Abstract
Midbrain dopamine neurons are implicated in various psychiatric and neurological disorders. The GABAergic tail of the ventral tegmental area (tVTA), also named the rostromedial tegmental nucleus (RMTg), displays dense projections to the midbrain and exerts electrophysiological control over dopamine cells of the VTA. However, the influence of the tVTA on the nigrostriatal pathway, from the substantia nigra pars compacta (SNc) to the dorsal striatum, and on related functions remains to be addressed. The present study highlights the role played by the tVTA as a GABA brake for the nigrostriatal system, demonstrating a critical influence over motor functions. Using neuroanatomical approaches with tract tracing and electron microscopy, we reveal the presence of a tVTA–SNc–dorsal striatum pathway. Using in vivo electrophysiology, we prove that the tVTA is a major inhibitory control center for SNc dopamine cells. Using behavioral approaches, we demonstrate that the tVTA controls rotation behavior, motor coordination, and motor skill learning. The motor enhancements observed after ablation of the tVTA are in this regard comparable with the performance-enhancing properties of amphetamine, a drug used in doping. These findings demonstrate that the tVTA is a major GABA brake for nigral dopamine systems and nigrostriatal functions, and they raise important questions about how the tVTA is integrated within the basal ganglia circuitry. They also warrant further research on the tVTA’s role in motor and dopamine-related pathological contexts such as Parkinson’s disease.
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References
Albin RL, Young AB, Penney JB (1989). The functional anatomy of basal ganglia disorders. Trends Neurosci 12: 366–375.
Akita H, Ogata M, Jitsuki S, Ogura T, Oh-Nishi A, Hoka S et al (2006). Nigral injection of antisense oligonucleotides to synaptotagmin I using HVJ-liposome vectors causes disruption of dopamine release in the striatum and impaired skill learning. Brain Res 1095: 178–189.
Balcita-Pedicino JJ, Omelchenko N, Bell R, Sesack SR (2011). The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial tegmental nucleus. J Comp Neurol 519: 1143–1164.
Barrot M, Sesack SR, Georges F, Pistis M, Hong S, Jhou TC (2012). Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions. J Neurosci 32: 14094–14101.
Beeler JA, Cao ZF, Kheirbek MA, Ding Y, Koranda J, Murakami M et al (2010). Dopamine-dependent motor learning: insight into levodopa's long-duration response. Ann Neurol 67: 639–647.
Bourdy R, Barrot M (2012). A new control center for dopaminergic systems: pulling the VTA by the tail. Trends Neurosci 35: 681–690.
Calabresi P, Picconi B, Tozzi A, Di Filippo M (2007). Dopamine-mediated regulation of corticostriatal synaptic plasticity. Trends Neurosci 30: 211–219.
Cornish JL, Hunt GE, Robins L, McGregor IS (2012). Regional c-Fos and FosB/DeltaFosB expression associated with chronic methamphetamine self-administration and methamphetamine-seeking behavior in rats. Neuroscience 206: 100–114.
Dang MT, Yokoi F, Yin HH, Lovinger DM, Wang Y et al (2006). Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc Natl Acad Sci USA 103: 15254–15259.
Deumens R, Blokland A, Prickaerts J (2002). Modeling Parkinson’s disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 175: 303–317.
Durieux PF, Schiffmann SN, de Kerchove d’Exaerde A (2012). Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J 31: 640–653.
Ferreira JG, Del-Fava F, Hasue RH, Shammah-Lagnado SJ (2008). Organization of ventral tegmental area projections to the ventral tegmental area-nigral complex in the rat. Neuroscience 153: 196–213.
Geisler S, Marinelli M, Degarmo B, Becker ML, Freiman AJ, Beales M et al (2008). Prominent activation of brainstem and pallidal afferents of the ventral tegmental area by cocaine. Neuropsychopharmacology 33: 2688–2700.
Gerald MC, Gupta TK (1977). The effects of amphetamine isomers on rotarod performance. Psychopharmacology 55: 83–86.
Groenewegen HJ (2003). The basal ganglia and motor control. Neural Plast 10: 107–120.
Hong S, Jhou TC, Smith M, Saleem KS, Hikosaka O (2011). Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J Neurosci 31: 11457–11471.
Jalabert M, Bourdy R, Courtin J, Veinante P, Manzoni OJ, Barrot M et al (2011). Neuronal circuits underlying acute morphine action on dopamine neurons. Proc Natl Acad Sci USA 108: 16446–16450.
Johnson SW, North RA (1992). Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12: 483–488.
Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS (2009a). The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol 513: 566–596.
Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC (2009b). The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61: 786–800.
Jhou TC, Xu SP, Lee MR, Gallen CL, Ikemoto S (2012). Mapping of reinforcing and analgesic effects of the mu opioid agonist Endomorphin-1 in the ventral midbrain of the rat. Psychopharmacology 224: 303–312.
Jhou TC, Good CH, Rowley CS, Xu SP, Wang H, Burnham NW et al (2013). Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways. J Neurosci 33: 7501–7512.
Kaufling J, Veinante P, Pawlowski SA, Freund-Mercier MJ, Barrot M (2009). Afferents to the GABAergic tail of the ventral tegmental area in the rat. J Comp Neurol 513: 597–621.
Kaufling J, Veinante P, Pawlowski SA, Freund-Mercier MJ, Barrot M (2010a). Gamma-aminobutyric acid cells with cocaine-induced DeltaFosB in the ventral tegmental area innervate mesolimbic neurons. Biol Psychiatry 67: 88–92.
