Role Of The Anterior Hippocampus In The Pathogenesis Of Major Depression - PROJECT SUMMARY: Improving our understanding of the mechanisms underlying the pathophysiology of major depressive disorder (MDD) is critical for reducing disease burden and improving treatment strategies. The hippocampus, a critical hub in the limbic system, is implicated in the pathogenesis of cognitive and emotional symptoms of MDD. The hippocampus differs functionally along its longitudinal axis. The posterior is preferentially involved with visuospatial navigation and memory, and the anterior with stress processing and mood. Preclinical studies find that neurogenesis is impaired in the anterior hippocampus in primate and rodent models of depression and in postmortem studies of unmedicated depressed individuals compared with healthy volunteers (HV) and medicated MDD. Despite ample evidence implicating the anterior hippocampus in the pathogenesis and treatment of MDD, hippocampal functioning along the anterior-posterior axis has not been examined in clinical studies, comparing untreated patients in a major depressive episode (MDE) with HV and remitted MDD subjects, as well as currently treated versus untreated remitted MDD. This study aims to bridge pre-clinical and postmortem findings by leveraging functional magnetic resonance imaging (fMRI) and an emotional pattern separation task, which is designed to engage the anterior and posterior hippocampus. Our fMRI pilot data suggest that unmedicated MDD (N=16) have diminished anterior-specific hippocampal activity during this pattern separation task compared with HV (N=12). In the present study, we aim to examine anterior hippocampal functioning and connectivity during this fMRI emotional pattern separation task in unmedicated patients with MDD during a MDE (N=35), remitted MDD subjects (N=30), and HV (N=25). The remitted MDD group will include currently unmedicated remitted MDD and remitted MDD patients on antidepressants to explore if fMRI activity and connectivity changes of the anterior hippocampus are related to MDD remission or antidepressant effects. These data have potential clinical significance because they could lead to the identification of a) a state or trait- dependent biomarker of MDD and b) form the basis for targeted interventions. The following K23 proposal presents a research and training program that will support the applicant on the path to becoming an independent investigator and an expert in functional neuroimaging and the study of hippocampal and hippocampal-dependent network dysfunction in MDD. The mentorship, formal coursework, educational seminars, and hands-on experience in this training plan will facilitate development in areas of (1) fMRI design, preprocessing, hippocampal-specific methods, and advanced analyses, (2) neuroscience of mood disorders, neurobiology of the hippocampus, and hippocampal dysfunction in MDD, (3) the role of the hippocampus in memory encoding and retrieval, (4) biostatistics (5) clinical research, RO1 grantsmanship & professional development. The training and research plan proposed in the K-23 will give me the professional and technical skills needed to launch my independent research career and become a future leader in the field.
