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bioRxiv2026

Horizontally acquired mitochondrial alternative oxidase contributes to springtail bioenergetics and life belowground

Springtails are tiny hexapods that occupy habitats ranging from above the soil surface to hypoxia-prone belowground environments, yet the physiological mechanisms enabling this ecological expansion have remained unresolved. Here, I take an evolutionary bioenergetics approach to show that a mitochondrial alternative oxidase (AOX) acquired by horizontal gene transfer in the springtail ancestor became functionally integrated into animal physiology and was preferentially retained in lineages occupying low-oxygen habitats. Surveying 202 springtail genome assemblies, I identified 65 high-confidence AOX loci in 48 species, each embedded within otherwise typical springtail genomic neighborhoods. Phylogenetic and motif-based analyses support an oomycete donor and indicate ancestral acquisition followed by repeated loss, especially in aboveground taxa. High-resolution respirometry and hypoxia-exposure experiments further show that AOX is active only in AOX-positive species and is associated with hypoxia tolerance. These results identify horizontal gene transfer as a source of ecophysiological innovation in animals and suggest that acquired mitochondrial functions can help shape ecological sorting across environmental gradients, with implications for soil ecosystem processes. Significance StatementHorizontal gene transfer can introduce new genes into animal genomes, but few cases connect gene origin to physiology and ecology. Springtails are abundant soil mesofauna that help define ecological systems and nutrient flux yet physiological challenges that subterranean environments impose raise questions regarding the mechanisms of adaptation to life below ground. This study shows that springtails acquired mitochondrial alternative oxidase (AOX), a respiratory enzyme widely associated with stress tolerance in plants, fungi, protists, and some animals, from an oomycete donor early in their evolutionary history and that AOX has been retained in hypoxia-tolerant species and incorporated it into the physiology as a potential mechanism for tolerance of belowground conditions. These findings link macroevolutionary patterns to bioenergetic processes that help shape ecological distribution and tolerance of environmental stressors, with implications for biodiversity and ecosystem function.

evolutionary biology↗

bioRxiv2026

Autonomic challenge uncovers hidden link between diastolic blood pressure and mental imagery vividness

Mental imagery is viewed as a fundamental component of human cognition, supporting memory, emotional processing, future simulation, and conscious experience. Although mental imagery vividness has traditionally been attributed to differences in sensory processing, emerging evidence suggests that internally generated images are also shaped by ongoing bodily and interoceptive signals. Here, we investigated whether cardiovascular physiology contributes to individual differences in mental imagery vividness using a virtual reality paradigm in which participants encoded and reconstructed emotional and neutral scenes during a tilt-table-induced autonomic challenge. Acute autonomic changes induced by a tilt table did not alter imagery vividness. However, elevated diastolic blood pressure during the tilt-up condition predicted reduced mental imagery vividness, with the strongest effects observed for disgust and neutral imagery. Our findings provide direct evidence that the vividness of the "minds eye" is linked to cardiovascular physiology and support interoceptive accounts of consciousness in which mental imagery emerges from dynamic interactions between neural and bodily systems. More broadly, these results identify cardiovascular function as a potential physiological contributor to altered imagery experiences, including those observed in aphantasia and related clinical conditions. Significance statementVisual mental imagery has traditionally been explained as a top-down process driven by the brain. We investigated whether bottom-up physiological signals from the cardiovascular system also contribute to imagery vividness. An autonomic challenge revealed a hidden relationship between diastolic blood pressure and the vividness of emotional mental imagery, indicating that ongoing cardiovascular signals influence internally generated visual experiences. These findings identify bottom-up autonomic physiology as a previously unrecognized contributor to mental imagery and broaden current understanding of how top-down and bottom-up processes interact to shape conscious mental imagery experience.

neuroscience↗

bioRxiv2026

Dissociating the intensity and phase origins of sleepiness through a threshold-distance model of sleep-wake dynamics

