Neurobiology Of Stress Research Articles

Multidimensional Effects of Stress on Neuronal Exosome Levels and Simultaneous Transcriptomic Profiles

BackgroundAn excess of exosomes, nanovesicles released from all cells and key regulators of brain plasticity, is an emerging therapeutic target for stress-related mental illnesses. The effects of chronic stress on exosome levels are unknown; even less is known about molecular drivers of exosome levels in the stress response. MethodsWe used our state-of-the-art protocol with 2 complementary strategies to isolate neuronal exosomes from plasma, ventral dentate gyrus, basolateral amygdala, and olfactory bulbs of male mice to determine the effects of chronic restraint stress (CRS) on exosome levels. Next, we used RNA sequencing and bioinformatic analyses to identify molecular drivers of exosome levels. ResultsWe found that CRS led to an increase in the levels of neuronal but not total (not neuronally enriched) exosomes assayed in plasma and the ventral dentate gyrus, whereas CRS led to a decrease in neuronal but not total exosome levels in the basolateral amygdala. There was a specificity of effects as shown by a lack of changes in olfactory bulb exosome levels. In pursuit of advancing translational applications, we showed that acetyl-L-carnitine administration restored a CRS-induced increase in neuronal exosome levels assayed in plasma (the most accessible specimen). Furthermore, CRS-induced transcriptional changes in the ventral dentate gyrus and basolateral amygdala mirrored the opposite pattern of CRS-induced changes in neuronal exosome levels, with β-estradiol signaling as a potential upstream driver of exosome levels. ConclusionsThis study provides a foundation for future studies of new forms of local and distant communication in stress neurobiology by demonstrating specific relationships between peripheral and central neuronal exosomes and providing new candidate targets for the normalization of exosome levels.

Abstract P150: Epigenetic Mechanisms Linking Early-Life Stress to Hypertension Development: Implications for Prevention and Treatment

Purpose: Adverse childhood experiences (ACEs) and early-life stress (ELS) have been identified as significant risk factors for the development of hypertension later in life. This review synthesizes current evidence on how ELS induces epigenetic modifications, particularly DNA methylation and histone modifications, that predispose individuals to hypertension and discusses the implications for prevention and treatment strategies. Methods: A comprehensive literature review was conducted to identify studies examining the relationship between ELS, epigenetic modifications, and hypertension development. The search included studies investigating specific genes involved in stress response, inflammation, and cardiovascular regulation, such as NR3C1, SLC6A4, BDNF, OXTR, and FKBP5. Results: Studies have shown that ELS exposure can lead to persistent epigenetic alterations in genes involved in stress response, inflammation, and cardiovascular regulation. These modifications may contribute to impaired stress reactivity, heightened inflammation, and dysregulation of the renin-angiotensin system and endothelial function, potentially leading to the development of hypertension. The identification of ELS-induced epigenetic signatures opens up new avenues for early detection and intervention. DNA methylation biomarkers could be used to identify individuals at increased risk for hypertension due to ELS exposure, allowing for targeted prevention strategies. Moreover, the reversibility of epigenetic modifications presents an opportunity for novel treatment approaches, such as the use of epigenetic drugs and lifestyle interventions to mitigate the adverse cardiovascular effects of ELS. Conclusion: Understanding the epigenetic mechanisms linking ELS to hypertension development provides valuable insights for designing targeted prevention and treatment strategies. Future research should focus on translating these findings into clinical practice and developing personalized interventions based on an individual's ELS exposure and epigenetic profile. A multidisciplinary approach integrating epigenetics, stress neurobiology, and preventive medicine is required to address the long-term cardiovascular consequences of ELS effectively.

Influence of footshock number and intensity on the behavioral and endocrine response to fear conditioning and cognitive fear generalization in male rats

