Biology subjects

Keene, A. C.

Publications and source records attributed to Keene, A. C..

At least 19 recordsLinked to original sources

bioRxiv2026

Progressive behavioral and cognitive decline in Drosophila harboring AD-associated APOE4 variants

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and its incidence is rising rapidly with population aging. Pathologically, AD is characterized by the accumulation of amyloid-beta (Abeta) plaques and hyperphosphorylated Tau neurofibrillary tangles. Human genomic studies have identified numerous risk alleles, with the APOE4 variant representing the strongest and most common genetic risk factor, present in approximately 75 percent of AD patients. However, APOE4 is neither necessary nor sufficient to cause disease, suggesting that additional genetic and environmental factors contribute to AD pathogenesis. Emerging evidence highlights a central role for oxidized lipid metabolism in AD. Disruption of lipid metabolism leads to lipid accumulation, reactive oxygen species (ROS) toxicity, and neurodegeneration, suggesting that oxidative stress may be a critical factor in enhancing AD susceptibility. To systematically investigate APOE function in vivo, we tested humanized Drosophila expressing the human APOE3 or APOE4 variants in place of the Drosophila ortholog Glial Lazarillo (GLaz). The lifespan of APOE3 and APOE4 flies does not differ under standard housing conditions, but the lifespan of APOE4 flies is significantly reduced when exposed to the ROS-promoting drug rotenone, supporting a multi-hit model of disease pathogenesis. APOE4 flies exposed to rotenone exhibit several AD-associated phenotypes, including age-related memory loss and chemosensory deficits, supporting the use of this model to investigate AD pathogenesis. Furthermore, progressive AD-associated phenotypes are also observed in APOE4 flies maintained on an obesogenic diet, suggesting that enhanced disease susceptibility is not specific to rotenone-induced stress but reflects a broader vulnerability to metabolic challenges. Together, these findings establish a scalable model to dissect APOE-dependent mechanisms and identify therapeutic targets in AD.

genetics↗

bioRxiv2026

Cave adaptation drives coordinated transcriptional remodeling across diverse cell types in the brain of a teleost fish

Adaptation of organisms to extreme environments requires dramatic phenotypic changes. Studying these changes can elucidate mechanisms underlying phenotypic differences in the context of both evolution and human disease. The Mexican tetra, Astyanax mexicanus, is a powerful model of extreme adaptation over a short evolutionary time scale. This fish species includes surface- and cave-dwelling ecotypes, with cavefish displaying many adaptations to subterranean life, including behavioral changes such as sleep loss, increased appetite, and reduced aggression. Unraveling the mechanisms underlying these changes has been challenging, presumably because they are complex traits that required coordinated changes across multiple cell types to evolve. Here, we present a spatially integrated comparative cell atlas of whole adult brains of surface and cavefish. After establishing the molecular signatures of 35 cell types, we show that cave colonization drove canalized regulatory changes to gene expression across diverse cell types. Cavefish brains show shifts in cell-type composition compared to their surface counterparts, as well as complex regulatory changes to pathways governing hypoxia response and circadian rhythm. Microglia in the cavefish brain underwent extensive transcriptional remodelling, including changes in senescence and AMPK pathways. Further, cell-cell communication analysis identified a cave-enriched ligand-receptor communication pattern centered on signals sent from glial cells to diverse populations of neurons. This atlas identifies genetic changes associated with neural and behavioral evolution and provides a resource for mechanistic studies examining brain evolution.

genomics↗

bioRxiv2026

A comparative brain atlas of Mexican cavefish identifies naturally-occurring changes in cellular composition and gene expression

