Anatomo‐Functional Mapping of the Primate Mesencephalic Locomotor Region Using Stereotactic Lesions

Abstract

A BS TRACT: Background: Dysfunction of the mesencephalic locomotor region has been implicated in gait disorders. However, the role of its 2 components, the pedunculopontine and the cuneiform nuclei, in locomotion is poorly understood in primates. Objectives: To analyze the effect of cuneiform lesions on gait and balance in 2 monkeys and to compare them with those obtained after cholinergic pedunculopontine lesions in 4 monkeys and after lesions in both the cuneiform and pedunculopontine nuclei in 1 monkey. Methods: After each stereotactic lesion, we performed a neurological examination and gait and balance assessments with kinematic measures during a locomotor task. The 3-dimensional location of each lesion was analyzed on a common brainstem space. Results: After each cuneiform lesion, we observed a contralateral cervical dystonia including an increased tone in the proximal forelimb and an increase in knee angle, back curvature and walking speed. Conversely, cholinergic pedunculopontine lesions increased tail rigidity and back curvature and an imbalance of the muscle tone between the ipsiand contralateral hindlimb with decreased knee angles. The walking speed was decreased. Moreover, pedunculopontine lesions often resulted in a longer time to waking postsurgery. Conclusions: The location of the lesions and their behavioral effects revealed a somatotopic organization of muscle tone control, with the neck and forelimb represented within the cuneiform nucleus and hindlimb and tail represented within the pedunculopontine nucleus. Cuneiform lesions increased speed, whereas pedunculopontine lesions decreased it. These findings confirm the complex and specific role of the cuneiform and pedunculopontine nuclei in locomotion and suggest the role of the pedunculopontine in sleep control.

Dystonia and the pedunculopontine nucleus: Current evidences and potential mechanisms

“…When the cholinergic cell-specific lesion was performed on the PPN, the primates showed imbalanced muscle tone between the hindlimbs of the lesioned and non-lesioned sides. Additionally, the rigidity of the tail and proximal part of the limb contralateral to the lesioned side also appeared along with the back curvature ( 12 ). Moreover, when wild-type human tau was specifically expressed in the cholinergic neurons of the PPN, rats showed dystonia-like behavior of the hindlimb (hindlimb retracted toward body, crossing, and immobility) while suspended ( 38 ).…”

“…Pathologic changes of the PPN have been reported in patients of different types of dystonia, and the manifestation of dystonia could be alleviated through DBS of the PPN, reflecting a crucial role of the PPN in the development of dystonia ( 8 – 11 ). So far, increasing preclinical evidences also showed alterations of the muscle tone, locomotion, cognitive functions and sleep following lesion or neuromodulation of the PPN, which mimicked the motor and non-motor manifestations of dystonia ( 2 , 5 , 12 – 14 ). Moreover, from the anatomical aspects, the PPN has dense connections with the dystonia-related basal ganglia-cerebello-thalamo-cortical circuit, which lays the foundation of the PPN involved in dystonia ( 15 ).…”

The Mesencephalic Locomotor Region: Multiple Cell Types, Multiple Behavioral Roles, and Multiple Implications for Disease

“…The MLR is strongly conserved in vertebrates (Figure 1A-E). Electrical stimulation of the MLR controls locomotor output in lamprey (Sirota and others 2000;Figure 1F), zebrafish (Carbo-Tano and others 2022; Figure 1G), stingray (Bernau and others 1991), salamander (Cabelguen and others 2003;Figure 1H), rat (Bachmann and others 2013;Garcia-Rill and others 1987;Hofer and others 2022;Figure 1I), mouse (Roseberry and others 2016), rabbit (Musienko and others 2008), goose (Steeves and others 1987), pig (Chang, Santamaria, and others 2021), cat (Opris and others 2019;Shik and others 1966), and monkey (Eidelberg and others 1981;Gay and others 2020;Goetz and others 2016).…”

“…The MLR is strongly conserved in vertebrates ( Figure 1A–E ). Electrical stimulation of the MLR controls locomotor output in lamprey ( Sirota and others 2000 ; Figure 1F ), zebrafish ( Carbo-Tano and others 2022 ; Figure 1G ), stingray ( Bernau and others 1991 ), salamander ( Cabelguen and others 2003 ; Figure 1H ), rat ( Bachmann and others 2013 ; Garcia-Rill and others 1987 ; Hofer and others 2022 ; Figure 1I ), mouse ( Roseberry and others 2016 ), rabbit ( Musienko and others 2008 ), goose ( Steeves and others 1987 ), pig ( Chang, Santamaria, and others 2021 ), cat ( Opris and others 2019 ; Shik and others 1966 ), and monkey ( Eidelberg and others 1981 ; Gay and others 2020 ; Goetz and others 2016 ). It does so by providing direct glutamatergic input to reticulospinal neurons in the reticular formation—as demonstrated in lamprey ( Brocard and Dubuc 2003 ; Le Ray and others 2003 ), zebrafish ( Carbo-Tano and others 2022 ), salamander ( Ryczko, Auclair, and others 2016 ), and mouse ( Bretzner and Brownstone 2013 ; Capelli and others 2017 )—which send direct input to interneurons of the central pattern generator for locomotion, as shown in lamprey ( Buchanan and Grillner 1987 ; for review, Grillner and El Manira 2020 ; Leiras and others 2022 ; Figure 1A ).…”