title: Cognitive deficits in transgenic and knock-in HTT mice parallel those in Huntington's disease.
abstract: BACKGROUND
  Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline.
  
  
  OBJECTIVE
  The BACHD and zQ175 mouse models present a more slowly progressing disease phenotype in both motor and cognitive domains, and might therefore offer a better opportunity to measure cognitive decline over a longer timeframe; such models could be useful in screening therapeutic compounds. In order to better define the cognitive impairments evident in BACHD and zQ175 HD mice, both were tested in an instrumental touchscreen visual discrimination assay designed to assess discrimination learning and cognitive flexibility.
  
  
  METHODS
  BACHD and zQ175 mice, as well as their WT controls were tested for their ability to discriminate two complex visual stimuli. Following this discrimination phase, the reinforcement contingencies were reversed and the previously incorrect stimulus became the correct stimulus. In a final, third phase of testing, two novel stimuli were introduced and mice were required to undergo a second round of discrimination testing with these stimuli.
  
  
  RESULTS
  Our results show that learning during the discrimination phase was similar between the WT and BACHD mice. In contrast, the zQ175 at 26 weeks of age showed decreased accuracy over the last 10 days of discrimination, compared to WT controls. During subsequent reversal and novel stimuli phases, both BACHD and zQ175 mice exhibited significant deficits compared to WT controls.
  
  
  CONCLUSIONS
  Our results suggest that the BACHD, and for the first time, zQ175 HD models exhibit cognitive inflexibility and psychomotor slowing, a phenotype that is consistent with cognitive symptoms described in HD patients.
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: Andrew M
authors: AM
authors: Farrar
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: Carol A
authors: CA
authors: Murphy
authors: PsychoGenics Inc., Tarrytown, NY, USA Present address: Department of Psychiatry and Biobehavioral Sciences, The Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
authors: Neil E
authors: NE
authors: Paterson
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: Stephen
authors: S
authors: Oakeshott
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: Dansha
authors: D
authors: He
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: William
authors: W
authors: Alosio
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: Kristi
authors: K
authors: McConnell
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: Liliana B
authors: LB
authors: Menalled
authors: PsychoGenics Inc., Tarrytown, NY, USA.
authors: Sylvie
authors: S
authors: Ramboz
authors: CHDI Management/CHDI Foundation, Princeton, NJ, USA.
authors: Larry C
authors: LC
authors: Park
authors: CHDI Management/CHDI Foundation, Princeton, NJ, USA.
authors: David
authors: D
authors: Howland
authors: PsychoGenics Inc., Tarrytown, NY, USA Department of Psychiatry, Columbia University, NYSPI, NY, USA.
authors: Dani
authors: D
authors: Brunner
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D003201:Computers; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D011597:Psychomotor Performance / Q000502:physiology; D011930:Reaction Time / Q000235:genetics; D012193:Reversal Learning / Q000502:physiology; D014796:Visual Perception / Q000502:physiology
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
keywords: BACHD; mouse; reversal learning; touchscreen; visual discrimination; zQ175