Sleepiness is a leading proximate cause of drowsy-driving fatalities, medical errors and industrial accidents, yet it has resisted mechanistic prediction; although it arises from well-characterized sleep-wake physiology, it is experienced as a subjective state and has lacked a quantitative link to the underlying dynamics. We previously showed that subjective sleepiness maps linearly, with a protocol-invariant form, onto the signed distance H - H+ between the homeostatic pressure H and the circadian-modulated sleep-onset threshold H+. This single quantity predicts sleepiness accurately but is mechanistically ambiguous: the same value can arise either because H sits far from the boundary or because the threshold H+(t) has shifted with circadian phase, and these two origins call for entirely different interpretations and interventions. Here we resolve this ambiguity by decomposing H - H+ into two mechanistically separable axes-intensity and phase. The intensity axis is the time-averaged margin [<] H - H+[>], set by how far, on average, H sits from the sleep boundary: slowed homeostatic accumulation accounts for the paradoxically blunted sleepiness of older adults, and pharmacological suppression of H accounts for the dose-dependent alerting effect of caffeine. The phase axis is set by the circadian modulation of H+(t): under a forced-desynchrony protocol, in which the pacemaker free-runs and the homeostatic and circadian processes are experimentally decoupled, sleepiness tracks the circadian profile of H+(t) across all phases while the intensity mapping itself remains unchanged-a clean dissociation of the two axes. By resolving felt sleepiness into these two physiological degrees of freedom, this framework renders previously isolated phenomena-aging, caffeine and circadian misalignment-commensurable within a single theory and provides a physiologically interpretable basis for prospective fatigue-risk prediction. Author summaryWhy people feel sleepy after sleep loss, or at particular times of day, remains difficult to predict from physiology alone. Sleep and wake are shaped by two interacting processes: a daily circadian rhythm and a homeostatic pressure that builds during wakefulness. In earlier work, we linked subjective sleepiness ratings to a simple geometric quantity-how close sleep pressure sits to a circadian sleep-onset boundary. That link is useful, but ambiguous: the same distance can arise either because pressure itself has changed, or because the boundary has moved with circadian phase. Here we use a computational model of the sleep-wake switch, extended to include the wake-stabilizing orexin system, to separate these contributions into an intensity axis and a phase axis. We find that aging and caffeine mainly alter how large the average distance to the boundary becomes, whereas forced desynchrony mainly alters how that distance varies across circadian phase. This dissociation offers a compact way to interpret several otherwise separate observations within one quantitative picture, and a step toward more physiologically grounded fatigue-risk assessment.

neuroscience↗

bioRxiv2026

Detection of Stress in Naturalistic Settings Through Passive Mobile Sensing

Unobtrusive stress detection using wearable sensors could enable scalable, continuous mental-health monitoring. However, stress is an inherently subjective state that can only be inferred indirectly from physiological signals, making generalizable detection in naturalistic settings challenging. Although prior work has focused on improving model performance, it remains unclear whether wearable physiology supports a shared cross-individual mapping to subjective stress or whether this relationship is fundamentally person-specific. We evaluated feature-based and deep-learning models across multiple physiological modalities using ecological momentary assessment (EMA) as the reference standard, comparing within- and between-individual modeling approaches. Within-individual models achieved modest but consistent improvements in stress detection, whereas between-individual models consistently failed to generalize, yielding negative R2 values despite multimodal fusion and high-capacity architectures. Error analyses revealed regression to the mean, reduced sensitivity to high-stress states, and residual associations with general physiological activation, highlighting the limited stress specificity of wearable physiology. These findings suggest that wearable stress detection is fundamentally a personalized inference problem and that future systems should prioritize individual adaptation and contextual modeling over universal stress predictors.

neuroscience↗

bioRxiv2026

Hormonal Modulation of Subjective Sleep Quality and Perivascular Space Volume Across the Menstrual Cycle: An Observational Dense-Sampling Study

