Neurobiology of Stress最新文献

{"title":"Dynamic changes of serotonin transporter expression in the prefrontal cortex evoked by aggressive social interactions","authors":"Huba Szebik ,&nbsp;Christina Miskolczi ,&nbsp;Bíborka Bruzsik ,&nbsp;Gyula Balla ,&nbsp;Soma Szabó ,&nbsp;László Biró ,&nbsp;Éva Mikics","doi":"10.1016/j.ynstr.2025.100722","DOIUrl":"10.1016/j.ynstr.2025.100722","url":null,"abstract":"<div><div>Aggression is a complex behavior influenced by developmental experiences, internal state, and social context, yet its neurobiological underpinnings remain insufficiently understood. The serotonergic system, particularly the serotonin transporter (SERT), plays a crucial role in aggression regulation. Here, we investigated region-specific, dynamic changes in SERT expression following aggressive interactions and in mice subjected to early-life social adversity. We found that aggressive encounters (resident-intruder test) triggered a significant, rapid increase in SERT immunoreactivity within 90 min, accompanied by neuronal activation in aggression-related brain regions, including the medial prefrontal cortex (mPFC), lateral septum (LS), medial amygdala (MeA), ventromedial hypothalamus (VMHvl), lateral habenula (LH), and dorsal raphe (DR), but not in the paraventricular thalamus (PVT). Notably, this SERT upregulation occurred across the aggression circuitry but was accompanied by a significant increase in 5-HT levels only in the mPFC, a key region in top-down regulation of social and aggressive behavior. This SERT upregulation was not observed following exposure to a non-social challenge, suggesting that it may be more specifically associated with social contexts. Using super-resolution microscopy, we identified an increased density of SERT localization points within serotonergic mPFC axons after an aggressive encounter. Social isolation during adolescence, a model of early social neglect, impaired this rapid SERT response, particularly in the ventral and medial orbitofrontal regions, and altered the relationship between SERT levels and aggression-related behaviors. These findings demonstrate that SERT expression undergoes rapid, experience-dependent plasticity in response to social aggression, and that early-life adversity disrupts this adaptive mechanism, providing new insights into the serotonergic regulation of aggression and its potential relevance for stress-related social dysfunctions.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100722"},"PeriodicalIF":4.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific regulation of microglial MyD88 in HMGB1-Induced anxiety phenotype in mice","authors":"Ashleigh Rawls ,&nbsp;Julia Dziabis ,&nbsp;Dang Nguyen ,&nbsp;Dilara Anbarci ,&nbsp;Madeline Clark ,&nbsp;Grace Zhang ,&nbsp;Kafui Dzirasa ,&nbsp;Staci D. Bilbo","doi":"10.1016/j.ynstr.2025.100721","DOIUrl":"10.1016/j.ynstr.2025.100721","url":null,"abstract":"<div><div>Stress is a significant risk factor for the development and recurrence of anxiety disorders. Stress can profoundly impact the immune system, and lead to microglial functional alterations in the medial prefrontal cortex (mPFC), a brain region involved in the pathogenesis of anxiety. High mobility group box 1 protein (HMGB1) is a potent pro-inflammatory stimulus and danger-associated molecular pattern (DAMP) released from neuronal and non-neuronal cells following stress. HMGB1 provokes pro-inflammatory responses in the brain and, when administered locally, alters behavior in the absence of other stressors. In this study, we administered dsHMGB1 into the mPFC of male and female mice for 5 days to investigate the cellular and molecular mechanisms underlying HMGB1-induced behavioral dysfunction, with a focus on cell-type specificity and potential sex differences. Here, we demonstrate that dsHMGB1 infusion into the mPFC elicited behavior changes in both sexes but only altered microglial morphology robustly in female mice. Moreover, preventing microglial changes with cell-specific ablation of the MyD88 pathway prevented anxiety-like behaviors only in females. These results support the hypothesis that microglial MyD88 signaling is a critical mediator of HMGB1-induced stress responses, particularly in adult female mice.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100721"},"PeriodicalIF":4.3,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinguishing neural ensembles in the infralimbic cortex that regulate stress vulnerability and coping behavior","authors":"Jenna L. Laymon ,&nbsp;Conner J. Whitten ,&nbsp;Anna F. Radford ,&nbsp;Alonnah R. Brewer ,&nbsp;Yash S. Deo ,&nbsp;Mackenzie K. Hooker ,&nbsp;Akhil A. Geddati ,&nbsp;Matthew A. Cooper","doi":"10.1016/j.ynstr.2025.100720","DOIUrl":"10.1016/j.ynstr.2025.100720","url":null,"abstract":"<div><div>Neural ensembles in the medial prefrontal cortex regulate several types of responses to stress. We used a Syrian hamster model to investigate the role of infralimbic (IL) neurons in coping with social defeat stress and vulnerability to subsequent anxiety-like behavior. We created social dominance relationships in male and female hamsters, used a robust activity marker (RAM) approach to label IL neural ensembles activated during social defeat stress, and employed