Abstract
Dopaminergic signaling within the primary motor cortex (M1) is necessary for successful motor skill learning. Dopaminergic neurons projecting to M1 are located in the ventral tegmental area (VTA, nucleus A10) of the midbrain. It is unknown which behavioral correlates are encoded by these neurons. The objective here is to investigate whether VTA-M1 fibers are collaterals of projections to prefrontal cortex (PFC) or nucleus accumbens (NAc) or if they form a distinct pathway. In rats, multiple-site retrograde fluorescent tracers were injected into M1, PFC and the core region of the NAc and VTA sections investigated for concomitant labeling of different tracers. Dopaminergic neurons projecting to M1, PFC and NAc were found in nucleus A10 and to a lesser degree in the medial nucleus A9. Neurons show high target specificity, minimal collateral branching to other than their target area and hardly cross the midline. Whereas PFC- and NAc-projecting neurons are indistinguishably intermingled within the ventral portion of dopaminergic nuclei in middle and caudal midbrain, M1-projecting neurons are only located within the dorsal part of the rostral midbrain. Within M1, the forelimb representation receives sevenfold more dopaminergic projections than the hindlimb representation. This strong rostro-caudal gradient as well as the topographical preference to dorsal structures suggest that projections to M1 emerged late in the development of the dopaminergic systems in and form a functionally distinct system.
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Arias-Carrion O, Stamelou M, Murillo-Rodriguez E, Menendez-Gonzalez M, Poppel E (2010) Dopaminergic reward system: a short integrative review. Int Arch Med 3:24. doi:10.1186/1755-7682-3-24
Awenowicz PW, Porter LL (2002) Local application of dopamine inhibits pyramidal tract neuron activity in the rodent motor cortex. J Neurophysiol 88:3439–3451. doi:10.1152/jn.00078.2002
Berger B, Gaspar P, Verney C (1991) Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci 14:21–27
Bjorklund A, Dunnett SB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci 30:194–202. doi:10.1016/j.tins.2007.03.006
Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68:815–834. doi:10.1016/j.neuron.2010.11.022
Choi D, Li D, Raisman G (2002) Fluorescent retrograde neuronal tracers that label the rat facial nucleus: a comparison of Fast Blue, Fluoro-ruby, Fluoro-emerald, Fluoro-gold and Dil. J Neurosci Methods 117:167–172
Conner JM, Culberson A, Packowski C, Chiba AA, Tuszynski MH (2003) Lesions of the basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron 38:819–829
Dahlstrom A, Fuxe K (1964) Localization of monoamines in the lower brain stem. Experientia 20:398–399
Dawson TM, Barone P, Sidhu A, Wamsley JK, Chase TN (1986a) Quantitative autoradiographic localization of D-1 dopamine receptors in the rat brain: use of the iodinated ligand [125I]SCH 23982. Neurosci Lett 68:261–266
Dawson TM, Gehlert DR, Wamsley JK (1986b) Quantitative autoradiographic localization of central dopamine D-1 and D-2 receptors. Adv Exp Med Biol 204:93–118
Descarries L, Lemay B, Doucet G, Berger B (1987) Regional and laminar density of the dopamine innervation in adult rat cerebral cortex. Neuroscience 21:807–824
Fallon JH (1981) Collateralization of monoamine neurons: mesotelencephalic dopamine projections to caudate, septum, and frontal cortex. J Neurosci 1:1361–1368
German DC, Manaye KF (1993) Midbrain dopaminergic neurons (nuclei A8, A9, and A10): three-dimensional reconstruction in the rat. J Comp Neurol 331:297–309. doi:10.1002/cne.903310302
Hosp JA, Luft AR (2013) Dopaminergic meso-cortical projections to M1: role in motor learning and motor cortex plasticity. Front Neurol 4:145. doi:10.3389/fneur.2013.00145
Hosp JA, Molina-Luna K, Hertler B, Atiemo CO, Luft AR (2009) Dopaminergic modulation of motor maps in rat motor cortex: an in vivo study. Neuroscience 159:692–700. doi:10.1016/j.neuroscience.2008.12.056
Hosp JA, Pekanovic A, Rioult-Pedotti MS, Luft AR (2011) Dopaminergic projections from midbrain to primary motor cortex mediate motor skill learning. J Neurosci 31:2481–2487. doi:10.1523/JNEUROSCI.5411-10.2011
Jiang X, Johnson RR, Burkhalter A (1993) Visualization of dendritic morphology of cortical projection neurons by retrograde axonal tracing. J Neurosci Methods 50:45–60
Kehr W, Lindqvist M, Carlsson A (1976) Distribution of dopamine in the rat cerebral cortex. J Neural Transm 38:173–180
Kleim JA, Lussnig E, Schwarz ER, Comery TA, Greenough WT (1996) Synaptogenesis and Fos expression in the motor cortex of the adult rat after motor skill learning. J Neurosci 16:4529–4535
Kobbert C, Apps R, Bechmann I, Lanciego JL, Mey J, Thanos S (2000) Current concepts in neuroanatomical tracing. Prog Neurobiol 62:327–351
Leonard CM (1969) The prefrontal cortex of the rat. I. Cortical projection of the mediodorsal nucleus. II. Efferent connections. Brain Res 12:321–343
