Pub Date : 2026-01-01Epub Date: 2025-11-27DOI: 10.1016/j.ynstr.2025.100773
Moonseok Choi , Jisu Jeong , Dongsoo Kim , Hong Seok Choi , Junghwa Ryu , Hye Jin Choi , Mookyung Cheon , Yun Ha Jeong
Modern people are exposed to various stressful situations. Stress is a significant factor in emotional changes and social behavior and is associated with imbalances in physiological and psychological homeostasis, including brain function and structure. Stress has multiple causes, each of which has different impacts on social behavior throughout life. However, little is known about how stress influences social behavior across the life cycle. To understand this further, this study exposed mice to chronic stress at three different ages: adolescence, early adulthood, and adulthood. Chronic stresses were induced by combining chronic traumatic and isolation stress. Chronic stress has been shown to enhance social dominance behavior, especially in adolescence, and changes in the expression of genes and proteins, including Fabp7 and Cxcl12, were observed to change in the opposite direction compared to adulthood, confirming that it is related to changes in social dominance behavior. This study may provide important insights into factors related to adolescence social behavior abnormalities.
{"title":"Age-dependent effects of chronic traumatic and social isolation stress on mice social behavior","authors":"Moonseok Choi , Jisu Jeong , Dongsoo Kim , Hong Seok Choi , Junghwa Ryu , Hye Jin Choi , Mookyung Cheon , Yun Ha Jeong","doi":"10.1016/j.ynstr.2025.100773","DOIUrl":"10.1016/j.ynstr.2025.100773","url":null,"abstract":"<div><div>Modern people are exposed to various stressful situations. Stress is a significant factor in emotional changes and social behavior and is associated with imbalances in physiological and psychological homeostasis, including brain function and structure. Stress has multiple causes, each of which has different impacts on social behavior throughout life. However, little is known about how stress influences social behavior across the life cycle. To understand this further, this study exposed mice to chronic stress at three different ages: adolescence, early adulthood, and adulthood. Chronic stresses were induced by combining chronic traumatic and isolation stress. Chronic stress has been shown to enhance social dominance behavior, especially in adolescence, and changes in the expression of genes and proteins, including Fabp7 and Cxcl12, were observed to change in the opposite direction compared to adulthood, confirming that it is related to changes in social dominance behavior. This study may provide important insights into factors related to adolescence social behavior abnormalities.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"40 ","pages":"Article 100773"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683063","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}
Pub Date : 2026-01-01Epub Date: 2025-11-26DOI: 10.1016/j.ynstr.2025.100772
Mathias V. Schmidt
The concept that early life experiences profoundly program adult physiology and behavior is now a cornerstone of neurobiology, a paradigm shift largely founded on the visionary work of Seymour “Gig” Levine. This review traces the intellectual lineage from Levine's pioneering behavioral and physiological studies to the modern molecular era, underscoring his indispensable contribution to understanding developmental stress. Levine's initial elegant experiments established the critical regulatory role of maternal care and the hypothalamic-pituitary-adrenal (HPA) axis, culminating in the discovery of the Stress Hyporesponsive Period (SHRP)—a crucial, sensitive window for developmental programming. Building on this legacy, subsequent research, including my own, has utilized advanced molecular tools to bridge the gap from these macroscopic observations to precise mechanistic detail. I highlight the role of gene-by-environment (G × E) interactions, particularly involving HPA axis modulators like FKBP51 and CRH signaling, in shaping vulnerability. Furthermore, I discuss how Levine's implicit recognition of individual differences has evolved into a central focus on biological sex differences, the match/mismatch hypothesis of adaptive programming, and the use of deep phenotyping to unravel the molecular bases of resilience and vulnerability. Ultimately, the journey from “Gig” to “Genes” provides a foundational understanding that is crucial for developing effective, targeted strategies to promote mental health and resilience across the lifespan.
