Advertisement

Brain Structure and Function

, Volume 224, Issue 1, pp 419–434 | Cite as

Medium spiny neurons of the anterior dorsomedial striatum mediate reversal learning in a cell-type-dependent manner

  • Xingyue Wang
  • Yanhua Qiao
  • Zhonghua Dai
  • Nan Sui
  • Fang Shen
  • Jianjun Zhang
  • Jing LiangEmail author
Original Article

Abstract

The striatum has been implicated in the regulation of cognitive flexibility. Abnormalities in the anterior dorsomedial striatum (aDMS) are revealed in many mental disorders in which cognitive inflexibility is commonly observed. However, it remains poorly understood whether the aDMS plays a special role in flexible cognitive control and what the regulation pattern is in different neuronal populations. Based on the reversal learning task in mice, we showed that optogenetic activation in dopamine receptor 1-expressing medium spiny neurons (D1R-MSNs) of the aDMS impaired flexibility; meanwhile, suppressing these neurons facilitated behavioral performance. Conversely, D2R-MSN activation accelerated reversal learning, but it induced no change through neuronal suppression. The acquisition and retention of discrimination learning were unaffected by the manipulation of any type of MSN. Through bi-direct optogenetic modulation in D1R-MSNs of the same subject in a serial reversal learning task, we further revealed the function of D1R-MSNs during different stages of reversal learning, where inhibiting and exciting the same group of neurons reduced perseverative errors and increased regressive errors. Following D1R- and D2R-MSN activation in the aDMS, neuronal activity of the mediodorsal thalamus decreased and increased, respectively, in parallel with behavioral impairment and facilitation, but not as a direct result of the activation of the striatal MSNs. We propose that D1R- and D2R-MSN sub-populations in the aDMS exert opposing functions in cognitive flexibility regulation, with more important and complex roles of D1R-MSNs involved. Mental disorders with cognitive flexibility problems may feature an underlying functional imbalance in the aDMS’ two types of neurons.

Keywords

Anterior dorsomedial striatum Behavioral flexibility Optogenetics Medium spiny neurons Dopamine receptors 

Notes

Acknowledgements

This work was supported by National Natural Science Foundation of China (31571108), Beijing Natural Science Foundation (5162023) and the National Key Basic Research Program of China (2015CB553501).

Author contributions

XYW, YHQ and ZHD performed experiments; XYW analyzed data and wrote the manuscript; JL and NS designed experiments; FS and JJZ managed animal and designed animal model; JL and XYW finished the paper.

Compliance with ethical standards

Ethical approval

Research involves animal participants. All procedures were approved by Institutional Review Board of the Institute of Psychology, Chinese Academy of Sciences, and were in compliance with the National Institutes of Health Guide for Care and Use of Laboratory Animals.

Informed consent

All the co-authors are informed and in agreement on this submission. The authors declare that there is no conflict of interests to this work.

