Advertisement

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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Krishnan V.
        • Han M.H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Vialou V.
        • Robison A.J.
        • Laplant Q.C.
        • Covington 3rd, H.E.
        • Dietz D.M.
        • Ohnishi Y.N.
        • et al.
        DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.
        Nat Neurosci. 2010; 13: 745-752
        • Christoffel D.J.
        • Golden S.A.
        • Dumitriu D.
        • Robison A.J.
        • Janssen W.G.
        • Ahn H.F.
        • et al.
        IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity.
        J Neurosci. 2011; 31: 314-321
        • Lim B.K.
        • Huang K.W.
        • Grueter B.A.
        • Rothwell P.E.
        • Malenka R.C.
        Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.
        Nature. 2012; 487: 183-189
        • Russo S.J.
        • Nestler E.J.
        The brain reward circuitry in mood disorders.
        Nat Rev Neurosci. 2013; 14: 609-625
        • Stuber G.D.
        • Sparta D.R.
        • Stamatakis A.M.
        • van Leeuwen W.A.
        • Hardjoprajitno J.E.
        • Cho S.
        • et al.
        Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking.
        Nature. 2011; 475: 377-380
        • Britt J.P.
        • Benaliouad F.
        • McDevitt R.A.
        • Stuber G.D.
        • Wise R.A.
        • Bonci A.
        Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens.
        Neuron. 2012; 76: 790-803
        • Covington 3rd, H.E.
        • Maze I.
        • LaPlant Q.C.
        • Vialou V.F.
        • Ohnishi Y.N.
        • Berton O.
        • et al.
        Antidepressant actions of histone deacetylase inhibitors.
        J Neurosci. 2009; 29: 11451-11460
        • Covington 3rd, H.E.
        • Lobo M.K.
        • Maze I.
        • Vialou V.
        • Hyman J.M.
        • Zaman S.
        • et al.
        Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex.
        J Neurosci. 2010; 30: 16082-16090
        • Kumar S.
        • Black S.J.
        • Hultman R.
        • Szabo S.T.
        • DeMaio K.D.
        • Du J.
        • et al.
        Cortical control of affective networks.
        J Neurosci. 2013; 33: 1116-1129
        • Chaudhury D.
        • Walsh J.J.
        • Friedman A.K.
        • Juarez B.
        • Ku S.M.
        • Koo J.W.
        • et al.
        Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
        Nature. 2013; 493: 532-536
        • Walsh J.J.
        • Friedman A.K.
        • Sun H.
        • Heller E.A.
        • Ku S.M.
        • Juarez B.
        • et al.
        Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway.
        Nat Neurosci. 2014; 17: 27-29
        • Lobo M.K.
        • Zaman S.
        • Damez-Werno D.M.
        • Koo J.W.
        • Bagot R.C.
        • DiNieri J.A.
        • et al.
        DeltaFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli.
        J Neurosci. 2013; 33: 18381-18395
        • Schlaepfer T.E.
        • Cohen M.X.
        • Frick C.
        • Kosel M.
        • Brodesser D.
        • Axmacher N.
        • et al.
        Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression.
        Neuropsychopharmacology. 2008; 33: 368-377
        • Mayberg H.S.
        Targeted electrode-based modulation of neural circuits for depression.
        J Clin Invest. 2009; 119: 717-725
        • Bewernick B.H.
        • Kayser S.
        • Sturm V.
        • Schlaepfer T.E.
        Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: Evidence for sustained efficacy.
        Neuropsychopharmacology. 2012; 37: 1975-1985
        • Schlaepfer T.E.
        • Bewernick B.H.
        Neuromodulation for treatment resistant depression: State of the art and recommendations for clinical and scientific conduct.
        Brain Topogr. 2014; 27: 12-19
        • Nauczyciel C.
        • Robic S.
        • Dondaine T.
        • Verin M.
        • Robert G.
        • Drapier D.
        • et al.
        The nucleus accumbens: A target for deep brain stimulation in resistant major depressive disorder.
        J Mol Psychiatry. 2013; 1: 17
        • Gerfen C.R.
        • Engber T.M.
        • Mahan L.C.
        • Susel Z.
        • Chase T.N.
        • Monsma Jr, F.J.
        • Sibley D.R.
        D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons.
        Science. 1990; 250: 1429-1432
        • Lobo M.K.