{"title":"From “Gig” to Genes: The enduring legacy of Seymour Levine in developmental stress neurobiology","authors":"Mathias V. Schmidt","doi":"10.1016/j.ynstr.2025.100772","DOIUrl":"10.1016/j.ynstr.2025.100772","url":null,"abstract":"<div><div>The concept that early life experiences profoundly program adult physiology and behavior is now a cornerstone of neurobiology, a paradigm shift largely founded on the visionary work of Seymour “Gig” Levine. This review traces the intellectual lineage from Levine's pioneering behavioral and physiological studies to the modern molecular era, underscoring his indispensable contribution to understanding developmental stress. Levine's initial elegant experiments established the critical regulatory role of maternal care and the hypothalamic-pituitary-adrenal (HPA) axis, culminating in the discovery of the Stress Hyporesponsive Period (SHRP)—a crucial, sensitive window for developmental programming. Building on this legacy, subsequent research, including my own, has utilized advanced molecular tools to bridge the gap from these macroscopic observations to precise mechanistic detail. I highlight the role of gene-by-environment (G × E) interactions, particularly involving HPA axis modulators like FKBP51 and CRH signaling, in shaping vulnerability. Furthermore, I discuss how Levine's implicit recognition of individual differences has evolved into a central focus on biological sex differences, the match/mismatch hypothesis of adaptive programming, and the use of deep phenotyping to unravel the molecular bases of resilience and vulnerability. Ultimately, the journey from “Gig” to “Genes” provides a foundational understanding that is crucial for developing effective, targeted strategies to promote mental health and resilience across the lifespan.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"40 ","pages":"Article 100772"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617532","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}
Pub Date : 2026-01-01Epub Date: 2025-11-08DOI: 10.1016/j.ynstr.2025.100770
Luisa B. Bertotto , Eleanna M. Sakoulas , Marian L. Logrip , Katrina Lin , Anastasia E. Pimentel , Lenwood Thompson , Bryan Cruz , Valentina Vozella , Cristiane A. Favoretto , Marisa Roberto , Eric P. Zorrilla
Stress-related emotional disorders, such as post-traumatic stress disorder (PTSD) and major depression, increase alcohol relapse risk. PTSD, depression, and alcohol use phenotypes associate with gene variants of FKBP prolyl isomerase 5 (FKBP5), a chaperone modulator of glucocorticoid receptors (GR). FKBP51 inhibitors can decrease ethanol intake, but FKBP51's role in recurrence of post-stress ethanol drinking is unknown. We tested the hypotheses that expression of Fkbp5 and immediate early genes (IEGs) in the central nucleus of the amygdala (CeA) is increased in rats with a history of defeat or foot-shock stress and associates with faster submission and increased reacquisition of ethanol self-administration. We tested if benztropine mesylate, an FDA-approved drug that inhibits FKBP51-GR binding, reduces reacquisition of ethanol self-administration in rats with a history of foot-shock stress. Wistar rats were studied after resident-intruder social defeat (n = 32) or in an ethanol self-administration reacquisition model, with or without repeated foot-shock history (n = 62). Acute social defeat stress increased CeA IEG expression within 1 h Fkbp5 expression by 6 h. CeA IEG activation correlated with Fkbp5 expression, and both correlated with faster submission to defeat. CeA Fkbp5 expression also associated with greater ethanol intake and blood ethanol concentration during reacquisition of ethanol self-administration. Benztropine (i.p., 5, 10 mg/kg) dose-dependently reduced relapse-like ethanol reacquisition, and sex-specific analyses suggest a more robust effect in males than females. The results warrant the study of CeA FKBP51 in passive stress coping and of drug-like selective FKBP51 inhibitors to reduce ethanol relapse after histories of repeated stress.
{"title":"Central amygdala Fkbp5 expression correlates with faster submission and ethanol self-administration reacquisition: Benztropine reduces ethanol relapse-like reacquisition in stressed rats","authors":"Luisa B. Bertotto , Eleanna M. Sakoulas , Marian L. Logrip , Katrina Lin , Anastasia E. Pimentel , Lenwood Thompson , Bryan Cruz , Valentina Vozella , Cristiane A. Favoretto , Marisa Roberto , Eric P. Zorrilla","doi":"10.1016/j.ynstr.2025.100770","DOIUrl":"10.1016/j.ynstr.2025.100770","url":null,"abstract":"<div><div>Stress-related emotional disorders, such as post-traumatic stress disorder (PTSD) and major depression, increase alcohol relapse risk. PTSD, depression, and alcohol use phenotypes associate with gene variants of FKBP prolyl isomerase 5 (<em>FKBP5</em>), a chaperone modulator of glucocorticoid receptors (GR). FKBP51 inhibitors can decrease ethanol intake, but FKBP51's role in recurrence of post-stress ethanol drinking is unknown. We tested the hypotheses that expression of <em>Fkbp5</em> and immediate early genes (IEGs) in the central nucleus of the amygdala (CeA) is increased in rats with a history of defeat or foot-shock stress and associates with faster submission and increased reacquisition of ethanol self-administration. We tested if benztropine mesylate, an FDA-approved drug that inhibits FKBP51-GR binding, reduces reacquisition of ethanol self-administration in rats with a history of foot-shock stress. Wistar rats were studied after resident-intruder social defeat (<em>n</em> = 32) or in an ethanol self-administration reacquisition model, with or without repeated foot-shock history (<em>n</em> = 62). Acute social defeat stress increased CeA IEG expression within 1 h <em>Fkbp5</em> expression by 6 h. CeA IEG activation correlated with <em>Fkbp5</em> expression, and both correlated with faster submission to defeat. CeA <em>Fkbp5</em> expression also associated with greater ethanol intake and blood ethanol concentration during reacquisition of ethanol self-administration. Benztropine (i.p., 5, 10 mg/kg) dose-dependently reduced relapse-like ethanol reacquisition, and sex-specific analyses suggest a more robust effect in males than females. The results warrant the study of CeA FKBP51 in passive stress coping and of drug-like selective FKBP51 inhibitors to reduce ethanol relapse after histories of repeated stress.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"40 ","pages":"Article 100770"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925266","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}