Kaufling J, Waltisperger E, Bourdy R, Valera A, Veinante P, Freund-Mercier MJ et al (2010b). Pharmacological recruitment of the GABAergic tail of the ventral tegmental area by acute drug exposure. Br J Pharmacol 161: 1677–1691.
Kelly PH, Moore KE (1976). Mesolimbic dopaminergic neurons in the rotational model of nigrostriatal function. Nature 263: 695–696.
Lavezzi HN, Parsley KP, Zahm DS, Lavezzi HN (2011). Mesopontine rostromedial tegmental nucleus neurons projecting to the dorsal raphe and pedunculopontine tegmental nucleus: psychostimulant-elicited Fos expression and collateralization. Brain Struct Funct 217: 719–734.
Lecca S, Melis M, Luchicchi A, Ennas MG, Castelli MP, Muntoni AL et al (2011). Effects of drugs of abuse on putative rostromedial tegmental neurons, inhibitory afferents to midbrain dopamine cells. Neuropsychopharmacology 36: 589–602.
Lecca S, Melis M, Luchicchi A, Muntoni AL, Pistis M (2012). Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse. Neuropsychopharmacology 37: 1164–1176.
Matsui A, Williams JT (2011). Opioid-sensitive GABA inputs from rostromedial tegmental nucleus synapse onto midbrain dopamine neurons. J Neurosci 31: 17729–17735.
Morikawa H, Paladini CA (2011). Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms. Neuroscience 198: 95–111.
Ogura T, Ogata M, Akita H, Jitsuki S, Akiba L, Noda K et al (2005). Impaired acquisition of skilled behavior in rotarod task by moderate depletion of striatal dopamine in a pre-symptomatic stage model of Parkinson's disease. Neurosci Res 51: 299–308.
Omelchenko N, Bell R, Sesack SR (2009). Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area. Eur J Neurosci 30: 1239–1250.
Paladini CA, Celada P, Tepper JM (1999). Striatal, pallidal, and pars reticulata evoked inhibition of nigrostriatal dopaminergic neurons is mediated by GABA(A) receptors in vivo. Neuroscience 89: 799–812.
Paxinos G, Watson C (2007) The Rat Brain In Stereotaxic Coordinates 4th edn. Academic: San Diego, CA, USA.
Penhune VB, Steele CJ (2012). Parallel contributions of cerebellar, striatal and M1 mechanisms to motor sequence learning. Behav Brain Res 226: 579–591.
Perrotti LI, Bolaños CA, Choi KH, Russo SJ, Edwards S, Ulery PG et al (2005). DeltaFosB accumulates in a GABAergic cell population in the posterior tail of the ventral tegmental area after psychostimulant treatment. Eur J Neurosci 21: 2817–2824.
Pisani A, Centonze D, Bernardi G, Calabresi P (2005). Striatal synaptic plasticity: implications for motor learning and Parkinson's disease. Mov Disord 20: 395–402.
Pryor GT, Larsen FF, Husain S (1978). Interactions of delta9-tetrahydrocannabinol with d-amphetamine, cocaine and nicotine in rats. Pharmacol Biochem Behav 8: 295–318.
Rebec GV (2006). Behavioral electrophysiology of psychostimulants. Neuropsychopharmacology 31: 2341–2348.
Redgrave P, Rodriguez M, Smith Y, Rodriguez-Oroz MC, Lehericy S, Bergman H et al (2010). Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease. Nat Rev Neurosci 11: 760–772.
Rotllant D, Márquez C, Nadal R, Armario A (2010). The brain pattern of c-fos induction by two doses of amphetamine suggests different brain processing pathways and minor contribution of behavioural traits. Neuroscience 168: 691–705.
Rozas G, Guerra MJ, Labandeira-Garcia JL (1997). An automated rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism. Brain Res Prot 2: 75–84.
Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS et al (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 20: 8620–8628.
Stamatakis AM, Stuber GD (2012). Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci 15: 1105–1107.
Sulzer D (2011). How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69: 628–649.
Tepper JM, Lee CR (2007). GABAergic control of substantia nigra dopaminergic neurons. Prog Brain Res 160: 189–208.
Ungless MA, Magill PJ, Bolam JP (2004). Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science 303: 2040–2042.
Watabe-Uchida M, Zhu L, Ogawa SK, Vamanrao A, Uchida N (2012). Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74: 858–873.
Willuhn I, Steiner H (2008). Motor-skill learning in a novel running-wheel task is dependent on D1 dopamine receptors in the striatum. Neuroscience 153: 249–258.
Wise RA (2004). Dopamine, learning and motivation. Nat Rev Neurosci 5: 483–494.
Yin HH, Mulcare SP, Hilário MR, Clouse E, Holloway T, Davis MI et al (2009). Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill. Nat Neurosci 12: 333–341.
Zahm DS, Becker ML, Freiman AJ, Strauch S, Degarmo B, Geisler S et al (2010). Fos after single and repeated self-administration of cocaine and saline in the rat: emphasis on the Basal forebrain and recalibration of expression. Neuropsychopharmacology 35: 445–463.
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We thank Ms Dorothée Daniel for her technical support.
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Bourdy, R., Sánchez-Catalán, MJ., Kaufling, J. et al. Control of the Nigrostriatal Dopamine Neuron Activity and Motor Function by the Tail of the Ventral Tegmental Area. Neuropsychopharmacol 39, 2788–2798 (2014). https://doi.org/10.1038/npp.2014.129
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DOI: https://doi.org/10.1038/npp.2014.129
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