Biology subjects

Kayser, M. S.

Publications and source records attributed to Kayser, M. S..

18 recordsLinked to original sources

bioRxiv2026

The evolutionarily conserved EHMT1/G9a histone methyltransferase family regulates sleep maintenance through ROS homeostasis in insulin-producing cells

Sleep disturbances are a common, still poorly characterized feature of Kleefstra syndrome (KLEFS1), a neurodevelopmental disorder caused by rare variants in the epigenetic regulator EHMT1. The gap in understanding the characteristics and origin of these sleep disturbances poses a major barrier for therapy development. In this cross-species study, we reveal that 70% of individuals with KLEFS1 experience severe sleep maintenance insomnia, marked by fragmented sleep due to frequent night awakenings. Furthermore, common genetic variation at the EHMT1 locus was associated with short sleep and insomnia symptoms in the general population. Drosophila mutants of the EHMT1 orthologue G9a recapitulate these phenotypes, exhibiting reduced and fragmented sleep. We show that G9a is required in insulin-producing cells (IPCs) and the fat body, in the latter during development, to ensure adult sleep integrity. Untargeted metabolomics revealed widespread metabolic dysregulation in G9a mutants, particularly affecting methionine metabolism. Mutants exhibited reduced methionine and elevated methionine sulfoxide (Met-SO), pointing to increased reactive oxygen species (ROS). Redox sensors revealed increased H2O2-dependent oxidation in the larval brain and an elevated glutathione redox potential in IPCs during development but not in adulthood. IPC-specific knockdown of MsrA, the enzyme that reduces Met-SO back to methionine, reproduced sleep fragmentation. Developmental, but not acute, antioxidant treatment fully restored adult sleep consolidation, demonstrating that G9a safeguards sleep via ROS homeostasis in early life. Finally, we show that a Drosophila sleep-restriction paradigm based on human sleep-restriction therapy can override the developmental defects and restore sleep continuity in adulthood. Our findings establish an evolutionarily conserved role for EHMT1/G9a in sleep regulation and provide a mechanistic framework to understand and treat sleep disturbances in KLEFS1.

genetics↗

bioRxiv2026

Sensory-sleep dysfunction is a shared phenotype across genetically distinct neurodevelopmental disorder models

Sensory abnormalities and sleep disruption frequently co-occur in neurodevelopmental disorders (NDDs), but how sensory input interacts with sleep regulation in NDDs remains poorly understood. Here, we examined vibration-induced sleep (VIS), in which prolonged gentle vibration promotes sleep in Drosophila, in three genetically distinct NDD models: dNf1, dNrx1, and dFmr1. Despite markedly different baseline sleep phenotypes, all three mutants exhibited impaired VIS, identifying disrupted sensory-sleep integration as a shared phenotype across these NDD models. Behavioral responses to vibration, activity-associated CRTC signaling in Nanchung-positive (Nan+) mechanosensory neurons, and thermogenetic activation of Nan+ neurons revealed distinct underlying abnormalities across the three models, indicating that disruption at different points along the sensory-sleep axis can converge on the same behavioral phenotype. The effect of mechanosensory stimulation was also strongly shaped by homeostatic sleep drive: following sleep deprivation, vibration promoted sleep in dNf1 mutants, remained ineffective in dNrx1 mutants, and opposed recovery sleep in dFmr1 mutants. Together, these findings identify impaired sensory regulation of sleep as a point of convergence across genetically distinct NDD models and demonstrate that the expression of this shared phenotype depends on internal state.

neuroscience↗

bioRxiv2026

Cross-trait clustering of sub-threshold sleep genetic signals identifies EGR2 as a conserved regulator of sleep

