Neurobiology of Stress最新文献

{"title":"Adverse childhood experiences and internalizing symptoms: the moderating role of neural responses to threat","authors":"Carola Dell’Acqua ,&nbsp;Claudio Imperatori ,&nbsp;Rita B. Ardito ,&nbsp;Benedetto Farina ,&nbsp;Mauro Adenzato ,&nbsp;Giuseppe Carbone ,&nbsp;Aurelia Lo Presti ,&nbsp;Daniela Palomba ,&nbsp;Simone Messerotti Benvenuti","doi":"10.1016/j.ynstr.2025.100740","DOIUrl":"10.1016/j.ynstr.2025.100740","url":null,"abstract":"<div><div>Adverse childhood experiences (ACEs) increase vulnerability to internalizing symptoms, namely symptoms characterized primarily by processes within the self, such as anxiety and depression, but the underlying processes are still unclear. One possible mechanism is that ACEs alter the neural correlates responsible for the preferential processing unpleasant stimuli, a key feature of anxiety. Another mechanism could be a stress-induced disruption in the processing of pleasant stimuli, which is mostly linked with depressive symptoms. In this study, we examined how ACEs and neural correlates of different emotional processing stages (affective engagement, anticipation, elaboration) interact in the association with internalizing symptoms in a sample of university students (<em>n</em> = 46, 28 females). Participants completed the Adverse Childhood Experiences Questionnaire (ACE-Q), and the anxiety and depression subscale of the Brief Symptoms Inventory Checklist to assess depression and anxiety. An S1-S2 paradigm, a task in which a cue (S1) anticipates the valence of a succeeding emotional image (S2), was used during an electroencephalographic (EEG) recording. Three event-related potentials (ERPs) reflecting different stages of emotional processing were assessed: the Cue-P300 (reflecting cue-evaluation and affective engagement), the Stimulus Preceding Negativity (SPN; reflecting outcome anticipation), and the P300/late positive potential (LPP) complex (reflecting affective processing). ACEs were linked to greater P300/LPP for unpleasant stimuli, suggesting that childhood adversities may be related to increased elaboration of threatening information. Moreover, ACEs were associated with dampened engagement (Cue-P300) and processing (P300/LPP) of pleasant content. Interestingly, the interaction between the P300/LPP to unpleasant stimuli and ACEs was significantly associated with greater symptoms of anxiety, whereas there was no effect in the link with depression. Specifically, individuals exposed to ACEs only reported heightened anxiety symptoms when their P300/LPP complex to unpleasant stimuli was larger. No significant effect emerged for the other ERPs components. Taken together, these findings suggest that an increased sensitivity to unpleasant content in adulthood might moderate the association between ACEs and anxiety symptoms.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100740"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of childhood trauma: an integrative review of a multimodal, transdiagnostic pathway","authors":"J.M. Pasteuning ,&nbsp;C. Broeder ,&nbsp;T.A.A. Broeders ,&nbsp;R.G.G. Busby ,&nbsp;A.W. Gathier ,&nbsp;E. Kuzminskaite ,&nbsp;F. Linsen ,&nbsp;C.P. Souama ,&nbsp;J.E. Verhoeven ,&nbsp;M.S.C. Sep ,&nbsp;C.H. Vinkers","doi":"10.1016/j.ynstr.2025.100737","DOIUrl":"10.1016/j.ynstr.2025.100737","url":null,"abstract":"<div><div>Childhood trauma (CT), conceptualized as emotional, physical or sexual abuse or emotional or physical neglect before the age of 18, is a risk factor for the emergence and poorer course of many mental and somatic disorders. The mechanisms underlying the impact of CT range from (neuro)biological changes (e.g., epigenetics, hypothalamic–pituitary–adrenal axis, and brain structure/function) to psychosocial mechanisms (e.g., personality, attachment, emotion regulation, and coping), and behavioral factors (e.g., smoking and exercise). Given the interrelatedness of mechanisms, there is a need for research that integrates the effects of CT across modalities. We aim to integrate (neuro)biological, psychosocial and behavioral mechanisms of CT in health and across mental and somatic disorders. The multimodal impact of CT requires more recognition in research and clinical practice and should be considered independent of current health status and diagnostic categories. Additionally, research should incorporate the impact of (daily life) stress to provide a more comprehensive understanding of the impact of CT. These recommendations may improve understanding, treatment and eventually prevention of CT-related health problems.