About

Matthew S. Kayser, MD, PhD, is the Karl E. Rickels Associate Professor of Psychiatry at the University of Pennsylvania School of Medicine. He is an attending psychiatrist in the Department of Psychiatry and a member of the Chronobiology and Sleep Institute. Dr. Kayser specializes in issues related to sleep and mental health, with a focus on understanding how neural circuits give rise to complex behaviors and how dysfunctions in neural processes can lead to mental illness. His research primarily investigates the role of sleep in brain development and function, exploring how sleep contributes to the formation of neural circuits and its impact on psychiatric disorders. Utilizing the genetic model organism Drosophila melanogaster, his lab employs techniques such as genetics, behavioral assays, molecular biology, and imaging to study sleep, synapse formation, and behavior. His work aims to connect sleep abnormalities to the pathogenesis and treatment of neuropsychiatric diseases, with particular interest in how sleep influences brain development and behavior across the lifespan.

Research topics

• Neuroscience
• Biology
• Medicine
• Psychology
• Psychiatry

Selected publications

• Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2

  Nature Communications · 2026-01-12 · 2 citations

  articleOpen accessSenior author

  Idiopathic hypersomnia (IH) is a poorly understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish and flies, we uncover a role for beat-Ia/CADM2, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of Drosophila beat-Ia results in sleepy flies and loss of the vertebrate ortholog of beat-Ia, CADM2, results in sleepy fish. We delineate a developmental function for beat-Ia in synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain. Brain connectome and experimental evidence demonstrate these NPF outputs synapse onto a subpopulation of SEZ GABAergic neurons to stabilize arousal. NPF is the Drosophila homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lacking CADM2. These findings point towards NPY modulation as a treatment target for human hypersomnia. Cross-species studies show that loss of the synaptic adhesion molecules beat-Ia/CADM2 causes excessive sleepiness by disrupting development of wake-promoting NPF/NPY brain circuits. Targeting NPY signaling may offer treatment for human hypersomnia.

  PublisherOA PDFDOI

• A switch in arousal circuit architecture shapes sleep across the lifespan

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-06 · 1 citations

  preprintOpen accessSenior authorCorresponding

  , but it is unknown whether disparate sleep regulatory mechanisms underlie these changes. Here, we identify distinct populations of octopaminergic (OA) neurons that promote arousal in larval and adult flies, thus revealing a developmental switch in sleep-wake circuit architecture. Of eight OA neurons present in the sub-esophageal zone (SEZ) of the nervous system at both life stages, dedicated, non-overlapping subsets drive arousal in larvae versus adults. Morphologic and connectomic analyses show that larval OA arousal neurons project primarily to the ventral nerve cord and lack substantial sensory input, suggesting a circuit logic optimized for internally driven arousal during early development. In contrast, adult OA arousal neurons target higher brain regions involved in cognition and receive rich multimodal sensory input, supporting wakefulness in response to environmental cues. These findings highlight a developmental transition in arousal circuitry that mirrors changing ecological demands, with juvenile systems organized to prioritize growth and feeding, insulated from sensory disturbance, and mature systems supporting sensory-guided behavior. Our results support a model of sleep regulation as a developmentally dynamic process, in which shared neuromodulators like OA operate through distinct cellular substrates tailored to life stage-specific behavioral priorities.

  PublisherOA PDFDOI

• Treatment of Insomnia with Zaleplon in HIV+ Significantly Improves Sleep and Depression

  Psychopharmacology Bulletin · 2025-08-12 · 6 citations

  articleOpen accessSenior author

  More than 50% of individuals who are HIV positive report insomnia, which can reduce HIV treatment adherence, impair quality of life, and contribute to metabolic dysfunction. Major depressive disorder is also highly comorbid in this population, leading to further impairment. There is evidence that treating insomnia may improve not only sleep, but depression and metabolic function, as well. The present study aimed to examine the effects of pharmacotherapeutic treatment of insomnia on sleep, depression, and metabolic functioning in individuals with HIV. 20 individuals with asymptomatic seropositive HIV and comorbid insomnia and depression were administered zaleplon for 6 weeks. Insomnia severity was assessed using the Insomnia Severity Index and Epworth Sleepiness Scale, and depression severity was assessed using the Quick Inventory of Depression, both prior to treatment and 6 weeks post treatment. Metabolomic changes were assessed using a comprehensive platform measuring ~2000 lipid features and polar metabolites. Linear mixed effects models demonstrated that 6 weeks of treatment with zaleplon significantly improved symptoms of both insomnia and depression. Metabolomic analyses also demonstrated that changes in insomnia severity were associated with significant changes in key branched chain amino acid metabolites. Our results show that improvement in insomnia is associated with reduced depressive symptoms and beneficial metabolomic changes. Additionally, changes in key branched chain amino acid metabolites following treatment may serve as useful biomarkers of treatment response.

  PublisherOA PDFDOI

• Insomnia disorder and cerebrospinal fluid markers of dementia

  Journal of Alzheimer s Disease · 2025-11-17

  articleOpen accessSenior author

  Sleep disturbance may increase risk of Alzheimer's disease and related dementias (ADRD). Acute sleep deprivation increases cerebrospinal fluid (CSF) levels of amyloid-β, but the impact of chronic insomnia remains unclear. We compared 13 adults aged 30-60 with Insomnia Disorder to matched good sleepers. After overnight polysomnography a lumbar puncture was performed to collect CSF for assays of ADRD biomarkers. Contrary to our hypotheses, we found no significant differences in objective sleep measures or any CSF biomarkers, except for lower levels of neurofilament light. These findings suggest that mild-to-moderate Insomnia Disorder may not increase ADRD biomarkers, contrasting with effects of acute sleep deprivation.

  PublisherDOI

• Developmental sleep reallocation enables metabolic adaptation in desert flies

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15

  preprintOpen accessSenior authorCorresponding

  Abstract Sleep is essential for adaptation and survival across the lifespan, yet the ecological pressures shaping sleep ontogeny remain poorly understood. We investigated sleep across early developmental stages in Drosophila mojavensis , a stress-resilient desert-adapted species. While adult D.mojavensis exhibit prolonged and consolidated sleep, along with enhanced starvation tolerance and survival compared to Drosophila melanogaster , the developmental trajectory underlying these adaptation strategies for surviving in harsh environments is unknown. Moreover, during developmental (larval) periods, animals do not encounter the same environmental stressors experienced by adults (e.g., food scarcity, extreme temperatures). We find that in contrast to adults, D.mojavensis larvae exhibit reduced and fragmented sleep relative to D.melanogaster . D.mojavensis larval sleep is also deeper, reflecting a shift toward increased sleep efficiency rather than simple sleep loss. D.mojavensis larvae consume more food than D.melanogaster and survive longer under starvation, suggesting a strategic tradeoff by suppressing sleep to prioritize nutrient intake and energy storage early in life while resources are more abundant. Metabolic analyses reveal elevated triglyceride accumulation in D.mojavensis across their lifespan, indicating enhanced energy storage capacity. These findings provide an example of how, within a fixed genetic background, an animal can reallocate sleep in opposing manners to maximize survival and energetics depending upon ecological pressures unique to each phase of life.

  PublisherOA PDFDOI

• Author response: Energetic demands regulate sleep-wake rhythm circuit development

