Alterations in Blood-Brain Barrier Integrity and Lateral Ventricle Differ in Rats Exposed to Space Radiation and Social Isolation.

The proposed Mars missions will expose astronauts to long durations of social isolation (SI) and space radiation (SR). These stressors have been shown to alter the brain's macrostructure and microenvironment, including the blood-brain barrier (BBB). Breakdown of the BBB is linked to impaired executive functions and physical deficits, including sensorimotor and neurocognitive impairments. However, the precise mechanisms mediating these effects remain unknown. Additionally, the synergistic effects of combined exposure to SI and SR on the structural integrity of the BBB and brain remain unknown. We assessed the BBB integrity and morphology in the brains of male rats exposed to ground-based analogs of SI and SR. The rats exposed to SR had enlarged lateral ventricles and increased BBB damage associated with a loss of astrocytes and an increased number of leaky vessels. Many deficits observed in SR-treated animals were attenuated by dual exposure to SI (DFS). SI alone did not show BBB damage but did show differences in astrocyte morphology compared to the Controls. Thus, determining how single and combined inflight stressors modulate CNS structural integrity is crucial to fully understand the multiple pathways that could impact astronaut performance and health, including the alterations to the CNS structures and cell viability observed in this study.

Evidence for a role of the basolateral amygdala in regulating regional metabolism in the stressed brain.

The brain regulates every physiological process in the body, including metabolism. Studies investigating brain metabolism have shown that stress can alter major metabolic processes, and that these processes can vary between regions. However, no study has investigated how metabolic pathways may be altered by stressor perception, or whether stress-responsive brain regions can also regulate metabolism. The basolateral amygdala (BLA), a region important for stress and fear, has reciprocal connections to regions responsible for metabolic regulation. In this study, we investigated how BLA influences regional metabolic profiles within the hippocampus (HPC) and medial prefrontal cortex (mPFC), regions involved in regulating the stress response and stress perception, using optogenetics in male C57BL/6 mice during footshock presentation in a yoked shuttlebox paradigm based on controllable (ES) and uncontrollable (IS) stress. RNA extracted from HPC and mPFC were loaded into NanoString® Mouse Neuroinflammation Panels, which also provides a broad view of metabolic processes, for compilation of gene expression profiles. Results showed differential regulation of carbohydrate and lipid metabolism, and insulin signaling gene expression pathways in HPC and mPFC following ES and IS, and that these differences were altered in response to optogenetic excitation or inhibition of the BLA. These findings demonstrate for the first time that individual brain regions can utilize metabolites in a way that are unique to their needs and function in response to a stressor, and that vary based on stressor controllability and influence by BLA.

Effects of social isolation and galactic cosmic radiation on fine motor skills and behavioral performance.

Future NASA missions will require astronauts to travel farther and spend longer durations in space than ever before. This will also expose astronauts to longer periods of several physical and psychological challenges, including exposure to space radiation (SR) and periods of social isolation (SI), which could have unknown negative effects on physical and mental health. Each also has the potential to negatively impact sleep which can reduce the ability to cope with stressful experiences and lead to sensorimotor, neurocognitive, and physical deficits. The effects of SI and SR on gross motor performance has been shown to vary, and depend on, individual differences in stress resilience and vulnerability based on our established animal model in which stress produces different effects on sleep. In this study, the impact that SI and SR, either alone or together, had on fine motor skill performance (bilateral tactile adhesive removal task (BTAR)) was assessed in male rats. We also examined emotional, exploratory, and other off-task behavioral responses during testing and assessed whether sensorimotor performance and emotion varied with individual differences in resilience and vulnerability. BTAR task performance was differentially impacted by SI and SR, and were further influenced by the stress resilience/vulnerability phenotype of the rats. These findings further demonstrate that identifying individual responses to stressors that can impact sensorimotor ability and behavior necessary to perform mission-related tasks will be of particular importance for astronauts and future missions. Should similar effects occur in humans, there may be considerable inter-individual variability in the impact that inflight stressors have on astronauts and their ability to perform mission-related tasks.

