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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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

Purpose:  To determine femoral construct fixation strength as bone plug length decreases in anterior cruciate ligament reconstruction (ACLR)., Methods:  Sixty fresh-frozen bone-patellar tendon-bone allografts were utilized and divided into 20-, 15-, and 10-mm length bone plug groups, subdivided further so that half utilized the patella side (P) for testing and half used the tibial side (T). Ten mm diameter recipient tunnels were created within the anatomic anterior cruciate ligament footprint of 60 cadaveric femurs. All bone plugs were 10 mm in diameter; grafts were fixed using a 7 × 23 mm metal interference screw. An Instron was used to determine the load to failure of each group. A one-way multivariate analysis of variance (MANOVA) was conducted to test the hypothesis that there would be one or more mean differences in fixation stability between 20- or 15-mm plug lengths (P or T) versus 10 mm T plug lengths when cross-compared, with no association between other P or T subgroups., Results:  The mean load to failure of the 20 mm plugs (20 P + T) was 457 ± 66N, 15 mm plugs (15 P + T) was 437 ± 74N, and 10 mm plugs (10 P + T) was 407 ± 107N. There was no significant difference between P + T groups: 20-versus 15-mm ( p  = 1.000), 15-versus 10-mm ( p  = 0.798), and 20-versus 10-mm ( p  = 0.200); P + T MANOVA ( p  = 0.291). Within groups, there was no significant difference between patella and tibial bone plug subgroups with a pullout force range between 469 ± 56N and 374 ± 116N and p -value ranging from p  = 1.000 for longer bone plugs to p  = 0.194 for shorter bone plugs; P versus T MANOVA ( p  = 0.113)., Conclusion:  In this human time zero cadaver model, there was no significant difference in construct failure between 20-,15-, and 10-mm bone plugs when fixed with an interference screw within the femoral tunnel, although fixation strength did trend down when from 20- to 15- to 10-mm bone plugs., Clinical Relevance:  There is a balance between optimal bone plug length on the femoral side for achieving adequate fixation as well as minimizing donor site morbidity and facilitating graft passage in ACLR. This study reveals utilizing shorter plugs with interference screw fixation is potentially acceptable on the femoral side if shorter plugs are harvested., Competing Interests: None declared., (Thieme. All rights reserved.)

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: The authors declare no conflict of interest. Larry D. Sanford and Laurie L. Wellman are serving as the Guest editors of this journal. We declare that Larry D. Sanford and Laurie L. Wellman had no involvement in the peer review of this article and had no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gernot Riedel., (© 2023 The Author(s). Published by IMR Press.)

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., (© 2023. The Author(s).)

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.

Given the growing prevalence of Alzheimer's disease (AD), we assessed the impact of virtually embodying someone with progressive AD. This pilot explored students' understanding of individuals' needs with dementia, as well as, the efficacy of virtual reality (VR) as a curricular tool. Second-year medical students (n = 150) completed a pre-survey, Embodied Labs, Inc. Beatriz Lab VR module, and a post-survey. Most students knew someone with dementia (72%), were a family member of someone with dementia (52%) or had worked with a patient (61%) with dementia. Using paired survey questions, students reported significant increases in understanding how their lives would be affected by dementia (71% vs. 94%) and the needs of a person with dementia (64% vs. 95%) after VR. They reported increased understanding of being a caregiver of someone with dementia (24% vs. 81%) and the impact it can have on the entire family (64% vs. 97%). Overall students agreed this simulation made them think about their approach to clinical skills (94%) and should be utilized more in the curriculum (76%). This pilot study indicated that this VR experience can be used to advance understanding of a person's experiences with dementia and that integrating VR into the medical curricula should be considered.

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.

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., Competing Interests: None., (© 2023 The Authors.)

Chronic sleep disturbances (CSDs) including insomnia, insufficient sleep time, and poor sleep quality are major public health concerns around the world, especially in developed countries. CSDs are major health risk factors linked to multiple neurodegenerative and neuropsychological diseases. It has been suggested that CSDs could activate microglia (Mg) leading to increased neuroinflammation levels, which ultimately lead to neuronal dysfunction. However, the detailed mechanisms underlying CSD-mediated microglial activation remain mostly unexplored. In this study, we used mice with three-weeks of sleep fragmentation (SF) to explore the underlying pathways responsible for Mg activation. Our results revealed that SF activates Mg in the hippocampus (HP) but not in the striatum and prefrontal cortex (PFc). SF increased the levels of corticotropin-releasing hormone (CRH) in the HP. In vitro mechanism studies revealed that CRH activation of Mg involves galectin 3 (Gal3) upregulation and autophagy dysregulation. CRH could disrupt lysosome membrane integrity resulting in lysosomal cathepsins leakage. CRHR2 blockage mitigated CRH-mediated effects on microglia in vitro. SF mice also show increased Gal3 levels and autophagy dysregulation in the HP compared to controls. Taken together, our results show that SF-mediated hippocampal Mg activation involves CRH mediated galectin 3 and autophagy dysregulation. These findings suggest that targeting the hippocampal CRH system might be a novel therapeutic approach to ameliorate CSD-mediated neuroinflammation and neurodegenerative diseases.

