Neurobiology of Stress最新文献

Exposure to chronic stress contributes considerably to the development of cognitive impairments in psychiatric disorders such as depression, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and addictive behavior. Unfortunately, unlike mood-related symptoms, cognitive impairments are not effectively treated by available therapies, a situation in part resulting from a still incomplete knowledge of the neurobiological substrates that underly cognitive domains and the difficulty in generating interventions that are both efficacious and safe.

In this review, we will present an overview of the cognitive domains affected by stress with a specific focus on cognitive flexibility, behavioral inhibition, and working memory. We will then consider the effects of stress on neuronal correlates of cognitive function and the factors which may modulate the interaction of stress and cognition. Finally, we will discuss intervention strategies for treatment of stress-related disorders and gaps in knowledge with emerging new treatments under development.

Understanding how cognitive impairment occurs during exposure to chronic stress is crucial to make progress towards the development of new and effective therapeutic approaches.

Adverse early life experiences are strongly associated with reduced cognitive function throughout life. The link is strong in many human studies, but these do not enable assigning causality, and the limited access to the live human brain can impede establishing the mechanisms by which early-life adversity (ELA) may induce cognitive problems. In experimental models, artificially imposed chronic ELA/stress results in deficits in hippocampus dependent memory as well as increased vulnerability to the deleterious effects of adult stress on memory. This causal relation of ELA and life-long memory impairments provides a framework to probe the mechanisms by which ELA may lead to human cognitive problems. Here we focus on the consequences of a one-week exposure to adversity during early postnatal life in the rodent, the spectrum of the ensuing memory deficits, and the mechanisms responsible. We highlight molecular, cellular and circuit mechanisms using convergent trans-disciplinary approaches aiming to enable translation of the discoveries in experimental models to the clinic.

The lateral preoptic area (LPO) is a component of the hypothalamus involved in various physiological functions including sleep-wakefulness transition, thermoregulation, and water-salt balance. In this study, we discovered that distinct LPO excitatory neurons project separately to the aversive processing center lateral habenula (LHb) and the reward processing hub ventral tegmental area (VTA). Following chronic restraint stress (CRS), the LHb-projecting and VTA-projecting LPO neurons exhibited increased and decreased neuronal activities, respectively. Optogenetic activation of LHb-projecting LPO excitatory neurons and LPO excitatory neuronal terminals within LHb evoked aversion and avoidance behaviors, while activation of VTA-projecting LPO excitatory neurons and LPO excitatory neuronal terminals within VTA produced preference and exploratory behaviors in mice. Furthermore, either optogenetic inhibition of LHb-projecting LPO excitatory neurons or activation of VTA-projecting LPO excitatory neurons during CRS effectively prevented the development of depressive-like behaviors. Our study unveils, for the first-time, divergent pathways originating from LPO that regulate opposite affective states in mice and implicates that an imbalance of their activities could lead to depressive-like behaviors. These circuitries represent promising therapeutic targets to relieve emotional dysfunctions in neuropsychiatric disorders.

With the recent rise in the rate of alcohol use disorder (AUD) in women, the historical gap between men and women living with this condition is narrowing. While there are many commonalities in how men and women are impacted by AUD, an accumulating body of evidence is revealing sex-dependent adaptations that may require distinct therapeutic approaches. Preclinical rodent studies are beginning to shed light on sex differences in the effects of chronic alcohol exposure on synaptic activity in a number of brain regions. Prior studies from our laboratory revealed that, while withdrawal from chronic intermittent ethanol (CIE), a commonly used model of AUD, increased excitability in the ventral hippocampus (vHC) of male rats, this same treatment had the opposite effect in females. A follow-up study not only expanded on the synaptic mechanisms of these findings in male rats, but also established a CIE-dependent increase in the excitatory-inhibitory (E-I) balance of a glutamatergic projection from the basolateral amygdala to vHC (BLA-vHC). This pathway modulates anxiety-like behavior and could help explain the comorbid occurrence of anxiety disorders in individuals suffering from AUD. The present study sought to conduct a similar analysis of CIE effects on both synaptic mechanisms in the vHC and adaptations in the BLA-vHC pathway of female rats. Our findings indicate that CIE increases the strength of inhibitory neurotransmission in the vHC and that this sex-specific adaptation blocks, or at least delays, the increases in intrinsic vHC excitability and BLA-vHC synaptic transmission observed in males. Our findings establish the BLA-vHC pathway and the vHC as important circuitry to consider for future studies directed at identifying sex-dependent therapeutic approaches to AUD.

Purpose

Sexual minority young adults are at increased risk for hazardous drinking and alcohol use disorder compared to heterosexual adults. Heterosexism-based stressors contribute and often explain inequities in alcohol outcomes. However, the extant research primarily relies on correlational designs, and often neglects the importance of alcohol craving, despite its foundational role in addiction. Leveraging a novel experimental mood induction paradigm, this study examined the effects of exposure to vicarious heterosexism-based stress on alcohol craving and negative affect among sexual minority young adults who drink heavily. We also examined its effects on cannabis and nicotine craving among participants who used cannabis and nicotine, respectively. Lastly, we examined moderating factors that could influence the impact of exposure to heterosexism-based stress on alcohol craving.

Methods

Participants were 101 heavy drinking sexual minority young adults, ages 20–35 (M = 26.46 years old; SD = 3.49), recruited from the community (51.5% female sex assigned at birth; 76.3% cisgender; 51.5% plurisexual; and 42.6% racial and ethnic minorities). They completed three mood induction trials counterbalanced over three visits on different days: heterosexism stress, general stress, and neutral. Structured interviews assessed criteria for DSM-5 alcohol use disorder (AUD) and substance use, and self-report measures assessed lifetime traumatic stressors.

Results

Most participants met criteria for past-year AUD (74.7%). Exposure to heterosexism stress produced more negative affect and substance craving than the neutral mood induction, even while controlling for demographic variables and lifetime exposure to traumatic and heterosexism stressors. Exposure to heterosexism-based stress had large effects on alcohol craving among participants who had greater drinking to cope motives and heterosexism-specific rejection sensitivity, whereas the effects were small for those who had lower drinking to cope motives and heterosexism-specific rejection sensitivity. Demographic, lifetime stress, prior alcohol use, and AUD symptom severity variables were not significant moderators. Greater substance craving induced by heterosexism-based stress in the laboratory was associated with greater recent and current substance use.

Conclusions

This study findings show that vicarious exposure to heterosexism elicits negative mood and alcohol, cannabis, and nicotine craving among sexual minority young adults who engaged in heavy drinking. The effects for alcohol craving were largest among those who endorse high levels of drinking to cope motives and heterosexism-based rejection sensitivity. These findings have implications for oppression-based stress and motivational models of addiction.

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.

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.