Neurobiology of Stress

IntroductionAdolescence is a sensitive developmental period during which chronic stress can induce lasting adaptations in corticolimbic circuits involved in stress regulation, cognition, and emotional behavior. We examined the long-term behavioral, endocrine, and molecular consequences of adolescent chronic variable stress (CVS) in male and female rats, focusing on the infralimbic cortex (IL) and basolateral amygdala (BLA) MethodsSprague Dawley rats of both sexes were exposed to CVS during late adolescence and evaluated in adulthood after an extensive recovery period. Behavioral testing included cued fear conditioning and extinction recall, delayed spatial win-shift, novel object recognition, Morris water maze, three-chamber social behavior, and passive avoidance. HPA-axis reactivity to acute restraint was assessed. Targeted qPCR was used to measure stress-related gene expression in the IL and BLA immediately after stress or after a 5-week recovery period ResultsAdolescent CVS did not cause generalized cognitive impairment, but instead produced selective, sex-specific effects. Females had reduced HPA responses to acute stress and mild deficits in delayed spatial win-shift performance, together with long-term IL changes in genes related to adrenergic signaling, plasticity, and GABA clearance. Males showed enhanced Morris water maze probe retention, weaker novel object discrimination, altered passive avoidance with marked inter-individual variability, and enhanced social preference. At the molecular level, males exhibited long-term upregulation of Fkbp5 in IL and downregulation of PACAP, 1D adrenergic receptor, and proenkephalin in BLA, whereas females showed delayed PACAP upregulation in BLA DiscussionAdolescent CVS induces persistent, sex- and region-specific recalibration of corticolimbic function, supporting distinct patterns of vulnerability and resilience, rather than uniform stress pathology.

Traumatic events increase the risk for anxiety disorders, yet knowledge of how trauma modulates neuronal activity to induce anxiety is incomplete. The amygdala, which processes stressful sensory information, is enriched with interneurons that release the anxiolytic neurotransmitter neuropeptide Y (NPY). Amygdala NPY levels are reduced one week after an aversive event, suggesting chronic alteration of NPY+ interneurons; however, studies of in vivo amygdalar NPY+ cell activity during stressors are lacking. Here, we use a genetically encoded calcium sensor together with fiber photometry to investigate in vivo activation of NPY+ cells in basolateral amygdala (BLA) to aversive stimuli in mice. NPY+ cell activation was evaluated in response to two aversive stimuli, air puffs to the face (mild) and footshocks (strong). Air puffs caused a transient elevation of calcium in BLA NPY+ cells, indicating robust neuronal activation, in both male and female mice with no sex-dependent differences. Interestingly, there was habituation of the calcium signal in NPY+ cells to later air puff iterations. Strong footshocks also caused calcium elevation in both male and female mice with no sex-dependent differences. Excitingly, footshock induces a larger calcium response compared to air-puff. In contrast to air puff, the calcium signal to footshock was prolonged in later iterations. BLA NPY+ cell calcium signals were consistent in response to the same footshock protocol delivered 1 week later, indicating that activation of NPY+ cells by footshock is stable across this timeframe. Taken together, these results reveal a potential role for NPY+ interneurons in basolateral amygdala during aversive events.