Understanding how naturally occurring genetic variation shapes human health and disease is critical for improving diagnosis and treatment strategies. The Mexican cavefish, Astyanax mexicanus, represents a powerful system for evolutionary medicine, enabling investigation of naturally evolved mechanisms of resilience to disease-related traits including diabetes, obesity, insomnia, and eye loss. Larval A. mexicanus, like zebrafish, are transparent, allowing whole-brain imaging, circuit mapping, and the generation of computationally derived atlases that precisely quantify neuroanatomical differences between surface and cave populations. Developing a molecular map of brain cell types provides a foundation for identifying evolved differences in neural circuits and physiology. Here, we present a single-cell atlas of the larval cavefish brain that reveals widespread divergence in the abundance and molecular signatures of neurons and glia. Our cell type map validates known neuroanatomical differences, including a reduction of the optic tectum and expansion of the pineal gland in cavefish. We uncover substantial changes in multiple glial cell classes that are linked to neural regulation of behavior, including microglia. Analysis of differential gene expression between surface and cavefish microglia revealed enhanced genes associated with synaptic pruning and clearance of neural debris, suggesting cavefish increased microglia activity to shape brain development. We also analyzed cell types that did not classify as canonical neurons or glia and identified notable divergence in transcriptomes and cell composition, including reduced meningeal fibroblasts in cavefish and substantial transcriptional changes related to phototransduction in non-visual photoreceptors within the pineal gland. Together, these findings provide a comprehensive atlas of cell type-specific gene expression differences between A. mexicanus surface and cavefish, establishing a platform for dissecting the molecular and cellular basis of evolved disease resilience in cavefish

evolutionary biology↗

bioRxiv2026

Evolved differences in microglial cell biology between surface and cave populations of Astyanax mexicanus

Microglia govern multiple aspects of brain architecture and function by eliminating dying cells, stimulating neurogenesis, refining neural connections, and orchestrating immune responses. The Mexican tetra, Astyanax mexicanus, is a powerful model system for investigating the evolution of brain function, yet microglia have not been investigated in this system. A. mexicanus exists as surface-dwelling and cave morphotypes with prominent behavioral and physiological differences. Notably, these evolved behavioral and physiological changes in cavefish, including diminished immune response, sleep, circadian rhythms, and sensory processing, are directly linked to known microglial functions. These observations suggest that evolved differences in microglia may shape brain circuitry adaptations in cavefish. Here we develop an experimental toolbox to examine microglial specification, dynamics, and function in A. mexicanus to perform comparative analysis of microglial cell biology between the surface and cave morphotypes. We find that the cave populations show increased numbers of microglia over developmental time relative to their surface counterparts. Microglia in Astyanax rapidly expand in response to inflammatory cues, distinct from microglial responses in the related teleost, zebrafish. Furthermore, lysosomal compartments of microglia in the cave populations exhibit increased enhanced proteolytic activity and reduced pH relative to surface morphotypes. Together, our observations reveal evolved differences in microglial cell biology between surface and cave populations of A. mexicanus and provide a framework to uncover novel neuroimmune mechanisms underlying the remarkable adaptations of A. mexicanus.

evolutionary biology↗

bioRxiv2026

Cell-specific variant-to-gene mapping identifies conserved neural and glial regulators of sleep

Excessive daytime sleepiness (EDS) is a heterogeneous phenotype with little known of its genetic basis. Large-scale genome-wide association studies (GWAS) have reported genomic loci associated with EDS, though since most of these are non-coding, the causal gene(s) underlying the association are not known. Additionally, the cell types in which these genes exert their effects on sleep have not been functionally explored in vivo. Here, we employed a chromatin-based variant-to-gene mapping approach to first implicate candidate effector genes at EDS GWAS loci in human-derived neural and glial cell lines. Subsequent cell type-specific RNAi knockdown of orthologous genes using neural and glial GAL4 drivers in Drosophila confirmed cell-specific regulation of sleep by these GWAS-implicated effector genes. Among these, ruby (ortholog to AP3B2), a component of the AP-3 vesicular trafficking complex emerged as a robust sleep regulator. Targeted knockdown in flies localized ruby function to astrocyte-like glia, where loss of ruby increased sleep duration. The conserved role of ruby/ ap3b2 was validated in zebrafish where CRISPR-mediated loss increased daytime sleep. Together, these findings show that physical variant-to-gene mapping predicted cell-type-specific gene function for complex sleep traits and revealed ruby/AP3B2 as a conserved glial regulator of sleep and arousal. This work provides a generalizable framework for connecting non-coding GWAS variants and their corresponding effector genes to identify novel and highly conserved regulators of sleep.

