The relationship between sleep and autonomic health.

Objective: To examine the relationship between sleep and resting autonomic nervous system (ANS) functioning in college students. Participants: Participants were 141 undergraduate students (52 males) recruited from a large southeastern university during September-October 2017. Methods: Participants completed self-report inventories (demographic and sleep characteristics). Resting state skin conductance (SC) and heart rate variability (HRV) were measured in a laboratory setting for ANS functioning. Results: SC was positively associated with sleep quality (p = 0.027), sleep latency (p = 0.040), and use of sleep medication (p < 0.001). Analyses yielded a negative association between the standard deviation of the normal-normal interval of heart beats (SDNN) and the self-reported amount of time to fall asleep each night (p = 0.041). Sleep efficiency was negatively correlated with low frequency HRV (p = 0.002). Conclusions: Sleep components are associated with resting ANS activity, and targeted interventions focused on improved ANS functioning may benefit sleep quality in college students.

A pilot study exploring the relationship between wellness and physical fitness: an examination into autonomic health.

Objective: To explore the relationship between physical fitness and wellness in order to determine if perceptions of wellness can be predicted by physical fitness level.Participants: Sixty-seven college students (41 females; M = 20.86 years, SD = 4.23 years) were recruited from a large southeastern university during March-May 2018.Methods: Baseline measures for skin conductance and heart rate variability were obtained. Participants completed a wellness questionnaire and a series of tests (body composition, cardiorespiratory fitness, flexibility, and muscular fitness) designed to determine physical fitness levels. Correlation and regression analyses were run to explore relationships between physical fitness and wellness measures.Results: Muscular fitness and composite physical fitness significantly predicted perceived wellness. Heart rate variability was significantly related to physical fitness components.Conclusion: College students endorse muscular fitness as representative of health status; suggesting that by remaining physically active, in particular through muscular fitness, college student quality of life and cardiovascular health can be improved.

Wellness among African-American and Caucasian students attending a predominantly White institution.

The wellness movement is growing on college campuses; however, the examination of race is lacking. We examined aspects of physical and emotional well-being as a function of race in 197 college students at a predominantly White institution. Results revealed racial differences on diet, F(1, 196) = 7.537, p = 0.007 and resilient coping, F(1, 196) = 8.614, p = 0.004. Furthermore, regression analyses revealed that the association between stress and coping was moderated by race (F(1, 196) = 8.196, p = 0.005), demonstrating that Whites and Blacks experience and cope with stressors in differing ways. Findings of this study suggest that race is an influential factor of wellness and subsequent well-being in college students.

Dominance relationships in Syrian hamsters modulate neuroendocrine and behavioral responses to social stress.

Stress is a well-known risk factor for psychopathology and rodent models of social defeat have strong face, etiological, construct and predictive validity for these conditions. Syrian hamsters are highly aggressive and territorial, but after an acute social defeat experience they become submissive and no longer defend their home territory, even from a smaller, non-aggressive intruder. This defeat-induced change in social behavior is called conditioned defeat (CD). We have shown that dominant hamsters show increased neural activity in the ventromedial prefrontal cortex (vmPFC) following social defeat stress and exhibit a reduced CD response at social interaction testing compared to subordinates. Although the vmPFC can inhibit the neuroendocrine stress response, it is unknown whether dominants and subordinates differ in stress-induced activity of the extended hypothalamic-pituitary-adrenal (HPA) axis. Here, we show that, following acute social defeat, dominants exhibit decreased submissive and defensive behavior compared to subordinates but do not differ from subordinates or social status controls (SSCs) in defeat-induced cortisol concentrations. Furthermore, both dominants and SSCs show greater corticotropin-releasing hormone (CRH) mRNA expression in the basolateral/central amygdala compared to subordinates, while there was no effect of social status on CRH mRNA expression in the paraventricular nucleus of the hypothalamus or bed nucleus of the stria terminalis. Overall, status-dependent differences in the CD response do not appear linked to changes in stress-induced cortisol concentrations or CRH gene expression, which is consistent with the view that stress resilience is not a lack of a physiological stress response but the addition of stress coping mechanisms. Lay summary Dominant hamsters show resistance to the behavioral effects of acute social defeat compared to subordinates, but it is unclear whether social status modulates the neuroendocrine stress response in Syrian hamsters. This study indicates that dominant social status does not alter stress-induced activity of the extended hypothalamic-pituitary-adrenal (HPA) axis, which suggests that the ability of dominants to cope with social defeat stress is not associated with changes in their neuroendocrine stress response.

