Regulation of REM and Non-REM Sleep by Periaqueductal GABAergic Neurons

Weber, Franz; Hoang, Johnny Phong; Chung, Shinjae; Beier, Kevin T.; Bikov, Mike; Doost, Mohammad Saffari; Dan, Yang

doi:10.1038/s41467-017-02765-w

Cited by 161 publications

(196 citation statements)

References 44 publications

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“…Microendoscopy has been used to image the activity of various phenotypes of brain neurons during quiet waking and sleep (Weber et al, 2015(Weber et al, , 2018Cox et al, 2016;Chung et al, 2017;Chen et al, 2018). We took advantage of the versatility of the miniscope by also imaging the same neurons while the mice were exploring novel objects and discovered that 70% of the MCH neurons that were active in REM sleep were also active during the exploration of novel objects.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Network Activation of Hypothalamic MCH Neurons in REM Sleep and Exploratory Behavior

et al. 2019

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Most brain neurons are active in waking, but hypothalamic neurons that synthesize the neuropeptide melanin-concentrating hormone (MCH) are claimed to be active only during sleep, particularly rapid eye movement (REM) sleep. Here we use deep-brain imaging to identify changes in fluorescence of the genetically encoded calcium (Ca 2ϩ ) indicator GCaMP6 in individual hypothalamic neurons that contain MCH. An in vitro electrophysiology study determined a strong relationship between depolarization and Ca 2ϩ fluorescence in MCH neurons. In 10 freely behaving MCH-cre mice (male and female), the highest fluorescence occurred in all recorded neurons (n ϭ 106) in REM sleep relative to quiet waking or non-REM sleep. Unexpectedly, 70% of the MCH neurons had strong fluorescence activity when the mice explored novel objects. Spatial and temporal mapping of the change in fluorescence between pairs of MCH neurons revealed dynamic activation of MCH neurons during REM sleep and activation of a subset of the same neurons during exploratory behavior. Functional network activity maps will facilitate comparisons of not only single-neuron activity, but also network responses in different conditions and disease.

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Section: Discussionmentioning

confidence: 99%

Dynamic Network Activation of Hypothalamic MCH Neurons in REM Sleep and Exploratory Behavior

et al. 2019

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“…Instead, AgRP neurons could elicit wake-promoting effects via inhibition of local inhibitory neurons or via multiple synapses to activate wake-promoting circuits and/or inhibit NREM-promoting circuits. Alternatively, AgRP neurons send projections to the ventrolateral periaqueductal gray (vlPAG) [58], a region that has recently been shown to consolidate NREM sleep [59]. Therefore, it is possible that vlPAG neurons mediate at least part of AgRP neuron-mediated effects on NREM sleep reduction.…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic Neurons that Regulate Feeding Can Influence Sleep/Wake States Based on Homeostatic Need

et al. 2018

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SUMMARY Eating and sleeping represent two mutually exclusive behaviors that satisfy distinct homeostatic needs. Because an animal cannot eat and sleep at the same time, brain systems that regulate energy homeostasis are likely to influence sleep/wake behavior. Indeed, previous studies indicate that animals adjust sleep cycles around periods of food need and availability. Furthermore, hormones that affect energy homeostasis also affect sleep/wake states: the orexigenic hormone ghrelin promotes wakefulness, while the anorexigenic hormones leptin and insulin increase the duration of slow wave sleep. However, whether neural populations that regulate feeding can influence sleep/wake states is unknown. The hypothalamic arcuate nucleus contains two neuronal populations that exert opposing effects on energy homeostasis: agouti-related protein (AgRP)-expressing neurons detect caloric need and orchestrate food-seeking behavior, while activity in pro-opiomelanocortin (POMC)-expressing neurons induces satiety. We tested the hypotheses that AgRP neurons affect sleep homeostasis by promoting states of wakefulness, while POMC neurons promote states of sleep. Indeed, optogenetic or chemogenetic stimulation of AgRP neurons in mice promoted wakefulness while decreasing the quantity and integrity of sleep. Inhibition of AgRP neurons rescued sleep integrity in food-deprived mice, highlighting the physiological importance of AgRP neuron activity for the suppression of sleep by hunger. Conversely, stimulation of POMC neurons promoted sleep states and decreased sleep fragmentation in food-deprived mice. Interestingly, we also found that sleep deprivation attenuated the effects of AgRP neuron activity on food intake and wakefulness. These results indicate that homeostatic feeding neurons can hierarchically affect behavioral outcomes depending on homeostatic need.