Early adversity increases vulnerability for adult psychopathology. Across multiple pre-clinical models of early adversity, there are reports of glial dysfunction and disrupted amino acid neurotransmission, along with maladaptive behavioral responses in adulthood. Disrupted G-protein coupled receptor signaling is known to phenocopy specific consequences of early life adversity. Enhanced Gq signaling in the forebrain excitatory neurons in early postnatal life programs anxio-depressive behaviors in adulthood, accompanied by altered neuronal glutamate and GABA metabolism in mouse models. We hypothesized that enhancing Gq signaling in forebrain excitatory neurons in early postnatal life may also impact glial function in adulthood. Our results show that postnatal hM3Dq-mediated chemogenetic activation of CaMKII-positive forebrain excitatory neurons not only increases anxiety-like behavior, but also evokes bidirectional transcriptional regulation of multiple glia-associated genes in the neocortex and hippocampi. While Gfap, Aldh1l1, S100{beta}, Eaat1, Eaat2 and Eaat3, mRNA levels were reduced in the neocortex, they were enhanced in the hippocampus, and a similar pattern was noted for GFAP protein levels. Transient, postnatal chemogenetic activation of CaMKII-positive neurons did not alter astrocyte cell density in both the neocortex and the hippocampus. Using (1H-(13C)) NMR spectroscopy, we observed a significant decline in astrocyte-specific glutamate and GABA neurotransmitter turnover, and a reduction in astrocyte metabolic flux within the neocortex and the hippocampus in adulthood in animals with a history of postnatal chemogenetic activation of forebrain excitatory neurons. Our findings indicate that chemogenetically driving Gq signaling transiently during the postnatal window in forebrain excitatory neurons results in persistent changes well into adulthood, with enhanced anxiety-like behaviors and disrupted glial function and metabolism, phenocopying specific changes in glial function noted following early adversity.

Linking environmental contexts with stressful experiences is critical for engaging adaptive responses necessary to avoid future threats. Yet, active context-dependent avoidance remains poorly understood. Here, we establish a restraint-induced conditioned place aversion (CPA) paradigm to examine how an acute physiological stressor acquires negative motivational value through contextual association. We found that mice repeatedly exposed to physical restraint in a contextually distinguishable chamber later avoid that location, demonstrating that restraint stress can drive learned aversion in the absence of continued exposure. To identify potential neuronal correlates underlying this learned association, we quantified c-Fos expression in several areas implicated in aversive motivation, emotional salience, and contextual encoding. We found that restraint within the context of the CPA paradigm was associated with increased c-Fos in the nucleus accumbens (NAc) and basolateral amygdala (BLA) while c-Fos expression increased in the ventral hippocampus in response to exposure to the contextual cues alone. These findings reveal region-specific engagement in processing aversive contextual memories induced by restraint stress. This work bridges classical stress models with associative learning frameworks, providing a platform to further dissect the neural mechanisms underlying stress-related negative affect and avoidance behaviors.

Separate research has evaluated trajectories of posttraumatic stress symptoms (PTSS) and obsessive-compulsive symptoms (OCS), but no study has evaluated OCS trajectories following trauma exposure nor combined PTSS/OCS trajectories. The present study evaluated combined PTSS/OCS trajectories among 585 survivors of Hurricane Helene, spanning three waves of data collection over 12 months. A 3-class solution was supported, including resilient (i.e., consistently low PTSS and OCS), chronic (i.e., elevated PTSS and OCS with gradual reduction over time), and moderate-yet-diverging (i.e., moderate elevations in PTSS and OCS with gradually declining PTSS and persistent and increasing OCS over time) classes. This study shows both overlap and differentiation in symptom trajectories from earlier research, with the moderate-yet-diverging trajectory suggesting unique OCS pathways distinct from PTSS.

BackgroundResponding appropriately to threats is critical for survival. Dysregulated defensive responses are core features of psychiatric illnesses including panic disorder and post-traumatic stress disorder. Carbon dioxide (CO2) inhalation evokes defensive behaviors in both humans and mice. Here we investigated the role of acid-sensing ion channels (ASICs) in CO2-evoked jumping in mice. MethodsDefensive behaviors (jumping and freezing) were assessed in response to CO2 inhalation and basolateral amygdala (BLA) acidification. We tested the role of ASICs using global knockout mice and Asic1aloxP/loxP mice transduced with AAV-CMV-Cre or AAV-CaMKII-Cre in the BLA. Effects of CO2 on single neuron firing and local field potentials were studied via BLA microwire arrays. ResultsASIC1A disruption increased CO2-evoked jumping while reducing freezing, paralleled by increased BLA c-Fos induction. Acidification of the BLA recapitulated these effects. Virus-mediated ASIC1A disruption in BLA did not resolve the locus of ASIC1A action in jumping. CO2 inhalation suppressed firing in most BLA neurons, though a small number increased firing. ASIC1A disruption enhanced CO2-induced suppression of narrow waveform neurons (putative interneurons), and facilitated excitation of wide waveform neurons (putative principal neurons). Additionally, CO2 produced concentration-dependent broadband power suppression with selective theta enhancement, effects that were augmented by ASIC1A disruption. ConclusionsTogether, these findings suggest that ASIC1A promotes interneuron activity during acidosis and that its loss may reduce inhibition of principal neuron output, shifting defensive responses from freezing toward jumping. These results advance our understanding of how brain pH and ASICs regulate defensive behavior, with potential implications for understanding dysregulated defensive responses.