High stability of EEG spectral power across polysomnography and multiple sleep latency tests in good sleepers and chronic insomniacs.

To assess the stability of electroencephalographic (EEG) spectral features across overnight polysomnography (PSG) and daytime multiple sleep latency tests (MSLTs) in chronic insomniacs (CIs) and normal controls (NCs). A total of 20 NCs and 22 CIs underwent standard PSG and MSLTs. Spectral analyses were performed on EEG data from PSG and MSLTs and absolute and relative power in central, frontal and occipital channels were obtained for wake (W) and non-rapid eye movement sleep stage 1 and 2 (N1, N2). Intraclass correlation coefficients (ICCs) were used to assess the stability of EEG spectral power across PSG and MSLTs for W, N1 and N2. The absolute power of all frequency bands except delta exhibited high stability across PSG and MSLTs in both NCs and CIs (ICCs ranged from 0.430 to 0.978). Although delta absolute power was stable in NCs during N1 and N2 stages (ICCs ranged from 0.571 to 0.835), it tended to be less stable in CIs during W and sleep stages (ICCs ranged from 0.042 to 0.807). We also observed lower stability of relative power compared to absolute power though the majority of relative power outcomes maintained high stability in both groups (ICCs in relative power ranged from 0.044 to 0.962). Most EEG spectral bandwidths across PSG and MSLT in W, N1 and N2 show high stability in good sleepers and chronic insomniacs. EEG signals from either an overnight PSG or a daytime MSLT may be useful for reliably exploring EEG spectral features during wakefulness or sleep.

Polysomnographic findings of myotonic dystrophy type 1/type 2: evidence from case-control studies.

STUDY OBJECTIVES: This study explores polysomnographic and multiple sleep latency test (MSLT) differences between myotonic dystrophy type 1/type 2 (DM1/DM2) patients and controls. METHODS: An electronic literature search was conducted in MEDLINE, EMBASE, All EBM databases, and Web of Science from inception to Aug 2023. RESULTS: Meta-analyses revealed significant reductions in sleep efficiency, N2 percentage, mean SpO2, and MSLT measured mean sleep latency, and increases in N3 sleep, wake time after sleep onset, apnea hypopnea index, and periodic limb movement index in DM1 patients compared with controls. However, any differences of polysomnographic sleep change between DM2 patients and controls could not be established due to limited available studies. CONCLUSIONS: Multiple significant polysomnographic abnormalities are present in DM1. More case-control studies evaluating polysomnographic changes in DM2 compared with controls are needed.

Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential.

Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis is poorly understood. The heritability estimate of MDD is 30-40%, suggesting that genetics alone do not account for most of the risk of major depression. Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress. Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications. These epigenetic modification alterations contribute to abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission and neuroglia dysfunction, which are involved in the pathophysiology of MDD. Furthermore, epigenetic marks have been associated with the diagnosis and treatment of MDD. The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD, and may identify new therapeutic targets. Here, we review preclinical and clinical epigenetic findings, including DNA methylation, histone modification, noncoding RNA, RNA modification, and chromatin remodeling factor in MDD. In addition, we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.

Cocaine Regulates NLRP3 Inflammasome Activity and CRF Signaling in a Region- and Sex-Dependent Manner in Rat Brain.

Cocaine, one of the most abused drugs worldwide, is capable of activating microglia in vitro and in vivo. Several neuroimmune pathways have been suggested to play roles in cocaine-mediated microglial activation. Previous work showed that cocaine activates microglia in a region-specific manner in the brains of self-administered mice. To further characterize the effects of cocaine on microglia and neuroimmune signaling in vivo, we utilized the brains from both sexes of outbred rats with cocaine self-administration to explore the activation status of microglia, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activity, corticotropin-releasing factor (CRF) signaling, and NF-κB levels in the striatum and hippocampus (HP). Age-matched rats of the same sex (drug naïve) served as controls. Our results showed that cocaine increased neuroinflammation in the striatum and HP of both sexes with a relatively higher increases in male brains. In the striatum, cocaine upregulated NLRP3 inflammasome activity and CRF levels in males but not in females. In contrast, cocaine increased NLRP3 inflammasome activity in the HP of females but not in males, and no effects on CRF signaling were observed in this region of either sex. Interestingly, cocaine increased NF-κB levels in the striatum and HP with no sex difference. Taken together, our results provide evidence that cocaine can exert region- and sex-specific differences in neuroimmune signaling in the brain. Targeting neuroimmune signaling has been suggested as possible treatment for cocaine use disorders (CUDs). Our current results indicate that sex should be taken into consideration when determining the efficacy of these new therapeutic approaches.