Idiopathic hypersomnia (IH) is a highly heritable sleep disorder characterized by excessive daytime sleepiness, yet few genetic pathways contributing to hypersomnolence have been identified. To expand genetic discovery beyond the limited number of genome-wide significant loci associated with sleepiness-related traits, we applied multi-trait clustering to sleep-associated genetic variation that did not reach conventional significance thresholds. Integration with our cell-type-specific variant-to-gene mapping prioritized candidate effector genes for cross-species functional screening. Among the strongest candidates was EGR2, which emerged as a distal effector gene at the ADO-EGR2 locus in neurons. Neuronal knockdown of the Drosophila EGR2 ortholog stripe increased sleep duration and sleep consolidation, while mutation of zebrafish egr2 orthologs similarly increased sleep. Together, these findings demonstrate that sleep-regulatory pathways can be identified from genetic signals below conventional significance thresholds and establish EGR2 as a conserved regulator of sleep across species.

neuroscience↗

bioRxiv2026

Peripheral Metabolic Reprogramming Links TDP-43 Proteinopathy to Sleep Disruption

Sleep disruption is an early and prevalent feature of neurodegenerative disease, commonly attributed to neuronal circuit dysfunction or cell loss. However, sleep is tightly coupled to metabolic state, raising the possibility that systemic metabolic abnormalities contribute to disease-associated sleep phenotypes. Using Drosophila models of TDP-43 proteinopathy, we investigated whether peripheral metabolic dysfunction plays a causal role in sleep disruption. We show that TDP-43 expression induces a chronic, starvation-like metabolic state characterized by depletion of peripheral carbohydrate stores despite normal feeding. Restoration of sleep fails to correct these metabolic defects, whereas improving peripheral metabolic state robustly rescues sleep. A modifier screen of [~]650 RNAi lines identified Salt-inducible kinase 3 (SIK3) as a potent suppressor of both sleep loss and starvation sensitivity. Transcriptomic and spatial metabolomic analyses reveal that SIK3 selectively remodels a peripheral metabolic program centered on the pentose phosphate pathway and redox-associated metabolites without globally restoring energy stores. Together, these findings identify systemic metabolic dysfunction as a key driver of sleep disruption in TDP-43 proteinopathy and highlight peripheral metabolism as a potential therapeutic entry point for sleep dysfunction in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Reverse electron transfer at mitochondrial complex I restrains dopaminergic neuron activity to promote early-life sleep in Drosophila

Sleep is especially abundant during early life, yet the cellular mechanisms that maintain elevated juvenile sleep drive remain poorly understood. To identify cell-intrinsic regulators of juvenile sleep, we profiled gene expression in Drosophila dopaminergic neurons (DANs) at different ages and performed a targeted RNAi screen of genes with enriched juvenile expression. We found that the magnitude of mitochondrial complex I (MCI) disruption produced strikingly distinct physiological outcomes. Severe MCI loss-of-function caused profound mitochondrial dysfunction, reduced dopaminergic activity, and locomotor impairment. In contrast, partial MCI inhibition left overall mitochondrial function intact but instead reduced sleep, with disproportionately strong effects on juvenile sleep fragmentation and depth, consistent with a gain of dopaminergic signaling. Multiple genetic manipulations that deplete the reduced coenzyme Q pool (CoQH2) converged on a phenotype of increased dopaminergic activity and wakefulness, indicating that coenzyme Q redox balance itself regulates dopaminergic output. These findings support a model in which CoQH2-driven reverse electron transfer (RET) at MCI restrains dopaminergic arousal. By dissociating mitochondrial redox signaling from catastrophic mitochondrial failure, our work identifies a physiological role for coenzyme Q-dependent signaling in the regulation of neural activity and behavioral state. More broadly, these findings suggest that sleep phenotypes may serve as sensitive indicators of emerging mitochondrial dysfunction and reveal a potential link between the regulation of early-life sleep and later dopaminergic vulnerability.

neuroscience↗

bioRxiv2026

Allele-specific rescue of neurexin behavioral phenotypes by monoamine-targeting compounds