Lack of social interaction results in various behavioral abnormalities in rodents, including increased anxiety levels, altered sociability, and impaired cognitive ability. Epigenetic factors regulate gene expression, however, how they contribute to juvenile social isolation (jSI)-induced behavioral alterations remains largely unknown. Here, we focused on the nucleus accumbens (NAc), a critical brain region of the reward system that regulates motivation-related behaviors. We first performed RNA-seq on neuronal nuclei and found alterations in genes related to neuronal function, as well as in transcriptional and epigenetic regulation. Protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) showed that top key nodes among down-regulated genes include membrane receptors (Ntrk2, Grin3a, and Grik1) and an apoptosis regulator (Bcl2). To further investigate whether jSI-induced gene expression alterations are mediated by histone modifications, we next performed CUT&Tag for four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K27me3), and the results implied that epigenetic alterations may also play a role in neuronal function as well as transcriptional regulation. Reanalysis of previously published RNA-seq data on the manipulation of histone modification-associated factors (including Kdm6b, Brd4, and Setd1a) suggested that these enzymes were probably involved in jSI-induced gene expression alterations. Taken together, our comprehensive analysis implies the involvement of histone modification regulation in jSI-related alterations of gene expression in NAc.

Learning in adulthood is embedded in everyday social life, in which periods of psychosocial stress alternate with recovery. The autonomic nervous system regulates how the body responds to environmental demands, yet individuals differ markedly in this regulation. It remains unknown whether such individual differences in bodily regulation modulate the ability to learn probabilistic patterns from sensory input. Here, we investigated statistical learning of probabilistic patterns in speech streams in a six-hour experiment incorporating psychosocial stress and recovery to approximate everyday conditions. Sixty-five adults were exposed to novel speech streams in high- and low-stress contexts, with learning assessed immediately after exposure and following a rest period. Heart rate variability was recorded throughout the experiment to capture individual differences in autonomic reactivity to stress and recovery. From these measures, we constructed composite proxies of sympathetic (SNS) and parasympathetic (PNS) nervous system reactivity. Individuals with congruent SNS-PNS reactivity--either jointly high or jointly low--showed superior statistical learning outcomes across stress contexts. SNS reactivity preferentially supported encoding, whereas PNS reactivity supported consolidation. Moreover, the effect of SNS activation during speech exposure on statistical learning depended on individuals SNS reactivity profiles. These findings demonstrate that individual differences in bodily regulation are tightly linked to the ability to learn statistical dependencies in stressful environments. Overall, the findings highlight the essential role of brain-body-environment interactions in statistical learning.