Changes in Brain-Derived Neurotrophic Factor Expression Influence Sleep-Wake Activity and Homeostatic Regulation of Rapid Eye Movement Sleep.

STUDY OBJECTIVES: Brain-derived neurotrophic factor (BDNF) expression and homeostatic regulation of rapid eye movement (REM) sleep are critical for neurogenesis and behavioral plasticity. Accumulating clinical and experimental evidence suggests that decreased BDNF expression is causally linked with the development of REM sleep-associated neuropsychiatric disorders. Therefore, we hypothesize that BDNF plays a role in sleep-wake (S-W) activity and homeostatic regulation of REM sleep. METHODS: Male and female wild-type (WT; BDNF +/+) and heterozygous BDNF (KD; BDNF +/-) rats were chronically implanted with S-W recording electrodes to quantify baseline S-W activity and REM sleep homeostatic regulatory processes during the light phase. RESULTS: Molecular analyses revealed that KD BDNF rats had a 50% decrease in BDNF protein levels. During baseline S-W activity, KD rats exhibited fewer REM sleep episodes that were shorter in duration and took longer to initiate. Also, the baseline S-W activity did not reveal any sex difference. During the 3-hour selective REM sleep deprivation, KD rats failed to exhibit a homeostatic drive for REM sleep and did not exhibit rebound REM sleep during the recovery S-W period. CONCLUSION: Interestingly, both genotypes did not reveal any sex difference in the quality and/or quantity of REM sleep. Collectively, these results, for the first time, unequivocally demonstrate that an intact BDNF system in both sexes is a critical modulator for baseline and homeostatic regulation of REM sleep. This study further suggests that heterozygous BDNF knockdown rats are a useful animal model for the study of the cellular and molecular mechanisms of sleep regulation and cognitive functions of sleep.

A sympathetic nervous system evaluation of obesity stigma.

The portrayal of obesity in the media is often one of negativity. Consequently, it may generate an increase in stigma. Obesity stigma, a form of social discrimination, is responsible for many of the negative psychological and physiological effects on individual wellness. These effects not only impact individual health, but also affect the economy, and ultimately, societal wellness. In an attempt to examine the influence of the media on obesity stigma, this study tested the hypothesis that positive priming would lead to a reduction in obesity stigma. To further our understanding of this relationship, we: 1) examined the role of priming on physiological measures (e.g. salivary alpha amylase and skin conductance) in 70 college students by introducing positive and negative media images of individuals with obesity, and 2) assessed psychological measures (e.g. perceived stress, need to belong, and self-esteem, and Body Mass Index). After the priming manipulation, participants read a vignette depicting the discrimination of an individual with obesity and answered subsequent questions assessing participants' attributional blame of obesity. Results of this study revealed that priming affects physiological responding to obesity stigmatization. In conclusion, these findings suggest that incorporating positive media images of individuals with obesity may be an effective tool for reducing stigma and the various physiological consequences associated with it, which in turn, can enhance societal health and wellness.

Cellular and Molecular Mechanisms of REM Sleep Homeostatic Drive: A Plausible Component for Behavioral Plasticity.

Homeostatic regulation of REM sleep drive, as measured by an increase in the number of REM sleep transitions, plays a key role in neuronal and behavioral plasticity (i.e., learning and memory). Deficits in REM sleep homeostatic drive (RSHD) are implicated in the development of many neuropsychiatric disorders. Yet, the cellular and molecular mechanisms underlying this RSHD remain to be incomplete. To further our understanding of this mechanism, the current study was performed on freely moving rats to test a hypothesis that a positive interaction between extracellular-signal-regulated kinase 1 and 2 (ERK1/2) activity and brain-derived neurotrophic factor (BDNF) signaling in the pedunculopontine tegmentum (PPT) is a causal factor for the development of RSHD. Behavioral results of this study demonstrated that a short period (<90 min) of selective REM sleep restriction (RSR) exhibited a strong RSHD. Molecular analyses revealed that this increased RSHD increased phosphorylation and activation of ERK1/2 and BDNF expression in the PPT. Additionally, pharmacological results demonstrated that the application of the ERK1/2 activation inhibitor U0126 into the PPT prevented RSHD and suppressed BDNF expression in the PPT. These results, for the first time, suggest that the positive interaction between ERK1/2 and BDNF in the PPT is a casual factor for the development of RSHD. These findings provide a novel direction in understanding how RSHD-associated specific molecular changes can facilitate neuronal plasticity and memory processing.

Sleep-Dependent Oscillatory Synchronization: A Role in Fear Memory Consolidation.