Pub Date : 2026-01-01Epub Date: 2025-12-19DOI: 10.1016/j.ynstr.2025.100779
Hayley Ross , Makayla Adelman , Juan E. Castillo , Ann Walker , Joseph Latham , Liya Qin , Victoria Macht , Fulton T. Crews , Ryan P. Vetreno
Adolescence is a critical period of neurodevelopment characterized by heightened neuroplasticity and refinement of executive functioning and cognition. Basal forebrain cholinergic neurons mature during this period, coinciding with development of adult cognitive function. Exposure to adolescent adversity has been linked to long-lasting neurobiological and cognitive consequences, yet the mechanisms underlying these outcomes remain poorly understood. Using a preclinical model of adolescent intermittent restraint stress (AIRS), we tested the hypothesis that adolescent adversity induces lasting proinflammatory innate immune signaling, loss of basal forebrain cholinergic neurons, and cognitive deficits in adult female rats. We report that AIRS elevated plasma levels of corticosterone and proinflammatory high mobility group box 1 (HMGB1), consistent with HPA axis activation and systemic inflammation. In the late adolescent (P55) basal forebrain, AIRS caused an increase of the proinflammatory signaling molecule HMGB1, the HMGB1 receptors TLR4 and RAGE, the downstream proinflammatory transcription activation marker pNF-κB p65, and proinflammatory cytokines that persisted into adulthood (P95). This was accompanied by persistent adult increases of microglial activation markers, Iba-1 and CD11b. Importantly, AIRS caused a reduction of ChAT+ and TrkA + basal forebrain cholinergic neurons that persisted into adulthood, paralleling significant impairments in recognition memory on the novel object recognition memory test. Together, these findings suggest that adolescent adversity induces persistent proinflammatory HMGB1-TLR4/RAGE-pNF-κB signaling, microglial priming, and reductions of basal forebrain cholinergic neurons as well as enduring cognitive impairment. The HMGB1 proinflammatory pathway may represent a promising therapeutic target for mitigating the long-term neurobiological and behavioral consequences of adolescent adversity.
{"title":"Adolescent adversity persistently induces proinflammatory HMGB1 signaling and disrupts the basal forebrain cholinergic system in female rats","authors":"Hayley Ross , Makayla Adelman , Juan E. Castillo , Ann Walker , Joseph Latham , Liya Qin , Victoria Macht , Fulton T. Crews , Ryan P. Vetreno","doi":"10.1016/j.ynstr.2025.100779","DOIUrl":"10.1016/j.ynstr.2025.100779","url":null,"abstract":"<div><div>Adolescence is a critical period of neurodevelopment characterized by heightened neuroplasticity and refinement of executive functioning and cognition. Basal forebrain cholinergic neurons mature during this period, coinciding with development of adult cognitive function. Exposure to adolescent adversity has been linked to long-lasting neurobiological and cognitive consequences, yet the mechanisms underlying these outcomes remain poorly understood. Using a preclinical model of adolescent intermittent restraint stress (AIRS), we tested the hypothesis that adolescent adversity induces lasting proinflammatory innate immune signaling, loss of basal forebrain cholinergic neurons, and cognitive deficits in adult female rats. We report that AIRS elevated plasma levels of corticosterone and proinflammatory high mobility group box 1 (HMGB1), consistent with HPA axis activation and systemic inflammation. In the late adolescent (P55) basal forebrain, AIRS caused an increase of the proinflammatory signaling molecule HMGB1, the HMGB1 receptors TLR4 and RAGE, the downstream proinflammatory transcription activation marker pNF-κB p65, and proinflammatory cytokines that persisted into adulthood (P95). This was accompanied by persistent adult increases of microglial activation markers, Iba-1 and CD11b. Importantly, AIRS caused a reduction of ChAT+ and TrkA + basal forebrain cholinergic neurons that persisted into adulthood, paralleling significant impairments in recognition memory on the novel object recognition memory test. Together, these findings suggest that adolescent adversity induces persistent proinflammatory HMGB1-TLR4/RAGE-pNF-κB signaling, microglial priming, and reductions of basal forebrain cholinergic neurons as well as enduring cognitive impairment. The HMGB1 proinflammatory pathway may represent a promising therapeutic target for mitigating the long-term neurobiological and behavioral consequences of adolescent adversity.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"40 ","pages":"Article 100779"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925268","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}
Pub Date : 2026-01-01Epub Date: 2025-12-02DOI: 10.1016/j.ynstr.2025.100776
Lejla Colic , Anna Karoline Seiffert , Lydia Bahlmann , Ani Zerekidze , Johanna Walther , Larissa McClain , Bianca Besteher , Fabricio Pereira , Mocrane Abbar , Martin Walter , Fabrice Jollant , Gerd Wagner
Background
Stressful events and dysregulation of the hypothalamic-pituitary-adrenal (HPA)- axis contribute to the risk of suicide attempt (SA) in persons in depressive episodes. Hair cortisol, cortisone and dehydroepiandrosterone (DHEA) concentrations may serve as reliable indicators of HPA axis dysregulation prior to SA.