genetics↗

bioRxiv2026

Cave evolution on repeat: reuse of the same genomic regions across lineages but not across traits in Astyanax mexicanus

Similar traits repeatedly evolve across independent populations in response to similar environmental conditions. For many repeatedly evolved traits it is unknown if populations evolve similar traits through the same or different genetic mechanisms. To address this question, we leveraged the Mexican tetra fish, Astyanax mexicanus, which has evolved repeatedly through altering many traits including reduced sleep duration, eye degeneration, and metabolic shifts to accommodate limited nutrient availability. We defined whether shared or independent genetic architecture govern the repeated evolution of sleep loss, increased food consumption, early onset adipose deposition, and eye loss in different evolutionary origins of the cavefish phenotype by using Quantitative Trait Locus (QTL) mapping across three cave x surface F2 mapping populations. We found that, among the traits evaluated, eye loss exhibits the most genetic repeatability, with [~]43% of QTL shared across lineages. Sleep loss and metabolic traits (i.e., feeding, adiposity) were genetically less repeatable, with only [~]25-33% of QTL shared across lineages. Next, we explored whether QTL for metabolism, eye loss, and sleep traits in cavefish co-localize in the cavefish genome and could be inherited together to facilitate potential cavefish adaptation. Although these traits have repeatedly co-evolved in cave populations, we did not find evidence for extensive genetic linkage among them. Overall, we found that genetic repeatability is a common feature in the repeated evolution of cave traits, the extent of genetic repeatability varies across cave traits, and that there is little evidence for widespread co-localization of sleep, eye loss, and metabolic traits within the genome. SummaryIndependent populations that evolve similar traits in response to similar environmental conditions provide us with natural replicates for studying what constrains evolutionary change. Iconic examples of repeated trait evolution often involve repeated mutations in the same genes, suggesting there are limits on the type of genes and mutations that can contribute to phenotypic evolution. Here we conduct a multi-trait, multi-population QTL analysis for similar eye loss, sleep loss and metabolic shifts across two lineages of Astyanax mexicanus. Genetic repeatability is present for most traits, but its extent is highly trait dependent and occurs at the level of genomic regions rather than specific genes, highlighting the mosaic of constraint and flexibility involved in genetic repeatability.

evolutionary biology↗

bioRxiv2025

Early life sleep is associated with longevity in Drosophila

Sleep is a universal behavior that is critical for brain function and physiological homeostasis. While growing epidemiological and experimental evidence suggests reduced sleep quality is associated with negative health outcomes, the causal relationship between sleep loss and reduced longevity remains poorly understood. Here, we examine sleep across the lifespan and its relationship to longevity in Drosophila melanogaster. We examined the associations between numerous components of sleep at different life stages to longevity. Early life sleep, but not middle and late-life sleep, was positively associated with longevity. Age-dependent changes in sleep were consistent but accelerated, when flies are housed under stressful conditions including nutrient and temperature stress. Further, pharmacological restoration of sleep in the first 10 days of life, but not at later time points, increases longevity. Together, this work provides a systematic investigation of how different components of sleep impact longevity and suggests early life sleep may be particularly important in promoting sleep across the lifespan.

neuroscience↗

bioRxiv2025

A pangenome framework uncovers the role of deletions in repeated evolution of cave-derived traits

Structural variants (SVs) are increasingly recognized as key contributors to adaptive evolution, yet they remain underexplored compared to single-nucleotide variation. To understand how large-scale genomic changes shape repeated evolution, we leveraged multiple levels of sequence data across the powerful evolutionary model system of the Mexican tetra fish (Astyanax mexicanus). Cavefish populations have repeatedly evolved similar and dramatic phenotypes compared to surface fish such as eye loss, pigmentation loss, and sleep loss, suggesting a potential role for loss-of-function variants in cave adaptation. We constructed one of the first pangenome graphs from a naturally evolving vertebrate, enabling comprehensive discovery of SVs among 120 fish from 11 populations. We identified over 2,400 high-confidence cave-specific deletions that are enriched in biological pathways involved in vision, metabolism, and behavior and cluster non-randomly in quantitative trait loci linked to cavefish traits. Strikingly, 67 genes harbor unique deletions between independent cavefish lineages. These reused genes show strong evidence of population-specific selection (99% are under selection, compared to 8-15% in genes lacking SVs), indicating that deletions rose in frequency through repeated positive selection rather than drift. Together, these results reveal that recurrent deletion events have repeatedly contributed to the evolution of cave-adapted phenotypes and highlight deletions as underexplored contributors of adaptive evolution in a system characterized by trait loss.

