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.

中文翻译：

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发育中的大鼠遭受两次打击的逆境模型揭示了对前额叶皮层结构和行为的性别特异性影响

生命早期的逆境极大地影响了前额叶皮层（PFC）的发育以及对以后的精神病理学的脆弱性。重要的是，整个儿童时期反复的不良经历增加了PFC介导的行为缺陷在女性中的风险。动物模型的证据表明，逆境对以后的神经和行为功能障碍有影响。然而，很少有研究研究多种发育应激源的性别特异性，长期后果的神经生物学基础。我们通过母体分离（产后一天（P）2-20）和青少年社交孤立（P21-35）对大鼠的早期生活逆境建模。评估成年（P85）雄性和雌性大鼠在包裹表达小白蛋白（PV）的中间神经元的PFC神经周围神经网络（PNN）的存在和结构完整性方面的差异。PNN是在产后发育关键时期形成的细胞外基质结构，在PV细胞的可塑性中起关键作用。暴露于多重逆境中的雌性而非雄性表现出成年后PFC PV细胞的减少。我们还观察到了PV + PNN结构完整性的性别特异性增强反应。此外，在男性和女性中，逆境改变了神经干扰与多动/风险评估行为之间的相关性。这些发现表明，反复逆境会对神经结构发育产生性别特异性影响，并暗示PNNs是导致相关行为障碍的原因。暴露于多重逆境中的雌性而非雄性表现出成年后PFC PV细胞的减少。我们还观察到了PV + PNN结构完整性的性别特异性增强反应。此外，在男性和女性中，逆境改变了神经干扰与多动/风险评估行为之间的相关性。这些发现表明，反复逆境会对神经结构发育产生性别特异性影响，并暗示PNNs是导致相关行为障碍的原因。暴露于多重逆境中的雌性而非雄性表现出成年后PFC PV细胞的减少。我们还观察到了PV + PNN结构完整性的性别特异性增强反应。此外，在男性和女性中，逆境改变了神经干扰与多动/风险评估行为之间的相关性。这些发现表明，反复逆境会对神经结构发育产生性别特异性影响，并暗示PNNs是导致相关行为障碍的原因。