Mapping mesocortical contributions to estrous-dependent learning processes

摘要 女性在创伤后患创伤后应激障碍(PTSD)的可能性是男性的两倍，但 这种差异的神经生物学基础还知之甚少。虽然有大量证据表明 创伤本身会以不同的方式影响男性和女性的大脑，但对 创伤后应激障碍的治疗有可能以性别依赖的方式发挥作用。对机制有更好的理解 特异性地调解女性创伤后应激障碍的康复可能会导致治疗方法的改进和更高的成功率 症状缓解率。特别是，卵巢激素调节灭绝的神经过程 学习代表着一个很有希望的重点领域。在这里，我们将研究循环雌激素对 连接腹侧被盖区和边缘下区的神经回路的结构和功能 大鼠的内侧前额叶皮质(MPFC)和杏仁核基底外侧区(BLA)。我们提出了一个 高雌激素状态通过以下途径促进IL-BLA连接和增强消光保持的系统 消退学习过程中VTA-IL DA释放的上游调节。为了检验这一假设，我们将使用 神经解剖示踪剂、交叉病毒技术和3D重建的组合，从而 定义整个发情周期中与恐惧消退相关的神经活动和可塑性。这项工作将导致 女性大脑中消亡回路的多突触图谱，潜在地识别新的机制 哪种雌激素可以调节学习过程。

Summary Women are twice as likely as men to develop Post-Traumatic Stress Disorder (PTSD) after a trauma, but the neurobiological basis for this discrepancy is poorly understood. While there is a great deal of evidence that trauma itself can impact the male and female brain in discrete ways, less attention has been paid to the potential for PTSD treatments to work in a sex-dependent manner. A better understanding of the mechanisms that specifically mediate PTSD recovery in women could lead to improved therapeutics and a higher success rate for symptom reduction. In particular, the neural processes by which ovarian hormones modulate extinction learning represent a promising area of focus. Here, we will investigate the influence of circulating estrogen on the structure and function of neural circuitry connecting the ventral tegmental area (VTA), infralimbic area (IL) of the medial prefrontal cortex (mPFC), and basolateral area of the amygdala (BLA) in rats. We propose a system by which high estrogen states facilitate IL-BLA connectivity and enhanced extinction retention through upstream modulation of VTA-IL DA release during extinction learning. To test this hypothesis, we will use a combination of neuroanatomical tracers, intersectional viral techniques, and 3D reconstructions, thereby defining fear extinction-associated neural activity and plasticity across the estrous cycle. This work will result in a multi-synaptic map of extinction circuitry in the female brain, potentially identifying novel mechanisms by which estrogen can modulate learning processes.