Investigating single cell transcriptomics and epigenetic regulation to enable stress-resistant brain network activity - Summary: Chronic stress is a growing public health problem that contributes to the development of mental illnesses such as major depressive disorder (MDD). While maladaptive responses to environmental stressors are clearly fundamental to some individuals developing pathology, we still do not know why others remain resilient to chronic stress. Recently, using recording electrodes in a mouse model of chronic stress-induced maladaptation, we identified a robust and specific brain network signature prior to chronic stress exposure that predicts which animals will show a susceptible behavioral phenotype following chronic stress. Animals with this predictive pattern of network activity before stress exposure have been termed vulnerable while animals with a depressive-like phenotype after chronic stress are termed susceptible. This study opens the door for identifying underlying mechanistic causes of stress vulnerability-conferring neural signature that may be useful for the development of therapeutics targeting specific brain networks. It also enables us to study a brain state that has largely not been characterized: stress-naïve vulnerability to chronic stress. To examine the naturally occurring regulation of the stress-naïve vulnerable brain state, our specific aims combine the use of multi-site in vivo neurophysiology, fMRI, behavioral and telemetric measurements, single cell RNA-Seq, spatial transcriptomics, epigenetic investigations, and viral manipulations. This project will help us to better understand and quantify the relationship between our brain network signature and behavior following chronic stress. Further, it will provide an in-depth assessment of the similarities and differences in brain networks that predispose males and females to the ill effects of chronic stress. It will also reveal new insight into how individual differences in gene expression and epigenetics can produce such brain network signatures. These studies will provide an important first step in the development of therapeutics that are designed to target specific network activity that can prevent network activity that confers vulnerability. We will apply molecular profiling and validations to the stress-naïve vulnerable brain to determine pre-existing molecular alterations that predict stress susceptibility. This work fills an important gap in stress neurobiology, which has focused primarily on defining the molecular hallmarks of stress susceptibility (i.e., compensatory changes after stress), not vulnerability (i.e., before stress exposure). Identifying the molecular signatures of the vulnerable brain state enables the possibility of preventative therapeutic approaches. Furthermore, by identifying molecular contributions to brain network activity, this study enables the possibility of brain network-based pharmacotherapeutics, which could be useful for targeting medications to specific individuals (i.e. precision medicine).
