This 5-year R61/R33 phased-innovation award, “Developing KCNQ Channel Modulators for Mood Disorders,” is designed to efficiently examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a novel treatment target for depression and related conditions. Depressive disorders are among the most disabling medical conditions worldwide and currently available treatments fall short of addressing this large public health burden. Dysfunction within the brain reward system is emerging as a core feature of depressive disorders, in particular giving rise to deficits in motivation, interest, and response to pleasure (e.g., anhedonia). The proposed R61/R33 project capitalizes on a series of preclinical studies from our group that highlight the KCNQ subtype of neuronal potassium (K+) channel as a novel target for the treatment of depressive disorders. In model systems, up-regulation of KCNQ channels normalizes pathological functioning within the brain reward circuit, reversing an anhedonic phenotype. Building on these data, the current project will assess reward circuit activity following treatment with the KCNQ-selective channel opener ezogabine in depressed patients with anhedonia [Aim 1], and will examine the relationship between change in reward circuit activity and clinically relevant symptom and behavior outcomes [Aim 2]. Our project capitalizes on recent advances in conceptualizing and measuring reward-processing alterations across species, and utilizes the Research Domain Criteria (RDoC) domain of Positive Valence Systems (PVS) as a unifying framework. In particular, our animal and human work indicate that enhancing KCNQ channel function within the reward circuit normalizes behavioral processes that map to the PVS constructs of approach motivation (reward expectancy) and initial responsiveness to reward. The project takes advantage of (1) availability of ezogabine (Potiga, GlaxoSmithKline) for human use as a unique first-in-class KCNQ channel opener [FDA-approved for the treatment of seizure disorders], and (2) availability of reliable methods for measuring reward processing at the level of neural, behavioral, and clinical levels in humans. The proposed studies have significant potential to advance treatment discovery for depression within an RDoC framework.