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PD/PI：Atsak，Piray 项目摘要 我的职业目标是成为神经电路机制的专家 发育压力的下降和压力的个体差异 反应和灵敏度。我计划领导研究神经生理学的研究实验室 早期应激的机制（EL）和个体差异的出现 成人压力反应。 ELS为抑郁和焦虑症带来长期风险， 特别是在成年期间面临压力大事件之后。但是，对 ELS如何在神经回路水平上产生持续变化的持续变化 对以后生活的压力的敏感性。这种详细的电路解剖不能是 在人类中进行，因此使用最近建立的两次命中模型 小鼠的成年压力，在特定产后窗口中的压力增加了 成年强调的可能性会引起抑郁般的行为。带有K01赠款 在RFMH和哥伦比亚大学的Rene Hen博士的指导下，我将测试 远程前额叶电路在ELS引起的成人压力敏感性中的作用。我 将结合建立的两次打击应力模型与先进方法这样的 作为多站点电生理记录和途径的交叉方法 特定的化学发生操作。这些研究代表了许多首次 发展/系统神经科学领域：1）第一个测试一些长期作用 范围前额叶皮层相关电路（前额叶 - acccumbens，杏仁核，腹侧 海马）的活动和压力敏感性的交流； 2）第一个剖析 神经电路活动和沟通源于ELS诱导的成人变化 压力反应； 3）第一个研究EL在压力敏感性和 女性的基本神经回路； 4）第一个将发展应力与 特定于途径的同时多站点记录和交叉方法 操纵。这些研究代表了重大的职业变革和研究 我的重定向。这个K01奖将为我提供指导和额外的培训 这将使我为实现职业目标做好准备，并建立独立的研究 旨在调查ELS导致终生的神经回路的程序 对抑郁和精神疾病的敏感性。 项目摘要/摘要