Projections from D2 Neurons in Different Subregions of Nucleus Accumbens Shell to Ventral Pallidum Play Distinct Roles in Reward and Aversion

Abstract

The nucleus accumbens shell (NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing (D2) neurons are assumed to function in aversion. However, this has been challenged by recent reports which attribute positive motivational roles to D2 neurons. Using optogenetics and multiple behavioral tasks, we found that activation of D2 neurons in the dorsomedial NAcSh drives preference and increases the motivation for rewards, whereas activation of ventral NAcSh D2 neurons induces aversion. Stimulation of D2 neurons in the ventromedial NAcSh increases movement speed and stimulation of D2 neurons in the ventrolateral NAcSh decreases movement speed. Combining retrograde tracing and in situ hybridization, we demonstrated that glutamatergic and GABAergic neurons in the ventral pallidum receive inputs differentially from the dorsomedial and ventral NAcSh. All together, these findings shed light on the controversy regarding the function of NAcSh D2 neurons, and provide new insights into understanding the heterogeneity of the NAcSh.

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References

  1. 1.

    Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 2005, 8: 1481.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Castro DC, Berridge KC. Opioid hedonic hotspot in nucleus accumbens shell: mu, delta, and kappa maps for enhancement of sweetness “liking” and “wanting”. J Neurosci 2014, 34: 4239–4250.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 2011, 34: 441–466.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Kupchik YM, Robyn MB, Jasper AH, Mary KL, Danielle JS, Peter WK. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat Neurosci 2015, 18: 1230.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Haber SN. The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat 2003, 26: 317–330.

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Zhou L, Furuta T, Kaneko T. Chemical organization of projection neurons in the rat accumbens nucleus and olfactory tubercle. Neurosci 2003, 120: 783–798.

    CAS  Article  Google Scholar 

  8. 8.

    Verharen JPH, Adan RAH, Vanderschuren JMJ. Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making. Neuropsychopharmacology 2019, 44: 2195–2204.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Lobo MK, Covington HE, Chaudhury D, Friedman AK, Sun H, Damez-Werno D, et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 2010, 330: 385–390.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci 1989, 12: 366–375.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Stefanik MT, Kalivas PW. Optogenetic dissection of basolateral amygdala projections during cue-induced reinstatement of cocaine seeking. Front Behav Neurosci 2013, 7: 213.

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Kravitz AV, Freeze BS, Parker PR, Kay K, Thwin MT, Deisseroth K, et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 2010, 466: 622–626.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Vicente AM, Galvao-Ferreira P, Tecuapetla F, Costa RM. Direct and indirect dorsolateral striatum pathways reinforce different action strategies. Curr Biol 2016, 26: R267–R269.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Pena CJ, et al. In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward. PNAS 2016, 113: 2726–2731.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Soares-Cunha C, Coimbra B, David-Pereira A, Borges S, Pinto L, Costa P, et al. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation. Nat Commun 2016, 7: 11829.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Oginsky MF, Goforth PB, Nobile CW, Lopez-Santiago LF, Ferrario CR. Eating ‘junk-food’ produces rapid and long-lasting increases in nac cp-ampa receptors: implications for enhanced cue-induced motivation and food addiction. Neuropsychopharmacology 2016, 41: 2977–2986.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Oleson EB, Gentry RN, Chioma VC, Cheer JF. Subsecond dopamine release in the nucleus accumbens predicts conditioned punishment and its successful avoidance. J Neurosci 2012, 32: 14804–14808.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Boschen SL, Wietzikoski EC, Winn P, Cunha C. The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning. Neurobiol Learn Mem 2011, 96: 254–262.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Ramirez F, Moscarello JM, LeDoux JE, Sears RM. Active avoidance requires a serial basal amygdala to nucleus accumbens shell circuit. J Neurosci 2015, 35: 3470–3477.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Trifilieff P, Feng B, Urizar E, Winger V, Ward RD, Taylor KM, et al. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol Psychiatry 2013, 18: 1025–1033.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Soares-Cunha C, Coimbra B, Borges S, Carvalho MM, Rodrigues AJ, Sousa N. The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure. Transl Psychiatry 2014, 4: e397.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Cole SL, Robinson MJF, Berridge KC. Optogenetic self-stimulation in the nucleus accumbens: D1 reward versus D2 ambivalence. PLoS One 2018, 13: e0207694.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Song SS, Kang BJ, Wen L, Lee HJ, Sim HR, Kim TH, et al. Optogenetics reveals a role for accumbal medium spiny neurons expressing dopamine D2 receptors in cocaine-induced behavioral sensitization. Front Behav Neurosci 2014, 8: 336.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Francis TC, Chandra R, Friend DM, 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.

