JAK Signaling as a Mechanism of Inflammation-related Reward and Motor Circuit Deficits in Depression

Emory University, Atlanta GA

Investigators

Abstract

Project Summary This project will test the hypothesis that signaling through Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways is a key mechanism mediating the effects of inflammation on corticostriatal circuits related to motivation and motor activity as well as symptoms of anhedonia and psychomotor slowing in patients with major depression (MD). The role of JAK/STAT pathways will be examined using a FDA-approved JAK inhibitor, baricitinib, and an innovative biomarker-driven, brain-targeted approach. MD is a disabling disorder, with over 1/3 of MD patients failing to respond to conventional antidepressant therapies. Thus, the elucidation of novel pathways to pathology and related treatment targets is imperative. One pathophysiologic pathway thought to contribute to symptoms of depression and particularly anhedonia is inflammation. A significant proportion of patients with MD exhibit elevated biomarkers of inflammation in the peripheral blood and central nervous system (CNS), e.g., C-reactive protein (CRP) and inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor, which are in turn associated with antidepressant nonresponse. A rich literature demonstrates that inflammation affects dopamine (DA) in key brain circuits involving the striatum and prefrontal cortex that are critical for motivation and motor activity. Our group has established that MD patients with higher endogenous inflammation (as indexed by peripheral blood CRP and inflammatory cytokines) have low functional connectivity (FC) within DA-rich corticostriatal reward and motor circuits in association with anhedonia and psychomotor slowing, which is improved by drugs that increase DA. Interestingly, our published and preliminary data indicate that JAK/STAT signaling is a key transcriptional pathway that is reliably associated with inflammation’s effects on DA and motivation and motor circuits and related symptoms. Thus, small molecule JAK inhibitors like baricitinib may be an optimal strategy to target these immune pathways in MD, especially given known advantages of these agents over anti-cytokine antibodies including notably CNS penetrance. Indeed, baricitinib was found to reverse the inhibitory effects of IL-6 on DA neurons derived from human induced pluripotent stem cells through inhibition of JAK/STAT3 signaling, while also blocking inflammation and reducing depressive-like behavior in a laboratory animal model. These data are intriguing given evidence from laboratory animals that IL-6 has direct access to the DA-rich ventral striatum through breaches in the blood brain barrier in the context of stress. Of note, STAT3 was recently identified as a top upstream mediator of the molecular pathology of MD. Given the wealth of clinical and translational evidence regarding the role of JAK/STAT pathways in the pathophysiology of MD, this project will examine whether JAK inhibition with baricitinib can improve inflammation-related deficits in reward and motor circuits (Aim 1) in association with improved motivation and motor function (Aim 2) in MD patients enriched for high CRP, while exploring additional CNS and peripheral immune pathways (Aim 3) that may inform avenues for future work.