Hypothalamic MCH Neuron Activity Dynamics during Cataplexy of Narcolepsy

Sun, Yuanyuan; Li, Meng

doi:10.1523/eneuro.0017-20.2020

Cited by 8 publications

(8 citation statements)

References 34 publications

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“… Izawa et al (2019) used fiber photometry to characterize population level calcium-dependent activity in MCH neurons, showing that MCH neurons were maximally active in REM sleep and pre-REM sleep (the transition between non-REM and REM sleep), with less activity during waking and very little activity during non-REM sleep. Further characterization of single-neuron activity by several groups has shown that neurons were largely either REM- or wake-active, with a subset of neurons showing activity in both states ( Blanco-Centurion et al, 2019 ; Izawa et al, 2019 ; Sun and Liu, 2020 ). These studies are consistent in their finding that MCH neurons are maximally active during REM sleep, with evidence for significant activity during waking, and some evidence for activity during non-REM sleep.…”

Section: The Role Of the Melanin-concentrating Hormone System In Sleepmentioning

confidence: 99%

The melanin-concentrating hormone system as a target for the treatment of sleep disorders

Potter

Burgess²

2022

Front. Neurosci.

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Given the widespread prevalence of sleep disorders and their impacts on health, it is critical that researchers continue to identify and evaluate novel avenues of treatment. Recently the melanin-concentrating hormone (MCH) system has attracted commercial and scientific interest as a potential target of pharmacotherapy for sleep disorders. This interest emerges from basic scientific research demonstrating a role for MCH in regulating sleep, and particularly REM sleep. In addition to this role in sleep regulation, the MCH system and the MCH receptor 1 (MCHR1) have been implicated in a wide variety of other physiological functions and behaviors, including feeding/metabolism, reward, anxiety, depression, and learning. The basic research literature on sleep and the MCH system, and the history of MCH drug development, provide cause for both skepticism and cautious optimism about the prospects of MCH-targeting drugs in sleep disorders. Extensive efforts have focused on developing MCHR1 antagonists for use in obesity, however, few of these drugs have advanced to clinical trials, and none have gained regulatory approval. Additional basic research will be needed to fully characterize the MCH system’s role in sleep regulation, for example, to fully differentiate between MCH-neuron and peptide/receptor-mediated functions. Additionally, a number of issues relating to drug design will continue to pose a practical challenge for novel pharmacotherapies targeting the MCH system.

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Section: The Role Of the Melanin-concentrating Hormone System In Sleepmentioning

confidence: 99%

The melanin-concentrating hormone system as a target for the treatment of sleep disorders

Potter

Burgess²

2022

Front. Neurosci.

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“…The activity of these neurons can be blocked to show that it also blocks cataplexy. Activity of the MCH neurons in the hypothalamus was found to be unchanged indicating that these neurons are not triggering the cataplexy ( Sun and Liu, 2020 ). Indeed, mice with double ablation of the orexin and MCH neurons show more severe cataplexy compared to single deletion of the orexin neurons ( Hung et al, 2020 ).…”

Section: Calcium Imaging Identifies Network Activationmentioning

confidence: 99%

Mapping Network Activity in Sleep

2021

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It was in the influenza pandemic of 1918 that von Economo identified specific brain regions regulating sleep and wake. Since then researchers have used a variety of tools to determine how the brain shifts between states of consciousness. In every enterprise new tools have validated existing data, corrected errors and made new discoveries to advance science. The brain is a challenge but new tools can disentangle the brain network. We summarize the newest tool, a miniature microscope, that provides unprecedented view of activity of glia and neurons in freely behaving mice. With this tool we have observed that the activity of a majority of GABA and MCH neurons in the lateral hypothalamus is heavily biased toward sleep. We suggest that miniscope data identifies activity at the cellular level in normal versus diseased brains, and also in response to specific hypnotics. Shifts in activity in small networks across the brain will help identify point of criticality that switches the brain from wake to sleep.

