Neurobiology of Stress最新文献

Post-traumatic stress disorder (PTSD) is a severe stress-dependent psychiatric disorder characterized by impairment of fear memory extinction; however, biological markers to determine impaired fear memory extinction in PTSD remain unclear. In male mice with PTSD-like behaviors elicited by single prolonged stress (SPS), 19 differentially expressed proteins in the hippocampus were identified compared with controls. Among them, a biological macromolecular protein named deleted in colorectal cancer (DCC) was highly upregulated. Specific overexpression of DCC in the hippocampus induced similar impairment of long-term potentiation (LTP) and fear memory extinction as observed in SPS mice. The impairment of fear memory extinction in SPS mice was improved by inhibiting the function of hippocampal DCC using a neutralizing antibody. Mechanistic studies have shown that knocking down or inhibiting μ-calpain in hippocampal neurons increased DCC expression and induced impairment of fear memory extinction. Additionally, SPS-triggered impairment of hippocampal LTP and fear memory extinction could be rescued through activation of the Rac1–Pak1 signaling pathway. Our study provides evidence that calpain-mediated regulation of DCC controls hippocampal LTP and fear memory extinction in SPS mice, which likely through activation of the Rac1–Pak1 signaling pathway.

Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10–25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of contextual conditioned fear, we characterized distinct resilient and susceptible subpopulations based on lasting generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and ii.) expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing unsupervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Resilient subjects showed elevated prelimbic and lower ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient and non-shocked control subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) prefrontal, hippocampal and amygdalar neuronal hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.

Aim

Prior research has indicated a connection between CD4⁺ T cells and the development of anxiety, but the specific CD4⁺ T cell subsets linked to anxiety disorders remain uncertain. Our study seeks to investigate the relationship between distinct CD4⁺ T cell subsets and anxiety, as well as to explore whether CD4⁺ T cell subsets mediate the effect of chronic psychological stress on anxiety.

Methods

56 eligible matched participants were recruited in Peking Union Medical College Hospital. The diagnosis was made based on DSM-5 diagnostic criteria. The severity of anxiety and depression symptoms was assessed using the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale, respectively. The Life Events Scale (LES) evaluated the chronic stress level. CD4⁺ T cell subsets were characterized using multiparametric flow cytometry. To assess the impact of CD4⁺ T cells on the effect of chronic psychological stress on anxiety, Partial Least Squares Structural Equation Modeling (PLS-SEM) analysis was employed.

Results

We discovered fifteen notably distinct CD4⁺ T-cell subsets in anxiety disorder patients compared to healthy controls. Multiple linear regression analysis unveiled an association between anxiety severity and CD27⁺CD45RA⁻ Th cells, CD27⁺CD28⁺ Tregs, and the total Life Events Scale (LES) score. The PLS-SEM analysis demonstrated that CD4⁺ T cell subsets and LES could explain 80.2% of the variance in anxiety. Furthermore, it was observed that CD27⁺CD28⁺ Th/Treg cells acted as inverse mediators of the effects of LES on anxiety (P = 0.031).

Conclusions

Drug naïve anxiety disorder patients exhibited significant alterations in numerous CD4⁺ T-cell subsets. Specifically, the memory subset of CD27⁺CD45RA⁻ Th cells and the naïve subset of CD27⁺CD28⁺ Treg cells were found to be independent factors associated with the severity of anxiety. Additionally, the CD27⁺CD28⁺ Th and Treg cell subsets played a significant mediating role in the influence of long-term psychological stress on anxiety.

Chronic stress is well known to erode cognitive functions. Yet, our understanding of how repeated stress exposure impacts one of the fundamental bases of cognition: sensory processing, remains limited. The posterior parietal cortex (PPC) is a high order visual region, known for its role in visually guided decision making, multimodal integration, attention, and working memory. Here, we used functional measures to determine how repeated exposure to multiple concurrent stressors (RMS) affects sensory processing in the PPC in adult male mice. A longitudinal experimental design, repeatedly surveying the same population of neurons using in vivo two-photon imaging, revealed that RMS disrupts the balanced turnover of visually responsive cells in layer 2/3 of the PPC. Across the population, RMS-induced changes in visual responsiveness followed a bimodal distribution suggesting idiosyncratic stress effects. In cells that maintained their responsiveness across recording sessions, we found that stress reduced visual response magnitudes and feature selectivity. While we did not observe stress-induced elimination of excitatory synapses, noise correlation statistics indicated that RMS altered visual input to the neuronal population. The impact of RMS was restricted to visually evoked responses and was not evident in neuronal activity associated with locomotion onset. Together, our results indicate that despite no apparent synaptic reorganization, stress exposure in adulthood can disrupt sensory processing in the PPC, with the effects showing remarkable individual variation.