Stress induces neuroinflammation and disrupts sleep, which together can promote a number of stress-related disorders. Fear memories associated with stress can resurface and reproduce symptoms. Our previous studies have demonstrated sleep outcomes can be modified by stressor controllability following stress and fear memory recall. However, it is unknown how stressor controllability alters neuroinflammatory signaling and its association with sleep following fear memory recall. Mice were implanted with telemetry transmitters and experienced escapable or inescapable footshock and then were re-exposed to the shuttlebox context one week later. Gene expression was assessed with Nanostring ® panels using RNA extracted from the basolateral amygdala and hippocampus. Freezing and temperature were examined as behavioral measures of fear. Increased sleep after escapable stress was associated with a down-regulation in neuro-inflammatory and neuro-degenerative related genes, while decreased sleep after inescapable stress was associated with an up-regulation in these genes. Behavioral measures of fear were virtually identical. Sleep and neuroimmune responses appear to be integrated during fear conditioning and reproduced by fear memory recall. The established roles of disrupted sleep and neuroinflammation in stress-related disorders indicate that these differences may serve as informative indices of how fear memory can lead to psychopathology.

Sleep disorders have high comorbidity with drug addiction and function as major risk factors for developing drug addiction. Recent studies have indicated that both sleep disturbance (SD) and abused drugs could activate microglia, and that increased neuroinflammation plays a critical role in the pathogenesis of both diseases. Whether microglia are involved in the contribution of chronic SDs to drug addiction has never been explored. In this study, we employed a mouse model of sleep fragmentation (SF) with cocaine treatment and examined their locomotor activities, as well as neuroinflammation levels and dopamine signaling in the striatum, to assess their interaction. We also included mice with, or without, SF that underwent cocaine withdrawal and challenge. Our results showed that SF significantly blunted cocaine-induced locomotor stimulation while having marginal effects on locomotor activity of mice with saline injections. Meanwhile, SF modulated the effects of cocaine on neuroimmune signaling in the striatum and in ex vivo isolated microglia. We did not observe differences in dopamine signaling in the striatum among treatment groups. In mice exposed to cocaine and later withdrawal, SF reduced locomotor sensitivity and also modulated neuroimmune and dopamine signaling in the striatum. Taken together, our results suggested that SF was capable of blunting cocaine-induced psychoactive effects through modulating neuroimmune and dopamine signaling. We hypothesize that SF could affect neuroimmune and dopamine signaling in the brain reward circuitry, which might mediate the linkage between sleep disorders and drug addiction.

The central nucleus of the amygdala (CNA) projects to brainstem regions that generate and regulate rapid eye movement sleep (REM). We used optogenetics to assess the influence of CNA inputs into reticularis pontis oralis (RPO), pedunculopontine tegmentum (PPT) and nucleus subcoeruleus (SubC) on dark period sleep. We compared these results to effects of microinjections into CNA of the GABA A agonist, muscimol (MUS, inhibition of cell bodies) and tetrodotoxin (TTX, inhibition of cell bodies and fibers of passage). For optogenetics, male Wistar rats received excitatory (AAV5-EF1a-DIO -hChR2(H134R)-EYFP) or inhibitory (AAV-EF1a-DIO-eNpHR3.0-EYFP; DIO-eNpHR3.0) opsins into CNA and AAV5-EF1a-mCherry-IRES-WGA-Cre into RPO, PPT, or SubC. This enabled only CNA neurons synaptically connected to each region to express opsin. Optic cannulae for light delivery into CNA and electrodes for determining sleep were implanted. Sleep was recorded with and without blue or amber light stimulation of CNA. Separate rats received MUS or TTX into CNA prior to recording sleep. Optogenetic activation of CNA neurons projecting to RPO enhanced REM and did not alter non-REM (NREM) whereas activation of CNA neurons projecting to PPT or SubC did not significantly affect sleep. Inhibition of CNA neurons projecting to any region did not significantly alter sleep. TTX inactivation of CNA decreased REM and increased NREM whereas muscimol inactivation did not significantly alter sleep. Thus, the amygdala can regulate decreases and increases in REM, and RPO is important for CNA promotion of REM. Fibers passing through CNA, likely from the basolateral nucleus of the amygdala, also play a role in regulating sleep., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The basolateral amygdala (BLA) mediates the effects of stress and fear on rapid eye movement sleep (REM) and on REM-related theta (θ) oscillatory activity in the electroencephalograph (EEG), which is implicated in fear memory consolidation. We used optogenetics to assess the potential role of BLA glutamate neurons (BLA Glu ) in regulating behavioral, stress and sleep indices of fear memory, and their relationship to altered θ. An excitatory optogenetic construct targeting glutamatergic cells (AAV-CaMKIIα-hChR2-eYFP) was injected into the BLA of mice. Telemetry was used for real-time monitoring of EEG, activity, and body temperature to determine sleep states and stress-induced hyperthermia (SIH). For 3 h following shock training (ST: 20 footshocks, 0.5 mA, 0.5 s, 1 min interval), BLA was optogenetically stimulated only during REM (REM + L) or NREM (NREM + L). Mice were then re-exposed to the fear context at 24 h, 48 h, and 1 week after ST and assessed for behavior, SIH, sleep and θ activity. Control mice were infected with a construct without ChR2 (eYFP) and studied under the same conditions. REM + L significantly reduced freezing and facilitated immediate recovery of REM tested at 24 h and 48 h post-ST during contextual re-exposures, whereas NREM + L had no significant effect. REM + L significantly reduced post-ST REM-θ, but attenuated REM-θ reductions at 24 h compared to those found in NREM + L and control mice. Fear-conditioned SIH persisted regardless of treatment. The results demonstrate that BLA Glu activity during post-ST REM mediates the integration of behavioral and sleep indices of fear memory by processes that are associated with θ oscillations within the amygdalo-hippocampal pathway. They also demonstrate that fear memories can remain stressful (as indicated by SIH) even when fear conditioned behavior (freezing) and changes in sleep are attenuated.

