Advertisement

Comparative Transcriptional Analyses in the Nucleus Accumbens Identifies RGS2 as a Key Mediator of Depression-Related Behavior

      Abstract

      Background

      Major depressive disorder is one of the most commonly diagnosed mental illnesses worldwide, with a higher prevalence in women than in men. Although currently available pharmacological therapeutics help many individuals, they are not effective for most. Animal models have been important for the discovery of molecular alterations in stress and depression, but difficulties in adapting animal models of depression for females has impeded progress in developing novel therapeutic treatments that may be more efficacious for women.

      Methods

      Using the California mouse social defeat model, we took a multidisciplinary approach to identify stress-sensitive molecular targets that have translational relevance for women. We determined the impact of stress on transcriptional profiles in male and female California mouse nucleus accumbens (NAc) and compared these results with data from postmortem samples of the NAc from men and women diagnosed with major depressive disorder.

      Results

      Our cross-species computational analyses identified Rgs2 (regulator of G protein signaling 2) as a transcript downregulated by social defeat stress in female California mice and in women with major depressive disorder. RGS2 plays a key role in signal regulation of neuropeptide and neurotransmitter receptors. Viral vector–mediated overexpression of Rgs2 in the NAc restored social approach and sucrose preference in stressed female California mice.

      Conclusions

      These studies show that Rgs2 acting in the NAc has functional properties that translate to changes in anxiety- and depression-related behavior. Future studies should investigate whether targeting Rgs2 represents a novel target for treatment-resistant depression in women.