Controllable Stress Increases Rapid Eye Movement Sleep in Rats: Regulation by the Central Nucleus of the Amygdala.

BACKGROUND: Training with inescapable shock (IS; uncontrollable stressor) is followed by significant decreases in rapid eye movement sleep (REM). However, controllability is important in the effects of stress. We examined the effects of escapable shock (ES; controllable stressor) on sleep and whether the central nucleus of the amygdala (CNA) plays a role in regulating these effects. METHODS: Six Wistar rats implanted with a cannula located in CNA underwent two days of ES training (20 shock presentations; 0.5 mA; 5.0 s maximum duration; 1.0 min interstimulus interval). Five days later, they were re-exposed to the shock context. RESULTS: Following shock training, REM was significantly increased in both light and dark periods. Non-REM (NREM) and total sleep (TS) duration were decreased during the light period. Similar effects on REM and NREM were observed following re-exposure to the training context alone. Microinjections of saline into CNA immediately following ES also produced similar increases in REM, whereas microinjections of muscimol (MUS; GABAA (γ-aminobutyric acid) antagonist) subsequent to ES blocked the increases in REM. CONCLUSIONS: These data, along with previous work with ES and IS, demonstrate that stressor controllability is important in determining how stress impacts sleep. Moreover, the results of the microinjection study indicate that the effects of ES on REM are regulated through the CNA.

Stressor control and regional inflammatory responses in the brain: regulation by the basolateral amygdala.

Increasing evidence has connected the development of certain neuropsychiatric disorders, as well as neurodegenerative diseases, to stress-induced dysregulation of the immune system. We have shown that escapable (ES) and inescapable (IS) footshock stress, and memories associated with ES or IS, can differentially alter inflammatory-related gene expression in brain in a region dependent manner. We have also demonstrated that the basolateral amygdala (BLA) regulates stress- and fear memory-induced alterations in sleep, and that differential sleep and immune responses in the brain to ES and IS appear to be integrated during fear conditioning and then reproduced by fear memory recall. In this study, we investigated the role of BLA in influencing regional inflammatory responses within the hippocampus (HPC) and medial prefrontal cortex (mPFC) by optogenetically stimulating or inhibiting BLA in male C57BL/6 mice during footshock stress in our yoked shuttlebox paradigm based on ES and IS. Then, mice were immediately euthanized and RNA extracted from brain regions of interest and loaded into NanoString® Mouse Neuroinflammation Panels for compilation of gene expression profiles. Results showed differential regional effects in gene expression and activated pathways involved in inflammatory-related signaling following ES and IS, and these differences were altered depending on amygdalar excitation or inhibition. These findings demonstrate that the stress-induced immune response, or "parainflammation", is affected by stressor controllability and that BLA influences regional parainflammation to ES or IS in HPC and mPFC. The study illustrates how stress-induced parainflammation can be regulated at the neurocircuit level and suggests that this approach can be useful for uncovering circuit and immune interactions in mediating differential stress outcomes.

Sleep in amyotrophic lateral sclerosis: A systematic review and meta-analysis of polysomnographic findings.