Foot-shock paradigms have provided valuable insights into the neurobiology of stress and fear conditioning. An extensive body of literature indicates that shock exposure can elicit both conditioned and unconditioned effects, although delineating between the two is a challenging task. This distinction holds crucial implications not only for the theoretical interpretation of fear conditioning, but also for properly evaluating putative preclinical models of post-traumatic stress disorder (PTSD) involving shock exposure. The characteristics of shocks (intensity and number) affect the strength of learning, but how these characteristics interact to influence conditioned and unconditioned consequences of shocks are poorly known. In this study, we aimed to investigate in adult male rats the impact of varying shock number and intensity on the endocrine and behavioral response to contextual fear conditioning and fear generalization to a novel environment markedly distinct from the shock context (i.e., fear generalization). Classical biological markers of stress (i.e., ACTH, corticosterone, and prolactin) were sensitive to manipulations of shock parameters, whereas these parameters had a limited effect on contextual fear conditioning (evaluated by freezing and distance traveled). In contrast, behavior in different novel contexts (fear generalization) was specifically sensitive to shock intensity. Notably, altered behavior in novel contexts markedly improved, but not completely normalized after fear extinction, hypoactivity apparently being the result of both conditioned and unconditioned effects of foot-shock exposure. The present results will contribute to a better understanding of shock exposure as a putative animal model of PTSD.

A single-arm, open-label pilot study of neuroimaging, behavioral, and peripheral inflammatory correlates of mindfulness-based stress reduction in multiple sclerosis

Multiple sclerosis (MS) is a chronic neurological disease frequently associated with significant fatigue, anxiety, depression, and stress. These symptoms are difficult to treat, and prominently contribute to the decreases in quality of life observed with MS. The underlying mechanisms of these “silent” symptoms are not well understood and include not just the psychological responses to a chronic disease, but also biological contributions from bidirectional psycho-neuro-immune (dys)regulation of systemic inflammatory biology. To address these issues, we conducted a prospective, observational pilot study to investigate the psychological, biological, and neuroarchitecture changes associated with a mindfulness-based stress reduction (MBSR) program in MS. The overarching hypothesis was that MBSR modulates systemic and central nervous system inflammation via top-down neurocognitive control over forebrain limbic areas responsible for the neurobiological stress response. 23 patients were enrolled in MBSR and assessed pre/post-program with structural 3 T MRI, behavioral measures, hair cortisol, and blood measures of peripheral inflammation, as indexed by the Conserved Transcriptional Response to Adversity (CTRA) profile. MBSR was associated with improvements across a variety of behavioral outcomes, as well as on-study enlargement of the head of the right hippocampus. The CTRA analyses revealed that greater inflammatory gene expression was related to worse patient-reported anxiety, depression, stress, and loneliness, in addition to lower eudaimonic well-being. Hair cortisol did not significantly change from pre- to post-MBSR. These results support the use of MBSR in MS and elucidate inflammatory mechanisms related to key patient-reported outcomes in this population.

Developing a Diverse, Equitable, and Inclusive Curriculum for Trainees

The importance of diversity in medical education has become increasingly clear with strong evidence showing its benefits in helping to reduce healthcare disparities and mortality, increase access to medical care, increase the number of clinicians practicing in medically underserved and rural communities, increased patient trust, improvement in patient-physician relationships, and better financial outcomes for health systems. As leaders in graduate medical education, the Teaching and Training Committee of the American Association for Geriatric Psychiatry (AAGP) proposed the creation and development of a curriculum that fosters an inclusive learning environment for our fellows, promotes open dialogue among everyone involved in the clinical process, and establishes anti-bias principles as integral parts of geriatric psychiatry education. The AAGP Diversity, Equity, and Inclusion (DEI) Curriculum Development subcommittee was established to carry out this task. Themes to be explored include ageism, racism and bias, social determinants of health, cultural humility, ethics of decision making in older adults, substance use, neurobiology of stress, the mental health of minoritized older adults, psychosocial and cultural aspects of aging, and laws that impact this population.This session details the process of establishing this important curricular thread as a template or framework that can be used in Geriatric Psychiatry training programs throughout the country and, in acknowledgement of the importance of the workforce that cares for older adults, ensures that it is practical and applicable to clinicians in non-academic settings. The panelists will highlight DEI curricular development in one fellowship program from the view of a trainee, the impact on recruiting a more representative workforce, and how to improve trainee and faculty engagement within and across programs.This presentation is sponsored by the Teaching and Training Committee.

