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

• Published in: Nature communications 2022-01, Vol.13 (1), p.504-504, Article 504
• Main Authors: Masini, Débora, Kiehn, Ole
• Format: Article
• Language: English
• Subjects: 14/19; 14/35; 631/1647/2198; 631/378/1689/1718; 631/378/2632; 64/110; 64/60; Animal models; Animals; Basal ganglia; Brain diseases; Brain stem; Cell activation; Central nervous system diseases; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine receptors; Excitatory Amino Acid Agents - pharmacology; Female; Ganglia; Genetics; Glutamatergic transmission; Humanities and Social Sciences; Locomotion; Male; Mesencephalon; Mesencephalon - drug effects; Mesencephalon - metabolism; Mesencephalon - physiopathology; Mice; Mice, Inbred C57BL; Movement disorders; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinson's disease; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - physiopathology; Pedunculopontine tegmental nucleus; Pedunculopontine Tegmental Nucleus - metabolism; Pedunculopontine Tegmental Nucleus - physiopathology; Recovery of function; Restoration; Science; Science (multidisciplinary); Signs and symptoms; γ-Aminobutyric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28075-4

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. Here, the authors use cell-type specific stimulation of brainstem neurons within the caudal pedunculopontine nucleus to show that activation of excitatory neurons can normalize severe locomotor deficit in mouse models of parkinsonism. The study defines a potential target for neuromodulatory restoration of locomotor function in Parkinson’s disease.