BACKGROUND: This study explores the polysomnographic differences between amyotrophic lateral sclerosis (ALS) patients and healthy controls. METHODS: An electronic literature search was conducted in MEDLINE, EMBASE, All EBM databases, Web of Science, and CNKI from inception to Oct 2022. RESULTS: Meta-analyses revealed significant reductions in sleep efficiency, total sleep time, N2%, slow wave sleep percentage, minimum SpO2, and mean SpO2, and increases in wake time after sleep onset and N1%, sleep latency, rapid eye movement sleep latency, time spent with SpO2 < 90%, oxygen desaturation index, and apnea hypopnea index in ALS patients compared with controls. Sensitivity analyses showed that some heterogeneity was explained by excluding patients taking medications impacting sleep, whether studies employed an adaptation night, and the use of different PSG scoring rules. CONCLUSIONS: Significant polysomnographic abnormalities are present in ALS. Our findings underscore the need for a comprehensive PSG assessment of sleep changes in ALS patients. When performing PSG examinations in ALS, whether the patients are taking medication impacting sleep and the scoring system used should be considered.

Sleep and Core Body Temperature Alterations Induced by Space Radiation in Rats.

Sleep problems in astronauts can arise from mission demands and stress and can impact both their health and ability to accomplish mission objectives. In addition to mission-related physical and psychological stressors, the long durations of the proposed Mars missions will expose astronauts to space radiation (SR), which has a significant impact on the brain and may also alter sleep and physiological functions. Therefore, in this study, we assessed sleep, EEG spectra, activity, and core body temperature (CBT) in rats exposed to SR and compared them to age-matched nonirradiated rats. Male outbred Wistar rats (8-9 months old at the time of the study) received SR (15 cGy GCRsim, n = 15) or served as age- and time-matched controls (CTRL, n = 15) without irradiation. At least 90 days after SR and 3 weeks prior to recording, all rats were implanted with telemetry transmitters for recording EEG, activity, and CBT. Sleep, EEG spectra (delta, 0.5-4 Hz; theta, 4-8 Hz; alpha, 8-12 Hz; sigma, 12-16 Hz; beta, 16-24 Hz), activity, and CBT were examined during light and dark periods and during waking and sleeping states. When compared to the CTRLs, SR produced significant reductions in the amounts of dark period total sleep time, total nonrapid eye movement sleep (NREM), and total rapid eye movement sleep (REM), with significant decreases in light and dark period NREM deltas and dark period REM thetas as well as increases in alpha and sigma in NREM and REM during either light or dark periods. The SR animals showed modest increases in some measures of activity. CBT was significantly reduced during waking and sleeping in the light period. These data demonstrate that SR alone can produce alterations to sleep and temperature control that could have consequences for astronauts and their ability to meet mission demands.

Differential Impact of Social Isolation and Space Radiation on Behavior and Motor Learning in Rats.

Future missions to Mars will expose astronauts to several physical and psychological challenges, including exposure to space radiation (SR) and periods of social isolation (SI). Each of these stressors, in addition to mission demands, can affect physical and mental health and potentially negatively impact sleep. The effects of inflight stressors may vary with duration and time course, may be additive or compounding, and may vary with individual differences in stress resilience and vulnerability. Determining how individual differences in resilient and vulnerable phenotypes respond to these mission-related stressors and their interactions with sleep will be crucial for understanding and mitigating factors that can impair performance and damage health. Here, we examined the single and compound effects of ground-based analogs of SI and SR on sensorimotor performance on the balance beam (BB) in rats. We also assessed emotional responses during testing on the BB and assessed whether sensorimotor performance and emotion varied with individual differences in stress resiliency using our established animal model in which stress produces different effects on sleep. Results showed differential motor performance and emotion in the BB task between SI and SR, and these varied based on resilient and vulnerable phenotypes. These findings demonstrate that identifying individual responses to stressors that can impact sensorimotor ability and behavior necessary to perform mission-related tasks will be of particular importance for astronauts and future missions. Should similar effects occur in humans, there may be considerable inter-individual variability in the impact that flight stressors have on the mental health of astronauts and their ability to perform mission-related tasks.

Modeling integrated stress, sleep, fear and neuroimmune responses: Relevance for understanding trauma and stress-related disorders.