Methods
Participants (n = 75; mean age [standard deviation] = 30.0 [10.2] years; n = 49 [65 %] women; Jena site) comprised three groups: individuals with a history of SA approximately one month (SA; n = 22); individuals with a current depressive episode without SA history (CC; n = 31) and healthy individuals (HC; n = 22). SA was defined as self-initiated, potentially injurious behavior accompanied by some intent to die. Stress hormones were measured using LC-MS/MS protocol (days from sampling to analysis = 342 [171]) and logarithmic transformed. Group differences in hair stress hormones with hair segments representing time were tested using linear mixed models on a p < .05 threshold. Exploratory models further examined the effects of childhood abuse, frequency of SAs, suicide intent level and impulsiveness of the last SA of mean hormone levels, on a corrected pcorr< .012 threshold.
Results
There was a main effect of group for the DHEA-log (p = .02) and post-hoc tests indicated that SA group had higher DHEA compared to CC (pcorr = .01) and HC (pcorr = .08) in the peri-suicidal period. There were no significant (p < .05) interaction or group effects on cortisol-log and cortisone-log. Preliminary exploratory analyses showed that SA with multiple attempts had higher mean DHEA-log compared to SA with a single suicide attempt (puncorr = .05). Furthermore, there were positive associations between level of suicide intent and both mean cortisol-log (puncorr = .02) and mean cortisone-log (puncorr = .02). Childhood abuse and impulsiveness of the last SA were not related to hair stress hormones.
Conclusions
Individuals with a recent history of SA showed alterations in the DHEA hair levels. These results partially support dysregulation of the HPA axis as a biopsychosocial feature of SA. Future longitudinal and experimental studies should investigate whether hair HPA axis hormones can serve as markers of suicidal crisis and vulnerability.
{"title":"Hair stress hormones in individuals with a recent suicide attempt experiencing a depressive episode","authors":"Lejla Colic , Anna Karoline Seiffert , Lydia Bahlmann , Ani Zerekidze , Johanna Walther , Larissa McClain , Bianca Besteher , Fabricio Pereira , Mocrane Abbar , Martin Walter , Fabrice Jollant , Gerd Wagner","doi":"10.1016/j.ynstr.2025.100776","DOIUrl":"10.1016/j.ynstr.2025.100776","url":null,"abstract":"<div><h3>Background</h3><div>Stressful events and dysregulation of the hypothalamic-pituitary-adrenal (HPA)- axis contribute to the risk of suicide attempt (SA) in persons in depressive episodes. Hair cortisol, cortisone and dehydroepiandrosterone (DHEA) concentrations may serve as reliable indicators of HPA axis dysregulation prior to SA.</div></div><div><h3>Methods</h3><div>Participants (n = 75; mean age [standard deviation] = 30.0 [10.2] years; n = 49 [65 %] women; Jena site) comprised three groups: individuals with a history of SA approximately one month (SA; n = 22); individuals with a current depressive episode without SA history (CC; n = 31) and healthy individuals (HC; n = 22). SA was defined as self-initiated, potentially injurious behavior accompanied by some intent to die. Stress hormones were measured using LC-MS/MS protocol (days from sampling to analysis = 342 [171]) and logarithmic transformed. Group differences in hair stress hormones with hair segments representing time were tested using linear mixed models on a p < .05 threshold. Exploratory models further examined the effects of childhood abuse, frequency of SAs, suicide intent level and impulsiveness of the last SA of mean hormone levels, on a corrected p<sub>corr</sub>< .012 threshold.</div></div><div><h3>Results</h3><div>There was a main effect of group for the DHEA-log (p = .02) and post-hoc tests indicated that SA group had higher DHEA compared to CC (p<sub>corr</sub> = .01) and HC (p<sub>corr</sub> = .08) in the peri-suicidal period. There were no significant (p < .05) interaction or group effects on cortisol-log and cortisone-log. Preliminary exploratory analyses showed that SA with multiple attempts had higher mean DHEA-log compared to SA with a single suicide attempt (p<sub>uncorr</sub> = .05). Furthermore, there were positive associations between level of suicide intent and both mean cortisol-log (p<sub>uncorr</sub> = .02) and mean cortisone-log (p<sub>uncorr</sub> = .02). Childhood abuse and impulsiveness of the last SA were not related to hair stress hormones.</div></div><div><h3>Conclusions</h3><div>Individuals with a recent history of SA showed alterations in the DHEA hair levels. These results partially support dysregulation of the HPA axis as a biopsychosocial feature of SA. Future longitudinal and experimental studies should investigate whether hair HPA axis hormones can serve as markers of suicidal crisis and vulnerability.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"40 ","pages":"Article 100776"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683062","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}
Pub Date : 2026-01-01Epub Date: 2026-01-05DOI: 10.1016/j.ynstr.2026.100780
