Advertisement

Behavioral Engagement With Playable Objects Resolves Stress-Induced Adaptive Changes by Reshaping the Reward System

      Abstract

      Background

      The reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood.

      Methods

      Mice subjected to chronic restraint stress show long-lasting depressive-like behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools, are used to investigate the neural mechanisms of antidepressive effects of playable objects.

      Results

      Here, we show that repeated restraint induces dopamine surges into the nucleus accumbens–lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of dopamine D1 receptors over the action of D2 receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D1 receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress–induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces antidepressive effects by reshaping the ventral tegmental area–to–NAc-lSh and NAc-lSh–to–ventral pallidum circuits.

      Conclusions

      These results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.

      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

        • de Wit S.
        • Dickinson A.
        Associative theories of goal-directed behaviour: A case for animal-human translational models.
        Psychol Res. 2009; 73: 463-476
        • Dolan R.J.
        • Dayan P.
        Goals and habits in the brain.
        Neuron. 2013; 80: 312-325
        • Simpson E.H.
        • Balsam P.D.
        The behavioral neuroscience of motivation: An overview of concepts, measures, and translational applications.
        Curr Top Behav Neurosci. 2016; 27: 1-12
        • Fiorillo C.D.
        • Tobler P.N.
        • Schultz W.
        Discrete coding of reward probability and uncertainty by dopamine neurons.
        Science. 2003; 299: 1898-1902
        • Tobler P.N.
        • Fiorillo C.D.
        • Schultz W.
        Adaptive coding of reward value by dopamine neurons.
        Science. 2005; 307: 1642-1645
        • Rangel A.
        • Camerer C.
        • Montague P.R.
        A framework for studying the neurobiology of value-based decision making.
        Nat Rev Neurosci. 2008; 9: 545-556
        • Schultz W.
        Dopamine reward prediction-error signalling: A two-component response.
        Nat Rev Neurosci. 2016; 17: 183-195
        • Hogarth L.
        • Attwood A.S.
        • Bate H.A.
        • Munafò M.R.
        Acute alcohol impairs human goal-directed action.
        Biol Psychol. 2012; 90: 154-160
        • Gillan C.M.
        • Kosinski M.
        • Whelan R.
        • Phelps E.A.
        • Daw N.D.
        Characterizing a psychiatric symptom dimension related to deficits in goal-directed control.
        Elife. 2016; 5e11305
        • Ersche K.D.
        • Gillan C.M.
        • Jones P.S.
        • Williams G.B.
        • Ward L.H.E.
        • Luijten M.
        • et al.
        Carrots and sticks fail to change behavior in cocaine addiction.
        Science. 2016; 352: 1468-1471
        • Hogarth L.
        Addiction is driven by excessive goal-directed drug choice under negative affect: Translational critique of habit and compulsion theory.
        Neuropsychopharmacology. 2020; 45: 720-735
        • Gillan C.M.
        • Apergis-Schoute A.M.
        • Morein-Zamir S.
        • Urcelay G.P.
        • Sule A.
        • Fineberg N.A.
        • et al.
        Functional neuroimaging of avoidance habits in obsessive-compulsive disorder.
        Am J Psychiatry. 2015; 172: 284-293
        • Simmler L.D.
        • Ozawa T.
        Neural circuits in goal-directed and habitual behavior: Implications for circuit dysfunction in obsessive-compulsive disorder.
        Neurochem Int. 2019; 129: 104464
        • Morris R.W.
        • Quail S.
        • Griffiths K.R.
        • Green M.J.
        • Balleine B.W.
        Corticostriatal control of goal-directed action is impaired in schizophrenia.
        Biol Psychiatry. 2015; 77: 187-195
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        5th ed. American Psychiatric Publishing, Washington, DC2013
        • Griffiths K.R.
        • Morris R.W.
