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电路机制的专家 在压力反应中的发育压力和个体差异的基本传播和 灵敏度。我计划领导一个研究早期神经生理机制的研究实验室 压力（EL）和成人压力反应中个体差异的出现。 Els创造 抑郁症和焦虑症的长期风险，特别是在面对压力之后 成年期间的事件。但是，关于ELS如何产生持续的知之甚少 在神经回路水平上的变化，以稍后增加对压力的敏感性 生活。这种详细的电路解剖不能在人类中进行，因此 使用最近建立的两次打击模型的早期生活和成人压力，其中压力在其中 在特定的产后窗口中，会增加成年应力的可能性 引起类似抑郁症的行为。通过这项K01赠款，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电路的作用 ELS引起的对成人压力的敏感性。我将结合一只已建立的两击鼠标 用高级方法（例如多站点电生理记录）的应力模型 以及途径特定化学发生操作的交叉方法。这些研究 代表发育/系统神经科学领域的许多第一：1） 测试一些远程前额叶皮层相关电路的作用 （前额叶 - acccumbens，杏仁核，腹侧海马）的活动和交流 敏感性； 2）第一个剖析神经电路活动和通信的 ELS引起的成人压力反应变化的基础； 3）第一个 研究EL在应力敏感性和潜在神经回路中的影响 女性； 4）第一个将发育应力与同时发生应力相结合的 用于途径特定操作的记录和交叉方法。这些研究 对我来说代表了重大的职业变革和研究重定向。这个K01奖将 给我提供指导和其他培训，这将使我能够实现自己的能力 职业目标并建立一个旨在调查的独立研究计划 ELS的神经回路会导致终身对抑郁和精神病的敏感性 疾病。