James T. Moore , Matthew J. Sunthimer , Ethan White , Jeffrey G. Mellott , Merri J. Rosen
Early life stress (ELS) is a well-known predictor of neuropsychiatric disease and contributes to the development of sensory processing deficits that persist throughout life. Organisms are particularly susceptible to the deleterious effects of stress during critical periods, when neuroplasticity is heightened, and initial representations of the sensory environment are mapped to cortex. When ELS is induced during the auditory cortical (ACx) critical period, it impairs both neural and behavioral responses to a variety of auditory stimuli that rely on temporal processing. Mechanisms by which ELS may alter critical period plasticity are of particular interest in understanding ELS-related pathology, including the 5-HT3R interneuron system, which has been implicated in regulating neural activity during critical periods. Here we examined two principal subpopulations of interneurons in primary ACx: VIP and NDNF cells, which account for a majority of cortical neurons expressing 5-HT3R. The expression of the Htr3a gene during normal development and under ELS conditions was quantified using multiplex fluorescent in situ hybridization. We show that densities of cells expressing NDNF and VIP decrease following ear opening and across the ACx critical period, and that ELS results in the maintenance of elevated cell densities compared to age-matched controls. Further, Htr3a in VIP neurons is developmentally upregulated, and its expression is further increased by ELS beyond normal physiologic levels. Stress-induced shifts in these serotonergic interneurons may contribute to deficits that arise in auditory cortical and perceptual responses via effects on local cortical circuitry.
{"title":"Developmental and early-life stress-induced effects on 5-HT3R-expressing interneurons within auditory cortex","authors":"James T. Moore , Matthew J. Sunthimer , Ethan White , Jeffrey G. Mellott , Merri J. Rosen","doi":"10.1016/j.ynstr.2026.100780","DOIUrl":"10.1016/j.ynstr.2026.100780","url":null,"abstract":"<div><div>Early life stress (ELS) is a well-known predictor of neuropsychiatric disease and contributes to the development of sensory processing deficits that persist throughout life. Organisms are particularly susceptible to the deleterious effects of stress during critical periods, when neuroplasticity is heightened, and initial representations of the sensory environment are mapped to cortex. When ELS is induced during the auditory cortical (ACx) critical period, it impairs both neural and behavioral responses to a variety of auditory stimuli that rely on temporal processing. Mechanisms by which ELS may alter critical period plasticity are of particular interest in understanding ELS-related pathology, including the 5-HT3R interneuron system, which has been implicated in regulating neural activity during critical periods. Here we examined two principal subpopulations of interneurons in primary ACx: VIP and NDNF cells, which account for a majority of cortical neurons expressing 5-HT3R. The expression of the Htr3a gene during normal development and under ELS conditions was quantified using multiplex fluorescent <em>in situ</em> hybridization. We show that densities of cells expressing NDNF and VIP decrease following ear opening and across the ACx critical period, and that ELS results in the maintenance of elevated cell densities compared to age-matched controls. Further, Htr3a in VIP neurons is developmentally upregulated, and its expression is further increased by ELS beyond normal physiologic levels. Stress-induced shifts in these serotonergic interneurons may contribute to deficits that arise in auditory cortical and perceptual responses via effects on local cortical circuitry.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"40 ","pages":"Article 100780"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925265","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}
Pub Date : 2025-11-01Epub Date: 2025-11-19DOI: 10.1016/j.ynstr.2025.100771
Leland L. Fleming , Kyoko Ohashi , Michelle Bosquet Enlow , Jennifer Khoury , Torsten Klengel , Karlen Lyons-Ruth , Martin Teicher , Kerry J. Ressler
Background
Childhood maltreatment (CM) is associated with the early onset of psychopathology and accelerated biological aging. However, outcomes vary widely among individuals with CM history. This variability may, in part, be explained by differences in age of exposure to CM. In this study, we examined whether CM was associated with accelerated brain aging, depending on the timing of exposure (i.e., ‘sensitive periods’).
Method
A machine learning algorithm of brain age trained prior to the current study in 3377 healthy individuals was employed in a CM dataset of 150 adult postnatal women, 92 of whom provided MRI data. CM history was retrospectively assessed from birth to age 18 years. Brain-predicted age was calculated from T1-weighted MRI scans. Brain age gap (BAG) was quantified as the disparity between brain-predicted age, relative to chronological age. Sensitive periods were identified using random forest regression with conditional inference trees.