        • Balleine B.W.
        Translational studies of goal-directed action as a framework for classifying deficits across psychiatric disorders.
        Front Syst Neurosci. 2014; 8: 101
        • Dickinson A.
        • Balleine B.
        Motivational control of goal-directed action.
        Anim Learn Behav. 1994; 22: 1-18
        • Balleine B.W.
        • O’Doherty J.P.
        Human and rodent homologies in action control: Corticostriatal determinants of goal-directed and habitual action.
        Neuropsychopharmacology. 2010; 35: 48-69
        • Kelley A.E.
        • Berridge K.C.
        The neuroscience of natural rewards: Relevance to addictive drugs.
        J Neurosci. 2002; 22: 3306-3311
        • Milgram N.W.
        • Siwak-Tapp C.T.
        • Araujo J.
        • Head E.
        Neuroprotective effects of cognitive enrichment.
        Ageing Res Rev. 2006; 5: 354-369
        • Nithianantharajah J.
        • Hannan A.J.
        Enriched environments, experience-dependent plasticity and disorders of the nervous system.
        Nat Rev Neurosci. 2006; 7: 697-709
        • Bromberg-Martin E.S.
        • Matsumoto M.
        • Hikosaka O.
        Dopamine in motivational control: Rewarding, aversive, and alerting.
        Neuron. 2010; 68: 815-834
        • Berridge K.C.
        Evolving concepts of emotion and motivation.
        Front Psychol. 2018; 9: 1647
        • Burghardt G.M.
        The Genesis of Animal Play: Testing the Limits.
        MIT Press, Cambridge, MA2005
        • Vanderschuren L.J.M.J.
        How the brain makes play fun.
        Am J Play. 2010; 2: 315-337
        • Held S.D.E.
        • Špinka M.
        Animal play and animal welfare.
        Anim Behav. 2011; 81: 891-899
        • Riede F.
        • Johannsen N.N.
        • Högberg A.
        • Nowell A.
        • Lombard M.
        The role of play objects and object play in human cognitive evolution and innovation.
        Evol Anthropol. 2018; 27: 46-59
        • Rubin K.H.
        • Howe N.
        Toys and play behaviors: An overview.
        Top Early Child Spec Educ. 1985; 5: 1-9
        • Garvey C.
        Play with objects.
        in: Bruner J. Cole M. Karmiloff-Smith A. Play. Harvard University Press, Cambridge1990: 41-58
        • Burghardt G.M.
        Defining and recognizing play.
        in: Nathan P. Pellegrini A.D. The Oxford Handbook of the Development of Play. Oxford University Press, Oxford2011: 9-18
        • Yogman M.
        • Garner A.
        • Hutchinson J.
        • Hirsh-Pasek K.
        • Golinkoff R.M.
        • COMMITTEE ON PSYCHOSOCIAL ASPECTS OF CHILD AND FAMILY HEALTH, COUNCIL ON COMMUNICATIONS AND MEDIA
        The power of play: A pediatric role in enhancing development in young children.
        Pediatrics. 2018; 142e20182058
        • Golden L.
        • Pagala M.
        • Sukhavasi S.
        • Nagpal D.
        • Ahmad A.
        • Mahanta A.
        Giving toys to children reduces their anxiety about receiving premedication for surgery.
        Anesth Analg. 2006; 102: 1070-1072
        • Ray D.C.
        • Blanco P.J.
        • Sullivan J.M.
        • Holliman R.
        An exploratory study of child-centered play therapy with aggressive children.
        Int J Play Ther. 2009; 18: 162-175
        • Ray D.C.
        • Lee K.R.
        • Meany-Walen K.K.
        • Carlson S.E.
        • Carnes-Holt K.L.
        • Ware J.N.
        Use of toys in child-centered play therapy.
        Int J Play Ther. 2013; 22: 43-57
        • Ghabeli F.
        • Moheb N.
        • Hosseini Nasab S.D.
        Effect of toys and preoperative visit on reducing children’s anxiety and their parents before surgery and satisfaction with the treatment process.
        J Caring Sci. 2014; 3: 21-28
        • Nabors L.
        • Kichler J.
        Play therapy with children experiencing medical illness and trauma.
        in: O’Connor K.J. Schaefer C.E. Braverman L.D. Handbook of Play Therapy. 2nd ed. Wiley, New York2015: 437-454
        • Salter K.
        • Beamish W.
        • Davies M.
        The effects of child-centered play therapy (CCPT) on the social and emotional growth of young Australian children with autism.