Background Hormonal fluctuations during the menstrual cycle (and their suppression) are accompanied by altered mood, cognition, and sleep, yet their relationship to subjective sleep quality and glymphatic function - a sleep-dependent brain waste-clearance pathway that involves perivascular spaces (PVS) - is unclear. Methods We examined daily oestradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), subjective sleep quality, and MRI-derived PVS volume (PVSV) in a single healthy woman across two 30-day periods: during her physiological menstrual cycle and, one year later, under oral contraceptive pill (OCP) use. We employed linear regression models to examine whether hormones are associated with sleep quality and PVSV, and whether they moderate the sleep quality-PVSV association during the physiological menstrual cycle. Subsequently, we conducted permutation-based Spearman rank correlations to assess whether day-to-day changes in sleep quality were associated with corresponding changes in PVSV across the physiological menstrual cycle and OCP use. False discovery rate (FDR) correction was used to control for multiple comparisons. Findings Higher LH levels were associated with poorer sleep quality during the physiological cycle (b=2.15, 95% CI 0.64 to 3.67, pFDR=0.028), while FSH moderated the sleep quality-PVSV association (b=-92.98, 95% CI -160.15 to -25.81, pFDR=0.034), suggesting that lower FSH was associated with lower PVSV, whereas this association reversed at elevated FSH levels characteristic of the periovulatory window. During the physiological menstrual cycle, day-to-day decreases in sleep quality were associated with synchronous increases in PVSV, driven by centrum semiovale PVSV ({rho}=0.55, 95% CI 0.30 to 0.67, pperm=0.0095). This association was absent during OCP use and differed between hormonal milieus ({Delta} {rho}=0.72, p=0.040). Interpretation Ovulation is characterized by poor sleep quality and reduced PVSV, potentially reflecting noradrenergic modulation. The association between sleep quality and PVSV day-to-day changes is shaped by the hormonal milieu, being absent under OCP. PVSV increase associated with poor sleep may reflect elevated sleep pressure promoting vasomotor-mediated cerebrospinal fluid inflow.

neuroscience↗

bioRxiv2020

Sponge Physioecology On Moorea, French Polynesia: Local Distribution And Filtration Efficiency Of Lamellodysidea Under Varying Temperatures

This physio-ecological study investigated the physiology and distribution of Lamellodysidea sp. in Moorea, French Polynesia. Specifically, its distribution was described across three reef types--fringing, mid-barrier, and barrier reefs--as well as across sites between Cooks Bay and Opunohu Bay. Additionally, filtration experiments were conducted to test how temperature impacts filtration efficiency. This is informative when predicting how future ocean temperatures are going to affect sponges success and distribution. Sponge abundance was found to decrease from the fringing reef out to the barrier reef, with the highest number of sponges in the fringing reef, less in the mid-barrier reef, and none found in the barrier reef. Sponges were also unevenly distributed across sites, with sponge abundance clearly increasing as you move away from Cooks Bay. Together, these data show that sponges demonstrate habitat preference that is related to their physiological tolerances. Filtration data showed that over a 3-hour period sponges increase their physiological output when introduced to environments 3-6 degrees Celsius above normal. This suggests that as ocean temperatures warm, sponges are likely to increase their filtration efficiency, thus increasing their ecological role as filter feeders, or struggle to survive at this new level of physiological function.

physiology↗

bioRxiv2020

The luteinizing hormone receptor knock-out mouse as a tool to probe the in vivo actions of gonadotropic hormones/receptors in females

Mouse models with altered gonadotropin functions have provided invaluable insight into the functions of these hormones/receptors. Here we describe the repurposing of the infertile and hypogonadal LHR knockout mouse model (LuRKO), to address outstanding questions in reproductive physiology. Using crossbreeding strategies and physiological and histological analyses, we first addressed the physiological relevance of forced LHR homomerization in female mice using BAC expression of two mutant LHR, that have previously shown to undergo functional complementation and rescue the hypogonadal phenotype of male LuRKO mice. In female LuRKO mice, co-expression of signal and binding deficient LHR mutants failed to rescue the hypogonadal and anovulatory phenotype. This was apparently due to the low-level expression of the two mutant LHR and potential lack of LH/LHR-dependent pleiotropic signaling that has previously been shown to be essential for ovulation. Next, we utilized a mouse model overexpressing human chorionic gonadotropin (hCG) with increased circulating LH/hCG-like bioactivity to ~40 fold higher than WT females, to determine if high circulating hCG could reveal putative LHR-independent actions. No effects were found, thus, suggesting that LH/hCG mediate their gonadal and non-gonadal effects solely via LHR. Finally, targeted expression of a constitutively active FSHR progressed antral follicles to pre-ovulatory follicles and displayed phenotypic markers of enhanced estrogenic activity but failed to induce ovulation in LuRKO mice. This study highlights the critical importance and precise control of LHR and FSHR for mediating ovarian functions and of the potential re-purposing existing genetically modified mouse models in answering outstanding physiological questions.

