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bioRxiv2024

Individual variability in the relationship between physiological and resting-state fMRI metrics

Cerebrovascular Reactivity (CVR), the brains vascular response to a vasodilatory stimulus, can be measured using fMRI during breathing challenges that modulate arterial CO2 levels. CVR is an important indicator of cerebrovascular health, although its estimation can be challenging due to the extra experimental setup and/or the subject compliance required. To overcome these limitations, summary metrics based on resting state fluctuations (RSF), such as the (fractional) amplitude of low frequency fluctuations (f/ALFF) and the resting state fluctuation amplitude (RSFA), have been proposed as alternative estimates of CVR, as they are frequently associated with vascular and physiological factors. Previous studies have reported a significant relationship between CVR estimates obtained by means of respiratory paradigms and RSF metrics. However, the total sample sizes, considering both subjects and sessions, are typically small, and not all studies agree on the degree of the relationship. Furthermore, to our knowledge, these studies have only reported cross-sectional analyses, whereas intra-subject longitudinal relationships between CVR estimates and RSF metrics are unknown. Leveraging a unique dense sampling dataset in which resting state and breath-hold multi-echo fMRI were collected in 7 subjects with 10 sessions each, we provide evidence of high individual variability in the inter-session (i.e. intra-subject) relationship between RSF metrics and CVR. These results indicate that RSF metrics might not be a suitable proxy of CVR in clinical settings or for BOLD signal calibration as they may not properly account for intra-individual physiological variations in BOLD fMRI data.

neuroscience↗

bioRxiv2024

Chronic ethanol exposure produces long-lasting, subregion-specific physiological adaptations in RMTg-projecting mPFC neurons

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) which facilitate the maladaptive behaviors interfering with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is a GABAergic midbrain region involved in aversive signaling and is functionally altered by chronic ethanol exposure. Our recent work identified a dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE significantly increased intrinsic excitability as well as excitatory and inhibitory synaptic drive in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE also increased excitatory synaptic drive in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol.

neuroscience↗

bioRxiv2024

Physiological Evaluation of Far Infrared-Emitting Garments on Sleep and Thermoregulation

Garments engineered to emit far-infrared (FIR) spectral frequencies have potential conditioning benefits. This study aimed to explore the physiological effects of FIR-emitting clothes on sleep propensities involving thermoregulation and autonomic nervous function. In this double-blind, randomized, placebo-controlled, crossover study, fifteen healthy male participants (age 21.6 {+/-} 1.5 years, body mass index 23.1 {+/-} 1.9, Pittsburgh Sleep Quality Index 5.0 {+/-} 2.0) wore a whole-body FIR garment (wavelength: 5-20 m at 40{degrees}C), while a total body garment with the 100% polyester fiber without ceramic components was used as control for the intervention. To compare the physiological variables between the two electroencephalograms, the tympanic membrane temperature, sweating rate, skin temperature, and humidity were measured during sleep. Heart rate variability during sleep was also calculated. The percentage of rapid eye movement (REM) sleep was significantly higher in the FIR compared than in control (p = 0.027). We found a significant main effect of tympanic membrane temperature in time, equivalent to core body temperature. (2-way ANOVA; (F(26, 234)=4.046, p<0.001). Furthermore, the sweating rate was significantly lower when sleeping with FIR predominantly in the final phase of sleep (garment x time interaction (F(26,572)=55.05, p<0.001). Although there were no significant differences in skin surface temperature between the two garments, FIR provided significantly lower skin humidity during the middle of night sleep compared with the control. Regarding LF, a significant garment type x time interaction (F(1.87, 48.57)=3.36, p=0.046). Post-hoc analysis revealed that the LF value of FIR was higher in the final phase of sleep than that of control (p=0.027). Then present results suggest that sleeping with FIR in comparison to with control, has a beneficial effect to facilitate restorative sleep, presumably involving proper thermoregulation.

