The Silvio O. Conte Center at the University of Washington was funded by the National Institute on Mental Health (NIMH) in April 2015 and is focused on the question: “How does stress increase the risk of depression and other mood disorders?” Its primary goal is to understand the cellular and molecular mechanisms underlying stress vulnerability so that new treatments capable of promoting stress-resilience can be developed to help individuals suffering from these profoundly disabling syndromes. Scientists working in the Departments of Pharmacology and Psychiatry & Behavioral Sciences in the University of Washington School of Medicine collaborate on the projects described on this page. The UW Conte Center organizes collaborative research, public seminars, student training, and public outreach activities. Please contact the Center Director: Dr. Charles Chavkin <cchavkin@uw.edu> with specific questions or for additional information.
Projects
Project 1: Therapeutic Potential of Kappa Opioid Receptor Antagonists in the Treatment of Depression (Chavkin)
Goals: Project 1 will specifically determine how dynorphin acts in this DRN-VTA-NAc neural circuit to control serotonergic and dopaminergic tone and dynorphin’s roles in aversion and cognition. We are testing the hypothesis that dynorphin encodes the dysphoric effects of stress by affecting the balance between 5HT and DA inputs to NAc. By blocking these dynorphin effects, KOR antagonists have the potential to act differently and more selectively than conventional antidepressant medications (monoamine reuptake inhibitors). The proposed studies are designed to characterize these dynorphinergic stress mechanisms with the goal of predicting how a selective kappa receptor antagonist might have therapeutic potential in the treatment of depressive disorders.
Project 2: Circuit dissection of dopamine and serotonin interactions in depression (Zweifel)
Goals: Project 2 will use in vivo electrophysiological and calcium-imaging techniques to determine how repeated social defeat stress affects excitability of dopaminergic neurons in the VTA. The underlying hypothesis is that repeated stress exposure alters the serotonergic inputs to DA-neurons in VTA in a manner that controls stress vulnerability. The detailed circuit analysis proposed and the identification of the effects of stress exposure on this circuit in male & female mice are expected to provide new mechanistic insights to the changes in brain that contribute to the heightened stress vulnerability of clinically depressed individuals.
Project 3: Stress-induced plasticity in serotonin neurons: vulnerability and resilience (Neumaier)
Goals: Project 3 will use DREADD technologies to manipulate serotonergic pathways originating in DRN to identify their roles in depression-like and anxiety-like behaviors with the goal of understanding how these pathways contribute to establishing and maintaining stress-vulnerability. The project will also ask how gene expression in these DRN neurons is affected by stress exposure with the goal of defining the possible genetic basis for differences between stress-vulnerable and stress-resilient mice.
Project 5: Dopamine/CRF interactions in the genesis of depressive disorders (Phillips)
Goals: Project 5 will use chronic in vivo FSCV to measure evoked dopamine signals in NAc during behavioral assessment of anhedonia in response to stress with the goal of understanding how CRF & glucocorticoid exposure in male and female mice regulates mood. Prior studies established that forced swim stress exposure produces lasting changes in the DA-VTA neuronal response to CRF by switching CRF from being stimulatory to inhibitory. The overarching goal of project 5 is to assess the hypothesis that heightened stress-vulnerability involves a switch from CRF being appetitive to aversive caused by stress exposure. The immediate goal of project 5 is to understand how repeated forced swim stress exposure affects sucrose preference and the underlying DA signaling in NAc of both male and female mice.