      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

        • Goel N.
        • Bale T.L.
        Examining the intersection of sex and stress in modelling neuropsychiatric disorders.
        J Neuroendocrinol. 2009; 21: 415-420
        • Bale T.L.
        • Epperson C.N.
        Sex differences and stress across the lifespan.
        Nat Neurosci. 2015; 18: 1413-1420
        • Laman-Maharg A.
        • Trainor B.C.
        Stress, sex, and motivated behaviors.
        J Neurosci Res. 2017; 95: 83-92
        • Culpepper L.
        Why do you need to move beyond first-line therapy for major depression?.
        J Clin Psychiatry. 2010; 71: 4-9
      1. Depression: How effective are antidepressants? Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, Germany2017 (Available at:)
        • Enneking V.
        • Krüssel P.
        • Zaremba D.
        • Dohm K.
        • Grotegerd D.
        • Förster K.
        • et al.
        Social anhedonia in major depressive disorder: A symptom-specific neuroimaging approach.
        Neuropsychopharmacology. 2019; 44: 883-889
        • 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
        • Delaloye S.
        • Holtzheimer P.E.
        Deep brain stimulation in the treatment of depression.
        Clin Res. 2014; 16: 83-91
        • Russo S.J.
        • Nestler E.J.
        The brain reward circuitry in mood disorders [published correction appears in Nat Rev Neurosci 2013; 14:736.
        Nat Rev Neurosci. 2013; 14: 609-625
        • Carlezon Jr., W.A.
        • Thomas M.J.
        Biological substrates of reward and aversion: A nucleus accumbens activity hypothesis.
        Neuropharmacology. 2009; 56: 122-132
        • 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
        • Sesack S.R.
        • Grace A.A.
        Cortico-basal ganglia reward network: Microcircuitry.
        Neuropsychopharmacology. 2010; 35: 27-47
        • Mogenson G.J.
        • Jones D.L.
        • Yim C.Y.
        From motivation to action: Functional interface between the limbic system and the motor system.
        Prog Neurobiol. 1980; 14: 69-97
        • Roitman M.F.
        • Wheeler R.A.
        • Carelli R.M.
        Nucleus accumbens neurons are innately tuned for rewarding and aversive taste stimuli, encode their predictors, and are linked to motor output.
        Neuron. 2005; 45: 587-597
        • Humphries M.D.
        • Prescott T.J.
        The ventral basal ganglia, a selection mechanism at the crossroads of space, strategy, and reward.
        Prog Neurobiol. 2010; 90: 385-417
        • Parkinson J.A.
        • Willoughby P.J.
        • Robbins T.W.
        • Everitt B.J.
        Disconnection of the anterior cingulate cortex and nucleus accumbens core impairs Pavlovian approach behavior: Further evidence for limbic cortical-ventral striatopallidal systems.
        Behav Neurosci. 2000; 114: 42-63
        • Stefanik M.T.
        • Kupchik Y.M.
        • Brown R.M.
        • Kalivas P.W.
        Optogenetic evidence that pallidal projections, not nigral projections, from the nucleus accumbens core are necessary for reinstating cocaine seeking.
        J Neurosci. 2013; 33: 13654-13662
        • Williams A.V.
        • Trainor B.C.
        The impact of sex as a biological variable in the search for novel antidepressants.
        Front Neuroendocrinol. 2018; 50: 107-117
        • Will T.R.
        • Proaño S.B.
        • Thomas A.M.
        • Kunz L.M.
        • Thompson K.C.
        • Ginnari L.A.
        • et al.
        Problems and progress regarding sex bias and omission in neuroscience research.
        eNeuro. 2017; 4 (ENEURO.0278-17.2017)
        • Labonté B.
        • Engmann O.
        • Purushothaman I.
        • Menard C.
        • Wang J.
        • Tan C.
        • et al.
        Sex-specific transcriptional signatures in human depression [published correction appears in Nat Med 2018; 24:525.
        Nat Med. 2017; 23: 1102-1111
        • Seney M.L.
        • Huo Z.
        • Cahill K.
        • French L.
        • Puralewski R.
        • Zhang J.
        • et al.
        Opposite molecular signatures of depression in men and women.
