Exercise attenuates neuropathology and has greater benefit on cognitive than motor deficits in the R6/1 Huntington's disease mouse model

Exp Neurol. 2013 Oct:248:457-69. doi: 10.1016/j.expneurol.2013.07.014. Epub 2013 Jul 30.


Huntington's disease (HD) is a neurodegenerative disease caused by a mutation within the huntingtin gene that induces degeneration within the striatal nuclei, progressing to widespread brain atrophy and death. The neurodegeneration produces symptoms that reflect a corticostriatal disconnection syndrome involving motor, cognitive and psychiatric disturbance. Environmental enrichment has been demonstrated to be beneficial to patients with neurological disorders, with exercise being central to this effect. Rodent studies have confirmed exercise-induced neurogenesis and increased growth factor levels in the brain and improved behavioural function. The present study sought to determine whether an extended regime of exercise could retard disease progression in the R6/1 mouse model of HD. The study was designed specifically with a translational focus, selecting behavioural assessments with high clinical predictive validity. We found that exercise improved gait function in both control and HD mice and selectively improved performance in the R6/1 mice on a motor coordination aspect of the balance beam task. Exercise also retarded the progression of cognitive dysfunction on water T-maze procedural and reversal learning probes presented serially to probe cognitive flexibility. In addition, exercise reduced striatal neuron loss in the R6/1 mice but increased striatal neuronal intra-nuclear inclusion size and number relative to non-exercised R6/1 mice which demonstrated increased numbers of extra-neuronal inclusions, suggesting that the functional effects were striatally mediated. These results confirm and extend those from previous studies that demonstrate that HD may be amenable to exercise-mediated therapeutics, but suggest that the impact of such interventions may be primarily cognitive.

Keywords: Cognitive training; Enrichment; Exercise; Huntington's disease; R6/1; Striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Brain / pathology*
  • Brain / physiopathology
  • Cognition / physiology*
  • Cognition Disorders / pathology
  • Cognition Disorders / physiopathology
  • Cognition Disorders / therapy*
  • Disease Models, Animal
  • Disease Progression
  • Exercise Therapy / methods*
  • Gait / physiology
  • Hand Strength / physiology
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology
  • Huntington Disease / therapy*
  • Maze Learning / physiology
  • Mice
  • Motor Activity / physiology*
  • Neurons / pathology
  • Physical Conditioning, Animal / methods
  • Reversal Learning / physiology