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DREADD activation of pedunculopontine cholinergic neurons reverses motor deficits and restores striatal dopamine signaling in parkinsonian rats
Version 2 2023-06-12, 09:18
Version 1 2023-06-09, 20:06
journal contribution
posted on 2023-06-12, 09:18 authored by Puneet K Sharma, Lisa Wells, Gaia Rizzo, Joanna L Elson, Jan Passchier, Eugenii A Rabiner, Roger N Gunn, David T Dexter, Ilse PienaarThe 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 mecha-nism(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 (PET) imaging for in vivo in-terrogation of discrete neural networks in this rat model of PD. Stimulation of excitatory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) expressed within PPN cholinergic neurons activated residual nigrostriatal dopaminergic neurons to produce pro-found motor recovery, which correlated with striatal dopamine efflux as well as restored dopamine receptor (DR) 1- and DR2-based medium spiny neuron (MSN) activity, as was ascertained with c-Fos-based immunohistochemistry and stereological cell counts. By revealing that the improved axi-al-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 (SNpc) 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 PPD-DBS as a promising treatment modality available to PD patients.
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Publication status
- Published
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- Published version
Journal
NeurotherapeuticsISSN
1933-7213Publisher
Springer VerlagExternal DOI
Department affiliated with
- BSMS Neuroscience Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2020-01-06First Open Access (FOA) Date
2020-01-24First Compliant Deposit (FCD) Date
2020-01-06Usage metrics
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