The Impacts of Age and Sex in a Mouse Model of Childhood Narcolepsy

Coffey, A; Joyal, Adam; Yamanaka, Akihiro; Scammell, Thomas E.

doi:10.3389/fnins.2021.644757

Cited by 13 publications

(22 citation statements)

References 71 publications

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“… 19 , 41 Won et al found that females are less likely to report lifestyle impairments in the areas of personal relationships and physical activity compared to males in spite of being objectively sleepier; however both patients with narcolepsy with and without cataplexy were involved in this study. 41 Recent studies reported that in narcolepsy mouse models, females have larger number of cataplexy bouts 42 and increased wake 43 compared to males, with unclear findings in humans with narcolepsy. 19 , 41 Our result of sex differences in narcolepsy diagnostic delay in adults suggest that social factors (eg, different roles of males/females in their households and employment) may play an important role in narcolepsy diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis

Zhang¹,

Dauvilliers²,

Plazzi³

et al. 2022

NSS

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Purpose Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990–2018) and the factors associated with the delay in Europe. Patients and Methods We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7−13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

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Section: Discussionmentioning

confidence: 99%

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis

Zhang¹,

Dauvilliers²,

Plazzi³

et al. 2022

NSS

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“…Although the consequences of dietary DOX withdrawal and subsequent Hcrt neuron degeneration has been well-documented in male orexin-tTA; TetO DTA mice 30 , similar information for female mice of this strain has been lacking. This is not unusual as, with some notable exceptions [35][36][37][38][39][40][41][42] , female mice have been rarely used in sleep studies 27,43 . The primary symptoms of human narcolepsy that can be assessed in a mouse model of this disorder are excessive daytime sleepiness (EDS), nocturnal sleep disruption and cataplexy, the pathognomonic symptom of NT1.…”

Section: Discussionmentioning

confidence: 99%

The Development of Sleep/Wake Disruption and Cataplexy as Hypocretin/Orexin Neurons Degenerate in Male vs. Female Orexin/tTA; TetO-DTA Mice

Sun

Tisdale

Park

et al. 2021

Preprint

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Narcolepsy Type 1 (NT1), a sleep disorder with similar prevalence in both sexes, is thought to be due to loss of the hypocretin/orexin (Hcrt) neurons. Several transgenic strains have been created to model this disorder and are increasingly being used for preclinical drug development and basic science studies, yet most studies have solely used male mice. We compared the development of narcoleptic symptomatology in male vs. female orexin-tTA; TetO-DTA mice, a model in which Hcrt neuron degeneration can be initiated by removal of doxycycline (DOX) from the diet. EEG, EMG, body temperature, gross motor activity and video recordings were conducted for 24-h at baseline and 1, 2, 4 and 6 weeks after DOX removal. Female DTA mice exhibited cataplexy, the pathognomonic symptom of NT1, by Week 1 in the DOX(-) condition but cataplexy was not consistently present in males until Week 2. By Week 2, both sexes showed an impaired ability to sustain long wake bouts during the active period, the murine equivalent of excessive daytime sleepiness in NT1. Body temperature appeared to be regulated at lower levels in both sexes as the Hcrt neurons degenerated. During degeneration, both sexes also exhibited the Delta State, characterized by sudden cessation of activity, high delta activity in the EEG, maintenance of muscle tone and posture, and the absence of phasic EMG activity. Since the phenotypes of the two sexes were indistinguishable by Week 6, we conclude that both sexes can be safely combined in future studies to reduce cost and animal use.

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“…In another study, FAA was attenuated in orexin KO mice but not eliminated, and core body temperatures and food consumption in the orexin KO mice and control mice were similar ( Kaur et al, 2008 ). Research also demonstrated that KO of the orexin system results in narcolepsy and sleep fragmentation ( Coffey et al, 2021 ). These results suggest that orexin neurons may sense the metabolic status and modulate arousal to promote food-seeking behavior during RF regimes.…”

Section: Discussionmentioning

confidence: 99%

Effect of Restricted Feeding on Metabolic Health and Sleep-Wake Rhythms in Aging Mice

Qian

et al. 2021

Front. Neurosci.

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Aging, an irreversible and unavoidable physiological process in all organisms, is often accompanied by obesity, diabetes, cardiovascular diseases, sleep disorders, and fatigue. Thus, older adults are more likely to experience metabolic symptoms and sleep disturbances than are younger adults. Restricted feeding (RF) is a dietary regimen aimed at improving metabolic health and extending longevity, as well as reorganizing sleep-wake cycles. However, the potential of RF to improve metabolic health and sleep quality in older adults who are known to show a tendency toward increased weight gain and decreased sleep is unknown. To elucidate this issue, aged mice were assigned to an RF protocol during the active phase for 2 h per day for 2 weeks. Sleep-wake cycles were recorded during the RF regime in RF group and control mice. At the end of this period, body weight and blood biochemistry profiles, including blood glucose, cholesterol, and enzyme activity, in addition to dopamine concentrations in the brain, were measured in the RF group and age-matched controls. RF for 2 weeks improved the metabolic health of aged mice by reducing their body weights and blood glucose and cholesterol levels. At the beginning of the RF regime, sleep decreased in the dark period but not in the light period. After stable food entrainment was achieved (7 days post-RF commencement), the amount of time spent in wakefulness during the light period dramatically increased for 2 h before food availability, thereby increasing the mean duration of awake episodes and decreasing the number of wakefulness episodes. There was no significant difference in the sleep-wake time during the dark period in the RF group, with similar total amounts of wakefulness and sleep in a 24-h period to those of the controls. During the RF regime, dopamine levels in the midbrain increased in the RF group, pointing to its potential as the mechanism mediating metabolic symptoms and sleep-wake regulation during RF. In conclusion, our study suggested that RF during aging might prohibit or delay the onset of age-related diseases by improving metabolic health, without having a severe deleterious effect on sleep.

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The Impacts of Age and Sex in a Mouse Model of Childhood Narcolepsy

Cited by 13 publications

References 71 publications

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis

The Development of Sleep/Wake Disruption and Cataplexy as Hypocretin/Orexin Neurons Degenerate in Male vs. Female Orexin/tTA; TetO-DTA Mice

Effect of Restricted Feeding on Metabolic Health and Sleep-Wake Rhythms in Aging Mice

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