Bi-directional interactions amongst the gut microbiota, immune system, and brain function are thought to be critical mediators of health and disease. The role sleep plays in mediating these interactions is not known. We assessed the effects of sleep fragmentation (SF) on the microbiota-gut-brain axis. Male C57BL/6NCrl mice (4 to 5 per cage, fed standard lab chow) experienced SF via mechanical stimulation at 2 min intervals during the light (SF) and dark (DD, dark disturbances) periods. Home cage (HC) controls were undisturbed. After 10 days, fecal samples were collected at light onset, midday, light offset, and midnight. Samples were also collected after 10 days without SF. Subsequently, the mice were randomized across groups and allowed 20 additional days of recovery followed by 10 days of SF or DD. To assess effects on the microbiota, 16S rRNA sequencing was used, and mesenteric lymph nodes (MLNs) and cortex and medial prefrontal cortex were analyzed using cytokine arrays. SF and DD produced significant alterations in the microbiota compared to HC, and DD had greater impact than SF on some organisms. SF produced marked suppression in MLNs of chemokines that regulate inflammation (CCL3, CCL4 and their receptor CCR5) and maintain the immune mucosal barrier (Cxcl13) at the same time that cortical cytokines (IL-33) indicated neuroinflammation. DD effects on immune responses were similar to HC. These data suggest that SF alters the microbiome and suppresses mucosal immunity at the same time that mediators of brain inflammation are upregulated. The translational implications for potential application to clinical care are compelling.

In this study, we investigated autophagy, glial activation status, and corticotropin releasing factor (CRF) signaling in the brains of mice after 5 days of sleep fragmentation (SF). Three different brain regions including the striatum, hippocampus, and frontal cortex were selected for examination based on roles in sleep regulation and sensitivity to sleep disruption. For autophagy, we monitored the levels of various autophagic induction markers including beclin1, LC3II, and p62 as well as the levels of lysosomal associated membrane protein 1 and 2 (LAMP1/2) and the transcription factor EB (TFEB) which are critical for lysosome function and autophagy maturation stage. For the status of microglia and astrocytes, we determined the levels of Iba1 and GFAP in these brain regions. We also measured the levels of CRF and its cognate receptors 1 and 2 (CRFR1/2). Our results showed that 5 days of SF dysregulated autophagy in the striatum and hippocampus but not in the frontal cortex. Additionally, 5 days of SF activated microglia in the striatum but not in the hippocampus or frontal cortex. In the striatum, CRFR2 but not CRFR1 was significantly increased in SF-experienced mice. CRF did not alter its mRNA levels in any of the three brain regions assessed. Our findings revealed that autophagy processes are sensitive to short-term SF in a region-specific manner and suggest that autophagy dysregulation may be a primary initiator for brain changes and functional impairments in the context of sleep disturbances and disorders.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1 ., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Pharmacological and optogenetic studies have demonstrated that the basolateral amygdala (BLA) plays a pivotal role in regulating fear-conditioned changes in sleep, in particular, rapid eye movement sleep (REM). However, the linkage between BLA and REM regulation has been minimally examined. In this study, we optogenetically activated or inhibited BLA selectively during spontaneous REM, and determined the effects on REM amounts and on hippocampus regulated EEG-theta (θ) activity. Excitatory (CaMKIIα-hChR2 (E123A)-eYFP-WPRE) or inhibitory (CaMKIIα-eNpHR3.0-eYFP-WPRE) optogenetic constructs were stereotaxically delivered targeting glutamatergic cells in BLA (BLA Glu ) of mice. Viral constructs without opsin (CaMKIIα-eYFP-WPRE) were used as controls. All mice were implanted with telemetry transmitters for monitoring electroencephalography (EEG), activity, and body temperature, and with optic cannulas for light delivery to the BLA. BLA Glu were optogenetically activated by blue light (473 nm), or inhibited by green light (532 nm), in 10 s epochs during REM, or non-REM (NREM), in undisturbed mice. Sleep amounts and EEG activity were analyzed. Projections from BLA Glu to neurons in hippocampus were immunohistochemically (IHC) examined. Brief optogenetic activation of BLA Glu during REM immediately reduced EEG theta activity (5-8 Hz, REM-θ), without affecting overall amount and propensity of sleep, while optogenetic inhibition increased REM-θ. Stimulation during NREM had no effect on EEG spectra or sleep. IHC results showed that glutamatergic and GABAergic cells in CA3 of the hippocampus received inputs from BLA Glu projection neurons. Activation of BLA Glu reduced, and inhibition increased, REM-θ without otherwise altering sleep. Optogenetic stimulation of BLA Glu may be useful for systematically manipulating sleep-related amygdalo-hippocampal interactions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Ground-based rodent models have established that space radiation doses (approximately those that astronauts will be exposed to on a mission to Mars) significantly impair performance in a wide range of cognitive tasks. Over the last 40 years there has been a progressive increase in both the complexity and the translatability (to humans) of the cognitive tasks investigated. This review outlines technical and conceptual advances in space radiation rodent testing approaches, along with the advances in analytical approaches, that will make data from ground based studies more amenable to probabilistic risk analysis. While great progress has been made in determining the impact of space radiation on many advanced cognitive processes, challenges remain that need to be addressed prior to commencing deep space missions. A summary of on-going attempts to address existing knowledge gaps and the critical role that rodent studies will have in establishing the impact of space radiation on even more complex (human) cognitive tasks are presented and discussed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Stress-related sleep disturbances are distressing clinical symptoms in posttraumatic stress disorder patients. Intensely stressful events and their memories change rapid eye movement (REM) sleep in animal models. REM sleep varies with individual differences of stress resilience or vulnerability. The basolateral amygdala (BLA) is a primary mediator of the effects of stress and fear memories on sleep. However, the molecular mechanisms in BLA regulating the effects of fear conditioning, shock training (ST) and context re-exposure (CTX) on REM sleep are not well known. MicroRNAs (miRNAs) are small, non-coding RNAs and posttranscriptional gene regulators of diverse biological processes. The aim of this study is to investigate ST- and CTX-altered miRNAs in the BLA of resilience and vulnerable animals and on REM sleep regulation. MiRNAs expression profiles in BLA were generated following ST and CTX using the Taqman Low Density rodent microRNA array. The altered BLA miRNAs expression and REM sleep reduction observed in ST and CTX vulnerable animals. AntagomiR-221 microinjection into BLA for one of the upregulated miRNAs, miR-221 in BLA, attenuated the REM sleep reduction. This study suggests that miRNAs in the BLA may play a significant role in mediating the effects of stress and fear memories on REM sleep.

