Advertisement

Crystallin mu (Crym) in medial amygdala mediates the impact of social experience on cocaine seeking in males but not females.

      ABSTRACT:

      Background

      Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experience. Social isolation during adolescence alters anxiety- and reward-related behaviors in adult males, but less is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how meA responds to drugs of abuse.

      Methods

      We used adolescent social isolation coupled with RNA-sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward.

      Results

      We show that social isolation in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine if transcriptional mechanisms within meA are important for these behavioral effects, we manipulated Crystallin mu (Crym) expression, a sex-specific key driver gene identified through differential gene expression and co-expression network analyses, specifically in the meA. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent social isolation.

      Conclusions

      These results demonstrate that meA is essential for modulating the sex-specific effects of social experience on drug reward, and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity.

      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:

        • Stone A.L.
        • Becker L.G.
        • Huber A.M.
        • Catalano R.F.
        Review of risk and protective factors of substance use and problem use in emerging adulthood.
        Addict Behav. 2012; 37: 747-775
        • Wills T.A.
        • Vaccaro D.
        • McNamara G.
        The role of life events, family support, and competence in adolescent substance use: a test of vulnerability and protective factors.
        Am J Community Psychol. 1992; 20: 349-374
        • Power C.
        • Estaugh V.
        The role of family formation and dissolution in shaping drinking behaviour in early adulthood.
        Br J Addict. 1990; 85: 521-530
        • Wilsnack S.C.
        • Klassen A.D.
        • Schur B.E.
        • Wilsnack R.W.
        Predicting onset and chronicity of women's problem drinking: a five-year longitudinal analysis.
        Am J Public Health. 1991; 81: 305-318
        • Gutkind S.
        • Gorfinkel L.R.
        • Hasin D.S.
        Prospective effects of loneliness on frequency of alcohol and marijuana use.
        Addict Behav. 2022; 124107115
        • Fairbairn C.E.
        • Briley D.A.
        • Kang D.
        • Fraley R.C.
        • Hankin B.L.
        • Ariss T.
        A meta-analysis of longitudinal associations between substance use and interpersonal attachment security.
        Psychol Bull. 2018; 144: 532-555
        • Bozarth M.A.
        • Murray A.
        • Wise R.A.
        Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats.
        Pharmacol Biochem Behav. 1989; 33: 903-907
        • Walker D.M.
        • Cunningham A.M.
        • Gregory J.K.
        • Nestler E.J.
        Long-Term Behavioral Effects of Post-weaning Social Isolation in Males and Females.
        Front Behav Neurosci. 2019; 13: 66
        • Bendersky C.J.
        • Milian A.A.
        • Andrus M.D.
        • De La Torre U.
        • Walker D.M.
        Long-Term Impacts of Post-weaning Social Isolation on Nucleus Accumbens Function.
        Front Psychiatry. 2021; 12745406
        • Sisk C.L.
        Hormone-dependent adolescent organization of socio-sexual behaviors in mammals.
        Curr Opin Neurobiol. 2016; 38: 63-68
        • Spear L.P.
        The adolescent brain and age-related behavioral manifestations.
        Neurosci Biobehav Rev. 2000; 24: 417-463
        • Larson RW, Richards, Maryse H.,Moneta, Giovanni,Holmbeck, Grayson,Duckett, Elena
        Changes in adolescents' daily interactions with their families from ages 10 to 18: Disengagement and transformation.
        Developmental Psychology. 1996; 32: 744-754
        • Gopnik A.
        • O'Grady S.
        • Lucas C.G.
        • Griffiths T.L.
