Integrative approaches to studying sleep, stress, and related disorders

There has been a rapid increase in evidence demonstrating the complex interplay between stress, sleep, and mental health (Goldstein and Walker, 2014; Scott et al., 2021; Richards et al., 2020). This work has fueled a growing emphasis on studying integrated stress responses across multiple systems (sleep macro and micro-architecture, fear memory, and neuroimmune responses) rather than focusing on isolated domains (Sanford et al., 2023). Sleep disruptions in response to stress and fear responding are relatively conserved across mammals, allowing for cross-species identification and validation of sleep biomarkers associated with stress and trauma disorders. New technologies have enabled longer-term, less intrusive measurements of multiple physiologic parameters during sleep (Birrer et al., 2024; Chinoy et al., 2021), providing more accurate and nuanced insights into the complex sleep disruptions associated with stress-related disorders. This complexity has required considering individual differences in resilience and vulnerability to stress (Palagini et al., 2018; Neylan et al., 2021), which may ultimately lead to more personalized interventions for stress-related disorders. Emerging preclinical studies are clarifying the molecular mechanisms underpinning synaptic plasticity during sleep following stress exposure (Abel et al., 2013; Gronli et al., 2013). Clinical experimental studies are demonstrating the importance of sleep spindles and other facets of sleep microarchitecture in emotional memory processing and stress responses (Tabarak et al., 2024; Denis et al., 2021; Rho et al., 2023), particularly in trauma-exposed individuals. Sleep-focused interventions are being explored as potential early interventions or adjuncts to PTSD treatment (Talbot et al., 2014; Colvonen et al., 2019; Carlsson et al., 2018). Improving sleep in the aftermath of trauma is seen as a promising approach to promote natural recovery and resilience.

In the setting of all of these developments, this special issue covers several interconnected themes related to sleep, stress exposure and reactivity, and mental health. Nine articles span both preclinical studies in rodents and clinical studies in healthy and subjects with PTSD and other mental health disorders. The main themes covered in the Special Issue are highlighted as follows.

1. Sleep and synaptic plasticity

Diering explores the molecular mechanisms underlying synaptic plasticity during sleep and their role in memory consolidation and forgetting (Diering, 2023). Key aspects include: 1) the role of immediate early genes (IEGs) like Arc and Homer1a in synaptic plasticity during sleep; 2) the synaptic homeostasis hypothesis (SHY) and how sleep promotes selective weakening or strengthening of synapses; and 3) the interaction between circadian rhythms and sleep-wake cycles in influencing synaptic plasticity. This review proposes that Arc and Homer1a provide mechanistic insights into the localized accumulation of sleep need within specific neurons and the selective synaptic plasticity that occurs during sleep. These mechanisms may offer a framework for understanding how sleep promotes both memory consolidation and adaptive forgetting. The review highlights the need for further research to fully elucidate the complex interactions between wake-sleep cycles, circadian rhythms, and synaptic plasticity in learning and memory processes.

2. Sleep disturbances and mental health in vulnerable populations

Dolsen and colleagues examines the relationships between sexual and gender minority (SGM) identity, sleep disturbance, and suicide-related thoughts and behaviors (STBs)(Dolsen et al., 2022). SGM individuals experience higher rates of STBs compared to cisgender and/or heterosexual people. Sexual minority individuals are 2–6 times more likely to attempt suicide, while 18–44% of gender minority individuals report suicide attempts. SGM people also experience higher rates of sleep disturbance. Both short sleep duration (≤5 hours) and long sleep duration (>9 hours) are more common among SGM groups compared to cisgender/heterosexual individuals. Minority stress theory is proposed as a framework to understand the elevated rates of mental health issues, including sleep disturbance and STBs, among SGM people. Experiences of discrimination, expectations of rejection, and internalized stigma contribute to chronic stress. Sleep disturbance is proposed as a potential mechanism through which minority stress increases suicide risk. Future research is expected to focus on developing tailored sleep interventions for SGM individuals.

3. Neurobiological mechanisms of sleep and stress disorders

Several articles focus on sleep mechanisms and comorbidities in post-traumatic stress disorder (PTSD), including insomnia and nightmares. Pace-Schott and colleagues review the relationship between sleep, fear extinction, and the development of post-traumatic stress disorder (PTSD) following trauma exposure (Pace-Schott et al., 2023). Sleep plays an important role in consolidating both fear and extinction memories. In healthy individuals, sleep, particularly REM sleep, helps strengthen extinction learning and recall. Sleep disturbances, especially in the acute post-trauma period, are associated with increased risk of developing PTSD. Pre-existing sleep disorders and poor sleep quality immediately after trauma predict worse outcomes. Sleep disturbances appear to be both a risk factor for and a maintaining factor in PTSD. Addressing sleep issues may be an important component of PTSD prevention and treatment.