Results
CM severity was associated with greater BAG (β = 0.34, p < 0.001). The most robust type/time risk factors for greater BAG were parental verbal abuse between ages 7 and 15 years, parental physical abuse between ages 4 and 6 years, witnessing sibling violence between ages 4 and 15 years, and sexual abuse between ages 4–6. Parental verbal abuse (7–15 years) and parental physical abuse (4–6) were the variables that were the most important predictors above and beyond duration, multiplicity (number of exposures), and cumulative maltreatment severity.
Conclusion
These findings suggest a link between CM and accelerated brain aging, with certain developmental periods appearing more sensitive to these effects. To the best of our knowledge, this study is the first to identify sensitive periods for the link between CM and brain aging in adults, and the first to examine the link between CM and brain aging in postnatal women. Together, these results suggest that CM's association with brain development is complex and warrants nuanced approaches to investigating the possible mechanisms underlying its effects.
{"title":"Sensitive periods for the link between childhood maltreatment and brain aging during adulthood","authors":"Leland L. Fleming , Kyoko Ohashi , Michelle Bosquet Enlow , Jennifer Khoury , Torsten Klengel , Karlen Lyons-Ruth , Martin Teicher , Kerry J. Ressler","doi":"10.1016/j.ynstr.2025.100771","DOIUrl":"10.1016/j.ynstr.2025.100771","url":null,"abstract":"<div><h3>Background</h3><div>Childhood maltreatment (CM) is associated with the early onset of psychopathology and accelerated biological aging. However, outcomes vary widely among individuals with CM history. This variability may, in part, be explained by differences in age of exposure to CM. In this study, we examined whether CM was associated with accelerated brain aging, depending on the timing of exposure (i.e., ‘sensitive periods’).</div></div><div><h3>Method</h3><div>A machine learning algorithm of brain age trained prior to the current study in 3377 healthy individuals was employed in a CM dataset of 150 adult postnatal women, 92 of whom provided MRI data. CM history was retrospectively assessed from birth to age 18 years. Brain-predicted age was calculated from T1-weighted MRI scans. Brain age gap (BAG) was quantified as the disparity between brain-predicted age, relative to chronological age. Sensitive periods were identified using random forest regression with conditional inference trees.</div></div><div><h3>Results</h3><div>CM severity was associated with greater BAG (β = 0.34, p < 0.001). The most robust type/time risk factors for greater BAG were parental verbal abuse between ages 7 and 15 years, parental physical abuse between ages 4 and 6 years, witnessing sibling violence between ages 4 and 15 years, and sexual abuse between ages 4–6. Parental verbal abuse (7–15 years) and parental physical abuse (4–6) were the variables that were the most important predictors above and beyond duration, multiplicity (number of exposures), and cumulative maltreatment severity.</div></div><div><h3>Conclusion</h3><div>These findings suggest a link between CM and accelerated brain aging, with certain developmental periods appearing more sensitive to these effects. To the best of our knowledge, this study is the first to identify sensitive periods for the link between CM and brain aging in adults, and the first to examine the link between CM and brain aging in postnatal women. Together, these results suggest that CM's association with brain development is complex and warrants nuanced approaches to investigating the possible mechanisms underlying its effects.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100771"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614864","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}
Pub Date : 2025-11-01Epub Date: 2025-09-09DOI: 10.1016/j.ynstr.2025.100755
Jakob Hartmann
The biological consequences of chronic stress and trauma are complex, influencing multiple systems and contributing to the development of psychiatric disorders such as MDD and PTSD. Yet, the underlying molecular mechanisms that confer susceptibility in some individuals but resilience in others remain incompletely understood. To help close these knowledge gaps, my work centers on glucocorticoid signaling as a core mechanism underlying stress-related adaptations. This includes the glucocorticoid receptor (GR), its co-chaperones FKBP5 and FKBP4, and regulatory partners such as SKA2. Through a combination of genetic, viral, pharmacological, and transcriptomic approaches, my lab has delineated how these molecules influence HPA axis feedback, fear-related learning, and stress recovery. Recently, we identified a novel, GR-independent role for SKA2 in regulating secretory autophagy, a non-lytic autophagy pathway involved in vesicular cargo release, including cytokine secretion in microglia. These findings established a mechanistic link between intracellular stress signaling and neuroinflammatory responses. In a parallel line of research, we are investigating how chronic stress alters the gut microbiome composition and function, and how these changes impact behavior. Our aim is to harness dietary and probiotic interventions to restore homeostatic balance and enhance stress resilience. By integrating molecular neuroscience with immune and microbiome research, my long-term goal is to build a comprehensive, systems-level model of stress vulnerability and resilience. This approach holds promise for identifying novel biomarkers and therapeutic targets that support mental health and resilience across the lifespan.
