Operant self-stimulation of thalamic terminals in the dorsomedial striatum is constrained by metabotropic glutamate receptor 2

Abstract

Dorsal striatal manipulations including stimulation of dopamine release and activation of medium spiny neurons (MSNs) are sufficient to drive reinforcement-based learning. Glutamatergic innervation of the striatum by the cortex and thalamus is a critical determinant of MSN activity and local regulation of dopamine release. However, the relationship between striatal glutamatergic afferents and behavioral reinforcement is not well understood. We evaluated the reinforcing properties of optogenetic stimulation of thalamostriatal terminals, which are associated with vesicular glutamate transporter 2 (Vglut2) expression, in the dorsomedial striatum (DMS), a region implicated in goal-directed behaviors. In mice expressing channelrhodopsin-2 (ChR2) under control of the Vglut2 promoter, optical stimulation of the DMS reinforced operant lever-pressing behavior. Mice also acquired operant self-stimulation of thalamostriatal terminals when ChR2 expression was virally targeted to the intralaminar thalamus. Stimulation trains that supported operant responding evoked dopamine release in the DMS and excitatory postsynaptic currents in DMS MSNs. Our previous work demonstrated that the presynaptic G protein-coupled receptor metabotropic glutamate receptor 2 (mGlu2) robustly inhibits glutamate and dopamine release induced by activation of thalamostriatal afferents. Thus, we examined the regulation of thalamostriatal self-stimulation by mGlu2. Administration of an mGlu2/3 agonist or an mGlu2-selective positive allosteric modulator reduced self-stimulation. Conversely, blockade of these receptors increased thalamostriatal self-stimulation, suggesting that endogenous activation of these receptors negatively modulates the reinforcing properties of thalamostriatal activity. These findings demonstrate that stimulation of thalamic terminals in the DMS is sufficient to reinforce a self-initiated action, and that thalamostriatal reinforcement is constrained by mGlu2 activation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Optical stimulation of Vglut2+ terminals in the DMS reinforces operant lever pressing.
Fig. 2: mGlu2/3 activation reduces operant responding for optical stimulation of Vglut2+ terminals in the DMS.
Fig. 3: The mGlu2-selective positive allosteric modulator BINA reduces operant responding for optical stimulation of Vglut2+ terminals in the DMS.
Fig. 4: Optical stimulation of thalamic terminals in the DMS reinforces operant lever pressing.
Fig. 5: mGlu2/3 activity constrains operant responding for thalamostriatal stimulation.

References

  1. 1.

    Graybiel AM, Grafton ST. The striatum: where skills and habits meet. Cold Spring Harb Perspect Biol. 2015;7:a021691.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Phillips AG, Carter DA, Fibiger HC. Dopaminergic substrates of intracranial self-stimulation in the caudate-putamen. Brain Res. 1976;104:221–32.

    CAS  PubMed  Google Scholar 

  3. 3.

    Prado-Alcala R, Wise RA. Brain stimulation reward and dopamine terminal fields. I. Caudate-putamen, nucleus accumbens and amygdala. Brain Res. 1984;297:265–73.

    CAS  PubMed  Google Scholar 

  4. 4.

    Rossi MA, Sukharnikova T, Hayrapetyan VY, Yang L, Yin HH. Operant self-stimulation of dopamine neurons in the substantia nigra. PLoS ONE. 2013;8:e65799

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Ilango A, Kesner AJ, Keller KL, Stuber GD, Bonci A, Ikemoto S. Similar roles of substantia nigra and ventral tegmental dopamine neurons in reward and aversion. J Neurosci. 2014;34:817–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Kravitz AV, Tye LD, Kreitzer AC. Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat Neurosci. 2012;15:816–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Vicente AM, Galvao-Ferreira P, Tecuapetla F, Costa RM. Direct and indirect dorsolateral striatum pathways reinforce different action strategies. Curr Biol. 2016;26:R267–269.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Lalive AL, Lien AD, Roseberry TK, Donahue CH, Kreitzer AC. Motor thalamus supports striatum-driven reinforcement. Elife. 2018;7:e34032

