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Nucleus Accumbens Medium Spiny Neuron Subtypes Differentially Regulate Stress-Associated Alterations in Sleep Architecture

      Abstract

      Background

      Stress is implicated in the pathophysiology of major depression and posttraumatic stress disorder. These conditions share core features, including motivational deficits, heighted anxiety, and sleep dysregulation. Chronic stress produces these same features in rodents, with some individuals being susceptible or resilient, as seen in humans. While stress-induced neuroadaptations within the nucleus accumbens are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear.

      Methods

      We used chemogenetics (DREADDs [designer receptors exclusively activated by designer drugs]) to examine the effects of selective alterations in activity of nucleus accumbens medium spiny neurons expressing dopamine D1 receptors (D1-MSNs) or dopamine D2 receptors (D2-MSNs) on sleep-related end points. Mice were implanted with wireless transmitters enabling continuous collection of data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility.

      Results

      D1- and D2-MSNs play dissociable roles in sleep regulation. Stimulation of inhibitory or excitatory DREADDs expressed in D1-MSNs exclusively affects rapid eye movement sleep, whereas targeting D2-MSNs affects slow wave sleep. The combined effects of D1-MSN inhibition and D2-MSN activation on sleep resemble those of chronic social defeat stress. Alterations in D1-MSN function also affect stress susceptibility in social behavior tests. Elevation of CREB (cAMP response element-binding protein) within D1-MSNs is sufficient to produce stress-like effects on rapid eye movement sleep.

      Conclusions

      In addition to regulation of motivational and emotional behaviors, the nucleus accumbens also influences sleep, an end point with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.