Mental health in rock climbing

Introduction
 Rock climbing is an increasingly popular sport in the alpine region. It consists of different disciplines such as sport climbing, trad climbing or bouldering. Besides the professionally organized Olympic disciplines of indoor lead/speed climbing and bouldering, there is a large number of athletes who participate in advanced outdoor climbing without professional supervision. Due to this, rock climbing is associated with specific risks and heterogenous attitudes towards risk-taking and management of emotional reactions such as fear. Rock climbing also contains some risk factors for mental health problems, such as the importance of the athlete’s weight and the possibility of traumatic situations.
 Methods
 We systematically reviewed the current literature using the keywords “rock climbing» and eating disorder, depression, drugs, anxiety disorder, psychosis, bipolar disorder, ADHD, personality traits, and psychology.
 Results
 From the initial findings, we included 29 papers in the review.
 Discussion
 We found that rock climbers are at increased risk for eating disorders. Furthermore, there was a surprisingly high number of athletes who practiced the sport while under the influence of drugs. Several models of risk-taking behavior and neurobiological stress reactions are discussed. Finally, rock climbers showed some risk of becoming addicted to the sport.
 Conclusion:
 There is a lack of evidence regarding the prevalence and risk factors of psychiatric diagnoses in rock climbers. Further research is needed to support these athletes.

Atherosclerosis as the Damocles' sword of human evolution: insights from nonhuman ape-like primates, ancient human remains, and isolated modern human populations.

Atherosclerosis is the leading cause of death worldwide, and the predominant risk factors are advanced age and high-circulating low-density lipoprotein cholesterol (LDL-C). However, the findings of atherosclerosis in relatively young mummified remains and a lack of atherosclerosis in chimpanzees despite high LDL-C call into question the role of traditional cardiovascular risk factors. The inflammatory theory of atherosclerosis may explain the discrepancies between traditional risk factors and observed phenomena in current literature. Following the divergence from chimpanzees several millennia ago, loss of function mutations in immune regulatory genes and changes in gene expression have resulted in an overactive human immune system. The ubiquity of atherosclerosis in the modern era may reflect a selective pressure that enhanced the innate immune response at the cost of atherogenesis and other chronic disease states. Evidence provided from the fields of genetics, evolutionary biology, and paleoanthropology demonstrates a sort of circular dependency between inflammation, immune system functioning, and evolution at both a species and cellular level. More recently, the role of proinflammatory stimuli, somatic mutations, and the gene-environment effect appear to be underappreciated elements in the development and progression of atherosclerosis. Neurobiological stress, metabolic syndrome, and traditional cardiovascular risk factors may instead function as intermediary links between inflammation and atherosclerosis. Therefore, considering evolution as a mechanistic process and atherosclerosis as part of the inertia of evolution, greater insight into future preventative and therapeutic interventions for atherosclerosis can be gained by examining the past.

Pre-COVID respiratory sinus arrhythmia moderates associations between COVID-19 stress and child externalizing behaviors: Testing neurobiological stress theories.

Exposure to stress related to the COVID-19 pandemic contributes to psychopathology risk, yet not all children are negatively impacted. The current study examined a parasympathetic biomarker of stress sensitivity, respiratory sinus arrhythmia (RSA), as a moderator of the effects of exposure to pandemic stress on child internalizing and externalizing behaviors in a sample of children experiencing economic marginalization. Three to five years pre-pandemic, when children were preschool-aged, RSA during baseline and a challenging parent-child interaction were collected. Mid-pandemic, between November 2020 and March 2021, children's exposure to pandemic stress and internalizing and externalizing behaviors were collected. Results demonstrated that children who, pre-pandemic, demonstrated blunted parasympathetic reactivity (i.e., no change in RSA relative to baseline) during the dyadic challenge exhibited elevated risk for externalizing behaviors mid-pandemic. Further, this risk was greatest for children exposed to high and moderate levels of pandemic stress. Consistent with diathesis stress and polyvagal frameworks, these conditional effects suggest that blunted parasympathetic reactivity in response to stress in early childhood may escalate the development of externalizing behaviors following stress exposure at school age.

The Impact of Early Life Experiences on Stress Neurobiology and the Development of Anxiety.

We examine the association between stress exposure during early development (i.e., the prenatal period through the first two postnatal years) and variation in brain structure and function relevant to anxiety. Evidence of stress-related effects occurring in regions essential for emotional processing and regulation may increase susceptibility to anxiety.

Trait sensitivity to stress and cognitive bias processes in fish: A brief overview.