neuroscience↗

bioRxiv2024

Predicting the physiological effects of multiple drugs using electronic health record

Various computational models have been developed to understand the physiological effects of drug-drug interactions, which can contribute to more effective drug treatments. However, they mostly focus on interactions of only two drugs, and do not consider the patient information. To address this challenge, we use publicly available electronic health record (EHR), MIMIC-IV, to develop machine learning models that predict the physiological effects of two or more drugs. This study involves extensive preprocessing of laboratory measurement data, prescription data and patient data. The resulting machine learning models predict potential abnormalities across 20 selected measurement items (e.g., concentrations of metabolites and blood cells) in the form of a sentence. The models showed an average AUROC of 0.75, and age, specific active pharmaceutical ingredients, and gender appeared to be the most influential features. The model development process showcased in this study can be extended to other measurement items for a target EHR.

systems biology↗

bioRxiv2024

A reaction norm for flowering time plasticity reveals physiological footprints of maize adaptation

Understanding how plant phenotypes are shaped by their environments is crucial for addressing questions about crop adaptation to new environments. This study focused on analyzing the genetic variability underlying genotype-by-environment interactions and adaptation for flowering time in maize. We present a physiological reaction norm for flowering time plasticity (PRN-FTP), modeled from multi-environment trial networks and decomposed into its physiological components. We show how genotype-specific differences in developmental responses to temperature fluctuations condition differences in photoperiod perceived among genotypes. This occurs not only across but also within common environments, as the perception of photoperiod is altered by variation in rates of development and durations for becoming sensitized to photoperiod. Using a new metric for envirotyping sensed photoperiods for maize, it was found that, at high latitudes, different genotypes in the same environment can experience up to hours-long differences in photoperiod. This emphasizes the importance of considering genotype-specific differences in the experienced environment when investigating plasticity. Modeling the PRN-FTP for globally representative breeding material showed that tropical and temperate germplasm occupy distinct territories of the trait space for PRN-FTP parameters. Placed in the historical context of maize, our findings suggest that the geographical spread and breeding of maize was mediated by a specific modality of ecophysiological adaptation of flowering time. Our study has implications for understanding crop adaptation and for future crop improvement efforts. Article SummaryMaize adjusts its flowering time across environments using genetic pathways tuned to cues like temperature and day length. This study models how different varieties perceive and respond to these factors, revealing that genotypes can perceive the same environment in distinct ways. By disentangling the ecophysiological basis of genotype-environment interactions, the research explores maize diversity and highlights how adaptation and breeding have shaped distinct strategies for flowering time regulation in tropical and temperate varieties.

plant biology↗

bioRxiv2024

7 Tesla MRS estimates of GABA concentration relate to physiological measures of tonic inhibition in the human motor cortex

GABAergic neurotransmission within the cortex plays a key role in learning and is altered in several brain diseases. Quantification of bulk GABA in the human brain is typically obtained by Magnetic Resonance Spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. A recent mathematical simulation contends that MRS detects extrasynaptic GABA, mediating tonic inhibition. Nevertheless, no empirical data have yet confirmed this hypothesis. Here we collected ultra-high field 7 Tesla MRS and Transcranial Magnetic Stimulation coupled with high-density Electroencephalography (TMS-hdEEG) from the motor cortex of twenty healthy participants (age 23.95{+/-}6.4), while they were at rest. We first applied a Neural Mass Model to TMS-evoked potentials to disentangle the contribution of different GABAergic pools. We then assessed to which of these different pools MRS-GABA was related to by means of Parametric Empirical Bayesian (PEB) analysis. We found that MRS-GABA was mostly positively related to the NMM-derived measures of tonic inhibition and overall functionality of the GABAergic synapse. This relationship was reliable enough to predict MRS-GABA from NMM-GABA. These findings clarify the mesoscopic underpinnings of GABA levels measured by MRS and will contribute to the concretization of MRS-GABA promises to improve our understanding of human behaviour, brain physiology and pathophysiology. Key pointsO_LIGABA neurotransmission is essential for synaptic plasticity and learning (especially motor learning) and is altered in several brain disorders, such as epilepsy and stroke. C_LIO_LIQuantification of GABA in the human brain is typically obtained by Magnetic Resonance Spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. C_LIO_LIBy using a biophysical Neural Mass Model, here we show that MRS-GABA relates to physiological measures of tonic inhibition in the human cortex. C_LI

