Cognitive Training at a Young Age Attenuates Deficits in the zQ175 Mouse Model of HD

Abstract

Huntington's Disease (HD) is a progressive neurodegenerative disorder that causes motor, cognitive, and psychiatric symptoms. In these experiments, we tested if operant training at an early age affected adult cognitive deficits in the zQ175 KI Het (zQ175) mouse model of HD. In Experiment 1 we trained zQ175 mice in a fixed-ratio/progressive ratio (FR/PR) task to assay learning and motivational deficits. We found pronounced deficits in response rates and task engagement in naïve adult zQ175 mice (32–33 weeks age), while deficits in zQ175 mice trained from 6–7 weeks age were either absent or less severe. When those mice were re-tested as adults, FR/PR performance deficits were absent or otherwise less severe than deficits observed in naïve adult zQ175 relative to wild type (WT) mice. In Experiment 2, we used a Go/No-go operant task to assess the effects of early cognitive testing on response inhibition deficits in zQ175 mice. We found that zQ175 mice that began testing at 7–8 weeks did not exhibit deficits in Go/No-go testing, but when re-tested at 28–29 weeks age exhibited an initial impairment that diminished with training. These transient deficits were nonetheless mild relative to deficits observed among adult zQ175 mice without prior testing experience. In Experiment 3 we trained mice in a two-choice visual discrimination test to evaluate cognitive flexibility. As in prior experiments, we found performance deficits were mild or absent in mice that started training at 6–9 weeks of age, while deficits in naive mice exposed to training at 28–29 weeks were severe. Re-testing mice at 28–29 weeks age, were previously trained starting at 6–9 weeks, revealed that deficits in learning and cognitive flexibility were absent or reduced relative to effects observed in naive adults. In Experiment 4, we tested working memory deficits with a delayed non-match to position (DNMTP) test. Mice with prior experience exhibited mild working memory deficits, with males zQ175 exhibiting no deficits, and females performing significantly worse than WT mice at a single delay interval, whereas naive zQ175 exhibited severe delay-dependent deficits at all intervals exceeding 1 s. In sum, these experiments indicate that CAG-dependent impairments in motivation, motor control, cognitive flexibility, and working memory are sensitive to the environmental enrichment and experience. These findings are of clinical relevance, as HD carrier status can potentially be detected at an early age.

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

“…In sum, this experiment indicates that RB5 acts as cognitive enhancer in females trained in a striatal-dependent procedural learning task and rescued procedural learning deficits in zQ175 HD mice. These data are in accordance with previous evidence showing that early experiences of environmental enrichment with cognitive testing not only ameliorated the severity of cognitive deficits in zQ175 mice but this beneficial effect was mostly evident in female mice 29 . At present, the sex difference is not fully understood and will require further investigation.…”

“…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 .…”

Quantitative Electroencephalographic Biomarkers in Preclinical and Human Studies of Huntington’s Disease: Are They Fit-for-Purpose for Treatment Development?

“…The EEG disturbances observed in the Het mice suggest HD pathology, but the link to phenoconversion remains unclear. Previous work has demonstrated that Het mice develop behavioral symptoms, and reason for the lack of apparent symptoms in this particular study is unknown (13, 15, 23). Further research is needed to establish a closer linkage between the symptoms and qEEG biomarkers in the zQ175 Het model.…”

Alterations in synaptic function and plasticity in Huntington disease

“…The behavioural relevance of these forms of plasticity is not well characterized, although they may play a role in cognitive and behavioural flexibility (Cui et al, ; Augustin and Lovinger, ). Disruption of cognitive flexibility is prominent in HD (Lawrence et al, ; Curtin et al, ) and further study of eCB‐mediated plasticity may improve our understanding of these symptoms.…”

“…The behavioural relevance of these forms of plasticity is not well characterized, although they may play a role in cognitive and behavioural flexibility (Cui et al, 2015;. Disruption of cognitive flexibility is prominent in HD (Lawrence et al, 1996;Curtin et al, 2016) and further study of eCB-mediated plasticity may improve our understanding of these symptoms. eCBs and the HD phenotype Loss of CB1 in HD patients begins at early stages of the disease (Glass et al, 2000;Laere et al, 2010) and occurs on both SPNs and interneurons (Horne et al, 2013).…”