Like other animals, fish have unique personalities that can affect their cognition and responses to environmental stressors. These individual personality differences are often referred to as "behavioural syndromes" or "stress coping styles" and can include personality traits such as boldness, shyness, aggression, exploration, locomotor activity, and sociability. For example, bolder or proactive fish may be more likely to take risks and present lower hypothalamo-pituitary-adrenal/interrenal axis reactivity as compared to shy or reactive individuals. Likewise, learning and memory differ between fish personalities. Reactive or shy individuals tend to have faster learning and better association recall with aversive stimuli, while proactive or bold individuals tend to learn more quickly when presented with appetitive incentives. However, the influence of personality on cognitive processes other than cognitive achievement in fish has been scarcely explored. Cognitive bias tests have been employed to investigate the interplay between emotion and cognition in both humans and animals. Fish present cognitive bias processes (CBP) in which fish's interpretation of stimuli could be influenced by its current emotional state and open to environmental modulation. However, no study in fish has explored whether CBP, like in other species, can be interpreted as long-lasting traits and whether other individual characteristics may explain its variation. We hold the perspective that CBP could serve as a vulnerability factor for the onset, persistence, and recurrence of stress-related disorders. Therefore, studying fish's CBP as a state or trait and its interactions with individual variations may be valuable in future efforts to enhance our understanding of anxiety and stress neurobiology in animal models and humans.

The neurobiology of stress: Vulnerability, resilience, and major depression.

The neurobiology of stress: Vulnerability, resilience, and major depression.

Chronic fatigue syndromes: real illnesses that people can recover from

The ‘Oslo Chronic Fatigue Consortium’ consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brain's response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation.Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them.

Corticosterone injection into the basolateral amygdala before and after memory reactivation impairs the subsequent expression of fear memory in rats: An interaction of glucocorticoids and β-adrenoceptors

AbstractGlucocorticoid administration, before or after fear memory reactivation, impairs subsequent fear memory expression, but the underlying mechanisms are not well understood. The present study examined the role of basolateral amygdala (BLA) β-adrenoceptors in the effects of intra-BLA corticosterone injection on fear memory in rats. Bilateral cannulae were implanted in the BLA of Wistar male rats. The rats were trained and tested using an inhibitory avoidance task (1 mA footshock for 3 s). Forty-eight hours after training, corticosterone (CORT, 5, 10, or 20 ng/0.5 µl/side) and the β2-adrenoceptor agonist clenbuterol (CLEN, 10 or 20 ng/0.5 µl/side) or the β-adrenoceptor antagonist propranolol (PROP, 250 or 500 ng/0.5 µl/side) were injected into the BLA before or right after memory reactivation (retrieval, Test 1). We performed subsequent tests 2 (Test 2), 5 (Test 3), 7 (Test 4), and 9 (Test 5) days after Test 1. The results demonstrated that CORT injection before Test 1 disrupted memory retrieval and reduced fear expression in Tests 2–5, possibly due to enhanced extinction or impaired reconsolidation. CORT injection after Test 1 also impaired reconsolidation and reduced fear expression in Tests 2–5. CLEN prevented, but PROP exacerbated, the effects of CORT on fear expression. The reminder shock did not recover fear memory in CORT-treated animals, suggesting that reconsolidation, not extinction, was affected. These results indicate that glucocorticoids and β-adrenoceptors in the BLA jointly modulate fear memory reconsolidation and expression. Comprehending the neurobiology of stress and the impact of glucocorticoids on fear memory may lead to new treatments for stress and trauma-induced disorders such as PTSD.

Assistive technology for autism spectrum disorder children that experiences stress and anxiety

With the development of current technology and influences that have been made by the Industry 4.0 utilizing ICTs, IoT, smart systems and products and many others, Assistive Technology (AT) is an important and integral part of the daily life of many people who experience disabilities. Autism Spectrum Disorder (ASD) is a special category of disorder that can greatly benefit from its use. The purpose of this research is to collect data of Assistive Technology aimed at the detection, prevention and improvement of anxiety and stress (a characteristic of which has been proven to exist and is expressed in various ways in people with ASD). In the introduction, basic definitions regarding the neurobiology of stress and ASD are analyzed. In the main part AT, stress and anxiety correlations are made with ASD and AT devices are described and documented regarding their use for anxiety and stress in children and adolescents with ASD. The Assistive equipment and devices are divided into 2 main categories, 1) Low-tech and 2) Mid-High tech. The results of the research reveal a significant research gap in the use of AT to combat stress and anxiety and the difficulty of many promising options (especially in the domain of Mid-High tech) to be an easy and economical solution in integrating them into the daily life of people with ASD.

