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.
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This work was funded by a One Mind/ Janssen Rising Star Translational Research Award (MKL), NIH R01MH106500 (MKL) and NIH F32MH116574 (MEF).
MEF and MKL designed the study. MEF, EJL, and HN conducted CSDS. MEF and RC prepared viral constructs. MEF and ME performed virus surgeries. MEF and MSM conducted morphology and immunolabeling experiments. MEF and EJL conducted ROCK activity and qPCR experiments. MEF conducted behavioral, pharmacologic, and RhoA activity experiments. MEF wrote the manuscript and prepared the figures with contributions from all authors. TCF conducted pilot experiments that inspired the study.
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The authors declare that they have no conflict of interest.
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Fox, M.E., Chandra, R., Menken, M.S. et al. Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry 25, 1022–1034 (2020). https://doi.org/10.1038/s41380-018-0211-5
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