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.
Early-life stress induces sensitivity to stress later in life, and is one of the best-characterized risk factors for developing depression and anxiety disorders. This research proposal will identify the neural circuit activity underlying the early-life stress induced susceptibility later in life in male and females. This work will contribute to a novel understanding of depression susceptibility with the long-term goal of developing novel therapeutic targets.
