Project 461468

While there is strong evidence supporting the role of the anterior cingulate cortex, basolateral amygdala, and the hippocampus (ACC, BLA, HIPP) as a key neural network regulating mood, and therefore central to the pathophysiology of major depressive disorder (MDD), much remains unknown, including which gene pathways and which specific cell types play a primary causal role mediating alterations in this circuit, and what cell-type connections, within and between these regions, are particularly altered in depressive states. The proposed project is a large-scale, systematic investigation in the ACC, BLA, and HIPP to interrogate the transcriptome at single-nucleus resolution to identify, at the single-cell level changes in gene expression profiles associated with MDD. The proposed research is innovative because it is the first large-scale investigation of the ACC-BLA-HIPP circuit in humans and will represent the largest single-cell transcriptional resource of the human brain. This research is significant because it will greatly advance our understanding of the cellular and molecular pathways involved in mood regulation and MDD. Through a better understanding of the mechanisms of depressive illness, we may be one step closer to developing novel treatment strategies and personalize interventions.