Regulation of REM sleep by inhibitory neurons in the dorsomedial medulla

Stucynski, Joseph A.; Schott, Amanda L.; Baik, Justin; Chung, Shinjae; Weber, Franz

doi:10.1016/j.cub.2021.10.030

Cited by 31 publications

(47 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the galenic formulation and use of solvents can alter the pharmacokinetic properties of DREADD actuators (Campbell and Marchant 2018). The hydrochloride salt preparations of CNO used here and in other recent sleep studies (Fernandez et al 2018; Stucynski et al 2021) have reduced back-metabolism to clozapine and an improved water solubility and bioavailability compared to equivalent doses of CNO-DMSO preparations (D. C. Allen et al 2019). The increased bioavailability and thereby supposedly amplified off-target receptor binding might explain that we find sleep-modulating effects of CNO already at doses where other studies have shown no effects.…”

Section: Discussionmentioning

confidence: 83%

“…In addition, the galenic formulation and use of solvents can alter the pharmacokinetic properties of DREADD actuators (Campbell and Marchant 2018). The hydrochloride salt preparations of CNO used here and in other recent sleep studies (Fernandez et al 2018;Stucynski et al 2021) shows that avoiding clozapine back-metabolism of CNO by using novel DREADD actuators such as C21 does not prevent behavioural side effects. Interestingly, another next generation DREADD agonist, perlapine, which is structurally similar to C21 (Chen et al 2015;Thompson et al 2018), is a REM-suppressing sedative and muscle relaxant used in the treatment of insomnia (Ando et al 1970; S. R. Allen and Oswald 1973;Stille et al 1973).…”

Section: Implications For Future Use Of Chemogenetics In Sleep Researchmentioning

confidence: 90%

“…The dihydrochloride preparation of CNO undergoes less back-metabolism to clozapine but has a higher bioavailability compared to CNO-DMSO as indicated by pharmacokinetic work in rhesus macaques (D. C. Allen et al 2019). This product has previously been used in sleep studies on mice at concentrations between 1 mg/kg and 5 mg/kg (Fernandez et al 2018; Stucynski et al 2021). For C21 injections we used the water-soluble version of DREADD agonist compound 21 (compound 21 dihydrochloride, Tocris, Bio-Techne LTD, Abingdon, UK, catalog no.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice

Traut

Prius-Mengual

Meijer

et al. 2022

Preprint

View full text Add to dashboard Cite

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools that modulate a targeted cell population using chemical ligands which bind specifically to modified receptors. Despite the common use of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep, which could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors, have never been systematically tested. Here we show that intraperitoneal injections of commonly used doses of CNO alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found that CNO suppresses rapid eye-movement (REM) sleep, changes EEG spectral power during non-REM (NREM) sleep, and alters sleep architecture in a pattern previously reported for clozapine. Interestingly, we found that the novel DREADD actuator, compound 21 (C21), similarly modulates sleep despite not being able to back convert to clozapine. Our results demonstrate that CNO and C21 can affect the sleep of wild-type mice, which do not express DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators and therefore any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21 or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.

show abstract

Section: Discussionmentioning

confidence: 83%

“…In addition, the galenic formulation and use of solvents can alter the pharmacokinetic properties of DREADD actuators (Campbell and Marchant 2018). The hydrochloride salt preparations of CNO used here and in other recent sleep studies (Fernandez et al 2018;Stucynski et al 2021) shows that avoiding clozapine back-metabolism of CNO by using novel DREADD actuators such as C21 does not prevent behavioural side effects. Interestingly, another next generation DREADD agonist, perlapine, which is structurally similar to C21 (Chen et al 2015;Thompson et al 2018), is a REM-suppressing sedative and muscle relaxant used in the treatment of insomnia (Ando et al 1970; S. R. Allen and Oswald 1973;Stille et al 1973).…”

Section: Implications For Future Use Of Chemogenetics In Sleep Researchmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice

Traut

Prius-Mengual

Meijer

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In relation to slow rhythms oscillations interlacing with more abrupt changes, in a recent study using opto‐ and chemogenetic manipulation in mice, it has been confirmed that GABAergic neurons in the DPGi promote PS and that their activity is not only strongly increased during PS but also seems to be synchronized with infraslow oscillations of the EEG, possibly coordinating the timing of PS episodes with infraslow brain rhythms (Stucynski et al, 2022).…”

Section: Basis Of Ps Homeostasismentioning

confidence: 92%

“…Different populations of PS‐on GABAergic neurons localized in the LHA, vlPAG (see above also), LPGi and dorsal paragigantocellular nuclei (DPGi) have been also identified (Sapin et al, 2009, 2010). It has been proposed that these neurons inactivate the PS‐off orexin and histaminergic neurons and the monoaminergic neurons during PS (Clément et al, 2014; Goutagny et al, 2008; Sirieix et al, 2012; Stucynski et al, 2022; Weber et al, 2015). Conversely, the inhibition of these GABAergic and that of the glutamatergic PS‐on neurons by wake‐arousing systems would be responsible for the exit from PS state (Luppi & Fort, 2019).…”

Section: Neuronal Network Generating Psmentioning

confidence: 99%

Is paradoxical sleep setting up innate and acquired complex sensorimotor and adaptive behaviours?: A proposed function based on literature review

Casaglia

Luppi

2022

Journal of Sleep Research

View full text Add to dashboard Cite

Summary We summarize here the progress in identifying the neuronal network as well as the function of paradoxical sleep and the gaps of knowledge that should be filled in priority. The core system generating paradoxical sleep localized in the brainstem is now well identified, and the next step is to clarify the role of the forebrain in particular that of the hypothalamus including the melanin‐concentrating hormone neurons and of the basolateral amygdala. We discuss these two options, and also the discovery that cortical activation during paradoxical sleep is restricted to a few limbic cortices activated by the lateral supramammillary nucleus and the claustrum. Such activation nicely supports the findings recently obtained showing that neuronal reactivation occurs during paradoxical sleep in these structures, and induces both memory consolidation of important memory and forgetting of less relevant ones. The question that still remains to be answered is whether paradoxical sleep is playing more crucial roles in processing emotional and procedural than other types of memories. One attractive hypothesis is that paradoxical sleep is responsible for erasing negative emotional memories, and that this function is not properly functioning in depressed patients. On the other hand, the presence of a muscle atonia during paradoxical sleep is in favour of a role in procedural memory as new types of motor behaviours can be tried without harm during the state. In a way, it also fits with the proposed role of paradoxical sleep in setting up the sensorimotor system during development.

show abstract

Neural Control of REM Sleep and Motor Atonia: Current Perspectives

Vetrivelan,

Bandaru

2023

Curr Neurol Neurosci Rep

View full text Add to dashboard Cite

Regulation of REM sleep by inhibitory neurons in the dorsomedial medulla

Cited by 31 publications

References 59 publications

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice

Is paradoxical sleep setting up innate and acquired complex sensorimotor and adaptive behaviours?: A proposed function based on literature review

Neural Control of REM Sleep and Motor Atonia: Current Perspectives

Contact Info

Product

Resources

About