Prenatal stress (PNS) is a well-established risk factor for psychiatric disorders, yet the underlying neurobiological mechanisms remain unclear. Here, we demonstrate that PNS induces long-term behavioral abnormalities, including increased anxiety- and depressive-like behaviors specifically in adult male mice. To investigate potential neurodevelopmental disruptions, we analyzed the medial prefrontal cortex (mPFC) at key postnatal stages. RNA sequencing at postnatal day 1 (P1) revealed significant transcriptional changes, particularly in genes associated with neuronal migration and differentiation, with a diminished effect by P14. Histological analysis identified a transient imbalance in inhibitory neuron subpopulations, PNS decreased the density of early-born neurons derived from the medial ganglionic eminence (MGE) while increasing late-born neurons derived from the caudal ganglionic eminence (CGE) at P1. EdU labeling confirmed that these shifts were time- and subtype-specific, affecting inhibitory neuron proliferation at distinct embryonic stages. By P15, these neuroanatomical alterations largely resolved, yet behavioral abnormalities persisted into adulthood. Our findings suggest that PNS disrupts inhibitory neuron development during a critical early window, leading to lasting behavioral consequences despite the transient nature of anatomical changes. This study highlights the selective vulnerability of inhibitory neuron subtypes to early-life stress and provides insight into potential mechanisms underlying stress-related psychiatric disorders.
{"title":"Prenatal stress induces transient developmental alterations in distinct GABAergic populations and leads to long-lasting behavioral abnormalities","authors":"Keren Shoshani-Haye , Gilgi Friedlander , Ofra Golani , Suellen Almeida-Correa , Yair Shemesh , Alon Chen","doi":"10.1016/j.ynstr.2025.100749","DOIUrl":"10.1016/j.ynstr.2025.100749","url":null,"abstract":"<div><div>Prenatal stress (PNS) is a well-established risk factor for psychiatric disorders, yet the underlying neurobiological mechanisms remain unclear. Here, we demonstrate that PNS induces long-term behavioral abnormalities, including increased anxiety- and depressive-like behaviors specifically in adult male mice. To investigate potential neurodevelopmental disruptions, we analyzed the medial prefrontal cortex (mPFC) at key postnatal stages. RNA sequencing at postnatal day 1 (P1) revealed significant transcriptional changes, particularly in genes associated with neuronal migration and differentiation, with a diminished effect by P14. Histological analysis identified a transient imbalance in inhibitory neuron subpopulations, PNS decreased the density of early-born neurons derived from the medial ganglionic eminence (MGE) while increasing late-born neurons derived from the caudal ganglionic eminence (CGE) at P1. EdU labeling confirmed that these shifts were time- and subtype-specific, affecting inhibitory neuron proliferation at distinct embryonic stages. By P15, these neuroanatomical alterations largely resolved, yet behavioral abnormalities persisted into adulthood. Our findings suggest that PNS disrupts inhibitory neuron development during a critical early window, leading to lasting behavioral consequences despite the transient nature of anatomical changes. This study highlights the selective vulnerability of inhibitory neuron subtypes to early-life stress and provides insight into potential mechanisms underlying stress-related psychiatric disorders.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"38 ","pages":"Article 100749"},"PeriodicalIF":3.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858037","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 : 2025-07-23eCollection Date: 2025-09-01DOI: 10.1016/j.ynstr.2025.100745
Sonia Torres-Sanchez, Andre L Curtis, Rita J Valentino, Esther Berrocoso
Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) stands as an innovative therapeutic approach for treatment-resistant depression. Previous preclinical investigations utilizing DBS targeted at the ventromedial prefrontal cortex (vmPFC), considered the rodent equivalent of the human SCC, have demonstrated antidepressant-like effects, as well as enhancement in the activity of the locus coeruleus (LC)-norepinephrine (NE) system and pontine-cortical network oscillations. Given the association between social stress and depression and other psychiatric disorders, we assessed the impact of vmPFC DBS on social stress-induced changes in LC neuronal activity in awake rats. Spontaneous and auditory-evoked LC single unit activity were compared between control and DBS male rats during the first (acute) and fifth (repeated) day of social defeat stress. In stark contrast to LC activation observed in controls, both acute and repeated stress robustly inhibited LC neurons of DBS rats. While both groups experienced an acute stress-induced reduction in auditory-evoked LC discharge, the duration of the evoked response was only decreased in control animals. LC auditory-evoked activity was increased after repeated stress and DBS effectively counteracted these stress-induced alterations. These findings suggest that DBS treatment shifts stress-induced regulation of LC activity such that it favors the engagement of inhibitory modulation. This may serve to promote resistance of the LC-NE system to stress-induced excitation and contribute to the mitigation of neuropsychiatric consequences of stress.