Neurexins are synaptic adhesion molecules associated with neurologic changes in humans, including neurodevelopmental delay, autism, schizophrenia, Tourette syndrome, and seizures. The NRXN1 gene produces >100 protein isoforms through alternative promoters and extensive splicing, which are differentially impacted by NRXN1 variants found in patients. Yet pharmacologic targeting of NRXN1 isoforms or deletions has not been comprehensively studied. Here, we developed a behavioral screening approach in C. elegans to identify small molecule compounds that modify the decreased activity levels caused by isoform-specific deletions of neurexin(nrx-1). Screening 190 compounds, we discovered that monoamine-targeting compounds differentially improve behavioral phenotypes depending on which nrx-1 isoforms are disrupted. Broad modulation of monoamine signaling, or antagonism of specific serotonin receptors, are required to increase the activity of both alleles tested. The FDA-approved atypical antipsychotic olanzapine was the sole validated compound achieving Z-scores >2 in both screens, which notably also rescued behavioral phenotypes of C. elegans harboring a conserved autism-associated NRXN1 missense variant (L18Q/L16Q) identified in human patients. In Drosophila Nrx-1 mutants, olanzapine uniquely and significantly improved activity deficits and extended survival, demonstrating evolutionary conservation of our findings. Multi-behavior testing revealed pharmacological specificity: olanzapine improved both activity and social feeding phenotypes of nrx-1 alleles, while asenapine maleate improved activity, but worsened social feeding, indicating distinct impacts across behavioral domains. Our findings establish monoamine modulation as a conserved compensatory mechanism for neurexin loss, identify olanzapine as a lead compound for targeting neurexin loss, and demonstrate that allele stratification and pharmacogenomic approaches are needed for precision intervention in behavioral conditions. Neurexins are synaptic adhesion molecules implicated in autism, schizophrenia, and neurodevelopmental disorders. NRXN1 produces over 100 isoforms differentially affected by patient variants, yet pharmacologic targeting has not been systematically studied. We developed a C. elegans behavioral screen to identify compounds rescuing activity deficits caused by isoform-specific deletions. Screening 190 compounds, we discovered that monoamine-targeting drugs differentially improved behavioral phenotypes depending on which isoforms were disrupted. The FDA-approved antipsychotic olanzapine uniquely achieved robust rescue (Z-scores >2) across all genetic backgrounds tested, including a conserved autism-associated NRXN1 missense variant (L18Q/L16Q) identified in patients. Olanzapines efficacy was conserved in Drosophila Nrx-1 mutants, improving activity and extending survival. Multi-behavior testing revealed pharmacological specificity: olanzapine rescued both activity and social feeding phenotypes, while asenapine differentially affected behavioral domains. Our findings establish monoamine modulation as a compensatory mechanism for neurexin loss and identify olanzapine as a therapeutic lead for precision intervention in neurexin-associated disorders.

neuroscience↗

bioRxiv2025

A switch in arousal circuit architecture shapes sleep across the lifespan

Sleep is a continuous behavior across the lifespan, yet its features and functions evolve markedly with development1-4. In Drosophila melanogaster, as in mammals, early life sleep differs from mature sleep5,6, 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.

neuroscience↗

bioRxiv2025

Developmental sleep reallocation enables metabolic adaptation in desert flies

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.

neuroscience↗

bioRxiv2024

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

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.

neuroscience↗

bioRxiv2023

Stem cell-specific ecdysone signaling regulates the development and function of a Drosophila sleep homeostat

Complex behaviors arise from neural circuits that are assembled from diverse cell types. Sleep is a conserved and essential behavior, yet little is known regarding how the nervous system generates neuron types of the sleep-wake circuit. Here, we focus on the specification of Drosophila sleep-promoting neurons--long-field tangential input neurons that project to the dorsal layers of the fan-shaped body neuropil in the central complex (CX). We use lineage analysis and genetic birth dating to identify two bilateral Type II neural stem cells that generate these dorsal fan-shaped body (dFB) neurons. We show that adult dFB neurons express Ecdysone-induced protein E93, and loss of Ecdysone signaling or E93 in Type II NSCs results in the misspecification of the adult dFB neurons. Finally, we show that E93 knockdown in Type II NSCs affects adult sleep behavior. Our results provide insight into how extrinsic hormonal signaling acts on NSCs to generate neuronal diversity required for adult sleep behavior. These findings suggest that some adult sleep disorders might derive from defects in stem cell-specific temporal neurodevelopmental programs.

