Neurobiology of Stress最新文献

An inverted U-shaped relationship between chronic stress and the motivation to expend effort for reward

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-04-05 DOI: 10.1016/j.ynstr.2025.100724

Wei Yi , Xin Li , Wangxiao Chen , Linlin Yan , Fei Xin , Tony W. Buchanan , Jianhui Wu

Dysfunction in the motivation to expend effort for reward is considered a crucial symptom of stress-related mental illness. Few studies have explored the relationship between chronic stress and the motivation to exert effort for reward, along with its underlying neural mechanisms. We investigated this relationship in ninety undergraduates who were undergoing a chronic stressor: preparing for the National Postgraduate Entrance Examination (NPEE). Students engaged in an effort-reward task while EEG signals were recorded, wherein they could accept or reject an offer to expend effort for another opportunity to obtain the reward. Participants’ chronic stress levels were assessed using the Perceived Stress Scale (PSS) and their decision was further captured by a drift-diffusion model (DDM). Compared to reward omission, reward delivery led to increased amplitude of the reward positivity (RewP) ERP waveform, particularly in extra reward trials relative to regular trials. Importantly, the PSS score showed an inverted U-shaped relationship with the motivation indicators, including offer acceptance rate (behavioral index), drift rate (model parameter), and ΔRewP (i.e., the difference in RewP in response to reward delivery compared to reward omission, ERP component). These findings suggest an inverted U-shaped relationship between chronic stress and motivation, suggesting that individuals display diminished motivation when exposed to low or high levels, relative to moderate levels, of chronic stress. Our study holds significant implications for understanding both vulnerability and resilience to stress-related mental disorders.

{"title":"An inverted U-shaped relationship between chronic stress and the motivation to expend effort for reward","authors":"Wei Yi , Xin Li , Wangxiao Chen , Linlin Yan , Fei Xin , Tony W. Buchanan , Jianhui Wu","doi":"10.1016/j.ynstr.2025.100724","DOIUrl":"10.1016/j.ynstr.2025.100724","url":null,"abstract":"<div><div>Dysfunction in the motivation to expend effort for reward is considered a crucial symptom of stress-related mental illness. Few studies have explored the relationship between chronic stress and the motivation to exert effort for reward, along with its underlying neural mechanisms. We investigated this relationship in ninety undergraduates who were undergoing a chronic stressor: preparing for the National Postgraduate Entrance Examination (NPEE). Students engaged in an effort-reward task while EEG signals were recorded, wherein they could accept or reject an offer to expend effort for another opportunity to obtain the reward. Participants’ chronic stress levels were assessed using the Perceived Stress Scale (PSS) and their decision was further captured by a drift-diffusion model (DDM). Compared to reward omission, reward delivery led to increased amplitude of the reward positivity (RewP) ERP waveform, particularly in extra reward trials relative to regular trials. Importantly, the PSS score showed an inverted U-shaped relationship with the motivation indicators, including offer acceptance rate (behavioral index), drift rate (model parameter), and ΔRewP (i.e., the difference in RewP in response to reward delivery compared to reward omission, ERP component). These findings suggest an inverted U-shaped relationship between chronic stress and motivation, suggesting that individuals display diminished motivation when exposed to low or high levels, relative to moderate levels, of chronic stress. Our study holds significant implications for understanding both vulnerability and resilience to stress-related mental disorders.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100724"},"PeriodicalIF":4.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777062","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}

引用次数: 0

The insular cortex-nucleus tractus solitarius glutamatergic pathway involved in acute stress-induced gastric mucosal damage in rats

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-04-01 DOI: 10.1016/j.ynstr.2025.100723

Zepeng Wang , Xinyu Li , Yuanyuan Li , Xuehan Sun , Yuxue Wang , Tong Lu , Dongqin Zhao , Xiaoli Ma , Haiji Sun

Previous studies have shown that acute stress-induced gastric mucosal damage is linked to excessive activation of parasympathetic nervous system. The Insular Cortex (IC), the higher centers of the parasympathetic nervous system, serves as both the integration site of gastric sensory information and play a crucial role in the regulation of gastric function. However, whether the IC is involved in Restraint water-immersion stress (RWIS)-induced gastric mucosal damage has not been reported. In this study, we examined the expression of neuronal c-Fos, PSD95 and SYN-1 protein expression in IC during RWIS by immunofluorescence and western blot techniques, as well as assessed IC blood oxygenation level dependant (BOLD) through functional MRI. Chemical genetics techniques specifically modulate the activity of IC glutamatergic neurons and IC-nucleus tractus solitary (NTS) glutamatergic pathway to elucidate their contributions to RWIS-induced gastric mucosal damage. The results showed that the expression of c-Fos, PSD95, and SYN-1 protein in IC increased significantly after RWIS, along with a noticeable enhancement in fMRI signal intensity. Furthermore, inhibiting IC glutamatergic neurons and the IC-NTS glutamatergic neural pathway resulted in a significant reduction in gastric mucosal damage, an increase in the expression of Occludin, Claudin-1, and PCNA in the gastric wall, while the expression of nNOS decreased and CHAT increased. These findings suggest that during RWIS, IC glutaminergic neurons are activated, promoting stress-induced gastric mucosal damage through the IC-NTS-vagal nerve pathway.