      Keywords

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      References

        • Nutt D.
        • Wilson S.
        • Paterson L.
        Sleep disorders as core symptoms of depression.
        Dialogues Clin Neurosci. 2008; 10: 329-336
        • Richards A.
        • Kanady J.C.
        • Neylan T.C.
        Sleep disturbance in PTSD and other anxiety-related disorders: An updated review of clinical features, physiological characteristics, and psychological and neurobiological mechanisms.
        Neuropsychopharmacology. 2020; 45: 55-73
        • Riemann D.
        • Krone L.B.
        • Wulff K.
        • Nissen C.
        Sleep, insomnia, and depression.
        Neuropsychopharmacology. 2020; 45: 74-89
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
        American Psychiatric Association, Washington, DC2013
        • Giles D.E.
        • Jarrett R.B.
        • Biggs M.M.
        • Guzick D.S.
        • Rush A.J.
        Clinical predictors of recurrence in depression.
        Am J Psychiatry. 1989; 146: 764-767
        • Giles D.E.
        • Jarrett R.B.
        • Roffwarg H.P.
        • Rush A.J.
        Reduced rapid eye movement latency: A predictor of recurrence in depression.
        Neuropsychopharmacology. 1987; 1: 33-39
        • Tsuno N.
        • Besset A.
        • Ritchie K.
        Sleep and depression.
        J Clin Psychiatry. 2005; 66: 1254-1269
        • Armitage R.
        • Hoffmann R.
        • Trivedi M.
        • Rush A.J.
        Slow-wave activity in NREM sleep: Sex and age effects in depressed outpatients and healthy controls.
        Psychiatry Res. 2000; 95: 201-213
        • Rush A.J.
        • Giles D.E.
        • Jarrett R.B.
        • Feldman-Koffler F.
        • Debus J.R.
        • Weissenburger J.
        • et al.
        Reduced REM latency predicts response to tricyclic medication in depressed outpatients.
        Biol Psychiatry. 1989; 26: 61-72
        • Ross R.J.
        • Ball W.A.
        • Sullivan K.A.
        • Caroff S.N.
        Sleep disturbance as the hallmark of posttraumatic stress disorder.
        Am J Psychiatry. 1989; 146: 697-707
        • Wells A.M.
        • Ridener E.
        • Bourbonais C.A.
        • Kim W.
        • Pantazopoulos H.
        • Carroll F.I.
        • et al.
        Effects of chronic social defeat stress on sleep and circadian rhythms are mitigated by kappa-opioid receptor antagonism.
        J Neurosci. 2017; 37: 7656-7668
        • Fujii S.
        • Kaushik M.K.
        • Zhou X.
        • Korkutata M.
        • Lazarus M.
        Acute social defeat stress increases sleep in mice.
        Front Neurosci. 2019; 13: 322
        • Baker J.T.
        • Germine L.T.
        • Ressler K.J.
        • Rauch S.L.
        • Carlezon Jr., W.A.
        Digital devices and continuous telemetry: Opportunities for aligning psychiatry and neuroscience.
        Neuropsychopharmacology. 2018; 43: 2499-2503
        • Bale T.L.
        • Abel T.
        • Akil H.
        • Carlezon Jr., W.A.
        • Moghaddam B.
        • Nestler E.J.
        • et al.
        The critical importance of basic animal research for neuropsychiatric disorders.
        Neuropsychopharmacology. 2019; 44: 1349-1353
        • Heshmati M.
        • Russo S.J.
        Anhedonia and the brain reward circuitry in depression.
        Curr Behav Neurosci Rep. 2015; 2: 146-153
        • 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
        • Russo S.J.
        • Nestler E.J.
        The brain reward circuitry in mood disorders.
        Nat Rev Neurosci. 2013; 14: 609-625
        • Lammel S.
        • Lim B.K.
        • Malenka R.C.
        Reward and aversion in a heterogeneous midbrain dopamine system.
        Neuropharmacology. 2014; 76: 351-359
        • Nestler E.J.
        • Carlezon Jr., W.A.
        The mesolimbic dopamine reward circuit in depression.
        Biol Psychiatry. 2006; 59: 1151-1159
        • Gunaydin L.A.
        • Grosenick L.
        • Finkelstein J.C.
        • Kauvar I.V.
        • Fenno L.E.
        • Adhikari A.
        • et al.
        Natural neural projection dynamics underlying social behavior.
        Cell. 2014; 157: 1535-1551
        • Carlezon Jr., W.A.
        • Thomas M.J.
        Biological substrates of reward and aversion: A nucleus accumbens activity hypothesis.
        Neuropharmacology. 2009; 56: 122-132
        • Golden S.A.
        • Jin M.
        • Heins C.
        • Venniro M.
        • Michaelides M.
        • Shaham Y.
        Nucleus accumbens Drd1-expressing neurons control aggression self-administration and aggression seeking in mice.
