Cognitive training modifies disease symptoms in a mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is an incurable neurodegenerative disorder which causes a triad of motor, cognitive and psychiatric disturbances. Cognitive disruptions are a core feature of the disease, which significantly affect daily activities and quality of life, therefore cognitive training interventions present an exciting therapeutic intervention possibility for HD. We aimed to determine if specific cognitive training, in an operant task of attention, modifies the subsequent behavioural and neuropathological phenotype of the HdhQ111 mouse model of HD.Three testing groups comprising both HdhQ111 mice and wildtype controls were used. The first group received cognitive training in an operant task of attention at 4 months of age. The second group received cognitive training in a comparable non-attentional operant task at 4 months of age, and the third group were control animals that did not receive cognitive training. All groups were then tested in an operant task of attention at 12 months of age. Relative to naïve untrained mice, both wildtype and HdhQ111 mice that received cognitive training in the operant task of attention demonstrated an increased number of trials initiated, greater accuracy, and fewer ‘time out’ errors. A specific improvement in response time performance was observed in HdhQ111 mice, relative to naïve untrained HdhQ111 mice. Relative to the group that received comparable training in a non-attentional task, both wildtype and HdhQ111 mice that received attentional training demonstrated superior accuracy in the task and made fewer ‘time out’ errors. Despite significant behavioural change, in both wildtype and HdhQ111 mice that had received cognitive training, no significant changes in neuropathology were observed between any of the testing groups. These results demonstrate that attentional cognitive training implemented at a young age significantly improves attentional performance, at an older age, in both wildtype and HdhQ111 mice. Attentional cognitive training also improved motor performance in HdhQ111 mice, thus leading to the conclusion that cognitive training can improve disease symptoms in a mouse model of HD.

Cognitive training increases dendritic arborization in the dorsal hippocampal CA1 and CA3 neurons of female and male Long–Evans rats

“…For example, the type of cognitive training regime applied to animals is an important factor influencing efficacy; cognitive training in attentional tasks significantly improves attention relative to cognitive training in nonattentional tasks. Another factor is animal age, particularly because the brain may demonstrate a degree of plasticity if training can be implemented at a young age and can prevent cognitive decline during animal aging (Yhnell et al, ).…”

“…Training on a hippocampal‐dependent task of spatial maze learning has been associated with transient increases in dendritic spine density, whereas training on other hippocampus‐dependent tasks, for example, trace eyeblink conditioning, are associated with changes in synaptic structure (Leuner, Falduto, & Shors, ). Furthermore, cognitive training that is focused on tasks of executive function prevents cognitive declines that appear as part of the normal aging process in both mice and humans (Yhnell, Lelos, Dunnet, & Brooks, ). At the molecular level, cognitive training has been associated with increases in serum BDNF, which is associated with neuronal development and functional plasticity (Haut, Lim, & MacDonald, ).…”

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

“…The observation that nuclear ERK modulation ameliorates cognitive deficits in HD models as well as in WT animals suggests an interesting hypothesis. It has been previously shown in a number of HD models, including HdhQ111 and zQ175, that behavioural training or environmental enrichment (EE) can lead to a significant delay in cognitive decline 29,41–43 . Interestingly, these effects in HD mouse models have been shown to be gender biased, with females better responding to the treatment, and were paralleled by the alleviation of depression-like behaviour normally more pronounced in females than in males 44 .…”

Automated Operant Assessments of Huntington’s Disease Mouse Models

“…Operant testing has been used as a therapeutic intervention in HD mice which modifies disease related symptoms [18,19]. Therefore, the future use of operant training or testing in HD mice may well be as part of a combinatorial therapy when translated into the patient clinic.…”