Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Inhibition of striatal indirect pathway during second postnatal week leads to long-lasting deficits in motivated behavior

Neuropsychopharmacology volume 50, pages 651–661 (2025)Cite this article

Subjects

Abstract

Schizophrenia is a neuropsychiatric disorder with postulated neurodevelopmental etiology. Genetic and imaging studies have shown enhanced dopamine and D2 receptor occupancy in the striatum of patients with schizophrenia. However, whether alterations in postnatal striatal dopamine can lead to long-lasting changes in brain function and behavior is still unclear. Here, we approximated striatal D2R hyperfunction in mice via designer receptor-mediated activation of inhibitory Gi-protein signaling during a defined postnatal time window. We found that Gi-mediated inhibition of the indirect pathway (IP) during postnatal days 8–15 led to long-lasting decreases in locomotor activity and motivated behavior measured in the adult animal. In vivo photometry further showed that the motivational deficit was associated with an attenuated adaptation of outcome-evoked dopamine levels to changes in effort requirements. These data establish a sensitive time window of D2R-regulated striatal development with long-lasting impacts on neuronal function and behavior.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Selective neonatal inhibition of striatal indirect pathway leads to reduced Open Field locomotion.
Fig. 2: Developmentally inhibited A2a-Cre/hM4Ddev mice display reduced willingness to work for food.
Fig. 3: Developmentally inhibited mice show effort-sensitive reduction of task-evoked NAc DA release across several days.
Fig. 4: Developmentally inhibited mice have less adaptable reward-aligned DA release in response to rapidly increasing effort requirement.
Fig. 5: Correlation analyses show loss of positive relationship between reward-aligned DA and time to complete ratios in J60-treated A2a/hM4Ddev mice.

Similar content being viewed by others

References

  1. Marder SR, Umbricht D. Negative symptoms in schizophrenia: newly emerging measurements, pathways, and treatments. Schizophr Res. 2023;258:71–7.

    PubMed  Google Scholar 

  2. Waltz JA, Gold JM. Motivational deficits in schizophrenia and the representation of expected value. Curr Top Behav Neurosci. 2016;27:375–410.

    PubMed  PubMed Central  Google Scholar 

  3. Strauss GP, Bartolomeo LA, Harvey PD. Avolition as the core negative symptom in schizophrenia: relevance to pharmacological treatment development. NPJ Schizophr. 2021;7:16.

    PubMed  PubMed Central  Google Scholar 

  4. Gold JM, Strauss GP, Waltz JA, Robinson BM, Brown JK, Frank MJ. Negative symptoms of schizophrenia are associated with abnormal effort-cost computations. Biol Psychiatry. 2013;74:130–6.

    PubMed  PubMed Central  Google Scholar 

  5. Bailey MR, Simpson EH, Balsam PD. Neural substrates underlying effort, time, and risk-based decision making in motivated behavior. Neurobiol Learn Mem. 2016;133:233–56.

    PubMed  PubMed Central  Google Scholar 

  6. Singh T, Poterba T, Curtis D, Akil H, Al Eissa M, Barchas JD, et al. Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature. 2022;604:509–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Trubetskoy V, Pardinas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604:502–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Canetta SE, Brown AS. Prenatal infection, maternal immune activation, and risk for schizophrenia. Transl Neurosci. 2012;3:320–27.

    PubMed  Google Scholar 

  9. Stilo SA, Murray RM. Non-genetic factors in schizophrenia. Curr Psychiatry Rep. 2019;21:100.

    PubMed  PubMed Central  Google Scholar 

  10. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192:481–3.

    CAS  PubMed  Google Scholar 

  11. Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188:1217–9.

    CAS  PubMed  Google Scholar 

  12. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS. et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA. 2000;97:8104–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A. Pathway-specific dopamine abnormalities in schizophrenia. Biol Psychiatry. 2017;81:31–42.