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100737"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Youth mental health crisis: A translational view of the COVID-19 pandemic","authors":"Thorhildur Halldorsdottir","doi":"10.1016/j.ynstr.2025.100738","DOIUrl":"10.1016/j.ynstr.2025.100738","url":null,"abstract":"<div><div>Mental health problems among children and adolescents have increased over the past two decades, a trend that was further exacerbated by the COVID-19 pandemic. To improve prevention and treatment strategies, developmentally informed and data-driven multidisciplinary approaches are urgently needed to clarify the mechanisms underlying youth vulnerability and resilience. Stress and trauma exposure are among the strongest predictors of youth mental health problems; however, most children and adolescents remain resilient despite such exposures. The widespread and heterogeneous challenges posed by the COVID-19 pandemic offer a unique opportunity to examine, at scale, who develops mental health problems under stress and who remains resilient. Integrating emerging findings on pandemic-related risk and protective factors with evidence from animal models can illuminate sensitive developmental periods of heightened susceptibility to environmental influence and biological embedding. This approach can identify when, how, and through what pathways mental health problems emerge, including gene–environment interactions and epigenetic mechanisms. Such knowledge will inform both behavioral and pharmacological interventions, pinpointing not only specific treatment targets but also the optimal timing for intervention to be the most effective.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100738"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144313740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probiotics restore impaired spatial cognition and synaptic plasticity of prenatally-stressed male rats: focus on hippocampal and intestinal tight junctions","authors":"Fatemeh Aghighi Bidgoli ,&nbsp;Sayyed Alireza Talaei ,&nbsp;Abolfazl Azami Tameh ,&nbsp;Mahmoud Salami","doi":"10.1016/j.ynstr.2025.100736","DOIUrl":"10.1016/j.ynstr.2025.100736","url":null,"abstract":"<div><div>Bidirectional communication between the gut microbiota and the nervous system founded the gut-microbiota-brain axis, substantially affects numerous vital functions of the body. Stress, as the body's natural reaction to stressful situations, in turn, affects the functioning of various organs. Through evaluating long-term potentiation (LTP) and spatial memory assessment using the Morris water maze, we aimed to examine the effect of prenatal stress on the electrophysiological and behavioral aspects of hippocampus-dependent spatial memory. The relationship of the synaptic plasticity and learning and memory with the hypothalamus-pituitary-adrenal (HPA) axis and the integrity of blood-brain and intestinal barriers were also examined. The experimental subjects were introduced to probiotic treatment to assess how the supplementation influences stress-related alterations. The prenatal stress effectively impaired both LTP occurrence and behavioral function. It also led to disruption of blood-brain and gut barriers and increased serum level of corticosterone. The probiotic supplementation positively affected the synaptic plasticity and learning and memory. It also improved the integrity of both barriers and reduced the stress hormone corticosterone. Whereas there is a reverse relationship between stress and the hippocampus-dependent spatial memory, normal stress hormone, and the integrity of intestinal and brain barriers, the probiotic supplements improve all impairments. We conclude that the HPA axis plus the blood-brain and intestinal barriers play a role in hippocampus-dependent spatial memory that are substantially affected by the beneficial gut and probiotic bacteria.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100736"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding our understanding of (mal)adapted stress physiology in psychiatric disorders: achieving single-cell characterisation of steroids and neuropeptides","authors":"Katrina Z. Edmond ,&nbsp;Natalie Matosin","doi":"10.1016/j.ynstr.2025.100739","DOIUrl":"10.1016/j.ynstr.2025.100739","url":null,"abstract":"<div><div>Steroid hormones and neurosteroids (collectively neuroactive steroids), alongside neuropeptides, are key modulators of the central nervous system. These signalling molecules integrate environmental cues into neurobiological responses by regulating gene and protein expression in a cell-type-specific manner. Specifically, neuroactive steroids and neuropeptides modulate the hypothalamic-pituitary-adrenal axis to influence excitatory/inhibitory balance in the brain and broadly impact mood, cognition, and memory. Despite their central role in brain function, these signalling systems remain historically understudied, exposing a major gap in our understanding of stress-related psychiatric disorders, and posing a valuable opportunity for therapeutic innovation. Foundational studies using histology, genetic manipulation, and bulk transcriptomic approaches, primarily in rodent models, have provided critical insights into their roles. However, these traditional methods lack the resolution to capture region- and cell-specific mechanisms, which are needed to develop precision medicine approaches. The emergence of single-cell and spatial technologies now offers unprecedented insight into the precise cellular, molecular and spatial context in which neuroactive steroid and neuropeptide signalling occurs. By moving beyond cell-type-averaged measures, these tools enable detailed mapping of transcriptional and proteomic changes across specific brain areas and cell-types, helping to identify the microenvironments in which these systems become dysregulated. This review synthesises current knowledge of neuroactive steroids and neuropeptides in stress biology and psychiatric illness and discusses how cutting-edge molecular profiling technologies are beginning to transform our ability to study, and therapeutically target, this complex and dynamic neuroendocrine network.