Allyson K. Friedman, PhD - US grants

DESCRIPTION (provided by applicant): There is an urgent need for mechanistically distinct new antidepressants as less than 50% of major depressive disorder (MDD) patients achieve full remission. Moreover, despite over 50 years of tremendous efforts, only one or two mechanistically new drug classes have been developed for MDD treatment. Due to a limitation of available techniques, it has been extremely difficult to investigate the function of a selective type of neurons in the complex brain, and to further define potential drug targets. By employing viral-mediated gene transfer and optogenetic approaches, we defined neuronal plasticity, in ventral tegmental area (VTA) dopamine (DA) neurons of the brain reward circuitry, that are both sufficient and necessary to underlie susceptibility and resilience to chronic social defeat, a model of depression. In this model, some mice exposed to chronic social defeat exhibit depression-like behaviors such as social avoidance behavior or lower sucrose intake (anhedonia) (susceptibility to depression), while others are normal (resilience to depression). At the cellular level, chronic defeat increased the in vivo firing rate and bursting events of VTA DA neurons in susceptible mice, but not in the resilient subgroup. In freely-behaving resilient mice, light activation of channelrhodopsin-2 (ChR2) (mimicking bursting events) in VTA DA neurons increased avoidance behavior during social interaction test. To explore potential drug targets in these neurons, we investigated the ionic mechanisms that underlie the higher pathological firing. I found that the current of Ih (hyperpolarization-activated cation channels), an important channel in the VTA that plays a key role in the regulation of burst firing, was increased in susceptible mice, and surprisingly, increased even significantly more in the resilient subgroup. I also found that potassium (K+) channel function was selectively increased only in resilient mice. These data strongly support that Ih channels of VTA DA neurons are one of the passive pathological ion mechanisms that underlie the susceptible phenotype, while K+ channels are an important active ion mechanism that drive the higher firing back to normal levels and provides the ability of resilient mice to successfully cope with stressful conditions and avoid developing depression-like behaviors. We therefore hypothesize, in this translational project, that both passive ion channel blockers or active ion channel activators, that inhibit the higher pathological firing of VTA DA neurons, are antidepressant or pro-resilient. Highly consistent with this hypothesis, I found interesting rapid and long-lasting antidepressant effects of Ih inhibitors, which is very different from standard antidepressants that take weeks to have treatment effects. And more importantly, my data showed that a K+ channel activator tended to reverse avoidance behavior in the same manner as traditional antidepressants. These consistent studies, based on defining VTA DA neurons as cellular targets with viral-mediated gene transfer and optogenetic techniques, provide very promising new drug targets for MDD treatment, which are mechanistically different from traditional monoamine-based antidepressants. PUBLIC HEALTH RELEVANCE: In this translational project, we propose to define mechanistically new drug targets for the treatment of major depressive disorder on the basis of our solid, exciting basic research findings in a well-established model of depression. The proposed research is highly clinically relevant because these studies would ultimately expand the limited field of therapeutics treatments for depression and fully benefit depressed patients. The findings from this project therefore are highly relevant to NIMH's mission.

Abstract There are wide variations in behavioral responses to social stress. Some individuals successfully employ coping strategies in response to stress, and become resilient. In others, social stress can precipitate psychiatric dysfunction, such as depression and anxiety. While coping mechanisms are known to be crucial for the maintenance of healthy mental functioning and a proper, successful coping strategy decreases the impact of stress and protects from long-term pathological states, there is less known about the neurophysiological basis of how this occurs. Importantly, it is clinically evident that vulnerability to stress-induced neuropsychiatric diseases is highly individual and may in part depend on these coping style. Human studies suggest that passive coping during stressful life events is associated with the development of stress-induced depression, whereas proactive coping is correlated with resiliency. Interestingly, males and females demonstrate different social stress coping strategies, suggesting potentially non-overlapping neural circuitry adaptations occurring in response to stress. Despite these clear gender differences and the increased incidence of major depression in females, translational work in this field has focused primarily on males. Identifying the neurobiological gender differences in stress coping responses may inform greatly needed mechanistically driven therapeutics for depression. The animal models proposed in this award will provide crucial mechanistic and neural circuit understanding of stress coping strategies influence on the stress response. Vulnerability to stress-induced diseases is highly individual and may in part depend on variable coping styles. Following repeated stress, there is increased arousal, expectancy and anxiety. It is these functions that facilitate coping at the circuit level, therefore our work focuses on those related brain regions. Recent studies have revealed the critical and opposing roles of the anterior bed nucleus of the stria terminalis (BNST). Furthermore, the BNST projects to and regulates the firing of dopaminergic cells via GABAergic interneurons within the ventral tegmental area (VTA), a region which has been shown to be linked to stress-related depressive phenotype. Thus the VTA projecting BNST neurons are uniquely positioned to receive stress axis information and integrate it into reward/motivation circuitry. The two specific aims outlined this proposal will fully characterize these behavioral models and identify neurophysiological changes that occur within the BNST-VTA pathway Research leading towards further understanding of the neurophysiological mechanisms of active stress coping strategies, and how they can enhance resistance to stress induced depression may provide novel pharmacological targets to enhance coping skills and reverse depressive symptoms. In summary, the research proposed in this Support of Competitive Research Pilot Project Award (SC2) is critical for the development of my independent research path. This mechanism will provide the financial, and mentorship support for the next steps in my career at Hunter College at the City University of New York.