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“…In support of this hypothesis, it has recently been demonstrated that cataplexy expression is markedly increased in Hcrt and MCH double-ablated mice 16 . Moreover, calcium imaging using the Inscopix miniscope shows that cataplexy is associated with a general absence of MCH activity 15 . These data suggest that inactivity of both the Hcrt and MCH systems may further exacerbate behavioral state instability and thus favor cataplexy.…”

Section: Ambient Temperature and Cataplexymentioning

confidence: 99%

“…Indeed, using genetically modified hypocretin knockout (Hcrt-KO) mice to specifically target MCH neurons, recent work shows that chemogenetic activation of the MCH system increases both REM sleep and cataplexy, whereas MCH antagonism reverses this effect 14 . However, another study using calcium imaging found contradictory results, showing that MCH neurons are indeed active in REM sleep but silent during cataplexy 15 . Moreover, MCH-Hcrt double ablated mice show a marked increase in cataplexy and decrease in REM sleep compared to selective Hcrt ablated animals 16 .…”

Section: Introductionmentioning

confidence: 99%

Narcolepsy and the Dissociation of REM Sleep and Cataplexy through Ambient Temperature Manipulation

Viberti

Branca

Bellini

et al. 2021

Preprint

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Narcolepsy is characterized by increased REM sleep propensity and cataplexy. Although narcolepsy is caused by the selective loss or dysfunction of hypocretin (Hcrt) neurons within the lateral hypothalamus (LH), mechanisms underlying REM sleep propensity and cataplexy remain to be elucidated. We have recently shown that wild type (WT) mice increase REM sleep expression when exposed to thermoneutral ambient temperature (Ta) warming during the light (inactive) phase. We hypothesized that the loss of Hcrt may lead to exaggerated responses with respect to increased REM sleep and cataplexy during Ta warming. To test this hypothesis, Hcrt-KO mice were implanted for chronic sleep recordings and housed in a temperature-controlled cabinet. Sleep-wake expression and both spontaneous cataplexy and food-elicited cataplexy were evaluated at constant Ta and during a Ta manipulation protocol. Here we show several unexpected findings. First, Hcrt-KO mice show opposite circadian patterns with respect to REM sleep responsiveness to thermoneutral Ta warming compared to WT mice. As previously demonstrated, WT mice increased REM sleep when Ta warming is presented during the inactive (light) phase, whereas Hcrt-KO showed a significant decrease in REM sleep expression. In contrast, Hcrt-KO mice increased REM sleep expression upon exposure to Ta warming when presented during the active (dark) phase, a circadian time when WT mice showed no significant changes in REM sleep as a function of Ta. Second, we found that REM sleep and cataplexy can be dissociated through Ta manipulation. Specifically, although Ta warming significantly increased REM sleep expression in Hcrt-KO mice during the active phase, cataplexy bout number and total cataplexy duration significantly decreased. In contrast, cataplexy expression was favoured during Ta cooling when REM sleep expression significantly decreased. Finally, video actigraphy and sleep-wake recordings in Hcrt-KO mice demonstrated that Ta manipulation did not significantly alter waking motor activity patterns or waking or NREM sleep durations. These data suggest that neural circuits gating REM sleep and cataplexy expression can be dissociated with Ta manipulation.

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Hypothalamic MCH Neuron Activity Dynamics during Cataplexy of Narcolepsy

Abstract: guidance, and technical support on animal surgery and calcium imaging data processing. We thank Dr. Jiexiang Li at the College of Charleston for advice on data processing.

Cited by 8 publications

References 34 publications

The melanin-concentrating hormone system as a target for the treatment of sleep disorders

The melanin-concentrating hormone system as a target for the treatment of sleep disorders

Mapping Network Activity in Sleep

Narcolepsy and the Dissociation of REM Sleep and Cataplexy through Ambient Temperature Manipulation

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