Sleep plays an important role in memory consolidation through the facilitation of neuronal plasticity; however, how sleep accomplishes this remains to be completely understood. It has previously been demonstrated that neural oscillations are an intrinsic mechanism by which the brain precisely controls neural ensembles. Inter-regional synchronization of these oscillations is also known to facilitate long-range communication and long-term potentiation (LTP). In the present study, we investigated how the characteristic rhythms found in local field potentials (LFPs) during non-REM and REM sleep play a role in emotional memory consolidation. Chronically implanted bipolar electrodes in the lateral amygdala (LA), dorsal and ventral hippocampus (DH, VH), and the infra-limbic (IL), and pre-limbic (PL) prefrontal cortex were used to record LFPs across sleep-wake activity following each day of a Pavlovian cued fear conditioning paradigm. This resulted in three principle findings: (1) theta rhythms during REM sleep are highly synchronized between regions; (2) the extent of inter-regional synchronization during REM and non-REM sleep is altered by FC and EX; (3) the mean phase difference of synchronization between the LA and VH during REM sleep predicts changes in freezing after cued fear extinction. These results both oppose a currently proposed model of sleep-dependent memory consolidation and provide a novel finding which suggests that the role of REM sleep theta rhythms in memory consolidation may rely more on the relative phase-shift between neural oscillations, rather than the extent of phase synchronization.

BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power.

Brain derived neurotrophic factor (BDNF) plays a pivotal role in structural plasticity, learning, and memory. Electroencephalogram (EEG) spectral power in the cortex and hippocampus has also been correlated with learning and memory. In this study, we investigated the effect of globally reduced BDNF levels on learning behavior and EEG power via BDNF heterozygous (KO) rats. We employed several behavioral tests that are thought to depend on cortical and hippocampal plasticity to varying degrees: novel object recognition, a test that is reliant on a variety of cognitive systems; contextual fear, which is highly hippocampal-dependent; and cued fear, which has been shown to be amygdala-dependent. We also examined the effects of BDNF reduction on cortical and hippocampal EEG spectral power via chronically implanted electrodes in the motor cortex and dorsal hippocampus. We found that BDNF KO rats were impaired in novelty recognition and fear memory retention, while hippocampal EEG power was decreased in slow waves and increased in fast waves. Interestingly, our results, for the first time, show sexual dimorphism in each of our tests. These results support the hypothesis that BDNF drives both cognitive plasticity and coordinates EEG activity patterns, potentially serving as a link between the two.

Beyond Emotional and Spatial Processes: Cognitive Dysfunction in a Depressive Phenotype Produced by Long Photoperiod Exposure.

Cognitive dysfunction in depression has recently been given more attention and legitimacy as a core symptom of the disorder. However, animal investigations of depression-related cognitive deficits have generally focused on emotional or spatial memory processing. Additionally, the relationship between the cognitive and affective disturbances that are present in depression remains obscure. Interestingly, sleep disruption is one aspect of depression that can be related both to cognition and affect, and may serve as a link between the two. Previous studies have correlated sleep disruption with negative mood and impaired cognition. The present study investigated whether a long photoperiod-induced depressive phenotype showed cognitive deficits, as measured by novel object recognition, and displayed a cognitive vulnerability to an acute period of total sleep deprivation. Adult male Wistar rats were subjected to a long photoperiod (21L:3D) or a normal photoperiod (12L:12D) condition. Our results indicate that our long photoperiod exposed animals showed behaviors in the forced swim test consistent with a depressive phenotype, and showed significant deficits in novel object recognition. Three hours of total sleep deprivation, however, did not significantly change novel object recognition in either group, but the trends suggest that the long photoperiod and normal photoperiod groups had different cognitive responses to total sleep deprivation. Collectively, these results underline the extent of cognitive dysfunction present in depression, and suggest that altered sleep plays a role in generating both the affective and cognitive symptoms of depression.

An examination of college student wellness: A research and liberal arts perspective.

Promoting wellness within academia reduces disease frequency and enhances overall health. This study examined wellness factors among undergraduate students attending a research university (n = 85) or a small liberal arts college (n = 126). Participants were administered surveys which measured physical, emotional, social, intellectual, and occupational wellness. Significant institutional differences emerged on measures of physical and social wellness. When collapsed across academic institutions, students who were gainfully employed reported greater self-efficacy compared with unemployed students. Gender differences emerged on measures of physical and social well-being. Our findings support the need for targeted interventions that facilitate enhanced college student development and well-being.

Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep.

