Gene Expression Profiling of Stress Resilient Mice within the Nucleus Accumbens

Research Plan Abstract: Major depressive disorder (MDD) is a leading cause of disability and a leading contributor to suicide according to the World Health Organization. Chronic stress is a primary risk factor for MDD and is modeled in rodents using the chronic social defeat stress (CSDS) paradigm. Importantly, this paradigm allows for the identification of animals that develop depression-like behavioral abnormalities, termed susceptible, from those that maintain mostly normal behavioral function, termed resilient. This approach has proven to be highly useful but has been extensively performed in male mice leaving the examination of female mice understudied. Given that depression is more prevalent in women, it is crucial to investigate potential sex-specific molecular mechanisms underlying resilience. To address this gap, we conducted, for the first time, RNA- sequencing on female mice subjected to an adapted model of CSDS and identified transcriptional changes associated with resilience and susceptibility in multiple brain regions. Our findings demonstrated many concordant transcriptional changes across sex in the nucleus accumbens (NAc) of resilient male and female mice. Furthermore, we observed significant concordance in gene expression between the NAc and prefrontal cortex (PFC) within both sexes. Notably, we identified a cluster of genes uniquely upregulated in resilient mice within the NAc, exhibiting a 50% overlap across sexes and substantial overlap with a previously identified resilient-specific gene network in male mice. Within this gene network, two key driver genes, Gprin1 and Stx1a, were predicted bioinformatically to regulate other genes in this resilient network. To elucidate the causal role of these key driver genes, we are currently investigating the consequences of viral manipulation within the two major medium spiny neuron subtypes of the NAc in both male and female mice prior to CSDS. Bilateral overexpression of GPRIN1 and STX1a in all NAc neurons in male mice produces a pro-resilient effect. Ongoing research aims to characterize the effects of cell-type-specific manipulation in both sexes and examine changes in neuronal and circuit function to promote behavioral resilience. Together, this study provides novel insights into the molecular mechanisms underlying stress resilience and offers valuable guidance for future efforts in antidepressant drug discovery. Our findings also highlight the importance of considering sex-specific factors in understanding depression and other human stress disorders and in developing targeted interventions. Project Number: 1F99NS143880-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Trevonn Gyles | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $49,114 | Activity Code: F99 | Study Section: Special Emphasis Panel[ZRG1 CN-X (54)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11210787