evolutionary biology↗

bioRxiv2025

Analysis of multi-trait evolution across independently evolved cavefish populations reveals shared and independent evolution of suites of cave-associated traits

Environmental perturbations often lead to the evolution of multiple traits. Determining whether shared genetic factors underlie multi-trait evolution is a central question in evolutionary biology. In the Mexican tetra, Astyanax mexicanus, cave-dwelling populations have repeatedly evolved multiple traits. The repeated evolution of these traits, paired the robust environmental differences between the surface and cave habitats, provide an opportunity to investigate the genetic basis of multi-trait evolution. Here, we investigate the extent to which shared genetic mechanisms underlie the repeated evolution of multiple traits in cavefish. Across cave populations, we find evidence for shared and distinct genetic mechanisms contributing to the evolution of individual traits. Further, multiple traits covary in cave-surface F2 hybrids and many of the same trait correlations are found across independently evolved cave populations. Finally, we assessed traits that differ between pigmented and albino F2 fish in surface fish with mutations in the albinism gene oculocutaneous albinism 2 (oca2). This revealed that mutations in oca2 reduce bottom-dwelling behavior in A. mexicanus. Together, these findings suggest that multi-trait evolution occurs repeatedly through shared genetic factors across A. mexicanus cave populations. These results are consistent with pleiotropy or linkage playing a large role in multi-trait evolution in this species.

evolutionary biology↗

bioRxiv2025

Blood-derived dietary protein promotes sleep in the mosquito Aedes aegypti

Sleep is a ubiquitous, yet highly variable, behavior across species. The duration and timing of sleep are influenced by ecological demands and dietary context. In the mosquito Aedes aegypti, a blood-feeding insect with specialized nutritional requirements, the relationship between feeding and sleep remains poorly understood. Here, we investigated how blood-derived dietary protein influences sleep regulation. Using postural analysis, videography, and arousal-threshold assays, we established that immobility bouts of [≥]10 minutes reliably define sleep in Ae. aegypti. Mosquitoes lacking the circadian clock gene cycle still maintained daily sleep rhythms but exhibited reduced sleep duration and heightened overall activity. Infrared activity monitoring revealed that blood-fed females showed a marked increase in sleep beginning immediately after feeding and persisting for several days, accompanied by reduced locomotor activity. Notably, this sleep elevation lasted well beyond the cessation of previously reported host-seeking phases, raising the possibility of distinct phases of opportunistic versus targeted host pursuit. To determine the dietary basis of this effect, we tested mosquitoes fed a bovine serum albumin (BSA)-based diet. BSA feeding alone was sufficient to mimic the sleep-promoting and activity-reducing effects of blood, suggesting dietary protein is a major nutritional regulator. Moreover, RNAi-mediated knockdown of the leucokinin receptor (Lkr), which has previously been associated with fluid homeostasis and feeding behavior, resulted in enhanced sleep and reduced activity, implicating mosquito LK signaling in the modulation of postprandial sleep. Together, these findings demonstrate that blood-derived proteins drive sustained increases in sleep and reductions in locomotor activity in Ae. aegypti. This work positions Ae. aegypti as a model for dissecting nutrient-specific regulation of sleep and highlights potential adaptive functions of protein-induced quiescence, such as energy conservation and predator avoidance. More broadly, it provides insight into how specialized diets shape the neural and behavioral architecture of sleep.