        • Wente A.
        • Bridgers S.
        • et al.
        Changes in cognitive flexibility and hypothesis search across human life history from childhood to adolescence to adulthood.
        Proc Natl Acad Sci U S A. 2017;
        • Loades M.E.
        • Chatburn E.
        • Higson-Sweeney N.
        • Reynolds S.
        • Shafran R.
        • Brigden A.
        • et al.
        Rapid Systematic Review: The Impact of Social Isolation and Loneliness on the Mental Health of Children and Adolescents in the Context of COVID-19.
        J Am Acad Child Adolesc Psychiatry. 2020; 59 (1218-1239 e1213)
        • Mates D.
        • Allison K.R.
        Sources of stress and coping responses of high school students.
        Adolescence. 1992; 27: 461-474
        • Thapar A.
        • Collishaw S.
        • Pine D.S.
        • Thapar A.K.
        Depression in adolescence.
        Lancet. 2012; 379: 1056-1067
        • Wagner E.F.
        • Myers M.G.
        • McIninch J.L.
        Stress-coping and temptation-coping as predictors of adolescent substance use.
        Addict Behav. 1999; 24: 769-779
        • Wills T.A.
        Stress and coping in early adolescence: relationships to substance use in urban school samples.
        Health Psychol. 1986; 5: 503-529
        • Schulz K.M.
        • Sisk C.L.
        The organizing actions of adolescent gonadal steroid hormones on brain and behavioral development.
        Neurosci Biobehav Rev. 2016; 70: 148-158
        • Hankin B.L.
        • Abramson L.Y.
        • Moffitt T.E.
        • Silva P.A.
        • McGee R.
        • Angell K.E.
        Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study.
        J Abnorm Psychol. 1998; 107: 128-140
        • Hankin B.L.
        • Young J.F.
        • Abela J.R.
        • Smolen A.
        • Jenness J.L.
        • Gulley L.D.
        • et al.
        Depression from childhood into late adolescence: Influence of gender, development, genetic susceptibility, and peer stress.
        J Abnorm Psychol. 2015; 124: 803-816
        • Patterson T.L.
        • Smith L.W.
        • Smith T.L.
        • Yager J.
        • Grant I.
        Symptoms of illness in late adulthood are related to childhood social deprivation and misfortune in men but not in women.
        J Behav Med. 1992; 15: 113-125
        • Begni V.
        • Zampar S.
        • Longo L.
        • Riva M.A.
        Sex Differences in the Enduring Effects of Social Deprivation during Adolescence in Rats: Implications for Psychiatric Disorders.
        Neuroscience. 2020; 437: 11-22
        • Fosnocht A.Q.
        • Lucerne K.E.
        • Ellis A.S.
        • Olimpo N.A.
        • Briand L.A.
        Adolescent social isolation increases cocaine seeking in male and female mice.
        Behav Brain Res. 2019; 359: 589-596
        • Bergan J.F.
        • Ben-Shaul Y.
        • Dulac C.
        Sex-specific processing of social cues in the medial amygdala.
        Elife. 2014; 3e02743
        • Li Y.
        • Mathis A.
        • Grewe B.F.
        • Osterhout J.A.
        • Ahanonu B.
        • Schnitzer M.J.
        • et al.
        Neuronal Representation of Social Information in the Medial Amygdala of Awake Behaving Mice.
        Cell. 2017; 171 (1176-1190 e1117)
        • Miller S.M.
        • Marcotulli D.
        • Shen A.
        • Zweifel L.S.
        Divergent medial amygdala projections regulate approach-avoidance conflict behavior.
        Nat Neurosci. 2019; 22: 565-575
        • Unger E.K.
        • Burke Jr., K.J.
        • Yang C.F.
        • Bender K.J.
        • Fuller P.M.
        • Shah N.M.
        Medial amygdalar aromatase neurons regulate aggression in both sexes.
        Cell Rep. 2015; 10: 453-462
        • De Lorme K.C.
        • Schulz K.M.
        • Salas-Ramirez K.Y.
        • Sisk C.L.
        Pubertal testosterone organizes regional volume and neuronal number within the medial amygdala of adult male Syrian hamsters.
        Brain Res. 2012; 1460: 33-40