        J Neurosci. 2019; 39: 2482-2496
        • Berton O.
        • Nestler E.J.
        New approaches to antidepressant drug discovery: Beyond monoamines.
        Nat Rev Neurosci. 2006; 7: 137-151
        • Donahue R.J.
        • Muschamp J.W.
        • Russo S.J.
        • Nestler E.J.
        • Carlezon Jr., W.A.
        Effects of striatal ΔFosB overexpression and ketamine on social defeat stress–induced anhedonia in mice.
        Biol Psychiatry. 2014; 76: 550-558
        • Takahashi A.
        • Chung J.-R.
        • Zhang S.
        • Zhang H.
        • Grossman Y.
        • Aleyasin H.
        • et al.
        Establishment of a repeated social defeat stress model in female mice.
        Sci Rep. 2017; 7: 12838
        • Fox M.E.
        • Lobo M.K.
        The molecular and cellular mechanisms of depression: A focus on reward circuitry.
        Mol Psychiatry. 2019; 24: 1798-1815
        • Soares-Cunha C.
        • Coimbra B.
        • Sousa N.
        • Rodrigues A.J.
        Reappraising striatal D1- and D2-neurons in reward and aversion.
        Neurosci Biobehav Rev. 2016; 68: 370-386
        • Kreitzer A.C.
        • Malenka R.C.
        Striatal plasticity and basal ganglia circuit function.
        Neuron. 2008; 60: 543-554
        • Wall N.R.
        • De La Parra M.
        • Callaway E.M.
        • Kreitzer A.C.
        Differential innervation of direct- and indirect-pathway striatal projection neurons.
        Neuron. 2013; 79: 347-360
        • Francis T.C.
        • Lobo M.K.
        Emerging role for nucleus accumbens medium spiny neuron subtypes in depression.
        Biol Psychiatry. 2017; 81: 645-653
        • Gerfen C.R.
        • Surmeier D.J.
        Modulation of striatal projection systems by dopamine.
        Annu Rev Neurosci. 2011; 34: 441-466
        • Ramirez F.
        • Moscarello J.M.
        • LeDoux J.E.
        • Sears R.M.
        Active avoidance requires a serial basal amygdala to nucleus accumbens shell circuit.
        J Neurosci. 2015; 35: 3470-3477
        • Tejeda H.A.
        • Wu J.
        • Kornspun A.R.
        • Pignatelli M.
        • Kashtelyan V.
        • Krashes M.J.
        • et al.
        Pathway- and cell-specific kappa-opioid receptor modulation of excitation-inhibition balance differentially gates D1 and D2 accumbens neuron activity.
        Neuron. 2017; 93: 147-163
        • Francis T.C.
        • Chandra R.
        • Friend D.M.
        • Finkel E.
        • Dayrit G.
        • Miranda J.
        • et al.
        Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress.
        Biol Psychiatry. 2015; 77: 212-222
        • Nam H.
        • Chandra R.
        • Francis T.C.
        • Dias C.
        • Cheer J.F.
        • Lobo M.K.
        Reduced nucleus accumbens enkephalins underlie vulnerability to social defeat stress.
        Neuropsychopharmacology. 2019; 44: 1876-1885
        • Muir J.
        • Lorsch Z.S.
        • Ramakrishnan C.
        • Deisseroth K.
        • Nestler E.J.
        • Calipari E.S.
        • et al.
        In vivo fiber photometry reveals signature of future stress susceptibility in nucleus accumbens.
        Neuropsychopharmacology. 2018; 43: 255-263
        • Heshmati M.
        • Aleyasin H.
        • Menard C.
        • Christoffel D.J.
        • Flanigan M.E.
        • Pfau M.L.
        • et al.
        Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.
        Proc Natl Acad Sci U S A. 2018; 115: 1111-1116
        • Hamilton P.J.
        • Burek D.J.
        • Lombroso S.I.
        • Neve R.L.
        • Robison A.J.
        • Nestler E.J.
        • Heller E.A.
        Cell-type-specific epigenetic editing at the fosb gene controls susceptibility to social defeat stress.
        Neuropsychopharmacology. 2018; 43: 272-284
        • Dias C.
        • Feng J.
        • Sun H.
        • Shao N.-Y.
        • Mazei-Robison M.S.
        • Damez-Werno D.
        • et al.
        β-Catenin mediates stress resilience through Dicer1/microRNA regulation.
        Nature. 2014; 516: 51-55
        • Maze I.
        • Chaudhury D.
        • Dietz D.M.
        • Von Schimmelmann M.
        • Kennedy P.J.
        • Lobo M.K.
        • et al.
        G9a influences neuronal subtype specification in striatum.
        Nat Neurosci. 2014; 17: 533-539
        • 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
        • Carlezon Jr., W.A.
        • Krystal A.D.
        Kappa-opioid antagonists for psychiatric disorders: From bench to clinical trials.
        Depress Anxiety. 2016; 33: 895-906
        • Yamaguchi H.
        • Hopf F.W.
        • Li S.B.