neuroscience↗

bioRxiv2025

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development

Genome wide association study (GWAS) reports substantially outpace subsequent functional characterization. Pinpointing the causal effector gene(s) at GWAS loci remains challenging given the non-coding genomic residency of >98% of these signals. We previously implicated effector genes at GWAS loci for the complex and polygenic disorder of human insomnia using a high-resolution cell-specific, chromatin capture-based variant-to-gene mapping protocol, paired with sleep phenotyping in Drosophila. In this study, we leveraged a diurnal vertebrate model with higher genomic conservation, namely zebrafish, to screen our six highest confidence candidate genes and identify those whose loss-of-function impaired sleep characteristics related to human insomnia-like behaviors. Of these genes, we observed that CRISPR-mediated deletion of the zebrafish ortholog of MEIS1 produced nighttime specific sleep fragmentation and increased latency to sleep, pointing to a conserved role for MEIS1 in sleep maintenance. Comparing our human cell-based chromatin accessibility and contact maps with publicly available zebrafish spatial genomic data revealed highly conserved genomic architecture harboring the insomnia GWAS variant of interest. Notably, this genomic conservation was selective for the zebrafish ortholog which contributed to the sleep phenotype, meis1b, while the duplicated ohnolog meis1a proved dispensable. Motivated by this, we characterized the spatio-temporal expression of meis1b in zebrafish, showing it is comparable to human with respect to cerebellar granule progenitors. Ultimately, we found that loss of meis1b impairs cerebellar development. Together, our work provides a powerful model for screening human disorder risk genes for sleep fragmentation using a tractable vertebrate and supports a conserved cerebellar role for MEIS1 in sleep disturbance.

neuroscience↗

bioRxiv2025

The Intergenerational Classroom: A Case Study Integrating Undergraduate and Lifelong Learning Curricula for Biology Education

According to the US Census Bureau (2019) there are approximately 95 million people in the US 55 years of age and older, and that number is expected to increase dramatically in the next decade. This growing population results in an increasing need for STEM learning opportunities for older adults. This need is partially met by lifelong learning communities across the country that offer non-degree programs on a broad range of topics. While many of these programs are located on a college campus, there are few opportunities for interaction between lifelong learners and students in degree-oriented programs. To improve access to STEM education for lifelong learners, we generated an intergenerational classroom composed of lifelong learners and undergraduate students. The semester-long course focused on the biography and medical writings of the late neurologist Oliver Sacks. Our analysis revealed a high level of satisfaction from both undergraduate students and lifelong learners. Both groups overwhelmingly found the intergenerational format beneficial to learning. Furthermore, self-assessments revealed that students felt more positively about intergenerational interactions following completion of the course. Overall, this course provides a framework for increasing access to STEM for the growing older adult population and fostering positive intergenerational interactions. This model could be readily implemented across the country given the abundance of lifelong learning programs currently affiliated with colleges and universities.

scientific communication and education↗

bioRxiv2025

Sleep rescues age-associated loss of glial engulfment

Neuronal injury due to trauma or neurodegeneration is a common feature of aging. The clearance of damaged neurons by glia is thought to be critical for maintenance of proper brain function. Sleep loss has been shown to inhibit the motility and function of glia that clear damaged axons while enhancement of sleep promotes clearance of damaged axons. Despite the potential role of glia in maintenance of brain function and protection against neurodegenerative disease, surprisingly little is known about how sleep loss impacts glial function in aged animals. Axotomy of the Drosophila antennae triggers Wallerian degeneration, where specialized olfactory ensheathing glia engulf damaged neurites. This glial response provides a robust model system to investigate the molecular basis for glial engulfment and neuron-glia communication. Glial engulfment is impaired in aged and sleep-deprived animals, raising the possibility that age-related sleep loss underlies deficits in glial function. To define the relationship between sleep- and age-dependent reductions in glial function, we restored sleep to aged animals and examined the effects on glial clearance of damaged axons. Both pharmacological and genetic induction of sleep restores clearance of damaged neurons in aged flies. Further analysis revealed that sleep restored post-injury induction of the engulfment protein Draper to aged flies, fortifying the notion that loss of sleep contributes to reduced glial-mediated debris clearance in aged animals. To identify age-related changes in the transcriptional response to neuronal injury, we used single-nucleus RNA-seq of the central brains from axotomized young and old flies. We identified broad transcriptional changes within the ensheathing glia of young flies, and the loss of transcriptional induction of autophagy-associated genes. We also identify age-dependent loss of transcriptional induction of 18 transcripts encoding for small and large ribosomal protein subunits following injury in old flies, suggesting dysregulation of ribosomal biogenesis contributes to loss of glial function. Together, these findings demonstrate a functional link between sleep loss, aging and Wallerian degeneration.

