The Neuroimmune Circuitry in Depression: A Multimodal Mapping Approach

About This Grant

Major Depressive Disorder (MDD) is a serious problem that keeps aggravating yearly. Its pathophysiology remains unclear despite vast amounts of research and the advancements in diagnostics. Common antidepressants have delayed onsets and are unsuccessful in 30% of patients, suggesting other factors play a role. Indeed, a very strong link exists between neuroinflammation and treatment resistant depression (TRD). Hallmarks of depression, like disruption of monoaminergic activity and neural structural/functional abnormalities within mesolimbic regions, have been observed to occur after inflammatory response. However, it remains unclear how inflammation affects circuits dysfunction and MDD development. Our long-term goal is to elucidate the neurobiological correlates of MDD by enabling the investigation of the core neural circuits that underpin its pathomechanisms in humans in vivo. The goal of this project is to elucidate the circuits connecting limbic regions with the nucleus tract solitarii (NTS) in the brainstem. Converging evidence from clinical and preclinical studies points to this circuitry as a major neural route through which inflammatory processes affect limbic regions involved in MDD. We will leverage multi-modal data in non-human primates (NHPs) and humans to: 1. map ground truth anatomy of the limbic-NTS circuits using tracer in NHPs and guide in vivo reconstructions of these connections from high-resolution diffusion MRI (dMRI) in healthy volunteers; 2. map the glia populations of the limbic-NTS circuits using immunohistochemistry in NHPs and guide the interpretation of changes in dMRI measures of glia processes in subjects with TRD in relation to changes in depression severity. DMRI allows to noninvasively delineate neural circuits and detect microstructure changes along them, making it a promising tool to elucidate the relationship between neuroinflammation and depression. However, the study of neural circuitries in depression has been largely limited to major cortical pathways, due to the resolution limits of conventional dMRI and the lack of anatomical ground truth for finer subcortical circuits. Here, we propose a multi-modal approach to generate a novel, validated atlas of the circuits involved in neuroimmune communication between visceral and limbic regions, that will allow accessing the anatomical substrates of neuroinflammation in vivo at unprecedented resolution and accuracy. We will use this atlas to perform retrospective analyses of high- resolution longitudinal dMRI from TRD patients undergoing long-term ketamine treatment. In TRD, ketamine has a rapid antidepressant effect that has been linked to anti-inflammatory mechanisms. The evaluation of advanced dMRI measures of neuroinflammation along these circuits in relation to changes in depression severity will provide novel insights into the interplay between depression and inflammation. By providing a validated atlas for the in vivo investigation of the NTS circuits and candidate imaging biomarkers of neuroinflammation we will unlock more specific approaches to probe the mechanisms of MDD in relation to neuroinflammation, monitor progression, and evaluate treatment response.