physiology↗

bioRxiv2020

Machine-learning model led design to experimentally test species thermal limits: the case of kissing bugs (Triatominae)

Species Distribution Modelling (SDM) determines habitat suitability of a species across geographic areas using macro-climatic variables; however, micro-habitats can buffer or exacerbate the influence of macro-climatic variables, requiring links between physiology and species persistence. Experimental approaches linking species physiology to micro-climate are complex, time consuming and expensive. E.g., what combination of exposure time and temperature is important for a species thermal tolerance is difficult to judge a priori. We tackled this problem using an active learning approach that utilized machine learning methods to guide thermal tolerance experimental design for three kissing-bug species (Hemiptera: Reduviidae: Triatominae), vectors of the parasite causing Chagas disease. As with other pathogen vectors, triatomines are well known to utilize micro-habitats and the associated shift in microclimate to enhance survival. Using a limited literature-collected dataset, our approach showed that temperature followed by exposure time were the strongest predictors of mortality; species played a minor role, and life stage was the least important. Further, we identified complex but biologically plausible nonlinear interactions between temperature and exposure time in shaping mortality, together setting the potential thermal limits of triatomines. The results from this data led to the design of new experiments with laboratory results that produced novel insights of the effects of temperature and exposure for the triatomines. These results, in turn, can be used to better model micro-climatic envelope for the species. Here we demonstrate the power of an active learning approach to explore experimental space to design laboratory studies testing species thermal limits. Our analytical pipeline can be easily adapted to other systems and we provide code to allow practitioners to perform similar analyses. Not only does our approach have the potential to save time and money: it can also increase our understanding of the links between species physiology and climate, a topic of increasing ecological importance. Author summarySpecies Distribution Modelling determines habitat suitability of a species across geographic areas using macro-climatic variables; however, micro-habitats can buffer or exacerbate the influence of macro-climatic variables, requiring links between physiology and species persistence. We tackled the problem of the combination of exposure time and temperature (a combination difficult to judge a priori) in determining species thermal tolerance, using an active learning approach that utilized machine learning methods to guide thermal tolerance experimental design for three kissing-bug species, vectors of the parasite causing Chagas disease. These bugs are found in micro-habitats with associated shifts in microclimate to enhance survival. Using a limited literature-collected dataset, we showed that temperature followed by exposure time were the strongest predictors of mortality, that species played a minor role, that life stage was the least important, and a complex nonlinear interaction between temperature and exposure time in shaping mortality of kissing bugs. These results led to the design of new laboratory experiments to assess the effects of temperature and exposure for the triatomines. These results can be used to better model micro-climatic envelope for species. Our active learning approach to explore experimental space to design laboratory studies can also be applied to other environmental conditions or species.

physiology↗

bioRxiv2021

Targeted Neuronal Activation of the Gastrointestinal Tract Shapes the Environment of the Gut in Mice

The gastrointestinal (GI) tract is extensively innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia, which together regulate gut physiology. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Herein, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites, as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic migrating motor complexes and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally-activated ENS neurons differentially regulate the gut microbiome and GI physiology in mice, without involvement of signals from the brain.

physiology↗

bioRxiv2022

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

ObjectiveThe metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. MethodsWe used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. ResultsADAM17adipoq-cre{Delta}/{Delta} mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues that acts to dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to dampen the expression of genes involved in thermogenesis, adipogenesis, lipid uptake, storage and catabolism. ConclusionOur findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that may act to limit uncontrolled energy depletion during thermogenesis.

physiology↗

bioRxiv2023

Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT)

