A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior

Abstract

Adversity early in life substantially impacts prefrontal cortex (PFC) development and vulnerability to later-life psychopathology. Importantly, repeated adverse experiences throughout childhood increase the risk for PFC-mediated behavioral deficits more commonly in women. Evidence from animal models points to effects of adversity on later-life neural and behavioral dysfunction; however, few studies have investigated the neurobiological underpinnings of sex-specific, long term consequences of multiple developmental stressors. We modeled early life adversity in rats via maternal separation (postnatal day (P)2-20) and juvenile social isolation (P21-35). Adult (P85) male and female rats were assessed for differences in the presence and structural integrity of PFC perineuronal nets (PNNs) enwrapping parvalbumin (PV)-expressing interneurons. PNNs are extracellular matrix structures formed during critical periods in postnatal development that play a key role in the plasticity of PV cells. Females - but not males - exposed to multiple hits of adversity demonstrated a reduction in PFC PV cells in adulthood. We also observed a sex-specific, potentiated reduction in PV+ PNN structural integrity. Moreover, correlations between neural disruption and hyperactivity/risk-assessment behavior were altered by adversity differently in males and females. These findings suggest a sex-specific impact of repeated adversity on neurostructural development and implicate PNNs as a contributor to associated behavioral dysfunction.

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“…Fear-related behaviors were decreased in postweaning and adult SI animals. Decreased anxiety-related behavior was confirmed in adult female (but not male) rats after SI in adolescence and testing in adulthood [ 25 ]. Moreover, rats reared in SI from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression was again escalated in a novel environment [ 133 ].…”

“…It should be noted that effects of adolescent SI could be more severe if such exposure occurs as a second “hit” after early adversity (e.g., after early maternal separation or neglect). Gildawie et al demonstrated sex-specific impact of early life adversity combined with SI in adolescence on adult locomotion and risk-assessment behavior, where females are more sensitive to adversity-induced deviations in performance [ 25 ]. Parvalbumin-positive interneurons’ counts and perineuronal nets integrity in medial PFC were also affected in sex-specific manner, suggesting that females could be at higher risk of long-term neural and extracellular consequences following multiple hits of adversity.…”