    CAS  PubMed  Google Scholar 

  14. McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci. 2019;42:205–20.

  15. Kegeles LS, Slifstein M, Xu X, Urban N, Thompson JL, Moadel T. et al. Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F] fallypride positron emission tomography. Biol Psychiatry. 2010;68:634–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66:13–20.

    PubMed  Google Scholar 

  17. Simpson EH, Kellendonk C, Kandel E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron. 2010;65:585–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    Google Scholar 

  19. Tepper JM, Sharpe NA, Koos TZ, Trent F. Postnatal development of the rat neostriatum: electrophysiological, light- and electron-microscopic studies. Dev Neurosci. 1998;20:125–45.

    CAS  PubMed  Google Scholar 

  20. Krajeski RN, Macey-Dare A, van Heusden F, Ebrahimjee F, Ellender TJ. Dynamic postnatal development of the cellular and circuit properties of striatal D1 and D2 spiny projection neurons. J Physiol. 2019;597:5265–93.

    CAS  PubMed  Google Scholar 

  21. Lieberman OJ, McGuirt AF, Mosharov EV, Pigulevskiy I, Hobson BD, Choi S, et al. Dopamine triggers the maturation of striatal spiny projection neuron excitability during a critical period. Neuron. 2018;99:540–54.e4.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kozorovitskiy Y, Saunders A, Johnson CA, Lowell BB, Sabatini BL. Recurrent network activity drives striatal synaptogenesis. Nature. 2012;485:646–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Peixoto RT, Wang W, Croney DM, Kozorovitskiy Y, Sabatini BL. Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice. Nat Neurosci. 2016;19:716–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Aberman JE, Salamone JD. Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement. Neuroscience. 1999;92:545–52.

    CAS  PubMed  Google Scholar 

  25. Nunes EJ, Randall PA, Podurgiel S, Correa M, Salamone JD. Nucleus accumbens neurotransmission and effort-related choice behavior in food motivation: effects of drugs acting on dopamine, adenosine, and muscarinic acetylcholine receptors. Neurosci Biobehav Rev. 2013;37:2015–25.

    CAS  PubMed  Google Scholar 

  26. Randall PA, Pardo M, Nunes EJ, Lopez Cruz L, Vemuri VK, Makriyannis A, et al. Dopaminergic modulation of effort-related choice behavior as assessed by a progressive ratio chow feeding choice task: pharmacological studies and the role of individual differences. PLoS ONE. 2012;7:e47934.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Mingote S, Font L, Farrar AM, Vontell R, Worden LT, Stopper CM, et al. Nucleus accumbens adenosine A2A receptors regulate exertion of effort by acting on the ventral striatopallidal pathway. J Neurosci. 2008;28:9037–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Carvalho Poyraz F, Holzner E, Bailey MR, Meszaros J, Kenney L, Kheirbek MA, et al. Decreasing striatopallidal pathway function enhances motivation by energizing the initiation of goal-directed action. J Neurosci. 2016;36:5988–6001.

    PubMed  PubMed Central  Google Scholar 

  29. Olivetti PR, Balsam PD, Simpson EH, Kellendonk C. Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders. Basic Clin Pharmacol Toxicol. 2019;126:47–55.

  30. Simpson EH, Gallo EF, Balsam PD, Javitch JA, Kellendonk C. How changes in dopamine D2 receptor levels alter striatal circuit function and motivation. Mol Psychiatry. 2022;27:436–44.

    CAS  PubMed  Google Scholar 

  31. Gallo EF, Meszaros J, Sherman JD, Chohan MO, Teboul E, Choi CS, et al. Accumbens dopamine D2 receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum. Nat Commun. 2018;9:1086.

    PubMed  PubMed Central  Google Scholar 

  32. Trifilieff P, Feng B, Urizar E, Winiger V, Ward RD, Taylor KM, et al. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol Psychiatry. 2013;18:1025–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.[see comment]. Neuron. 2006;49:603–15.

