Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a “two-hit” stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.

早年压力通常被认为是精神疾病的主要风险，但许多研究人员发现，早年的逆境可能会增强晚年的压力恢复能力。很少有研究在啮齿类动物中进行，以解决暴露于早年生活压力可能增强压力恢复能力的可能性，并且潜在的神经机制远未被理解。在这里，我们通过应用两种不同的早期生活压力范式在大鼠中建立了一个“双重打击”压力模型：可预测和不可预测的母体分离 (MS)。产后可预测的 MS 促进了对成人束缚压力的恢复，而不可预测的 MS 增加了压力敏感性。我们证明，在患有不可预测 MS 的大鼠中，内侧前额叶皮层 (mPFC) 锥体神经元的谷氨酸能突触中会发生结构和功能障碍，但在患有可预测 MS 的大鼠中则不会。然后，我们使用来自成年男性 PFC 的 RNA 测序数据的差异表达基因 (DEG) 分析来识别负责压力恢复的中枢基因。催产素是一种肽激素，是这些改变基因中排名最高的差异表达基因。与正常升高和不可预测的 MS 大鼠相比，可预测的 MS 增加了 mPFC 中催产素的表达。条件性敲除 mPFC 中的催产素受体足以在患有可预测 MS 的大鼠中产生兴奋性突触功能障碍和焦虑行为，而 mPFC 中催产素受体表达的恢复改变了遭受不可预测的 MS 的大鼠的兴奋性突触功能和焦虑行为。这些发现得到了以下证据的进一步支持：阻断从下丘脑室旁核 (PVN) 到 mPFC 的催产素投射足以加剧暴露于可预测 MS 的大鼠的焦虑行为。我们的研究结果为可预测的 MS 促进压力恢复能力，而不可预测的 MS 通过 mPFC 催产素信号在大鼠中增加压力敏感性的概念提供了直接证据。这些发现得到了以下证据的进一步支持：阻断从下丘脑室旁核 (PVN) 到 mPFC 的催产素投射足以加剧暴露于可预测 MS 的大鼠的焦虑行为。我们的研究结果为可预测的 MS 促进压力恢复能力，而不可预测的 MS 通过 mPFC 催产素信号在大鼠中增加压力敏感性的概念提供了直接证据。这些发现得到了以下证据的进一步支持：阻断从下丘脑室旁核 (PVN) 到 mPFC 的催产素投射足以加剧暴露于可预测 MS 的大鼠的焦虑行为。我们的研究结果为可预测的 MS 促进压力恢复能力，而不可预测的 MS 通过 mPFC 催产素信号在大鼠中增加压力敏感性的观点提供了直接证据。