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/525989v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1980dc7org.highwire.dtl.DTLVardef@1b0c22eorg.highwire.dtl.DTLVardef@19c9244org.highwire.dtl.DTLVardef@46e79b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO ELAM Binds Directly to ANT and ATP Synthase and ELAM Treatment Improves ADP Sensitivity, Increases ATP Production, and Improves Physiological Function in Old Muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (Adenine nucleotide translocator), H+ (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2 (flavin adenine dinucleotide), O2 (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein). C_FIG

physiology↗

bioRxiv2023

Pregnancy and postpartum dynamics revealed by an atlas of millions of lab tests

Pregnancy and delivery involve dynamic alterations in many physiological systems. However, the physiological dynamics during pregnancy and after delivery have not been systematically analyzed at high temporal resolution in a large human population. Here we present the dynamics of 76 lab tests based on a cross-sectional analysis of roughly 41 million measurements from over 300,000 pregnancies. We analyzed each test at weekly intervals from 20 weeks preconception to 80 weeks postpartum, providing detailed temporal profiles. About half of the tests take three months to a year to return to baseline during postpartum, highlighting the physiological load of childbirth. The precision of the data revealed effects of preconception supplements, overshoots after delivery and intricate temporal responses to changes in blood volume and renal filtration rate. Pregnancy complications - gestational diabetes, pre-eclampsia and postpartum hemorrhage - showed distinct dynamical changes. These results provide a comprehensive dynamic portrait of the systems physiology of pregnancy.

physiology↗

bioRxiv2024

Bisphenol A induces sex-dependent alterations in the dynamics of neuroendocrine seasonal adaptation in Djungarian hamsters

In nature, species synchronize reproduction and energy metabolism with seasons to optimize survival and growth. While the effects of endocrine-disrupting chemicals (EDCs) exposure on conventional laboratory rodents are increasingly studied, their impacts on mammalian seasonal adaptation remain unexplored. This study investigates the effect of oral exposure to bisphenol A (BPA) on physiological and neuroendocrine seasonal adaptation in Djungarian hamsters. Adult female and male hamsters were orally exposed to BPA (5, 50, or 500 {micro}g/kg/d) or vehicle during a 10-week transition from a long (LP) to short (SP) photoperiod (winter transition) or vice versa (summer transition). Changes in body weight, food intake, and pelage color were monitored weekly and, at the end of the exposure, gene expression of hypothalamic markers of photoperiodic, reproductive and metabolic integration, reproductive organ activity, and glycemia were assessed. Our results revealed sex-specific effects of BPA on acquiring SP and LP phenotypes. During LP to SP transition, females exposed to 500 {micro}g/kg/d BPA exhibited delayed body weight loss and reduced feed efficiency associated with a lower expression of somatostatin in the arcuate nucleus (ARC), while males exposed to 5 {micro}g/kg/d BPA showed an accelerated acquisition of SP-induced metabolic parameters. During SP to LP transition, females exposed to 5 {micro}g/kg/d BPA displayed a faster LP adaptation in reproductive and metabolic parameters, along with quicker ARC kisspeptin downregulation and delayed ARC Pomc upregulation, while males exposed to BPA exhibited decreased expression of central photoperiodic integrators without changes in the physiological LP acquisition. This pioneering study investigating EDC impacts on mammalian seasonal physiology shows that BPA alters the dynamic of metabolic adaptation to both SP and LP transitions with marked sex dimorphism, causing temporal discordance in seasonal adaptation between males and females. These findings emphasize the importance of investigating EDCs impact on non-conventional animal models, providing insights into wildlife physiology. HighlightsO_LIDjungarian hamsters seasonal adaptation is disrupted by BPA oral exposure C_LIO_LIBPA delays in females and accelerates in males the metabolic adaptation to short days C_LIO_LIBPA accelerates in females, not in males, metabolic/reproductive adaptation to long days C_LIO_LIBPA affects the photoperiodic expression of central reproductive and metabolic genes C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/580037v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@3ddec8org.highwire.dtl.DTLVardef@1ed3536org.highwire.dtl.DTLVardef@4083c8org.highwire.dtl.DTLVardef@18bd837_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

physiology↗

bioRxiv2024

Sex-Specific Cardiac Remodeling in Aged Rats after Early-Life Chronic Stress: Associations with Endocrine and Metabolic Factors

