Circadian regulation of sleep in a pre-clinical model of Dravet syndrome: dynamics of sleep stage and siesta re-entrainment

Abstract Study Objectives Sleep disturbances are common co-morbidities of epileptic disorders. Dravet syndrome (DS) is an intractable epilepsy accompanied by disturbed sleep. While there is evidence that daily sleep timing is disrupted in DS, the difficulty of chronically recording polysomnographic sleep from patients has left our understanding of the effect of DS on circadian sleep regulation incomplete. We aim to characterize circadian sleep regulation in a mouse model of DS. Methods Here we exploit long-term electrocorticographic recordings of sleep in a mouse model of DS in which one copy of the Scn1a gene is deleted. This model both genocopies and phenocopies the disease in humans. We test the hypothesis that the deletion of Scn1a in DS mice is associated with impaired circadian regulation of sleep. Results We find that DS mice show impairments in circadian sleep regulation, including a fragmented rhythm of non-rapid eye movement (NREM) sleep and an elongated circadian period of sleep. Next, we characterize re-entrainment of sleep stages and siesta following jet lag in the mouse. Strikingly, we find that re-entrainment of sleep following jet lag is normal in DS mice, in contrast to previous demonstrations of slowed re-entrainment of wheel-running activity. Finally, we report that DS mice are more likely to have an absent or altered daily “siesta”. Conclusions Our findings support the hypothesis that the circadian regulation of sleep is altered in DS and highlight the value of long-term chronic polysomnographic recording in studying the role of the circadian clock on sleep/wake cycles in pre-clinical models of disease.

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4067 Cancer-related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

Journal of Clinical and Translational Science ◽

10.1017/cts.2020.373 ◽

2020 ◽

Vol 4 (s1) ◽

pp. 125-125

Author(s):

Josephine K. Liwang ◽

Li Rebekah Feng ◽

Brian Wolff ◽

Jeniece Regan ◽

Sarah Alshawi ◽

...

Keyword(s):

Mouse Model ◽

Synergistic Effect ◽

Mitochondrial Dysfunction ◽

Androgen Deprivation Therapy ◽

Mitochondrial Function ◽

Wheel Running ◽

Combined Treatment ◽

Coupling Efficiency ◽

Androgen Deprivation ◽

Wheel Running Activity

OBJECTIVES/GOALS: Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. METHODS/STUDY POPULATION: Sixty-four participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy–Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants’ whole blood. An ADT/RT-induced fatigue mouse model was developed with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using Western blot analysis of Glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). RESULTS/ANTICIPATED RESULTS: Fatigue in the ADT group was exacerbated during RT compared to the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated a synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model, and its mechanism may be related to bioenergetics in the CNS.

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Cessation of Nightly Voluntary Wheel Running Activity Following Exposure to a Mouse Model of Posttraumatic Stress

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.588.14 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Courtney M. Stroh ◽

Erin M. Kinney ◽

Sarah C. Coste

Keyword(s):

Mouse Model ◽

Posttraumatic Stress ◽

Wheel Running ◽

Voluntary Wheel Running ◽

Running Activity ◽

Wheel Running Activity ◽

Voluntary Wheel

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Long-term voluntary wheel running does not alter vascular amyloid burden but reduces neuroinflammation in the Tg-SwDI mouse model of cerebral amyloid angiopathy

Journal of Neuroinflammation ◽

10.1186/s12974-019-1534-0 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 6

Author(s):

Lisa S. Robison ◽

Dominique L. Popescu ◽

Maria E. Anderson ◽

Nikita Francis ◽

Joshua Hatfield ◽

...

Keyword(s):

Mouse Model ◽

Cerebral Amyloid Angiopathy ◽

Wheel Running ◽

Amyloid Angiopathy ◽

Amyloid Burden ◽

Voluntary Wheel Running ◽

Cerebral Amyloid ◽

Voluntary Wheel

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The Dorsal Medial Habenula Minimally Impacts Circadian Regulation of Locomotor Activity and Sleep

Journal of Biological Rhythms ◽

10.1177/0748730417730169 ◽

2017 ◽

Vol 32 (5) ◽

pp. 444-455 ◽

Cited By ~ 3

Author(s):

Yun-Wei A. Hsu ◽

Jennifer J. Gile ◽

Jazmine G. Perez ◽

Glenn Morton ◽

Miriam Ben-Hamo ◽

...

Keyword(s):

Rem Sleep ◽

Clock Genes ◽

Wheel Running ◽

Circadian System ◽

Sleep Stages ◽

Constant Darkness ◽

Running Activity ◽

Medial Habenula ◽

Wheel Running Activity ◽

Central Pacemaker

In nocturnal rodents, voluntary wheel-running activity (WRA) represents a self-reinforcing behavior. We have previously demonstrated that WRA is markedly reduced in mice with a region-specific deletion of the transcription factor Pou4f1 (Brn3a), which leads to an ablation of the dorsal medial habenula (dMHb). The decrease in WRA in these dMHb-lesioned (dMHbCKO) mice suggests that the dMHb constitutes a critical center for conveying reinforcement by exercise. However, WRA also represents a prominent output of the circadian system, and the possibility remains that the dMHb is a source of input to the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. To test this hypothesis, we assessed the integrity of the circadian system in dMHbCKO mice. Here we show that the developmental lesion of the dMHb reduces WRA under both a light-dark cycle and constant darkness, increases the circadian period of WRA, but has no effect on the circadian amplitude or period of home cage activity or the daily amplitude of sleep stages, suggesting that the lengthening of period is a result of the decreased WRA in the mutant mice. Polysomnographic sleep recordings show that dMHbCKO mice have an overall unaltered daily amplitude of sleep stages but have fragmented sleep and an overall increase in total rapid eye movement (REM) sleep. Photoresponsiveness is intact in dMHbCKO mice, but compared with control animals, they reentrain faster to a 6-h abrupt phase delay protocol. Circadian changes in WRA of dMHbCKO mice do not appear to emerge within the central pacemaker, as circadian expression of the clock genes Per1 and Per2 within the SCN is normal. We do find some evidence for fragmented sleep and an overall increase in total REM sleep, supporting a model in which the dMHb is part of the neural circuitry encoding motivation and involved in the manifestation of some of the symptoms of depression.

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