Individuals might be exposed to intense acute stress while having to make decisions with far-reaching consequences. Acute stress impairs processes required for decision-making by activating different biological stress cascades that in turn affect the brain. By knowing which stress system, brain areas, and receptors are responsible for compromised decision-making processes, we can effectively find potential pharmaceutics that can prevent the deteriorating effects of acute stress. We used a systematic review procedure and found 44 articles providing information on this topic. Decision-making processes could be subdivided into 4 domains (cognitive, motivational, affective, and predictability) and could be referenced to specific brain areas, while mostly being impaired by molecules associated with the sympathetic-adrenal-medullar and hypothalamic-pituitary-adrenal axes. Potential drugs to alleviate these effects included α₁ and β adrenoceptor antagonists, α₂ adrenoceptor agonists, and corticotropin releasing factor receptor_1/2 antagonists, while consistent stress-like effects were found with yohimbine, an α₂ adrenoceptor antagonist. We suggest possible avenues for future research.

Impairments in sleep and affect regulation are evident across a wide range of mental disorders. Understanding the sleep factors that relate to affect regulatory difficulties will inform mechanistic understanding and aid in treatment. Despite rising interest, some research challenges in this area include integrating across different clinical and non-clinical literatures investigating the role of sleep architecture (measured with polysomnography) and experimentally manipulated sleep, as well as integrating more explicit versus implicit affect regulation processes. In this comprehensive review, we use a unifying framework to examine sleep's relationship with implicit-automatic regulation and explicit-controlled regulation, both of which are relevant to mental health (e.g., PTSD and depression). Many studies of implicit-automatic regulation (e.g., fear extinction and safety learning) demonstrate the importance of sleep, and REM sleep specifically. Studies of explicit-controlled regulation (e.g., cognitive reappraisal and expressive suppression) are less consistent in their findings, with results differing depending on the type of affect regulation and/or way that sleep was measured or manipulated. There is a clear relationship between objective sleep and affect regulation processes. However, there is a need for 1) more studies focusing on sleep and explicit-controlled affect regulation; 2) replication with the same types of regulation strategies; 3) more studies experimentally manipulating sleep to examine its impact on affect regulation and vice versa in order to infer cause and effect; and 4) more studies looking at sleep's impact on next-day affect regulation (not just overnight change in affect reactivity).

Introduction

At the maternal-fetal interface in pregnancy, stress during pregnancy can lead to an increased vulnerability to later psychopathology of the fetus. Potential mediators of this association have scarcely been studied and may include early alterations of fetal brain-derived neurotrophic factor (BDNF). Amniotic fluid is of particular interest for effects on fetal endocrine alterations, as the assessment in amniotic fluid allows for measurements over a time integral. This study hypothesized that maternal psychometrics, socioeconomic status and glucocorticoids are related to BDNF levels in amniotic fluid at birth. The association of fetal BDNF with newborn anthropometrics was tested.

Methods

Women near term who underwent elective cesarean section and their newborns were investigated (n = 37). Maternal psychometrics, socioeconomic status and glucocorticoids (the sum of cortisol and cortisone) in amniotic fluid at birth were analyzed for an association with fetal BDNF in amniotic fluid at birth. Newborn anthropometrics were assessed by length, weight, head circumference and gestational age at birth.

Results

In bivariate analysis, maternal psychometrics and socioeconomic status were not related to fetal BDNF in amniotic fluid at birth. The sum of cortisol and cortisone related to increased fetal BDNF in amniotic fluid at birth (r = 0.745, p < 0.001). BDNF in amniotic fluid was associated negatively with fetal birth weight per gestational age (r = −0.519, p < 0.001), length per gestational age (r = −0.374, p = 0.023), head circumference per gestational age (r = −0.508, p = 0.001), but not with gestational age at birth. In multiple regression analysis, the sum of cortisol and cortisone (p < 0.001) and birth weight per gestational age (p = 0.012) related to higher fetal BDNF levels in amniotic fluid at birth (R² = 0.740, p < 0.001) when controlling for fetal sex and maternal age. Head circumference per gestational age predicted fetal BDNF with borderline significance (p = 0.058) when controlling for confounders.

Conclusion

Glucocorticoids in amniotic fluid were positively associated with high fetal BDNF at birth, which may be an adaptive fetal response. Maternal psychological variables and socioeconomic status did not link to fetal BDNF. Birth weight and head circumference per gestational age were inversely associated with fetal BDNF at birth, which may represent a compensatory upregulation of BDNF in fetuses with low anthropometrics. Longitudinal studies are needed to assess the role of stress during pregnancy on later offspring development. The analysis of additional fetal growth factors and inflammation upon maternal stress in further biomaterials such as the placenta is warranted, to understand mechanistic alterations of how maternal stress links to fetal development and an increased vulnerability for psychopathology.