neuroscience↗

bioRxiv2024

Physiological oxygen concentration during sympathetic primary neuron culture improves neuronal health and reduces HSV-1 reactivation

Herpes simplex virus-1 (HSV-1) establishes a latent infection in peripheral neurons and periodically reactivates in response to a stimulus to permit transmission. In vitro models using primary neurons are invaluable to studying latent infection because they use bona fide neurons that have undergone differentiation and maturation in vivo. However, culture conditions in vitro should remain as close to those in vivo as possible. This is especially important when considering minimizing cell stress, as it is a well-known trigger of HSV reactivation. We recently developed an HSV-1 model system that requires neurons to be cultured for extended lengths of time. Therefore, we sought to refine culture conditions to optimize neuronal health and minimize secondary effects on latency and reactivation. Here, we demonstrate that culturing primary neurons under conditions closer to physiological oxygen concentrations (5% oxygen) results in cultures with features consistent with reduced stress. Furthermore, culture in these lower oxygen conditions diminishes the progression to full HSV-1 reactivation despite minimal impacts on latency establishment and earlier stages of HSV-1 reactivation. We anticipate that our findings will be useful for the broader microbiology community as they highlight the importance of considering physiological oxygen concentration in studying host-pathogen interactions.

microbiology↗

bioRxiv2024

Headwinds to Understanding Stress Response Physiology: A Systematic Review Reveals Mismatch between Real and Simulated Marine Heatwaves

Laboratory experiments have long been used to guide predictions of organismal stress in response to our rapidly changing climate. However, the ability to simulate real world conditions in the laboratory can be a major barrier to prediction accuracy, creating obstacles to efforts informing ecosystem conservation and management. Capitalizing on an extensive experimental literature of coral bleaching physiology, we performed a systematic review of the literature and assembled a database to identify the methods being used to measure coral bleaching in heating experiments and assess how closely heating experiments resembled marine heatwaves (MHWs) on coral reefs. Observations of the maximum photochemical yield of Photosystem II (FV/FM), though not a direct measure of bleaching, vastly outnumbered Symbiodiniaceae density and chlorophyll (g cm-2, pg cell-1) observations in the available literature, indicating the widespread misuse of FV/FM as a proxy for coral bleaching. Laboratory studies in our database used significantly higher maximum temperatures, degree heating times ([~] 1.7 x) and heating rates ([~] 7.3 x), and significantly shorter durations ([~] 1.5 x), than MHWs on coral reefs. We then asked whether exposure differences between lab and reef altered the relationship between coral bleaching and heating metrics using the example of hormesis, the biphasic dose response wherein low to moderate doses elicit some benefit, while high doses are deleterious. We fit curves on the data both with and without ecologically relevant heating metrics and found hormetic curves in some response variables were altered with the exclusion of exposures that fell outside of the bounds of MHWs on coral reefs. Differences between lab exposures and real-world MHWs were large enough to alter the relationships, indicating a high likelihood of prediction error. We recommend laboratory-based studies of coral bleaching use ecologically relevant exposures to improve our predictions of the coral physiological response to our rapidly warming oceans.

ecology↗

bioRxiv2024

Predicting in vivo concentrations of dietary hop phytoestrogens by physiologically based kinetic modeling

