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      Nucleus Accumbens Medium Spiny Neuron Subtypes Mediate Depression-Related Outcomes to Social Defeat Stress

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          Abstract

          BACKGROUND

          The nucleus accumbens is a critical mediator of depression-related outcomes to social defeat stress. Previous studies demonstrate distinct neuroplasticity adaptations in the two medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D1 versus dopamine receptor D2, in reward and reinforcement leading to opposing roles for these MSNs in these behaviors. However, the distinct roles of nucleus accumbens MSN subtypes, in depression, remain poorly understood.

          METHODS

          Using whole-cell patch clamp electrophysiology, we examined excitatory input to MSN subtypes and intrinsic excitability measures in D1-green fluorescent protein and D2-green fluorescent protein bacterial artificial chromosome transgenic mice that underwent chronic social defeat stress (CSDS). Optogenetic and pharmacogenetic approaches were used to bidirectionally alter firing of D1-MSNs or D2-MSNs after CSDS or before a subthreshold social defeat stress in D1-Cre or D2-Cre bacterial artificial chromosome transgenic mice.

          RESULTS

          We demonstrate that the frequency of excitatory synaptic input is decreased in D1-MSNs and increased in D2-MSNs in mice displaying depression-like behaviors after CSDS. Enhancing activity in D1-MSNs results in resilient behavioral outcomes, while inhibition of these MSNs induces depression-like outcomes after CSDS. Bidirectional modulation of D2-MSNs does not alter behavioral responses to CSDS; however, repeated activation of D2-MSNs in stress naïve mice induces social avoidance following subthreshold social defeat stress.

          CONCLUSIONS

          Our studies uncover novel functions of MSN subtypes in depression-like outcomes. Notably, bidirectional alteration of D1-MSN activity promotes opposite behavioral outcomes to chronic social stress. Therefore, targeting D1-MSN activity may provide novel treatment strategies for depression or other affective disorders.

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          Author and article information

          Journal
          0213264
          1117
          Biol Psychiatry
          Biol. Psychiatry
          Biological psychiatry
          0006-3223
          1873-2402
          13 October 2016
          28 July 2014
          01 February 2015
          29 July 2017
          : 77
          : 3
          : 212-222
          Affiliations
          Department of Anatomy and Neurobiology (TCF, RC, EF, GD, JM, JMB, PO, MKL), University of Maryland School of Medicine, Baltimore; Diabetes, Endocrinology, and Obesity Branch (DMF, AK), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; Department of Psychology (GD, SDI), California State University, San Bernardino, California; and Unidad de Biomedicina (JM), Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
          Author notes
          Address correspondence to Mary Kay Lobo, Ph.D., University of Maryland, School of Medicine, Department of Anatomy and Neurobiology, 20 Penn Street, HSF2, Rm 265, Baltimore, MD 21201; mklobo@ 123456umary-land.edu
          Article
          PMC5534173 PMC5534173 5534173 nihpa822719
          10.1016/j.biopsych.2014.07.021
          5534173
          25173629
          Categories
          Article

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