Group II metabotropic glutamate receptors (mGluR2/3s) have been implicated in stress and trauma related disorders including post-traumatic stress disorder (PTSD). PTSD is characterized by flashbacks, anxiety, and sleep disturbances. While many people are exposed to trauma in their lifetime, only a small percentage go on to develop PTSD, indicating individual differences in stress and emotional processing. Wistar strain rats display directionally different rapid-eye movement sleep (REM) responses to footshock stress, with resilient rats having no change or an increase in REM and vulnerable rats having a significant reduction in REM compared to baseline. The basolateral nucleus of the amygdala (BLA) is key in regulating individual differences in stress-induced alterations in sleep. Group II metabotropic glutamate receptors (mGluR2/3s) negatively modulate glutamate and are implicated in fear, fear memory, and sleep. The current study evaluated the effect of mGluR2/3 agonist LY379268 (LY37) in BLA on stress and fear memory induced changes in sleep, EEG spectra, behavioral fear expression and physiological stress. These data indicate that vulnerable rats treated with LY37 have an attenuation of the REM reductions generally seen in vulnerable rats. Furthermore, LY37 altered EEG spectra in the delta (0.5-4.5 Hz) and theta (5-9.5 Hz) frequency. LY37 did not impact behavioral fear expression or physiological stress. Therefore, mGluR2/3s within BLA are implicated in regulating individual differences in sleep responses to fear- and stress-related memories., Competing Interests: Declaration of Competing Interest The authors do not have any conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Astronauts on the planned missions to Mars are expected to have to work more autonomously than on previous missions. Thus mission success may be influenced by the astronauts' ability to respond quickly to unexpected problems, processes that require several executive functions. The purpose of this study was to determine the impact that prolonged low dose and low dose rate exposure to neutrons had on two executive functions, and whether the severity and incidence of cognitive impairment was altered by sleep fragmentation., Materials and Methods: In this study we assessed the impact that prolonged (six month) low dose rate neutron exposure had on the ability of male Wistar rats to perform in two executive function tasks (i.e. attentional set shifting (ATSET) - a constrained cognitive flexibility task and the UCFlex assay - an unconstrained cognitive flexibility task). In recognition of the fact that astronauts also have to contend with inadequate sleep quantity and quality for much of their time in space, we determined the impact that relatively mild sleep disruption had on the ability to perform in the ATSET test in sham and neutron-irradiated rats., Results: Chronic low dose (18 cGy) and dose-rate (1 mGy/day) exposure of rats to mixed neutron and photon over the course of six months resulted in significant impairment of simple discrimination (SD) performance. Should similar effects occur in astronauts subjected to low dose rate exposure to Space Radiation, the impairment of SD performance would result in a decreased ability to identify and learn the 'rules' required to respond to a new task or situation. Analysis of the behavioral data by kernel density estimation revealed that 40% of rats had severe ATSET impairments. This value may be a best-case scenario because exposure to neutrons also adversely impacted performance in the UCFlex task. Furthermore, when the good performing rats were reevaluated after they had been subjected to sleep fragmentation, additional ATSET performance decrements were observed in the set shifting stages of the ATSET test, with only 7.4% of the neutron exposed rats able to successfully perform ATSET under normal and sleep fragmented conditions, as opposed to ∼55% of shams., Conclusion: Protracted low dose and low dose rate neutron exposures impairs executive functions in a high percentage of rats that were normally rested, however further detriments in performance become evident when the rats are subjected to sleep fragmentation.