References

  1. Agnoli L, Mainolfi P, Invernizzi RW, Carli M (2013) Dopamine D1-like and D2-like receptors in the dorsal striatum control different aspects of attentional performance in the five-choice serial reaction time task under a condition of increased activity of corticostriatal inputs. Neuropsychopharmacology 38(5):701–714.  https://doi.org/10.1038/npp.2012.236 Google Scholar
  2. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12(10):366–375.  https://doi.org/10.1016/0166-2236(89)90074-X Google Scholar
  3. Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381.  https://doi.org/10.1146/annurev.ne.09.030186.002041 Google Scholar
  4. Berendse HW, Galis-de Graaf Y, Groenewegen HJ (1992) Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol 316(3):314–347.  https://doi.org/10.1002/cne.903160305 Google Scholar
  5. Bestmann S, Ruge D, Rothwell J, Galea JM (2015) The role of dopamine in motor flexibility. J Cogn Neurosci 27(2):365–376.  https://doi.org/10.1162/jocn_a_00706 Google Scholar
  6. Boulougouris V, Dalley JW, Robbins TW (2007) Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res 179(2):219–228.  https://doi.org/10.1016/j.bbr.2007.02.005 Google Scholar
  7. Boulougouris V, Castane A, Robbins TW (2009) Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior. Psychopharmacology 202(4):611–620.  https://doi.org/10.1007/s00213-008-1341-2 Google Scholar
  8. Bussey TJ, Muir JL, Everitt BJ, Robbins TW (1997) Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat. Behav Neurosci 111(5):920–936.  https://doi.org/10.1037/0735-7044.111.5.920 Google Scholar
  9. Calaminus C, Hauber W (2007) Intact discrimination reversal learning but slowed responding to reward-predictive cues after dopamine D1 and D2 receptor blockade in the nucleus accumbens of rats. Psychopharmacology 191(3):551–566.  https://doi.org/10.1007/s00213-006-0532-y Google Scholar
  10. Charntikov S, Pittenger ST, Swalve N, Li M, Bevins RA (2017) Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus. Neuropharmacology 121:111–119.  https://doi.org/10.1016/j.neuropharm.2017.04.026 Google Scholar
  11. Cheng Y, Huang CCY, Ma T, Wei X, Wang X, Lu J, Wang J (2017) Distinct synaptic strengthening of the striatal direct and indirect pathways drives alcohol consumption. Biol Psychiatry 81(11):918–929.  https://doi.org/10.1016/j.biopsych.2016.05.016 Google Scholar
  12. Chudasama Y, Bussey TJ, Muir JL (2001) Effects of selective thalamic and prelimbic cortex lesions on two types of visual discrimination and reversal learning. Eur J Neurosci 14(6):1009–1020.  https://doi.org/10.1046/j.0953-816x.2001.01607.x Google Scholar
  13. Chuhma N, Tanaka KF, Hen R, Rayport S (2011) Functional connectome of the striatal medium spiny neuron. J Neurosci 31(4):1183–1192.  https://doi.org/10.1523/JNEUROSCI.3833-10.2011 Google Scholar
  14. Clarke HF, Robbins TW, Roberts AC (2008) Lesions of the medial striatum in monkeys produce perseverative impairments during reversal learning similar to those produced by lesions of the orbitofrontal cortex. J Neurosci 28(43):10972–10982.  https://doi.org/10.1523/JNEUROSCI.1521-08.2008 Google Scholar
  15. Cools R, Barker RA, Sahakian BJ, Robbins TW (2001) Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb Cortex 11(12):1136–1143.  https://doi.org/10.1093/cercor/11.12.1136 Google Scholar
  16. Cools R, Barker RA, Sahakian BJ, Robbins TW (2003) L-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson’s disease. Neuropsychologia 41(11):1431–1441.  https://doi.org/10.1016/S0028-3932(03)00117-9 Google Scholar
  17. Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW (2007a) L-DOPA disrupts activity in the nucleus accumbens during reversal learning in Parkinson’s disease. Neuropsychopharmacology 32(1):180–189.  https://doi.org/10.1038/sj.npp.1301153 Google Scholar
  18. Cools R, Sheridan M, Jacobs E, D’Esposito M (2007b) Impulsive personality predicts dopamine-dependent changes in frontostriatal activity during component processes of working memory. J Neurosci 27(20):5506–5514.  https://doi.org/10.1523/JNEUROSCI.0601-07.2007 Google Scholar