Grafe and colleagues provides a comprehensive overview of sleep disturbances in post-traumatic stress disorder (PTSD), focusing on insights from both clinical studies and animal models. Various animal models have been developed to study PTSD-like sleep disturbances. These include repeated social defeat, repeated restraint stress, and fear conditioning paradigms. These models have shown insomnia-like features such as increased sleep onset latency, reduced sleep efficiency, and increased wake time after sleep onset. They examine the role of REM fragmentation in PTSD and review the neurobiological substrates of REM sleep regulation, including the roles of cholinergic and monoaminergic neurons in the brainstem, as well as orexin neurons in the hypothalamus (Grafe et al., 2024). Future research is expected to develop more comprehensive animal models that examine responses across multiple interacting systems to better understand stress-related psychopathology.

Natraj and Richards examine the role of sleep spindles in stress responses and emotional memory processing and relevance to PTSD (Natraj and Richards, 2023). Some studies have found associations between spindle activity and consolidation of negative emotional memories or intrusive trauma memories. However, other findings suggest spindles may play a beneficial role in emotion regulation and processing of stressful information. They propose that focusing on specific neurocognitive functions known to be associated with spindles, rather than broad PTSD vs. control comparisons, may be a more fruitful research approach. They recommend using established spindle detection methods, examining multiple spindle features, and linking findings to specific behavioral and clinical outcomes.

Sanford and colleagues discuss the complex interactions between stress, sleep, fear memory, and neuroimmune responses, and their relevance for understanding trauma and stress-related disorders (Sanford et al., 2023). Sleep, particularly REM sleep, plays an important role in processing emotional memories and stress. Disruptions in sleep are associated with stress-related psychopathology. The neuroimmune system is activated by stress and can lead to neuroinflammation, which is implicated in psychiatric disorders. Controllable stress (escapable shock) tends to produce adaptive responses like increased REM sleep and suppressed neuroinflammation. Uncontrollable stress (inescapable shock) leads to decreased REM and increased neuroinflammation. Their report emphasizes the need to consider stress responses as integrated across multiple interacting systems, rather than relying on single behavioral or physiological measures.

Another important potential mechanism that is explored in this series is the role of the autonomic nervous system in sleep effects on PTSD. Woodward reviews blood pressure "dipping", the normal decrease in BP during sleep, and heart rate variability (HRV), particularly high-frequency HRV (HF-HRV) which reflects parasympathetic nervous system activity, during sleep in PTSD patients (Woodward, 2022). Studies on BP dipping in PTSD have shown mixed results, with only one out of four studies finding evidence of reduced BP dipping in PTSD. HF-HRV studies have more consistently found evidence of reduced parasympathetic activity during sleep in PTSD. The findings suggest that PTSD may be associated with impaired parasympathetic function during sleep rather than increased sympathetic activity. Future studies are likely to use multi-night recordings to examine night-to-night variability in sleep patterns and autonomic function.

4. Sleep and affect regulation

Straus and colleagues examine the relationship between objective sleep measures and affect regulation, focusing on explicit-controlled and implicit-automatic regulation strategies (Straus et al., 2024). The authors analyzed 50 studies that used polysomnography or sleep manipulation techniques to investigate these connections. Sleep, particularly REM sleep, appears to play a critical role in affective processes, especially for implicit-automatic regulation. The relationship between sleep and explicit-controlled affect regulation is less clear and requires further investigation. They highlight the need for more research on explicit-controlled affect regulation and sleep, including studies with consistent operationalizations and replications of specific regulation strategies, and experimental manipulation of sleep to examine its causal impact on affect regulation and vice versa.

5. Sex differences in sleep and stress responses

Wright and colleagues examines sex-specific neurobiological outcomes of sleep deprivation (Wright et al., 2023). Specifically, they focus on differences in stress responses, cardiovascular effects, and cognitive impairments between males and females following sleep loss. They review the role of sex hormones and other biological factors in mediating these differences. The authors emphasize that more research directly comparing males and females is needed, as many studies have been male-only or underpowered to detect sex differences. Understanding sex-specific mechanisms could lead to more personalized treatments for sleep disorders and associated health issues.

Collectively the topics covered in this special issue highlight the complex interplay between sleep, stress, and various neurobiological systems, emphasizing the importance of sleep in emotional regulation, memory consolidation, and stress disorders. Emerging trends suggest a move towards more integrative, personalized, and technologically advanced approaches to studying sleep, stress, and related disorders. The field is increasingly recognizing the complexity of these processes and the need for multifaceted research strategies to fully understand and address sleep-related health issues. This underscores the potential for sleep-focused interventions in both prevention and treatment of mood and anxiety disorders.