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.
Highlights
In our previous studies [10,11,12,13], we demonstrated that the unilateral nigral lactacystin model of Parkinson’s disease (PD) produced a partial lesion of the DAergic nigrostriatal pathway, and cholinergic neuronal loss in the pedunculopontine nucleus (PPN), thereby mirroring what is observed in PD patients, and highlighting the suitability of this model for the current study
In lactacystin-lesioned rats, stereological counts made of PPN cholinergic neurons (identified by fluorescent tagging of choline acetyltransferase (ChAT) demonstrated robust expression of hM3Dq-mCherry (Fig. 1F), with a 72.6 ± 2% of all PPN cholinergic neurons that showed overlap (Fig. 1G)
In all cases, representing both lesioned and sham control animals, no hM3Dq-mCherry expression, in the absence of ChAT coexpression, was observed in any of the stained sections. These results indicate that our use of Cre-dependent viral vectors, to permit restricted expression of hM3Dq in neurons defined by the expression of the cholinergic genetic marker ChAT, is an effective strategy for targeting the PPN cholinergic neurons of rats, in order to enable cell-typespecific manipulations
Summary
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 the side effects of dopamine (DA) replacement strategies (e.g., dyskinesias) for more than 2 decades [1]. Low-frequency DBS can be targeted to the pedunculopontine nucleus (PPN), leading to an improvement in motor-related symptoms, gait and postural abnormalities, which affect a significant number of PD patients [2,3,4,5]. Clinical interest in the PPN as a DBS target stems from the partial denervation of PPN cholinergic neurons (where in the intact brain, such neurons innervate the basal ganglia motor loop [9, 14]) observed in DREADD Activation of Pedunculopontine Cholinergic Neurons Reverses Motor Deficits and Restores Striatal
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
