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Chemogenetic activation of ventral tegmental area GABA neurons, but not mesoaccumbal GABA terminals, disrupts responding to reward-predictive cues

Neuropsychopharmacology (2018) | Download Citation

Abstract

Cues predicting rewards can gain motivational properties and initiate reward-seeking behaviors. Dopamine projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) are critical in regulating cue-motivated responding. Although, approximately one third of mesoaccumbal projection neurons are GABAergic, it is unclear how this population influences motivational processes and cue processing. This is largely due to our inability to pharmacologically probe circuit level contributions of VTA-GABA, which arises from diverse sources, including multiple GABA afferents, interneurons, and projection neurons. Here we used a combinatorial viral vector approach to restrict activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to GABA neurons in the VTA of wild-type rats trained to respond during a distinct audiovisual cue for sucrose. We measured different aspects of motivation for the cue or primary reinforcer, while chemogenetically activating either the VTA-GABA neurons or their projections to the NAc. Activation of VTA-GABA neurons decreased cue-induced responding and accuracy, while increasing latencies to respond to the cue and obtain the reward. Perseverative and spontaneous responses decreased, yet the rats persisted in entering the reward cup when the cue and reward were absent. However, activation of the VTA-GABA terminals in the accumbens had no effect on any of these behaviors. Together, we demonstrate that VTA-GABA neuron activity preferentially attenuates the ability of cues to trigger reward-seeking, while some aspects of the motivation for the reward itself are preserved. Additionally, the dense VTA-GABA projections to the NAc do not influence the motivational salience of the cue.

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References

  1. 1.

    Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev. 1998;28:309–69.

  2. 2.

    Berridge KC, Robinson TE. Liking, wanting, and the incentive-sensitization theory of addiction. Am Psychol. 2016;71:670–9.

  3. 3.

    Berridge KC, Robinson TE, Aldridge JW. Dissecting components of reward: ‘liking’, ‘wanting’, and learning. Curr Opin Pharmacol. 2009;9:65–73.

  4. 4.

    Hodge CW, Haraguchi M, Chappelle AM, Samson HH. Effects of ventral tegmental microinjections of the GABAA agonist muscimol on self-administration of ethanol and sucrose. Pharmacol Biochem Behav. 1996;53:971–7.

  5. 5.

    Miner P, Borkuhova Y, Shimonova L, Khaimov A, Bodnar RJ. GABA-A and GABA-B receptors mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions. Brain Res. 2010;1355:86–96.

  6. 6.

    Yun IA, Wakabayashi KT, Fields HL, Nicola SM. The ventral tegmental area is required for the behavioral and nucleus accumbens neuronal firing responses to incentive cues. J Neurosci. 2004;24:2923–33.

  7. 7.

    Fields HL, Hjelmstad GO, Margolis EB, Nicola SM. Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement. Annu Rev Neurosci. 2007;30:289–316.

  8. 8.

    Sesack SR, Grace AA. Cortico-Basal Ganglia reward network: microcircuitry. Neuropsychopharmacology. 2010;35:27–47.

  9. 9.

    Watabe-Uchida M, Zhu L, Ogawa SK, Vamanrao A, Uchida N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron. 2012;74:858–73.

  10. 10.

    Xia Y, Driscoll JR, Wilbrecht L, Margolis EB, Fields HL, Hjelmstad GO. Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area. J Neurosci. 2011;31:7811–6.

  11. 11.

    Zahm DS, Heimer L. Specificity in the efferent projections of the nucleus accumbens in the rat: comparison of the rostral pole projection patterns with those of the core and shell. J Comp Neurol. 1993;327:220–32.

  12. 12.

    Geisler S, Zahm DS. Afferents of the ventral tegmental area in the rat-anatomical substratum for integrative functions. J Comp Neurol. 2005;490:270–94.

  13. 13.

    Yau HJ, Wang DV, Tsou JH, Chuang YF, Chen BT, Deisseroth K, et al. Pontomesencephalic tegmental afferents to VTA non-dopamine neurons are necessary for appetitive pavlovian learning. Cell Rep. 2016;16:2699–710.

  14. 14.

    Creed MC, Ntamalti NR, Tan KR. VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems. Front Behav Neurosci. 2014;8:8.

  15. 15.

    Taylor SR, Badurek S, Dileone RJ, Nashmi R, Minichiello L, Picciotto MR. GABAergic and glutamatergic efferents of the mouse ventral tegmental area. J Comp Neurol. 2014;522:3308–34.

  16. 16.

    Van Bockstaele EJ, Pickel VM. GABA-containing neurons in the ventral tegmental area project to the nucleus accumbens in rat brain. Brain Res. 1995;682:215–21.

  17. 17.

    Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature. 2012;482:85–8.

  18. 18.

    Eshel N, Bukwich M, Rao V, Hemmelder V, Tian J, Uchida N. Arithmetic and local circuitry underlying dopamine prediction errors. Nature. 2015;525:243–6.

  19. 19.

    van Zessen R, Phillips JL, Budygin EA, Stuber GD. Activation of VTA GABA neurons disrupts reward consumption. Neuron. 2012;73:1184–94.

  20. 20.

