Effects of early life stress on functional development of prefrontal-amygdala connectivity

项目摘要 早期生活压力（ELS）与发展压力相关病理学的风险显著增加有关， 包括抑郁、焦虑和创伤后应激障碍（PTSD）。然而， ELS增加病理风险的原因尚不清楚。研究ELS对产后的影响 我们利用了一个特征良好的神经元回路，即听觉恐惧回路。这里我们 研究早期生活压力（ELS）改变发育中小鼠厌恶性学习的机制。 我们假设早期生活压力加速了基底外侧杏仁核的发育成熟 (BLA)而内侧前额叶皮质的前边缘区（PL）则无此现象。在目标1中，我们证明， 生活压力导致青春期前（出生后第21天）的恐惧表达受到抑制。我们的数据表明 ELS加速BLA中小清蛋白阳性（PV+）中间神经元的分化。这些神经元可以 引起BLA的低活化，导致观察到的恐惧表型降低。通过光遗传学 通过抑制BLA中的PV+神经元，我们能够挽救我们的ELS小鼠中的恐惧表达缺陷。在Aim中 2，实验2.1和2.2，PL到BLA和BLA到PL投影的解剖学和功能连接将 进行评估。在出生后早期发育期间使用逆行示踪剂注射和体内电生理学 （约出生后16-30天），我们将测试ELS如何改变这种皮质-边缘连接。我们期待ELS 动物具有加速的BLA到PL投射的解剖和功能连接，但延迟PL到 BLA.在实验2.3中，我们试图通过加速来诱导非应激小鼠的恐惧表达减少， BLA中的PV+成熟。此外，我们试图通过一种新的方法来恢复应激小鼠的恐惧表达。 PL到BLA连通性的加速。在目标3中，我们描绘了博士后计划 研究，包括确定博士后研究金导师和机构，以及钙的使用- 成像以在行为测定期间引导神经元集合。在K 00阶段，申请人建议 获得其余的写作，演示，网络和职业技能所必需的成功过渡到 独立研究员。通过研究和培训计划，申请人将加深她的理论 和概念知识的发展，认知和神经机制的基础学习， 行为，同时获得先进的系统级技术，包括体内电生理学，钙， 成像以及编码完善和数据分析。通过这项赠款获得的培训将使 申请人在解决申请人未来的发展问题时使用多层次方法 实验室总的来说，拟议的工作将增加丰富的知识，关于机制，早期生活 经验导致在整个发展过程中学习的差异。它还将提供深入了解电路 这可能有助于解释为什么早期生活创伤会增加情绪障碍的倾向。

PROJECT SUMMARY Early life stress (ELS) is associated with a significant increase in risk for developing stress-related pathology, including depression, anxiety, and post-traumatic stress disorder (PTSD). However, the mechanisms by which ELS increases the risk for pathologies is not well understood. To study the effects of ELS on postnatal development we take advantage of a well characterized neuronal circuit, the auditory fear circuit. Here we investigate the mechanisms by which early life stress (ELS) alters aversive learning in the developing mouse. We hypothesize that early life stress is accelerating the developmental maturation of the basolateral amygdala (BLA), but not the prelimbic (PL) subregion of the medial prefrontal cortex. In Aim 1, we demonstrate that early life stress leads to suppression of fear expression during pre-adolescence (postnatal day 21). Our data suggests that ELS accelerates differentiation of parvalbumin positive (PV+) interneurons in the BLA. These neurons could be causing hypoactivation of the BLA, resulting in the observed decreased fear phenotype. Through optogenetic inhibition of PV+ neuron in the BLA we were able to rescue the fear expression deficit in our ELS mice. In Aim 2, Experiments 2.1 and 2.2, anatomical and functional connectivity of PL to BLA and BLA to PL projections will be assessed. Using retrograde tracer injections and in-vivo electrophysiology during early postnatal development (approx. postnatal days 16-30) we will test how ELS alters this cortico-limbic connectivity. We expect ELS animals to have accelerated anatomical and functional connectivity of BLA to PL projection, but delayed PL to BLA. In Experiment 2.3, we attempt to induce decreased fear expression in unstressed mice through acceleration of PV+ maturation in BLA. Furthermore, we attempt to recover fear expression in stressed mice through a pharmacologically induced acceleration of PL to BLA connectivity. In Aim 3, we delineate plans for postdoctoral research, including the identification of a postdoctoral fellowship mentor and institution, and the use of calcium- imaging to tract neuronal ensembles during a behavioral assay. During the K00 phase the applicant proposes to acquire the remaining writing, presenting, networking and career skills necessary for a successful transition to an independent researcher. Through the Research and Training Plan, the applicant will deepen her theoretical and conceptual knowledge of developmental, cognitive and neural mechanisms underlying learning and behavior, while acquiring advanced system level techniques, including in-vivo electrophysiology, calcium- imaging, as well as perfecting coding and data analysis. The training acquired through this grant will allow the applicant to use a multilevel approach when addressing developmental questions within the applicant's future lab. Overall the work proposed will add a wealth of knowledge regarding the mechanisms by which early life experiences lead to differences in learning throughout development. It will also provide insight into circuit vulnerabilities that could help explain why early life trauma increases the propensity to emotional disorders.