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Journal of neuroscience research
09, 2022;100 (9): 1707-1720.

Cuprizone-mediated demyelination reversibly degrades voiding behavior in mice while sparing brainstem reflex.

Ramalakshmi Ramasamy, Cara C Hardy, Stephen J Crocker, Phillip P Smith
Author Information
  1. Ramalakshmi Ramasamy: Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
  2. Cara C Hardy: Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
  3. Stephen J Crocker: Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut, USA. ORCID
  4. Phillip P Smith: Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
PMID: 35596557 DOI: 10.1002/jnr.25065

Abstract

Multiple sclerosis (MS) is a chronic, progressively debilitating demyelinating disease of the central nervous system (CNS). Nearly 80% of MS patients experience lower urinary tract dysfunction early in their diagnosis. This significantly affects the quality of life, and in latter stages of disease is a leading cause of hospitalization. Previously, animal models have shown that inflammatory Demyelination in the CNS causes profound bladder dysfunction, but the confounding influence of systemic inflammation limits the potential interpretation of the contribution of CNS Demyelination to bladder dysfunction. Since the micturition circuit has myelinated neuronal connections in the cortex, brainstem, and spinal cord, we examined alterations in bladder function in the Cuprizone model characterized by demyelinating lesions in the cortex and corpus callosum that are independent of T-cell-mediated autoimmunity. Herein, we report that a 4-week dietary Cuprizone treatment in C57Bl/6J mice induced alterations in voiding behavior with increased micturition frequency and reduced volume voided, similar to human MS bladder dysfunction. Subsequently, recovery from Cuprizone treatment restored normal bladder function. Demyelination and remyelination were confirmed by Luxol Fast Blue staining of the corpus callosum. Additionally, we also determined that an 8-week Cuprizone treatment, resulting in chronic Demyelination lacking spontaneous remyelination potential, is associated with an exacerbated voiding phenotype. Interestingly, while Cuprizone-induced CNS Demyelination severely affected conscious (cortical) urinary behavior, the brainstem and spinal cord reflex remained unchanged, as confirmed by urethane-anesthetized cystometry. This is the first study to show that cortical Demyelination independent of inflammation can negatively impact urinary function.

Keywords

RRID:SCR_001620 RRID:SCR_002285 RRID:SCR_002798 bladder dysfunction conscious urinary behavior cuprizone cystometry demyelination

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Grants

  1. R01AG058814/NIH HHS
  2. R21 NS125332-01/NIH HHS

MeSH Term

Animals
Brain Stem
Corpus Callosum
Cuprizone
Demyelinating Diseases
Disease Models, Animal
Humans
Inflammation
Mice
Mice, Inbred C57BL
Multiple Sclerosis
Myelin Sheath
Oligodendroglia
Quality of Life
Reflex
Urination

Chemicals

Cuprizone
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural
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