        Int J Play Ther. 2016; 25: 78-90
        • Hall S.L.
        Object play in adult animals.
        in: Bekoff M. Byers J.A. Animal Play: Evolutionary, Comparative, and Ecological Perspectives. Cambridge University Press, Cambridge, UK1998: 45-60
        • Schultz W.
        Dopamine signals for reward value and risk: Basic and recent data.
        Behav Brain Funct. 2010; 6: 24
        • Hamid A.A.
        • Pettibone J.R.
        • Mabrouk O.S.
        • Hetrick V.L.
        • Schmidt R.
        • Vander Weele C.M.
        • et al.
        Mesolimbic dopamine signals the value of work.
        Nat Neurosci. 2016; 19: 117-126
        • Missale C.
        • Nash S.R.
        • Robinson S.W.
        • Jaber M.
        • Caron M.G.
        Dopamine receptors: From structure to function.
        Physiol Rev. 1998; 78: 189-225
        • Jacob S.N.
        • Nienborg H.
        Monoaminergic neuromodulation of sensory processing.
        Front Neural Circuits. 2018; 12: 51
        • Weiner D.M.
        • Levey A.I.
        • Sunahara R.K.
        • Niznik H.B.
        • O’Dowd B.F.
        • Seeman P.
        • Brann M.R.
        D1 and D2 dopamine receptor mRNA in rat brain.
        Proc Natl Acad Sci U S A. 1991; 88: 1859-1863
        • Levey A.I.
        • Hersch S.M.
        • Rye D.B.
        • Sunahara R.K.
        • Niznik H.B.
        • Kitt C.A.
        • et al.
        Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies.
        Proc Natl Acad Sci U S A. 1993; 90: 8861-8865
        • Hurd Y.L.
        • Suzuki M.
        • Sedvall G.C.
        D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain.
        J Chem Neuroanat. 2001; 22: 127-137
        • 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
        • Lobo M.K.
        • Zaman S.
        • Damez-Werno D.M.
        • Koo J.W.
        • Bagot R.C.
        • DiNieri J.A.
        • et al.
        ΔFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli.
        J Neurosci. 2013; 33: 18381-18395
        • 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
        • Lee E.H.
        • Han P.L.
        Reciprocal interactions across and within multiple levels of monoamine and cortico-limbic systems in stress-induced depression: A systematic review.
        Neurosci Biobehav Rev. 2019; 101: 13-31
        • 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
        • Heinsbroek J.A.
        • Neuhofer D.N.
        • Griffin 3rd, W.C.
        • Siegel G.S.
        • Bobadilla A.C.
        • Kupchik Y.M.
        • Kalivas P.W.
        Loss of plasticity in the D2-accumbens pallidal pathway promotes cocaine seeking.
        J Neurosci. 2017; 37: 757-767
        • 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
        • de Kloet E.R.
        • Joëls M.
        • Holsboer F.
        Stress and the brain: From adaptation to disease.
        Nat Rev Neurosci. 2005; 6: 463-475
        • 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
        • Dunlop B.W.
        • Nemeroff C.B.
        The role of dopamine in the pathophysiology of depression.
        Arch Gen Psychiatry. 2007; 64: 327-337
        • Belujon P.
        • Grace A.A.
        Dopamine system dysregulation in major depressive disorders.
        Int J Neuropsychopharmacol. 2017; 20: 1036-1046
        • Hill M.N.
        • Hellemans K.G.C.
        • Verma P.
        • Gorzalka B.B.
        • Weinberg J.
        Neurobiology of chronic mild stress: Parallels to major depression.
        Neurosci Biobehav Rev. 2012; 36: 2085-2117
        • Zhong P.
        • Vickstrom C.R.
        • Liu X.
        • Hu Y.
        • Yu L.
        • Yu H.G.
        • Liu Q.S.
        HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress.
        Elife. 2018; 7e32420
        • Cabib S.
        • Puglisi-Allegra S.
        Stress, depression and the mesolimbic dopamine system.
        Psychopharmacology (Berl). 1996; 128: 331-342
        • Tye K.M.
        • Mirzabekov J.J.
        • Warden M.R.
        • Ferenczi E.A.
        • Tsai H.C.
        • Finkelstein J.
        • et al.
