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病的重大危险因素，在 青春期特别重要。不利的童年经历（ACE）对心理和 身体健康和推动适应不良行为，但是这些结果的神经机制 不全面地理解。与ACE相关的许多疾病都涉及改变的活动 与异常行为相对应的情感处理涉及的大脑区域。更好地理解 该提案旨在调查网络功能失调和损害情感处理的功能失调和损害情感处理 早期生命压力（ELS）对成人本地现场潜力（LFP）网络与价分配有关的影响 以及与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导致网络状态不同，与募集相对应 负价通路通过涉及BLA PV间神经元功能障碍的机制。 反对网络国家控制着不同的行为结果，我们的实验室证明了不同的行为结果 行为状态涉及独特下游途径的选择性激活。恐惧和安全是相关的 具有独特的LFP网络状态，我们的实验室表明，操纵分数人群的活动 Gabaergic Parvalbumin（PV）中间神经元足以夹住这些相互矛盾的状态。我们的初步数据 表明ELS会改变该区域PV中间神经元的发展和功能，即基底外侧 杏仁核（BLA），这对于价值处理和情绪调节至关重要。此外，Els引起了诱因 与掠夺性压力相关的社会行为和LFP网络状态不同。电流的目标 建议是研究介导ELS对BLA网络和行为状态的影响的机制。 该项目将基于我们新颖的初步数据，以研究ELS对价处理的影响。 要观察LFP网络状态中的这些变化如何影响通过BLA在细胞处的信息路由 PV中神经元和投影特异性主神经元的膜和突触特性的水平将是 使用全细胞斑块夹，逆行示踪和光遗传学监测。观察EL的影响如何 通过网络级别通过BLA的信息路由，来自单独的BLA投影仪的钙成像 在亲压范式期间，将在体内进行与正价和负价相关的途径。 该项目将促进我们对发展压力如何影响情感的理解 通过大脑的信息，有可能推动新颖的有针对性疗法的发展 在经历过ACE的成年人中治疗精神疾病。这个项目由四个 每个人都将提供指导解释结果和设计与专业有关的实验的专家 整个项目除了提供职业建议。我们已经制定了量身定制的培训计划 协助实现我的研究目标，并理想地将我定位为学术研究的职业。