        Biol Psychiatry. 2018; 84: 18-27
        • Hodes G.E.
        • Pfau M.L.
        • Purushothaman I.
        • Ahn H.F.
        • Golden S.A.
        • Christoffel D.J.
        • et al.
        Sex Differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress.
        J Neurosci. 2015; 35: 16362-16376
        • Ordoñes Sanchez E.
        • Bavley C.C.
        • Deutschmann A.U.
        • Carpenter R.
        • Peterson D.R.
        • Karbalaei R.
        • et al.
        Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes [published correction appears in Proc Natl Acad Sci U S A 2022; 119:e2204210119].
        Proc Natl Acad Sci U S A 118. 2021;
        • Bangasser D.A.
        • Cuarenta A.
        Sex differences in anxiety and depression: Circuits and mechanisms.
        Nat Rev Neurosci. 2021; 22: 674-684
        • Kuske J.X.
        • Trainor B.C.
        Mean girls: Social stress models for female rodents.
        Curr Top Behav Neurosci. 2022; 54: 95-124
        • Trainor B.C.
        • Pride M.C.
        • Villalon Landeros R.
        • Knoblauch N.W.
        • Takahashi E.Y.
        • Silva A.L.
        • Crean K.K.
        Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus).
        PLoS One. 2011; 6e17405
        • Watson N.
        • Linder M.E.
        • Druey K.M.
        • Kehrl J.H.
        • Blumer K.J.
        RGS family members: GTPase-activating proteins for heterotrimeric G-protein alpha-subunits.
        Nature. 1996; 383: 172-175
        • Butler-Struben H.M.
        • Kentner A.C.
        • Trainor B.C.
        What’s wrong with my experiment?: The impact of hidden variables on neuropsychopharmacology research.
        Neuropsychopharmacology. 2022; 47: 1285-1291
        • Percie du Sert N.
        • Hurst V.
        • Ahluwalia A.
        • Alam S.
        • Avey M.T.
        • Baker M.
        • et al.
        The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.
        PLoS Biol. 2020; 18e3000410
        • Williams A.V.
        • Laman-Maharg A.
        • Armstrong C.V.
        • Ramos-Maciel S.
        • Minie V.A.
        • Trainor B.C.
        Acute inhibition of kappa opioid receptors before stress blocks depression-like behaviors in California mice.
        Prog Neuropsychopharmacol Biol Psychiatry. 2018; 86: 166-174
        • Williams A.V.
        • Duque-Wilckens N.
        • Ramos-Maciel S.
        • Campi K.L.
        • Bhela S.K.
        • Xu C.K.
        • et al.
        Social approach and social vigilance are differentially regulated by oxytocin receptors in the nucleus accumbens.
        Neuropsychopharmacology. 2020; 45: 1423-1430
        • Streett D.A.
        • Petersen K.R.
        • Gerritsen A.T.
        • Hunter S.S.
        • Settles M.L.
        expHTS: Analysis of high throughput sequence data in an experimental framework.
        in: Proceedings of the 6th ACM Conference on Bioinformatics, Computational Biology and Health Informatics, September 9. 2015: 523-524
        • Li H.
        Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM.
        Quant Biol. 2013; (arXiv)
        • Robinson M.D.
        • McCarthy D.J.
        • Smyth G.K.
        edgeR: A Bioconductor package for differential expression analysis of digital gene expression data.
        Bioinformatics. 2010; 26: 139-140
        • Ritchie M.E.
        • Phipson B.
        • Wu D.
        • Hu Y.
        • Law C.W.
        • Shi W.
        • Smyth G.K.
        limma powers differential expression analyses for RNA-sequencing and microarray studies.
        Nucleic Acids Res. 2015; 43: e47
        • Alexa A.
        • Rahnenfuhrer J.
        R package.
        in: topGO: Enrichment Analysis for Gene Ontology. 2020
        Version: version 2.41.0
        • Cahill K.M.
        • Huo Z.
        • Tseng G.C.
        • Logan R.W.
        • Seney M.L.
        Improved identification of concordant and discordant gene expression signatures using an updated rank-rank hypergeometric overlap approach.
        Sci Rep. 2018; 8: 9588
        • Greenberg G.D.
        • Laman-Maharg A.
        • Campi K.L.
        • Voigt H.