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Smith Y, Galvan A, Ellender TJ, Doig N, Villalba RM, Huerta-Ocampo I, et al. The thalamostriatal system in normal and diseased states. Front Syst Neurosci. 2014;8:5.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hunnicutt BJ, Jongbloets BC, Birdsong WT, Gertz KJ, Zhong H, Mao T. A comprehensive excitatory input map of the striatum reveals novel functional organization. Elife. 2016;5:e19103

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Hintiryan H, Foster NN, Bowman I, Bay M, Song MY, Gou L. et al. The mouse cortico-striatal projectome. Nat Neurosci. 2016;19:1100–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Balleine BW, O’Doherty JP. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology 2010;35:48–69.

    PubMed  Google Scholar 

  13. 13.

    Bradfield LA, Hart G, Balleine BW. The role of the anterior, mediodorsal, and parafascicular thalamus in instrumental conditioning. Front Syst Neurosci. 2013;7:51.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lacey CJ, Bolam JP, Magill PJ. Novel and distinct operational principles of intralaminar thalamic neurons and their striatal projections. J Neurosci. 2007;27:4374–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Ellender TJ, Harwood J, Kosillo P, Capogna M, Bolam JP. Heterogeneous properties of central lateral and parafascicular thalamic synapses in the striatum. J Physiol. 2013;591:257–72.

    CAS  PubMed  Google Scholar 

  16. 16.

    Huerta-Ocampo I, Mena-Segovia J, Bolam JP. Convergence of cortical and thalamic input to direct and indirect pathway medium spiny neurons in the striatum. Brain Struct Funct. 2014;219:1787–1800.

    PubMed  Google Scholar 

  17. 17.

    Doig NM, Moss J, Bolam JP. Cortical and thalamic innervation of direct and indirect pathway medium-sized spiny neurons in mouse striatum. J Neurosci 2010;30:14610–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 2012;75:58–64.

    CAS  PubMed  Google Scholar 

  19. 19.

    Cover KK, Gyawali U, Kerkhoff WG, Patton MH, Mu C, White MG, et al. Activation of the rostral intralaminar thalamus drives reinforcement through striatal dopamine release. Cell Rep. 2019;26:1389–98 e1383.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Clavier RM, Gerfen CR. Intracranial self-stimulation in the thalamus of the rat. Brain Res Bull. 1982;8:353–8.

    CAS  PubMed  Google Scholar 

  21. 21.

    Johnson KA, Lovinger DM. Presynaptic G protein-coupled receptors: gatekeepers of addiction? Front Cell Neurosci. 2016;10:264.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Atwood BK, Lovinger DM, Mathur BN. Presynaptic long-term depression mediated by Gi/o-coupled receptors. Trends Neurosci. 2014;37:663–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Johnson KA, Mateo Y, Lovinger DM. Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum. Neuropharmacology. 2017;117:114–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kupferschmidt DA, Lovinger DM. Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABA(B) and mGlu2/3 receptors. J Physiol. 2015;593:2295–310.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lovinger DM, McCool BA. Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3. J Neurophysiol. 1995;73:1076–83.

    CAS  PubMed  Google Scholar 

  26. 26.

    Kahn L, Alonso G, Robbe D, Bockaert J, Manzoni OJ. Group 2 metabotropic glutamate receptors induced long term depression in mouse striatal slices. Neurosci Lett. 2001;316:178–82.

    CAS  PubMed  Google Scholar 

  27. 27.

    Martella G, Platania P, Vita D, Sciamanna G, Cuomo D, Tassone A. et al. Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin. Exp Neurol. 2009;215:388–96.

    CAS  PubMed  Google Scholar 

  28. 28.