Rapid eye movement (REM) sleep dysregulation is a symptom of many neuropsychiatric disorders, yet the mechanisms of REM sleep homeostatic regulation are not fully understood. We have shown that, after REM sleep deprivation, the pedunculopontine tegmental nucleus (PPT) plays a critical role in the generation of recovery REM sleep. In this study, we used multidisciplinary techniques to show a causal relationship between brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the PPT and the development of REM sleep homeostatic drive. Rats were randomly assigned to conditions of unrestricted sleep or selective REM sleep deprivation (RSD) with PPT microinjections of vehicle control or a dose of a TrkB receptor inhibitor (2, 3, or 4 nmol K252a or 4 nmol ANA-12). On experimental days, rats received PPT microinjections and their sleep-wake physiological signals were recorded for 3 or 6 h, during which selective RSD was performed in the first 3 h. At the end of all 3 h recordings, rats were killed and the PPT was dissected out for BDNF quantification. Our results show that K252a and ANA-12 dose-dependently reduced the homeostatic responses to selective RSD. Specifically, TrkB receptor inhibition reduced REM sleep homeostatic drive and limited REM sleep rebound. There was also a dose-dependent suppression of PPT BDNF up-regulation, and regression analysis revealed a significant positive relationship between REM sleep homeostatic drive and the level of PPT BDNF expression. These data provide the first direct evidence that activation of BDNF-TrkB signaling in the PPT is a critical step for the development of REM sleep homeostatic drive.

The homeostatic regulation of REM sleep: A role for localized expression of brain-derived neurotrophic factor in the brainstem.

Homeostatic regulation of REM sleep plays a key role in neural plasticity and deficits in this process are implicated in the development of many neuropsychiatric disorders. Little is known, however, about the molecular mechanisms that underlie this homeostatic regulation process. This study examined the hypothesis that, during selective REM sleep deprivation (RSD), increased brain-derived neurotrophic factor (BDNF) expression in REM sleep regulating areas is critical for the development of homeostatic drive for REM sleep, as measured by an increase in the number of REM sleep transitions. Rats were assigned to RSD, non-sleep deprived (BSL), or total sleep deprivation (TSD) groups. Physiological recordings were obtained from cortical, hippocampal, and pontine EEG electrodes over a 6h period, in which sleep deprivation occurred during the first 3h. In the RSD, but not the other conditions, homeostatic drive for REM sleep increased progressively. BDNF protein expression was significantly greater in the pedunculopontine tegmentum (PPT) and subcoeruleus nucleus (SubCD) in the RSD as compared to the TSD and BSL groups, areas that regulate REM sleep, but not in the medial preoptic area, which regulates non-REM sleep. There was a significant positive correlation between RSD-induced increases in number of REM sleep episodes and increased BDNF expression in the PPT and SubCD. These increases positively correlated with levels of homeostatic drive for REM sleep. These results, for the first time, suggest that selective RSD-induced increased expression of BDNF in the PPT and SubCD are determinant factors in the development of the homeostatic drive for REM sleep.

Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum.

Sleep-wake (S-W) disturbances are frequently associated with alcohol use disorders (AUD), occurring during periods of active drinking, withdrawal, and abstinence. These S-W disturbances can persist after months or even years of abstinence, suggesting that chronic alcohol consumption may have enduring negative effects on both homeostatic and circadian sleep processes. It is now generally accepted that S-W disturbances in alcohol-dependent individuals are a significant cause of relapse in drinking. Although significant progress has been made in identifying the socio-economic burden and health risks of alcohol addiction, the underlying neurobiological mechanisms that lead to S-W disorders in AUD are poorly understood. Marked progress has been made in understanding the basic neurobiological mechanisms of how different sleep stages are normally regulated. This review article in seeking to explain the neurobiological mechanisms underlying S-W disturbances associated with AUD, describes an evidence-based, easily testable, novel hypothesis that chronic alcohol consumption induces neuroadaptive changes in the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT). These changes include increases in N-methyl-d-aspartate (NMDA) and kainate receptor sensitivity and a decrease in gamma-aminobutyric acid (GABAB)-receptor sensitivity in the CCC-PPT. Together these changes are the primary pathophysiological mechanisms that underlie S-W disturbances in AUD. This review is targeted for both basic neuroscientists in alcohol addiction research and clinicians who are in search of new and more effective therapeutic interventions to treat and/or eliminate sleep disorders associated with AUD.

The Kv7 potassium channel activator retigabine decreases alcohol consumption in rats.

