The operant serial implicit learning task reveals early onset motor learning deficits in the Hdh^Q92 knock‐in mouse model of Huntington's disease

Abstract

A range of genetic mouse models of Huntington's disease have been created. However, as knock-in models typically have milder phenotypes, they have frequently been overlooked as therapeutic tools in favour of the transgenic models that display severe behavioural symptoms. More sensitive tests are therefore required to reveal abnormalities and release the potential of knock-in lines. An implicit learning task for mice has been developed in the nine-hole operant box test apparatus, in which mice must respond to a sequence of lights in order to earn a reward. A light stimulus was presented randomly in one of five holes, to which a nose poke response resulted in the light being extinguished and a second light illuminated in a different hole. Response to the second light resulted in a liquid reward. To probe implicit learning, a predictable stimulus sequence was embedded among many unpredictable sequences. In the current study, the Hdh(Q92) mouse model of Huntington's disease was examined. At 4 months of age, Hdh(Q92/Q92) mice demonstrated clear and significant deficits in both accuracy and reaction time on all trials of the implicit learning task, with improved performance on predictable trials. We believe this to be the earliest reported behavioural deficit in the Hdh(Q92) knock-in mouse line. The results of this study validate the serial implicit learning task as a sensitive tool for the examination of implicit and motor learning deficits in mutant mice, and may provide a powerful test for probing potential treatments for Huntington's disease.

A two years longitudinal study of a transgenic Huntington disease monkey

“…The impairment in hippocampal-dependent memory functions was consistent with the reduction in hippocampal size at 24 months of age (Figure 1e). These findings replicate the hippocampal-dependent memory deficits found in HD patients even before the onset of motor symptoms [5,7,8,45,59,60], which have also been reported in all analyzed mouse models of the disease [11,20,44,61]. …”

An operant serial implicit learning task (SILT) in rats: Task acquisition, performance and the effects of striatal lesions

“…In subsequent versions of the programmes, we now include more a systematic recording of all correct and incorrect responses (different classes of error), as well as imposing a limited hold within which the animal must respond or the trial is aborted (as a further class of error). Moreover, we have now inserted the options to present either or both stimuli for progressively brief periods and although it is not the purpose to make these very brief (as, for example, in the conventional 5-choice reaction time task, where the purpose is to probe attentional function), nevertheless reducing S1 and S2 from 2 to 0.5 s significantly challenges performance to an extent necessary to enhance sensitivity in situations where very well-trained animals are performing close to ceiling (Trueman et al, 2007).…”

Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice

“…Differences are particularly striking in the age of onset of the earliest reported behavioral deficits, with a deficit in grip strength reported at 1.5 months in one line with 150 CAG repeats inserted into the mouse gene (Woodman et al, 2007), but no deficit in muscle power is noted in mice with the same mutation in another background (Heng et al, 2007). Several studies have reported cognitive impairments (Trueman et al, 2007, Trueman et al, 2008) and subtle balance and motor coordination deficits (Kennedy et al, 2003) at 4 months in various other KI lines.…”