  19. D’Cruz AM, Mosconi MW, Ragozzino ME, Cook EH, Sweeney JA (2016) Alterations in the functional neural circuitry supporting flexible choice behavior in autism spectrum disorders. Transl Psychiatry 6(10):e916.  https://doi.org/10.1038/tp.2016.161 doiGoogle Scholar
  20. Darvas M, Henschen CW, Palmiter RD (2014) Contributions of signaling by dopamine neurons in dorsal striatum to cognitive behaviors corresponding to those observed in Parkinson’s disease. Neurobiol Dis 65:112–123.  https://doi.org/10.1016/j.nbd.2014.01.017 Google Scholar
  21. Daum I, Schugens MM, Channon S, Polkey CE, Gray JA (1991) T-maze discrimination and reversal learning after unilateral temporal or frontal lobe lesions in man. Cortex 27(4):613–622.  https://doi.org/10.1016/S0010-9452(13)80010-X Google Scholar
  22. Deisseroth K (2015) Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 18(9):1213–1225.  https://doi.org/10.1038/nn.4091 Google Scholar
  23. Dickson PE, Rogers TD, Del Mar N, Martin LA, Heck D, Blaha CD, Goldowitz D, Mittleman G (2010) Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss. Neurobiol Learn Mem 94(2):220–228.  https://doi.org/10.1016/j.nlm.2010.05.010 Google Scholar
  24. Dickson PE, Corkill B, McKimm E, Miller MM, Calton MA, Goldowitz D, Blaha CD, Mittleman G (2013) Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome. Behav Brain Res 252:126–135.  https://doi.org/10.1016/j.bbr.2013.05.060 Google Scholar
  25. Durieux PF, Bearzatto B, Guiducci S, Buch T, Waisman A, Zoli M, Schiffmann SN, de Kerchove d’Exaerde A (2009) D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci 12(4):393–395.  https://doi.org/10.1038/nn.2286 Google Scholar
  26. Fellows LK, Farah MJ (2003) Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm. Brain 126 (Pt 8):1830–1837.  https://doi.org/10.1093/brain/awg180
  27. Floresco SB, Zhang Y, Enomoto T (2009) Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav Brain Res 204(2):396–409.  https://doi.org/10.1016/j.bbr.2008.12.001 Google Scholar
  28. Fox CA, Rafols JA (1976) The striatal efferents in the globus pallidus and in the substantia nigra. Res Publ Assoc Res Nerv Ment Dis 55:37–55Google Scholar
  29. Gage GJ, Stoetzner CR, Wiltschko AB, Berke JD (2010) Selective activation of striatal fast-spiking interneurons during choice execution. Neuron 67(3):466–479.  https://doi.org/10.1016/j.neuron.2010.06.034 Google Scholar
  30. Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250(4986):1429–1432.  https://doi.org/10.1126/science.2147780 Google Scholar
  31. Ghahremani DG, Monterosso J, Jentsch JD, Bilder RM, Poldrack RA (2010) Neural components underlying behavioral flexibility in human reversal learning. Cereb Cortex 20(8):1843–1852.  https://doi.org/10.1093/cercor/bhp247 Google Scholar
  32. Graybeal C, Feyder M, Schulman E, Saksida LM, Bussey TJ, Brigman JL, Holmes A (2011) Paradoxical reversal learning enhancement by stress or prefrontal cortical damage: rescue with BDNF. Nat Neurosci 14(12):1507–1509.  https://doi.org/10.1038/nn.2954 Google Scholar
  33. Grillner S, Robertson B (2016) The basal ganglia over 500 million years. Curr Biol 26(20):R1088–Rr1100.  https://doi.org/10.1016/j.cub.2016.06.041 Google Scholar
  34. Haluk DM, Floresco SB (2009) Ventral striatal dopamine modulation of different forms of behavioral flexibility. Neuropsychopharmacology 34(8):2041–2052.  https://doi.org/10.1038/npp.2009.21 Google Scholar
  35. Heien ML, Wightman RM (2006) Phasic dopamine signaling during behavior, reward, and disease states. CNS Neurol Disord Drug Targets 5(1):99–108.  https://doi.org/10.2174/187152706784111605 Google Scholar
  36. Hikida T, Kimura K, Wada N, Funabiki K, Nakanishi S (2010) Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior. Neuron 66(6):896–907.  https://doi.org/10.1016/j.neuron.2010.05.011 Google Scholar
  37. Hollerman JR, Tremblay L, Schultz W (1998) Influence of reward expectation on behavior-related neuronal activity in primate striatum. J Neurophysiol 80(2):947–963.  https://doi.org/10.1152/jn.1998.80.2.947 Google Scholar
