Circadian Abnormalities in Motor Activity in a BAC Transgenic Mouse Model of Huntington’s Disease

Oakeshott, Stephen; Balcı, Fuat; Filippov, I K; Murphy, Carol A.; Port, Russell G.; Connor, David; Paintdakhi, Ahmad; LeSauter, Joseph; Menalled, Liliana; Ramboz, Sylvie; Kwak, Seung; Howland, David; Silver, Rae; Brunner, Dani

doi:10.1371/currents.rrn1225

Cited by 40 publications

(29 citation statements)

References 29 publications

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“…By twelve weeks of age, an altered circadian rhythm activity was seen in R6/2 mice with hypoactivity during the dark phase and hyperactivity in the light phase (Rudenko et al, 2009). Similarly, at 42 weeks of age, there was a lengthened circadian cycle in BAC Huntington's Disease transgenic mice (Oakeshott et al, 2011). Changes in behaviour were also frequently specific to either the dark or light period.…”

Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 95%

“…Neurodegenerative diseases in mice have been the only conditions characterized by automated technologies with the majority of studies examining genetically altered mouse models of Huntington's disease (Steele et al, 2007b;Wood et al, 2008;Rudenko et al, 2009;Mochel et al, 2011;Oakeshott et al, 2011;Mochel et al, 2012;Zarringhalam et al, 2012;Balci et al, 2013). Huntington's disease is characterized by a progressive decline in cognitive and motor functions and patients frequently suffer from sleep disturbances and affective disorders (Rudenko et al, 2009;Mochel et al, 2011;Balci et al, 2013).…”

Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 99%

“…Using automated homecages, hypoactivity was detected in a number of mouse models of disease including genetically altered models of Huntington's disease (Oakeshott et al, 2011). Compared to wild-type control animals, BAC Huntington's Disease transgenic mice spent significantly more time immobile at both 42 and 60 weeks of age.…”

Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 99%

“…there is often only one study per disease), it is currently difficult to determine whether the differences detected are actual differences between different disease states, artefacts or the result of the choice of timepoints sampled. Changes in circadian rhythm were commonly seen in mouse models of Huntington's disease (Steele et al, 2007b;Wood et al, 2008;Rudenko et al, 2009;Oakeshott et al, 2011;Zarringhalam et al, 2012). By twelve weeks of age, an altered circadian rhythm activity was seen in R6/2 mice with hypoactivity during the dark phase and hyperactivity in the light phase (Rudenko et al, 2009).…”

Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 99%

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The power of automated behavioural homecage technologies in characterizing disease progression in laboratory mice: A review

Richardson

2015

Applied Animal Behaviour Science

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a b s t r a c tBehavioural changes that occur as animals become sick have been characterized in a number of species and include the less frequent occurrence of 'luxury behaviours' such as playing, grooming and socialization. 'Sickness behaviours' or behavioural changes following exposure to infectious agents, have been particularly well described; animals are typically less active, sleep more, exhibit postural changes and consume less food/water. Disease is frequently induced in laboratory mice to model pathophysiological processes and investigate potential therapies but despite what is known about behavioural changes as animals become sick, behavioural phenotyping of mice involved in disease studies is relatively rare. A detailed understanding of how behaviour changes as mice get sick could be applied to improve welfare of laboratory mice and support the underlying biomedical research. Specifically, characterizing behavioural changes in ill health could help those working with laboratory mice to recognize when refinements should be introduced, when severity limits are being approached and when humane endpoints should be implemented. Understanding how behaviour changes with illness may also help to identify compounds that have a clinical effect as well as when these agents act. There are an increasing number of automated systems to monitor the behaviour of laboratory mice in their homecages incorporating technologies such as the quantification of cage movement, automated video analysis and radiofrequency identification transponders/readers. Mouse models of neurodegenerative diseases particularly Huntington's disease have been well characterized using these systems and behavioural biomarkers of pathology, including changes in the animals' use of environmental enrichment, changes in food/water consumption and alterations in circadian rhythms, are now monitored by laboratories worldwide and used to refine studies and develop therapies. In contrast, automated behavioural technologies have not been used to characterize the behaviour of mice with systemic diseases such as cancer and liver disease. In this review, common behavioural changes that occur in animals with declining health will be discussed with an emphasis on progressive disease studies involving mice. Automated homecage behaviour recording technologies will then be summarized, studies in which these systems have been used to characterize the behaviour of mice with progressive diseases will be reviewed and the potential to apply automated technologies to refine disease studies involving mice will be discussed.

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Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 95%

Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 99%

Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 99%

Section: Assessment Of Disease Progression Using Automated Behaviouramentioning

confidence: 99%

See 2 more Smart Citations

The power of automated behavioural homecage technologies in characterizing disease progression in laboratory mice: A review

Richardson

2015

Applied Animal Behaviour Science

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“…15). HD patients display sleep disturbances, including insomnia and altered circadian rhythms [Taylor et al, 1997;Morton et al, 2005], and this aspect of the disease is mirrored in animal models [Morton et al, 2005;Rudenko et al, 2009;Gonzales and Yin, 2010;Kudo et al, 2011;Oakeshott et al, 2011]. In two recently published studies, SIRT1 was shown to counteract the activity of the clock machinery and regulate several circadian genes [Asher et al, 2008;Nakahata et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of specific histone deacetylases suppresses pathogenesis in a Drosophila model of Huntington’s disease

Pallos

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Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

Smarr

Cutler

Loh

et al. 2019

J of Neuroscience Research

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Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock‐in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.

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Circadian Abnormalities in Motor Activity in a BAC Transgenic Mouse Model of Huntington’s Disease

Cited by 40 publications

References 29 publications

The power of automated behavioural homecage technologies in characterizing disease progression in laboratory mice: A review

The power of automated behavioural homecage technologies in characterizing disease progression in laboratory mice: A review

Inhibition of specific histone deacetylases suppresses pathogenesis in a Drosophila model of Huntington’s disease

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

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