Prefrontal circuits underlying the maturation of learned avoidance

内侧前额叶皮层（mPFC）对学习，情绪， 和决策，包括评估和应对威胁。与其他电路相比，mPFC电路 为了支持复杂的行为，经历可能必要的延长的成熟。然而， 前额叶回路的发展使得适应性行为成熟，但人们对此知之甚少。此外，委员会认为， 其扩展的发展使得mPFC电路非常容易受到环境损害的破坏， 早期生活逆境（ELA）。即使在不利的环境条件改善后，ELA也能产生持久的 认知和情绪处理的改变，使个体处于许多精神疾病的风险中 包括焦虑和抑郁虽然mPFC电路是明确的治疗目标， 精神疾病，我们对典型mPFC电路发展的理解存在重大差距，以及这是如何发生的。 成熟使复杂的认知和情感行为的出现阻止我们设计 有效干预。我们的研究将通过结合威胁回避行为分析来填补这一知识空白 用投射特异性光遗传学操作、活性监测和ELA模型来检验假设 PL-BLA和PL-NAc回路的精确定时成熟决定了年龄特异性回避行为， 通过改变回路发展的轨迹，ELA导致学习性回避的年龄特异性改变。 在目标1中，我们将使用光遗传学来检验特定mPFC回路的行为贡献 改变发展。在目标2中，我们将使用纤维光度法来暴露电路和区域特异性活动 学习性回避的模式。最后，在目标3中，我们将应用上述 探讨早期生活逆境的模型，以了解慢性早期压力如何影响 威胁规避电路的开发这项建议直接解决了迫切需要了解 早期逆境，mPFC电路发展和适应性威胁反应之间的复杂关系。我们 研究可以为利用各种发展机会的个性化心理健康治疗提供信息， 这取决于症状出现的阶段。

PROJECT SUMMARY The medial prefrontal cortex (mPFC) makes essential contributions to learning, mood, and decision making, including evaluating and responding to threats. Compared to other circuits, mPFC circuits undergo prolonged maturation that is likely necessary in order to support complex behaviors. Yet how the development of prefrontal circuits enables the maturation of adaptive behaviors is poorly understood. Moreover, its extended development renders mPFC circuits highly vulnerable to disruption by environmental insults such as early life adversity (ELA). Even after adverse environmental conditions improve, ELA can produce lasting alterations in cognitive and emotional processing that put individuals at risk for many psychiatric disorders including anxiety disorders and depression. Although mPFC circuits are clear therapeutic targets for psychiatric disorders, substantial gaps in our understanding of typical mPFC circuit development and how this maturation enables emergence of complex cognitive and emotional behaviors prevent us from designing effective interventions. Our research will fill this knowledge gap by combining threat avoidance behavioral assays with projection-specific optogenetic manipulations, activity monitoring, and a model of ELA to test the hypothesis that precisely timed maturation of PL-BLA and PL-NAc circuits determines age-specific avoidance behaviors, and by altering the trajectory of circuit development, ELA leads to age-specific alterations in learned avoidance. In Aim 1, we will use optogenetics to test the hypothesis that the behavioral contribtions of specific mPFC circuits change over development. In Aim 2, we will use fiber photometry to expose circuit and region-specific activity patterns during learned avoidance across development. Finally, in Aim 3, we will apply the aforementioned approaches to a model of early life adversity to understand how chronic early stress impacts the trajectory of threat avoidance circuit development. This proposal directly addresses a pressing need to understand the complex relationships between early adversity, mPFC circuit development, and adaptive threat resposnes. Our research can inform individualized mental health treatments that exploit a variety of developmental opportunities, depending on the stage at which symptoms emerge.