Perceived control ameliorates the impact of adverse childhood experiences on downstream mental health.

BACKGROUND: Previous scholarship has illustrated the pernicious role of adverse childhood experiences (ACEs) in self-reported mental health, namely depressive and anxiety-related symptoms. Given these insights, highlighting protective factors that may diminish the magnitude of this relationship is important. The present study explored the moderating role of perceived control on the relationship between ACEs and depressive and anxiety symptoms, respectively. METHODS: Participants consisted of a US-based non-clinical sample of 567 undergraduate students who completed a battery of surveys related to psychological wellbeing and individual differences. A series of hierarchical linear regression analyses were utilized for hypothesis testing. RESULTS: Consistent with our main hypotheses, perceived control moderated the relationship between ACEs and both anxiety and depressive symptoms, respectively. Namely, at low levels of perceived control, ACEs were associated with significantly greater levels of anxiety and depressive symptoms, respectively. However, for those reporting high levels of perceived control, we found no association between ACEs and self-reported symptoms. CONCLUSION: We offer evidence that perceived control may serve as a protective factor for mental health and wellbeing against the influence of adverse childhood experiences.

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders.

Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA is a process that generates various transcript isoforms of the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.

Derailment is associated with increased depressed mood at lower levels of stress: An experimental approach.

BACKGROUND: As an emergent developmental construct, derailment - an individual difference hallmarked by a temporal discordance of the self - has been positively associated with depressive features, though less is known about the role of stress in this relationship. The aim of the present study was to explore the interaction between derailment and subjective stress on depressed mood. METHODS: 265 adults recruited through Prolific - a crowd sourcing platform were first tasked with completing baseline measures, then were randomly assigned to a low stress or high stress condition. We utilized an adapted version of the Online Trier Stress Test to manipulate stress levels. Next, depressed mood and post-test perceived stress were measured. We analyzed data through STATA using a two-tailed independent samples t-test and multiple linear regression. RESULTS: Findings suggested the experimental manipulation increased subjective stress within the high stress condition compared to the low stress condition (Mdiff = 36.14, SE = 4.4, t = 8.21, p < .001). Further, we found the interaction between derailment and stress conditions was associated with increased depressed mood (ß = -0.11, SE = 0.05, p = .038, R2 = 0.5). Notably, we found significant between-condition differences in depressed mood for those who endorsed either low (d = 0.22, SE = 0.07, p = .003) or moderate levels of derailment (d = 0.11, SE = 0.05, p = .033), but not for those who endorsed high levels of derailment (d = 0.01, SE = 0.07, p = .92). LIMITATIONS: This study utilized self-report measures, which may be susceptible to biased responses. CONCLUSIONS: Derailment may play a role in the persistence of depressed mood regardless of varying contexts of stress.

Identification of sleep and circadian alternative polyadenylation sites associated with APA-linked human brain disorders.

Sleep and circadian rhythm disruptions are comorbid features of many pathologies and can negatively influence numerous health conditions, including degenerative diseases, metabolic illnesses, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. Thus, associations between sleep and/or circadian rhythm and alternative polyadenylation (APA), particularly in the context of other health challenges, are largely undescribed. APA is a process that generates various transcript isoforms from the same gene, resulting in effects on mRNA translation, stability, localization, and subsequent function. Here, we have identified unique APAs in rat brain that exhibit time-of-day-dependent oscillations in expression as well as APAs that are altered by sleep deprivation and the subsequent recovery period. Genes affected by APA usage include Mapt/Tau, Ntrk2, Homer1A, Sin3band Sorl. Sorl1 has two APAs which cycle with a 24 h period, one additional APA cycles with a 12 h period and one more that is reduced during recovery sleep. Finally, we compared sleep- or circadian-associated APAs with recently described APA-linked brain disorder susceptibility genes and found 46 genes in common.

Humanization of the mouse Tert gene reset telomeres to human length.

Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert, wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene. Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert-knockout mice. Through successive intercrosses of Terth/- mice, telomere length progressively declined, stabilizing below 10-kb. Terth/h mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Terth/h mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Terth/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres. Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.

FABP7: a glial integrator of sleep, circadian rhythms, plasticity, and metabolic function.

Sleep and circadian rhythms are observed broadly throughout animal phyla and influence neural plasticity and cognitive function. However, the few phylogenetically conserved cellular and molecular pathways that are implicated in these processes are largely focused on neuronal cells. Research on these topics has traditionally segregated sleep homeostatic behavior from circadian rest-activity rhythms. Here we posit an alternative perspective, whereby mechanisms underlying the integration of sleep and circadian rhythms that affect behavioral state, plasticity, and cognition reside within glial cells. The brain-type fatty acid binding protein, FABP7, is part of a larger family of lipid chaperone proteins that regulate the subcellular trafficking of fatty acids for a wide range of cellular functions, including gene expression, growth, survival, inflammation, and metabolism. FABP7 is enriched in glial cells of the central nervous system and has been shown to be a clock-controlled gene implicated in sleep/wake regulation and cognitive processing. FABP7 is known to affect gene transcription, cellular outgrowth, and its subcellular localization in the fine perisynaptic astrocytic processes (PAPs) varies based on time-of-day. Future studies determining the effects of FABP7 on behavioral state- and circadian-dependent plasticity and cognitive processes, in addition to functional consequences on cellular and molecular mechanisms related to neural-glial interactions, lipid storage, and blood brain barrier integrity will be important for our knowledge of basic sleep function. Given the comorbidity of sleep disturbance with neurological disorders, these studies will also be important for our understanding of the etiology and pathophysiology of how these diseases affect or are affected by sleep.

Fibers in smaller fascicles have lower activation thresholds with cuff electrodes due to thinner perineurium and smaller cross-sectional area.

Objective. In nerve stimulation therapies, fibers in larger fascicles generally have higher activation thresholds, but the mechanisms are not well understood. We implemented and analyzed computational models to uncover the effects of morphological parameters on activation thresholds.Approach. We implemented finite element models of human vagus nerve stimulation to quantify the effects of morphological parameters on thresholds in realistic nerves. We also implemented simplified models to isolate effects of perineurium thickness, endoneurium diameter, fiber diameter, and fascicle location on current density, potential distributions (Ve), and activation thresholds across cuff geometries and stimulation waveforms. UsingVefrom each finite element model, we simulated activation thresholds in biophysical cable models of mammalian axons.Main results. Perineurium thickness increases with fascicle diameter, and both thicker perineurium and larger endoneurial diameter contributed to higher activation thresholds via lower peak and broader longitudinal potentials. Thicker perineurium caused less current to enter the fascicle transversely, decreasing peakVe. Thicker perineurium also inhibited current from leaving the fascicle, causing more constant longitudinal current density, broadeningVe. With increasing endoneurial diameter, intrafascicular volume increased faster than surface area, thereby decreasing intrafascicular current density and peakVe. Additionally, larger fascicles have greater cross-sectional area, thereby facilitating longitudinal intrafascicular current flow and broadeningVe. A large neighboring fascicle could increase activation thresholds, and for a given fascicle, fiber diameter had the greatest effect on thresholds, followed by fascicle diameter, and lastly, fascicle location within the epineurium. The circumneural cuff elicited robust activation across the nerve, whereas a bipolar transverse cuff with small contacts delivering a pseudo-monophasic waveform enabled more selective activation across fiber diameters and locations.Significance. Our computational studies provide mechanistic understanding of neural responses across relevant morphological parameters of peripheral nerves, thereby informing rational design of effective therapies.

Corrigendum: Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

[This corrects the article DOI: 10.3389/fnsys.2022.1052441.].

Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

Introduction: Insufficient sleep is pervasive worldwide, and its toll on health and safety is recapitulated in many settings. It is thus important to understand how poor sleep affects the brain and decision making. A robust literature documents the adverse effects of sleep deprivation on cognitive processes including cognitive flexibility, which is the capacity to appraise new feedback and make behavioral adjustments to respond appropriately. Animal models are often used to unravel the molecules, genes and neural circuits that are altered by sleep loss. Herein we take a translational approach to model the effects of sleep deprivation on cognitive rigidity, i.e., impaired cognitive flexibility in rats. Methods: There are several approaches to assess cognitive rigidity; in the present study, we employ a pairwise discrimination reversal task. To our knowledge this is the first time this paradigm has been used to investigate sleep deprivation. In this touchscreen operant platform, we trained rats to select one of two images to claim a sucrose pellet reward. If the non-rewarded image was selected the rats proceeded to a correction trial where both images were presented in the same position as before. This image presentation continued until the rat selected the correct image. Once rats reached performance criteria, the reward contingencies were reversed. In one group of rats the initial reversal session was preceded by 10 h of sleep deprivation. We compared those rats to controls with undisturbed sleep on the number of sessions to reach performance criteria, number of trials per session, response latencies, correct responses, errors, perseverative errors and perseveration bouts in the initial training and reversal phases. Results: We report that on reversal session one, sleep deprived rats completed a fraction of the trials completed by controls. On subsequent reversal sessions, the sleep deprived rats struggled to adapt to the reversed contingencies despite completing a similar number of trials, suggesting an effect of cognitive rigidity separate from fatigue. Discussion: We discuss the delayed performance dynamics incurred by sleep loss in the context of fatigue and the implications of using pairwise discrimination reversal as a model to further examine the effects of sleep loss on adaptive decision making.

The rat Lux Actuating Search Task (LAST) and effects of sleep deprivation on task reversal performance.

Sleep deprivation (SD) causes significant deficits in multiple aspects of cognition, including sustained attention and working memory. Investigating the neural processes underpinning these cognitive losses has proven challenging due to the confounds of current animal tasks; many employ appetitive or aversive stimuli to motivate behavior, while others lack task complexity that translates to human studies of executive function. We established the Lux Actuating Search Task (LAST) to circumvent these issues. The LAST is performed in a circular, open-field arena that requires rats to find an unmarked, quasi-randomly positioned target. Constant low-level floor vibrations motivate ambulation, while light intensity (determined by the rodent's proximity to the target destination) provides continuous visual feedback. The task has two paradigms that differ based on the relationship between the light intensity and target proximity: the Low Lux Target (LLT) paradigm and the High Lux Target paradigm (HLT). In this study, on days 1-6, the rats completed nine trials per day on one of the two paradigms. On day 7, the rats were either sleep deprived by gentle handling or were left undisturbed before undertaking the opposite (reversal) paradigm on days 7-9. Our results showed that SD significantly impeded the ability of Long Evans rats to learn the reversal paradigm, as indicated by increased times to target and increased failure percentages compared to rats whose sleep was undisturbed. Rats also showed reduced learning with the HLT paradigm, as the initial task or as the reversal task, likely due to the rodents' photophobia limiting their motivation to navigate toward a bright light, which is required to succeed.

A Dichotomous Role for FABP7 in Sleep and Alzheimer's Disease Pathogenesis: A Hypothesis.

Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer's pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX-2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-γ transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson's disease.

Multicomponent drug Neurexan mitigates acute stress-induced insomnia in rats.