Sex differences in neuroendocrine, sympathetic nervous system, and affect responses to acute stress in cannabis users.

Cannabis is the most widely used illicit substance in the USA and is often reportedly used for stress reduction. Indeed, cannabinoids modulate signaling of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. However, the role of biological sex in this interaction between cannabis use and stress is poorly understood, despite sex differences in neurobiological stress responsivity, endocannabinoid signaling, and clinical correlates of cannabis use. The study aims to examine the role of biological sex in multisystem stress responsivity in cannabis users. Frequent cannabis users (> 3 times/week, n = 48, 52% male) and non-users (n = 41, 49% male) participated in an acute psychosocial stress paradigm. Saliva was collected at eight timepoints and analyzed for hypothalamic-pituitary-adrenal (cortisol) and sympathetic (alpha-amylase) indices of stress responsivity, and basal estradiol. Subjective ratings of negative affect, including distress, were collected at three timepoints. Cannabis users showed blunted pre-to-post-stress cortisol reactivity. Female cannabis users demonstrated greater blunted cortisol reactivity than their male counterparts. Sex moderated the effect of cannabis use on alpha-amylase responsivity over time, wherein female cannabis users showed flattened alpha-amylase responses across the stressor compared to male cannabis users and both non-user groups. Qualitatively, female cannabis users demonstrated the greatest pre-to-post-stress change in subjective distress. Differences in stress responding were not explained by estradiol or distress intolerance. Biological sex impacts multisystem stress responding in cannabis users. Paradoxically, female cannabis users showed the least physiological, but greatest subjective, responses to the stressor. Further research into sex differences in the effects of cannabis use is warranted to better understand mechanisms and clinical implications.

Connecting dots in disorders of gut-brain interaction: the interplay of stress and sex hormones in shaping visceral pain.

Visceral pain and stress are tightly intertwined bodily and emotional phenomena, which enable a flexible adaptation to environmental challenges by activating a response repertoire to restore homeostasis along the gut-brain axis. However, visceral pain and stress can persist widely independent of the initial cause, acquiring independent disease values and posing major health burdens as predominant features in disorders of gut-brain interaction (DGBI). Epidemiological data consistently documents an increased prevalence for women to suffer from chronic visceral pain, possibly shaped by sex hormones and modulated by stress and its biological and psychosocial correlates. Yet, mechanisms underlying the complex interactions between altered visceroception, stress and sex remain widely elusive, especially in clinical populations with DGBI. We herein selectively review mechanisms of interactions between stress and sex in the complex pathophysiology of DGBI. A particular emphasis is laid on visceral pain, in which stress constitutes a major risk factor as well as mediator, and sex-related differences are particularly pronounced. Building on the neurobiology of stress and mechanisms of gut-brain interactions, we highlight putative target mechanisms via which visceral pain and stress may converge with sex effects into a triad. Accommodating a global demographic shift, we propose a lifespan perspective in future research, which may enable a more fine-tuned evaluation of this complex interplay exerting distinct challenges during vulnerable developmental phases. This viewpoint may advance our understanding of pathophysiological processes and can ultimately inspire novel tailored prevention strategies and therapeutic approaches in the treatment of chronic visceral pain and DGBI across the lifespan.

Blunted neurobiological reactivity and attentional bias to threat underlie stress-related disorders in women survivors of intimate partner violence.

Intimate partner violence (IPV) alters women's neurobiological stress response systems. We propose that individual differences early in the attentional processing of threats are associated with these neurobiological mechanisms and contribute to mental illness in this population. We assessed attentional bias in relation to threat (AB) in women survivors of IPV (n = 69) and controls (n = 36), and examined overall cortisol secretion using hair cortisol (HC), and stress responsiveness measuring salivary cortisol and α-amylase (sAA) before (T0), and after (T1, T2) an acute psychosocial stress task (Trier Social Stress Test). We used repeated-measures ANCOVAs to explore the associations between Group (IPV, control) and AB with acute stress response, and regression models to examine the associations with mental health symptoms. There were no between-group differences in HC levels. An interaction between Group and AB was found regarding cortisol reactivity (p < 0.05). IPV women with threat avoidance AB showed a blunted cortisol response compared to controls and to IPV participants with threat vigilance AB. The association between sAA reactivity and the interaction between Group, AB, and time approached significance (p = 0.07), with a trend to lower sAA levels particularly in IPV women with threat avoidance AB. Group and cortisol reactivity were associated with symptoms of depression, generalized anxiety, and post-traumatic stress disorder (8-20% explained variance). Threat avoidance AB is associated with blunted acute cortisol response among women exposed to chronic stress (IPV). Experiencing IPV and acute cortisol response appear to be clearly implicated in long-term mental health problems.

