Cerebellar deep brain stimulation as a dual-function therapeutic for restoring movement and sleep in dystonic mice.
| Autor: | Salazar Leon LE; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, 77030, USA., Kim LH; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, 77030, USA., Sillitoe RV; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, 77030, USA. Electronic address: sillitoe@bcm.edu. |
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| Jazyk: | angličtina |
| Zdroj: | Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2024 Oct; Vol. 21 (6), pp. e00467. Date of Electronic Publication: 2024 Oct 23. |
| DOI: | 10.1016/j.neurot.2024.e00467 |
| Abstrakt: | 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-Ptf1a Cre ;Vglut2 fx/fx and Pdx1 Cre ;Vglut2 fx/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 Ptf1a Cre ;Vglut2 fx/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. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roy V. Sillitoe reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by The Hamill Foundation. Roy V. Sillitoe reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by National Institute of Neurological Disorders and Stroke. Roy V. Sillitoe reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by Dystonia Medical Research Foundation. Roy V. Sillitoe reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by National Institute of Child Health and Human Development. Linda H. Kim reports financial support, article publishing charges, equipment, drugs, or supplies, and travel were provided by Dystonia Medical Research Foundation. Roy V. Sillitoe reports a relationship with Raynor Cerebellum Foundation that includes: board membership. Roy V. Sillitoe serves on the Board of Reviewing Editors at eLife. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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