        • Schulz K.M.
        • Molenda-Figueira H.A.
        • Sisk C.L.
        Back to the future: The organizational-activational hypothesis adapted to puberty and adolescence.
        Horm Behav. 2009; 55: 597-604
        • Cooke B.M.
        • Chowanadisai W.
        • Breedlove S.M.
        Post-weaning social isolation of male rats reduces the volume of the medial amygdala and leads to deficits in adult sexual behavior.
        Behav Brain Res. 2000; 117: 107-113
        • Hodges T.E.
        • Louth E.L.
        • Bailey C.D.C.
        • McCormick C.M.
        Adolescent social instability stress alters markers of synaptic plasticity and dendritic structure in the medial amygdala and lateral septum in male rats.
        Brain Struct Funct. 2019; 224: 643-659
        • Fekete E.M.
        • Zhao Y.
        • Li C.
        • Sabino V.
        • Vale W.W.
        • Zorrilla E.P.
        Social defeat stress activates medial amygdala cells that express type 2 corticotropin-releasing factor receptor mRNA.
        Neuroscience. 2009; 162: 5-13
        • Jordan C.J.
        • Andersen S.L.
        Sensitive periods of substance abuse: Early risk for the transition to dependence.
        Dev Cogn Neurosci. 2017; 25: 29-44
        • Archer J.
        Rodent sex differences in emotional and related behavior.
        Behav Biol. 1975; 14: 451-479
        • Goel N.
        • Bale T.L.
        Examining the intersection of sex and stress in modelling neuropsychiatric disorders.
        J Neuroendocrinol. 2009; 21: 415-420
        • Voikar V.
        • Koks S.
        • Vasar E.
        • Rauvala H.
        Strain and gender differences in the behavior of mouse lines commonly used in transgenic studies.
        Physiol Behav. 2001; 72: 271-281
        • Hines M.
        • Allen L.S.
        • Gorski R.A.
        Sex differences in subregions of the medial nucleus of the amygdala and the bed nucleus of the stria terminalis of the rat.
        Brain Res. 1992; 579: 321-326
        • Chen P.B.
        • Hu R.K.
        • Wu Y.E.
        • Pan L.
        • Huang S.
        • Micevych P.E.
        • et al.
        Sexually Dimorphic Control of Parenting Behavior by the Medial Amygdala.
        Cell. 2019; 176 (1206-1221 e1218)
        • Knapska E.
        • Radwanska K.
        • Werka T.
        • Kaczmarek L.
        Functional internal complexity of amygdala: focus on gene activity mapping after behavioral training and drugs of abuse.
        Physiol Rev. 2007; 87: 1113-1173
        • Rudzinskas S.A.
        • Williams K.M.
        • Mong J.A.
        • Holder M.K.
        Sex, Drugs, and the Medial Amygdala: A Model of Enhanced Sexual Motivation in the Female Rat.
        Front Behav Neurosci. 2019; 13: 203
        • Walker D.M.
        • Zhou X.
        • Cunningham A.M.
        • Lipschultz A.P.
        • Ramakrishnan A.
        • Cates H.M.
        • et al.
        Sex-Specific Transcriptional Changes in Response to Adolescent Social Stress in the Brain’s Reward Circuitry.
        Biological Psychiatry. 2021;
        • Bagot R.C.
        • Cates H.M.
        • Purushothaman I.
        • Lorsch Z.S.
        • Walker D.M.
        • Wang J.
        • et al.
        Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.
        Neuron. 2016; 90: 969-983
        • Issler O.
        • van der Zee Y.Y.
        • Ramakrishnan A.
        • Wang J.
        • Tan C.
        • Loh Y.E.
        • et al.
        Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression.
        Neuron. 2020; 106 (912-926 e915)
        • Labonte B.
        • Engmann O.
        • Purushothaman I.
        • Menard C.
        • Wang J.
        • Tan C.
        • et al.
        Sex-specific transcriptional signatures in human depression.
        Nat Med. 2017; 23: 1102-1111
        • Patisaul H.B.
        • Sullivan A.W.
        • Radford M.E.
        • Walker D.M.
        • Adewale H.B.
        • Winnik B.
        • et al.