{"title":"The insular cortex-nucleus tractus solitarius glutamatergic pathway involved in acute stress-induced gastric mucosal damage in rats","authors":"Zepeng Wang , Xinyu Li , Yuanyuan Li , Xuehan Sun , Yuxue Wang , Tong Lu , Dongqin Zhao , Xiaoli Ma , Haiji Sun","doi":"10.1016/j.ynstr.2025.100723","DOIUrl":"10.1016/j.ynstr.2025.100723","url":null,"abstract":"<div><div>Previous studies have shown that acute stress-induced gastric mucosal damage is linked to excessive activation of parasympathetic nervous system. The Insular Cortex (IC), the higher centers of the parasympathetic nervous system, serves as both the integration site of gastric sensory information and play a crucial role in the regulation of gastric function. However, whether the IC is involved in Restraint water-immersion stress (RWIS)-induced gastric mucosal damage has not been reported. In this study, we examined the expression of neuronal c-Fos, PSD95 and SYN-1 protein expression in IC during RWIS by immunofluorescence and western blot techniques, as well as assessed IC blood oxygenation level dependant (BOLD) through functional MRI. Chemical genetics techniques specifically modulate the activity of IC glutamatergic neurons and IC-nucleus tractus solitary (NTS) glutamatergic pathway to elucidate their contributions to RWIS-induced gastric mucosal damage. The results showed that the expression of c-Fos, PSD95, and SYN-1 protein in IC increased significantly after RWIS, along with a noticeable enhancement in fMRI signal intensity. Furthermore, inhibiting IC glutamatergic neurons and the IC-NTS glutamatergic neural pathway resulted in a significant reduction in gastric mucosal damage, an increase in the expression of Occludin, Claudin-1, and PCNA in the gastric wall, while the expression of nNOS decreased and CHAT increased. These findings suggest that during RWIS, IC glutaminergic neurons are activated, promoting stress-induced gastric mucosal damage through the IC-NTS-vagal nerve pathway.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100723"},"PeriodicalIF":4.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768513","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}

引用次数: 0

Dynamic changes of serotonin transporter expression in the prefrontal cortex evoked by aggressive social interactions

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-03-26 DOI: 10.1016/j.ynstr.2025.100722

Huba Szebik , Christina Miskolczi , Bíborka Bruzsik , Gyula Balla , Soma Szabó , László Biró , Éva Mikics

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.

{"title":"Dynamic changes of serotonin transporter expression in the prefrontal cortex evoked by aggressive social interactions","authors":"Huba Szebik , Christina Miskolczi , Bíborka Bruzsik , Gyula Balla , Soma Szabó , László Biró , 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}

引用次数: 0

Sex-specific regulation of microglial MyD88 in HMGB1-Induced anxiety phenotype in mice

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-03-23 DOI: 10.1016/j.ynstr.2025.100721

Ashleigh Rawls , Julia Dziabis , Dang Nguyen , Dilara Anbarci , Madeline Clark , Grace Zhang , Kafui Dzirasa , Staci D. Bilbo

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.

{"title":"Sex-specific regulation of microglial MyD88 in HMGB1-Induced anxiety phenotype in mice","authors":"Ashleigh Rawls , Julia Dziabis , Dang Nguyen , Dilara Anbarci , Madeline Clark , Grace Zhang , Kafui Dzirasa , 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}

引用次数: 0

Distinguishing neural ensembles in the infralimbic cortex that regulate stress vulnerability and coping behavior

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-03-20 DOI: 10.1016/j.ynstr.2025.100720

Jenna L. Laymon , Conner J. Whitten , Anna F. Radford , Alonnah R. Brewer , Yash S. Deo , Mackenzie K. Hooker , Akhil A. Geddati , Matthew A. Cooper

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.

{"title":"Distinguishing neural ensembles in the infralimbic cortex that regulate stress vulnerability and coping behavior","authors":"Jenna L. Laymon , Conner J. Whitten , Anna F. Radford , Alonnah R. Brewer , Yash S. Deo , Mackenzie K. Hooker , Akhil A. Geddati , 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}

引用次数: 0

Effects of social isolation on locus coeruleus opioid receptor expression and affective behavior

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-03-14 DOI: 10.1016/j.ynstr.2025.100717

John Tkaczynski, Jordan Riser, Maya Patel, Nicole Shellenbarger, Jin Park, Daniel Manvich, Daniel J. Chandler

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.

{"title":"Effects of social isolation on locus coeruleus opioid receptor expression and affective behavior","authors":"John Tkaczynski, Jordan Riser, Maya Patel, Nicole Shellenbarger, Jin Park, Daniel Manvich, 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}

引用次数: 0

The link between early-life adversity and later alcohol use disorder: A role for microglia?

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-03-01 DOI: 10.1016/j.ynstr.2025.100714

Hannah D. Lichtenstein, Michelle K. Sequeira, Jessica L. Bolton

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.

{"title":"The link between early-life adversity and later alcohol use disorder: A role for microglia?","authors":"Hannah D. Lichtenstein, Michelle K. Sequeira, 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}

引用次数: 0

The impact of distal stress on the spontaneous recovery of conditioned defensive responses

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-03-01 DOI: 10.1016/j.ynstr.2025.100715

Christopher M. Klinke , Maren D. Lange , Marta Andreatta

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.

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引用次数: 0

Early-life stress sensitizes response to future stress: Evidence and mechanisms

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-03-01 DOI: 10.1016/j.ynstr.2025.100716

Catherine Jensen Peña

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.

引用次数: 0

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

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-02-08 DOI: 10.1016/j.ynstr.2025.100713

Emilio Merlo Pich , Ioannis Tarnanas , Patrizia Brigidi , Ginetta Collo

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.

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.

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引用次数: 0