Hop extracts containing prenylated polyphenols such as 8-prenylnaringenin (8-PN) and its precursor isoxanthohumol (iXN) are popular among women seeking natural alternatives to hormone therapy for postmenopausal symptoms. Due to structural similarities with estrogens, these compounds act as estrogen receptor agonists. Especially 8-PN, described as the most potent phytoestrogen known to date, poses a potential risk for endocrine disruption. Therefore, its use as a hormone replacement raises concerns for human health. However, a significant challenge in assessing the potential endocrine-disruptive effects of hop polyphenols is the lack of data on their toxicokinetics. Particularly, information on in vivo concentrations in target tissues is lacking. To address this gap, we developed a physiologically based kinetic (PBK) model tailored to female physiology. The model was used to predict the levels of hop polyphenols in human blood and target tissues under realistic exposure scenarios. The predictions suggest that iXN and 8-PN concentrations in target tissues reach the low nanomolar range after dietary supplementation. This study enhances our understanding of the safety profile of hop polyphenols and highlights the need for further research into their use as an alternative to hormone therapy in menopausal women.

pharmacology and toxicology↗

bioRxiv2024

Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system

Huntingtons Disease (HD) is a neurodegenerative disorder, part of the nine identified inherited polyglutamine (polyQ) diseases. Most commonly, HD pathophysiology manifests in middle-aged adults with symptoms including progressive loss of motor control, cognitive decline, and psychiatric disturbances. Associated with the pathophysiology of HD is the formation of insoluble fragments of the huntingtin protein (htt) that tend to aggregate in the nucleus and cytoplasm of neurons. To track both the intracellular progression of the aggregation phenotype as well as the physiological deficits associated with mutant htt, two constructs of human HTT were expressed with varying polyQ lengths, non-pathogenic-htt (Q15, NP-htt) and pathogenic-htt (Q138, P-htt), with an N-terminal RFP tag for in vivo visualization. P-htt aggregates accumulate in the ventral nerve cord cell bodies as early as 24 hours post hatching and significant aggregates form in the segmental nerve branches at 48 hours post hatching. Organelle trafficking up-and downstream of aggregates formed in motor neurons showed severe deficits in trafficking dynamics. To explore putative downstream deficits of htt aggregation, ultrastructural changes of presynaptic motor neurons and muscles were assessed, but no significant effects were observed. However, the force and kinetics of muscle contractions were severely affected in P-htt animals, reminiscent of human chorea. Reduced muscle force production translated to altered locomotory behavior. A novel HD aggregation model was established to track htt aggregation throughout adulthood in the wing, showing similar aggregation patterns with larvae. Expressing P-htt in the adult nervous system resulted in significantly reduced lifespan, which could be partially rescued by feeding flies the mTOR inhibitor rapamycin. These findings advance our understanding of htt aggregate progression as well the downstream physiological impacts on the nervous system and peripheral tissues.

neuroscience↗

bioRxiv2024

Quantitative physiology and biomass composition of Cyberlindnera jadinii in ethanol-grown cultures