{"title":"Deep brain stimulation changes locus coeruleus responses to social stress from activation to inhibition.","authors":"Sonia Torres-Sanchez, Andre L Curtis, Rita J Valentino, Esther Berrocoso","doi":"10.1016/j.ynstr.2025.100745","DOIUrl":"10.1016/j.ynstr.2025.100745","url":null,"abstract":"<p><p>Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) stands as an innovative therapeutic approach for treatment-resistant depression. Previous preclinical investigations utilizing DBS targeted at the ventromedial prefrontal cortex (vmPFC), considered the rodent equivalent of the human SCC, have demonstrated antidepressant-like effects, as well as enhancement in the activity of the locus coeruleus (LC)-norepinephrine (NE) system and pontine-cortical network oscillations. Given the association between social stress and depression and other psychiatric disorders, we assessed the impact of vmPFC DBS on social stress-induced changes in LC neuronal activity in awake rats. Spontaneous and auditory-evoked LC single unit activity were compared between control and DBS male rats during the first (acute) and fifth (repeated) day of social defeat stress. In stark contrast to LC activation observed in controls, both acute and repeated stress robustly inhibited LC neurons of DBS rats. While both groups experienced an acute stress-induced reduction in auditory-evoked LC discharge, the duration of the evoked response was only decreased in control animals. LC auditory-evoked activity was increased after repeated stress and DBS effectively counteracted these stress-induced alterations. These findings suggest that DBS treatment shifts stress-induced regulation of LC activity such that it favors the engagement of inhibitory modulation. This may serve to promote resistance of the LC-NE system to stress-induced excitation and contribute to the mitigation of neuropsychiatric consequences of stress.</p>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"38 ","pages":"100745"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874216","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}
Pub Date : 2025-07-10DOI: 10.1016/j.ynstr.2025.100744
Isabell Int-Veen , Beatrix Barth , Ramona Täglich , Betti Schopp , Hans-Christoph Nuerk , Christian Plewnia , Stefanie De Smet , Marie-Anne Vanderhasselt , Andreas J. Fallgatter , Ann-Christine Ehlis , David Rosenbaum
This study investigated the neuromodulatory effects of Theta Burst Stimulation (TBS) on resting-state functional connectivity (FC) following psychosocial stress induced by the Trier Social Stress Test (TSST). Given its key role in cognitive control and emotion regulation — processes highly relevant for rumination — we focused on the frontoparietal network. Across two studies, intermittent (iTBS) and continuous (cTBS) protocols were applied to the left Dorsolateral Prefrontal Cortex (DLPFC; study 1) and right Ventrolateral Prefrontal Cortex (VLPFC; study 2) prior to stress induction. Functional Near-Infrared Spectroscopy (fNIRS) was used to assess neural changes. A total of 88 (study 1) and 89 (study 2) healthy participants were recruited, balanced for low and high trait rumination. Each participant received both active and sham TBS (iTBS or cTBS), in a randomized, counterbalanced design. Results indicated that iTBS elicited excitatory effects on prefrontal and fronto-parietal connectivity, whereas cTBS effects were more variable. Trait rumination emerged as a modulator of TBS effects: In study 1, significant interactions for FC between the right VLPFC and Somatosensory Association Cortex (SAC) when stimulating the left DLPFC emerged, while study 2 revealed similar interactions for FC between the left DLPFC and SAC and intra-SAC FC when stimulating the right VLPFC. Correlations between post-stress state rumination and FC changes further support these findings. These results underscore the importance of neural assessments in TBS research and highlight the complexity of individual differences in state and trait rumination. Understanding the interplay between TBS, fronto-parietal connectivity, and rumination may provide valuable insights into personalized neuromodulation strategies.