The aim of this study was to determine whether the multicomponent drug Neurexan could mitigate acute insomnia after exposure to a psychosocial stressor. We administered Neurexan orally to rats and examined stress-induced insomnia using the male rat dirty cage exchange method. The neurocircuitry and electrophysiological correlates of the model are characterised, and it represents various human insomnia conditions. Male rats were randomly assigned in a crossover design to six treatment groups and electroencephalography (EEG) electrodes attached. Three groups were exposed to a cage inhabited by another male rat for a week and the other three groups received a clean cage. Prior to cage change, rats were given either no drug, vehicle control or Neurexan. Non-rapid eye movement (NREM) sleep, REM sleep, and waking were assessed manually via EEG recordings. Group means were compared for sleep latency and for the 2 h after cage change for: time in each state, state-specific episode duration/frequency, in addition to NREM delta, gamma and REM theta EEG spectral power. Rats administered Neurexan fell asleep faster than vehicle-treated rats and spent less time awake with shorter, albeit more waking episodes and increased NREM episodes after dirty cage exposure. Neurexan-treated rats given dirty cages were not statistically different on any outcomes from Neurexan-treated rats given clean cages, thereby mitigating the stressor. In the EEG power spectra analysed, changes between treatment groups were not detected. This research confirms that Neurexan treatment has somnogenic effects and ameliorates psychological stressor-induced acute insomnia.

Floor vibrations for motivation and feedback in the rat vibration actuating search task.

Motivating rodents to perform cognitive tasks often relies on the application of aversive stimuli. The Vibration Actuating Search Task (VAST) is a novel open-field task in which gradient floor vibration provides motivation for the rodent to navigate in the direction of diminishing vibration to an unmarked target destination. Using floor vibration as a motivational stimulus may overcome several of the potential confounds associated with stimuli used in other tasks. In a series of three experiments, we determined whether (1) rats exhibit place preference for floor vibration over other aversive stimuli (i.e., water, foot shock, and bright light), (2) exposure to floor vibration is associated with a lower corticosterone response than exposure to these other stimuli, (3) rats successfully acquire the VAST, and (4) VAST performance is sensitive to 6 h of sleep deprivation (SD). Our results showed that rats exhibited place preference for vibration over water, foot shock, and bright light environments, and that corticosterone levels were lower in rats exposed to vibration than those exposed to water. VAST performance also significantly improved over two days of testing for some metrics, and SD impaired VAST performance. Overall, we conclude that (1) rats exhibit place preference for vibration over other stimuli commonly used to motivate task performance, (2) the vibrations employed by the VAST produce lower concentrations of circulating corticosterone than forced swimming, (3) rats can learn to use gradient floor vibration as a mode of performance feedback within two days of testing, and (4) VAST performance is substantially impaired by SD. Thus, the VAST is an effective and practical testbed for studying the mechanisms by which SD causes deficits in feedback-dependent decision making.

Single prolonged stress blocks sleep homeostasis and pre-trauma sleep deprivation does not exacerbate the severity of trauma-induced fear-associated memory impairments.

Sleep is intimately linked to cognitive performance and exposure to traumatic stress that leads to post-traumatic stress disorder (PTSD) impairs both sleep and cognitive function. However, the contribution of pre-trauma sleep loss to subsequent trauma-dependent fear-associated memory impairment remains unstudied. We hypothesized that sleep deprivation (SD) prior to trauma exposure may increase the severity of a PTSD-like phenotype in rats exposed to single prolonged stress (SPS), a rodent model of PTSD. Rats were exposed to SPS alone, SD alone, or a combination of SPS+SD and measures of fear-associated memory impairments and vigilance state changes were compared to a group of control animals not exposed to SPS or SD. We found that SPS, and SPS+SD animals showed impaired fear-associated memory processing and that the addition of SD to SPS did not further exaggerate the effect of SPS alone. Additionally, the combination of SPS with SD results in a unique homeostatic sleep duration phenotype when compared to SD, SPS, or control animals. SPS exposure following SD represses homeostatic rebound and eliminates sleep-deprivation-induced increases in NREM sleep delta power. This work identifies a unique time frame where trauma exposure and sleep interact and identifies this window of time as a potential therapeutic treatment window for staving off the negative consequences of trauma exposure.

Optogenetic sleep enhancement improves fear-associated memory processing following trauma exposure in rats.