Astronauts on deep space missions will be required to work autonomously and thus their ability to perform executive functions could be critical to mission success. Ground-based rodent experiments have shown that low (<25 cGy) doses of several space radiation (SR) ions impair various aspects of executive function. Translating ground-based rodent studies into tangible risk estimates for astronauts remains an enormous challenge, but should similar neurocognitive impairments occur in astronauts exposed to low-SR doses, a Numbers-Needed-to-Harm analysis (of the rodent data) predicts that approximately 30% of the astronauts could develop severe cognitive flexibility decrements. In addition to the health risks associated with SR exposure, astronauts have to contend with other stressors, of which inadequate sleep quantity and quality are considered to be major concerns. We have shown that a single session of fragmented sleep uncovered latent attentional set-shifting (ATSET) performance deficits in rats exposed to protracted neutron radiation that had no obvious defects in performance under rested wakefulness conditions. It is unclear if the exacerbating effect of sleep fragmentation (SF) only occurs in rats receiving protracted low-dose-rate-neutron radiation. In this study, we assessed whether SF also unmasks latent ATSET deficits in rats exposed to 5 cGy 600 MeV/n 28Si ions. Only sham and Si-irradiated rats that had good ATSET performance (passing every stage of the test on their first attempt) were selected for study. Sleep fragmentation selectively impaired performance in the more complex IDR, EDS and EDR stages of the ATSET test in the Si-irradiated rats. Set-shifting performance has rarely been affected by SR exposure in our studies conducted with rats tested under rested wakefulness conditions. The consistent SF-related unmasking of latent set-shifting deficits in both Si- and neutron-irradiated rats suggests that there is a unique interaction between sleep fragmentation and space radiation on the functionality of the brain regions that regulate performance in the IDR, EDS and EDR stages of ATSET. The uncovering of these latent SR-induced ATSET performance deficits in both Si- and neutron-irradiated rats suggests that the true impact of SR-induced cognitive impairment may not be fully evident in normally rested rats, and thus cognitive testing needs to be conducted under both rested wakefulness and sleep fragmentation conditions., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Study Objectives: To examine the rapid eye movement sleep (REM) response to mild stress as a predictor of the REM response to intense stress and brain-derived neurotrophic factor (BDNF) as a potential biomarker of stress resilience and vulnerability., Methods: Outbred Wistar rats were surgically implanted with electrodes for recording electroencephalography (EEG) and electromyogram (EMG) and intraperitoneal Data loggers to record body temperature. Blood was also obtained to measure circulating BDNF. After recovery, rats were exposed to mild stress (novel chamber, NC) and later intense stress (shock training, ST), followed by sleep recording. Subsequently, rats were separated into resilient (Res; n=27) or vulnerable (Vul; n = 15) based on whether or not there was a 50% or greater decrease in REM after ST compared to baseline. We then compared sleep, freezing, and the stress response (stress-induced hyperthermia, SIH) across groups to determine the effects of mild and intense stress to determine if BDNF was predictive of the REM response., Results: REM totals in the first 4 hours of sleep after exposure to NC predicted REM responses following ST with resilient animals having higher REM and vulnerable animals having lower REM. Resilient rats had significantly higher baseline peripheral BDNF compared to vulnerable rats., Conclusions: These results show that outbred rats display significant differences in post-stress sleep and peripheral BDNF identifying these factors as potential markers of resilience and vulnerability prior to traumatic stress., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Study Objectives: Sleep, in particular rapid eye movement (REM), has been linked to fear learning and extinction; however, their relationship is poorly understood. We determined how different delays of extinction training (ET) impact fear-conditioned behaviors, changes in sleep, and stress responses., Methods: EEG activity, movement, and body temperature in mice were monitored via telemetry. Following contextual fear conditioning (shock training [ST]), separate groups of mice were reexposed to the context at 24-hour post-ST (24h ET-1) and at 48-hour post-ST (48h ET-1). Post-ET sleep amount and sleep-associated EEG (delta and theta) activity were compared to baseline and to post-ST sleep. Freezing, locomotion, grooming, and rearing were monitored to determine effects of ET on fear behaviors. Body temperature immediately after ET was monitored to assess stress-induced hyperthermia (SIH)., Results: 24h ET-1 and 48h ET-1 produced similar freezing and REM reductions, but dissimilar rearing activity and SIH. 24h ET-1 was followed by periods of suppressed REM-associated theta (REM-θ) activity, immediately after ET and during the subsequent dark period. Suppressed REM-θ was specific to sleep after 24h ET-1, and did not occur after ST, nor after 48h ET-1., Conclusions: ET-1 at 24 and 48 hours after ST was associated with similar freezing and REM amounts, but with differences in other overt behaviors, in REM-θ, and in SIH. Freezing was not predictive of changes in other fear-associated responses. This study demonstrated that consideration of time delay from fear acquisition to extinction is important when assessing the relationships between extinction and behavior, sleep, and stress responses., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Intranasal instillation of vesicular stomatitis virus (VSV) into mice given controllable stress (modeled by escapable foot shock, ES) resulted in enhanced pathogenicity and decreased survival relative to infected mice given uncontrollable stress (modeled by inescapable foot shock, IS) and non-shocked control mice. Survival likely reflected differential cytokine gene expression that may have been regulated by miR146a, a predicted stress-responsive upstream regulator. Controllability also enhanced the accumulation of brain T resident memory cells that persisted long after viral clearance. The unexpected facilitatory effect of ES on antiviral neuroimmune responses and pathogenicity may arise from differential immunoactivating and immunosuppressive effects of uncontrollable and controllable stress., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction : The androgen receptor (AR) regulates immune-related epithelial-to-mesenchymal transition (EMT), and prostate cancer (PCa) metastasis. Primary tumor-infiltrating lymphocytes (TILs) [CD3 + , CD4 + , and CD8 + TILs] are potential prognostic indicators in PCa, and variations may contribute to racial disparities in tumor biology and PCa outcomes. Aim : To assess the technical feasibility of tumor microarray (TMA)-based methods to perform multi-marker TIL profiling in primary resected PCa. Methods : Paraffin-embedded tissue cores of histopathologically-confirmed primary PCa ( n = 40; 1 TMA tissue specimen loss) were arrayed in triplicate on TMAs. Expression profiles of AR, CD3 + , CD4 + , and CD8 + TILs in normal prostate, and the center and periphery of both the tumor-dominant nodule and highest Gleason grade were detected by IHC and associated with clinical and pathological data using standard statistical methodology. An independent pathologist, blinded to the clinical data, scored all samples (percent and intensity of positive cells). Results : TMAs were constructed from 21 (53.8%) Black and 18 (46.2%) White males with completely-resected, primarily pT2 stage PCa [pT2a ( n = 3; 7.7%); pT2b ( n = 2; 5.1%); pT2c ( n = 27; 69.2%); pT3a ( n = 5; 12.8%); mean pre-op PSA = 8.17 ng/ml]. The CD3, CD4, CD8, and CD8/CD3 cellular protein expression differed from normal in the periphery of the dominant nodule, the center of the highest Gleason grade, and the periphery of the highest Gleason grade ( P < 0.05). Correlations between TIL expression in the center and periphery of the dominant nodule, with corresponding center and periphery of the highest Gleason grade, respectively, were robust, and the magnitude of these correlations differed markedly by race ( P < 0.05). Conclusions : Multi-marker (AR, CD3, CD4, CD8) profiling with IHC analysis of TMAs consisting of primary, non-metastatic resected prostate cancer is technically feasible in this pilot study. Future studies will evaluate primary tumor immunoscore using semi-quantitative, IHC-based methodology to assess differences in the spectrum, quantity, and/or localization of TILs, and to gain insights into racial disparities in PCa tumor biology and clinical outcomes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The basolateral nucleus of the amygdala (BLA) plays a significant role in mediating individual differences in the effects of fear memory on sleep. Here, we assessed the effects of antagonizing corticotropin releasing factor receptor 1 (CRFR1) after shock training (ST) on fear-conditioned behaviors and sleep. Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at BLA. Data loggers were placed intraperitoneally to record core body temperature. The CRFR1 antagonist, antalarmin (ANT; 4.82 mM) was microinjected into BLA after shock training (ST: 20 footshocks, 0.8 mA, 0.5 s duration, 60 s interstimulus interval), and the effects on sleep, freezing and the stress response (stress-induced hyperthermia, SIH) were examined after ST and fearful context re-exposure alone at 7 days (CTX1) and 21 days (CTX2) post-ST. EEG and EMG recordings were scored for non-rapid eye movement sleep (NREM), rapid eye movement sleep (REM) and wakefulness. The rats were separated into 4 groups: Vehicle-vulnerable (Veh-Vul; n = 10), Veh-resilient (Veh-Res; n = 11), ANT-vulnerable (ANT-Vul; n = 8) and ANT-resilient (ANT-Res; n = 8) based on whether, compared to baseline, the rats showed a decrease or no change/increase in REM during the first 4 h following ST. Post-ST ANT microinjected into BLA attenuated the fear-conditioned reduction in REM in ANT-Vul rats on CTX1, but did not significantly alter REM in ANT-Res rats. However, compared to Veh treated rats, REM was reduced in ANT treated rats on CTX2. There were no group differences in freezing or SIH across conditions. Therefore, CRFR1 in BLA plays a role in mediating individual differences in sleep responses to stress and in the extinction of fear conditioned changes in sleep., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Study Objectives: Stressful events can directly produce significant alterations in subsequent sleep, in particular rapid eye movement sleep (REM); however, the neural mechanisms underlying the process are not fully known. Here, we investigated the role of the basolateral nuclei of the amygdala (BLA) in regulating the effects of stressful experience on sleep., Methods: We used optogenetics to briefly inhibit glutamatergic cells in BLA during the presentation of inescapable footshock (IS) and assessed effects on sleep, the acute stress response, and fear memory. c-Fos expression was also assessed in the amygdala and the medial prefrontal cortex (mPFC), both regions involved in coping with stress, and in brain stem regions implicated in the regulation of REM., Results: Compared to control mice, peri-shock inhibition of BLA attenuated an immediate reduction in REM after IS and produced a significant overall increase in REM. Moreover, upon exposure to the shock context alone, mice receiving peri-shock inhibition of BLA during training showed increased REM without altered freezing (an index of fear memory) or stress-induced hyperthermia (an index of acute stress response). Inhibition of BLA during REM under freely sleeping conditions enhanced REM only when body temperature was high, suggesting the effect was influenced by stress. Peri-shock inhibition of BLA also led to elevated c-Fos expression in the central nucleus of the amygdala and mPFC and differentially altered c-Fos activity in the selected brain stem regions., Conclusions: Glutamatergic cells in BLA can modulate the effects of stress on REM and can mediate effects of fear memory on sleep that can be independent of behavioral fear., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

