Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease
Carine Karachi, … , Etienne C. Hirsch, Chantal François
Carine Karachi, … , Etienne C. Hirsch, Chantal François
Published July 12, 2010
Citation Information: J Clin Invest. 2010;120(8):2745-2754. https://doi.org/10.1172/JCI42642.
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Research Article Neuroscience

Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease

Abstract

Gait disorders and postural instability, which are commonly observed in elderly patients with Parkinson disease (PD), respond poorly to dopaminergic agents used to treat other parkinsonian symptoms. The brain structures underlying gait disorders and falls in PD and aging remain to be characterized. Using functional MRI in healthy human subjects, we have shown here that activity of the mesencephalic locomotor region (MLR), which is composed of the pedunculopontine nucleus (PPN) and the adjacent cuneiform nucleus, was modulated by the speed of imagined gait, with faster imagined gait activating a discrete cluster within the MLR. Furthermore, the presence of gait disorders in patients with PD and in aged monkeys rendered parkinsonian by MPTP intoxication correlated with loss of PPN cholinergic neurons. Bilateral lesioning of the cholinergic part of the PPN induced gait and postural deficits in nondopaminergic lesioned monkeys. Our data therefore reveal that the cholinergic neurons of the PPN play a central role in controlling gait and posture and represent a possible target for pharmacological treatment of gait disorders in PD.

Authors

Carine Karachi, David Grabli, Frédéric A. Bernard, Dominique Tandé, Nicolas Wattiez, Hayat Belaid, Eric Bardinet, Annick Prigent, Hans-Peter Nothacker, Stéphane Hunot, Andreas Hartmann, Stéphane Lehéricy, Etienne C. Hirsch, Chantal François

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Figure 5

Loss of NADPH+ neurons after bilateral PPN lesion.

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Loss of NADPH+ neurons after bilateral PPN lesion. (A) Nissl-stained...
(A) Nissl-stained section showing the anatomical localization of the PPN (boxed region) in a control macaque brainstem. (B) Photomicrographs of PPN sections labeled for NADPH diaphorase histochemistry, showing a 20% toxin injection site into the PPN compared with a control. (C) Computer-generated maps of NADPH+ neurons (blue) in 4 regularly spaced sections covering the anteroposterior extent of the structure in lesioned animal M4. Each dot represents an NADPH+ neuron; gray areas represent the extent of the injection site; hatched areas denote myelinated nerve fibers. (D) All injection sites of the 5 macaques were transferred onto the corresponding brainstem map of macaque M4. Each individual is represented by a different color. Note that the cholinergic part of the PPN was lesioned in all animals. (E) Quantification of the total number of NADPH+ neurons in the PPN, showing that neuronal loss reached 39% in lesioned animals (n = 5) compared with controls (n = 5). **P < 0.01, Mann-Whitney U test. (F) Adjacent PPN sections, labeled for NADPH diaphorase histochemistry and for myelin staining with luxol fast blue, and mapping of NADPH+ neurons showed that myelinated fibers were preserved after toxin injections at 20%. Arrows indicate the center of 2 lesions. IC, inferior colliculus; SCP, superior cerebellar peduncle. Scale bars: 5 mm (A and C); 1 mm (B and F).