Synaptic regulation of affective behaviors

描述（由申请人提供）：女性抑郁症和焦虑症等情感性障碍的发病率是男性的两倍。这种性别差异在青春期出现，表明雌二醇可能起作用。有趣的是，情感症状的严重程度与内源性雌二醇水平呈负相关。然而，内源性雌二醇调节与情感行为相关的突触回路的机制尚不清楚。我们建议研究雌二醇水平的变化是否以及如何调节内侧前额叶皮层（mPFC）中的突触，mPFC是调节情感行为的关键大脑区域。我们还将测试雌激素受体的药理激活是否能改善内源性雌二醇水平较低期间的情感行为。初步结果表明，雌二醇对mPFC突触的影响需要脑源性神经营养因子（BDNF），一种参与情感行为的分泌性营养蛋白。实验将阐明雌二醇和BDNF在mPFC突触中相互作用的机制。这些实验可能会揭示情感行为中性别差异的机制，以及低雌二醇水平时期对环境和遗传挑战的脆弱性。此外，我们的研究将为调节mPFC突触以治疗情感性障碍提供可能的治疗靶点和机会窗口。

DESCRIPTION (provided by applicant): The incidence of affective disorders including depression and anxiety disorders in women is twice that of men. This gender difference, which emerges during puberty, suggests a potential role of estradiol. Interestingly, the severity of affective symptoms is negatively correlated with the endogenous estradiol levels. However, the mechanism by which endogenous estradiol modulates synaptic circuits relevant to affective behaviors is not well understood. We propose to investigate whether and how variations in estradiol levels modulate synapses in the medial prefrontal cortex (mPFC), a brain region critical for the regulation of affective behaviors. We will also test whether pharmacological activation of estrogen receptors improves affective behaviors during periods of low endogenous estradiol. Preliminary results indicate that the effects of estradiol on the mPFC synapses require brain derived neurotrophic factor (BDNF), a secreted trophic protein involved in affective behaviors. Experiments will be carried out to elucidate the mechanism by which estradiol and BDNF interact at mPFC synapses. These experiments are likely to shed light on the mechanism of sex differences in affective behaviors and the vulnerability of periods of low estradiol levels to environmental and genetic challenges. In addition, our studies will provide insights into possible therapeutic targets and windows of opportunity to modulate the mPFC synapses for the management of affective disorders.