BackgroundCardiovascular disease is a leading cause of death worldwide. Rates of cardiovascular disease vary both across the lifespan and between sexes. While multiple factors, including adverse life experiences, impact the development and progression of cardiovascular disease, the potential interactions of biological sex and stress history on the aged heart are unknown. To this end, we examined sex- and stress-specific impacts on left ventricular hypertrophy (VH) after aging. We hypothesized that early life chronic stress exposure impacts behavioral and physiologic responses that predict cardiac remodeling in a sex-specific manner. MethodsHistological analysis was conducted on hearts of male and female rats previously exposed to chronic variable stress during the late adolescent period (postnatal days 43-62). These animals were challenged with a forced swim test and a glucose tolerance test before aging to 15 months and again being challenged. Predictive analyses were then used to isolate factors that relate to cardiac remodeling among these groups. ResultsEarly-life chronic stress impacted cardiac remodeling in a sex-specific manner. Among rats with a history of chronic stress, females had increased inward VH. However, there were few associations within the female groups among individual behavioral and physiologic parameters and cardiac remodeling. While males as a group did not have VH after chronic stress, they exhibited multiple individual associations with cardiac susceptibility. Passive coping in young males and active coping in aged males related to VH in a stress history-dependent manner. Moreover, baseline corticosterone positively correlated with VH in unstressed males, while chronically-stressed males had positive correlations between VH and visceral adiposity. ConclusionsThese results indicate that females as a group are uniquely susceptible to the effects of early-life stress on cardiac remodeling later in life. Conversely, males have more individual differences in vulnerability, where susceptibility to cardiac remodeling relates to endocrine, metabolic, and behavioral measures depending on stress history. These results ultimately support a framework for accessing cardiovascular risk based on biological sex and prior adverse experiences. HighlightsO_LIAged female rats had greater left ventricular hypertrophy (VH) than males after early-life chronic variable stress. C_LIO_LITertile divisions based on susceptibility or resilience to inward VH indicated interactions between VH, sex, and stress on multiple behavioral and physiological measures. C_LIO_LIIn males, VH correlated with endocrine and metabolic parameters in a stress history-dependent manner. C_LIO_LIPrior adverse experience and biological sex interact across the lifespan to impact cardiovascular risk. C_LI Plain English SummaryCardiovascular disease is the leading cause of death worldwide. Multiple factors influence the incidence and severity of cardiovascular disease including adverse life experiences, biological sex, and age. Alterations of heart structure predict negative cardiovascular health by impacting blood circulation; however, the potential interactions of stress history and biological sex on the aged heart are unknown. In this study, we examined how chronic stress exposure impacts heart structure in male and female rats after aging. Adolescent male and female rats were chronically stressed and then acutely challenged to examine behavioral, endocrine, and metabolic parameters both immediately following chronic stress and after aging. Heart morphology was quantified to examine how behavioral and physiological responses related to cardiac remodeling. Our results indicate that, as a group, female rats previously exposed to chronic stress were uniquely susceptible to inward remodeling of the heart. Subjects were further divided into sub-groups based on the level of inward remodeling of the ventricle. While male rats did not exhibit group effects on heart structure, individual variability in male heart morphology related to endocrine and metabolic parameters in a stress history-dependent manner. Here, there were interactions with multiple systems including coping behavior, stress hormones, and body composition. Moreover, males without a prior history of chronic stress had correlations between stress hormones and the degree of heart remodeling. However, males that were exposed to chronic stress had correlations between heart structure and abdominal fat. Overall, our results indicate that biological sex and stress history interact to predict cardiovascular susceptibility.

physiology↗

bioRxiv2024

Cardiac acetylcholinesterase and butyrylcholinesterase have distinct localization and function