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Yang H, de-Jong JW, Tak Y, Peck J, Bateup HS, Lammel S. Nucleus accumbens subnuclei regulate motivated behavior via direct inhibition and disinhibition of vta dopamine subpopulations. Neuron 2018, 97: 434–449.e4.

  26. 26.

    de-Jong JW, Afjei SA, Pollak DI, Peck JR, Liu C, Kim CK, et al. A neural circuit mechanism for encoding aversive stimuli in the mesolimbic dopamine system. Neuron 2019, 101: 133–151.

  27. 27.

    Al-Hasani R, McCall JG, Shin G, Gomez AM, Schmitz GP, Bernardi JM, et al. Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron 2015, 87: 1063–1077.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Beier KT, Steinberg EE, DeLoach KE, Xie S, Miyamichi K, Schwarz L. Circuit architecture of vta dopamine neurons revealed by systematic input-output mapping. Cell 2015, 162: 622–634.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Humphries MD, Prescott TJ. The ventral basal ganglia, a selection mechanism at the crossroads of space, strategy, and reward. Prog Neurobiol 2010, 90: 385–417.

    PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Heimer L, Switzer RD, Van-Hoesen GW. Ventral striatum and ventral pallidum: Components of the motor system? Trends Neurosci 1982, 5: 83–87.

    Article  Google Scholar 

  31. 31.

    Mogenson GJ, Yang CR. The contribution of basal forebrain to limbic-motor integration and the mediation of motivation to action, in the basal forebrain: anatomy to function. 1991, Springer US: Boston, MA. 267–290.

  32. 32.

    Creed M, Ntamati NR, Chandra R, Lobo MK, Luscher C. Convergence of reinforcing and anhedonic cocaine effects in the ventral pallidum. Neuron 2016, 92: 214–226.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Smith KS, Berridge KC. Opioid limbic circuit for reward: interaction between hedonic hotspots of nucleus accumbens and ventral pallidum. J Neurosci 2007, 27: 1594–1605.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Root DH, Tindell AJ, Aldridge JW, Berridge KC. The ventral pallidum: subregion-specific functional anatomy and roles in motivated behaviors. Prog Neurobiol 2015, 130: 29–70.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Smith KS, Tindell AJ, Aldridge JW, Berridge KC. Ventral pallidum roles in reward and motivation. Behav Brain Res 2009, 196: 155–167.

  36. 36.

    Faget L, Zell V, Souter E, McPherson A, Ressler R, Gutierrez-Reed N, et al. Opponent control of behavioral reinforcement by inhibitory and excitatory projections from the ventral pallidum. Nat Commun 2018, 9: 849.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Tooley J, Marconi L, Alipio JB, Matikainen-Ankney B, Georgiou P, Kravitz AV, et al. Glutamatergic ventral pallidal neurons modulate activity of the habenula-tegmental circuitry and constrain reward seeking. Biol Psychiatry 2018, 83: 1012–1023.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Mahler SV, Vazey EM, Beckley JT, Keistler CR, McGlinchey EM, Kaufling J, et al. Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci 2014, 17: 577–585.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Knowland D, Lilascharoen V, Pacia CP, Shin S, Wang EHJ, Lim BK. Distinct ventral pallidal neural populations mediate separate symptoms of depression. Cell 2017, 170: 284–297.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Sauer B. Functional expression of the cre-lox site-specific recombination system in the yeast Saccharomyces cerevisiae. Mol Cell Biol 1987, 7: 2087–2096.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Atasoy D, Aponte Y, Su HH, Sternson SM. A FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J Neurosci 2008, 28: 7025–7030.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Cardin JA, Carlén M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of Channelrhodopsin-2. Nat Protoc 2010, 5: 247–254.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2001, Amsterdam: Elsevier Science.