Sleep and stress have complex interactions that are implicated in both physical diseases and psychiatric disorders. These interactions can be modulated by learning and memory, and involve additional interactions with the neuroimmune system. In this paper, we propose that stressful challenges induce integrated responses across multiple systems that can vary depending on situational variables in which the initial stress was experienced, and with the ability of the individual to cope with stress- and fear-inducing challenges. Differences in coping may involve differences in resilience and vulnerability and/or whether the stressful context allows adaptive learning and responses. We provide data demonstrating both common (corticosterone, SIH and fear behaviors) and distinguishing (sleep and neuroimmune) responses that are associated with an individual's ability to respond and relative resilience and vulnerability. We discuss neurocircuitry regulating integrated stress, sleep, neuroimmune and fear responses, and show that responses can be modulated at the neural level. Finally, we discuss factors that need to be considered in models of integrated stress responses and their relevance for understanding stress-related disorders in humans.

Sleep in multiple sclerosis: a systematic review and meta-analysis of polysomnographic findings.

STUDY OBJECTIVES: This study aims to explore the polysomnographically measured sleep differences between patients with multiple sclerosis (MS) and healthy control patients. METHODS: An electronic literature search was conducted in EMBASE, MEDLINE, all EBM databases, CINAHL, and PsycINFO from inception to March 2022. A random-effects model was applied to explore the pooled effect sizes of polysomnographic differences between patients with MS and control patients. RESULTS: Thirteen studies were identified for meta-analysis. The meta-analyses revealed significant reductions in stage N2 sleep and sleep efficiency and increases in wake time after sleep onset, the periodic limb movement index, and the periodic limb movement arousal index in patients with MS compared with control patients. Meta-regression analyses showed that some of the heterogeneity was explained by age and daytime sleepiness of patients with MS. CONCLUSIONS: Our study showed that polysomnographic abnormalities are present in MS. Our findings also underscore the need for a comprehensive polysomnographic assessment of sleep changes in patients with MS. Furthermore, the effects of age and daytime sleepiness in patients with MS on sleep changes should also be carefully considered and closely monitored in the management of MS. CITATION: Zhang Y, Ren R, Yang L, et al. Sleep in multiple sclerosis: a systematic review and meta-analysis of polysomnographic findings. J Clin Sleep Med. 2023;19(2):253-265.

Patterns of polysomnography parameters in 27 neuropsychiatric diseases: an umbrella review.

BACKGROUND: We provide an umbrella review of the reported polysomnographic changes in patients with neuropsychiatric diseases compared with healthy controls. METHODS: An electronic literature search was conducted in EMBASE, MEDLINE, All EBM databases, CINAHL, and PsycINFO. Meta-analyses of case-control studies investigating the polysomnographic changes in patients with neuropsychiatric diseases were included. For each meta-analysis, we estimated the summary effect size using random effects models, the 95% confidence interval, and the 95% prediction interval. We also estimated between-study heterogeneity, evidence of excess significance bias, and evidence of small-study effects. The levels of evidence of polysomnographic changes in neuropsychiatric diseases were ranked as follows: not significant, weak, suggestive, highly suggestive, or convincing. RESULTS: We identified 27 articles, including 465 case-control studies in 27 neuropsychiatric diseases. The levels of evidence of polysomnographic changes in neuropsychiatric diseases were highly suggestive for increased sleep latency and decreased sleep efficiency (SE) in major depressive disorder (MDD), increased N1 percentage, and decreased N2 percentage, SL and REML in narcolepsy, and decreased rapid eye movement (REM) sleep percentage in Parkinson's disease (PD). The suggestive evidence decreased REM latency in MDD, decreased total sleep time and SE in PD, and decreased SE in posttraumatic stress disorder and in narcolepsy. CONCLUSIONS: The credibility of evidence for sleep characteristics in 27 neuropsychiatric diseases varied across polysomnographic variables and diseases. When considering the patterns of altered PSG variables, no two diseases had the same pattern of alterations, suggesting that specific sleep profiles might be important dimensions for defining distinct neuropsychiatric disorders.