Acetic acid-induced pain elicits stress-, and camouflage-related responses in zebrafish: Modulatory effects of opioidergic drugs on neurobehavioral phenotypes

While pain results from the activation of nociceptors following noxious stimuli, mounting evidence links pain- and stress-related responses in mammals. In zebrafish, the activation of hypothalamic-pituitary-interrenal (HPI) axis may also regulate body pigmentation (the camouflage response). Here, we aimed to investigate a putative relationship between pain-, stress-, and camouflage-related parameters in adult zebrafish. To answer this question, we assessed whether intraperitoneal acetic acid injection can activate the HPI axis, measuring whole-body cortisol and the camouflage response as physiological endpoints in the presence or absence of morphine or naloxone, an opioid antagonist. Acetic acid induced a stereotypic circling behavior in the top of the tank, accompanied by abdominal writhing-like response, a specific phenotype that reflects local nociceptive effect. Both whole-body cortisol levels and camouflage response increased in the acetic acid group, while morphine prevented these responses, and naloxone antagonized morphine-induced effects. Moreover, we observed positive correlations between representative behavioral, physiological and skin coloration endpoints, and a “pain index” was proposed to summarize phenotypic profile of zebrafish under different pharmacological manipulations. Collectively, these findings suggest a coordinated activation of pain, camouflage- and stress-related pathways following acetic acid injection in zebrafish. Our data also support that camouflage response represents a novel and relevant biomarker for future probing pain and stress neurobiology, with a robust sensitivity to opioidergic drugs.

Regular cannabis use is associated with history of childhood and lifetime trauma in a non-clinical community sample

Higher rate of substance use, including cannabis, has been reported in individuals with a history of childhood trauma, but less is known about the association between cannabis use with lifetime history of trauma and chronic stress, and potential gender differences in this association. This study systematically examined this association in a cross-sectional study of 841 individuals recruited between 2007 and 2012 from the community in New Haven, Connecticut. The Cumulative Adversity Index (CAI) was used to measure cumulative lifetime major life events, life trauma, and recent life events and chronic stress. Childhood Trauma Questionnaire (CTQ) was used to measure childhood trauma. Current and regular use of drugs were assessed using self-report questionnaires and objectively verified with urine drug testing. Higher rates of childhood trauma as well as lifetime trauma, and major life events were found in cannabis users, compared to non-users. The association between cannabis use with childhood trauma (total CTQ scores) was significant after controlling for age, gender, ethnicity and regular use of alcohol or cocaine. In logistic regression analysis, cannabis use had a significant positive association with major life events and lifetime trauma, but not with chronic stress, controlling for confounding factors including age, gender, ethnicity, and regular use of alcohol and cocaine. When analyzed separately, only in women the association between cannabis use and childhood trauma was significant. These associations point to further assessment of the impact of these gender differences on neurobiology of stress and cannabis misuse risk.

Sleep spindles, stress and PTSD: The state of the science and future directions

Sleep spindles are a signature feature of non-REM (NREM) sleep, with demonstrated relationships to sleep maintenance and learning and memory. Because PTSD is characterized by disturbances in sleep maintenance and in stress learning and memory, there is now a growing interest in examining the role of sleep spindles in the neurobiology of PTSD. This review provides an overview of methods for measuring and detecting sleep spindles as they pertain to human PTSD and stress research, presents a critical review of early findings examining sleep spindles in PTSD and stress neurobiology, and proposes several directions for future research. In doing so, this review underscores the extensive heterogeneity in sleep spindle measurement and detection methods, the wide range of spindle features that may be and have been examined, the many persisting unknowns about the clinical and functional relevance of those features, and the problems considering PTSD as a homogeneous group in between-group comparisons. This review also highlights the progress that has been made in this field and underscores the strong rationale for ongoing work in this area.