Cholinesterase (ChE) inhibitors are under consideration to be used in the treatment of cardiovascular pathologies. A prerequisite to advancing ChE inhibitors into the clinic is their thorough characterization in the heart. The aim here was to provide a detailed analysis of cardiac ChE to understand their molecular composition, localization, and physiological functions. A battery of biochemical, microscopic, and physiological experiments was used to analyze two known ChE, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hearts of mutant mice lacking different ChE molecular forms. Overall, AChE activity was exceeded by BChE, while it was localized mainly in the atria and the ventricular epicardium of the heart base. AChE was anchored by ColQ in the basal lamina or by PRiMA at the plasma membrane and co-localized with the neuronal marker TUJ1. In absence of anchored AChE, heart rate was unresponsive to a ChE inhibitor. BChE, the major ChE in heart, was detected predominantly in ventricles, presumably as a precursor (soluble monomers/dimers). Mice lacking BChE were more sensitive to a ChE inhibitor. Nevertheless, the overall impact on heart physiology was subtle, showing mainly a role in cholinergic antagonism to the positive inotropic effect of {beta}-adrenergic stimulation. Our results help to unravel the mechanisms of ChE in cardiovascular pathologies and provide a foundation to facilitate the design of a novel, more effective pharmacotherapies, which may reduce morbidity and mortality of patients with various heart diseases. Abstract figure legend O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/596481v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@136068corg.highwire.dtl.DTLVardef@1e8118corg.highwire.dtl.DTLVardef@d83298org.highwire.dtl.DTLVardef@1e1cde7_HPS_FORMAT_FIGEXP M_FIG C_FIG Acetylcholinesterase (AChE) has the highest activity in the atria. It is present in the heart in molecular forms anchored by a proline-rich membrane anchor (PRiMA) and by collagen Q (ColQ) and hydrolyzes acetylcholine of neuronal origin (neuronal ACh). Butyrylcholinesterase (BChE) is predominant in the ventricles. It is secreted in the form of a soluble tetramer and hydrolyzes acetylcholine originating from cardiomyocytes (non-neuronal ACh). Key pointsO_LIInhibition of cholinesterases has therapeutic potential in cardiovascular pathologies C_LIO_LIBoth known cholinesterases are present in heart C_LIO_LIEach cholinesterase has distinct localization patterns in the heart and functions in cardiac physiology C_LIO_LISelective inhibition of acetylcholinesterase or butyrylcholinesterase may be used to alter specific cardiac functions C_LIO_LIButyrylcholinesterase polymorphism may have an impact on the outcome of the cholinesterase inhibitor treatment C_LI

physiology↗

bioRxiv2025

Effects of Arginine Vasopressin on Islet Cells in Pancreatic Tissue Slices: Glucose-Dependent Modulation of IP3 Receptor-Specific Responses

Arginine vasopressin (AVP) is well known for regulating fluid volume, osmotic balance, and vascular tone. Its role in the regulation of pancreatic and {beta} cell function has been reported, yet its effects are not fully understood, particularly regarding its interaction with plasma glucose levels. The osmotic and volume challenges posed by hyper- and hypoglycaemia in diabetes can be a significant complication of effective hormonal regulation of metabolism. In this study, we primarily investigated the effects of AVP and synthetic peptide receptor agonists and antagonists on and {beta} cells in pancreatic tissue slices using live confocal Ca2+ imaging. Our findings demonstrate that AVP exerts glucose-dependent effects on both cell types. At low glucose concentrations, AVP, in combination with physiologically or pharmacologically increased cAMP levels, selectively activated cells without significantly affecting {beta} cells. In contrast, at higher glucose concentrations and pharmacologically elevated cAMP levels, physiological levels of AVP enhanced {beta} cell activity, leading to increased Ca2+ oscillations and insulin release. In both cell types, AVP displayed a bell-shaped concentration dependence, with lower AVP concentrations stimulating hormone release and higher concentrations leading to diminished responses, consistent with inositol trisphosphate receptor (IP3R) activation and inactivation properties. Furthermore, our results indicate that AVP acts primarily through V1b receptors in {beta} cells, with no involvement of V1a, V2 or oxytocin receptors. These findings provide new insights into the modulation of glucose-dependent release of pancreatic hormones by AVP in the context of changed blood osmolality due to hyper- or hypoglycemia in diabetes. Importantly, our results emphasize the potential of targeting AVP signaling pathways as a therapeutic approach in diabetes research, aiming to improve hormone regulation and nutrient homeostasis. HighlightsO_LIHighly spatio-temporally resolved imaging of islet Ca2+ oscillations on pancreatic tissue slices provides an in situ-like model for physiological and pharmacological approaches. C_LIO_LIPhysiological glucose stimulation triggers non-linear {beta} cell collective responses that must be taken into account when interpreting single concentration pharmacological experiments. C_LIO_LIIn a high cAMP context, AVP acts through V1b receptors on islet and {beta} cells, exhibiting a bell-shaped dependence driven by the activation-inactivation properties of IP receptors. C_LIO_LIAVP modulates glucose-dependent effects on and {beta} cells in a physiological concentration range, in the presence of altered blood osmolality or volume due to hyperglycemia, or to the direct effects of hypoglycemia in diabetes. C_LI

physiology↗

bioRxiv2025

Brain-blood biomarkers take a walk on the wild side: glial responses to environmental conditions and individual traits in wild frogs