BackgroundElimination of greenhouse gas emissions in industrial biotechnology requires replacement of carbohydrates by alternative carbon substrates, produced from CO2 and waste streams. Ethanol is already industrially produced from agricultural residues and waste gas and is miscible with water, self-sterilising and energy-dense. The yeast C. jadinii can grow on ethanol and has a history in the production of single-cell protein (SCP) for feed and food applications. To address a knowledge gap in quantitative physiology of C. jadinii during growth on ethanol, this study investigates growth kinetics, growth energetics, nutritional requirements, and biomass composition of C. jadinii strains in batch, chemostat and fed-batch cultures. ResultsIn aerobic, ethanol-limited chemostat cultures, C. jadinii CBS 621 exhibited a maximum biomass yield on ethanol (Yx/smax) of 0.83 gbiomass (gethanol)-1 and an estimated maintenance requirement for ATP (mATP) of 2.7 mmol{middle dot}(gbiomass)-1{middle dot}h-1. Even at specific growth rates below 0.05 h-1, a stable protein content of approximately 0.54 gprotein{middle dot}(gbiomass)-1 was observed. At low specific growth rates, up to 17% of the proteome consisted of alcohol dehydrogenase proteins, followed by aldehyde dehydrogenases and acetyl-CoA synthetase. Of 13 C. jadinii strains evaluated, 11 displayed fast growth on ethanol (max > 0.4 h-1) in mineral medium without vitamins, and CBS 621 was found to be a thiamine auxotroph. The prototrophic strain C. jadinii CBS 5947 was grown on an inorganic salts medium in fed-batch cultures (10-L scale) fed with pure ethanol. Biomass concentrations in these cultures increased up to 100 gbiomass{middle dot}(kgbroth)-1, with a biomass yield of 0.65 gbiomass{middle dot}(gethanol)-1. Model-based simulation, based on quantitative parameters determined in chemostat cultures, adequately predicted biomass production. A different protein content of chemostat- and fed-batch-grown biomass (54% and 42%, respectively) may reflect the more dynamic conditions in fed-batch cultures. ConclusionsAnalysis of ethanol-grown batch, chemostat and fed-batch cultures provided a quantitative physiology baseline for fundamental and applied research on C. jadinii. Its high maximum growth rate, high energetic efficiency of ethanol dissimilation, simple nutritional requirements and high protein content, make C. jadinii a highly interesting platform for production of SCP and other products from ethanol.

microbiology↗

bioRxiv2024

Engineering the auxin-inducible degron system for tunable in vivo control of organismal physiology

The physiological mechanisms governing health and disease exhibit complex interactions between multiple genes and gene products. To study the dynamics of living systems, researchers need experimental methods capable of producing calibrated, quantitative perturbations in vivo -- perturbations that cannot be obtained using classical genetics, RNAi interference, or small molecule drugs. Recently, an auxin-inducible degron (AID) system has been developed to allow targeted degradation of proteins using small-molecule activators, providing spatiotemporal control of protein abundance. However, a better understanding of the biochemical activities of AID system components in their physiological context is needed to design quantitative interventions. Here, we apply engineering approaches to characterize and understand the performance of several AID technologies and then improve this performance in the multicellular animal Caenorhabditis elegans. We 1) develop new technologies that allow for a careful calibration of AID activity for specific purposes; 2) develop new TIR1 enzyme constructs with improved performance over existing constructs; 3) develop an approach to simultaneously and independently degrade target proteins in distinct tissues; and finally, 4) develop an approach for pan-organismal protein degradation by re-engineering the TIR1 enzyme. Taken together, these advances enable new quantitative experimental approaches to study the cellular and systems dynamics of animals.

systems biology↗

bioRxiv2024

A high-resolution microscopy system for biological studies of cold-adapted species under physiological conditions

The fundamental processes governing life are sensitively dependent on temperature. Whilst much is known about the constraints on how proteins operate at 37{degrees}C, little knowledge exists about how biological function is maintained sub-zero temperature conditions, where proteins are less stable and oxidative damage is high. However, almost 90% of habitable environments on Earth are permanently below 5{degrees}C (i.e. the deep sea and polar regions). This means that we do not understand how a large and diverse proportion of the global biome functions. To address this question at the cellular level, tools are required for imaging biological systems at high resolution under physiological conditions. This poses severe technical challenges that cannot be addressed with traditional optical microscopy techniques. High-resolution imaging objectives require short working distances and the use of immersion media, which lead to rapid heat transfer from the microscope to the sample. This affects the viability of live specimens and the interpretability of the results when the sample function optimally at low temperatures. Condensation and temperature-induced shrinking of components pose further challenges, reducing image resolution and contrast. Here, we address these issues and provide a method for high-fidelity imaging of live biological samples at temperatures of around, or below, 0{degrees}C. Our method is compatible with different microscopy modalities, including super-resolution imaging. It relies on hardware additions to traditional microscopy systems that can be straightforwardly implemented, namely, a cooling collar, 10% ethanol as an immersion medium, and nitrogen flow to mitigate condensation. We demonstrate the method in live cell cultures derived from Antarctic fish species and highlight the need to maintain physiological conditions for these fragile biological samples. Future applications are diverse and include evolutionary biology and the study of cold-adapted organisms, as well as cellular biophysics and several applications in biotechnology.

