Dissecting the role of long range prefrontal circuits in early-life stress induced susceptibility

我的职业目标是成为一名神经电路级机制的专家 发育应激与应激反应和个体差异的传递 敏感度。我计划领导一个研究实验室，研究早期生命的神经生理机制 应激(ELS)和成人应激反应的个体差异的出现。ELS创建 抑郁和焦虑症的长期风险，特别是在面临压力之后 成人期发生的事情。然而，关于ELS如何产生可持续的 神经回路水平的变化会增加稍后对应激的敏感性 生活。这种详细的电路解剖不能在人类身上进行，因此通过 使用最近建立的小鼠早期和成年应激的两次打击模型，在该模型中 在特定的产后窗口期会增加成年后应激的可能性 诱发类似抑郁的行为。在K01的资助下，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回路在 ELS诱导的成人应激敏感性。我将结合一只老牌的两次击打的老鼠 用多点电生理记录等先进方法建立应激模型 以及途径特定的化学发生操作的交叉方法。这些研究 代表了发育/系统神经科学领域的多个第一：1)第一到 测试一些长程前额叶皮质相关回路的作用 (前额-伏隔核、杏仁核、腹侧海马体)应激状态下的活动和交流 敏感度；2)首次剖析神经回路活动和通讯 ELS诱导的成人应激反应变化的基础；3)第一 研究ELS对大鼠应激敏感性和潜在神经回路的影响 雌性；4)第一个将发育应激与同时多部位相结合 路径特定操作的记录和交叉方法。这些研究 对我来说，这代表着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，让我为实现我的 职业目标，并建立一个独立的研究计划，旨在调查 ELS导致终生易患抑郁症和精神疾病的神经回路 精神错乱。

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.