本研究探讨了Theta Burst Stimulation （TBS）对Trier Social stress Test （TSST）诱导的心理社会应激后静息状态功能连通性（FC）的神经调节作用。鉴于其在认知控制和情绪调节（与反刍高度相关的过程）中的关键作用，我们将重点放在了额顶叶网络上。在两项研究中，间歇（iTBS）和连续（cTBS）方案应用于左背外侧前额叶皮层(DLPFC；研究1)和右侧腹外侧前额叶皮层（VLPFC）；研究2)应力诱导前。功能近红外光谱（fNIRS）评估神经变化。共招募了88名（研究1）和89名（研究2）健康参与者，平衡了低特质反刍和高特质反刍。在一个随机、平衡的设计中，每个参与者都接受了主动和假TBS （iTBS或cTBS）。结果表明，iTBS对前额叶和额顶叶连通性有兴奋作用，而cTBS对前额叶和额顶叶连通性的影响变化较大。特质反刍是TBS效应的调节因子：在研究1中，当刺激左侧DLPFC时，右侧VLPFC与躯体感觉关联皮层（SAC）之间出现了显著的FC相互作用，而研究2显示，当刺激右侧VLPFC时，左侧DLPFC与SAC和SAC内FC之间也出现了类似的FC相互作用。应激后状态反刍与FC变化之间的相关性进一步支持了这些发现。这些结果强调了神经评估在TBS研究中的重要性，并强调了状态和特质反刍个体差异的复杂性。了解TBS、额顶叶连接和反刍之间的相互作用可能为个性化神经调节策略提供有价值的见解。
{"title":"Interhemispheric Effects of iTBS on the Fronto-Parietal Network: Evidence from Dual-Site Stimulation","authors":"Isabell Int-Veen , Beatrix Barth , Ramona Täglich , Betti Schopp , Hans-Christoph Nuerk , Christian Plewnia , Stefanie De Smet , Marie-Anne Vanderhasselt , Andreas J. Fallgatter , Ann-Christine Ehlis , David Rosenbaum","doi":"10.1016/j.ynstr.2025.100744","DOIUrl":"10.1016/j.ynstr.2025.100744","url":null,"abstract":"<div><div>This study investigated the neuromodulatory effects of Theta Burst Stimulation (TBS) on resting-state functional connectivity (FC) following psychosocial stress induced by the Trier Social Stress Test (TSST). Given its key role in cognitive control and emotion regulation — processes highly relevant for rumination — we focused on the frontoparietal network. Across two studies, intermittent (iTBS) and continuous (cTBS) protocols were applied to the left Dorsolateral Prefrontal Cortex (DLPFC; study 1) and right Ventrolateral Prefrontal Cortex (VLPFC; study 2) prior to stress induction. Functional Near-Infrared Spectroscopy (fNIRS) was used to assess neural changes. A total of 88 (study 1) and 89 (study 2) healthy participants were recruited, balanced for low and high trait rumination. Each participant received both active and sham TBS (iTBS or cTBS), in a randomized, counterbalanced design. Results indicated that iTBS elicited excitatory effects on prefrontal and fronto-parietal connectivity, whereas cTBS effects were more variable. Trait rumination emerged as a modulator of TBS effects: In study 1, significant interactions for FC between the right VLPFC and Somatosensory Association Cortex (SAC) when stimulating the left DLPFC emerged, while study 2 revealed similar interactions for FC between the left DLPFC and SAC and intra-SAC FC when stimulating the right VLPFC. Correlations between post-stress state rumination and FC changes further support these findings. These results underscore the importance of neural assessments in TBS research and highlight the complexity of individual differences in state and trait rumination. Understanding the interplay between TBS, fronto-parietal connectivity, and rumination may provide valuable insights into personalized neuromodulation strategies.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100744"},"PeriodicalIF":4.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633523","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}
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.
{"title":"Chronic stress and cytogenesis ablation disrupt hippocampal neuron connectivity, with fluoxetine restoring function with sex-specific effects","authors":"Inês Ribeiro , Tiago Silveira-Rosa , Joana Martins-Macedo , Luísa Marques-Ferraz , Ana Rita Dourado , Gonçalo Martins-Ferreira , Fanny Farrugia , Ana João Rodrigues , Djoher Nora Abrous , Nuno Dinis Alves , Patrícia Patrício , 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}
Pub Date : 2025-06-19DOI: 10.1016/j.ynstr.2025.100742
Hannah C. Smith , Zhe Yu , Patrick Yazigi , Benjamin Turley , Adam P. Swiercz , Jeanie Park , Paul J. Marvar
Post-traumatic stress disorder (PTSD) is a complex and prevalent neuropsychiatric condition that arises in response to exposure to a traumatic event. A common diagnostic criterion for PTSD includes heightened physiological reactivity to trauma-related sensory cues, in safe or familiar environments. Understanding complex PTSD criteria requires new pre-clinical paradigms and technologies that integrate sensory physiology (e.g., auditory, visual, olfactory) with behavior. Here we present a novel Pavlovian-based paradigm using an open-source software plus deep learning-based pose estimation to investigate the effects of a recurrent conditioned stimulus (CS) on fear behaviors in pair-housed mice within the home cage. Simultaneous home cage video recording and analysis of CS-evoked freezing behaviors were performed using a deep learning model, with consideration for light-dark circadian cycles. Fear-conditioned dyad mice exhibited high CS-evoked freezing, with evidence of extinction learning (characterized by low freezing) during the mid-phase of the 2-week paradigm. Females exhibited reduced CS-evoked home cage freezing compared to males with circadian differences between the light (low freezing) and dark (high freezing) periods. Following the 2-week paradigm, fear-conditioned mice, compared to controls, exhibited heightened context-dependent freezing, while males but not females showed heightened startle reactivity. Taken together, these results demonstrate a novel software application for examining conditioned defensive and fear behaviors over time in mouse dyads within an ethologically relevant environment. Future applications could be used for more integrative analysis and understanding of neural circuits and heightened sensory threat reactivity, potentially improving the understanding and treatment of PTSD.