Early-life stress elevates the risk of developing neuropsychiatric disorders. However, the mechanism underlying this vulnerability, and how they contribute to sex differences in these disorders, remain to be understood. Here, we use multivariate brain-based predictive models to examine how the number, positive or negative appraisal, and impact of adolescent stressful life events reported either by the youth or their caregivers are reflected in neuroanatomy (cortical thickness, surface area, cortical and subcortical gray matter volume, and T1 intensity measures). We used data from the Adolescent Brain Cognitive Development (ABCD) study at 2-year (N = 6,301, age 11-12), 4-year (N = 5,000, age 13-14) and 6-year (N = 3,226, age 15-16) follow-up time points to examine the sex-independent and sex-specific neural correlates of stressful life events. Our analyses showed mostly non-significant associations between stressful life events and neuroanatomy. However, we did find that the number of positively appraised stressful life events reported by the caregivers at the 4-year follow-up was significantly associated with cortical thickness, independent of sex, and with surface area in females only. Across three developmental timepoints, seven neuroanatomical measures, two reporting perspectives, and both sex-independent and sex-specific analyses, we show that the number, appraisal, and impact of stressful life events are largely not reflected in adolescent neuroanatomy.

RATIONALEEnvironmental enrichment (EE) paradigms in rodents have long demonstrated that enhanced sensory, cognitive, social, and motor stimulation positively impacts brain function, improving learning, memory, and neuroplasticity. These effects have significant implications for understanding cognitive development and mitigating cognitive decline and brain aging. While numerous transcriptomic studies have explored EE-induced molecular changes, a unified view of the genes and pathways consistently modulated remains lacking. METHODSTo address this gap, we performed a systematic review and meta-analysis. We conducted a comprehensive PubMed search for all studies published up to February 2025 that matched all the following inclusion criteria: (1) employed EE paradigms; (2) were conducted on rodents; (3) utilized genome-wide transcriptomic methods; (4) examined brain regions or neuronal populations. The 323 retrieved articles were manually screened for relevance to the study aims and data availability. Datasets from 20 eligible RNA-seq reports were reprocessed using a unified analysis pipeline and subjected to a meta-analysis with three complementary statistical methods. RESULTSDespite considerable heterogeneity across studies, our integrative analysis identified consistent gene expression signatures linked to synaptic function, plasticity and their transcriptional regulation. These molecular insights advance our understanding of how EE impacts on neuronal and behavioural outcomes, and may inform therapeutic strategies aimed at replicating or enhancing EE benefits. To promote open science and foster further research, we developed an accessible web application, mEEtaBrain, that enables the neuroscience community to navigate and interrogate our meta-analysis results.

Rhesus macaques (Macaca mulatta) are widely used as non-human primate models for biomedical research. When housed in captivity, it is essential to provide an environment that supports their natural behaviours; otherwise, they risk developing mood disorders, stereotypies, and other behavioural issues that may lead to physical harm. The objective of this preliminary study was to monitor the behaviour of three aged rhesus macaques ([≥] 20 y.o.), relocated from a laboratory to a Rescue Centre for Exotic Animals (Italy), and to assess the impact of novel food enrichments. Behavioural data were collected over 18 weeks, beginning at their arrival, using continuous focal sampling from video recordings. Simultaneously, faecal samples were gathered for cortisol analysis. The study was divided into three phases: a control phase without enrichments, a feeding enrichment phase (divided into two periods), and a final control phase without enrichments. Each phase comprised 900 minutes of observations for each subject. Data were analysed using generalized linear mixed models. Results showed an increase in locomotion during the enrichment and final phase compared to the initial phase. Additionally, a reduction in scratching and body-shaking behaviours was observed in the final phase compared to the initial phase. These findings suggest that implementing an enrichment program can enhance the welfare of aged non-human primates and can be considered a valuable tool in the rehabilitation of non-human primates previously housed in laboratories. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/719840v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@152a3a1org.highwire.dtl.DTLVardef@74b53forg.highwire.dtl.DTLVardef@275b21org.highwire.dtl.DTLVardef@1d004d8_HPS_FORMAT_FIGEXP M_FIG C_FIG RESEARCH HIGHLIGHTSO_LIEnvironmental enrichment positively affected activity and stress indicators in aged ex-laboratory rhesus macaques. C_LIO_LILocomotion rates increased while scratching, body-shaking, and cortisol levels decreased. C_LIO_LIEnrichment enhance welfare during rehabilitation, even in older individuals. C_LI