        • Orr V.N.
        • Schaal L.
        • Trainor B.C.
        Sex differences in stress-induced social withdrawal: Role of brain derived neurotrophic factor in the bed nucleus of the stria terminalis.
        Front Behav Neurosci. 2014; 7: 223
        • Peña C.J.
        • Smith M.
        • Ramakrishnan A.
        • Cates H.M.
        • Bagot R.C.
        • Kronman H.G.
        • et al.
        Early life stress alters transcriptomic patterning across reward circuitry in male and female mice.
        Nat Commun. 2019; 10: 5098
        • Wu M.V.
        • Tollkuhn J.
        Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior.
        Horm Behav. 2017; 95: 3-12
        • Neve R.L.
        • Neve K.A.
        • Nestler E.J.
        • Carlezon Jr., W.A.
        Use of herpes virus amplicon vectors to study brain disorders.
        Biotechniques. 2005; 39: 381-391
        • 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
        • Keppel G.
        Design and Analysis: A Researcher’s Handbook.
        3rd ed. Prentice Hall, Englewood Cliffs, NJ1991
        • Trainor B.C.
        • Takahashi E.Y.
        • Campi K.L.
        • Florez S.A.
        • Greenberg G.D.
        • Laman-Maharg A.
        • et al.
        Sex differences in stress-induced social withdrawal: Independence from adult gonadal hormones and inhibition of female phenotype by corncob bedding.
        Horm Behav. 2013; 63: 543-550
        • Walker D.M.
        • Zhou X.
        • Ramakrishnan A.
        • Cates H.M.
        • Cunningham A.M.
        • Peña C.J.
        • et al.
        Adolescent social isolation reprograms the medial amygdala: Transcriptome and sex differences in reward.
        bioRxiv. 2020; https://doi.org/10.1101/2020.02.18.955187
        • Walker D.M.
        • Cates H.M.
        • Loh Y.H.E.
        • Purushothaman I.
        • Ramakrishnan A.
        • Cahill K.M.
        • et al.
        Cocaine self-administration alters transcriptome-wide responses in the brain’s reward circuitry.
        Biol Psychiatry. 2018; 84: 867-880
        • Ruiz-Ortiz J.
        • Tollkuhn J.
        Specificity in sociogenomics: Identifying causal relationships between genes and behavior.
        Horm Behav. 2021; 127104882
        • Wright E.C.
        • Hostinar C.E.
        • Trainor B.C.
        Anxious to see you: Neuroendocrine mechanisms of social vigilance and anxiety during adolescence.
        Eur J Neurosci. 2020; 52: 2516-2529
        • Laredo S.A.
        • Steinman M.Q.
        • Robles C.F.
        • Ferrer E.
        • Ragen B.J.
        • Trainor B.C.
        Effects of defeat stress on behavioral flexibility in males and females: Modulation by the mu-opioid receptor.
        Eur J Neurosci. 2015; 41: 434-441
        • Semplicini A.
        • Lenzini L.
        • Sartori M.
        • Papparella I.
        • Calò L.A.
        • Pagnin E.
        • et al.
        Reduced expression of regulator of G-protein signaling 2 (RGS2) in hypertensive patients increases calcium mobilization and ERK1/2 phosphorylation induced by angiotensin II.
        J Hypertens. 2006; 24: 1115-1124
        • Asselmann E.
        • Hertel J.
        • Schmidt C.O.
        • Homuth G.
        • Nauck M.
        • Beesdo-Baum K.
        • et al.
        Interplay between RGS2 and childhood adversities in predicting anxiety and depressive disorders: Findings from a general population sample.
        Depress Anxiety. 2018; 35: 1104-1113
        • Smoller J.W.
        • Paulus M.P.
        • Fagerness J.A.
        • Purcell S.
        • Yamaki L.H.
        • Hirshfeld-Becker D.
        • et al.
        Influence of RGS2 on anxiety-related temperament, personality, and brain function.
        Arch Gen Psychiatry. 2008; 65: 298-308
        • Koenen K.C.
        • Amstadter A.B.
        • Ruggiero K.J.
        • Acierno R.
        • Galea S.
        • Kilpatrick D.G.
        • Gelernter J.
        RGS2 and generalized anxiety disorder in an epidemiologic sample of hurricane-exposed adults.
        Depress Anxiety. 2009; 26: 309-315
        • Stein M.B.
        • Keshaviah A.
        • Haddad S.A.
        • Van Ameringen M.