        • Karsten S.L.
        • Gray M.
        • Geschwind D.H.
        • Yang X.W.
        FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains.
        Nat Neurosci. 2006; 9: 443-452
        • Heiman M.
        • Schaefer A.
        • Gong S.
        • Peterson J.D.
        • Day M.
        • Ramsey K.E.
        • et al.
        A translational profiling approach for the molecular characterization of CNS cell types.
        Cell. 2008; 135: 738-748
        • Gerfen C.R.
        The neostriatal mosaic: Multiple levels of compartmental organization.
        Trends Neurosci. 1992; 15: 133-139
        • Nicola S.M.
        The nucleus accumbens as part of a basal ganglia action selection circuit.
        Psychopharmacology (Berl). 2007; 191: 521-550
        • Smith R.J.
        • Lobo M.K.
        • Spencer S.
        • Kalivas P.W.
        Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways).
        Curr Opin Neurobiol. 2013; 23: 546-552
        • Lenz J.D.
        • Lobo M.K.
        Optogenetic insights into striatal function and behavior.
        Behav Brain Res. 2013; 255: 44-54
        • Albin R.L.
        • Young A.B.
        • Penney J.B.
        The functional anatomy of basal ganglia disorders.
        Trends Neurosci. 1989; 12: 366-375
        • Maia T.V.
        • Frank M.J.
        From reinforcement learning models to psychiatric and neurological disorders.
        Nat Neurosci. 2011; 14: 154-162
        • Kravitz A.V.
        • Kreitzer A.C.
        Striatal mechanisms underlying movement, reinforcement, and punishment.
        Physiology (Bethesda). 2012; 27: 167-177
        • Carlezon Jr, W.A.
        • Thomas M.J.
        Biological substrates of reward and aversion: A nucleus accumbens activity hypothesis.
        Neuropharmacology. 2009; 56: 122-132
        • Lobo M.K.
        • Nestler E.J.
        The striatal balancing act in drug addiction: Distinct roles of direct and indirect pathway medium spiny neurons.
        Front Neuroanat. 2011; 5: 41
        • Freeze B.S.
        • Kravitz A.V.
        • Hammack N.
        • Berke J.D.
        • Kreitzer A.C.
        Control of basal ganglia output by direct and indirect pathway projection neurons.
        J Neurosci. 2013; 33: 18531-18539
        • Hikida T.
        • Kimura K.
        • Wada N.
        • Funabiki K.
        • Nakanishi S.
        Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior.
        Neuron. 2010; 66: 896-907
        • Kravitz A.V.
        • Tye L.D.
        • Kreitzer A.C.
        Distinct roles for direct and indirect pathway striatal neurons in reinforcement.
        Nat Neurosci. 2012; 15: 816-818
        • Kravitz A.V.
        • Freeze B.S.
        • Parker P.R.
        • Kay K.
        • Thwin M.T.
        • Deisseroth K.
        • Kreitzer A.C.
        Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.
        Nature. 2010; 466: 622-626
        • Lobo M.K.
        • Covington 3rd, H.E.
        • Chaudhury D.
        • Friedman A.K.
        • Sun H.
        • Damez-Werno D.
        • et al.
        Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward.
        Science. 2010; 330: 385-390
        • Ferguson S.M.
        • Eskenazi D.
        • Ishikawa M.
        • Wanat M.J.
        • Phillips P.E.
        • Dong Y.
        • et al.
        Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization.
        Nat Neurosci. 2011; 14: 22-24
        • Tai L.H.
        • Lee A.M.
        • Benavidez N.
        • Bonci A.
        • Wilbrecht L.
        Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value.
        Nat Neurosci. 2012; 15: 1281-1289
        • Bock R.
        • Shin J.H.
        • Kaplan A.R.
        • Dobi A.
        • Markey E.
        • Kramer P.F.
        • et al.
        Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use.
        Nat Neurosci. 2013; 16: 632-638
        • Chandra R.
        • Lenz J.D.
        • Gancarz A.M.
        • Chaudhury D.
        • Schroeder G.L.
        • Han M.H.
        • et al.
        Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1.
        Front Mol Neurosci. 2013; 6: 13
        • Golden S.A.
        • Covington 3rd, H.E.
        • Berton O.
        • Russo S.J.
        A standardized protocol for repeated social defeat stress in mice.