The amygdala is an integrator of affective processing, and a key component of a network regulating social behavior. While decades of lesion studies in nonhuman primates have shown alterations in social interactions after amygdala damage, acute manipulations of the amygdala in primates have been underexplored. We recently reported (Wellman, Forcelli, Aguilar, & Malkova, 2016) that acute pharmacological inhibition of the basolateral complex of the amygdala (BLA) or the central nucleus of the amygdala increased affiliative social interactions in experimental dyads of macaques; this was achieved through microinjection of a GABA-A receptor agonist. Prior studies in rodents have shown similar effects achieved by blocking NMDA receptors or AMPA receptors within the BLA. Here, we sought to determine the role of these receptor systems in the primate BLA in the context of social behavior. In familiar dyads, we microinjected the NMDA receptor antagonist 2-amino-7-phosphonoheptanoic acid (AP7) or the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) and observed behaviors and social interactions in the immediate postinjection period. In striking contrast with our prior report using GABA agonists, and in contrast with prior reports in rodents using glutamate antagonists, we found that neither NMDA nor AMPA blockade increase social interaction. Both treatments, however, were associated with decreases in locomotion and manipulation and increases in passive behavior. These data suggest that local blockade of glutamatergic neurotransmission in BLA is not the functional equivalent of local activation of GABAergic signaling, and raise interesting questions regarding the functional microcircuitry of the nonhuman primate amygdala in the context of social behavior. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Rapid eye movement (REM) sleep is rapidly and persistently suppressed during vesicular stomatitis virus (VSV) encephalitis in C57Bl/6J (B6) mice. REM sleep suppression was associated with a complex global brain chemokine/cytokine response with bimodal kinetics although regionally distinct cytokine profiles were readily identified. Cytokine mRNA was translated either immediately or suppressed until the pathogen was cleared from the CNS. Innate signaling pathway (TLRs, RIG-I) activation occurred rapidly and sequentially prior to VSV neuroinvasion suggesting that antiviral states are quickly established in the CNS in advance of viral pathogen penetration. Il1β suppressed REM sleep mimicking aspects of VSV-induced sleep alterations whereas some robustly induced chemokines may be protective of REM. Thus, multiple brain chemokines may mediate sleep across VSV encephalitis via differential somnogenic effects., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Fear conditioning associated with inescapable shock training (ST) and fearful context re-exposure (CR) alone can produce significant behavioral fear, a stress response and alterations in subsequent REM sleep. These alterations may vary among animals and are mediated by the basolateral nucleus of the amygdala (BLA). Here, we used the GABA A agonist, muscimol (Mus), to inactivate BLA prior to CR and examined the effects on sleep, freezing and stress-induced hyperthermia (SIH). Wistar rats (n=28) were implanted with electrodes for recording sleep, data loggers for recording core body temperature, and with cannulae aimed bilaterally into BLA. After recovery, the animals were habituated to the injection procedure and baseline sleep was recorded. On experimental day 1, rats received ST (20 footshocks, 0.8mA, 0.5s duration, 60s interstimulus interval). On experimental day 7, the rats received microinjections (0.5μl) into BLA of either Mus (1.0μM; n=13) or vehicle (Veh; n=15) prior to CR (CR1). On experimental day 21, the animals experienced a second CR (CR2) without Mus. For analysis, the rats were separated into 4 groups: (Veh-vulnerable (Veh-Vul; n=8), Veh-resilient (Veh-Res; n=7), Mus-vulnerable (Mus-Vul; n=7), and Mus-resilient (Mus-Res; n=6)) based on whether or not REM was decreased, compared to baseline, during the first 4h following ST. Pre-CR1 inactivation of BLA did not alter freezing or SIH, but did block the reduction in REM in the Mus-Vul group compared to the Veh-Vul group. These data indicate that BLA is an important region for mediating the effects of fearful memories on sleep., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Brain circuitry underlying defensive behaviors includes forebrain modulatory sites, e.g. the amygdala and hypothalamus, and midbrain effector regions, such as the deep/intermediate layers of the superior colliculus (DLSC). When disinhibited, this network biases behavior towards reflexive defense reactions. While well characterized in rodent models, little is known about this system in the primate brain. Employing focal pharmacological manipulations, we have previously shown that activation of the DLSC triggers reflexive defensive responses, including cowering, escape behaviors and defensive vocalizations. Here, we show that activation of the DLSC also disrupts normal dyadic social interactions between familiar pairs of monkeys. When the basolateral complex of the amygdala (BLA) was inhibited concurrent with DLSC activation, cowering behavior was attenuated, whereas escape behaviors and defensive vocalizations were not. Moreover, inhibition of the BLA, previously shown to produce a profound increase in dyadic social interactions, was unable to normalize the decrease in social behavior resulting from DLSC activation. Together these data provide an understanding of forebrain-midbrain interactions in a species and circuit with translational relevance for the psychiatry of anxiety and post-traumatic stress disorders., (© The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Unlabelled: Both hypoactivity and hyperactivity in the amygdala are associated with perturbations in social behavior. While >60 years of experimental manipulations of the amygdala in animal models have shown that amygdala is critical for social behavior, many of these studies contradict one another. Moreover, several questions remain unaddressed. (1) What effect does activation of amygdala have on social behavior? (2) What is the effect of transient silencing, rather than permanent damage? (3) Is there a dissociation between the roles of the central (CeA) and basolateral amygdala (BLA) in regulating social behavior? (4) Can the prosocial effects of amygdala manipulations be explained by anxiolytic effects? We focally manipulated activity within the CeA or BLA in macaques by intracerebral microinjection of muscimol (to inactivate) or bicuculline (to activate) to these amygdaloid subregions. Social interactions were observed in pairs of highly familiar monkeys. We compared these effects to those achieved with systemic diazepam. Activation of the BLA but not CeA suppressed social behavior. Inhibition of either structure increased social behavior, although the effect was greater following inhibition of the BLA. Systemic diazepam was without effect. These studies, which are the first to bidirectionally manipulate the primate amygdala for effects on social behavior, revealed that (1) the amygdala, as a critical regulator of the social network, is bidirectionally sensitive to perturbations in activity, and (2) increased sociability after amygdala inactivation cannot be solely explained by decreased fear., Significance Statement: Many previous studies reported loss of social interactions following permanent damage to the amygdala in nonhuman primates. In contrast, we report that transient inhibition of the basolateral amygdala triggered a profound increase in social interactions in dyads of monkeys highly familiar with each other. We compared these effects to those of systemic diazepam, which failed to increase social behavior. While it has been suggested that suppression of "fear" could underlie the prosocial effects of amygdala manipulations, our data strongly suggest that impairment in fear processing per se cannot account for the prosocial effects of amygdala inhibition. Furthermore, our studies are the first to examine activation of the amygdala and to assess the separate roles of the amygdaloid nuclei in social behavior in primates., (Copyright © 2016 the authors 0270-6474/16/368746-11$15.00/0.)