        • de Lecea L.
        In vivo cell type-specific CRISPR knockdown of dopamine beta hydroxylase reduces locus coeruleus evoked wakefulness.
        Nat Commun. 2018; 9: 5211
        • Eban-Rothschild A.
        • Rothschild G.
        • Giardino W.J.
        • Jones J.R.
        • de Lecea L.
        VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors.
        Nat Neurosci. 2016; 19: 1356-1366
        • Luo Y.-J.
        • Li Y.-D.
        • Wang L.
        • Yang S.-R.
        • Yuan X.-S.
        • Wang J.
        • et al.
        Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors.
        Nat Commun. 2018; 9: 1576
        • Oishi Y.
        • Xu Q.
        • Wang L.
        • Zhang B.-J.
        • Takahashi K.
        • Takata Y.
        • et al.
        Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice.
        Nat Commun. 2017; 8: 734
        • Yuan X.-S.
        • Wang L.
        • Dong H.
        • Qu W.-M.
        • Yang S.-R.
        • Cherasse Y.
        • et al.
        Striatal adenosine A2A receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus.
        eLife. 2017; 6e29055
        • Bagot R.C.
        • Parise E.M.
        • Peña C.J.
        • Zhang H.-X.
        • Maze I.
        • Chaudhury D.
        • et al.
        Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression.
        Nat Commun. 2015; 6: 7062
        • McCullough K.M.
        • Daskalakis N.P.
        • Gafford G.
        • Morrison F.G.
        • Ressler K.J.
        Cell-type-specific interrogation of CeA Drd2 neurons to identify targets for pharmacological modulation of fear extinction.
        Transl Psychiatry. 2018; 8: 164
        • McCullough K.M.
        • Choi D.
        • Guo J.
        • Zimmerman K.
        • Walton J.
        • Rainnie D.G.
        • Ressler K.J.
        Molecular characterization of Thy1 expressing fear-inhibiting neurons within the basolateral amygdala.
        Nat Commun. 2016; 7: 13149
        • Penrod R.D.
        • Wells A.M.
        • Carlezon Jr., W.A.
        • Cowan C.W.
        Use of adeno-associated and herpes simplex viral vectors for in vivo neuronal expression in mice.
        Curr Prot Neurosci. 2015; 73: 4.37.1-4.37.31
        • Missig G.
        • Mokler E.L.
        • Robbins J.O.
        • Alexander A.J.
        • McDougle C.J.
        • Carlezon Jr., W.A.
        Perinatal immune activation produces persistent sleep alterations and epileptiform activity in male mice.
        Neuropsychopharmacology. 2018; 43: 482-491
        • Gomez J.L.
        • Bonaventura J.
        • Lesniak W.
        • Mathews W.B.
        • Sysa-Shah P.
        • Rodriguez L.A.
        • et al.
        Chemogenetics revealed: DREADD occupancy and activation via converted clozapine.
        Science. 2017; 357: 503-507
        • Vetere G.
        • Kenney J.W.
        • Tran L.M.
        • Xia F.
        • Steadman P.E.
        • Parkinson J.
        • et al.
        Chemogenetic interrogation of a brain-wide fear memory network in mice.
        Neuron. 2017; 94: 363-374.e4
        • Atkins J.B.
        • Chlan-Fourney J.
        • Nye H.E.
        • Hiroi N.
        • Carlezon Jr., W.A.
        • Nestler E.J.
        • et al.
        Region-specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs.
        Synapse. 1999; 33: 118-128
        • Missig G.
        • Robbins J.O.
        • Mokler E.L.
        • McCullough K.M.
        • Bilbo S.D.
        • McDougle C.J.
        • Carlezon Jr., W.A.
        Sex-dependent neurobiological features of prenatal immune activation via TLR7.
        Mol Psychiatry. 2020; 25: 2330-2341
        • Palagini L.
        • Baglioni C.
        • Ciapparelli A.
        • Gemignani A.
        • Riemann D.
        REM sleep dysregulation in depression: State of the art.
        Sleep Med Rev. 2013; 17: 377-390
        • Souêtre E.
        • Salvati E.
        • Belugou J.L.
        • Pringuey D.
        • Candito M.
        • Krebs B.
        • Ardisson J.L.
        • Darcourt G.
        Circadian rhythms in depression and recovery: Evidence for blunted amplitude as the main chronobiological abnormality.
        Psychiatry Res. 1989; 28: 263-278
        • Duncan Jr., W.C.
        Circadian rhythms and the pharmacology of affective illness.
        Pharmacol Ther. 1996; 71: 253-312
        • Kronfeld-Schor N.
        • Einat H.
        Circadian rhythms and depression: Human psychopathology and animal models.
        Neuropharmacology. 2012; 62: 101-114
        • Lezak K.R.
        • Missig G.
        • Carlezon Jr., W.A.
        Behavioral methods to study anxiety in rodents.