Sleep disturbances are commonly found in trauma-exposed populations. Additionally, trauma exposure results in fear-associated memory impairments. Given the interactions of sleep with learning and memory, we hypothesized that increasing sleep duration following trauma exposure would restore overall function and improve trauma-induced fear-associated memory dysfunction. Here, we utilized single prolonged stress, a validated rodent model of post-traumatic stress disorder, in combination with optogenetic activation of hypothalamic melanin-concentrating hormone containing cells to increase sleep duration. The goal of this work was to ascertain if post-trauma sleep increases are sufficient to improve fear-associated memory function. In our laboratory, optogenetic stimulation after trauma exposure was sufficient to increase REM sleep duration during both the Light and Dark Phase, whereas NREM sleep duration was only increased during the Dark Phase of the circadian day. Interestingly though, animals that received optogenetic stimulation showed significantly improved fear-associated memory processing compared to non-stimulated controls. These results suggest that sleep therapeutics immediately following trauma exposure may be beneficial and that post-trauma sleep needs to be further examined in the context of the development of post-traumatic stress disorder.

Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts.

Pyridine and related heterocyclic sulfinates have recently emerged as effective nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with (hetero)aryl halides. These sulfinate reagents are straightforward to prepare, stable to storage and coupling reaction conditions, and deliver efficient reactions, thus offering many advantages, compared to the corresponding boron-derived reagents. Despite the success of these reactions, there are only scant details of the reaction mechanism. In this study, we use structural and kinetic analysis to investigate the mechanism of these important coupling reactions in detail. We compare a pyridine-2-sulfinate with a carbocyclic sulfinate and establish different catalyst resting states, and turnover limiting steps, for the two classes of reagent. For the carbocyclic sulfinate, the aryl bromide oxidative addition complex is the resting state intermediate, and transmetalation is turnover-limiting. In contrast, for the pyridine sulfinate, a chelated Pd(II) sulfinate complex formed post-transmetalation is the resting-state intermediate, and loss of SO2 from this complex is turnover-limiting. We also investigated the role of the basic additive potassium carbonate, the use of which is crucial for efficient reactions, and deduced a dual function in which carbonate is responsible for the removal of free sulfur dioxide from the reaction medium, and the potassium cation plays a role in accelerating transmetalation. In addition, we show that sulfinate homocoupling is responsible for converting Pd(OAc)2 to a catalytically active Pd(0) complex. Together, these studies shed light on the challenges that must be overcome to deliver improved, lower temperature versions of these synthetically important processes.

Performance on the mouse vibration actuating search task is compromised by sleep deprivation.

As we go about our daily routines we are continuously bombarded with environmental feedback that requires appraisal and response. Sleep loss can compromise the efficiency by which these cognitive processes function. Operationally, poor performance caused by insufficient sleep translates to increased health and safety risks in settings where attention and timely and/or accurate decisions to respond are critical (e.g., at work, on the road, etc.). Current rodent tasks that assess altered cognition after sleep deprivation (SD) do not accurately model the continuous multisensory feedback that informs goal-oriented behavior in humans. Herein, we describe the vibration actuating search task (VAST), which consists of a vibrating open field with pseudo-randomly selected entrance and target destination points. To successfully complete a trial, mice use feedback from rotary motor-induced floor vibrations to navigate from the entrance point to the target destination. Sets of 20 trials were conducted on 3 consecutive days, and before testing on the third day control mice were undisturbed while other mice were sleep deprived for 10 h. On the first 2 days mice learned the task with high success rates. Alternatively, VAST performance was compromised following SD as measured by increased failures in task completion, time to target, time spent immobile, and decreased speed as compared with undisturbed mice. The VAST enables the analysis of continuous feedback via multiple sensory modalities in mice and is applicable to a variety of operational settings.NEW & NOTEWORTHY The vibration actuating search task (VAST) is a novel performance assay that uses continuous auditory and haptic feedback to motivate and direct search behaviors in mice. The VAST is rapidly acquired by mice and performance is disrupted by sleep deprivation. The VAST has practical application in occupational settings. The cognitive aspects of the sensorimotor integration in the VAST may prove useful for rodent models of neurodegenerative disease.

Discovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis.

PKCθ plays an important role in T cell biology and is a validated target for a number of disease states. A series of potent and selective PKCθ inhibitors were designed and synthesized starting from a HTS hit compound. Cell activity, while initially a challenge to achieve, was built into the series by transforming the nitrile unit of the scaffold into a primary amine, the latter predicted to form a new hydrogen bond to Asp508 near the entrance of the ATP binding site of PKCθ. Significant improvements in physiochemical parameters were observed on introduction of an oxetane group proximal to a primary amine leading to compound 22, which demonstrated a reduction of symptoms in a mouse model of multiple sclerosis.

Range position and climate sensitivity: The structure of among-population demographic responses to climatic variation.

Species' distributions will respond to climate change based on the relationship between local demographic processes and climate and how this relationship varies based on range position. A rarely tested demographic prediction is that populations at the extremes of a species' climate envelope (e.g., populations in areas with the highest mean annual temperature) will be most sensitive to local shifts in climate (i.e., warming). We tested this prediction using a dynamic species distribution model linking demographic rates to variation in temperature and precipitation for wood frogs (Lithobates sylvaticus) in North America. Using long-term monitoring data from 746 populations in 27 study areas, we determined how climatic variation affected population growth rates and how these relationships varied with respect to long-term climate. Some models supported the predicted pattern, with negative effects of extreme summer temperatures in hotter areas and positive effects on recruitment for summer water availability in drier areas. We also found evidence of interacting temperature and precipitation influencing population size, such as extreme heat having less of a negative effect in wetter areas. Other results were contrary to predictions, such as positive effects of summer water availability in wetter parts of the range and positive responses to winter warming especially in milder areas. In general, we found wood frogs were more sensitive to changes in temperature or temperature interacting with precipitation than to changes in precipitation alone. Our results suggest that sensitivity to changes in climate cannot be predicted simply by knowing locations within the species' climate envelope. Many climate processes did not affect population growth rates in the predicted direction based on range position. Processes such as species-interactions, local adaptation, and interactions with the physical landscape likely affect the responses we observed. Our work highlights the need to measure demographic responses to changing climate.

Interleukin 37 expression in mice alters sleep responses to inflammatory agents and influenza virus infection.

Multiple interactions between the immune system and sleep are known, including the effects of microbial challenge on sleep or the effects of sleep loss on facets of the immune response. Cytokines regulate, in part, sleep and immune responses. Here we examine the role of an anti-inflammatory cytokine, interleukin-37 (IL-37) on sleep in a mouse strain that expresses human IL-37b (IL37tg mice). Constitutive expression of the IL-37 gene in the brains of these mice under resting conditions is low; however, upon an inflammatory stimulus, expression increases dramatically. We measured sleep in three conditions; a) under baseline conditions and after 6 h of sleep loss, b) after bolus intraperitoneal administration of lipopolysaccharide (LPS) or IL-1ß and c) after intranasal influenza virus challenge. Under baseline conditions, the IL37tg mice had 7% more spontaneous non-rapid eye movement sleep (NREMS) during the light period than wild-type (WT) mice. After sleep deprivation both WT mice and IL37tg mice slept an extra 21% and 12%, respectively, during the first 6 h of recovery. NREMS responses after sleep deprivation did not significantly differ between WT mice and IL37tg mice. However, in response to either IL-1ß or LPS, the increases in time spent in NREMS were about four-fold greater in the WT mice than in the IL37tg mice. In contrast, in response to a low dose of mouse-adapted H1N1 influenza virus, sleep responses developed slowly over the 6 day recording period. By day 6, NREMS increased by 10% and REMS increased by 18% in the IL37tg mice compared to the WT mice. Further, by day 4 IL37tg mice lost less weight, remained more active, and retained their body temperatures closer to baseline values than WT mice. We conclude that conditions that promote IL-37 expression attenuate morbidity to severe inflammatory challenge.