biophysics↗

bioRxiv2024

Anatomically and Physiologically Accurate Engineered Neurovascular Unit and Blood-Brain Barrier Model Using Microvessels Isolated from Postmortem Human Brain Tissue

Brain vasculature is a complex and heterogeneous physiological structure that serves specialized roles in maintaining brain health and homeostasis. There is substantial interest in developing representative human models of the brain vasculature for drug screening and disease modeling applications. Many contemporary strategies have focused on culturing neurovascular cell types in hydrogels and microdevices, but it remains challenging to achieve anatomically relevant vascular structures that have physiologically similar function to their in vivo counterparts. Here, we present a strategy for isolating microvessels from cryopreserved human cortical tissue and culturing these vessels in a biomimetic gelatin-based hydrogel contained in a microfluidic device. We provide histological evidence of arteriole and capillary architectures within hydrogels, as well as anastomosis to the hydrogel edges allowing lumen perfusion. In capillaries, we demonstrate restricted diffusion of a 10 kDa dextran, indicating intact passive blood-brain barrier function. We anticipate this bona fide human brain vasculature-on-a-chip will be useful for various biotechnology applications.

bioengineering↗

bioRxiv2024

Integrative physiological plasticity of Agastache rugosa (Fisch. & C.A.Mey.) Kuntze reveals complex adaptation to light and nutrient gradients

We investigated the physiological plasticity of Agastache rugosa (Fisch. & C.A.Mey.) Kuntze, in response to different light and nutrient levels, demonstrating complex adaptive strategies. Through comprehensive analysis of leaf traits, photosynthetic parameters, and resource use efficiencies, we uncovered unexpected patterns in Rubisco dynamics and nutrient utilization, particularly in low- light conditions. A. rugosa exhibited subtle thermal regulation, maintaining relatively stable leaf temperatures across treatments through coordinated adjustments in morphology and gas exchange. Multivariate analyses showed distinct clustering of traits, underlining the integrated nature of plant responses to environmental heterogeneity. Leaf area increased under low-light conditions, while leaf mass area was higher in high-light environments, consistent with shade avoidance syndrome and leaf economics spectrum theory. Surprisingly, Rubisco concentration and use efficiency were generally increased under low light, suggesting a compensatory mechanism. Water use efficiency was higher in high-light conditions, but photosynthetic phosphorus and potassium use efficiencies displayed surprising increases under low light. The species exhibited tight coordination between CO2 supply and demand, as evidenced by strong correlations between net photosynthesis, stomatal conductance, and carboxylation efficiency. Our findings suggest that A. rugosa employs a suite of physiological and morphological adjustments to optimize resource acquisition and utilization that contribute to its ecological success. HighlightThis study reveals complex adaptive strategies in A. rugosa under varying light and nutrient levels, showing unexpected patterns in Rubisco dynamics and nutrient use efficiencies while maintaining subtle thermal regulation across environments.

plant biology↗

bioRxiv2024

Microgravity and low muon radiation affect viral pathogenesis and physiology in Caenorhabditis elegans