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“…In addition to the POA, sleeppromoting neurons have also been observed in other brain regions. For example, activation of gamma aminobutyric acid (GABA)ergic neurons in the parafacial zone (Anaclet et al, 2014), the ventrolateral periaqueductal gray (Weber et al, 2015;Weber et al, 2018), the ventral tegmental area (VTA) (Yang et al, 2018;Yu et al, 2019), or adenosine A 2A receptor-expressing neurons in the striatum (Oishi et al, 2017;Yuan et al, 2017) specifically promotes non-rapid eye movement (NREM) sleep, whereas subgroups of GABAergic neurons in the lateral hypothalamus (Jego et al, 2013;Konadhode et al, 2013;Tsunematsu et al, 2014) and the zona incerta (Liu et al, 2017) promote both REM and NREM sleep. With the exception of nitrergic/ glutamatergic neurons in the median and medial preoptic area that are excited by external warmth (Harding et al, 2018), the vast majority of sleep-promoting neuronal populations are GABAergic, and their sleep-promoting effects are likely mediated by the inhibition of wake-promoting populations.…”

Section: Introductionmentioning

confidence: 99%

An Excitatory Circuit in the Perioculomotor Midbrain for Non-REM Sleep Control

Zhang

Zhong

et al. 2019

Cell

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Graphical Abstract Highlights d Activity-dependent genetic labeling and gene profiling identify sleep-active neurons d CALCA-expressing glutamatergic neurons in pIII are NREM active and NREM promoting d pIII CCK neurons are NREM promoting and are reciprocally connected to CALCA neurons d Both cell types send long-range excitatory projections to other sleep-promoting areas In BriefIdentification of sleep-active excitatory midbrain neurons that are interconnected and promote sleep via long range projections to other sleep centers of the mouse brain. SUMMARYThe perioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largely neglected in subsequent studies. Using activity-dependent labeling and gene expression profiling, we identified pIII neurons that promote non-rapid eye movement (NREM) sleep. Optrode recording showed that pIII glutamatergic neurons expressing calcitonin gene-related peptide alpha (CALCA) are NREM-sleep active; optogenetic and chemogenetic activation/inactivation showed that they strongly promote NREM sleep. Within the pIII region, CALCA neurons form reciprocal connections with another population of glutamatergic neurons that express the peptide cholecystokinin (CCK). Activation of CCK neurons also promoted NREM sleep. Both CALCA and CCK neurons project rostrally to the preoptic hypothalamus, whereas CALCA neurons also project caudally to the posterior ventromedial medulla. Activation of each projection increased NREM sleep. Together, these findings point to the pIII region as an excitatory sleep center where different subsets of glutamatergic neurons promote NREM sleep through both local reciprocal connections and long-range projections.

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Regulation of REM and Non-REM Sleep by Periaqueductal GABAergic Neurons

Cited by 161 publications

References 44 publications

Dynamic Network Activation of Hypothalamic MCH Neurons in REM Sleep and Exploratory Behavior

Dynamic Network Activation of Hypothalamic MCH Neurons in REM Sleep and Exploratory Behavior

Hypothalamic Neurons that Regulate Feeding Can Influence Sleep/Wake States Based on Homeostatic Need

An Excitatory Circuit in the Perioculomotor Midbrain for Non-REM Sleep Control

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