DREADD Activation of Pedunculopontine Cholinergic Neurons Reverses Motor Deficits and Restores Striatal Dopamine Signali
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ORIGINAL ARTICLE
DREADD Activation of Pedunculopontine Cholinergic Neurons Reverses Motor Deficits and Restores Striatal Dopamine Signaling in Parkinsonian Rats Puneet K. Sharma 1 & Lisa Wells 2 & Gaia Rizzo 2 & Joanna L. Elson 3 & Jan Passchier 2 & Eugenii A. Rabiner 2 & Roger N. Gunn 1,2 & David T. Dexter 1 & Ilse S. Pienaar 1,4
# The Author(s) 2020
Abstract The brainstem-based pedunculopontine nucleus (PPN) traditionally associates with motor function, but undergoes extensive degeneration during Parkinson’s disease (PD), which correlates with axial motor deficits. PPN-deep brain stimulation (DBS) can alleviate certain symptoms, but its mechanism(s) of action remains unknown. We previously characterized rats hemi-intranigrally injected with the proteasomal inhibitor lactacystin, as an accurate preclinical model of PD. Here we used a combination of chemogenetics with positron emission tomography imaging for in vivo interrogation of discrete neural networks in this rat model of PD. Stimulation of excitatory designer receptors exclusively activated by designer drugs expressed within PPN cholinergic neurons activated residual nigrostriatal dopaminergic neurons to produce profound motor recovery, which correlated with striatal dopamine efflux as well as restored dopamine receptor 1- and dopamine receptor 2-based medium spiny neuron activity, as was ascertained with c-Fos-based immunohistochemistry and stereological cell counts. By revealing that the improved axial-related motor functions seen in PD patients receiving PPN-DBS may be due to stimulation of remaining PPN cholinergic neurons interacting with dopaminergic ones in both the substantia nigra pars compacta and the striatum, our data strongly favor the PPN cholinergic–midbrain dopaminergic connectome as mechanism for PPN-DBS’s therapeutic effects. These findings have implications for refining PPN-DBS as a promising treatment modality available to PD patients. Key Words Cholinergic . dopamine . DREADD . motor behavior . pedunculopontine nucleus . positron emission tomography.
Introduction
Puneet K. Sharma and Lisa Wells are shared first authors Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-019-00830-4) contains supplementary material, which is available to authorized users. * Ilse S. Pienaar [email protected] 1
Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK
2
Invicro, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
3
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
4
School of Life Sciences, University of Sussex, Falmer BN1 9PH, UK
Targeting of different brain regions using deep brain stimulation (DBS), as a therapeutic option available to Parkinson’s disease (PD) patients, has been successfully used as a surgical approach to treat both the symptoms (e.g., tremor) and also the side effects of dopamine (DA) replacement strategies (e.g
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