Luby-Phelps K, Taylor DL, Lanni F (1986) Probing the structure of cytoplasm. J Cell Biol 102:2015–2022
Luft AR, Schwarz S (2009) Dopaminergic signals in primary motor cortex. Int J Dev Neurosci 27:415–421. doi:10.1016/j.ijdevneu.2009.05.004
Luft AR, Buitrago MM, Ringer T, Dichgans J, Schulz JB (2004) Motor skill learning depends on protein synthesis in motor cortex after training. J Neurosci 24:6515–6520. doi:10.1523/JNEUROSCI.1034-04.2004
Margolis EB, Coker AR, Driscoll JR, Lemaitre AI, Fields HL (2010) Reliability in the identification of midbrain dopamine neurons. PLoS ONE 5:e15222. doi:10.1371/journal.pone.0015222
Martres MP, Bouthenet ML, Sales N, Sokoloff P, Schwartz JC (1985) Widespread distribution of brain dopamine receptors evidenced with [125I]iodosulpride, a highly selective ligand. Science 228:752–755
Molina-Luna K, Pekanovic A, Rohrich S, Hertler B, Schubring-Giese M, Rioult-Pedotti MS, Luft AR (2009) Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS ONE 4:e7082. doi:10.1371/journal.pone.0007082
Monfils MH, Plautz EJ, Kleim JA (2005) In search of the motor engram: motor map plasticity as a mechanism for encoding motor experience. Neuroscientist 11:471–483. doi:10.1177/1073858405278015
Novikova L, Novikov L, Kellerth JO (1997) Persistent neuronal labeling by retrograde fluorescent tracers: a comparison between Fast Blue, Fluoro-Gold and various dextran conjugates. J Neurosci Methods 74:9–15
Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press, Waltham
Preuss TM (1995) Do rats have prefrontal cortex? The Rose–Woolsey–Akert program reconsidered. J Cogn Neurosci 7:1–24. doi:10.1162/jocn.1995.7.1.1
Reiner A, Veenman CL, Medina L, Jiao Y, Del Mar N, Honig MG (2000) Pathway tracing using biotinylated dextran amines. J Neurosci Methods 103:23–37
Rioult-Pedotti MS, Friedman D, Donoghue JP (2000) Learning-induced LTP in neocortex. Science 290:533–536
Rose JE, Woolsey CN (1948) The orbitofrontal cortex and its connections with the mediodorsal nucleus in rabbit, sheep and cat. Res Publ Assoc Res Nerv Ment Dis 27(1 vol):210–232
Schultz W (2007a) Behavioral dopamine signals. Trends Neurosci 30:203–210. doi:10.1016/j.tins.2007.03.007
Schultz W (2007b) Multiple dopamine functions at different time courses. Annu Rev Neurosci 30:259–288. doi:10.1146/annurev.neuro.28.061604.135722
Swanson LW (1982) The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9:321–353
Takada M, Hattori T (1987) Organization of ventral tegmental area cells projecting to the occipital cortex and forebrain in the rat. Brain Res 418:27–33
Uylings HB, Groenewegen HJ, Kolb B (2003) Do rats have a prefrontal cortex? Behav Brain Res 146:3–17
Vitrac C, Peron S, Frappe I, Fernagut PO, Jaber M, Gaillard A, Benoit-Marand M (2014) Dopamine control of pyramidal neuron activity in the primary motor cortex via D2 receptors. Front Neural Circuits 8:13. doi:10.3389/fncir.2014.00013
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This study was funded by grants from the Swiss National Foundation (SNF, NCCR Neuro). We thank Clement Osei-Atiemo for his support.
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221_2015_4211_MOESM1_ESM.pdf
Supplementary figure 1. Schematic illustration of injection sites. On schematic drawings of representative brain sections, typical injection sites are indicated: (a) M1 forelimb representation, (b) M1 hindlimb representation, (c) prefrontal cortex and (d) core region of the nucleus accumbens. M1, primary motor cortex; M2, secondary motor cortex; S1, primary sensory cortex; PFC, prefrontal cortex; NAc, core region of the nucleus accumbens. Scale bar: 1 mm (PDF 338 kb)
221_2015_4211_MOESM2_ESM.pdf
Supplementary figure 2. Histological verification of injection sites. (a) Intracortical injection of the retrograde tracer Fast Blue. CC, corpus callosum; M1, primary motor cortex. Scale bar: 0.5 mm. (b) Injection site of the retrograde tracer Micro Ruby in the prefrontal cortex. Fluorescent image of a tracer depot (indicated by arrowhead) is merged with a structural image performed by brightfield microscopy. fmi, forceps minor of the corpus callosum; M1, primary motor cortex; M2, secondary motor cortex; and PFC, prefrontal cortex. Scale bar: 1 mm. (c) Injection side of the retrograde tracer Micro Ruby into the nucleus accumbens. Fluorescent image of a tracer deposit (indicated by arrowhead) is merged with a structural image performed by brightfield microscopy. fmi, forceps minor; CC, corpus callosum; cNA, core region of nucleus accumbens; cPu, caudate putamen; LV, lateral ventricle; and S1, primary sensory cortex. Scale bar: 1 mm (PDF 309577 kb)
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Hosp, J.A., Nolan, H.E. & Luft, A.R. Topography and collateralization of dopaminergic projections to primary motor cortex in rats. Exp Brain Res 233, 1365–1375 (2015). https://doi.org/10.1007/s00221-015-4211-2
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DOI: https://doi.org/10.1007/s00221-015-4211-2