BACKGROUND: Activation of Kv7 potassium channels may decrease the reactivity of mesolimbic dopaminergic neurons that are implicated in mediating the reinforcing effects of ethanol. OBJECTIVES: The objective of this study was to determine whether the administration of the Kv7 potassium channel opener retigabine would decrease ethanol intake in Long Evans rats. METHODS: A limited access two-bottle choice model of alcohol (10% solution) consumption was used in this study. A separate group of animals was tested to evaluate the actions of retigabine on sucrose (5% solution) consumption to determine whether this drug might produce non-selective impairment of the ability of rats to drink liquids. Animals were treated with either vehicle or increasing doses (2.5-7.5 mg/kg SC) of retigabine administered over a 3-day period. RESULTS: Compared to vehicle, retigabine at a dose of 7.5 mg/kg produced a reduction in the amount of ethanol consumed. These effects did not occur in association with significant changes in water consumption. A significant time effect was found for the actions of retigabine in sucrose-drinking rats with a trend for an increase in sucrose intake with the highest dose of retigabine administered. CONCLUSIONS: These results indicate that the administration of retigabine may produce a decrease in ethanol consumption by rats at doses that do not significantly reduce the drinking of either water or a sucrose solution. These findings are consistent with the hypothesis that activation of Kv7 channels facilitates the reduction of alcohol consumption in the rat.

Dorsal subcoeruleus nucleus (SubCD) involvement in context-associated fear memory consolidation.

The neurobiological mechanisms of emotional memory processing can be investigated using classical fear conditioning as a model system, and evidence from multiple lines of research suggests that sleep influences consolidation of emotional memory. In rodents, some of this evidence comes from a common finding that sleep deprivation from 0 to 6 h after fear conditioning training impairs processing of conditioned fear memory. Here, we show that during a 6-h session of sleep-wake (S-W) recording, immediately after a session of context-associated fear conditioning training, rats spent more time in wakefulness (W) and less time in slow-wave sleep (SWS) and rapid eye movement (REM) sleep. This context-associated fear conditioning training-induced reduction in SWS lasts for 2 h, and the REM sleep reduction lasts throughout the entire 6-h post-training S-W recording period. Interestingly, these reductions in SWS and REM sleep during this 6-h period did not impair memory consolidation for context-associated fear conditioning. The results of this study show, for the first time, that lesions within the dorsal part of the subcoeruleus nucleus (SubCD), which were unintentionally caused by the implantation of bipolar recording electrodes, impair consolidation of context-associated fear conditioning memory. Together, the results of these experiments suggest that emotional memory processing associated with fear conditioning can be completed successfully within less than a normal amount of sleep, but it requires a structurally and functionally intact SubCD, an area in the brain stem where phasic pontine wave (P-wave) generating cells are located.

Effect of five-consecutive-day exposure to an anxiogenic stressor on sleep-wake activity in rats.

Repeated exposure to an anxiogenic stressor (AS) is a known environmental factor for the development of depression, yet the progression of sleep-wake (S-W) changes associated with the onset of AS-induced depression (ASID) is not completely understood. Thus, the aim of this study was to identify these progressive S-W changes by developing ASID in rats, via repeated exposure to an AS, and compare this ASID-associated sleep phenotype with the sleep phenotype of human depression. To achieve this aim, rats were first recorded for a 6 h period of baseline S-W activity without AS. Then, rats were subjected to 5 days of AS [Day 1: inescapable foot-shock; 5 trials of 3 s foot-shocks (1.0 mA) at 3 min intervals; Days 3-5: 15 trials of 5 s foot-shocks at 45 s intervals]. S-W activity was recorded for 6 h immediately after each AS treatment session. Two days later rats were again recorded for 6 h of S-W activity, but with no exposure to the AS (NASD). Compared to the baseline day: Day 1 of AS (ASD-1) increased wakefulness, slow-wave sleep (SWS) latency, and rapid-eye movement (REM) sleep latency, but decreased the total amount of REM sleep; ASD-2 animals remained awake throughout the 6 h S-W recording period; ASD-3, ASD-4, and ASD-5 (ASDs-3-5) decreased wakefulness, SWS latency, and REM sleep latency, but increased the total amount of REM sleep. Interestingly, these results reveal that initial exposure to the AS versus later, repeated exposure to the AS produced opposing S-W changes. On NASD, animals exhibited baseline-like S-W activity, except slightly less REM sleep. These results suggest that repeated AS produces a sleep phenotype that resembles the sleep phenotype of depression in humans, but consistent re-exposure to the AS is required. These results are promising because the methodological simplicity and reversibility of the ASID-associated S-W phenotype could be more advantageous than other animal models for studying the pathophysiological mechanisms that underlie the expression of ASID.