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一名神经回路水平机制的专家， 传递潜在的发展压力和压力反应的个体差异， 灵敏度我计划领导一个研究实验室研究生命早期的神经生理机制 压力（ELS）和成人压力反应的个体差异的出现。ELS创建 抑郁症和焦虑症的长期风险，特别是在面临压力之后 成年期的事件。然而，人们对ELS如何产生持续的 神经回路水平的变化会增加以后对压力的敏感性 生活这种详细的电路解剖无法在人体中进行，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， 在一个特定的产后窗口增加成年压力的可能性， 导致类似抑郁的行为。有了这个K01补助金，并在Rene Hen博士的指导下， RFMH和哥伦比亚大学，我将测试长距离前额叶回路的作用， ELS诱导的对成年压力的敏感性。我会把联合收割机和一个两击鼠标 采用先进的方法（如多部位电生理记录）建立压力模型 以及用于途径特异性化学遗传学操作的交叉途径。这些研究 代表了发展/系统神经科学领域的许多第一：1）第一个 测试一些长距离前额叶皮层相关回路的作用 （前额叶-海马、杏仁核、腹侧海马）的活动和应激中的交流 敏感性; 2）第一个解剖神经回路活动和通信 潜在的ELS引起的变化，成人的压力反应; 3）第一个 研究ELS在应激易感性和潜在神经回路中的影响， 女性; 4）第一个将联合收割机发育压力与同时多位点结合起来 记录和交叉途径的途径特异性操作。这些研究 对我来说，这是一个重大的职业转变和研究方向。这个K01奖将 为我提供指导和额外的培训，使我做好准备，实现我的 职业目标，并建立一个独立的研究计划，面向调查 ELS的神经回路导致终身易患抑郁症和精神病 紊乱