        Dialogues Clin Neurosci. 2017; 19: 181-191
        • Muschamp J.W.
        • Van’t Veer A.
        • Parsegian A.
        • Gallo M.S.
        • Chen M.
        • Neve R.L.
        • et al.
        Activation of CREB in the nucleus accumbens shell produces anhedonia and resistance to extinction of fear in rats.
        J Neurosci. 2011; 31: 3095-3103
        • Carlezon Jr., W.A.
        • Wise R.A.
        Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex.
        J Neurosci. 1996; 16: 3112-3122
        • Pliakas A.M.
        • Carlson R.R.
        • Neve R.L.
        • Konradi C.
        • Nestler E.J.
        • Carlezon Jr., W.A.
        Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens.
        J Neurosci. 2001; 21: 7397-7403
        • Steiger A.
        • Kimura M.
        Wake and sleep EEG provide biomarkers in depression.
        J Psychiatr Res. 2010; 44: 242-252
        • Medina A.B.
        • Lechuga D.A.
        • Escandon O.S.
        • Moctezuma J.V.
        Update of sleep alterations in depression.
        Sleep Sci. 2014; 7: 165-169
        • 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
        • Matamales M.
        • Bertran-Gonzalez j
        • Salomon l
        • Degos B.
        • Deniau J.-M.
        • Valjent E.
        • et al.
        Striatal medium-sized spiny neurons: identification by nuclear staining and study of neuronal subpopulations in BAC transgenic mice.
        PLoS One. 2009; 4e4770
        • Peña C.J.
        • Kronman H.G.
        • Walker D.M.
        • Cates H.M.
        • Bagot R.C.
        • Purushothaman I.
        • et al.
        Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.
        Science. 2017; 356: 1185-1188
        • Li Y.
        • Missig G.
        • Finger B.C.
        • Landino S.M.
        • Alexander A.J.
        • Mokler E.L.
        • et al.
        Maternal and early postnatal immune activation produce dissociable effects on neurotransmission in mPFC–amygdala circuits.
        J Neurosci. 2018; 38: 3358-3372
        • Wallace D.L.
        • Han M.-H.
        • Graham D.L.
        • Green T.A.
        • Vialou V.
        • Iñiguez S.D.
        • et al.
        CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits.
        Nat Neurosci. 2009; 12: 200-209
        • Chavkin C.
        • James I.F.
        • Goldstein A.
        Dynorphin is a specific endogenous ligand of the kappa opioid receptor.
        Science. 1982; 215: 413-415
        • Carlezon Jr., W.A.
        • Thome J.
        • Olson V.G.
        • Lane-Ladd S.B.
        • Brodkin E.S.
        • Hiroi N.
        • et al.
        Regulation of cocaine reward by CREB.
        Science. 1998; 282: 2272-2275
        • Svingos A.L.
        • Colago E.E.
        • Pickel V.M.
        Cellular sites for dynorphin activation of κ-opioid receptors in the rat nucleus accumbens shell.
        J Neurosci. 1999; 19: 1804-1813
        • Carlezon Jr., W.A.
        • Béguin C.
        • DiNieri J.A.
        • Baumann M.H.
        • Richards M.R.
        • Todtenkopf M.S.
        • et al.
        Depressive-like effects of the κ-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.
        J Pharmacol Exp Ther. 2006; 316: 440-447
        • Mague S.D.
        • Pliakas A.M.
        • Todtenkopf M.S.
        • Tomasiewicz H.C.
        • Zhang Y.
        • Stevens Jr., W.C.
        • et al.
        Antidepressant-like effects of κ-opioid receptor antagonists in the forced swim test in rats.
        J Pharmacol Exp Ther. 2003; 305: 323-330
        • Knoll A.T.
        • Meloni E.G.
        • Thomas J.B.
        • Carroll F.I.
        • Carlezon Jr., W.A.
        Anxiolytic-like effects of κ-opioid receptor antagonists in models of unlearned and learned fear in rats.
        J Pharmacol Exp Ther. 2007; 323: 838-845
        • Krystal A.D.
        • Pizzagalli D.A.
        • Smoski M.
        • Mathew S.J.
        • Nurnberger Jr., J.
        • Lisanby S.H.
        • et al.
        A randomized proof-of-mechanism trial applying the “fast-fail” approach to evaluating κ-opioid antagonism as a treatment for anhedonia.
        Nat Med. 2020; 26: 760-768
        • Pizzagalli D.A.
        • Smoski M.
        • Ang Y.-S.
        • Whitton A.E.
        • Sanacora G.
        • Mathew S.J.
        • et al.
        Selective kappa-opioid antagonism ameliorates anhedonic behavior: Evidence from the Fast-Fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS).
        Neuropsychopharmacology. 2020; 45: 1656-1663
        • Jones B.E.
        Arousal and sleep circuits.
        Neuropsychopharmacology. 2020; 45: 6-20