Nucleus accumbens medium spiny neuron subtypes differentially regulate stress-associated alterations in sleep architecture

Abstract Background Stress is implicated in the pathophysiology of major depression and post-traumatic stress disorder. These conditions share core features, including motivational deficits, heighted anxiety, and sleep dysregulation. Chronic stress produces these same features in rodents, with some individuals being susceptible or resilient, as seen in humans. While stress-induced neuroadaptations within the nucleus accumbens (NAc) are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear. Methods We used chemogenetics (DREADDs) to examine the effects of selective alterations in activity of NAc medium spiny neurons (MSNs) expressing dopamine-1 receptors (D1-MSNs) or dopamine-2 receptors (D2-MSNs) on sleep-related endpoints. Mice were implanted with wireless transmitters enabling continuous collection of electroencephalography (EEG) data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility. Results D1- and D2-MSNs play dissociable roles in sleep regulation. Stimulation of inhibitory or excitatory DREADDs expressed in D1-MSNs exclusively affects rapid eye movement (REM) sleep, whereas targeting D2-MSNs affects slow wave sleep. The combined effects of D1-MSN inhibition and D2-MSN activation on sleep resemble those of chronic social defeat stress. Alterations in D1-MSN function also affect stress susceptibility in social behavior tests. Elevation of CREB (cAMP response element binding protein) within D1-MSNs is sufficient to produce stress-like effects on REM sleep. Conclusions In addition to regulation of motivational and emotional behaviors, the NAc also influences sleep, an endpoint with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.