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The psychological benefits of exposure to natural environments are well established. However, whether simply viewing nature images produce similar restorative effects and the brain mechanisms involved remain unclear. For study purposes, we recruited 131 healthy university students and randomly assigned them to a nature image viewing group (NG) or a city image viewing group (CG), with 49 participants further selected (NG = 26, CG = 23) to undergo functional magnetic resonance imaging while performing behavioral tasks. First, we compared changes in subjective ratings and salivary cortisol levels, related to affect and stress between the NG and CG after stress induction and image viewing. Next, we examined differences in functional connectivity (FC) patterns of the default mode network (DMN) between the groups during image viewing. Finally, we explored correlations between the recovery effects observed after viewing nature images, along with alterations in FC. Under stress, NG participants reported greater changes in subjective ratings of positive affect (t = 2.610, p = 0.010), lower negative affect (t = −3.008, p = 0.003), and less state rumination (t = −2.103, p = 0.037). Neural data also suggest that connectivity of the DMN subsystems with attentional and executive regions plays a crucial role in modulating stress-related responses during natural experiences. Increased FC between the medial DMN subsystem and other networks was significantly correlated with behavioral recovery scores for both affect and state rumination. These findings indicate that viewing images of natural scenes can aid in stress recovery, highlighting the potential for indoor nature viewing to help mitigate psychological challenges faced in urban environments.
暴露在自然环境中的心理益处是公认的。然而，是否仅仅观看自然图像就能产生类似的恢复效果，以及其中涉及的大脑机制尚不清楚。为了研究目的，我们招募了131名健康的大学生，将他们随机分为自然图像观看组（NG）和城市图像观看组（CG），并进一步选择49名参与者（NG = 26, CG = 23）在执行行为任务时进行功能磁共振成像。首先，我们比较了应激诱导和图像观看后NG和CG之间与情绪和压力相关的主观评分和唾液皮质醇水平的变化。接下来，我们检查了两组在图像观看过程中默认模式网络（DMN）的功能连接（FC）模式的差异。最后，我们探讨了在观看自然图像后观察到的恢复效果与FC变化之间的相关性。在压力下，NG参与者报告了积极情绪主观评分的较大变化（t = 2.610, p = 0.010），消极情绪较低（t = - 3.008, p = 0.003），状态反思较少（t = - 2.103, p = 0.037）。神经数据还表明，DMN子系统与注意和执行区域的连通性在自然体验中调节压力相关反应中起着至关重要的作用。内侧DMN子系统与其他网络之间的FC增加与情绪反刍和状态反刍的行为恢复得分显著相关。这些发现表明，观看自然场景的图像可以帮助压力恢复，强调室内自然观看有助于减轻城市环境中面临的心理挑战的潜力。
{"title":"Default mode network connectivity contributes the augment effect stress recovery by natural viewing","authors":"Zini Chen , Chanyu Wang , Timothea Toulopoulou , Xiayan Chen , Lijing Niu , Haowei Dai , Qingzi Zhu , Yuanyuan Zeng , Ruibin Zhang","doi":"10.1016/j.ynstr.2025.100759","DOIUrl":"10.1016/j.ynstr.2025.100759","url":null,"abstract":"<div><div>The psychological benefits of exposure to natural environments are well established. However, whether simply viewing nature images produce similar restorative effects and the brain mechanisms involved remain unclear. For study purposes, we recruited 131 healthy university students and randomly assigned them to a nature image viewing group (NG) or a city image viewing group (CG), with 49 participants further selected (NG = 26, CG = 23) to undergo functional magnetic resonance imaging while performing behavioral tasks. First, we compared changes in subjective ratings and salivary cortisol levels, related to affect and stress between the NG and CG after stress induction and image viewing. Next, we examined differences in functional connectivity (FC) patterns of the default mode network (DMN) between the groups during image viewing. Finally, we explored correlations between the recovery effects observed after viewing nature images, along with alterations in FC. Under stress, NG participants reported greater changes in subjective ratings of positive affect (<em>t</em> = 2.610, <em>p</em> = 0.010), lower negative affect (<em>t</em> = −3.008, <em>p</em> = 0.003), and less state rumination (<em>t</em> = −2.103, <em>p</em> = 0.037). Neural data also suggest that connectivity of the DMN subsystems with attentional and executive regions plays a crucial role in modulating stress-related responses during natural experiences. Increased FC between the medial DMN subsystem and other networks was significantly correlated with behavioral recovery scores for both affect and state rumination. These findings indicate that viewing images of natural scenes can aid in stress recovery, highlighting the potential for indoor nature viewing to help mitigate psychological challenges faced in urban environments.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100759"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145100088","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}
Pub Date : 2025-11-01Epub Date: 2025-10-19DOI: 10.1016/j.ynstr.2025.100765
Natascha Stoffel , Laure von der Weid , Josef Gross , Cristina Concetti , Rupert Bruckmaier , Selma Aybek
Introduction
Functional Neurological Disorder (FND) is shaped by psychosocial stress, early adversity, and neuroendocrine dysregulation. Oxytocin (OXT), a hormone central to stress regulation and interoception, remains largely unexplored in FND.
