Abstract：
BACKGROUND: Chronic childhood stress is a prominent risk factor for developing affective disorders, yet mechanisms underlying this association remain unclear. Maintenance of optimal serotonin (5-HT) levels during early postnatal development is critical for the maturation of brain circuits. Understanding the long-lasting effects of early-life stress (ELS) on serotonin-modulated brain connectivity is crucial to develop treatments for affective disorders arising from childhood stress.
METHODS: Using a mouse model of chronic developmental stress, we determined the long-lasting consequences of ELS on 5-HT circuits and behavior in females and males. Using FosTRAP mice, we cross-correlated regional c-Fos density to determine brain-wide functional connectivity of the raphe nucleus. We next performed in vivo fiber photometry to establish ELS-induced deficits in 5-HT dynamics and optogenetics to stimulate 5-HT release to improve behavior.
RESULTS: Adult female and male mice exposed to ELS showed heightened anxiety-like behavior. ELS further enhanced susceptibility to acute stress by disrupting the brain-wide functional connectivity of the raphe nucleus and the activity of 5-HT neuron population, in conjunction with increased orbitofrontal cortex (OFC) activity and disrupted 5-HT release in medial OFC. Optogenetic stimulation of 5-HT terminals in the medial OFC elicited an anxiolytic effect in ELS mice in a sex-dependent manner.
CONCLUSIONS: These findings suggest a significant disruption in 5-HT-modulated brain connectivity in response to ELS, with implications for sex-dependent vulnerability. The anxiolytic effect of the raphe-medial OFC circuit stimulation has potential implications for developing targeted stimulation-based treatments for affective disorders that arise from early life adversities.
METHODS: Using a mouse model of chronic developmental stress, we determined the long-lasting consequences of ELS on 5-HT circuits and behavior in females and males. Using FosTRAP mice, we cross-correlated regional c-Fos density to determine brain-wide functional connectivity of the raphe nucleus. We next performed in vivo fiber photometry to establish ELS-induced deficits in 5-HT dynamics and optogenetics to stimulate 5-HT release to improve behavior.
RESULTS: Adult female and male mice exposed to ELS showed heightened anxiety-like behavior. ELS further enhanced susceptibility to acute stress by disrupting the brain-wide functional connectivity of the raphe nucleus and the activity of 5-HT neuron population, in conjunction with increased orbitofrontal cortex (OFC) activity and disrupted 5-HT release in medial OFC. Optogenetic stimulation of 5-HT terminals in the medial OFC elicited an anxiolytic effect in ELS mice in a sex-dependent manner.
CONCLUSIONS: These findings suggest a significant disruption in 5-HT-modulated brain connectivity in response to ELS, with implications for sex-dependent vulnerability. The anxiolytic effect of the raphe-medial OFC circuit stimulation has potential implications for developing targeted stimulation-based treatments for affective disorders that arise from early life adversities.
摘要：
背景：儿童时期的慢性压力是发生情感障碍的主要危险因素，然而这种关联的潜在机制仍不清楚.在出生后早期发育过程中维持最佳的5-羟色胺（5-HT）水平对于脑回路的成熟至关重要。了解早期生活压力（ELS）对5-羟色胺调节的大脑连接的长期影响对于开发情感障碍的治疗至关重要。源于童年的压力。
方法：使用慢性发育应激小鼠模型，我们确定了ELS对雌性和雄性小鼠的5-HT回路和行为的长期影响。使用FosTRAP小鼠，我们交叉关联区域c-fos密度以确定中缝核的全脑功能连接。接下来，我们进行了体内纤维光度法，以建立ELS诱导的5-HT动力学和光遗传学缺陷，以刺激5-HT释放以改善行为。
结果：暴露于ELS的成年雌性和雄性小鼠表现出增强的焦虑样行为。ELS通过破坏中缝核的全脑功能连接和5-HT神经元群体的活动，进一步增强了对急性应激的易感性。与眶额皮质（OFC）活性增加和内侧OFC（mOFC）中5-HT释放中断有关。mOFC中5-HT末端的光遗传学刺激以性别依赖性方式在ELS小鼠中引起抗焦虑作用。
结论：这些研究结果表明，响应于ELS，5-HT调节的大脑连通性显著中断，对性别依赖脆弱性的影响。raphe-mOFC回路刺激的抗焦虑作用为开发针对早期生活逆境引起的情感障碍的基于靶向刺激的治疗提供了潜在意义。
方法：使用慢性发育应激小鼠模型，我们确定了ELS对雌性和雄性小鼠的5-HT回路和行为的长期影响。使用FosTRAP小鼠，我们交叉关联区域c-fos密度以确定中缝核的全脑功能连接。接下来，我们进行了体内纤维光度法，以建立ELS诱导的5-HT动力学和光遗传学缺陷，以刺激5-HT释放以改善行为。
结果：暴露于ELS的成年雌性和雄性小鼠表现出增强的焦虑样行为。ELS通过破坏中缝核的全脑功能连接和5-HT神经元群体的活动，进一步增强了对急性应激的易感性。与眶额皮质（OFC）活性增加和内侧OFC（mOFC）中5-HT释放中断有关。mOFC中5-HT末端的光遗传学刺激以性别依赖性方式在ELS小鼠中引起抗焦虑作用。
结论：这些研究结果表明，响应于ELS，5-HT调节的大脑连通性显著中断，对性别依赖脆弱性的影响。raphe-mOFC回路刺激的抗焦虑作用为开发针对早期生活逆境引起的情感障碍的基于靶向刺激的治疗提供了潜在意义。