  2024-07-22 · 1 citations

  peer-reviewOpen accessSenior author

  Like most young animals, babies must obtain enough nutrients and energy to grow, yet they also need to rest for their brains to mature properly. As many exhausted new parents know first-hand, balancing these conflicting needs results in frequent, rapid switches between eating and sleeping. Eventually, new-borns’ internal biological clock system, which is aligned with the 24-hour light cycle, becomes fully operational. Exactly how this then translates into allowing them to stay alert during the day and be sleepy at night is still unclear. Like humans, the larvae of fruit flies first sleep haphazardly before developing a circadian pattern whereby they sleep at night and eat during the day. This shift occurs when a group of nerve cells called DN1a, whose job is to ‘keep time’, connects with Dh44, a subset of neurons which, when active, promote wakefulness. The trigger for these changes, however, has remained elusive. In response, Poe et al. hypothesized that feeding behaviour and nutrient availability coordinated the emergence of sleep rhythms in fruit flies. Forcing fruit fly larvae to keep feeding in an ‘immature’ pattern – by either genetic manipulations or reducing the sugar content of their food – not only prevented them from developing ‘mature’ sleeping rhythms but also resulted in memory problems. These experiments also showed that the DN1a-Dh44 connection depends on nutrient availability, as it did not form in larvae raised on the low-sugar food. Further genetic experiments showed that the Dh44 cells themselves act like nutrient sensors during the emergence of sleeping patterns. These results shed new light on the factors triggering sleep rhythm development. Poe et al. hope that the understanding gained can be extended to humans and eventually help manage nervous system disorders and health problems associated with disrupted sleep during early life.

  PublisherDOI

• Development of sleep and circadian rhythms: Function and dysfunction

  Neurobiology of Sleep and Circadian Rhythms · 2024-07-14 · 1 citations

  editorialOpen access
  PublisherDOI

• Energetic Demands Regulate Sleep-Wake Rhythm Circuit Development

  eLife · 2024-06-28

  preprintOpen accessSenior author

  Abstract Sleep and feeding patterns lack strong daily rhythms during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. In Drosophila, circadian sleep patterns are initiated with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar larval period (L2), sleep and feeding are spread across the day; these behaviors become organized into daily patterns by the 3rd instar larval stage (L3). Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms trigger the formation of sleep-circadian circuits and behaviors.

  PublisherDOI

• Energetic demands regulate sleep-wake rhythm circuit development

  eLife · 2024-07-22 · 1 citations

  articleOpen accessSenior author

  Sleep and feeding patterns lack strong daily rhythms during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. In Drosophila , circadian sleep patterns are initiated with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar larval period (L2), sleep and feeding are spread across the day; these behaviors become organized into daily patterns by the 3rd instar larval stage (L3). Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms trigger the formation of sleep-circadian circuits and behaviors.

  PublisherDOI

• Energetic demands regulate sleep-wake rhythm circuit development

  eLife · 2024-04-29 · 5 citations

  articleOpen accessSenior author

  Sleep and feeding patterns lack strong daily rhythms during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. In Drosophila , circadian sleep patterns are initiated with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar larval period (L2), sleep and feeding are spread across the day; these behaviors become organized into daily patterns by the 3rd instar larval stage (L3). Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms trigger the formation of sleep-circadian circuits and behaviors.

  PublisherDOI

Recent grants

• Molecular and genetic analysis of the juvenile sleep state

  NIH · $1.2M · 2021–2025

• Molecular and genetic analysis of sleep ontogeny

  NIH · $405k · 2020–2021

• Building brains in our sleep: A Drosophila larval platform for examining sleep and neurogenesis

  NIH · $2.4M · 2018–2023

• A critical period of sleep required for normal brain development

  NIH · $952k · 2014–2019

Frequent coauthors

• Milán Szuperák

  University of Pennsylvania

  17 shared

• Josep Dalmau

  Hospital Clínic de Barcelona

  12 shared

• Tiong Yang Tan

  Royal Children's Hospital

  12 shared

• Naihua N. Gong

  University of Pennsylvania

  11 shared

• Matthew A. Deardorff

  California University of Pennsylvania

  10 shared

• David M. Raizen

  University of Pennsylvania

  10 shared

• Amy R. Poe

  University of Pennsylvania

  10 shared

• Emilia H. Moscato

  University of Pennsylvania

  9 shared

Labs

• Kayser LabPI

Education

• MD, PhD, Neuroscience

  University of Pennsylvania Perelman School of Medicine

  2009

• ScB, Neuroscience

  Brown University

  2000