Dissecting the role of long range prefrontal circuits in early-life stress induced susceptibility

剖析长程前额叶回路在早期压力诱发的易感性中的作用

• 批准号: 10460476
• 负责人: Piray Atsak
• 金额: $ 18.19万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460476
• 关键词: Adult; Affect; Amygdaloid structure; Animals; Anxiety Disorders; Behavior; Behavioral; Body Weight decreased; Brain; Brain region; Child; Chronic; Communication; Data; Development; Dissection; Elderly; Electrophysiology (science); Exposure to; Female; Gene Expression Profile; Goals; Grant; Hippocampus (Brain); Human; Individual Differences; Lead; Life; Literature; Measures; Medial; Mediating; Mental Depression; Mental disorders; Mentored Research Scientist Development Award; Mentorship; Methods; Modeling; Mood Disorders; Mus; Neurosciences; Nucleus Accumbens; Pathology; Pathway interactions; Personality Disorders; Phenotype; Physiology; Positioning Attribute; Predisposition; Prefrontal Cortex; Psychopathology; Recording of previous events; Reporting; Research; Research Proposals; Rewards; Risk; Risk Factors; Role; Site; Social Interaction; Stress; Stressful Event; Symptoms; Synaptic Transmission; System; Testing; Training; Universities; Work; base; biological adaptation to stress; career; childhood adversity; depressive symptoms; early life stress; experience; experimental study; in vivo; insight; male; maternal separation; mouse model; neural circuit; neuromechanism; neurophysiology; new therapeutic target; novel; postnatal; prevent; programs; relating to nervous system; resilience; response; social; social defeat; stress resilience

My career goal is to become an expert on the circuit level mechanisms of neural transmission underlying developmental stress and individual differences in stress response and sensitivity. I plan to lead a research lab studying the neurophysiological mechanisms of early-life stress (ELS) and the emergence of individual differences in adult stress response. ELS creates long-term risk to depression and anxiety disorders, particularly after facing stressful events during adulthood. However, little is known about how ELS produces sustained changes at the neural circuitry level that increase sensitivity to stress later in life. This kind of detailed circuit dissection cannot be performed in humans, thus by using a recently established two-hit model of early-life and adult stress in mice in which stress during a specific postnatal window increases the likelihood of adulthood stress to induce depressive-like behaviors. With this K01 grant and under the mentorship of Dr. Rene Hen at RFMH and Columbia University, I will test the role of long-range prefrontal circuits in the ELS-induced susceptibility to adult stress. I will combine an established two-hit mouse model of stress with advanced methods such as multi-site electrophysiological recordings and intersectional approaches for pathway specific chemogenetic manipulations. These studies represent a number of firsts in the developmental/systems neuroscience field: 1) the first to test the role of some of the long-range prefrontal cortex associated circuits (prefrontal-accumbens, amygdala, ventral hippocampus) activity and communication in stress susceptibility; 2) the first to dissect neural circuit activity and communication underlying the ELS-induced changes in adult stress response; 3) the first to investigate the impact of ELS in stress-susceptibility and underlying neural circuits in females; 4) the first to combine developmental stress with simultaneous multi-site recordings and intersectional approaches for pathway specific manipulations. These studies represent a significant career change and research redirection for me. This K01 award will afford me the mentorship and additional training that will prepare me to achieve my career goals and establish an independent research program geared towards investigating the neural circuits of which ELS leads to lifelong susceptibility to depression and psychiatric disorders.

我的职业目标是成为神经网络电路级机制的专家 发育压力的传播和压力反应的个体差异 敏感性。我计划领导一个研究实验室，研究生命早期的神经生理学机制 压力（ELS）和成人压力反应中个体差异的出现。 ELS 创造 患抑郁症和焦虑症的长期风险，尤其是在面临压力之后 成年期间发生的事件。然而，人们对 ELS 如何产生持续的影响知之甚少。 神经回路水平的变化会增加稍后对压力的敏感性 生活。这种详细的电路解剖无法在人类身上进行，因此 使用最近建立的小鼠早期和成年应激的两次打击模型，其中应激 在特定的产后窗口期间，成年期压力的可能性会增加 诱发抑郁样行为。凭借这笔 K01 资助并在 Rene Hen 博士的指导下 RFMH 和哥伦比亚大学，我将测试远程前额叶回路在 ELS 诱导的对成人压力的敏感性。我将结合既定的两次点击鼠标 采用多部位电生理记录等先进方法建立压力模型 以及途径特异性化学遗传学操作的交叉方法。这些研究 代表了发育/系统神经科学领域的多项第一：1）第一个 测试一些远程前额皮质相关电路的作用 （前额叶伏隔、杏仁核、腹侧海马）压力下的活动和沟通 易感性； 2）第一个剖析神经回路活动和通讯 ELS 引起的成人应激反应变化的基础； 3）第一个 研究 ELS 对压力敏感性和潜在神经回路的影响 女性； 4）第一个将发育应激与同时多部位结合起来 用于路径特定操作的记录和交叉方法。这些研究 对我来说代表着重大的职业转变和研究方向。此次K01奖将 为我提供指导和额外培训，帮助我做好实现我的目标的准备 职业目标并建立一个独立的研究计划，旨在调查 ELS 导致终生易患抑郁症和精神病的神经回路 失调。