Study Objectives: To examine the REM sleep response to stress and fearful memories as a potential marker of stress resilience and vulnerability and to assess the role of the basolateral amygdala (BLA) in mediating the effects of fear memory on sleep., Methods: Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at the BLA. Data loggers were placed intraperitoneally to record core body temperature. After recovery from surgery, the rats received shock training (ST: 20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval) and afterwards received microinjections of the GABAA agonist muscimol (MUS; 1.0 μM) to inactivate BLA or microinjections of vehicle (VEH) alone. Subsequently, the rats were separated into 4 groups (VEH-vulnerable (VEH-Vul; n = 14), VEH-resilient (VEH-Res; n = 13), MUS-vulnerable (MUS-Vul; n = 8), and MUS-resilient (MUS-Res; n = 11) based on whether or not REM was decreased, compared to baseline, during the first 4 h following ST. We then compared sleep, freezing, and the stress response (stress-induced hyperthermia, SIH) across groups to determine the effects of ST and fearful context re-exposure alone (CTX)., Results: REM was significantly reduced on the ST day in both VEH-Vul and MUS-Vul rats; however, post-ST MUS blocked the reduction in REM on the CTX day in the MUS-Vul group. The VEH-Res and MUS-Res rats showed similar levels of REM on both ST and CTX days. The effects of post-ST inactivation of BLA on freezing and SIH were minimal., Conclusions: Outbred Wistar rats can show significant individual differences in the effects of stress on REM that are mediated by BLA. These differences in REM can be independent of behavioral fear and the peripheral stress response, and may be an important biomarker of stress resilience and vulnerability., (© 2016 Associated Professional Sleep Societies, LLC.)

