Prolonged stressful life events can cause a variety of psychiatric disorders, including major depressive disorder, in some people (susceptibility), but not in others (resiliency). Our laboratory is interested in identifying neurophysiological basis of susceptibility and resilience to chronic stress at molecular (ion channel and receptor) and cellular levels. Recently, we segregated susceptible and resilient mice in a social defeat stress model of depression, and demonstrated that the activity of dopaminergic neurons in the ventral tegmental area (VTA, a brain region associated with natural and drug reward) is a key determinant for susceptibility versus resilience to social defeat stress. The firing rate and bursting properties of these neurons are consistently increased by chronic social defeat in susceptible mice, but not in the resilient subgroup. Furthermore, experimentally-induced decreased firing by viral-mediated potassium (K+) channel overexpression promotes resilience, while increased firing by overexpression of dominant negative K+ channel promotes susceptibility. At the molecular level, chronic defeat surprisingly regulates more genes in resilient mice than in the susceptible subgroup, and induces more than a five-fold upregulation in several K+ channels only in resilient mice. These findings strongly support the notion that resilience is not a simply passive absence of stress-induced pathophysiological consequence, but an active brain function by which some animals successfully cope with stressful conditions and avoid developing stress-induced depression-like behavioral abnormalities. In this active coping process, K+ channels seem to play an important role in counteracting the pathological hyperactivity of VTA dopamine neurons. Studies of resilience and susceptibility may help open a new avenue to identifying fundamentally novel drug targets for major depressive disorder treatments.

Our laboratory employs a “systematic research strategy” to study the nature of susceptibility and resilience from behavioral phenomenon to molecular mechanisms and back to the behavioral level, such that we are able to identify the molecular and cellular adaptations that are both sufficient and necessary to underlie the behavioral phenomena. We use the chronic social defeat stress model of depression, (1) obtain a stable behavioral phenotype; (2) focus on VTA dopamine neurons; (3) find firing/bursting neuroadaptations in these neurons; (4) explore ionic/receptor mechanisms of the firing/bursting adaptations; (5) imitate or block the ionic or firing adaptations in VTA dopamine neurons by molecular manipulations using viral-mediated gene transfer and optogenetic tools; and (6) further analyze key behavioral endpoints with these molecular manipulations in vivo (see figure below). This “systematic research strategy” is a key that helps us to find right drug targets, in the extremely complicated brain, for depression treatments .