Sex Differences in Circadian Dysfunction in the BACHD Mouse Model of Huntington’s Disease

Kuljis, Dika; Gad, Laura; Loh, Dawn H.; Kaswan, Zoë MacDowell; Hitchcock, Olivia N.; Ghiani, Cristina A.

doi:10.1371/journal.pone.0147583

Cited by 45 publications

(64 citation statements)

References 87 publications

(77 reference statements)

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“…Mouse models of HD also exhibit a progressive and rapid breakdown of the circadian rest/activity cycle that closely mimics the condition observed in human patients. Phenotype includes loss of consolidated sleep, increased wakeful activity during the rest phase, and more sleep during the active phase [153,[157][158][159]. Collectively this prior research supports the hypothesis that circadian dysfunction is an integral component of HD pathophysiology and could be contributing to the deficits in white matter.…”

Section: Huntington Disease (Hd)supporting

confidence: 59%

Potential Circadian Rhythms in Oligodendrocytes? Working Together Through Time

Colwell

2019

Neurochem Res

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Oligodendrocytes (OL) are the only myelinating cells of the central nervous system thus interferences, either environmental or genetic, with their maturation or function have devastating consequences. Albeit so far neglected, one of the less appreciated, nevertheless possible, regulators of OL maturation and function is the circadian cycle. Yet, disruptions in these rhythms are unfortunately becoming a common "disorder" in the today's world. The temporal patterning of behaviour and physiology is controlled by a circadian timing system based in the anterior hypothalamus. At the molecular level, circadian rhythms are generated by a transcriptional/translational feedback system that regulates transcription and has a major impact on cellular function(s). Fundamental cellular properties/functions in most cell types vary with the daily circadian cycle: OL are unlikely an exception! To be clear, the presence of circadian oscillators or the cell-specific function(s) of the circadian clock in OL has yet to be defined. Furthermore, we wish to entertain the idea of links between the "thin" evidence on OL intrinsic circadian rhythms and their interjection(s) at different stages of lineage progression as well as in supporting/regulating OL crucial function: myelination. Individuals with intellectual and developmental syndromes as well as neurodegenerative diseases present with a disrupted sleep/wake cycle; hence, we raise the possibility that these disturbances in timing can contribute to the loss of white matter observed in these disorders. Preclinical and clinical work in this area is needed for a better understanding of how circadian rhythms influence OL maturation and function(s), to aid the development of new therapeutic strategies and standards of care for these patients.

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Section: Huntington Disease (Hd)supporting

confidence: 59%

Potential Circadian Rhythms in Oligodendrocytes? Working Together Through Time

Colwell

2019

Neurochem Res

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“…We used male mice for these studies as we have previously demonstrated that there are sex differences in the circadian phenotype and SCN pathophysiology in the BACHD line (Kuljis et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…Like other mouse models of HD (Loh, Kudo, Truong, Wu, & Colwell, ; Menalled et al, ; Morton et al, ), the bacterial artificial chromosome transgenic mouse model of HD (BACHD) exhibits disrupted rhythms in sleep, activity, and physiology (Kudo, Loh, et al, ; Kuljis et al, ; Schroeder et al, ). Early in the disease progression (3 month of age), mutant dorsal SCN neurons lose their daily rhythms in electrical activity (Kudo, Schroeder, et al, ; Kuljis et al, ), suggesting circadian behavioral deficits are caused by pathophysiology of the SCN. In this study, we first sought to determine whether the SCN firing rate deficits continue when GABA‐mediated synaptic transmission is blocked, and whether the daily rhythms in resting membrane potential (RMP) and conductance are disrupted.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology in the suprachiasmatic nucleus in mouse models of Huntington’s disease

Kuljis

Kudo

Tahara

et al. 2018

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, are not well established. The BACHD mouse model of HD exhibits disrupted behavioral and physiological rhythms, including decreased electrical activity in the central circadian clock (suprachiasmatic nucleus, SCN). In this study, electrophysiological techniques were used to explore the ionic underpinning of the reduced spontaneous neural activity in male mice. We found that SCN neural activity rhythms were lost early in the disease progression and was accompanied by loss of the normal daily variation in resting membrane potential in the mutant SCN neurons. The low neural activity could be transiently reversed by direct current injection or application of exogenous N-methyl-d-aspartate (NMDA) thus demonstrating that the neurons have the capacity to discharge at WT levels. Exploring the potassium currents known to regulate the electrical activity of SCN neurons, our most striking finding was that these cells in the mutants exhibited an enhancement in the large-conductance calcium activated K (BK) currents. The expression of the pore forming subunit (Kcnma1) of the BK channel was higher in the mutant SCN. We found a similar decrease in daytime electrical activity and enhancement in the magnitude of the BK currents early in disease in another HD mouse model (Q175). These findings suggest that SCN neurons of both HD models exhibit early pathophysiology and that dysregulation of BK current may be responsible.

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“…In addition, our female mice outperformed male animals in cognitive, motor, and nest tests. Studies in HD mouse models have suggested sex-associated differences in the severity or the age of onset of the HD phenotype [15,49,50], with females displaying less severe symptoms or a later development of the disease than males. These findings in mice are reminiscent of clinical observations in HD patients, where a later onset of motor HD alterations has been reported in women [64].…”

Section: Discussionmentioning

confidence: 99%

“…We then tested whether Suvorexant injections over a prolonged period of 5 days might be effective for improving behavioral performances. R6/1 female mice were also included in addition to R6/1 male mice in this study because of the importance of gender differences reported in HD [15,49,50]. Animals were administered drug for 5 consecutive days at 7:00 a.m. daily, and tested in the above behavioral tasks on the 5th day, 12 h after the last injection (7:00 p.m.).…”

Section: Experiments 4: Orx Antagonism Alleviates Behavioral Impairmenmentioning

confidence: 99%

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington's Disease

et al. 2019

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Huntington's disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep-wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep-wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.

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Sex Differences in Circadian Dysfunction in the BACHD Mouse Model of Huntington’s Disease

Cited by 45 publications

References 87 publications

Potential Circadian Rhythms in Oligodendrocytes? Working Together Through Time

Potential Circadian Rhythms in Oligodendrocytes? Working Together Through Time

Pathophysiology in the suprachiasmatic nucleus in mouse models of Huntington’s disease

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington's Disease

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