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100739"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144240277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of gender-affirming hormones on diurnal cortisol concentrations: A prospective study","authors":"Margot W.L. Morssinkhof ,&nbsp;David Matthew Doyle ,&nbsp;Ysbrand D. van der Werf ,&nbsp;Martin den Heijer ,&nbsp;Annemieke Heijboer ,&nbsp;Birit F.P. Broekman ,&nbsp;Dirk Jan Stenvers","doi":"10.1016/j.ynstr.2025.100741","DOIUrl":"10.1016/j.ynstr.2025.100741","url":null,"abstract":"<div><div>The diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis is essential for physical and mental health. There are sex differences in this diurnal rhythm, including steeper diurnal cortisol slopes in females compared to males, and sex hormones likely contribute to this difference. While previous studies found changes in HPA axis responsivity and serum cortisol in transgender people starting gender-affirming hormone therapy (GAHT), no study examined the effect of GAHT on diurnal salivary cortisol. This study examined sex differences in diurnal cortisol and changes in diurnal cortisol after three months of GAHT.</div><div>We analyzed salivary cortisol levels in eleven transmasculine (TM) and seven transfeminine (TF) participants before GAHT and after three months of GAHT. Participants collected saliva samples at 30 min, 5.5 h and 10.5 h after awakening, and at bedtime. Absolute cortisol levels and diurnal cortisol slopes were compared between the groups at baseline, and in each group between baseline and three months of GAHT.</div><div>Before starting GAHT, the TM group showed a steeper diurnal cortisol slope compared to the TF group. Neither the TM group nor the TF group showed any significant changes in cortisol levels or slopes after GAHT.</div><div>We replicate previously reported sex differences in diurnal cortisol levels at baseline, but we find no significant changes in diurnal salivary cortisol after participants start GAHT. This could be associated with homeostatic adaptation of the HPA axis and cortisol-binding globulin concentrations. Future studies should focus on the role of bound and unbound cortisol and stress-related cortisol changes.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100741"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144471756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic stress and cytogenesis ablation disrupt hippocampal neuron connectivity, with fluoxetine restoring function with sex-specific effects","authors":"Inês Ribeiro ,&nbsp;Tiago Silveira-Rosa ,&nbsp;Joana Martins-Macedo ,&nbsp;Luísa Marques-Ferraz ,&nbsp;Ana Rita Dourado ,&nbsp;Gonçalo Martins-Ferreira ,&nbsp;Fanny Farrugia ,&nbsp;Ana João Rodrigues ,&nbsp;Djoher Nora Abrous ,&nbsp;Nuno Dinis Alves ,&nbsp;Patrícia Patrício ,&nbsp;Luisa Pinto","doi":"10.1016/j.ynstr.2025.100743","DOIUrl":"10.1016/j.ynstr.2025.100743","url":null,"abstract":"<div><div>Hippocampal Adult-Born neurons (hABNs) play a critical role in maintaining brain homeostasis, exhibiting unique properties during their maturation. The absence of hABNs impacts surrounding neuronal networks, but the mechanisms are not fully understood. In this study, we examined how perturbations to adult hippocampal cytogenesis affect the neuronal inputs to adult-born and mature neurons in the dentate gyrus. In particular, we analyzed connectivity changes in GFAP-Tk transgenic rats with ablated neurogenesis, and in unpredictable Chronic Mild Stress (uCMS) rats with reduced neurogenesis, with a focus on sex-differences in stress-affected hABNs. Additionally, we evaluated the action of the antidepressant fluoxetine on brain connectivity. Using a virus-mediated retrograde tracing approach, we quantified synaptic inputs to mature neurons and hABNs. Our findings reveal significant impairments in both intra- and extra-hippocampal connectivity following disruptions in cytogenesis, providing new insights into hippocampal network dynamics in the context of cytogenetic impairment, depression, and therapeutic interventions.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100743"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The insular cortex-nucleus tractus solitarius glutamatergic pathway involved in acute stress-induced gastric mucosal damage in rats","authors":"Zepeng Wang ,&nbsp;Xinyu Li ,&nbsp;Yuanyuan Li ,&nbsp;Xuehan Sun ,&nbsp;Yuxue Wang ,&nbsp;Tong Lu ,&nbsp;Dongqin Zhao ,&nbsp;Xiaoli Ma ,&nbsp;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":"2025-05-01","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}