Methods
In this cross-sectional study, salivary OXT was assessed at four timepoints across 87 participants (42 FND and 45 sex-age-matched healthy controls), including appetite and satiety and hormonal factors (intake of hormonal contraception or menstrual cycle phases) as covariates. Self-reported interoception, attachment style, childhood trauma and sexual functioning were assessed allowing analysis for association.
Results
Patients with FND exhibited higher OXT concentrations (averaged across four timepoints: d = 0.55, p = 0.031), which remained when controlling for covariates. Appetite and satiety specifically modulated OXT levels at different timepoints, underlying the group difference after lunch (p = 0.006) and at the end of the study visit (p = 0.035). Self-reported interoceptive accuracy was negatively correlated with OXT (r = −0.31, p = 0.014) and insecure attachment was positively correlated with OXT in controls (r = 0.42, p = 0.005), but not in FND. No associations of OXT and childhood trauma or sexual functioning reports were found.
Discussion
The elevated salivary OXT levels observed in patients with FND may reflect a dysregulated or compensatory neuroendocrine response. The combination of higher OXT and lower self-reported interoceptive accuracy suggests that OXT may be upregulated as an attempt to modulate bodily stress or restore homeostatic balance. The absent association of OXT with attachment style in FND specifically supports its role in dealing with socio-affiliative stress.
功能性神经障碍（FND）是由社会心理压力、早期逆境和神经内分泌失调形成的。催产素（OXT）是一种应激调节和内感受的核心激素，在FND中仍未得到充分研究。在这项横断面研究中，87名参与者（42名FND和45名性别年龄匹配的健康对照）的唾液OXT在四个时间点进行评估，包括食欲和饱腹感以及激素因素（激素避孕药的摄入或月经周期阶段）作为协变量。对自我报告的内感受、依恋类型、童年创伤和性功能进行了评估，以便进行关联分析。结果FND患者表现出较高的OXT浓度（四个时间点的平均值：d = 0.55, p = 0.031），在控制协变量后仍然存在。食欲和饱腹感在不同时间点特异性地调节了OXT水平，这是午餐后（p = 0.006）和研究访问结束时（p = 0.035）的组差异的基础。自我报告的内感受准确性与OXT呈负相关（r = - 0.31, p = 0.014），不安全依恋与对照组的OXT呈正相关（r = 0.42, p = 0.005），但在FND中没有。没有发现OXT与儿童创伤或性功能报告的关联。FND患者唾液OXT水平升高可能反映了失调或代偿性神经内分泌反应。较高的OXT和较低的自我报告的内感受准确性的结合表明，OXT可能作为调节身体压力或恢复内稳态平衡的一种尝试而上调。在FND中，情感行为与依恋类型之间不存在关联，这特别支持了情感行为在处理社会附属压力中的作用。
{"title":"Increased salivary oxytocin correlates with lower self-reported interoceptive accuracy in functional neurological disorders","authors":"Natascha Stoffel , Laure von der Weid , Josef Gross , Cristina Concetti , Rupert Bruckmaier , Selma Aybek","doi":"10.1016/j.ynstr.2025.100765","DOIUrl":"10.1016/j.ynstr.2025.100765","url":null,"abstract":"<div><h3>Introduction</h3><div>Functional Neurological Disorder (FND) is shaped by psychosocial stress, early adversity, and neuroendocrine dysregulation. Oxytocin (OXT), a hormone central to stress regulation and interoception, remains largely unexplored in FND.</div></div><div><h3>Methods</h3><div>In this cross-sectional study, salivary OXT was assessed at four timepoints across 87 participants (42 FND and 45 sex-age-matched healthy controls), including appetite and satiety and hormonal factors (intake of hormonal contraception or menstrual cycle phases) as covariates. Self-reported interoception, attachment style, childhood trauma and sexual functioning were assessed allowing analysis for association.</div></div><div><h3>Results</h3><div>Patients with FND exhibited higher OXT concentrations (averaged across four timepoints: d = 0.55, p = 0.031), which remained when controlling for covariates. Appetite and satiety specifically modulated OXT levels at different timepoints, underlying the group difference after lunch (p = 0.006) and at the end of the study visit (p = 0.035). Self-reported interoceptive accuracy was negatively correlated with OXT (r = −0.31, p = 0.014) and insecure attachment was positively correlated with OXT in controls (r = 0.42, p = 0.005), but not in FND. No associations of OXT and childhood trauma or sexual functioning reports were found.</div></div><div><h3>Discussion</h3><div>The elevated salivary OXT levels observed in patients with FND may reflect a dysregulated or compensatory neuroendocrine response. The combination of higher OXT and lower self-reported interoceptive accuracy suggests that OXT may be upregulated as an attempt to modulate bodily stress or restore homeostatic balance. The absent association of OXT with attachment style in FND specifically supports its role in dealing with socio-affiliative stress.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100765"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363253","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}
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