Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M4 Muscarinic Receptor

Mark S. Moehle; Tristano Pancani; Nellie Byun; Samantha E. Yohn; George H. Wilson; Johnathan W. Dickerson; Daniel H. Remke; Zixiu Xiang; Colleen M. Niswender; Jürgen Wess; Carrie K. Jones; Craig W. Lindsley; Jerri M. Rook; P. Jeffrey Conn

doi:10.1016/j.neuron.2017.12.008

Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M₄ Muscarinic Receptor

Mark S. Moehle, Tristano Pancani, Nellie Byun, Samantha E. Yohn, George H. Wilson, Johnathan W. Dickerson, Daniel H. Remke, Zixiu Xiang, Colleen M. Niswender, Jürgen Wess, Carrie K. Jones, Craig W. Lindsley, Jerri M. Rook, P. Jeffrey Conn^*

^*Corresponding author for this work

Neuroscience

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M₄) to oppose cAMP-dependent dopamine receptor subtype 1 (D₁) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D₁-mediated activation of motor activity. These studies provide important new insights into the unique role of M₄ in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output. Moehle et al. show activation of M₄ can induce inhibition of D₁ signaling. Interestingly, this mechanism occurs on direct pathway terminals in the SNr from acetylcholine released by hindbrain cholinergic projections, expanding the model of cholinergic regulation of the BG.

Original language	English (US)
Pages (from-to)	1358-1372.e4
Journal	Neuron
Volume	96
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2017.12.008
State	Published - Dec 20 2017

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Neuroscience(all)

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10.1016/j.neuron.2017.12.008

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Moehle, M. S., Pancani, T., Byun, N., Yohn, S. E., Wilson, G. H., Dickerson, J. W., Remke, D. H., Xiang, Z., Niswender, C. M., Wess, J., Jones, C. K., Lindsley, C. W., Rook, J. M., & Conn, P. J. (2017). Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M₄ Muscarinic Receptor. Neuron, 96(6), 1358-1372.e4. https://doi.org/10.1016/j.neuron.2017.12.008

@article{80779e72e28f45d48088cc445119f16a,

title = "Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M4 Muscarinic Receptor",

abstract = "Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M4) to oppose cAMP-dependent dopamine receptor subtype 1 (D1) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D1-mediated activation of motor activity. These studies provide important new insights into the unique role of M4 in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output. Moehle et al. show activation of M4 can induce inhibition of D1 signaling. Interestingly, this mechanism occurs on direct pathway terminals in the SNr from acetylcholine released by hindbrain cholinergic projections, expanding the model of cholinergic regulation of the BG.",

author = "Moehle, {Mark S.} and Tristano Pancani and Nellie Byun and Yohn, {Samantha E.} and Wilson, {George H.} and Dickerson, {Johnathan W.} and Remke, {Daniel H.} and Zixiu Xiang and Niswender, {Colleen M.} and J{\"u}rgen Wess and Jones, {Carrie K.} and Lindsley, {Craig W.} and Rook, {Jerri M.} and Conn, {P. Jeffrey}",

note = "Funding Information: We would like to thank Weimin Peng for her invaluable assistance and Dr. Allan Levey for the gracious gift of the M 4 antibody. This work was supported by grants from the Dystonia Medical Research Foundation , the Mahlon DeLong Young Investigator Award to M.S.M., and a research grant to P.J.C., as well as grants from the NIH ( MH073676 and NS031373 ) to P.J.C. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = dec,

day = "20",

doi = "10.1016/j.neuron.2017.12.008",

language = "English (US)",

volume = "96",

pages = "1358--1372.e4",

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Moehle, MS, Pancani, T, Byun, N, Yohn, SE, Wilson, GH, Dickerson, JW, Remke, DH, Xiang, Z, Niswender, CM, Wess, J, Jones, CK, Lindsley, CW, Rook, JM & Conn, PJ 2017, 'Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M₄ Muscarinic Receptor', Neuron, vol. 96, no. 6, pp. 1358-1372.e4. https://doi.org/10.1016/j.neuron.2017.12.008

TY - JOUR

T1 - Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M4 Muscarinic Receptor

AU - Moehle, Mark S.

AU - Pancani, Tristano

AU - Byun, Nellie

AU - Yohn, Samantha E.

AU - Wilson, George H.

AU - Dickerson, Johnathan W.

AU - Remke, Daniel H.

AU - Xiang, Zixiu

AU - Niswender, Colleen M.

AU - Wess, Jürgen

AU - Jones, Carrie K.

AU - Lindsley, Craig W.

AU - Rook, Jerri M.

AU - Conn, P. Jeffrey

N1 - Funding Information: We would like to thank Weimin Peng for her invaluable assistance and Dr. Allan Levey for the gracious gift of the M 4 antibody. This work was supported by grants from the Dystonia Medical Research Foundation , the Mahlon DeLong Young Investigator Award to M.S.M., and a research grant to P.J.C., as well as grants from the NIH ( MH073676 and NS031373 ) to P.J.C. Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/12/20

Y1 - 2017/12/20

N2 - Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M4) to oppose cAMP-dependent dopamine receptor subtype 1 (D1) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D1-mediated activation of motor activity. These studies provide important new insights into the unique role of M4 in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output. Moehle et al. show activation of M4 can induce inhibition of D1 signaling. Interestingly, this mechanism occurs on direct pathway terminals in the SNr from acetylcholine released by hindbrain cholinergic projections, expanding the model of cholinergic regulation of the BG.

AB - Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M4) to oppose cAMP-dependent dopamine receptor subtype 1 (D1) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D1-mediated activation of motor activity. These studies provide important new insights into the unique role of M4 in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output. Moehle et al. show activation of M4 can induce inhibition of D1 signaling. Interestingly, this mechanism occurs on direct pathway terminals in the SNr from acetylcholine released by hindbrain cholinergic projections, expanding the model of cholinergic regulation of the BG.

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Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M₄ Muscarinic Receptor

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