Chronic ethanol dependence and withdrawal activate corticotropin releasing factor (CRF)-containing GABAergic neurons in the medial prefrontal cortex (mPFC), which tightly regulate glutamatergic pyramidal neurons. Using male CRF1:GFP reporter mice, we recently reported that CRF1-expressing (mPFC^CRF1+) neurons predominantly comprise mPFC prelimbic layer 2/3 pyramidal neurons, undergo profound adaptations following chronic ethanol exposure, and regulate anxiety and conditioned rewarding effects of ethanol. To explore the effects of acute and chronic ethanol exposure on glutamate transmission, the impact of chronic alcohol on spine density and morphology, as well as persistent changes in dendritic-related gene expression, we employed whole-cell patch-clamp electrophysiology, diOlistic labeling for dendritic spine analysis, and dendritic gene expression analysis to further characterize mPFC^CRF1+ and mPFC^CRF1− prelimbic layer 2/3 pyramidal neurons. We found increased glutamate release in mPFC^CRF1+ neurons with ethanol dependence, which recovered following withdrawal. In contrast, we did not observe significant changes in glutamate transmission in neighboring mPFC^CRF1− neurons. Acute application of 44 mM ethanol significantly reduced glutamate release onto mPFC^CRF1+ neurons, which was observed across all treatment groups. However, this sensitivity to acute ethanol was only evident in mPFC^CRF1− neurons during withdrawal. In line with alterations in glutamate transmission, we observed a decrease in total spine density in mPFC^CRF1+ neurons during dependence, which recovered following withdrawal, while again no changes were observed in mPFC^CRF− neurons. Given the observed decreases in mPFC^CRF1+ stubby spines during withdrawal, we then identified persistent changes at the dendritic gene expression level in mPFC^CRF1+ neurons following withdrawal that may underlie these structural adaptations. Together, these findings highlight the varying responses of mPFC^CRF1+ and mPFC^CRF1− cell-types to acute and chronic ethanol exposure, as well as withdrawal, revealing specific functional, morphological, and molecular adaptations that may underlie vulnerability to ethanol and the lasting effects of ethanol dependence.

Post-traumatic stress disorder (PTSD) is a debilitating disorder characterized by excessive fear, hypervigilance, and avoidance of thoughts, situations or reminders of the trauma. Among these symptoms, relatively little is known about the etiology of pathological avoidance. Here we sought to determine whether acute stress influences avoidant behavior in adult male and female rats. We used a stress procedure (unsignaled footshock) that is known to induce long-term sensitization of fear and potentiate aversive learning. Rats were submitted to the stress procedure and, one week later, underwent two-way signaled active avoidance conditioning (SAA). In this task, rats learn to prevent an aversive outcome (shock) by performing a shuttling response when exposed to a warning signal (tone). We found that acute stress significantly enhanced SAA acquisition rate in females, but not males. Female rats exhibited significantly greater avoidance responding on the first day of training relative to controls, reaching similar levels of performance by the second day. Males that underwent the stress procedure showed similar rates of acquisition to controls but exhibited resistance to extinction. This was manifest as both elevated avoidance and intertrial responding across extinction days relative to non-stressed controls, an effect that was not observed in females. In a second experiment, acute stress sensitized footshock unconditioned responses in males, not females. However, males and females exhibited similar levels of stress-enhanced fear learning (SEFL), which was expressed as sensitized freezing to a shock-paired context. Together, these results reveal that acute stress facilitates SAA performance in both male and female rats, though the nature of this effect is different in the two sexes. We did not observe sex differences in SEFL, suggesting that the stress-induced sex difference in performance was selective for instrumental avoidance. Future work will elucidate the neurobiological mechanisms underlying the differential effect of stress on instrumental avoidance in male and female rats.

Many everyday decisions, including those concerning our health, finances and the environment, involve choosing between a smaller but imminent reward (e.g., €20 now) and a later but larger reward (e.g., €40 in a month). The extent to which an individual prefers smaller imminent rewards over larger delayed rewards can be measured using delay discounting tasks. Acute stress induces a cascade of biological and psychological responses with potential consequences for how individuals think about the future, process rewards, and make decisions, all of which can impact delay discounting. Several studies have shown that individuals focus more on imminent rewards under stress. These findings have been used to explain why individuals make detrimental choices under acute stress. Yet, the evidence linking acute stress to delay discounting is equivocal. To address this uncertainty, we conducted a meta-analysis of 11 studies (14 effects) to systematically quantify the effects of acute stress on monetary delay discounting. Overall, we find no effect of acute stress on delay discounting, compared to control conditions (SMD = −0.18, 95% CI [-0.57, 0.20], p = 0.32). We also find that neither the gender/sex of the participants, the type of stressor (e.g., physical vs. psychosocial) nor whether monetary decisions were hypothetical or incentivized (i.e. monetary decisions were actually paid out) moderated the impact of acute stress on monetary delay discounting. We argue that establishing the effects of acute stress on the separate processes involved in delay discounting, such as reward valuation and prospection, will help to resolve the inconsistencies in the field.