Transcriptional Profiling of D1-MSNs Reveals SIRT1-Dependent and -Independent Responses to Chronic Social Defeat Stress

Abstract

SIRT1 is a critical regulator of neuronal functions and has been implicated in various neurological disorders, including depression. In a previous study, we demonstrated the pro-depressive roles of SIRT1 in the nucleus accumbens (NAc) using the chronic social defeat stress (CSDS) model, a well-validated preclinical mouse model of depression. We found that SIRT1 modulates synaptic functions and exhibits pro-susceptible effects specifically in D1-medium spiny neurons in the NAc. In this study, we extended our investigation of SIRT1 functions by employing cell-type-specific transcriptomics to compare control and susceptible groups under CSDS. Our results revealed that in wild-type mice with functional SIRT1, cellular metabolism is crucial for inducing susceptibility to depression. Conversely, in the absence of functional SIRT1 expression, circadian clock-controlled transcriptional regulation becomes a key factor. These findings suggest that SIRT1 differentially modulates key pathophysiological mechanisms of depression via its deacetylase functions, highlighting its role in both metabolic and circadian regulation in the brain. This research provides new insights into the molecular underpinnings of depression and identifies potential targets for therapeutic intervention.