Depression alters the structure and function of brain reward circuitry. Preclinical evidence suggests that medium spiny neurons (MSNs) in the nucleus accumbens (NAc) undergo structural plasticity, however the molecular mechanism and behavioral significance is poorly understood. Here we report that atrophy of D1, but not D2 receptor containing MSNs is strongly associated with social avoidance in mice subject to social defeat stress. D1-MSN atrophy is caused by cell-type specific upregulation of the GTPase RhoA and its effector Rho-kinase. Pharmacologic and genetic reduction of activated RhoA prevents depressive outcomes to stress by preventing loss of D1-MSN dendritic arbor. Pharmacologic and genetic promotion of activated RhoA enhances depressive outcomes by reducing D1-MSN dendritic arbor and is sufficient to promote depressive-like behaviors in the absence of stress. Chronic treatment with Rho-kinase inhibitor Y-27632 after chronic social defeat stress reverses depression-like behaviors by restoring D1-MSN dendritic complexity. Taken together, our data indicate functional roles for RhoA and Rho-kinase in mediating depression-like behaviors via dendritic remodeling of NAc D1-MSNs and may prove a useful target for new depression therapeutics.

Stress alters the structure and function of brain reward circuitry and is an important risk factor for developing depression. In the nucleus accumbens (NAc), structural and physiological plasticity of medium spiny neurons (MSNs) have been linked to increased stress-related and depression-like behaviors. NAc MSNs have opposing roles in driving stress-related behaviors that is dependent on their dopamine receptor expression. After chronic social defeat stress, NAc MSNs exhibit increased dendritic spine density. However, it remains unclear if the dendritic spine plasticity is MSN subtype specific. Here we use viral labeling to characterize dendritic spine morphology specifically in dopamine D2 receptor expressing MSNs (D2-MSNs). After chronic social defeat, D2-MSNs exhibit increased spine density that is correlated with enhanced social avoidance behavior. Together, our data indicate dendritic spine plasticity is MSN subtype specific, improving our understanding of structural plasticity after chronic stress.

ObjectivePeer victimization is a substantial early life stressor linked to psychiatric symptoms and poor academic performance. However, the sex-specific cognitive or behavioral outcomes of bullying have not been well-described in preadolescent children.MethodsUsing the baseline dataset of the Adolescent Brain Cognitive Development (ABCD) Study 2.0.1 data repository (N = 11,875), we evaluated associations between parent-reported bullying victimization, suicidality (suicidal ideation, intent, and/or behavior), and non-suicidal self-injury (NSSI), as well as internalizing and externalizing behavioral problems, cognition, and academic performance.ResultsOf the 11,015 9-10-year-old children included in the analyses (5,263 girls), 15.3% experienced bullying victimization, as reported by the primary caregiver. Of these, boys were more likely to be bullied than girls (odds ratio [OR], 1.2 [95% CI, 1.1–1.3]; p = 0.004). Children who were bullied were more likely to display NSSI or passive suicidality (OR, 2.4 [95% CI, 2.0–2.9]; p < 0.001) and active suicidality (OR, 3.4 [95% CI, 2.7–4.2]; p < 0.001). Bullied children also had lower cognitive scores, greater behavioral problems, and poorer grades (p < 0.001). Across all participants, boys had poorer grades and greater behavioral problems than girls; however, bullied boys had greater behavioral problems than girls in several areas (p < 0.001). Compared to their non-bullied peers, bullied children with greater non-suicidal self-injury or suicidality also had greater behavioral problems and poorer grades (p < 0.001).ConclusionThese findings highlight the sex-specific effects of bullying, and the negative associations of bullying victimization with cognitive performance, behavioral problems, and academic performance. Future longitudinal studies will identify the natural history and neural correlates of these deficits during adolescence.

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