        Anxiogenic effects of developmental bisphenol A exposure are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy.
        PLoS One. 2012; 7e43890
        • Savell K.E.
        • Tuscher J.J.
        • Zipperly M.E.
        • Duke C.G.
        • Phillips 3rd, R.A.
        • Bauman A.J.
        • et al.
        A dopamine-induced gene expression signature regulates neuronal function and cocaine response.
        Sci Adv. 2020; 6eaba4221
        • 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
        • Walker D.M.
        • Cates H.M.
        • Loh Y.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;
        • Song W.M.
        • Zhang B.
        Multiscale Embedded Gene Co-expression Network Analysis.
        PLoS Comput Biol. 2015; 11e1004574
        • Ohkubo Y.
        • Sekido T.
        • Nishio S.I.
        • Sekido K.
        • Kitahara J.
        • Suzuki S.
        • et al.
        Loss of mu-crystallin causes PPARgamma activation and obesity in high-fat diet-fed mice.
        Biochem Biophys Res Commun. 2019; 508: 914-920
        • Vie M.P.
        • Evrard C.
        • Osty J.
        • Breton-Gilet A.
        • Blanchet P.
        • Pomerance M.
        • et al.
        Purification, molecular cloning, and functional expression of the human nicodinamide-adenine dinucleotide phosphate-regulated thyroid hormone-binding protein.
        Mol Endocrinol. 1997; 11: 1728-1736
        • Hallen A.
        • Cooper A.J.
        • Jamie J.F.
        • Haynes P.A.
        • Willows R.D.
        Mammalian forebrain ketimine reductase identified as mu-crystallin; potential regulation by thyroid hormones.
        J Neurochem. 2011; 118: 379-387
        • Francelle L.
        • Galvan L.
        • Gaillard M.C.
        • Guillermier M.
        • Houitte D.
        • Bonvento G.
        • et al.
        Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease.
        Hum Mol Genet. 2015; 24: 1563-1573
        • Avey D.
        • Sankararaman S.
        • Yim A.K.Y.
        • Barve R.
        • Milbrandt J.
        • Mitra R.D.
        Single-Cell RNA-Seq Uncovers a Robust Transcriptional Response to Morphine by Glia.
        Cell Rep. 2018; 24 (3619-3629 e3614)
        • Argue K.J.
        • VanRyzin J.W.
        • Falvo D.J.
        • Whitaker A.R.
        • Yu S.J.
        • McCarthy M.M.
        Activation of Both CB1 and CB2 Endocannabinoid Receptors Is Critical for Masculinization of the Developing Medial Amygdala and Juvenile Social Play Behavior.
        eNeuro. 2017; 4
        • Krebs-Kraft D.L.
        • Hill M.N.
        • Hillard C.J.
        • McCarthy M.M.
        Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior.
        Proc Natl Acad Sci U S A. 2010; 107: 20535-20540
        • Zehr J.L.
        • Todd B.J.
        • Schulz K.M.
        • McCarthy M.M.
        • Sisk C.L.
        Dendritic pruning of the medial amygdala during pubertal development of the male Syrian hamster.
        J Neurobiol. 2006; 66: 578-590
        • Barko K.
        • Paden W.
        • Cahill K.M.
        • Seney M.L.
        • Logan R.W.
        Sex-Specific Effects of Stress on Mood-Related Gene Expression.
        Mol Neuropsychiatry. 2019; 5: 162-175
        • 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
        • Becker J.B.
        • Koob G.F.
        Sex Differences in Animal Models: Focus on Addiction.
        Pharmacol Rev. 2016; 68: 242-263
        • Lazcano I.
        • Hernandez-Puga G.
        • Robles J.P.
        • Orozco A.
        Alternative ligands for thyroid hormone receptors.
        Mol Cell Endocrinol. 2019; 493110448
        • Batista G.
        • Hensch T.K.
        Critical Period Regulation by Thyroid Hormones: Potential Mechanisms and Sex-Specific Aspects.
        Front Mol Neurosci. 2019; 12: 77
        • Cates H.M.
        • Lardner C.K.
        • Bagot R.C.
        • Neve R.L.
        • Nestler E.J.
        Fosb Induction in Nucleus Accumbens by Cocaine Is Regulated by E2F3a.
        eNeuro. 2019; (6)