light-dark (LD), social avoidance (SA), and conditioned defeat (CD) tests to assess anxiety-like behavior. We found that dominant animals were less anxious in LD tests compared to subordinate animals after achieving their higher status. Also, status-dependent differences in anxiety-like behavior were maintained following social defeat in males, but not females. Subordinate males showed greater RAM-mKate2 expression in IL parvalbumin (PV) cells during social defeat exposure compared to dominant males, and submissive behavior during CD testing was correlated with RAM/PV co-expression. In contrast, greater RAM-mKate2 expression in IL neurons was correlated with a longer latency to submit during social defeat in dominant females, although the correlation of RAM/PV co-expression and defeat-induced anxiety in females was mixed. Overall, these findings suggest that activation of IL PV cells during social defeat predicts the development stress vulnerability in males, whereas activation of IL neurons is associated with a proactive response to social defeat exposure in females. Understanding how social dominance generates plasticity in IL PV cells should improve our understanding of the mechanisms by which behavioral treatments prior to stress might promote stress resilience.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100720"},"PeriodicalIF":4.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of social isolation on locus coeruleus opioid receptor expression and affective behavior","authors":"John Tkaczynski,&nbsp;Jordan Riser,&nbsp;Maya Patel,&nbsp;Nicole Shellenbarger,&nbsp;Jin Park,&nbsp;Daniel Manvich,&nbsp;Daniel J. Chandler","doi":"10.1016/j.ynstr.2025.100717","DOIUrl":"10.1016/j.ynstr.2025.100717","url":null,"abstract":"<div><div>Social isolation is a stressor that impairs homeostatic neuroendocrine functions and is associated with the development of several mood disorders characterized by persistent negative affect. Persistent feelings of loneliness have been growing public health concerns for several years and were greatly exacerbated by the onset of the COVID-19 pandemic. The problem has grown so severe the U.S. Surgeon General recently declared loneliness to be an epidemic health concern that is associated with poor mental and somatic health outcomes. Therefore, identifying mechanisms of neuroadaptation that contribute to the development of persistent negative affect is a critical step in the identifying better treatments for mood disorders. One region of the brain that becomes dysregulated in neuropsychiatric disease is the locus coeruleus. It is innervated by multiple stress-related peptidergic afferents, including those that release endogenous opioids to affect behavior. It is a major contributor to the behavioral limb of the stress response, but its role in the neurobiology of social behavior is understudied. Here we show that in laboratory rats, six weeks of social isolation leads to increased neophobia, reduced sociality, and passive stress coping. These behavioral changes are also associated with downregulation of the δ-opioid receptor and upregulation of the κ-opioid receptor in locus coeruleus. These findings suggest that extended social isolation promotes dysregulation of several opioid receptor subtypes in a brain structure that has an important role in regulating affective behavior, implicating them as potential targets for the treatment of neuropsychiatric disease associated with social isolation and loneliness.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100717"},"PeriodicalIF":4.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The link between early-life adversity and later alcohol use disorder: A role for microglia?","authors":"Hannah D. Lichtenstein,&nbsp;Michelle K. Sequeira,&nbsp;Jessica L. Bolton","doi":"10.1016/j.ynstr.2025.100714","DOIUrl":"10.1016/j.ynstr.2025.100714","url":null,"abstract":"<div><div>In the clinical literature, early-life adversity (ELA) has been highly associated with the later development of alcohol misuse and alcohol use disorder (AUD). Adolescence is a period of vulnerability for the development of neuropsychiatric disorders like depression and substance use disorders like AUD, both of which have been shown to have increased risk due to ELA. Experimentation with alcohol use in adolescence is quite common, but some adolescents that engage in alcohol experimentation become prone to alcohol misuse. Here, we review evidence that experiencing ELA prior to adolescent alcohol use could make individuals more susceptible to developing AUD, and consider the neural mechanisms that may underlie this vulnerability. We focus on the potential role of microglia, the resident immune cells of the brain, which are important for sculpting brain circuits during development and are highly sensitive to environmental perturbations. We discuss the microglia-mediated developmental processes within the stress- and reward-related regions of the brain, particularly those with corticotropin-releasing factor (CRF)-expressing neurons, and how these regions can be impacted by both ELA and alcohol use. Finally, we point to the gaps in the literature surrounding the link between ELA and AUD, and how investigating microglia in the context of this “2-hit model” may shed light on possible interventions and therapeutics that can be developed for this specific clinical population.