        • Simon N.M.
        • Pollack M.H.
        • Smoller J.W.
        Influence of RGS2 on sertraline treatment for social anxiety disorder.
        Neuropsychopharmacology. 2014; 39: 1340-1346
        • Hohoff C.
        • Weber H.
        • Richter J.
        • Domschke K.
        • Zwanzger P.M.
        • Ohrmann P.
        • et al.
        RGS2 ggenetic variation: Association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety.
        Am J Med Genet B Neuropsychiatr Genet. 2015; 168B: 211-222
        • Otowa T.
        • Shimada T.
        • Kawamura Y.
        • Sugaya N.
        • Yoshida E.
        • Inoue K.
        • et al.
        Association of RGS2 variants with panic disorder in a Japanese population.
        Am J Med Genet B Neuropsychiatr Genet. 2011; 156B: 430-434
        • Amstadter A.B.
        • Koenen K.C.
        • Ruggiero K.J.
        • Acierno R.
        • Galea S.
        • Kilpatrick D.G.
        • Gelernter J.
        Variant in RGS2 moderates posttraumatic stress symptoms following potentially traumatic event exposure.
        J Anxiety Disord. 2009; 23: 369-373
        • Amstadter A.B.
        • Koenen K.C.
        • Ruggiero K.J.
        • Acierno R.
        • Galea S.
        • Kilpatrick D.G.
        • Gelernter J.
        Variation in RGS2 is associated with suicidal ideation in an epidemiological study of adults exposed to the 2004 Florida hurricanes.
        Arch Suicide Res. 2009; 13: 349-357
        • Cui H.
        • Nishiguchi N.
        • Ivleva E.
        • Yanagi M.
        • Fukutake M.
        • Nushida H.
        • et al.
        Association of RGS2 gene polymorphisms with suicide and increased RGS2 immunoreactivity in the postmortem brain of suicide victims.
        Neuropsychopharmacology. 2008; 33: 1537-1544
        • Lifschytz T.
        • Broner E.C.
        • Zozulinsky P.
        • Slonimsky A.
        • Eitan R.
        • Greenbaum L.
        • Lerer B.
        Relationship between Rgs2 gene expression level and anxiety and depression-like behaviour in a mutant mouse model: Serotonergic involvement.
        Int J Neuropsychopharmacol. 2012; 15: 1307-1318
        • Oliveira-dos-Santos A.J.
        • Matsumoto G.
        • Snow B.E.
        • Bai D.
        • Houston F.P.
        • Whishaw I.Q.
        • et al.
        Regulation of T cell activation, anxiety, and male aggression by RGS2.
        Proc Natl Acad Sci U S A. 2000; 97: 12272-12277
        • Nakahara T.
        • Hashimoto K.
        • Hirano M.
        • Rajendram R.
        • Martin C.R.
        • Ar Preedy V.R.
        Gender differences in the relative abundance of RGS2 mRNA in brain-stem, cortex, cerebellum and midbrain and the effects of chronic alcohol feeding.
        Proc Nutr Soc. 2010; 69: E338
        • Okimoto N.
        • Bosch O.J.
        • Slattery D.A.
        • Pflaum K.
        • Matsushita H.
        • Wei F.Y.
        • et al.
        RGS2 mediates the anxiolytic effect of oxytocin.
        Brain Res. 2012; 1453: 26-33
        • Hepler J.R.
        Emerging roles for RGS proteins in cell signalling.
        Trends Pharmacol Sci. 1999; 20: 376-382
        • Heximer S.P.
        • Watson N.
        • Linder M.E.
        • Blumer K.J.
        • Hepler J.R.
        RGS2/G0S8 is a selective inhibitor of Gqalpha function.
        Proc Natl Acad Sci U S A. 1997; 94: 14389-14393
        • Phan H.T.N.
        • Sjögren B.
        • Neubig R.R.
        Human missense mutations in regulator of G protein signaling 2 affect the protein function through multiple mechanisms.
        Mol Pharmacol. 2017; 92: 451-458
        • Siderovski D.P.
        • Hessel A.
        • Chung S.
        • Mak T.W.
        • Tyers M.
        A new family of regulators of G-protein-coupled receptors?.
        Curr Biol. 1996; 6: 211-212
        • Koelle M.R.
        • Horvitz H.R.
        EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins.
        Cell. 1996; 84: 115-125
        • Sakloth F.
        • Polizu C.
        • Bertherat F.
        • Zachariou V.
        Regulators of G protein signaling in analgesia and addiction.
        Mol Pharmacol. 2020; 98: 739-750
