Neuromodulation modifies α-synuclein spreading dynamics in vivo and the pattern is predicted by changes in whole-brain function.

Parkinson’s Disease circuit function neuromodulation optogenetics α-synuclein

Journal

Brain stimulation
ISSN: 1876-4754
Titre abrégé: Brain Stimul
Pays: United States
ID NLM: 101465726

Informations de publication

Date de publication:
01 Aug 2024
Historique:
received: 16 04 2024
revised: 08 07 2024
accepted: 31 07 2024
medline: 4 8 2024
pubmed: 4 8 2024
entrez: 3 8 2024
Statut: aheadofprint

Résumé

Many neurodegenerative disease treatments, such as deep brain stimulation for Parkinson's Disease, can alleviate symptoms by primarily compensating for circuit dysfunctions. However, the stimulation's effect on the underlying disease progression remains relatively unknown. Here, we report that neuromodulation can not only modulate circuit function but also modulate the in vivo spreading dynamics of α-synuclein pathology, the primarily pathological hallmark observed in Parkinson's Disease. In a mouse model, pre-formed fibrils were injected into the striatum to induce widespread α-synuclein pathology. Two days after fibril injection, mice were treated for two weeks with daily optogenetic stimulation of the Secondary Motor Area, Layer V. Whole brains were then extracted, immunolabeled, cleared, and imaged with light-sheet fluorescent microscopy. Repeated optogenetic stimulation led to a decrease in pathology at the site of stimulation and at various cortical and subcortical regions, while the contralateral cortex saw a consistent increase. Aligning the pathology changes with optogenetic-fMRI measured brain activity, we found that the changes in pathology and brain function had similar spatial locations but opposite polarity. These results demonstrate the ability to modulate and predict whole brain pathology changes using neuromodulation, opening a new horizon for investigating optimized neuromodulation therapies.

Sections du résumé

BACKGROUND BACKGROUND
Many neurodegenerative disease treatments, such as deep brain stimulation for Parkinson's Disease, can alleviate symptoms by primarily compensating for circuit dysfunctions. However, the stimulation's effect on the underlying disease progression remains relatively unknown. Here, we report that neuromodulation can not only modulate circuit function but also modulate the in vivo spreading dynamics of α-synuclein pathology, the primarily pathological hallmark observed in Parkinson's Disease.
METHODS METHODS
In a mouse model, pre-formed fibrils were injected into the striatum to induce widespread α-synuclein pathology. Two days after fibril injection, mice were treated for two weeks with daily optogenetic stimulation of the Secondary Motor Area, Layer V. Whole brains were then extracted, immunolabeled, cleared, and imaged with light-sheet fluorescent microscopy.
RESULTS RESULTS
Repeated optogenetic stimulation led to a decrease in pathology at the site of stimulation and at various cortical and subcortical regions, while the contralateral cortex saw a consistent increase. Aligning the pathology changes with optogenetic-fMRI measured brain activity, we found that the changes in pathology and brain function had similar spatial locations but opposite polarity.
CONCLUSION CONCLUSIONS
These results demonstrate the ability to modulate and predict whole brain pathology changes using neuromodulation, opening a new horizon for investigating optimized neuromodulation therapies.

Identifiants

DOI: 10.1016/j.brs.2024.07.021 PMID: 39096960
pubmed: 39096960
pii: S1935-861X(24)00136-0
doi: 10.1016/j.brs.2024.07.021
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of Competing Interest J.H.L. is a founder, consultant, and board member of LVIS. The rest of the authors declare no potential conflicts of interest. None of the funding sources played a role in the design, collection, analysis, interpretation of the data, or in the decision to submit the manuscript for publication.

Auteurs

Ehsan Dadgar-Kiani (E)

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.

Gregor Bieri (G)

Department of Genetics, Stanford University, CA 94305, USA.

Ronald Melki (R)

Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France.

Aronee Hossain (A)

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.

Aaron D Gitler (AD)

Department of Genetics, Stanford University, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Jin Hyung Lee (JH)

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA. Electronic address: ljinhy@stanford.edu.

Classifications MeSH