Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism

Débora Masini,Ole Kiehn

doi:10.1038/s41467-022-28075-4

Débora Masini, Ole Kiehn

Open Access

https://doi.org/10.1038/s41467-022-28075-4

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Abstract

The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions are deficient in Parkinson’s disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the basal ganglia, the PPN may be a suitable target for ameliorating parkinsonian motor symptoms. Here, we use in vivo cell-type specific PPN activation to restore motor function in two mouse models of parkinsonism made by acute pharmacological blockage of dopamine transmission. With a combination of chemo- and opto-genetics, we show that excitation of caudal glutamatergic PPN neurons can normalize the otherwise severe locomotor deficit in PD, whereas targeting the local GABAergic population only leads to recovery of slow locomotion. The motor rescue driven by glutamatergic PPN activation is independent of activity in nearby locomotor promoting glutamatergic Cuneiform neurons. Our observations point to caudal glutamatergic PPN neurons as a potential target for neuromodulatory restoration of locomotor function in PD.

Highlights

The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance
Is characterized by the death of midbrain dopaminergic neurons. This hypodopaminergic disorder affects basal ganglia circuitries associated with selection and planning of movement, and as a result, patients suffer from severe motor impairment, including tremor, akinesia, bradykinesia, and difficulty in initiation of voluntary movement[1,2,3,4]
The ideal model of Parkinson’s disease (PD) should consist of clinical features including motor and nonmotor symptoms, develop progressively, and demonstrate the neurodegenerative hallmarks typical of PD

Summary

Introduction

The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance These motor actions are deficient in Parkinson’s disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Is characterized by the death of midbrain dopaminergic neurons This hypodopaminergic disorder affects basal ganglia circuitries associated with selection and planning of movement, and as a result, patients suffer from severe motor impairment, including tremor, akinesia (lack of movement), bradykinesia (slowness of movement), and difficulty in initiation of voluntary movement (freezing of gait or delayed initiation of a motor plan)[1,2,3,4]. The MLR contains two nuclei: the cuneiform (CnF) and the pedunculopontine (PPN)

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