James P. Herman

Introduction: The mammalian stress response relies on tightly regulated HPA axis signaling, and disruptions in glucocorticoid feedback are implicated in stress-related disorders such as PTSD. Although many individuals experience trauma, only some develop pathology, suggesting that individual differences in glucocorticoid responsivity may help predict susceptibility or resilience. Here, we examined whether corticosterone (CORT) responses to a mild stressor predict behavioral outcomes following single-prolonged stress (SPS) in male and female rats. Methods: Mild stress reactivity was quantified using area-under-the-curve (AUC) CORT responses to light-dark box exposure, after which animals underwent SPS, behavioral assays, and post-reinstatement cFos immunohistochemical analysis. Results: Females exhibited SPS-induced reductions in basal AM CORT and displayed a robust traumatic stress-related phenotype in which high CORT responders displayed increased anxiety-like behavior, impaired fear extinction, and enhanced reinstatement. Correlational and permutation analyses revealed a consistent pattern in SPS-exposed females in which lower pre-stress basal AM CORT and higher mild stress-induced CORT (AUC) predicted increased fear expression, indicating a dissociation between resting and stress-evoked glucocorticoid signals. In males, mild stress reactivity did not predict SPS-related outcomes; however, reduced pre-stress basal AM CORT in control males predicted increased fear expression, suggesting sex-specific differences in the potential predictive value of CORT dynamics. SPS and CORT responder status also differentially modulated cFos expression across stress-related brain regions, including the PVN, infralimbic cortex, and amygdala in both males and females. Conclusion: These findings demonstrate that mild stress reactivity and basal glucocorticoid dynamics can predict trauma-related phenotypes in a sex-specific manner, identifying them as a potential biomarker of PTSD susceptibility in females.

Introduction: Adolescence 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). Methods: Sprague 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. Results: Adolescent 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, α1D adrenergic receptor, and proenkephalin in BLA, whereas females showed delayed PACAP upregulation in BLA. Discussion: Adolescent CVS induces persistent, sex- and region-specific recalibration of corticolimbic function, supporting distinct patterns of vulnerability and resilience, rather than uniform stress pathology.

Introduction: Adolescence 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). Methods: Sprague 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. Results: Adolescent 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, α1D adrenergic receptor, and proenkephalin in BLA, whereas females showed delayed PACAP upregulation in BLA. Discussion: Adolescent CVS induces persistent, sex- and region-specific recalibration of corticolimbic function, supporting distinct patterns of vulnerability and resilience, rather than uniform stress pathology.

Of the 2.8 million individuals who seek medical attention for traumatic brain injury (TBI) each year, nearly 300,000 require hospitalization, with up to 60% of these needing intensive care. Intensive care treatment of TBI involves stressful events such as sleep disruption, noise, and painful procedures, potentially leading to chronic stress in patients undergoing such treatment. Given that physiologic stress can exacerbate neuroinflammation and impair normal neural function, we hypothesized that chronic variable stress (CVS) following TBI would exacerbate behavioral and pathological outcomes. We tested this hypothesis by subjecting adolescent male mice to blunt TBI, followed by two weeks of CVS or control conditions. We assessed brain pathologic responses to injury 2-, 5-, 20-, and 28-weeks post-injury. We found chronic optic tract degeneration by Fluoro-jade B staining in TBI groups. Unexpectedly, CVS+TBI mice did not show evidence of optic tract axon degeneration 20 weeks after injury, but did at the other time points. CVS led to increased microglial phagocytic markers early after injury, regardless of TBI status, and TBI led to increased microglial phagocytic markers in a delayed fashion as well. Notably, microglial phagocytosis markers were not elevated in TBI+CVS groups compared to TBI only groups 20 weeks post-injury. There was no effect of TBI or CVS on behavioral measures taken at the end of CVS. These findings suggest a delayed, but not permanent, protective effect on axonal degeneration after TBI, potentially related to altered microglial and astrocytic phagocytic activity.

Responses to acute stress function to restore homeostasis. Hence, the study of neurophysiological responses to acute stress helps to understand mechanisms underlying adaptive coping in the face of environmental demands. The infralimbic medial prefrontal cortex (IL-mPFC) modulates the switch between behavioral coping styles, and acute stress enhances glutamatergic neurotransmission on mPFC projection neurons. However, the role of acute stress responses and stress hormones on the physiology of IL-mPFC projection neurons during adulthood remains underexplored. Here, we studied rapid and slow effects of acute corticosterone exposure on synaptic transmission and intrinsic membrane excitability in layer 5 pyramidal neurons of the IL (L5-IL PNs) in adult male rats using ex vivo whole-cell patch-clamp of mPFC slices. We report that corticosterone dynamically modulates the physiology of L5-IL PNs in a time-dependent manner. Specifically, corticosterone elicits a strong rapid shift of the excitatory–inhibitory balance toward enhanced excitation with mineralocorticoid (MR) and glucocorticoid receptors (GR) playing complementarily roles. Also, corticosterone rapidly and transiently decreases the firing rate of L5-IL PNs via GR. Moreover, acute stress or corticosterone slowly enhances glutamatergic neurotransmission via MR and GR without modulating inhibitory neurotransmission or intrinsic excitability of adult L5-IL PNs. Our findings highlight the potential relevance of corticosterone effects on L5-IL PNs to promote a homeostatic response in adult male rats. First, corticosterone rapidly attenuates IL intrinsic excitability during the rapid initial phase of the acute stress response. Later on, corticosterone slowly restores IL output function over time to promote adaptive executive responses when context changes.

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an environmental enrichment removal (ER) paradigm in male rats. The basolateral amygdala (BLA) was identified as a region of interest, demonstrating differential Fos responsivity to ER and having an established role in stress processing and adaptation. A comprehensive multi-omics investigation of the BLA, spanning multiple cohorts, platforms, and analyses, revealed alterations in microglia and the extracellular matrix (ECM). Follow-up studies indicated that ER decreased microglia size, complexity, and phagocytosis, suggesting reduced immune surveillance. Loss also substantially increased ECM coverage, specifically targeting perineuronal nets surrounding parvalbumin interneurons, suggesting decreased plasticity and increased inhibition within the BLA following loss. Behavioral analyses suggest that these molecular effects are linked to impaired BLA salience evaluation, leading to a mismatch between stimulus and reaction intensity. These loss-like behaviors could be rescued by depleting BLA ECM during the removal period, helping us understand the mechanisms underlying loss and revealing novel molecular targets to ameliorate its impact.