        Dopamine neurons modulate neural encoding and expression of depression-related behaviour.
        Nature. 2013; 493: 537-541
        • 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
        • Cao J.L.
        • Covington 3rd, H.E.
        • Friedman A.K.
        • Wilkinson M.B.
        • Walsh J.J.
        • Cooper D.C.
        • et al.
        Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action.
        J Neurosci. 2010; 30: 16453-16458
        • Kim K.S.
        • Kwon H.J.
        • Baek I.S.
        • Han P.L.
        Repeated short-term (2h×14d) emotional stress induces lasting depression-like behavior in mice.
        Exp Neurobiol. 2012; 21: 16-22
        • Cabib S.
        • Puglisi-Allegra S.
        The mesoaccumbens dopamine in coping with stress.
        Neurosci Biobehav Rev. 2012; 36: 79-89
        • Plaisier S.B.
        • Taschereau R.
        • Wong J.A.
        • Graeber T.G.
        Rank-rank hypergeometric overlap: Identification of statistically significant overlap between gene-expression signatures.
        Nucleic Acids Res. 2010; 38: e169
        • 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
        • Dobbs L.K.
        • Kaplan A.R.
        • Bock R.
        • Phamluong K.
        • Shin J.H.
        • Bocarsly M.E.
        • et al.
        D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors.
        Neuropsychopharmacology. 2019; 44: 805-816
        • Lee Y.
        • Kim H.
        • Kim J.E.
        • Park J.Y.
        • Choi J.
        • Lee J.E.
        • et al.
        Excessive D1 dopamine receptor activation in the dorsal striatum promotes autistic-like behaviors.
        Mol Neurobiol. 2018; 55: 5658-5671
        • Salgado S.
        • Kaplitt M.G.
        The nucleus accumbens: A comprehensive review.
        Stereotact Funct Neurosurg. 2015; 93: 75-93
        • Francis T.C.
        • Lobo M.K.
        Emerging role for nucleus accumbens medium spiny neuron subtypes in depression.
        Biol Psychiatry. 2017; 81: 645-653
        • Rácz B.
        • Tamás A.
        • Kiss P.
        • Tóth G.
        • Gasz B.
        • Borsiczky B.
        • et al.
        Involvement of ERK and CREB signaling pathways in the protective effect of PACAP in monosodium glutamate-induced retinal lesion.
        Ann N Y Acad Sci. 2006; 1070: 507-511
        • Hebb D.O.
        The effects of early experience on problem solving at maturity.
        Am Psychol. 1947; 2: 306-307
        • Hebb D.O.
        The Organization of Behavior: A Neuropsychological Theory.
        Wiley, New York1949
        • van Praag H.
        • Kempermann G.
        • Gage F.H.
        Neural consequences of environmental enrichment.
        Nat Rev Neurosci. 2000; 1: 191-198
        • Zosh J.M.
        • Hirsh-Pasek K.
        • Hopkins E.J.
        • Jensen H.
        • Liu C.
        • Neale D.
        • et al.
        Accessing the inaccessible: Redefining play as a spectrum.
        Front Psychol. 2018; 9: 1124
        • Gray P.
        Play as a foundation for hunter-gatherer social existence.
        Am J Play. 2009; 1: 476-522
        • Brown S.
        • Eberle M.
        A closer look at play.
        in: Marks-Tarlow T. Siegel D.J. Solomon M. Play and Creativity in Psychotherapy. WW Norton & Company, New York2017: 21-38
        • Commons K.G.
        • Cholanians A.B.
        • Babb J.A.
        • Ehlinger D.G.
        The rodent forced swim test measures stress-coping strategy, not depression-like behavior.
        ACS Chem Neurosci. 2017; 8: 955-960
        • Molendijk M.L.
        • de Kloet E.R.
        Coping with the forced swim stressor: Current state-of-the-art.
        Behav Brain Res. 2019; 364: 1-10
        • Chang C.H.
        • Grace A.A.
        Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats.
        Biol Psychiatry. 2014; 76: 223-230
        • 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
        • Friedman A.K.
        • Walsh J.J.
        • Juarez B.
        • Ku S.M.
        • Chaudhury D.
        • Wang J.
        • et al.
        Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience.
        Science. 2014; 344: 313-319

      Linked Article