    Google Scholar 

  44. 44.

    Lerner, TN, Shilyansky C, Davidson TJ, Evans KE, Beier KT, Zalocusky KA, et al. Intact-brain analyses reveal distinct information carried by snc dopamine subcircuits. Cell 2015, 162: 635–647.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Li Z, Chen Z, Fan G, Li A, Yuan J, Xu T. Cell-type-specific afferent innervation of the nucleus accumbens core and shell. Front Neuroanat 2018, 12: 84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Xiu J, Zhang Q, Zhou T, Zhou T, Chen Y, Hu H. Visualizing an emotional valence map in the limbic forebrain by TAI-FISH. Nat Neurosci 2014, 17: 1552–1559.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Zhu C, Yao Y, Xiong Y, Cheng M, Chen J, Zhao R, et al. Somatostatin neurons in the basal forebrain promote high-calorie food intake. Cell Rep 2017, 20: 112–123.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Domingos AI, Vaynshteyn J, Voss HU, Ren X, Gradinaru V, Zang F, et al. Leptin regulates the reward value of nutrient. Nat Neurosci 2011, 14: 1562–1568.

  49. 49.

    Liu Z, Zhou J, Li Y, Hu F, Lu Y, Ma M, et al. Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron 2014, 81: 1360–1374.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Ikemoto S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 2007, 56: 27–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Castro DC, Berridge KC. Advances in the neurobiological bases for food ‘liking’ versus ‘wanting’. Physiol Behav 2014, 136: 22–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Bock R, Shin JH, Kaplan AR, Dobi A, Markey E, Kramer PF, et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat Neurosci 2013, 16: 632–638.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Tsutsui-Kimura I, Takiue H, Yoshida K, Xu M, Yano R, Ohta H, et al. Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation. Nat Commun 2017, 8: 14304.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Flanigan M, LeClair K. Shared motivational functions of ventral striatum d1 and d2 medium spiny neurons. J Neurosci 2017, 37: 6177–6179.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Durieux PF, Bearzatto B, Guiducci S, Buch T, Waisman A, Zoli M. D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci 2009, 12: 393–395.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990, 13: 281–285.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Zhou Y, Zhu H, Liu Z, Chen X, Su X, Ma C. A ventral CA1 to nucleus accumbens core engram circuit mediates conditioned place preference for cocaine. Nat Neurosci 2019, 22: 1986–1999.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Dong P, Wang H, Shen XF, Jiang P, Zhu XT, Li Y, et al. A novel cortico-intrathalamic circuit for flight behavior. Nat Neurosci 2019,22:941–949.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    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  Article  Google Scholar 

  60. 60.

    Li JM, Liu TA, D Y, Kondoh K, Lu ZH. Trans-synaptic neural circuit-tracing with neurotropic viruses. Neurosci Bull 2019, 35: 909–920.

  61. 61.

    Su YT, Gu MY, Chu X, Feng X, Yu YQ. Whole-brain mapping of direct inputs to and axonal projections from gabaergic neurons in the parafacial zone. Neurosci Bull 2018, 34:485–496.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

We thank Dr. Yi Rao for generously providing the D2-Cre mice. We thank Dr. MM Luo and Dr. KX Yuan for help with the virus. We also thank Dr. Wei Shen for generously providing the VGAT-ires-Cre and VGLUT2-ires-Cre mice. We thank Dr. FQ Xu in providing the Rabies virus (BrainVTA). This research was supported by National Science Foundation of China grants 31571095 and 91332122, a Key Scientific Technological Innovation Research project from the Ministry of Education, a grant from Insitute Guo Qiang at Tsinghua University and funding from the Beijing Program on the Study of Functional Chips and Related Core Technologies of Brain-inspired Computing Systems.

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Yao, Y., Gao, G., Liu, K. et al. Projections from D2 Neurons in Different Subregions of Nucleus Accumbens Shell to Ventral Pallidum Play Distinct Roles in Reward and Aversion. Neurosci. Bull. (2021). https://doi.org/10.1007/s12264-021-00632-9

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Keywords

  • Nucleus accumbens shell
  • Ventral pallidum
  • D2 neurons
  • Reward
  • Aversion
  • Motivation