neuroscience↗

bioRxiv2023

Energetic Demands Regulate Sleep-Wake Rhythm Circuit Development

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.

neuroscience↗

bioRxiv2022

Developmental emergence of sleep rhythms enables long-term memory capabilities in Drosophila

In adulthood, sleep-wake rhythms are one of the most prominent behaviors under circadian control. However, during early life, sleep is spread across the 24-hour day (1-4). The mechanism through which sleep rhythms emerge, and the consequent advantage conferred to a juvenile animal, are unknown. In 2nd instar Drosophila larvae (L2), like human infants, sleep is not under circadian control (5). Here, we identify the precise developmental timepoint when the circadian clock begins to regulate sleep in Drosophila, leading to the emergence of sleep rhythms at the early 3rd instar stage (L3). At this stage, a cellular connection forms between DN1a clock neurons and arousalpromoting Dh44 neurons, bringing arousal under clock control to drive the emergence of circadian sleep. Finally, we demonstrate that L3 but not L2 larvae exhibit long-term memory (LTM) of an aversive cue, and that this LTM depends upon deep sleep generated once sleep rhythms begin. We propose that the developmental emergence of circadian sleep enables more complex cognitive processes, including the onset of enduring memories.

neuroscience↗

bioRxiv2021

Intrinsic maturation of sleep output neurons regulates sleep ontogeny in Drosophila

The maturation of sleep behavior across a lifespan (sleep ontogeny) is an evolutionarily conserved phenomenon. Mammalian studies have shown that in addition to increased sleep duration, early life sleep exhibits stark differences compared to mature sleep with regard to the amount of time spent in certain sleep states. How intrinsic maturation of sleep output circuits contributes to sleep ontogeny is poorly understood. The fruit fly Drosophila melanogaster exhibits multifaceted changes to sleep from juvenile to mature adulthood. Here, we use a non-invasive probabilistic approach to investigate changes in sleep architecture in juvenile and mature flies. Increased sleep in juvenile flies is driven primarily by a decreased probability of transitioning to wake, and characterized by more time in deeper sleep states. Functional manipulations of sleep-promoting neurons in the dFB suggest these neurons differentially regulate sleep in juvenile and mature flies. Transcriptomic analysis of dFB neurons at different ages and a subsequent RNAi screen implicate genes involved in distinct molecular processes in sleep control of juvenile and mature flies. These results reveal that dynamic transcriptional states of sleep output neurons contribute to changes in sleep across the lifespan.

neuroscience↗

bioRxiv2020

The chromatin remodeler ISWI acts during Drosophila development to regulate adult sleep

Sleep disruptions are among the most commonly-reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From a Drosophila screen of human NDD-associated risk genes, we identified the chromatin remodeler Imitation SWItch/SNF (ISWI) to be required for adult fly sleep. Loss of ISWI also results in disrupted circadian rhythms, memory, and social behavior, but ISWI acts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically, ISWI expression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the human ISWI homologs SMARCA1 and SMARCA5 differentially rescue adult phenotypes. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs, and point towards chromatin remodeling machinery as critical for sleep circuit formation.

neuroscience↗

bioRxiv2019

Social behavioral deficits in NF1 emerge from peripheral chemosensory neuron dysfunction.

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder commonly associated with social and communicative disabilities. The cellular and circuit mechanisms by which loss of neurofibromin 1 (Nf1) function results in social deficits are unknown. Here, we identify social behavioral dysregulation with loss of Nf1 in Drosophila. These deficits map to primary dysfunction of a small group of peripheral sensory neurons, rather than central brain circuits. Specifically, Nf1 regulation of Ras signaling in adult, Ppk23+ chemosensory cells is required for normal social behaviors in flies. Loss of Nf1 results in attenuated ppk23+ neuronal activity in response to pheromonal cues, and circuit-specific manipulation of Nf1 expression or neuronal activity in ppk23+ neurons rescues social deficits. Unexpectedly, this disrupted sensory processing gives rise to persistent changes in behavior lasting beyond the social interaction, indicating a sustained effect of an acute sensory misperception. Together our data identify a specific circuit mechanism through which Nf1 acts to regulate social behaviors, and suggest social deficits in NF1 arise from propagation of sensory misinformation.