        Nat Protoc. 2011; 6: 1183-1191
        • Gong S.
        • Zheng C.
        • Doughty M.L.
        • Losos K.
        • Didkovsky N.
        • Schambra U.B.
        • et al.
        A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.
        Nature. 2003; 425: 917-925
        • Gerfen C.R.
        • Paletzki R.
        • Heintz N.
        GENSAT BAC cre-recombinase driver lines to study the functional organization of cerebral cortical and basal ganglia circuits.
        Neuron. 2013; 80: 1368-1383
      1. Francis TC, Lobo MK (in press): Optogenetic regulation of dopamine receptor-expressing neurons. In: Wolfgang W, Mario T, editors. Dopamine Receptor Technologies, Neuromethods ed. Springer Protocols.

        • Armbruster B.N.
        • Li X.
        • Pausch M.H.
        • Herlitze S.
        • Roth B.L.
        Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.
        Proc Natl Acad Sci U S A. 2007; 104: 5163-5168
        • Sparta D.R.
        • Stamatakis A.M.
        • Phillips J.L.
        • Hovelso N.
        • van Zessen R.
        • Stuber G.D.
        Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits.
        Nat Protoc. 2011; 7: 12-23
        • Ferguson S.M.
        • Phillips P.E.
        • Roth B.L.
        • Wess J.
        • Neumaier J.F.
        Direct-pathway striatal neurons regulate the retention of decision-making strategies.
        J Neurosci. 2013; 33: 11668-11676
        • Rogan S.C.
        • Roth B.L.
        Remote control of neuronal signaling.
        Pharmacol Rev. 2011; 63: 291-315
        • Ahmari S.E.
        • Spellman T.
        • Douglass N.L.
        • Kheirbek M.A.
        • Simpson H.B.
        • Deisseroth K.
        • et al.
        Repeated cortico-striatal stimulation generates persistent OCD-like behavior.
        Science. 2013; 340: 1234-1239
        • Sidor M.M.
        • McClung C.A.
        Timing matters: Using optogenetics to chronically manipulate neural circuitry and rhythms.
        Front Behav Neurosci. 2014; 8: 41
        • LaPlant Q.
        • Vialou V.
        • Covington 3rd, H.E.
        • Dumitriu D.
        • Feng J.
        • Warren B.L.
        • et al.
        Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.
        Nat Neurosci. 2010; 13: 1137-1143
        • Golden S.A.
        • Christoffel D.J.
        • Heshmati M.
        • Hodes G.E.
        • Magida J.
        • Davis K.
        • et al.
        Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression.
        Nat Med. 2013; 19: 337-344
        • Challis C.
        • Beck S.G.
        • Berton O.
        Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat.
        Front Behav Neurosci. 2014; 8: 43
        • Vialou V.
        • Bagot R.C.
        • Cahill M.E.
        • Ferguson D.
        • Robison A.J.
        • Dietz D.M.
        • et al.
        Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: Role of DeltaFosB.
        J Neurosci. 2014; 34: 3878-3887
        • MacAskill A.F.
        • Little J.P.
        • Cassel J.M.
        • Carter A.G.
        Subcellular connectivity underlies pathway-specific signaling in the nucleus accumbens.
        Nat Neurosci. 2012; 15: 1624-1626
        • Wilkinson M.B.
        • Xiao G.
        • Kumar A.
        • LaPlant Q.
        • Renthal W.
        • Sikder D.
        • et al.
        Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models.
        J Neurosci. 2009; 29: 7820-7832
        • Wilkinson M.B.
        • Dias C.
        • Magida J.
        • Mazei-Robison M.
        • Lobo M.
        • Kennedy P.
        • et al.
        A novel role of the WNT-dishevelled-GSK3beta signaling cascade in the mouse nucleus accumbens in a social defeat model of depression.
        J Neurosci. 2011; 31: 9084-9092
        • McCracken C.B.
        • Grace A.A.
        Nucleus accumbens deep brain stimulation produces region-specific alterations in local field potential oscillations and evoked responses in vivo.
        J Neurosci. 2009; 29: 5354-5363
        • Barik J.
        • Marti F.
        • Morel C.
        • Fernandez S.P.
        • Lanteri C.
        • Godeheu G.
        • et al.
        Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons.
        Science. 2013; 339: 332-335