    CAS  PubMed  Google Scholar 

  34. Drew MR, Simpson EH, Kellendonk C, Herzberg WG, Lipatova O, Fairhurst S, et al. Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing. J Neurosci. 2007;27:7731–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Krabbe S, Duda J, Schiemann J, Poetschke C, Schneider G, Kandel ER, et al. Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area. Proc Natl Acad Sci USA. 2015;112:E1498–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Filla I, Bailey MR, Schipani E, Winiger V, Mezias C, Balsam PD, et al. Striatal dopamine D2 receptors regulate effort but not value-based decision making and alter the dopaminergic encoding of cost. Neuropsychopharmacology. 2018;43:2180–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Cazorla M, Shegda M, Ramesh B, Harrison NL, Kellendonk C. Striatal D2 receptors regulate dendritic morphology of medium spiny neurons via Kir2 channels. J Neurosci. 2012;32:2398–409.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Labouesse MA, Sartori AM, Weinmann O, Simpson EH, Kellendonk C, Weber-Stadlbauer U. Striatal dopamine 2 receptor upregulation during development predisposes to diet-induced obesity by reducing energy output in mice. Proc Natl Acad Sci USA. 2018;115:10493–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Roth BL. DREADDs for neuroscientists. Neuron. 2016;89:683–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Olivetti PR, Lacefield CO, Kellendonk C. A device for stereotaxic viral delivery into the brains of neonatal mice. BioTechniques. 2020;69:307–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Benoit LJ, Holt ES, Posani L, Fusi S, Harris AZ, Canetta S, et al. Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function. Nat Neurosci. 2022;25:714–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bonaventura J, Eldridge MAG, Hu F, Gomez JL, Sanchez-Soto M, Abramyan AM, et al. High-potency ligands for DREADD imaging and activation in rodents and monkeys. Nat Commun. 2019;10:4627.

    PubMed  PubMed Central  Google Scholar 

  43. Martyniuk KM, Torres-Herraez A, Lowes DC, Rubinstein M, Labouesse MA, Kellendonk C. Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels. eLife. 2022;11:e76111.

  44. Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa-Shah P, Rodriguez LA, et al. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science. 2017;357:503–07.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Koffarnus MN, Franck CT, Stein JS, Bickel WK. A modified exponential behavioral economic demand model to better describe consumption data. Exp Clin Psychopharmacol. 2015;23:504–12.

    PubMed  PubMed Central  Google Scholar 

  46. Duvarci S, Simpson EH, Schneider G, Kandel ER, Roeper J, Sigurdsson T. Impaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression. Nat Commun. 2018;9:2822.

    PubMed  PubMed Central  Google Scholar 

  47. Labouesse MA, Patriarchi T. A versatile GPCR toolkit to track in vivo neuromodulation: not a one-size-fits-all sensor. Neuropsychopharmacology. 2021;46:2043–47.

    PubMed  PubMed Central  Google Scholar 

  48. Killeen PR, Posadas-Sanchez D, Johansen EB, Thrailkill EA. Progressive ratio schedules of reinforcement. J Exp Psychol Anim Behav Process. 2009;35:35–50.

    PubMed  PubMed Central  Google Scholar 

  49. Covey DP, Hernandez E, Lujan MA, Cheer JF. Chronic augmentation of endocannabinoid levels persistently increases dopaminergic encoding of reward cost and motivation. The. J Neurosci. 2021;41:6946–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Walton ME, Bouret S. What Is the relationship between dopamine and effort? Trends Neurosci. 2019;42:79–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wanat MJ, Kuhnen CM, Phillips PE. Delays conferred by escalating costs modulate dopamine release to rewards but not their predictors. J Neurosci. 2010;30:12020–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Faget L, Oriol L, Lee WC, Zell V, Sargent C, Flores A, et al. Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types. Nat Commun. 2024;15:4233.

  53. Bresnahan MA, Brown AS, Schaefer CA, Begg MD, Wyatt RJ, Susser ES. Incidence and cumulative risk of treated schizophrenia in the prenatal determinants of schizophrenia study. Schizophr Bull. 2000;26:297–308.