    Brown MT, Tan KR, O’Connor EC, Nikonenko I, Muller D, Luscher C. Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature. 2012;492:452–6.

  21. 21.

    Liu YJ, Ehrengruber MU, Negwer M, Shao HJ, Cetin AH, Lyon DC. Tracing inputs to inhibitory or excitatory neurons of mouse and cat visual cortex with a targeted rabies virus. Curr Biol. 2013;23:1746–55.

  22. 22.

    Gompf HS, Budygin EA, Fuller PM, Bass CE. Targeted genetic manipulations of neuronal subtypes using promoter-specific combinatorial AAVs in wild-type animals. Front Behav Neurosci. 2015;9:152.

  23. 23.

    Illiano P, Bass CE, Fichera L, Mus L, Budygin EA, Sotnikova TD, et al. Recombinant adeno-associated virus-mediated rescue of function in a mouse model of Dopamine Transporter Deficiency Syndrome. Sci Rep. 2017;7:46280.

  24. 24.

    Mikhailova MA, Bass CE, Grinevich VP, Chappell AM, Deal AL, Bonin KD, et al. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors. Neuroscience. 2016;333:54–64.

  25. 25.

    Wakabayashi KT, Fields HL, Nicola SM. Dissociation of the role of nucleus accumbens dopamine in responding to reward-predictive cues and waiting for reward. Behav Brain Res. 2004;154:19–30.

  26. 26.

    Anaclet C, Pedersen NP, Ferrari LL, Venner A, Bass CE, Arrigoni E, et al. Basal forebrain control of wakefulness and cortical rhythms. Nat Commun. 2015;6:8744.

  27. 27.

    Pedersen NP, Ferrari L, Venner A, Wang JL, Abbott SB, Vujovic N, et al. Supramammillary glutamate neurons are a key node of the arousal system. Nat Commun. 2017;8:1405.

  28. 28.

    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;17:577–85.

  29. 29.

    Ambroggi F, Ghazizadeh A, Nicola SM, Fields HL. Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition. J Neurosci. 2011;31:6820–30.

  30. 30.

    Nair-Roberts RG, Chatelain-Badie SD, Benson E, White-Cooper H, Bolam JP, Ungless MA. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience. 2008;152:1024–31.

  31. 31.

    Swanson LW. The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull. 1982;9:321–53.

  32. 32.

    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;357:503–7.

  33. 33.

    Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci. 2002;22:3306–11.

  34. 34.

    Meyer PJ, King CP, Ferrario CR. Motivational processes underlying substance abuse disorder. Curr Top Behav Neurosci. 2016;27:473–506.

  35. 35.

    Berridge KC. From prediction error to incentive salience: mesolimbic computation of reward motivation. Eur J Neurosci. 2012;35:1124–43.

  36. 36.

    Trevitt JT, Lyons M, Aberman J, Carriero D, Finn M, Salamone JD. Effects of clozapine, thioridazine, risperidone and haloperidol on behavioral tests related to extramyramidal motor function. Psychopharmacology. 1997;132:74–81.

  37. 37.

    MacLaren DA, Browne RW, Shaw JK, Krishnan Radhakrishnan S, Khare P, Espana RA, et al. Clozapine N-oxide administration produces behavioral effects in long-evans rats: implications for designing DREADD experiments. eNeuro. 2016;3:e0219_16:016 1–14.

  38. 38.

    López AJ, Kramár E, Matheos DP, White AO, Kwapis J, Vogel-Ciernia A, et al. Promoter-specific effects of DREADD modulation on hippocampal synaptic plasticity and memory formation. J Neurosci. 2016;36:3588–99.

  39. 39.

    Buchta WC, Mahler SV, Harlan B, Aston‐Jones GS, Riegel AC. Dopamine terminals from the ventral tegmental area gate intrinsic inhibition in the prefrontal cortex. Physiol Rep. 2017;5:e13198.

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Acknowledgements

We thank Dr. David C. Lyon for providing the GAD1 promoter used in these experiments. We thank Raquel Lima, Karie Chen, and Martin Leigh for technical assistance and Dr. Paul Meyer for very helpful comments on the manuscript. We also thank Dr. Wade Sigurdson and the University at Buffalo Confocal Microscopy Core for invaluable assistance. This research was supported by the State University of New York BRAIN Network of Excellence Postdoctoral Fellow program and T32 AA007583 (K.T.W.), the Whitehall Foundation 2017-08-43 (J.P.); 2017-12-98 (C.E.B.), as well as R01 AA024112 and R21 DA043190, (C.E.B.).

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Affiliations

  1. Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14203, USA

    • Ken T. Wakabayashi
    • , Malte Feja
    • , Ajay N. Baindur
    • , Michael J. Bruno
    •  & Caroline E. Bass
  2. Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, NY, 14203, USA

    • Ken T. Wakabayashi
    • , Kathryn Hausknecht
    • , Roh-Yu Shen
    • , Samir Haj-Dahmane
    •  & Caroline E. Bass
  3. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14214, USA

    • Rohan V. Bhimani
    •  & Jinwoo Park

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The authors declare no competing interests.

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Correspondence to Caroline E. Bass.

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DOI

https://doi.org/10.1038/s41386-018-0097-6