Prenatal stress shapes discrete responses during early recovery from repeated adult stress

Prenatal stress is associated with increased risk for psychiatric disorders in offspring, yet many exposed individuals do not develop psychopathology, suggesting prenatal stress may confer a latent vulnerability that emerges only under later-life challenge. We have previously demonstrated long term neuroinflammation and behavioral changes following exposure to prenatal stress, but had not examined whether the offspring were vulnerable to adult stressors, which is translationally relevant.

To test whether prenatal stress alters the stress response and stress recovery following repeated stress, pregnant dams underwent prenatal restraint stress (GD10.5-GD16.5), and adult offspring of both sexes were assigned to a 1-week adult restraint regimen or adult control in a 2 × 2 factorial design. Anxiety-like and social behavior was assessed after the stress paradigm in adulthood, and endocrine and transcriptional endpoints were measured immediately after stress and during early recovery.

Repeated adult restraint elicited a robust but transient corticosterone response and induced broad, largely time-limited stress-responsive transcription across prefrontal cortex, hippocampus, amygdala, and hypothalamus. Prenatal stress did not globally potentiate HPA-axis output or canonical glucocorticoid-responsive gene induction under this strong adult stressor, but instead produced selective, context-dependent effects on stress- related behavior and region- and sex-specific gene regulation during the acute and recovery phases.

Collectively, the data indicate that under a strong repeated adult stressor, prenatal stress is associated with selective differences in the pattern and timing of behavioral and transcriptional responses across stress-regulatory circuitry, rather than a uniform modulation in HPA-axis output. This pattern underscores a complex, long-term interplay between prenatal stress exposures and later-life stressors, which together may shape vulnerability or resilience to adult psychopathology.