Disruptions to early caregiving can alter the developing brain, yet how outcomes differ by when stress occurs, and an animal's sex, remains poorly understood. In this study, male and female rats were exposed to maternal separation during early (P2–P10), late (P11–P20), or prolonged (P2–P20) postnatal windows, then assessed for pubertal timing, spatial memory, anxiety, and social behavior during adolescence. The findings reveal that the same stressor can produce opposite or entirely different effects depending on developmental timing and sex. Puberty arrived earlier in females exposed to early or prolonged maternal separation, with no such effect observed in males. Spatial memory was impaired by early separation in males, but by prolonged separation in females. Anxiety-like behavior was blunted in separation-exposed males overall, while early separation actually enhanced stress reactivity in females. Social behavior was disrupted in both sexes, but the timing of separation that drove those changes differed between males and females. Together, these results underscore that developmental timing and sex are key determinants of how early-life adversity shapes the brain and behavior — and highlight the importance of distinguishing discrete postnatal periods when studying the consequences of early caregiving disruption.

Pubertal development is tightly regulated by hypothalamic neuroendocrine signals that are typically suppressed by stress-related pathways such as corticotropin-releasing hormone (CRH) signaling via the corticotropin-releasing hormone receptor 1 (CRHR1). Stress pathways arise from the hypothalamic–pituitary–adrenal (HPA) axis and pubertal maturation depends on the hypothalamic–pituitary–gonadal (HPG) axis. Therefore, CRH-mediated inhibition represents a key point of crosstalk between the HPA and HPG systems. The current study examined whether CRHR1 dysregulation mediates the effects of MS on both pubertal timing and anxiety-like behavior, as assessed by the acoustic startle response (ASR), in female rats. The findings support a potential model in which altered CRHR1 signaling during negative early environments disrupts HPA-HPG axis crosstalk, triggering early onset of puberty and increased anxiety-like behavior. Targeting CRHR1 signaling during sensitive developmental windows may provide a therapeutic avenue for mitigating these long-term impacts of early life stress.

Accelerated Puberty as a Therapeutic Biomarker for Lifelong Neurological Dysfunction

There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT2A receptors. Restoration of 5-HT2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior.