Early life stress impacts molecular and network properties that bias the recruitment of pro-stress BLA circuits

早期生活压力会影响分子和网络特性，从而影响促压力 BLA 回路的募集

• 批准号: 10820820
• 负责人: Garrett Scarpa
• 金额: $ 4.34万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2025-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10820820
• 关键词: Address; Adolescence; Adult; Advanced Development; Advisory Committees; Affective; Amygdaloid structure; Animal Model; Animals; Automobile Driving; Award; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Chronic stress; Communication; Coupling; Data; Development; Disease; Distress; Electrophysiology (science); Emotional; Emotional Stress; Endocrinology; Event; Experimental Designs; Fostering; Frequencies; Fright; Functional disorder; Goals; Health; Image; Immediate-Early Genes; Immunofluorescence Immunologic; Immunohistochemistry; Impairment; Interneuron function; Interneurons; Knowledge; Label; Laboratories; Life; Measures; Mediating; Membrane; Mental Health; Mental disorders; Mentors; Mission; Modeling; Molecular; Monitor; Moods; Mus; Nature; Negative Valence; Neurons; Neurosecretory Systems; Nucleus Accumbens; Outcome; Parvalbumins; Pathologic; Pathway interactions; Phenotype; Play; Population; Positioning Attribute; Positive Valence; Predisposition; Process; Property; Psychiatric therapeutic procedure; Psychopathology; Reporter; Research; Risk; Risk Factors; Rodent; Rodent Model; Role; Route; Safety; Slice; Social Behavior; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; System; Testing; Tracer; Training; Translating; United States National Institutes of Health; Work; acute stress; adverse childhood events; anxiety states; behavioral outcome; career; career development; conditioned fear; density; disability; early life stress; emotion regulation; experience; in vivo; insight; maladaptive behavior; maternal separation; medical specialties; neuromechanism; neuropsychiatric disorder; novel; optogenetics; patch clamp; physical conditioning; poor health outcome; recruit; resilience; response; social stress; targeted treatment; validation studies

Emotional stress is a substantial risk factor for numerous psychiatric illnesses, and distressing events during adolescence are particularly salient. Adverse childhood experiences (ACEs) negatively impact mental and physical health and drive maladaptive behaviors, however the neural mechanisms underlying these outcomes are not comprehensively understood. Many of the disorders associated with ACEs involve altered activity within brain regions involved in emotional processing, corresponding with aberrant behaviors. To better understand how networks become dysfunctional and impair emotional processing, this proposal aims to investigate the impact of early life stress (ELS) on adult local field potential (LFP) network states relating to valence assignment and stress-associated emotional processing, and to reveal the underlying molecular mechanisms and circuitry. We hypothesize that ELS results in divergent network states corresponding with the recruitment of negative valence pathways through a mechanism involving BLA PV interneuron dysfunction. Opposing network states govern different behavioral outcomes, and our lab has demonstrated that divergent behavioral states involve selective activation of unique downstream pathways. Fear and safety are associated with distinct LFP network states, and our lab has shown that manipulating the activity of a fractional population of GABAergic parvalbumin (PV) interneurons is sufficient to entrain these conflicting states. Our preliminary data suggests that ELS alters the development and function of PV interneurons in this region, the basolateral amygdala (BLA), which is critical for valence processing and emotional regulation. Further, ELS induces divergent social behavior and LFP network states associated with predatory stress. The goal of the current proposal is to investigate the mechanisms mediating the impact of ELS on BLA network and behavioral states. This project will build on our novel preliminary data to investigate the effects of ELS on valence processing. To observe how these changes in LFP network state impact information routing through the BLA at the cellular level, the membrane and synaptic properties of PV interneurons and projection-specific principal neurons will be monitored using whole cell patch clamp, retrograde tracing, and optogenetics. To observe how ELS impacts information routing through the BLA at the network level, calcium imaging of BLA projectors from separate pathways associated with positive and negative valence will be performed in vivo during pro-stress paradigms. This project will advance our understanding of how developmental stress impacts the routing of emotional information through the brain, with the potential to advance the development of novel, targeted therapies for the treatment of psychiatric disorders in adults who have experienced ACEs. This project is sponsored by four experts who will each provide guidance interpreting results and designing experiments relating to their specialties and the project as a whole, in addition to providing career advice. We have developed a tailored training plan to assist with achieving my research goals and to ideally position me for a career in academic research.

情绪压力是许多精神疾病的重要风险因素， 青春期尤为突出。不良童年经历（ACE）对心理和 身体健康和驱动适应不良行为，然而，这些结果背后的神经机制 并没有被全面理解。许多与ACE相关的疾病都涉及ACE内的活性改变， 与异常行为相关的情感处理区域。更好地了解 网络是如何变得功能失调并损害情绪处理的，这项建议旨在研究 早期生活应激（ELS）对成人局部场电位（LFP）网络状态影响 和压力相关的情绪处理，并揭示潜在的分子机制和电路。 我们假设ELS导致不同的网络状态，对应于 通过涉及BLA PV中间神经元功能障碍的机制的负价通路。 相反的网络状态控制着不同的行为结果，我们的实验室已经证明， 行为状态涉及独特下游途径的选择性激活。恐惧和安全感 具有不同的LFP网络状态，我们的实验室已经表明，操纵分数群体的活动 GABA能小清蛋白（PV）中间神经元的数量足以引起这些冲突状态。我们的初步数据 表明ELS改变了PV中间神经元在该区域的发育和功能，基底外侧 杏仁核（BLA），这是至关重要的效价处理和情绪调节。此外，ELS诱导 不同的社会行为和LFP网络状态与掠夺压力。当前的目标 本研究的目的是探讨ELS对BLA网络和行为状态的影响机制。 这个项目将建立在我们的新的初步数据，以调查的影响ELS价加工。 为了观察LFP网络状态中的这些变化如何影响通过蜂窝网络处的BLA的信息路由， 水平，PV中间神经元和投射特异性主神经元的膜和突触特性将被 使用全细胞膜片钳、逆行追踪和光遗传学监测。观察ELS如何影响 通过BLA在网络级的信息路由，BLA投影仪的钙成像从单独的 与正和负效价相关的途径将在促应激范例期间在体内进行。 这个项目将促进我们对发展压力如何影响情绪路径的理解。 通过大脑的信息，有可能促进新的，有针对性的治疗方法的发展， 治疗经历过ACE的成年人的精神疾病。该项目由四个 专家将提供指导，解释结果并设计与其专业相关的实验 和整个项目，除了提供职业建议。我们制定了量身定制的培训计划， 协助实现我的研究目标，并为我的学术研究生涯提供理想的定位。