Corticotropin releasing factor (CRF) is a major mediator of central nervous system responses to stressors, including alterations in wakefulness and sleep. However, its role in mediating stress-induced alterations in sleep has not been fully delineated. In this study, we assessed the role of CRF and the non-specific CRF antagonist, astressin (AST), in regulating changes in sleep produced by signaled, escapable shock (SES) and signaled inescapable shock (SIS), two stressors that can increase or decrease sleep, respectively. Male BALB/cJ mice were surgically implanted with transmitters (DataSciences ETA10-F20) for recording EEG, activity and core body temperature by telemetry and a cannula for intracerebroventricular (ICV) microinjections. After baseline (Base) sleep recording, mice were presented tones (90 dB, 2 kHz) that started 5.0 s prior to and co-terminated with footshock (0.5 mA; 5.0 s maximum duration). SES mice (n = 9) always received shock but could terminate it by moving to the non-occupied chamber in a shuttlebox. Yoked SIS mice (n = 9) were treated identically, but could not alter shock duration. Training with SES or SIS was conducted over 2 days to stabilize responses. Afterwards, the mice received saline, CRF [0.4 μg (0.42 mM) or AST (1.0 μg (1.4 mM)] prior to SES or SIS. Sleep was analyzed over 20 h post-stress recordings. After administration of saline, REM was significantly greater in SES mice than in SIS mice whereas after CRF or AST, REM was similar in both groups. Total 20 h NREM did not vary across condition or group. However, after administration of saline and CRF, NREM episode duration was significantly decreased, and NREM episode number significantly increased, in SIS mice compared to SES animals. SES and SIS mice showed similar stress induced hyperthermia (SIH) across all conditions. These data demonstrate that CRF can mediate stress-induced changes in sleep independently of SIH, an index of hypothalamic-pituitary-adrenal axis activation.

The perirhinal cortex (PRc) is essential for visual recognition memory, as shown by electrophysiological recordings and lesion studies in a variety of species. However, relatively little is known about the functional contributions of perirhinal subregions. Here we used a systematic mapping approach to identify the critical subregions of PRc through transient, focal blockade of glutamate receptors by intracerebral infusion of kynurenic acid. Nine macaques were tested for visual recognition memory using the delayed nonmatch-to-sample task. We found that inactivation of medial PRc (consisting of Area 35 together with the medial portion of Area 36), but not lateral PRc (the lateral portion of Area 36), resulted in a significant delay-dependent impairment. Significant impairment was observed with 30 and 60 s delays but not with 10 s delays. The magnitude of impairment fell within the range previously reported after PRc lesions. Furthermore, we identified a restricted area located within the most anterior part of medial PRc as critical for this effect. Moreover, we found that focal blockade of either NMDA receptors by the receptor-specific antagonist AP-7 or AMPA receptors by the receptor-specific antagonist NBQX was sufficient to disrupt object recognition memory. The present study expands the knowledge of the role of PRc in recognition memory by identifying a subregion within this area that is critical for this function. Our results also indicate that, like in the rodent, both NMDA and AMPA-mediated transmission contributes to object recognition memory., (Copyright © 2015 the authors 0270-6474/15/355043-08$15.00/0.)