  38. Ito R, Dalley JW, Robbins TW, Everitt BJ (2002) Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue. J Neurosci 22(14):6247–6253.  https://doi.org/10.1523/JNEUROSCI.22-14-06247.2002 Google Scholar
  39. Kravitz AV, Tye LD, Kreitzer AC (2012) Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat Neurosci 15(6):816–818.  https://doi.org/10.1038/nn.3100 Google Scholar
  40. Lange H, Thorner G, Hopf A (1976) Morphometric-statistical structure analysis of human striatum, pallidum and nucleus sub-thalamicus. III. Nucleus subthalamicus. J Hirnforsch 17(1):31–41Google Scholar
  41. Levitt JG, O’Neill J, Blanton RE, Smalley S, Fadale D, McCracken JT, Guthrie D, Toga AW, Alger JR (2003) Proton magnetic resonance spectroscopic imaging of the brain in childhood autism. Biol Psychiatry 54(12):1355–1366.  https://doi.org/10.1016/S0006-3223(03)00688-7 Google Scholar
  42. Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borrelli E, Fisone G (2003) Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci USA 100(7):4305–4309.  https://doi.org/10.1073/pnas.0730708100 Google Scholar
  43. Lisanby SH, McDonald WM, Massey EW, Doraiswamy PM, Rozear M, Boyko OB, Krishnan KR, Nemeroff C (1993) Diminished subcortical nuclei volumes in Parkinson’s disease by MR imaging. J Neural Transm Suppl 40:13–21Google Scholar
  44. Madisen L, Mao T, Koch H, Zhuo JM, Berenyi A, Fujisawa S, Hsu YW, Garcia III AJ, Gu X, Zanella S, Kidney J, Gu H, Mao Y, Hooks BM, Boyden ES, Buzsaki G, Ramirez JM, Jones AR, Svoboda K, Han X, Turner EE, Zeng H (2012) A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat Neurosci 15(5):793–802.  https://doi.org/10.1038/nn.3078 Google Scholar
  45. McCracken CB, Grace AA (2013) Persistent cocaine-induced reversal learning deficits are associated with altered limbic cortico-striatal local field potential synchronization. J Neurosci 33(44):17469–17482.  https://doi.org/10.1523/JNEUROSCI.1440-13.2013 Google Scholar
  46. McLean SL, Idris NF, Woolley ML, Neill JC (2009) D(1)-like receptor activation improves PCP-induced cognitive deficits in animal models: implications for mechanisms of improved cognitive function in schizophrenia. Eur Neuropsychopharmacol 19(6):440–450.  https://doi.org/10.1016/j.euroneuro.2009.01.009 Google Scholar
  47. Mitchell AS (2015) The mediodorsal thalamus as a higher order thalamic relay nucleus important for learning and decision-making. Neurosci Biobehav Rev 54:76–88.  https://doi.org/10.1016/j.neubiorev.2015.03.001 Google Scholar
  48. Moore A, Malinowski P (2009) Meditation, mindfulness and cognitive flexibility. Conscious Cogn 18(1):176–186.  https://doi.org/10.1016/j.concog.2008.12.008 Google Scholar
  49. Morita M, Wang Y, Sasaoka T, Okada K, Niwa M, Sawa A, Hikida T (2016) Dopamine D2L receptor is required for visual discrimination and reversal learning. Mol Neuropsychiatry 2(3):124–132.  https://doi.org/10.1159/000447970 Google Scholar
  50. Nagai T, Yoshimoto J, Kannon T, Kuroda K, Kaibuchi K (2016) Phosphorylation signals in striatal medium spiny neurons. Trends Pharmacol Sci 37(10):858–871.  https://doi.org/10.1016/j.tips.2016.07.003 Google Scholar
  51. Nakanishi S, Hikida T, Yawata S (2014) Distinct dopaminergic control of the direct and indirect pathways in reward-based and avoidance learning behaviors. Neuroscience 282:49–59.  https://doi.org/10.1016/j.neuroscience.2014.04.026 Google Scholar
  52. Orellana G, Slachevsky A (2013) Executive functioning in schizophrenia. Front Psychiatry 4:35.  https://doi.org/10.3389/fpsyt.2013.00035 Google Scholar
  53. Parker NF, Cameron CM, Taliaferro JP, Lee J, Choi JY, Davidson TJ, Daw ND, Witten IB (2016) Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target. Nat Neurosci 19(6):845–854.  https://doi.org/10.1038/nn.4287 Google Scholar
  54. Parnaudeau S, Taylor K, Bolkan SS, Ward RD, Balsam PD, Kellendonk C (2015) Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior. Biol Psychiatry 77(5):445–453.  https://doi.org/10.1016/j.biopsych.2014.03.020 Google Scholar
