Molecular (Ionic/Receptor) Mechanisms of Susceptibility and Resilience
In our previous work and preliminary studies, the increase in the excitability of VTA dopamine neurons in susceptible mice was consistently found both in vitro and in vivo. However, the ionic and receptor mechanisms that underlie this increased excitability remain incompletely understood. The purpose of this project is to intensively explore these mechanisms, with a particular focus on the ionic basis of active resilience in VTA dopamine neurons. In the successful coping process of resilient animals, K+ channels appear to play an important active role in driving the increased pathological firing back to normal level in resilient mice. Intrinsic K+ channel plasticity in VTA dopamine neurons is one of the major focuses of this project.

Relationship Between Cellular and Behavioral Plasticity
Our in vivo recording data show that the bursting properties of VTA dopamine neurons is dramatically increased by chronic social defeat in susceptible mice, but not in the resilient subgroup. The main purpose of this project is to test whether optical manipulation of the firing patterns of these neurons can reverse defeat-induced behavioral pathology in freely-behaving susceptible mice, by use of advanced optogenetic techniques. This study will provide insight into the cellular neurophysiological mechanisms of promoting resilience and susceptible phenotypes.

Neural Circuit Mechanisms of Susceptibility and Resilience
The VTA contains dopamine neurons that project to prefrontal cortex, nucleus accumbens and amygdala (see “emotional” neural circuit below). In this project, we investigate whether chronic social defeat selectively regulates VTA dopamine neurons that project to specific targets such as prefrontal cortex, nucleus accumbens or amygdala. The long-term goal of this project is to identify projection-specific biomarker for VTA dopamine neurons and further to study behavioral responses to stress by projection-specific manipulation of dopamine neurons in the VTA.

Antidepressant Action
Established antidepressants were discovered originally based on clinical efficacy and all clinically available antidepressants work through promoting serotonin or noradrenaline function in the brain. In our laboratory, we study antidepressant actions from a new angle: whether today’s antidepressants, or putative novel antidepressants, use any naturally occurring resilience (active coping) mechanisms. These studies will yield novel knowledge of antidepressant actions and offer critical information to imitate active resilience processes for new antidepressant development. Resilience mechanism-based antidepressants may provide more effective treatments for depression with fewer side effects.