Trauma-focused psychotherapies for post-traumatic stress disorder (PTSD) require waking re-engagement with traumatic memories, driving high dropout. We tested whether trauma-linked auditory cues delivered during slow-wave sleep are feasible. Of 13 patients who provided written informed consent, 6 (100% female) completed overnight Sound Exposure during Sleep (SES); none of the adverse events observed during overnight stimulation were judged by the study team to be attributable to the auditory intervention, and slow-wave sleep was preserved. Two sequential protocol versions were used: Version A (n = 2; capped at SUDs 30-40) and a no-ceiling amendment (Version B, n = 4). Post-hoc exploratory analyses (not powered for efficacy) showed Version B reduced subjective distress (mean difference -65.5%, 95% CI -104.2 to -26.7; nominal p = 0.012) and PCL-5 intrusion (-7.0; nominal p = 0.015). Findings are exploratory and require sham-controlled confirmation. Trial registration: jRCT1030230706.

Structured AbstractO_ST_ABSBackgroundC_ST_ABSPost-Traumatic Stress Disorder (PTSD) is a mental health condition affecting people who experience traumatic events. Trauma-exposed occupational groups report higher rates of PTSD than the general population. Current treatments, and access, often take months and may cause distress when people are required to talk about the trauma. ObjectiveTo determine the proof of concept of FIRST, a brief, non-trauma focussed therapy, in two separate populations with employment-associated PTSD. MethodTwo independent, single-arm, experimental therapy pilot trials were conducted. Trial one recruited 20 military veterans who received FIRST therapy via trained third-sector therapists. Trial two recruited 16 health and social care workers with FIRST therapy delivered by healthcare provider therapists. All participants were adults with PTSD (confirmed via CAPS-5 in trial one, and symptom score of [≥]33 on the PCL5 in trial two). Primary outcomes were recruitment feasibility, retention, data quality and reduction in PTSD symptoms. Secondary outcomes were anxiety and depression symptoms, daily life functioning and perceived health status. Veterans were followed up at 12 weeks post-enrolment and healthcare workers at 8 weeks. ResultsThe veteran trial progression criteria to main trial were met. Seventy-nine people screened eligible, 43 attended a CAPS-5 assessment; 20 had confirmed PTSD and were enrolled. Seventeen completed therapy and 12-week outcome measures. Mean PCL-5 scores decreased from 48.7 (SD = 13.02, n=20) at baseline to 23.5 (SD = 15.30, n=17) at 12-weeks. The healthcare worker trial obtained informed consent from 16 participants, 10 commenced therapy and were included in analysis with eight completing therapy. Mean PCL-5 scores decreased from 42.60 (12.23, (n=10) at baseline to 22.00 (19.92, n=8) at 8-weeks. ConclusionsProof of concept of FIRST was established. PTSD symptom reductions exceeded the PCL-5 minimal clinically important difference. Undertaking a fully powered randomised controlled trial of FIRST therapy is feasible within both healthcare and third sectors. HighlightsO_LIPost-traumatic stress disorder (PTSD) is more common in military veterans and health workers than the general population C_LIO_LITherapy can be challenging to commence and complete when it requires a focus on the trauma incident C_LIO_LIFIRST offers a promising, brief, non-trauma focused therapy for the treatment of PTSD C_LI

Birth occurs during a sensitive period in brain development wherein hormones facilitate the dramatic shift in physiology that accomplishes the transition to extrauterine homeostasis. The surge in birth signaling hormones is abridged in cases of delivery by cesarean section (CS), which accounts for 32% of all births in the U.S. Epidemiological studies have associated birth via CS with increased risk of obesity in later life. Here, we sought to investigate this association using an experimental preclinical animal model, the prairie vole. Subjects were delivered either via vaginal delivery (VD) or CS and then cross-fostered. CS delivery led to increased body weight across development, which could be prevented with hormone rescue of oxytocin (OXT) and arginine vasopressin (AVP), delivered to neonates immediately after CS. This weight gain could not be attributed to differences in birth weight, parenting, food consumption, or thermoregulation; however, CS subjects moved slower than VD subjects, which hormone rescue reversed. Hormone rescue also reduced adiposity in adulthood among CS subjects. The dopamine system was dysregulated in the caudate/putamen of CS offspring, suggesting a neural mechanism for the decreased locomotion. Hormone rescue of CS neonates restored dopamine synthesis in the caudate/putamen and increased spontaneous locomotor activity. These findings suggest CS can lead to increased weight gain in part through a reduction of locomotion driven by long-lasting changes in striatal dopamine regulation, all of which can be prevented by treating CS neonates with a single peripheral administration of two birth-signaling hormones, OXT and AVP.

