title: Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress.
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.
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.
authors.forename: T Chase
authors.initials: TC
authors.lastname: Francis
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chandra
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Friend
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Eric
authors.initials: E
authors.lastname: Finkel
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.; Department of Psychology, California State University, San Bernardino, California.
authors.forename: Genesis
authors.initials: G
authors.lastname: Dayrit
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.; Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Miranda
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Brooks
authors.affiliation: Department of Psychology, California State University, San Bernardino, California.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Iñiguez
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Patricio
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Alexxai
authors.initials: A
authors.lastname: Kravitz
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.. Electronic address: mklobo@umaryland.edu.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Lobo
mesh_terms: D000200:Action Potentials / Q000502:physiology; D059445:Anhedonia / Q000502:physiology; D000818:Animals; D003866:Depressive Disorder / Q000503:physiopathology*; D004291:Dominance-Subordination; D059330:GABAergic Neurons / Q000145:classification / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000503:physiopathology*; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D055500:Resilience, Psychological; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology*; D046509:Tissue Culture Techniques
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2
keywords: Depression; Medium spiny neurons; Nucleus accumbens; Optogenetics; Pharmacogenetics; Social defeat stress