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C4 Motivation and reward seeking in HD mouse lines: possible association with ventral striatal mHTT load and dopamine receptor loss
  1. Kyle Fears1,
  2. Timothy Stone2,
  3. Linda Elliston2,
  4. Zubeyde Bayram-Weston1,
  5. David Harrison1,
  6. Stephen B Dunnett1,
  7. Lesley Jones2,
  8. Simon Brooks1
  1. 1Neuroscience Division, Cardiff University School of Biosciences, Cardiff, UK
  2. 2MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK


Background Apathy and anhedonia are core symptoms of Huntington’s disease (HD) believed to be mediated by the ventral striatal dopamine system. Loss of dopamine D1 and D2 receptors within this region is an early disease feature in HD patients and mouse models.

Aims We sought to determine whether the onset of motivational deficits were associated with ventral striatal mutant huntingtin (mHTT) aggregates, and/or changes in striatal dopamine D1/D2 receptor RNA levels.

Methods/techniques Young HD mice (HdhQ111, HdhQ140, HdhQ150 and zQ175 knock-in models) were subjected to the following behavioural tests: the fixed ratio test probing cognitive function, the progressive-ratio test probing motivation, and the sucrose consumption test probing sucrose sensitivity. Immunohistochemistry (IHC) for striatal mHTT deposition was carried out and gene array analysis was used to determine striatal dopamine receptor RNA levels.

Results The number of rewards attained by Q111, Q150 and Q175 carriers were reduced on the fixed ratio task, while on the progressive ratio task the Q111, Q140 and Q175 mice demonstrated increased apathy. The Q111 and Q140 mice showed a reduction in food consumption but no difference in overall sucrose consumption. Our preliminary IHC and array data found a greater density of mHTT-positive cells in the ventral striatum relative to other striatal regions in all mouse lines, and gene arrays indicated striatal dopamine D1 and D2 receptor RNA levels were reduced in Q175 and Q140 mice by 6 months of age.

Conclusion Our data suggests that the early onset of motivational/anhedonic deficits may be related to ventral striatal neuropathology.

  • mouse models
  • behaviour
  • motivation
  • gene array
  • ventral striatum
  • dopamine

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