neuroscience↗

bioRxiv2019

Pdm3 directs sleep circuit development to control sleep maturation

Across species, sleep in young animals is critical for normal brain maturation. In contrast to mature adult sleep, the molecular determinants of early life sleep remain unknown. Through an RNAi-based screen, we identified a gene, pdm3, required for sleep maturation in Drosophila. Pdm3, a transcription factor, acts during nervous system development to coordinate the ingrowth of wake-promoting dopaminergic neurites to a sleep-promoting region. Loss of PDM3 prematurely increases dopaminergic inhibition of the sleep center, abolishing the juvenile sleep state. RNA-Seq/ChIP-Seq and a subsequent modifier screen reveal that pdm3 regulates expression of the synaptogenesis gene Msp300 to control sleep ontogeny. These studies define the molecular cues governing sleep behavioral and circuit development, and suggest sleep disorders may be of neurodevelopmental origin.

neuroscience↗

bioRxiv2018

Starvation resistance is associated with developmentally specified changes in sleep, feeding and metabolic rate

Food shortage represents a primary challenge to survival, and animals have adapted diverse developmental, physiological, and behavioral strategies to survive when food becomes unavailable. Starvation resistance is strongly influenced by ecological and evolutionary history, yet the genetic basis for the evolution of starvation resistance remains poorly understood. The fruit fly, Drosophila melanogaster, provides a powerful model for leveraging experimental evolution to investigate traits associated with starvation resistance. While control populations only live a few days without food, selection for starvation resistances results in populations that can survive weeks. We have previously shown that selection for starvation resistance results in increased sleep and reduced feeding in adult flies. Here, we investigate the ontogeny of starvation resistance-associated behavioral and metabolic phenotypes in these experimentally selected flies. We find that selection for starvation resistance results in delayed development and a reduction in metabolic rate in larvae that persists into adulthood, suggesting that these traits may allow for the accumulation of energy stores and an increase in body size within these selected populations. In addition, we find that sleep is largely unaffected by starvation- selection and that feeding increases during the late larval stages, suggesting that experimental evolution for starvation resistance produces developmentally specified changes in behavioral regulation. Together, these findings reveal a critical role for development in the evolution of starvation resistance and indicate that selection can selectively influence behavior during defined developmental timepoints.\n\nSUMMARY STATEMENTDrosophila melanogaster selected for starvation resistance take longer to develop and exhibit development-specific changes in traits associated with the accumulation and conservation of energy stores.

neuroscience↗

bioRxiv2018

A Drosophila Model for Behavioral Sleep Modification

Insomnia is the most common sleep disorder among adults, especially affecting individuals of advanced age or with neurodegenerative disease. Insomnia is also a common comorbidity across psychiatric disorders. Cognitive Behavioral Therapy for Insomnia (CBT-I) is the first-line treatment for insomnia; a key component of this intervention is restriction of sleep opportunity, which optimizes matching of sleep ability and opportunity, leading to enhanced sleep drive. Despite the well-documented efficacy of CBT-I, little is known regarding how CBT-I works at a cellular and molecular level to improve sleep, due in large part to an absence of experimentally-tractable animals models of this intervention. Here, guided by human behavioral sleep therapies, we developed a Drosophila model for behavioral modification of sleep. We demonstrate that restriction of sleep opportunity through manipulation of environmental cues improves sleep efficiency and quality in multiple short-sleeping Drosophila mutants. The response to sleep opportunity restriction requires ongoing environmental inputs, but is independent of the molecular circadian clock. We apply this sleep opportunity restriction paradigm to aging and Alzheimers disease fly models, and find that sleep impairments in these models are reversible with sleep restriction, with associated improvement in reproductive fitness and extended lifespan. This work establishes a model to investigate the neurobiological basis of CBT-I, and provides a platform that can be exploited towards novel treatment targets for insomnia.

neuroscience↗