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"35 ","pages":"Article 100714"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of distal stress on the spontaneous recovery of conditioned defensive responses","authors":"Christopher M. Klinke ,&nbsp;Maren D. Lange ,&nbsp;Marta Andreatta","doi":"10.1016/j.ynstr.2025.100715","DOIUrl":"10.1016/j.ynstr.2025.100715","url":null,"abstract":"<div><div>Intense and chronic stress strengthens fear memories and increases the risk for mental disorders. Often stressful situations are experienced long before the appearance of the symptoms, but so far, little has been investigated on how distal stress alters fear memories. In a four-day paradigm, 131 healthy individuals were either assigned to the stress-group by means of the socially evaluated cold-pressor test (SECPT) or to the sham-group (control condition). Twenty-four hours later, participants underwent fear acquisition during which two shapes were presented. The first shape (conditioned stimulus, CS+) was associated with an electro-tactile stimulation (unconditioned stimulus, US), whereas the second shape (CS-) were presented alone. During extinction training, both shapes were presented while the US was omitted. To investigate if stress induction alters extinction recall differently depending on the passage of time, participants were tested either one day (recent) or 15 days (remote) after extinction training. Learning was quantified via subjective ratings, startle reflex and skin conductance response. While we found successful acquisition and extinction of the conditioned defensive responses, there was no effect of stress on these learning processes. Stress induction did not alter the spontaneous recovery of the conditioned defensive verbal responses but of the physiological responses as stressed individuals tested two weeks after extinction training showed startle potentiation to CS + vs. CS-. In conclusion, distal stress, even if mild, can strengthen fear memories and weaken extinction memory by the passage of time. This could be a possible mechanism facilitating the onset of stress-related and anxiety disorders.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"35 ","pages":"Article 100715"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-life stress sensitizes response to future stress: Evidence and mechanisms","authors":"Catherine Jensen Peña","doi":"10.1016/j.ynstr.2025.100716","DOIUrl":"10.1016/j.ynstr.2025.100716","url":null,"abstract":"<div><div>Early-life stress sensitizes individuals to additional stressors and increases lifetime risk for mood and anxiety disorders. Research in both human populations and rodent models of early-life stress have sought to determine how different types of stressors contribute to vulnerability, and whether there are developmental sensitive periods for such effects. Although differences in the type and timing of rodent early-life stress paradigms have led to differences in specific behavioral outcomes, this complexity is present among humans as well. Robust rodent research now shows how early-life stress increases sensitivity to future stressors at behavioral, neural circuit, and molecular levels. These recent discoveries are laying the foundation for translation to more effective interventions relevant for those who experienced childhood stress and trauma.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"35 ","pages":"Article 100716"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Microbiome-Liver-Brain axis in Alcohol Use Disorder. The role of gut dysbiosis and stress in alcohol-related cognitive impairment progression: possible therapeutic approaches","authors":"Emilio Merlo Pich ,&nbsp;Ioannis Tarnanas ,&nbsp;Patrizia Brigidi ,&nbsp;Ginetta Collo","doi":"10.1016/j.ynstr.2025.100713","DOIUrl":"10.1016/j.ynstr.2025.100713","url":null,"abstract":"<div><div>The Gut Microbiome-Liver-Brain Axis is a relatively novel construct with promising potential to enhance our understanding of Alcohol Use Disorder (AUD), and its therapeutic approaches. Significant alterations in the gut microbiome occur in AUD even before any other systemic signs or symptoms manifest. Prolonged and inappropriate alcohol consumption, by affecting the gut microbiota and gut mucosa permeability, is thought to contribute to the development of behavioral and cognitive impairments, leading to Alcohol-Related Liver Disorders and potentially progressing into alcoholic cirrhosis, which is often associated with severe cognitive impairment related to neurodegeneration, such as hepatic encephalopathy and alcoholic dementia.