    Hu G, Duffy P, Swanson C, Ghasemzadeh MB, Kalivas PW. The regulation of dopamine transmission by metabotropic glutamate receptors. J Pharm Exp Ther. 1999;289:412–6.

    CAS  Google Scholar 

  29. 29.

    Kim JH, Austin JD, Tanabe L, Creekmore E, Vezina P. Activation of group II mGlu receptors blocks the enhanced drug taking induced by previous exposure to amphetamine. Eur J Neurosci. 2005;21:295–300.

    PubMed  Google Scholar 

  30. 30.

    D’Souza MS, Liechti ME, Ramirez-Nino AM, Kuczenski R, Markou A. The metabotropic glutamate 2/3 receptor agonist LY379268 blocked nicotine-induced increases in nucleus accumbens shell dopamine only in the presence of a nicotine-associated context in rats. Neuropsychopharmacology. 2011;36:2111–24.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Pehrson AL, Moghaddam B. Impact of metabotropic glutamate 2/3 receptor stimulation on activated dopamine release and locomotion. Psychopharmacology. 2010;211:443–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Bauzo RM, Kimmel HL, Howell LL. Interactions between the mGluR2/3 agonist, LY379268, and cocaine on in vivo neurochemistry and behavior in squirrel monkeys. Pharm Biochem Behav. 2009;94:204–10.

    CAS  Google Scholar 

  33. 33.

    Vong L, Ye C, Yang Z, Choi B, Chua S,Jr., Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron. 2011;71:142–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Madisen L, Mao T, Koch H, Zhuo JM, Berenyi A, Fujisawa S. et al. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat Neurosci. 2012;15:793–802.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Fremeau RT,Jr., Voglmaier S, Seal RP, Edwards RH. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 2004;27:98–103.

    CAS  PubMed  Google Scholar 

  36. 36.

    Kufahl PR, Martin-Fardon R, Weiss F. Enhanced sensitivity to attenuation of conditioned reinstatement by the mGluR 2/3 agonist LY379268 and increased functional activity of mGluR 2/3 in rats with a history of ethanol dependence. Neuropsychopharmacology. 2011;36:2762–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Justinova Z, Le Foll B, Redhi GH, Markou A, Goldberg SR. Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys. Psychopharmacology. 2016;233:1791–1800.

    CAS  PubMed  Google Scholar 

  38. 38.

    Poulin JF, Caronia G, Hofer C, Cui Q, Helm B, Ramakrishnan C. et al. Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches. Nat Neurosci. 2018;21:1260–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Trudeau LE, Hnasko TS, Wallen-Mackenzie A, Morales M, Rayport S, Sulzer D. The multilingual nature of dopamine neurons. Prog Brain Res. 2014;211:141–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Assous M, Dautan D, Tepper JM, Mena-Segovia J. Pedunculopontine glutamatergic neurons provide a novel source of feedforward inhibition in the striatum by selectively targeting interneurons. J Neurosci. 2019;39:4727–37.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Li X, Witonsky KR, Lofaro OM, Surjono F, Zhang J, Bossert JM. et al. Role of anterior intralaminar nuclei of thalamus projections to dorsomedial striatum in incubation of methamphetamine craving. J Neurosci. 2018;38:2270–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Kato S, Fukabori R, Nishizawa K, Okada K, Yoshioka N, Sugawara M, et al. Action selection and flexible switching controlled by the intralaminar thalamic neurons. Cell Rep. 2018;22:2370–82.

    CAS  PubMed  Google Scholar 

  43. 43.

    Testa CM, Friberg IK, Weiss SW, Standaert DG. Immunohistochemical localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the rat basal ganglia. J Comp Neurol. 1998;390:5–19.

    CAS  PubMed  Google Scholar 

  44. 44.