    CAS  PubMed  Google Scholar 

  54. van der Werf M, Hanssen M, Kohler S, Verkaaik M, Verhey FR, Investigators R, et al. Systematic review and collaborative recalculation of 133,693 incident cases of schizophrenia. Psychol Med. 2014;44:9–16.

    PubMed  Google Scholar 

  55. Solmi M, Seitidis G, Mavridis D, Correll CU, Dragioti E, Guimond S, et al. Incidence, prevalence, and global burden of schizophrenia—data, with critical appraisal, from the global burden of disease (GBD) 2019. Mol Psychiatry. 2023;28:5319–27.

    PubMed  Google Scholar 

  56. Petty A, Howes O, Eyles D. Animal models of relevance to the schizophrenia prodrome. Biol Psychiatry Glob Open Sci. 2023;3:22–32.

    PubMed  Google Scholar 

  57. Karam CS, Ballon JS, Bivens NM, Freyberg Z, Girgis RR, Lizardi-Ortiz JE, et al. Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci. 2010;31:381–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Alfimova MV, Kondratyev NV, Tomyshev AS, Lebedeva IS, Lezheiko TV, Kaleda VG, et al. Effects of a GWAS-supported schizophrenia variant in the DRD2 locus on disease risk, anhedonia, and prefrontal cortical thickness. J Mol Neurosci. 2019;68:658–66.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Vivian Zhou for assistance with immunohistochemistry and Dr. Kyo Iigaya for discussions about economic modeling.

Funding

This work has been supported by K08MH127379 to PO and R01MH093672, R01MH124858 to CK and MH068073 to PB. Additional support also provided by the Leon Levy Foundation Neuroscience Fellowship to PO.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

    Pedro R. Olivetti, Arturo Torres-Herraez, Meghan E. Gallo, Ricardo Raudales, MaryElena Sumerau, Sinead Moyles, Peter D. Balsam & Christoph Kellendonk

  2. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA

    Pedro R. Olivetti, Arturo Torres-Herraez, Meghan E. Gallo, Ricardo Raudales & Christoph Kellendonk

  3. Barnard College Undergraduate Program, Barnard College 3009 Broadway, New York, NY, USA

    MaryElena Sumerau & Sinead Moyles

  4. Department of Neuroscience and Behavior, Barnard College 3009 Broadway, New York, NY, USA

    Peter D. Balsam

  5. Department of Molecular Pharmacology & Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

    Christoph Kellendonk

Authors
  1. Pedro R. Olivetti
    View author publications

    Search author on:PubMed Google Scholar

  2. Arturo Torres-Herraez
    View author publications

    Search author on:PubMed Google Scholar

  3. Meghan E. Gallo
    View author publications

    Search author on:PubMed Google Scholar

  4. Ricardo Raudales
    View author publications

    Search author on:PubMed Google Scholar

  5. MaryElena Sumerau
    View author publications

    Search author on:PubMed Google Scholar

  6. Sinead Moyles
    View author publications

    Search author on:PubMed Google Scholar

  7. Peter D. Balsam
    View author publications

    Search author on:PubMed Google Scholar

  8. Christoph Kellendonk
    View author publications

    Search author on:PubMed Google Scholar

Contributions

PO, PB, and CK conceived the experiments, PO, MS, and SM performed all experiments. AH developed MATLAB data analysis scripts. MG performed the economical modeling. RR developed protocol and analyzed striatal cell counting. PO and CK wrote the manuscript with inputs from PB.

Corresponding author

Correspondence to Christoph Kellendonk.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Olivetti, P.R., Torres-Herraez, A., Gallo, M.E. et al. Inhibition of striatal indirect pathway during second postnatal week leads to long-lasting deficits in motivated behavior. Neuropsychopharmacol. 50, 651–661 (2025). https://doi.org/10.1038/s41386-024-01997-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41386-024-01997-x

This article is cited by

Search

Advanced search

Quick links