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一名神经电路级机制的专家 发展应激与个体应激差异的传递 反应和敏感度。我计划领导一个研究实验室研究神经生理学 早期生活应激(ELS)的机制与个体差异的出现 成人应激反应。ELS会造成抑郁症和焦虑症的长期风险， 尤其是在面对成年后的紧张事件之后。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 在以后的生活中对压力的敏感性。这种详细的电路解剖不能 在人类身上进行的，因此使用了最近建立的早期生命的两次成功模型 和成年应激小鼠，在特定的出生后窗口应激增加 成年后应激导致抑郁样行为的可能性。用这笔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 长程前额叶环路在ELS诱导的成人应激敏感性中的作用。我 将把已建立的两次击打应激小鼠模型与先进的方法相结合，如 多点电生理记录与径路交叉入路 特殊的化学发生操作。这些研究代表了许多第一次 发育/系统神经科学领域：1)第一个测试一些长期- 前额叶皮质相关环路(前额-伏隔、杏仁核、腹侧 海马体)应激易感性中的活动和交流；2)第一个解剖 ELS诱导的成人变化背后的神经回路活动和通讯 应激反应；3)首次研究ELS对应激敏感性的影响 女性潜在的神经回路；4)第一个将发育应激与 多点同步记录和特定径路的交叉方法 操纵。这些研究代表着职业生涯的重大转变和研究 为我重定向。K01奖将为我提供指导和额外的培训 这将为我实现我的职业目标做好准备，并建立独立的研究 旨在研究ELS导致终生的神经回路的计划 易患抑郁症和精神障碍。 项目摘要/摘要