        • Ladds G.
        • Goddard A.
        • Hill C.
        • Thornton S.
        • Davey J.
        Differential effects of RGS proteins on Gαq and Gα11 activity.
        Cell Signal. 2007; 19: 103-113
        • Taymans J.M.
        • Leysen J.E.
        • Langlois X.
        Striatal gene expression of RGS2 and RGS4 is specifically mediated by dopamine D1 and D2 receptors: Clues for RGS2 and RGS4 functions.
        J Neurochem. 2003; 84: 1118-1127
        • Taymans J.M.
        • Kia H.K.
        • Claes R.
        • Cruz C.
        • Leysen J.
        • Langlois X.
        Dopamine receptor-mediated regulation of RGS2 and RGS4 mRNA differentially depends on ascending dopamine projections and time.
        Eur J Neurosci. 2004; 19: 2249-2260
        • Stanwood G.D.
        • Parlaman J.P.
        • Levitt P.
        Genetic or pharmacological inactivation of the dopamine D1 receptor differentially alters the expression of regulator of G-protein signalling (Rgs) transcripts.
        Eur J Neurosci. 2006; 24: 806-818
        • Saunders A.
        • Macosko E.Z.
        • Wysoker A.
        • Goldman M.
        • Krienen F.M.
        • de Rivera H.
        • et al.
        Molecular diversity and specializations among the cells of the adult mouse brain.
        Cell. 2018; 174: 1015-1030.e16
        • Campi K.L.
        • Greenberg G.D.
        • Kapoor A.
        • Ziegler T.E.
        • Trainor B.C.
        Sex differences in effects of dopamine D1 receptors on social withdrawal.
        Neuropharmacology. 2014; 77: 208-216
        • Sutton L.P.
        • Khalatyan N.
        • Savas J.N.
        • Martemyanov K.A.
        Striatal RGS7 regulates depression-related behaviors and stress-induced reinstatement of cocaine conditioned place preference.
        eNeuro. 2021; 8 (ENEURO.0365-20.2020)
        • Stratinaki M.
        • Varidaki A.
        • Mitsi V.
        • Ghose S.
        • Magida J.
        • Dias C.
        • et al.
        Regulator of G protein signaling 4 [corrected] is a crucial modulator of antidepressant drug action in depression and neuropathic pain models [published correction appears in Proc Natl Acad Sci U S A 2013; 110:11660].
        Proc Natl Acad Sci U S A. 2013; 110: 8254-8259
        • Paden W.
        • Barko K.
        • Puralewski R.
        • Cahill K.M.
        • Huo Z.
        • Shelton M.A.
        • et al.
        Sex differences in adult mood and in stress-induced transcriptional coherence across mesocorticolimbic circuitry.
        Transl Psychiatry. 2020; 10: 59
        • Scarpa J.R.
        • Fatma M.
        • Loh Y.H.E.
        • Traore S.R.
        • Stefan T.
        • Chen T.H.
        • et al.
        Shared transcriptional signatures in major depressive disorder and mouse chronic stress models.
        Biol Psychiatry. 2020; 88: 159-168
        • McCann K.E.
        • Sinkiewicz D.M.
        • Rosenhauer A.M.
        • Beach L.Q.
        • Huhman K.L.
        Transcriptomic analysis reveals sex-dependent expression patterns in the basolateral amygdala of dominant and subordinate animals after acute social conflict.
        Mol Neurobiol. 2019; 56: 3768-3779
        • Gasser P.J.
        Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior.
        Neurochem Int. 2019; 123: 46-49
        • McReynolds J.R.
        • Taylor A.
        • Vranjkovic O.
        • Ambrosius T.
        • Derricks O.
        • Nino B.
        • et al.
        Corticosterone potentiation of cocaine-induced reinstatement of conditioned place preference in mice is mediated by blockade of the organic cation transporter 3.
        Neuropsychopharmacology. 2017; 42: 757-765
        • Amphoux A.
        • Vialou V.
        • Drescher E.
        • Brüss M.
        • Mannoury La Cour C.
        • Rochat C.
        • et al.
        Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.
        Neuropharmacology. 2006; 50: 941-952
        • Gegenhuber B.
        • Wu M.V.
        • Bronstein R.
        • Tollkuhn J.
        Gene regulation by gonadal hormone receptors underlies brain sex differences.
        Nature. 2022; 606: 153-159