{"title":"Tracking conditioned fear in pair-housed mice using deep learning and real-time cue delivery","authors":"Hannah C. Smith , Zhe Yu , Patrick Yazigi , Benjamin Turley , Adam P. Swiercz , Jeanie Park , Paul J. Marvar","doi":"10.1016/j.ynstr.2025.100742","DOIUrl":"10.1016/j.ynstr.2025.100742","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is a complex and prevalent neuropsychiatric condition that arises in response to exposure to a traumatic event. A common diagnostic criterion for PTSD includes heightened physiological reactivity to trauma-related sensory cues, in safe or familiar environments. Understanding complex PTSD criteria requires new pre-clinical paradigms and technologies that integrate sensory physiology (e.g., auditory, visual, olfactory) with behavior. Here we present a novel Pavlovian-based paradigm using an open-source software plus deep learning-based pose estimation to investigate the effects of a recurrent conditioned stimulus (CS) on fear behaviors in pair-housed mice within the home cage. Simultaneous home cage video recording and analysis of CS-evoked freezing behaviors were performed using a deep learning model, with consideration for light-dark circadian cycles. Fear-conditioned dyad mice exhibited high CS-evoked freezing, with evidence of extinction learning (characterized by low freezing) during the mid-phase of the 2-week paradigm. Females exhibited reduced CS-evoked home cage freezing compared to males with circadian differences between the light (low freezing) and dark (high freezing) periods. Following the 2-week paradigm, fear-conditioned mice, compared to controls, exhibited heightened context-dependent freezing, while males but not females showed heightened startle reactivity. Taken together, these results demonstrate a novel software application for examining conditioned defensive and fear behaviors over time in mouse dyads within an ethologically relevant environment. Future applications could be used for more integrative analysis and understanding of neural circuits and heightened sensory threat reactivity, potentially improving the understanding and treatment of PTSD.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"37 ","pages":"Article 100742"},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490495","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 : 2025-06-18DOI: 10.1016/j.ynstr.2025.100741
Margot W.L. Morssinkhof , David Matthew Doyle , Ysbrand D. van der Werf , Martin den Heijer , Annemieke Heijboer , Birit F.P. Broekman , Dirk Jan Stenvers
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.
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.
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.
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.
{"title":"Effects of gender-affirming hormones on diurnal cortisol concentrations: A prospective study","authors":"Margot W.L. Morssinkhof , David Matthew Doyle , Ysbrand D. van der Werf , Martin den Heijer , Annemieke Heijboer , Birit F.P. Broekman , 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":"2025-06-18","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}
Pub Date : 2025-06-10DOI: 10.1016/j.ynstr.2025.100740
Carola Dell’Acqua , Claudio Imperatori , Rita B. Ardito , Benedetto Farina , Mauro Adenzato , Giuseppe Carbone , Aurelia Lo Presti , Daniela Palomba , Simone Messerotti Benvenuti
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 (n = 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.
{"title":"Adverse childhood experiences and internalizing symptoms: the moderating role of neural responses to threat","authors":"Carola Dell’Acqua , Claudio Imperatori , Rita B. Ardito , Benedetto Farina , Mauro Adenzato , Giuseppe Carbone , Aurelia Lo Presti , Daniela Palomba , 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":"2025-06-10","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}
Pub Date : 2025-06-06DOI: 10.1016/j.ynstr.2025.100738
Thorhildur Halldorsdottir
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.
{"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":"2025-06-06","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}
Pub Date : 2025-06-06DOI: 10.1016/j.ynstr.2025.100739
Katrina Z. Edmond , Natalie Matosin
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.
{"title":"Expanding our understanding of (mal)adapted stress physiology in psychiatric disorders: achieving single-cell characterisation of steroids and neuropeptides","authors":"Katrina Z. Edmond , 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":"2025-06-06","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}
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.
{"title":"Mechanisms of childhood trauma: an integrative review of a multimodal, transdiagnostic pathway","authors":"J.M. Pasteuning , C. Broeder , T.A.A. Broeders , R.G.G. Busby , A.W. Gathier , E. Kuzminskaite , F. Linsen , C.P. Souama , J.E. Verhoeven , M.S.C. Sep , 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":"2025-06-03","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}
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