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

早期生活压力对前额叶-杏仁核连接功能发育的影响

• 批准号: 10328237
• 负责人: Gabriela Manzano Nieves
• 金额: $ 7.71万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328237
• 关键词: Acceleration; Acute; Address; Adult; Amygdaloid structure; Anatomy; Animal Model; Animals; Anxiety; Auditory; Bathing; Behavior; Behavioral; Behavioral Assay; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; Calcium; Cell Density; Cells; Code; Cognitive; Cues; Data; Data Analyses; Development; Early-life trauma; Educational Status; Electric Stimulation; Electrophysiology (science); Emotional; Emotional disorder; Ensure; Environment; Fellowship; Freezing; Fright; Future; Grant; Hippocampus (Brain); Image; Imaging Techniques; Immunohistochemistry; Impairment; Individual; Injections; Institution; Interneurons; Knowledge; Label; Lead; Learning; Life; Life Experience; Medial; Memory; Mental Depression; Mental disorders; Mentors; Mus; Neurons; Neurosciences; Output; Parvalbumins; Pathology; Pharmacology; Phase; Phenotype; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Professional Competence; Psychopathology; Recovery; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Resources; Risk; Rodent; Role; Shapes; Societies; Stimulus; Stress; Structure; System; Techniques; Testing; Tracer; Training; Viral; Viral Vector; Work; Writing; advanced system; awake; base; career development; cohort; conditioned fear; depressive symptoms; early adolescence; early life stress; experimental study; extracellular; fear memory; human model; in vivo; indexing; insight; interest; learned behavior; neurodevelopment; neuromechanism; neuronal circuitry; optogenetics; postnatal; postnatal development; preadolescence; premature; ranpirnase; relating to nervous system; response; skill acquisition; traumatic event

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.

项目摘要 早期生活压力（EL）与发展与压力相关的病理的风险显着增加， 包括抑郁症，焦虑和创伤后应激障碍（PTSD）。但是， ELS增加了病理风险的风险尚不清楚。研究EL对产后的影响 开发我们利用了良好的神经元电路，即听觉恐惧电路。我们在这里 研究早期生活压力（ELS）改变发育中的小鼠厌恶学习的机制。 我们假设早期生活压力正在加速基底外侧杏仁核的发育成熟 （BLA），但不是内侧前额叶皮层的前区域（PL）子区域。在AIM 1中，我们表明了这一点 生命压力会导致在青春期前的恐惧表达抑制（产后第21天）。我们的数据建议 ELS加速了BLA中白蛋白阳性（PV+）中间神经元的分化。这些神经元可以 导致BLA失活，从而导致观察到的恐惧表型减少。通过光遗传学 BLA中PV+神经元的抑制作用我们能够挽救ELS小鼠的恐惧表达不足。目标 2，实验2.1和2.2，PL与BLA和BLA与PL投影的解剖和功能连接 被评估。在产后早期发育期间使用逆行示踪剂注射和体内电生理学 （大约产后第16-30天）我们将测试ELS如何改变这种皮质膜连通性。我们期望Els 动物已经加速了BLA与PL投影的解剖和功能连接，但将PL推迟到 bla。在实验2.3中，我们试图通过加速诱导无重理小鼠的恐惧表达降低 BLA中的PV+成熟。此外，我们试图通过一个 药理诱导的PL加速度加速BLA连通性。在AIM 3中，我们描述了博士后的计划 研究，包括识别博士后奖学金指导和机构，以及钙的使用 在行为测定过程中成像到散发神经元合奏。在K00阶段，申请人建议 获得剩余的写作，呈现，网络和职业技能，成功过渡到 独立研究人员。通过研究和培训计划，申请人将加深她的理论 以及对学习的发展，认知和神经机制的概念知识以及 行为，同时获得高级系统水平技术，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允许 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。总体而言，提出的工作将增加有关早期生活的机制的丰富知识 经验会导致整个发展的学习差异。它还将提供对电路的见解 可以帮助解释为什么早期创伤会增加情绪障碍的倾向的脆弱性。