Environmental conditions fundamentally shape host-pathogen interactions, yet how multiple extreme abiotic stressors combine to influence infection outcomes remains poorly understood. Organisms evolved under specific gravitational and radiation regimes; deviations from these conditions --whether in extreme terrestrial environments or beyond Earth-- may alter immune function and pathogen replication. In this study, we investigated the effects of reduced gravity and lowered muon flux on Orsay virus infection in the nematode Caenorhabditis elegans. We employed a fully factorial experimental design, examining how each factor, alone and in combination, influences physiological traits and viral load. While below-background radiation radically affected viral accumulation dynamics, reduced gravity had a minor effect. Both factors significantly impacted reproduction and morphology, with some effects magnified by viral infection. These results reveal how even partial modifications of Earth-like gravity and radiation levels can alter pathogen-host interactions. By integrating experimental observations with mathematical modeling, we show that these environmental stressors primarily affect prezygotic reproductive processes and modulate viral replication through distinct and sometimes antagonistic mechanisms. Although this work does not encompass the full complexity of space environments, where cosmic radiation includes high-energy protons and heavy ions, it provides insight into how adjustable models of reduced gravity and radiation can advance our understanding of biological adaptation beyond standard terrestrial conditions. IMPORTANCEUnderstanding how extreme environmental conditions affect host-pathogen interactions is critical both for safeguarding biological systems during spaceflight and for exploring fundamental principles of stress biology. This study demonstrates that reduced gravity and diminished muon radiation flux can significantly alter viral infection dynamics and host physiology in Caenorhabditis elegans. By integrating experimental data with mathematical modeling, we reveal that these abiotic stresses impact prezygotic reproductive processes and modulate viral replication in distinct and sometimes antagonistic ways. Our findings suggest that even partial deviations from Earth-like conditions can reshape infection outcomes and developmental trajectories, highlighting the need for deeper mechanistic insights into biological adaptation beyond terrestrial norms. These results have implications for space biosciences, evolutionary virology, radiation hormesis theory, and the design of countermeasures to preserve organismal health in extreme or non-terrestrial habitats.

microbiology↗

bioRxiv2024

Reproductive experience drives changes in behavior and physiology in male California mice (Peromyscus californicus)

Paternal experience improves memory and reduces anxiety-like behavior in males, but it is unclear whether these changes are due to mating, siring offspring, or caregiving behavior. Likewise, paternal males have larger testes, a measure of sperm production, but again, the effects of siring and caregiving experience are difficult to disentangle. We examined behavioral and physiological outcomes in three groups of male mice: 1) virgins, 2) males paired with sterile females ( non-fathers), and 3) experienced fathers (Experiment 1). Compared to virgins and non-fathers, experienced fathers exhibited increased recognition memory (novel object recognition) and decreased anxiety-like behavior (elevated plus maze). Virgin males, however, had smaller testes and fewer sperm compared to non-fathers. We then compared the same traits in three additional groups of male mice: 1) non-fathers, 2) non-fathers with experience caring for unrelated pups ( pup-sensitized non-fathers), and 3) first-time fathers, to determine whether the behavioral and physiological observations in Experiment 1 were due to siring offspring or caregiving, and how rapidly these changes occur (Experiment 2). Recognition memory and anxiety-like behavior did not differ among these three groups, suggesting that caring for a single litter does not recapitulate the behavioral changes observed in experienced fathers (Experiment 1). Despite equal mating opportunity, we observed larger testes in first-time fathers compared to non-fathers, suggesting that investment in sperm production may be more plastic than behavioral changes. Finally, we compared pup interactions in pup-sensitized non-fathers and first-time fathers. While pup-sensitized non-fathers were slower to approach pups than first-time fathers, they spent more time grooming pups, whereas first-time fathers invested more time in nest building, suggesting different caregiving behaviors in pup-sensitized males and biological fathers. Taken together, our study revealed that mating, siring, and caregiving experience contributes to changes in memory, anxiety-like behavior, and reproductive investment in males of a biparental species.

animal behavior and cognition↗

bioRxiv2024

Cannabidiol (CBD) potentiates physiological and behavioral markers of hypothalamic-pituitary-adrenal (HPA) axis responsivity in female and male mice

RationaleClinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior. ObjectivesWe aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice. MethodsC57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol. ResultsCompared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC. ConclusionsCBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology.

neuroscience↗