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Deep Brain Stimulation of the Interposed Nucleus Reverses Motor Deficits and Stimulates Production of Anti-inflammatory Cytokines in Ataxia Mice

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Abstract

Cerebellum is one of the major targets of autoimmunity and cerebellar damage that leads to ataxia characterized by the loss of fine motor coordination and balance, with no treatment available. Deep brain stimulation (DBS) could be a promising treatment for ataxia but has not been extensively investigated. Here, our study aims to investigate the use of interposed nucleus of deep cerebellar nuclei (IN-DCN) for ataxia. We first characterized ataxia-related motor symptom of a Purkinje cell (PC)-specific LIM homeobox (Lhx)1 and Lhx5 conditional double knockout mice by motor coordination tests, and spontaneous electromyogram (EMG) recording. To validate IN-DCN as a target for DBS, in vivo local field potential (LFP) multielectrode array recording of IN-DCN revealed abnormal LFP amplitude surges in PCs. By synchronizing the EMG and IN-DCN recordings (neurospike and LFP) with high-speed video recordings, ataxia mice showed poorly coordinated movements associated with low EMG amplitude and aberrant IN-DCN neural firing. To optimize IN-DCN-DBS for ataxia, we tested DBS parameters from low (30 Hz) to high stimulation frequency (130 or 150 Hz), and systematically varied pulse width values (60 or 80 µs) to maximize motor symptom control in ataxia mice. The optimal IN-DCN-DBS parameter reversed motor deficits in ataxia mice as detected by animal behavioral tests and EMG recording. Mechanistically, cytokine array analysis revealed that anti-inflammatory cytokines such as interleukin (IL)-13 and IL-4 were upregulated after IN-DCN-DBS, which play key roles in neural excitability. As such, we show that IN-DCN-DBS is a promising treatment for ataxia and possibly other movement disorders alike.

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Data Availability

The datasets and supporting materials generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AD:

Alzheimer’s disease

AP:

Anteroposterior

BOSS:

Blackrock offline spike sorting

CSF:

Cerebrospinal fluid

DBS :

Deep brain stimulation

DCN:

Deep cerebellar nuclei

DKO:

Double knockout

DN:

Dentate nucleus

DV:

Dorsoventral

EMG:

Electromyogram

GAD:

Glutamic acid decarboxylase

GCM:

Gastrocnemius muscle

GPi :

Globus pallidus pars interna

G-CSF:

Granulocyte-colony stimulating factor

IL:

Interleukin

IN:

Interposed nucleus

IN-DCN:

Interposed nucleus of deep cerebellar nuclei

IN-DCN-DBS:

Interposed nucleus-deep cerebellar nuclei- deep brain stimulation

IR:

Infrared

LFP:

Local field potential

Lhx :

LIM homeobox

MATLAB:

Matrix laboratory

MEA:

Multielectrode array

ML:

Mediolateral

MS:

Multiple sclerosis

PC:

Purkinje cell

PD:

Parkinson’s disease

PCA:

Principal component analysis

RMS :

Root mean square

SCF:

Stem cell factor

STN:

Subthalamic nucleus

TBI:

Traumatic brain injury

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Funding

This work is supported in part by the Innovation and Technology Commission of the Hong Kong Special Administrative Region Government (ITS/151/17 and ITS/168/19FP) and The Health and Medical Research Fund (HMRF), Food and Health Bureau, and Hong Kong Special Administrative Region Government (07181356) award to Chi Him Eddie Ma.

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Authors and Affiliations

  1. Department of Neuroscience, City University of Hong Kong, Tat Chee Avenue, Hong Kong SAR, China

    Gajendra Kumar, Pallavi Asthana & Chi Him Eddie Ma

  2. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China

    Wing Ho Yung

  3. School of Life Sciences, Center for Cell and Developmental Biology and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China

    Kin Ming Kwan

  4. Department of Biomedical Engineering, City University of Hong Kong, Tat Chee Avenue, Hong Kong, SAR, China

    Chung Tin

Authors
  1. Gajendra Kumar
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  2. Pallavi Asthana
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  3. Wing Ho Yung
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  4. Kin Ming Kwan
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  5. Chung Tin
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  6. Chi Him Eddie Ma
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Contributions

G. K. performed the surgery, in vivo animal behavioral assessments, in vivo recordings, and electrophysiology data analysis. P. A. maintained the Lhx1/5 and Pcp2-Cre mouse colonies and genotyping, and performed the cytokine array analysis. W. H. Y. and C. T. provided technical support and advice on DBS. K. M. K. provided the Lhx1/5 ataxia mice and genotyping protocol. C. H. E. M. conceived the project, designed the study, and wrote the manuscript with inputs from all authors. All authors read and approved the manuscript.

Corresponding author

Correspondence to Chi Him Eddie Ma.

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Kumar, G., Asthana, P., Yung, W.H. et al. Deep Brain Stimulation of the Interposed Nucleus Reverses Motor Deficits and Stimulates Production of Anti-inflammatory Cytokines in Ataxia Mice. Mol Neurobiol 59, 4578–4592 (2022). https://doi.org/10.1007/s12035-022-02872-w

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