Proteins from brain cells, including Glial fibrillary acidic protein (GFAP), has been tested for diagnostic and prognostic of neurological dysfunctions. Release of GFAP into the blood-stream, may be a consequence of its up-regulation in reactive astrocytes. However, astrocytic-GFAP expression is also increased during brain remodeling after physiological perturbations such as osmotic challenge. The presence and quantification of GFAP in blood circulation have never been investigated in the context of brain responses to environmental variations in wildlife. In a wild amphibian (green frogs, Pelophylax sp.), captured in several ponds with different salinity, GFAP was detected in plasma. Males from more saline ponds exhibited higher plasmatic GFAP levels, independent to their blood osmolality, suggesting that plasmatic GFAP-level reflects cerebral response to osmotic challenge. Plasmatic-GFAP correlated with immune markers (hemoglobin binding proteins, lymphocytes, neutrophils and monocytes), size and body condition, reinforcing its role as a physiological biomarker. We also highlighted that captivity had a significant effect on plasmatic-GFAP levels with sex-specific dynamics, masking the response to a short-term experimental salinity exposure. For the very first time, we show that plasmatic-GFAP levels could be a biomarker of brain plasticity to environmental conditions, physiological traits, and stress responses in wildlife. Significant StatementWe investigated the use of brain Glial fibrillary acidic protein (GFAP), a cytoskeletal protein of astrocytes, that has been associated with brain disorders in clinical studies, as a biomarker of environmental conditions and individual traits in wildlife. In a wild amphibian, plasmatic GFAP-levels were correlated with the salinity of ponds, immune markers and size for males. GFAP-levels were correlated with body condition for both sexes. Interestingly, captivity induced transient increase of plasmatic-GFAP levels, probably due to stress. In our study, we demonstrate that plasmatic-GFAP levels may represent an excellent brain biomarker of its plasticity to environmental conditions, physiological traits, and stress responses in wildlife.

physiology↗

bioRxiv2025

Sex-biased expression of enteroendocrine cell-derived hormones contributes to higher fat storage in Drosophila females

Enteroendocrine (EE) cells in the Drosophila gut produce and release multiple factors, including Allatostatin A (AstA), Allatostatin C (AstC), neuropeptide F (NPF), tachykinin (Tk), Diuretic hormone 31 (Dh31), Bursicon, CCHamide 1, CCHamide 2, and short neuropeptide-F. Collectively, these peptides ensure that physiology (e.g., fat storage, fluid balance) and behavior (e.g., feeding, sleep) are coordinated with environmental factors such as nutrient quantity and quality. Despite notable sex differences in physiology and behavior, it remains unclear whether the regulation and function of these EE cell-derived factors are shared between males and females. Given that recent data identified sex-biased physiological effects of two EE cell-derived hormones on Drosophila food intake and energy mobilization, we performed a detailed characterization of these hormones in male and female flies. Despite an overall male bias in mRNA levels of AstA, AstC, Tk, NPF, Dh31 in whole-body and head samples, we observed a strong female bias in mRNA levels of AstC, Tk, and NPF in the gut. To determine whether this sex-biased regulation was physiologically significant, we monitored triglyceride levels in flies with gut-specific knock-down of EE cell-derived hormones. In 5-day-old flies, knock-down of EE cell-derived AstC significantly reduced fat storage in females with no effect in males, whereas knock-down of EE cell-derived Tk produced a non-significant trend toward reduced fat storage in females. These female-specific effects on fat storage were reproduced in flies with neuron-specific knock-down of the AstC (AstC-R2) and Tk receptors (TkR99D). Together, these data uncover strongly sex-biased regulation of EE cell-derived hormones, and show that gut-specific knock-down of at least one of these hormones had a female-specific effect on body fat. HighlightsO_LIEnteroendocrine cell-expressed hormones show strongly sex-biased expression C_LIO_LIKnock-down of enteroendocrine cell-derived AstC reduced body fat only in females C_LIO_LINeuronal knock-down of AstC or Tk receptors reduced stored fat only in females C_LI

physiology↗