Brainstem cholinergic cell loss causes slowly-developing motor impairments
- 1Georgetown University Medical Center
Abstract
Pedunculopontine nucleus (PPN) cholinergic degeneration is a feature of Parkinson's disease (PD), but it is difficult to isolate the symptoms and circuit alterations caused by cholinergic cell loss in PD, where multiple nuclei are simultaneously degenerating. Here we develop a novel mouse model of brainstem cholinergic cell loss to define the timeline of symptom development and map physiological adaptations within the brainstem. Mild motor symptoms, including balance and motor learning deficits reminiscent of early-stage PD, developed after cholinergic lesion with an unexpected long delay. Ex vivo whole-cell recordings showed that cholinergic cell loss increased excitatory synaptic drive onto glutamatergic PPN neurons and increased their intrinsic ability to generate sustained action potential output. In parallel, fiber photometry experiments revealed a slight increase in glutamatergic sensory responsiveness that closely tracked the delayed onset of behavioral symptoms. Together, these results reveal that brainstem cholinergic cell loss triggers the reorganization of motor-related brainstem circuits, providing critical insight into the consequences of non-dopaminergic degeneration in PD.
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BibTeX
@misc{udobi2026brainstem,
title = {{Brainstem cholinergic cell loss causes slowly-developing motor impairments}},
author = {K. Udobi and V. Aleman and V. Lewitus and M. Fallah and B. Bernstein and G. Zhang and M. Ezeiza Ortega and C. Konja and S. Grossen and P. A. Forcelli and N. Neckel and R. C. Evans},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759730},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759730v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Brainstem cholinergic cell loss causes slowly-developing motor impairments
AU - K. Udobi
AU - V. Aleman
AU - V. Lewitus
AU - M. Fallah
AU - B. Bernstein
AU - G. Zhang
AU - M. Ezeiza Ortega
AU - C. Konja
AU - S. Grossen
AU - P. A. Forcelli
AU - N. Neckel
AU - R. C. Evans
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759730
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759730v1
AB - Pedunculopontine nucleus (PPN) cholinergic degeneration is a feature of Parkinson's disease (PD), but it is difficult to isolate the symptoms and circuit alterations caused by cholinergic cell loss in PD, where multiple nuclei are simultaneously degenerating. Here we develop a novel mouse model of brainstem cholinergic cell loss to define the timeline of symptom development and map physiological adaptations within the brainstem. Mild motor symptoms, including balance and motor learning deficits reminiscent of early-stage PD, developed after cholinergic lesion with an unexpected long delay. Ex vivo whole-cell recordings showed that cholinergic cell loss increased excitatory synaptic drive onto glutamatergic PPN neurons and increased their intrinsic ability to generate sustained action potential output. In parallel, fiber photometry experiments revealed a slight increase in glutamatergic sensory responsiveness that closely tracked the delayed onset of behavioral symptoms. Together, these results reveal that brainstem cholinergic cell loss triggers the reorganization of motor-related brainstem circuits, providing critical insight into the consequences of non-dopaminergic degeneration in PD.
ER -