{"title":"Regulation of behavioral responses to single prolonged stress in male and female rats: Role of PACAP","authors":"Marissa A. Smail ,&nbsp;Evelin M. Cotella ,&nbsp;Susan E. Martelle ,&nbsp;James B. Chambers ,&nbsp;Ria K. Parikh ,&nbsp;Christine E. Moore ,&nbsp;Ben A. Packard ,&nbsp;Nawshaba Nawreen ,&nbsp;Rachel D. Moloney ,&nbsp;James P. Herman","doi":"10.1016/j.ynstr.2025.100727","DOIUrl":"10.1016/j.ynstr.2025.100727","url":null,"abstract":"<div><div>Post-Traumatic Stress Disorder (PTSD) is a debilitating condition in which a traumatic experience triggers symptoms related to re-experiencing, avoidance, arousal, and mood dysregulation. PTSD negatively impacts 6 % of people during their lifetime, with women being disproportionally affected and exhibiting different, more severe symptoms than men. Despite this widespread impact, the molecular mechanisms underlying PTSD and its sex differences remain poorly understood. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuropeptide which participates in fine-tuning circuitry throughout the brain and has been associated with PTSD in humans, especially in women. Here, we use Single Prolonged Stress (SPS), an animal model of PTSD, to explore the roles of PACAP and sex in PTSD-like behaviors. Specifically, a PACAP agonist or antagonist was infused into the infralimbic (IL) prefrontal cortex, a region key to regulating fear- and anxiety-related behaviors, prior to SPS in male and female rats. Rats were then tested in open field/novel object, elevated plus maze, and social interaction. Utilizing a behavioral indexing method, we were able to uncover SPS effects in PTSD-related behavioral domains that were differentially impacted by PACAP manipulations in males and females. While both sexes exhibited increased threat avoidance and decreased threat assessment following SPS, females increased sociability while males decreased sociability. Males also appeared to be protected by IL PACAP antagonism while female SPS phenotypes were exacerbated by IL PACAP agonism. Furthermore, RNAscope revealed that PACAP in the prefrontal cortex responds differently to SPS in males and females. Together, these findings suggest complex relationships between SPS, sex, and IL PACAP which may have important implications for treating PTSD in men and women.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100727"},"PeriodicalIF":4.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aggression as a contributing factor to social defeat and stress vulnerability","authors":"Megan M. John ,&nbsp;Melissa A. Pratt ,&nbsp;Jazmine D.W. Yaeger ,&nbsp;Renée A. Brummels ,&nbsp;Leighton J. Ledesma ,&nbsp;Lauren S. Meyer ,&nbsp;RaeAnn L. Hartwig ,&nbsp;Gabriel L. Legner ,&nbsp;Nathan G. Gilbertson ,&nbsp;Patrick J. Ronan ,&nbsp;Cliff H. Summers","doi":"10.1016/j.ynstr.2025.100728","DOIUrl":"10.1016/j.ynstr.2025.100728","url":null,"abstract":"<div><div>The Stress Alternatives Model (SAM) is a social defeat/avoidance paradigm developed in our lab that reveals evolutionarily conserved escape responses in fish, hamsters, rats, and mice. During social interactions in a neutral arena, available escape routes sized exclusively for smaller test animals allow for avoidance of a social aggressor. This 4-day social interaction protocol pairs C57BL/6N test mice and a larger, novel, aggressive CD1 mouse each day. Although escape portals are available, and the CD1 aggressor is unremittingly antagonistic, only half of the mice tested utilize the escape tunnels, while escape latency dramatically decreases over time in mice that escape. We sought to determine whether aggression provided the trigger of two stress-related phenotypes that are produced by the SAM. The results suggest threat of aggression, determined by the first attack, is necessary for phenotype development, but the intensity of aggression over time does not determine which phenotype is chosen. Phenotypes are determined by responsiveness and counterbalanced neurocircuits that promote stress-resilience or vulnerability. These stress neurocircuits are modulated by orexins, through orexin 1 and 2 receptors (Orx₁, Orx₂), which promote pro-stress behaviors. In the primary pro-stress neurocircuitry of the aBLA, we examined Akt and mToR gene expression in stress-resilient (Escape) and -vulnerable (Stay) mice. The quantity of <em>Hcrtr</em>_<em>1</em> mRNA/cell was elevated in Stay mice, as were the mRNA/cell numbers for <em>Mtor</em>. However, the increase of <em>Akt</em>_<em>2</em> and <em>Mtor</em> mRNA/cell was not evident specifically in <em>Hcrtr</em>_<em>1</em> expressing cells, suggesting these molecular markers of neuroplasticity are not being activated by Orx₁ receptors.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"36 ","pages":"Article 100728"},"PeriodicalIF":4.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}