  55. Piao C, Liu T, Ma L, Ding X, Wang X, Chen X, Duan Y, Sui N, Liang J (2017) Alterations in brain activation in response to prolonged morphine withdrawal-induced behavioral inflexibility in rats. Psychopharmacology 234(19):2941–2953.  https://doi.org/10.1007/s0021 Google Scholar
  56. Ragozzino ME (2007) The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann N Y Acad Sci 1121:355–375.  https://doi.org/10.1196/annals.1401.013 Google Scholar
  57. Rinne JO, Rummukainen J, Paljarvi L, Rinne UK (1989) Dementia in Parkinson’s disease is related to neuronal loss in the medial substantia nigra. Ann Neurol 26(1):47–50.  https://doi.org/10.1002/ana.410260107 Google Scholar
  58. Robinson S, Sandstrom SM, Denenberg VH, Palmiter RD (2005) Distinguishing whether dopamine regulates liking, wanting, and/or learning about rewards. Behav Neurosci 119(1):5–15.  https://doi.org/10.1037/0735-7044.119.1.5 Google Scholar
  59. Rolls ET, Thorpe SJ, Maddison SP (1983) Responses of striatal neurons in the behaving monkey. 1. Head of the caudate nucleus. Behav Brain Res 7(2):179–210.  https://doi.org/10.1016/0166-4328(83)90191-2 Google Scholar
  60. Ruge H, Wolfensteller U (2016) Distinct contributions of lateral orbito-frontal cortex, striatum, and fronto-parietal network regions for rule encoding and control of memory-based implementation during instructed reversal learning. Neuroimage 125:1–12.  https://doi.org/10.1016/j.neuroimage.2015.10.005 Google Scholar
  61. Sahlholm K, Gomez-Soler M, Valle-Leon M, Lopez-Cano M, Taura JJ, Ciruela F, Fernandez-Duenas V (2018) Antipsychotic-like efficacy of dopamine D2 receptor-biased ligands is dependent on adenosine A2A receptor expression. Mol Neurobiol 55(6):4952–4958.  https://doi.org/10.1007/s1203 Google Scholar
  62. Schiffmann SN, Vanderhaeghen JJ (1993) Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J Neurosci 13(3):1080–1087.  https://doi.org/10.1523/JNEUROSCI.13-03-01080.1993 Google Scholar
  63. Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferre S (2007) Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol 83(5):277–292.  https://doi.org/10.1016/j.pneurobio.2007.05.001 Google Scholar
  64. Schultz W (2001) Reward signaling by dopamine neurons. Neuroscientist 7(4):293–302.  https://doi.org/10.1177/107385840100700406 Google Scholar
  65. Soares-Cunha C, Coimbra B, Sousa N, Rodrigues AJ (2016) Reappraising striatal D1- and D2-neurons in reward and aversion. Neurosci Biobehav Rev 68:370–386.  https://doi.org/10.1016/j.neubiorev.2016.05.021 Google Scholar
  66. Surmeier DJ, Ding J, Day M, Wang Z, Shen W (2007) D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci 30(5):228–235.  https://doi.org/10.1016/j.tins.2007.03.008 Google Scholar
  67. Sweitzer MM, Geier CF, Joel DL, McGurrin P, Denlinger RL, Forbes EE, Donny EC (2014) Dissociated effects of anticipating smoking versus monetary reward in the caudate as a function of smoking abstinence. Biol Psychiatry 76(9):681–688.  https://doi.org/10.1016/j.biopsych.2013.11.013 Google Scholar
  68. Tessa C, Lucetti C, Giannelli M, Diciotti S, Poletti M, Danti S, Baldacci F, Vignali C, Bonuccelli U, Mascalchi M, Toschi N (2014) Progression of brain atrophy in the early stages of Parkinson’s disease: a longitudinal tensor-based morphometry study in de novo patients without cognitive impairment. Hum Brain Mapp 35(8):3932–3944.  https://doi.org/10.1002/hbm.22449 Google Scholar
  69. Voorn P, Vanderschuren LJ, Groenewegen HJ, Robbins TW, Pennartz CM (2004) Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci 27(8):468–474.  https://doi.org/10.1016/j.tins.2004.06.006 Google Scholar
  70. Zhang Y, Cazakoff BN, Thai CA, Howland JG (2012) Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats. Neuropharmacology 62(3):1299–1307.  https://doi.org/10.1016/j.neuropharm.2011.02.022 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.CAS Key Laboratory of Mental Health, Institute of PsychologyChinese Academy of SciencesBeijingChina
  2. 2.Department of PsychologyUniversity of Chinese Academy of SciencesBeijingChina

Personalised recommendations