Perinatal hypoxia is a major contributor to neurodevelopmental disorders; however, the consequences of mild-to-moderate perinatal hypoxia (MPH) remain insufficiently characterized. Here, we investigated cortical plasticity following MPH using a multimodal approach that combines behavioral assessment, histological analysis, and in vivo magnetic resonance imaging (MRI). Fifty-six Wistar Han rats were exposed to hypoxia or normoxia at postnatal day 1 (P1). Neurodevelopmental assessment from P3 to P14 revealed impaired rooting and vibrissae-placing reflexes in hypoxic rats. Histological analysis demonstrated: altered expression of microtubule-associated protein-2, apical dendrite bundling, reduced neurofilament-H expression, and decreased dendritic arbor complexity in large pyramidal neurons, indicating disrupted maturation of excitatory circuits. Increased parvalbumin expression, higher interneuron density, and its enhanced neurite elaboration indicated precocious development of inhibitory circuits, consistent with a compensatory response. MRI at P15, combined with whole-brain voxel-wise analysis, revealed a significant increase in fractional anisotropy in the anterior cingulate cortex (ACC). Convergent behavioral, histological, and imaging findings identified the ACC as the most vulnerable region following MPH, followed by the somatosensory cortex. These findings reveal early cytoarchitectural and MRI detectable correlates of a single episode of MPH, which, together with previous findings from this model, support the neurodevelopmental origin of persistent alterations in cortical structure and circuit function, characterized by an excitatory-inhibitory imbalance. The study identifies and defines a framework for understanding region-specific vulnerability and plasticity in the immature brain, with implications for improving the early detection of subtle perinatal brain injury, as a prerequisite for timely therapeutic intervention.

Relapse after treatment for various mental health disorders has been linked to tendency for reductions in responding to increase over time or following re-exposure to motivating stimuli. Here we show that, in rats, responding reduced through non-contingent outcome delivery does not recover in these ways, and that this learning depends on an intact lateral orbitofrontal cortex. These findings suggest that contingency degradation overwrites original learning which may support the development of relapse-resistant behavioural interventions.

Maladaptive consummatory behaviors can arise from dysregulated circuits, like the extended amygdala that governs motivation and feeding. Neurotensin (NTS) is expressed throughout the central, peripheral, and enteric nervous systems with well-established roles in energy balance and feeding. SBI-553, a {beta}-arrestin-biased allosteric modulator of NTSR1, recruits {beta}-arrestin while attenuating Gq-mediated signaling. We used SBI-553 to examine NTS modulation of extended amygdala GABAergic signaling, and probed its effects on food consumption in mice. Ex vivo, we found that NTS and SBI-553 differentially modulates GABAergic neurotransmission across extended amygdala subregions. In vivo, SBI-553 reduces palatable food consumption in both fed and food-deprived mice, with greater reductions under fasted conditions. SBI-553 alters activation across CeA subregions in a sex- and feeding-state-dependent manner: SBI-553 increases cFos immunofluorescence in the CeAL and CeAC, but not the CeAM. This work supports neurotensinergic modulation as a compelling target for further investigation into the neural substrates of consummatory behaviors. HighlightsO_LINTS enhances GABAergic transmission in the CeAL and the ovBNST C_LIO_LISBI-553 blocks NTS-induced modulation in the CeAL but not in the ovBNST C_LIO_LISBI-553 attenuates feeding of a palatable high-carbohydrate food C_LIO_LIThe effect of SBI-553 on feeding is driven by energy deficit/motivation to feed C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/722083v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@198a6fborg.highwire.dtl.DTLVardef@fae407org.highwire.dtl.DTLVardef@1909d9corg.highwire.dtl.DTLVardef@15b8c57_HPS_FORMAT_FIGEXP M_FIG C_FIG

