Cerebellar Deep Brain Stimulation as a Dual-Function Therapeutic for Restoring Movement and Sleep in Dystonic Mice

Authors

Luis E Salazar Leon
Linda H Kim
Roy V Sillitoe

Publication Date

10-1-2024

Journal

Neurotherapeutics

DOI

10.1016/j.neurot.2024.e00467

PMID

39448336

PMCID

PMC11585869

PubMedCentral® Posted Date

10-23-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Deep Brain Stimulation, Mice, Cerebellum, Dystonia, Sleep, Male, Disease Models, Animal, Sleep Wake Disorders, Mice, Transgenic, Movement, Mice, Inbred C57BL, Deep brain stimulation, Cerebellar nuclei, Dystonia, Sleep, Circadian rhythms

Abstract

Dystonia arises with cerebellar dysfunction, which plays a key role in the emergence of multiple pathophysiological deficits that range from abnormal movements and postures to disrupted sleep. Current therapeutic interventions typically do not simultaneously address both the motor and non-motor symptoms of dystonia, underscoring the necessity for a multi-functional therapeutic strategy. Deep brain stimulation (DBS) is effectively used to reduce motor symptoms in dystonia, with existing parallel evidence arguing for its potential to correct sleep disturbances. However, the simultaneous efficacy of DBS for improving sleep and motor dysfunction, specifically by targeting the cerebellum, remains underexplored. Here, we test the effect of cerebellar DBS in two genetic mouse models with dystonia that exhibit sleep defects—Ptf1aCre;Vglut2fx/fx and Pdx1Cre;Vglut2fx/fx—which have overlapping cerebellar circuit miswiring defects but differing severity in motor phenotypes. By targeting DBS to the fiber tracts located between the cerebellar fastigial and the interposed nuclei (FN + INT-DBS), we modulated sleep dysfunction by enhancing sleep quality and timing. This DBS paradigm improved wakefulness and rapid eye movement sleep in both mutants. Additionally, the latency to reach REM sleep, a deficit observed in human dystonia patients, was reduced in both models. Cerebellar DBS also induced alterations in the electrocorticogram (ECoG) patterns that define sleep states. As expected, DBS reduced the severe dystonic twisting motor symptoms that are observed in the Ptf1aCre;Vglut2fx/fx mice. These findings highlight the potential for using cerebellar DBS to simultaneously improve sleep and reduce motor dysfunction in dystonia and uncover its potential as a dual-effect in vivo therapeutic strategy.