    Liechti ME, Lhuillier L, Kaupmann K, Markou A. Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence. J Neurosci. 2007;27:9077–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Sidhpura N, Weiss F, Martin-Fardon R. Effects of the mGlu2/3 agonist LY379268 and the mGlu5 antagonist MTEP on ethanol seeking and reinforcement are differentially altered in rats with a history of ethanol dependence. Biol Psychiatry. 2010;67:804–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Augier E, Dulman RS, Rauffenbart C, Augier G, Cross AJ, Heilig M. The mGluR2 positive allosteric modulator, AZD8529, and cue-induced relapse to alcohol seeking in rats. Neuropsychopharmacology. 2016;41:2932–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Dhanya RP, Sheffler DJ, Dahl R, Davis M, Lee PS, Yang L, et al. Design and synthesis of systemically active metabotropic glutamate subtype-2 and -3 (mGlu2/3) receptor positive allosteric modulators (PAMs): pharmacological characterization and assessment in a rat model of cocaine dependence. J Med Chem. 2014;57:4154–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Dhanya RP, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, et al. Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats. J Med Chem. 2011;54:342–53.

    CAS  PubMed  Google Scholar 

  49. 49.

    Jin X, Semenova S, Yang L, Ardecky R, Sheffler DJ, Dahl R. et al. The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats. Neuropsychopharmacology. 2010;35:2021–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Li X, D’Souza MS, Nino AM, Doherty J, Cross A, Markou A. Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats. Psychopharmacology. 2016;233:1801–14.

    CAS  PubMed  Google Scholar 

  51. 51.

    Crawford JT, Roberts DC, Beveridge TJ. The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats. Drug Alcohol Depend. 2013;132:414–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Justinova Z, Panlilio LV, Secci ME, Redhi GH, Schindler CW, Cross AJ. et al. The novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, decreases nicotine self-administration and relapse in squirrel monkeys. Biol Psychiatry. 2015;78:452–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Zhou Z, Karlsson C, Liang T, Xiong W, Kimura M, Tapocik JD, et al. Loss of metabotropic glutamate receptor 2 escalates alcohol consumption. Proc Natl Acad Sci USA. 2013;110:16963–8.

    CAS  PubMed  Google Scholar 

  54. 54.

    Morishima Y, Miyakawa T, Furuyashiki T, Tanaka Y, Mizuma H, Nakanishi S. Enhanced cocaine responsiveness and impaired motor coordination in metabotropic glutamate receptor subtype 2 knockout mice. Proc Natl Acad Sci USA. 2005;102:4170–5.

    CAS  PubMed  Google Scholar 

  55. 55.

    Yang HJ, Zhang HY, Bi GH, He Y, Gao JT, Xi ZX. Deletion of type 2 metabotropic glutamate receptor decreases sensitivity to cocaine reward in rats. Cell Rep. 2017;20:319–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Gao JT, Jordan CJ, Bi GH, He Y, Yang HJ, Gardner EL. et al. Deletion of the type 2 metabotropic glutamate receptor increases heroin abuse vulnerability in transgenic rats. Neuropsychopharmacology. 2018;43:2615–26.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all members of the Lovinger laboratory for helpful discussions and Guoxiang Luo for assistance with genotyping. We thank Dr. David Kupferschmidt for technical advice and comments on the manuscript.

Author information

Affiliations

Authors

Contributions

K.A.J. and D.M.L. conceived the project and wrote the manuscript. Y.M. and L.V. performed and analyzed FSCV experiments. K.A.J. performed and analyzed whole-cell electrophysiology and behavioral experiments. G.C.L. contributed technical expertise and performed statistical analysis of behavioral data. L.V., G.C.L., and Y.M. provided feedback on the manuscript.

Corresponding author

Correspondence to David M. Lovinger.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Johnson, K.A., Voyvodic, L., Loewinger, G.C. et al. Operant self-stimulation of thalamic terminals in the dorsomedial striatum is constrained by metabotropic glutamate receptor 2. Neuropsychopharmacol. 45, 1454–1462 (2020). https://doi.org/10.1038/s41386-020-0626-y

Download citation