-16

  articleOpen access

  Influenza and other respiratory viral pathogens remain leading causes of mortality and morbidity. Circadian rhythms play a critical role in regulating immune responses and can confer temporal protection from influenza infection. Here, we investigated whether this protection requires rhythmic function after the initial infection by manipulating environmental cycles. We found that disrupting environmental lighting cues within a critical window of vulnerability abrogated the time-of-day-specific protection. This poor outcome was mediated by a dysregulated immune response, as evidenced by the accumulation of inflammatory monocytes and CD8+ T cells in the lungs and a transcriptomic profile indicative of an exaggerated inflammation. Disruption of the light cycle did not affect outcomes in a clock mutant, indicating that it acts through the host's circadian clock. Importantly, rhythmic meal timing mitigated the adverse effects of disrupted light cycles, supporting the idea that external cues acting through different body clocks can compensate for one another. Together, these findings underscore the critical interplay between environmental timing cues and endogenous circadian rhythms in determining influenza outcomes and offer translational insight into optimizing care for critically ill patients with respiratory viral infections.

  PublisherDOI

• Sleep drive, not total sleep amount, increases seizure risk

  Nature Communications · 2025-07-29 · 4 citations

  articleOpen accessSenior author

  Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic "sleep drive," not simply when total sleep amount falls. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep drive without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleep drive protects against seizures. Downregulation of the 5HT1A serotonin receptor in sleep-promoting cells mediates the effect of sleep drive on seizures, and we identify an FDA-approved 5HT1A agonist to mitigate seizures. Our findings demonstrate that while homeostatic sleep is needed to recoup lost sleep, sleep drive comes at the cost of increasing seizure susceptibility.

  PublisherOA PDFDOI

• Constant light impairs memory processing transgenerationally in D. melanogaster

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-08

  preprintOpen accessSenior authorCorresponding

  Environmental perturbations can have profound effects on our physiology and behavior, but their long-lasting impact remains debatable. We discovered that changes in standard light-dark conditions, such as exposure to constant light or simulated chronic jetlag, causes loss of associative memory in appetitive and aversive conditioning paradigms in D. melanogaster, and this behavior persists through three generations despite transfer of progeny to a standard light-dark cycle. Impaired memory is transmitted through females and is independent of any changes in fitness, brain or mushroom body architecture, or sensing acuity. Mechanistically, effects of constant light on memory are mediated by increased PIWI/piRNA pathway expression in the germline and its H3K9me3 writing capabilities, acting through altered expression of the Dopamine-1-like Receptor 1 (Dop1R1) in the brain. These findings suggest that irregular exposure to light, such as nighttime light pollution, can have negative consequences across generations.

  PublisherOA PDFDOI

• A paradoxical impact of alcohol on sleep-memory coupling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-04

  articleOpen accessSenior authorCorresponding

  Abstract Sleep serves a fundamental role in memory consolidation, and yet it must adapt to the organism’s physiological state. Acute ethanol consumption has a profound impact on animal physiology, but whether intoxication affects the role of sleep in memory consolidation remains unexplored. We demonstrate that acute ethanol exerts a paradoxical dual impact on sleep-memory coupling in Drosophila . Typically, satiated flies require sleep for memory consolidation, but starved flies that must forage for food switch to sleep-independent memory. Ethanol selectively impairs memory consolidation in satiated flies, whereas memories in starved flies remain intact despite intoxication. The observed impairment in satiated flies is due to a switch to sleep-independent memory, which then can’t be supported because of ethanol-induced sedation. Mechanistically, the ethanol-induced switch to sleep-independent memory is driven by neuropeptide F-mediated modulation of dopamine signaling. These findings reveal that ethanol intoxication inverts the canonical function of sleep, wherein it becomes detrimental to memory consolidation.

  PublisherDOI

• Clock gene signature predicts Insomnia and links to sleep/circadian parameters

  Research Square · 2025-06-25

  preprintOpen access
  PublisherOA PDFDOI

Recent grants

• Cycling in a circadian circuit

  NIH · $2.7M · 2005–2022

• NIH Grant P01AG017628

  NIH · $30.5M · 2019

• NIH Grant R56NS048471

  NIH · $400k · 2011

• Balance of sleep and circadian metabolic switches in Drosophila

  NIH · $2.1M · 2019–2024

• Interaction between circadian and sleep circuits

  NIH · $4.8M · 2005–2027

Frequent coauthors

• Shirley Zhang

  134 shared

• Zhifeng Yue

  Fourth Hospital of Hebei Medical University

  81 shared

• Xiangzhong Zheng

  University of Pennsylvania

  68 shared

• Yongjun Li

  University of Pennsylvania

  62 shared

• Cynthia T. Hsu

  Howard Hughes Medical Institute

  50 shared

• Nicholas F. Lahens

  Translational Therapeutics (United States)

  45 shared

• Aalim M. Weljie

  University of Pennsylvania

  39 shared

• Jessica E. Schwarz

  Howard Hughes Medical Institute

  37 shared

Education

• PhD, Cell Biology

  Joan and Sanford I Weill Medical College of Cornell University

  1987