neuroscience↗

bioRxiv2025

Automated behavioral profiling using neural networks reveals differences in stress-like behavior between cave and surface-dwelling Astyanax mexicanus

Behavioral stress responses allow animals to quickly adapt to local environments and are critical for survival. Stress responses provide an ideal model for investigating the evolution of complex behaviors due to their conservation across species, critical role in survival, and integration of behavioral and physiological components. The Mexican cavefish (Astyanax mexicanus) has evolved dramatically different stress responses compared to river-dwelling surface fish morphs, providing a model to investigate the neural and evolutionary basis of stress-like responses. Surface morphs inhabit predator-rich environments whereas cave-dwelling morphs occupy predator-free habitats. While these key ecological variables may underlie differences in stress responses, the complexity of the behavioral differences has not been thoroughly examined. By leveraging automated pose-tracking and machine learning tools, we quantified a range of behaviors associated with stress, including freezing, bottom-dwelling, and hyperactivity, during a novel tank assay. Surface fish exhibited heightened stress responses characterized by prolonged bottom-dwelling and frequent freezing, while cavefish demonstrated reduced stress behaviors, marked by greater exploration and minimal freezing. Analysis of F2 hybrids revealed that a subset of behaviors, freezing and bottom-dwelling, co-segregated, suggesting shared genetic or physiological underpinnings. Our findings illustrate the power of computational tools for high-throughput behavioral phenotyping, enabling precise quantification of complex traits and revealing the genetic and ecological factors driving their evolution. This study provides a framework for understanding how integrated behavioral and physiological traits evolve, offering broader insights into the mechanisms underlying the diversification of animal behavior in natural systems.

evolutionary biology↗

bioRxiv2024

Phylogenetic mapping of sleep loss in wild-caught cavefish

Sleep is an evolutionarily ancient and nearly universal behavior throughout the animal kingdom. Multiple cave-dwelling populations of the Mexican tetra, Astyanax mexicanus, have converged on sleep loss compared to river-dwelling surface fish. However, sleep has not been assessed in the vast majority of the 34 known A. mexicanus cave populations. Moreover, whether cavefish sleep less than surface individuals in their natural habitats is currently unknown. Analyzing the distribution of sleep loss and its relationship with other regressive traits in a phylogenetic framework is critical to inform the selective pressures across the different lineages. We measured sleep and locomotor activity in 15 distinct populations of A. mexicanus, including lineages that are broadly representative of the 34 cavefish populations identified to date. Sleep was drastically reduced in all cave and hybrid populations that were tested. A subset of caves contain hybrid populations of A. mexicanus, which show a broad range of eye and pigmentation phenotypes, yet have evolved near-complete loss of sleep. Mapping behavioral changes onto the phylogeny of A. mexicanus populations revealed that loss of sleep and elevated locomotor activity have evolved at least three times. Analysis of sleep in the wild confirms that the sleep loss phenotype observed in lab-reared fish is also present in the natural environment. Together, these findings reveal deep evolutionary convergence on sleep loss in cavefish and provide evidence for sleep loss as a primary trait contributing to cave adaptation.

evolutionary biology↗

bioRxiv2024

Targeted single cell expression profiling identifies integrators of sleep and metabolic state

