Neuroimmune Mechanisms of Depression and Anhedonia

About This Grant

PROJECT SUMMARY / ABSTRACT Depression is associated with more disability worldwide than any other medical illness. The current lack of widely effective treatments demonstrates our limited understanding of the etiology and biological mechanisms of this complex disorder. Gaps in knowledge regarding the fundamental pathophysiology of depression have served to limit novel diagnostic and treatment approaches, contributing in large measure to its enormous public health burden. Our proposed clinical and translational research project aims to provide a rigorous test of the hypothesis that heightened peripheral immune function and increased blood-brain barrier (BBB) permeability contribute to major depressive disorder (MDD) and anhedonia severity in humans. If successful, this work will establish essential, previously uncharacterized, neuroimmune aspects of the pathophysiology of MDD that will allow for refined treatment targeting and disorder subtyping in the future. The work will be conducted over three independent, yet synergistic study aims. In Aim 1, we will characterize peripheral myeloid cell biology in association with depression and anhedonia. In Aim 2, we will characterize BBB permeability and reward circuit functional connectivity in association with depression and anhedonia. In Aim 3, we will characterize the temporal dynamics of immune, BBB, and reward circuit features in association with depression and anhedonia over a 3- month follow up time. To support all Aims, we will enroll N=150 medically healthy adult individuals aged 18 to 55 years, including N=100 adults with MDD and N=50 unaffected adult volunteers with no history of psychiatric disorder. All individuals will undergo detailed clinical and behavioral assessment, blood collection for myeloid cell characterization including transcriptional and proteomic profiling, and neuroimaging with dynamic contrast enhancement (DCE) and diffusion-prepared arterial spin label (DP-ASL) MRI for estimation of BBB permeability and resting-state functional connectivity (RSFC) for assessment of the nucleus accumbens (NAc)-ventromedial prefrontal cortex (vmPFC) reward circuit. To characterize change in our measured neuroimmune metrics overtime, all participants will return to our laboratory for repeated characterization 3 months following the initial assessment. Based on an estimated 80% retention, N=120 total cases will be available to explore the temporal dynamics of our measured neuroimmune features and coherence with fluctuations in symptoms and other clinical and environmental factors overtime.