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: 10763297
• 负责人: Piray Atsak
• 金额: $ 5.67万
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10763297
• 关键词: Adult; Amygdaloid structure; Anxiety Disorders; Behavior; Communication; Development; Dissection; Electrophysiology (science); Female; Goals; Grant; Hippocampus; Human; Individual Differences; Life; Mental Depression; Mental disorders; Mentored Research Scientist Development Award; Mentorship; Methods; Modeling; Mus; Neurosciences; Pathway interactions; Predisposition; Prefrontal Cortex; Research; Risk; Role; Site; Stress; Stressful Event; Synaptic Transmission; System; Testing; Training; Universities; biological adaptation to stress; career; depressive symptoms; early life stress; genetic manipulation; mouse model; neural circuit; neuromechanism; neurophysiology; postnatal; programs

Contact PD/PI: Atsak, Piray Project Summary 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. Project Summary/Abstract

联系人 PD/PI：Atsak、Piray 项目概要 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的个体差异 反应和灵敏度。我计划领导一个研究神经生理学的研究实验室 早期生命压力（ELS）的机制和个体差异的出现 成人的应激反应。 ELS 会造成抑郁症和焦虑症的长期风险， 特别是在成年时期面临压力事件之后。然而，人们对此知之甚少 ELS 如何在神经回路水平上产生持续的变化，从而增加 晚年对压力的敏感性。这种详细的电路剖析是不可能的 在人类身上进行，因此通过使用最近建立的早期生命的两次打击模型 以及小鼠的成年压力，其中特定产后窗口期间的压力会增加 成年期压力诱发抑郁样行为的可能性。有了这笔 K01 补助金 在 RFMH 和哥伦比亚大学的 Rene Hen 博士的指导下，我将测试 长程前额叶回路在 ELS 诱导的成人压力易感性中的作用。我 将把已建立的两次击打小鼠压力模型与先进方法相结合，例如 作为多位点电生理记录和通路的交叉方法 特定的化学遗传学操作。这些研究代表了多项国内首创 发育/系统神经科学领域：1）首先测试一些长期的作用 范围前额皮质相关回路（前额叶伏隔、杏仁核、腹侧 海马体）应激敏感性的活动和交流； 2）首先剖析 ELS 引起的成人变化的神经回路活动和交流 应激反应； 3）第一个研究ELS对应激敏感性的影响 女性的潜在神经回路； 4）第一个将发展压力与 同时多站点记录和针对特定路径的交叉方法 操纵。这些研究代表了重大的职业转变和研究 为我重定向。这个 K01 奖项将为我提供指导和额外培训 这将使我做好实现职业目标并建立独立研究的准备 旨在研究 ELS 导致终生的神经回路的计划 容易患抑郁症和精神疾病。 项目概要/摘要