Animals modulate sleep in accordance with their internal and external environments. Metabolic cues are particularly potent regulators of sleep, allowing animals to alter their sleep timing and amount depending on food availability and foraging duration. The fruit fly, Drosophila melanogaster, suppresses sleep in response to acute food deprivation, presumably to forage for food. This process is dependent on a single pair of Lateral Horn Leucokinin (LHLK) neurons, that secrete the neuropeptide Leucokinin. These neurons signal to insulin producing cells and suppress sleep under periods of starvation. The identification of individual neurons that modulate sleep-metabolism interactions provides the opportunity to examine the cellular changes associated with sleep modulation. Here, we use single-cell sequencing of LHLK neurons to examine the transcriptional responses to starvation. We validate that a Patch-seq approach selectively isolates RNA from individual LHLK neurons. Single-cell CEL-Seq comparisons of LHLK neurons between fed and 24-hr starved flies identified 24 genes that are differentially expressed in accordance with starvation state. In total, 12 upregulated genes and 12 downregulated genes were identified. Gene-ontology analysis showed an enrichment for Attacins, a family of anti-microbial peptides, along with several transcripts with diverse roles in regulating cellular function. Targeted knockdown of differentially expressed genes identified multiple genes that function within LHLK neurons to regulate sleep-metabolism interactions. Functionally validated genes include an essential role for the E3 ubiquitin Ligase insomniac, the sorbitol dehydrogenase Sodh1, as well as AttacinC and AttacinB in starvation-induced sleep suppression. Taken together, these findings provide a pipeline for identifying novel regulators of sleep-metabolism interactions within individual neurons.

neuroscience↗

bioRxiv2024

A repeatedly evolved mutation in Cryptochrome-1 of subterranean animals alters behavioral and molecular circadian rhythms

The repeated evolution of similar phenotypes in independent lineages often occurs in response to similar environmental pressures, through similar or different molecular pathways. Recently, a repeatedly occurring mutation R263Q in a conserved domain of the protein Cryptochrome-1 (CRY1) was reported in multiple species inhabiting subterranean environments. Cryptochromes regulate circadian rhythms, and glucose and lipid metabolism. Subterranean species show changes to their circadian rhythm and metabolic pathways, making it likely that this mutation in CRY1 contributes to adaptive phenotypic changes. To identify the functional consequences of the CRY1 R263Q mutation, we generated a mouse model homozygous for this mutation. Indirect calorimetry experiments revealed delayed energy expenditure, locomotor activity and feeding patterns of mutant mice in the dark phase, but no further metabolic phenotypes - unlike a full loss of function of CRY1. Gene expression analyses showed altered expression of several canonical circadian genes in the livers of the mutant mice, fortifying the notion that CRY1 R263Q impacts metabolism. Our data provide the first characterization of a novel mutation that has repeatedly evolved in subterranean environments, supporting the idea that shared environmental constraints can drive the evolution of similar phenotypes through similar genetic changes.

evolutionary biology↗

bioRxiv2024

Evolution of a central dopamine circuit underlies adaptation of light-evoked sensorimotor response in the blind cavefish, Astyanax mexicanus.

Adaptive behaviors emerge in novel environments through functional changes in neural circuits. While relationships between circuit function and behavior have been well studied, how evolution shapes those circuits and leads to behavioral adpation is poorly understood. The Mexican cavefish, Astyanax mexicanus, provides a unique genetically amendable model system, equipped with above ground eyed surface fish and multiple evolutionarily divergent populations of blind cavefish that have evolved in complete darkness. These differences in environment and vision provide an opprotunity to examine how a neural circuit is functionally influenced by the presence of light. Here, we examine differences in the detection, and behavioral response induced by non visual light reception. Both populations exhibit photokinetic behavior, with surface fish becoming hyperactive following sudden darkness and cavefish becoming hyperactive following sudden illumination. To define these photokinetic neural circuits, we integrated whole brain functional imaging with our Astyanax brain atlas for surface and cavefish responding to light changes. We identified the caudal posterior tuberculum as the central modulator for both light or dark stimulated photokinesis. To unconver how spatiotemporal neuronal activity differed between surface fish and cavefish, we used stable pan-neuronal GCaMP Astyanax transgenics to show that a subpopulation of darkness sensitve neurons in surface fish are now light senstive in cavefish. Further functional analysis revealed that this integrative switch is dependent on dopmane signaling, suggesting a key role for dopamine and a highly conserved dopamine circuit in modulating the evolution of a circuit driving an essential behavior. Together, these data shed light into how neural circuits evolved to adapte to novel settings, and reveal the power of Astyanax as a model to elucidate mechanistic ingiths underlying sensory adaptation. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/605141v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@145efeforg.highwire.dtl.DTLVardef@8b41e6org.highwire.dtl.DTLVardef@936979org.highwire.dtl.DTLVardef@1f18c5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