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

项目总结 早期生活应激(ELS)与发生应激相关疾病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，通过这些机制 ELS增加了病理风险，但目前尚不清楚。研究ELS对产后的影响 在发展过程中，我们利用了一种特性良好的神经元回路，即听觉恐惧回路。在这里我们 研究早期生活压力(ELS)改变发育中的小鼠厌恶学习的机制。 我们假设早期生活应激正在加速杏仁基底外侧核的发育成熟。 (BLA)，而不是内侧前额叶皮质的前额叶(PL)亚区。在目标1中，我们很早就证明了 生活压力导致在青春期前(出生后第21天)抑制恐惧表达。我们的数据显示 ELS促进BLA内小白蛋白阳性中间神经元的分化。这些神经元可以 导致血乳酸失活，导致观察到的恐惧表型减少。通过光遗传 抑制BLA中的PV神经元我们能够挽救ELS小鼠的恐惧表达缺陷。在AIM 2，实验2.1和2.2，PL到BLA和BLA到PL投射的解剖和功能连接将 被评估。在出生后早期发育中使用逆行示踪剂注射和体内电生理 )出生后16-30天)我们将测试ELS如何改变这种皮质-边缘连接。我们希望ELS 动物的BLA向PL投射的解剖和功能连接加快，但PL向PL的投射延迟 BLA。在实验2.3中，我们试图通过加速来减少非应激小鼠的恐惧表达 光伏在白血球中成熟。此外，我们试图通过一种方法恢复应激小鼠的恐惧表达。 药物诱导的PL到BLA连接的加速。在目标3中，我们勾勒出博士后计划 研究，包括确定博士后奖学金导师和机构，以及钙的使用- 在行为分析过程中进行成像以追踪神经元集合。在K00阶段，申请者建议 获得成功过渡到以下目标所需的其余写作、演示、网络和职业技能 一名独立研究人员。通过研究和培训计划，申请者将深化她的理论 学习和学习的发展、认知和神经机制的概念性知识 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，以及完善编码和数据分析。通过这笔赠款获得的培训将使 申请人在解决未来发展问题时使用多层次方法 实验室。总体而言，拟议的工作将增加关于早期生命机制的丰富知识 在整个发展过程中，经验会导致学习上的差异。它还将提供对电路的深入了解 这可能有助于解释为什么早年的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.