Special Operations Forces (SOF) sustain repeated low-level blast (LLB) exposures; while most remain resilient, a subset develop depression, sleep disruption and reduced wellbeing that threaten readiness. We asked whether sub-concussive LLB chronically injures an insula-centered cortico-striato-thalamic network and whether network architecture explains divergent outcomes. In a mouse model parameterized to SOF blast exposure monitoring data, ninety 3-psi blasts over three weeks produced persistent diffusion and connectivity deficits across insular, striatal, pallidal and thalamic nodes, accompanied by tauopathy, neuroinflammation, vascular amyloid, and durable sleep and metabolic abnormalities. In SOF Soldiers, measures of cumulative LLB exposure predicted right insula-striatal diffusion/neurite disruption and increased depression risk. Interventional multi-mediator modeling showed that right insula-striatal microstructural injury mediated the effect of LLB to increase depression risk, while moderator screening identified features that amplify or buffer this mediation, defining risk and resilience zones. These findings enable precision blast-medicine integrating exposure dose, circuit biomarkers and moderator profiles.

Post-traumatic stress disorder (PTSD) remains a significant psychiatric burden; despite growing biomarker research, no blood-based molecular diagnostic tool has been clinically validated for routine use. In this study, we developed a machine learning classifier for PTSD using peripheral blood leukocyte RNA-seq data from combat-exposed U.S. Marines (GSE64813), diagnosed via the Clinician-Administered PTSD Scale (CAPS) under DSM-IV criteria. Differentially expressed genes (DEGs) were identified and further refined through additional filtering criteria, yielding a 90-gene feature set used to train and compare multiple machine learning models. The support vector machine (SVM) classifier achieved the best performance, with an accuracy of 89% and an AUC of 0.95, outperforming logistic regression and random forest approaches. Furthermore we evaluated our model on independent external datasets to assess generalizability. These findings highlight the promise of transcriptomic signatures as a foundation for objective, blood-based PTSD diagnostics, while emphasizing the critical need for robust cross-dataset generalizability. Code availabilityhttps://www.kaggle.com/code/persianexxx/ptsd-final

Stress is a commonly reported seizure precipitant and may contribute to the development of psychiatric comorbidities in epilepsy, yet how chronic stress interacts with epileptic circuits remains poorly understood. We investigated the impact of chronic restraint stress on physiological, behavioral, and synaptic outcomes in a mouse model of Dravet syndrome, specifically corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (BNST), a stress-responsive region implicated in epilepsy patients. Chronic restraint stress produced divergent hypothalamic-pituitary-adrenal axis responses, with stressed Dravet syndrome mice exhibiting elevated corticosterone, increased mortality in females, and increased locomotion and anxiety-like behavior. Ex vivo electrophysiological recordings revealed that chronic stress increased spontaneous excitatory event frequency onto BNST CRF neurons in both genotypes and selectively increased sEPSC and sIPSC amplitude in Dravet syndrome mice. Evoked recordings demonstrated genotype-specific effects of stress on glutamatergic transmission in CRF neurons of the DS group. This suggests greater stress-dependent remodeling of spontaneous and evoked synaptic activity in DS. These findings suggest chronic stress may worsen physiological and behavioral outcomes in Dravet syndrome and promote specific maladaptive alterations in BNST CRF circuitry. More broadly, these results suggest that stress interacts with seizure vulnerability and potentially contributes to neuropsychiatric comorbidities and epilepsy.