</div><div>The critical role of the gut microbiota is further supported by the efficacy of FDA-approved treatments for hepatic encephalopathy in alcoholic cirrhosis (i.e., lactulose and rifaximin). To stimulate new research, we hypothesize that interactions between a maladaptive stress response and a constitutional predisposition to neurodegeneration underlie the progression of AUD to conditions of Alcohol-Related Clinical Concerns with severe cognitive impairment, which represent a significant and costly burden to society. Early identification of AUD individuals at risk for developing these conditions could help to prioritize integrated therapeutic interventions targeting different substrates of the Gut Microbiome-Liver-Brain axis. Specifically, addiction medications, microbiome modulators, stress-reducing interventions, and, possibly soon, novel agents that reduce hepatic steatosis/fibrosis will be discussed in the context of digitally supported integrated therapeutic approaches. The explicit goal of this AUD treatment performed on the early stage of the disorder would be to reduce the transition from AUD to those conditions of Alcohol-Related Common Clinical Concerns associated with severe cognitive impairment, a strategy recommended for most neurological neurodegenerative disorders.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"35 ","pages":"Article 100713"},"PeriodicalIF":4.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Illuminating the impact of stress: In vivo approaches to track stress-related neural adaptations","authors":"Puja K. Parekh","doi":"10.1016/j.ynstr.2025.100712","DOIUrl":"10.1016/j.ynstr.2025.100712","url":null,"abstract":"<div><div>Stressful experiences can affect both daily life and long-term health outcomes in a variety of ways. Acute challenges may be adaptive, promoting arousal and enhancing memory and cognitive function. Importantly, however, chronic stress dysregulates the body's physiological regulatory mechanisms consisting of complex hormone interactions throughout the peripheral and central nervous systems. This disrupted signaling consequently alters the balance of synapse formation, maturation and pruning, processes which regulate neural communication, plasticity, learning, cognitive flexibility and adaptive behaviors - hallmarks of a healthy, functional brain. The chronically stressed brain state, therefore, is one which may be uniquely vulnerable. To understand the development of this state, how it is sustained and how behavior and neural function are transiently or indelibly impacted by it, we can turn to a number of advanced approaches in animal models which offer unprecedented insights. This has been the aim of my recent work within the field and the goal of my new independent research program. To achieve this, I have employed methods to uncover how key brain circuits integrate information to support motivated behaviors, how stress impacts their ability to perform this process and how best to operationalize behavioral readouts. Here I present an overview of research contributions that I find most meaningful for advancing our understanding of the impact of stress and propose new avenues which will guide my own framework to address the salient outstanding questions within the field.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"35 ","pages":"Article 100712"},"PeriodicalIF":4.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The zona incerta regulates burying behavior and normalizes anxiety-like behavior in inescapable stressful male mice by object cue","authors":"Yueqin Liu ,&nbsp;Lianli Qiu ,&nbsp;Jiahui Qian ,&nbsp;Qiang Xu ,&nbsp;Rongfeng Qi ,&nbsp;Yifeng Luo ,&nbsp;Zhihong Cao ,&nbsp;Zhiqiang Zhang ,&nbsp;Wei Wu ,&nbsp;Longjiang Zhang ,&nbsp;Guangming Lu","doi":"10.1016/j.ynstr.2024.100704","DOIUrl":"10.1016/j.ynstr.2024.100704","url":null,"abstract":"<div><div>Inescapable stressful events often precipitate long-term alterations in emotion-related behaviors and poor sleep quality, with anxiety being a prevalent associated disorder. The defensive burying behavior of rodents is a response to imminent threats that becomes markedly pronounced in response to anxiety. However, the neural foundations of defensive burying behavior and etiology of anxiety remain largely unknown. In this study, we established a model employing object binding to elicit increased burying behavior in mice, thereby enhancing fear resolution and subsequently reducing anxious behaviors. Notably, the mice that associated shock with an object exhibited less object exploration and the zona incerta (ZI) neurons showed higher calcium activity during object exploration as compared to the Shock only mice. Although the calcium activity in ZI neurons of the Object mice was identical to the Shock only mice, the Object mice exhibited more burying behavior. Furthermore, the time spent in the center of the open-field test was directly proportional to the duration of burying behavior. Chemogenetic activation of ZI neurons extended the burying time and concomitantly ameliorated anxiety-like behavior. Importantly, chemogenetic enhancement of projection from ZI neurons to the ventral periaqueductal gray (vPAG), a brain region that plays a critical role in autonomic function, normalizes anxious behavior without influencing burying behavior. Collectively, these findings systematically reveal the functions and underlying mechanisms of the ZI-vPAG circuit in controlling behaviors akin to anxiety, offering significant insights into ZI's role in the pathophysiology of anxiety disorders.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"34 ","pages":"Article 100704"},"PeriodicalIF":4.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143140572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}