Pharmacosynthetic Deconstruction of Sleep-Wake Circuits in the Brain

Varin, Christophe; Bonnavion, Patricia

doi:10.1007/164_2018_183

Cited by 7 publications

(7 citation statements)

References 221 publications

(382 reference statements)

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“…DREADD overexpression often occurs upon vector-mediated transgene delivery and could instigate receptor reserve, thereby avoiding receptor desensitization [ 3 ]. On the other hand, DREADD overexpression is also linked with constitutive activity of the receptor [ 71 , 72 ]. One study reported that DREADD overexpression perturbed endogenous GPCR signaling and alterations in both ion channel activity and intracellular signaling in the absence of the DREADD ligand [ 71 ].…”

Section: Dreaddful Hurdles In (Chronic) Chemogenetic Studiesmentioning

confidence: 99%

The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox

Claes

Groef

Moons

2022

Cells

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The chronic character of chemogenetics has been put forward as one of the assets of the technique, particularly in comparison to optogenetics. Yet, the vast majority of chemogenetic studies have focused on acute applications, while repeated, long-term neuromodulation has only been booming in the past few years. Unfortunately, together with the rising number of studies, various hurdles have also been uncovered, especially in relation to its chronic application. It becomes increasingly clear that chronic neuromodulation warrants caution and that the effects of acute neuromodulation cannot be extrapolated towards chronic experiments. Deciphering the underlying cellular and molecular causes of these discrepancies could truly unlock the chronic chemogenetic toolbox and possibly even pave the way for chemogenetics towards clinical application. Indeed, we are only scratching the surface of what is possible with chemogenetic research. For example, most investigations are concentrated on behavioral read-outs, whereas dissecting the underlying molecular signature after (chronic) neuromodulation could reveal novel insights in terms of basic neuroscience and deregulated neural circuits. In this review, we highlight the hurdles associated with the use of chemogenetic experiments, as well as the unexplored research questions for which chemogenetics offers the ideal research platform, with a particular focus on its long-term application.

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Section: Dreaddful Hurdles In (Chronic) Chemogenetic Studiesmentioning

confidence: 99%

The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox

Claes

Groef

Moons

2022

Cells

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“…In so doing, anesthetics may rely on molecular targets with intrinsic temperature-sensing ability such as the K 2P channels or mitochondrial targets in critical cellular populations to inextricably link reductions in body temperature with decreased metabolism as occurs with endogenous sleep [111]. Anesthetic Actions on Endogenous Arousal-promoting Systems Neurons within the pedunculopontine and laterodorsal tegmentum (cholinergic), pontine reticular formation (unknown population), locus coeruleus (noradrenergic), parabrachial nucleus (glutamatergic), dorsal raphe (serotonergic), ventral tegmental area (dopaminergic), perifornical, lateral, and posterior hypothalamus (orexinergic), lateral hypothalamus (GABAergic) and tuberomammillary nucleus (histaminergic) are all capable of promoting the waking state [112]. Many of these nuclei have been explored as targets of the inhibitory effects of general anesthetics [113] (Figure 4).…”

Section: Reviewmentioning

confidence: 99%

The Biology of General Anesthesia from Paramecium to Primate

Kelz

Mashour

2019

Current Biology

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General anesthesia serves a critically important function in the clinical care of human patients. However, the anesthetized state has foundational implications for biology because anesthetic drugs are effective in organisms ranging from paramecia, to plants, to primates. Although unconsciousness is typically considered the cardinal feature of general anesthesia, this endpoint is only strictly applicable to a select subset of organisms that are susceptible to being anesthetized. We review the behavioral endpoints of general anesthetics across species and propose the isolation of an organism from its environment-both in terms of the afferent arm of sensation and the efferent arm of action-as a generalizable definition. We also consider the various targets and putative mechanisms of general anesthetics across biology and identify key substrates that are conserved, including cytoskeletal elements, ion channels, mitochondria, and functionally coupled electrical or neural activity. We conclude with a unifying framework related to network function and suggest that general anesthetics-from single cells to complex brains-create inefficiency and enhance modularity, leading to the dissociation of functions both within an organism and between the organism and its surroundings. Collectively, we demonstrate that general anesthesia is not restricted to the domain of modern medicine but has broad biological relevance with wide-ranging implications for a diverse array of species.

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“…Powerful new tools to interrogate sleep-wake regulating circuits have revealed new molecular and cellular markers, as well as novel network mechanisms and pathways that regulate wakefulness and sleep. While the ascending arousal system was first described as a reticular network of neurons projecting widely to the cortex and the spinal cord (Moruzzi and Magoun, 1949), it has become clear in the last few years that wakefulness and sleep are governed by distinct populations and subtypes of neurons (Varin and Bonnavion, 2018). Although specific, these neuronal systems are often redundant and reinforce each other.…”

Section: Prospects Of Pharmacogenetics For Personalized Sleep-wake Mementioning

confidence: 99%

“…These recent insights may necessitate an adaptation of the basic sleep-wake neurochemistry described above. They have been discussed in comprehensive reviews and other chapters of this book (Adamantidis and Luthi, 2018 ;Saper and Fuller, 2017;Tyree and de Lecea, 2017;Eban-Rothschild et al, 2018;Luppi and Fort, 2018;Varin and Bonnavion, 2018), and are not the focus of this chapter. In this article, firstly, genetic aspects of the current pharmacotherapy of sleep-wake disorders will be reviewed.…”

Section: Introductionmentioning

confidence: 99%

Clinical and Experimental Human Sleep-Wake Pharmacogenetics

Landolt

Holst

Valomon

2018

Sleep-Wake Neurobiology and Pharmacology

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Sleep and wakefulness are highly complex processes that are elegantly orchestrated by finetuned neurochemical changes among neuronal and non-neuronal ensembles, nuclei, and networks of the brain. Important neurotransmitters and neuromodulators regulating the circadian and homeostatic facets of sleep-wake physiology include melatonin,-aminobutyric acid, hypocretin, histamine, norepinephrine, serotonin, dopamine, and adenosine. Dysregulation of these neurochemical systems may cause sleep-wake disorders, which are commonly classified into insomnia disorder, parasomnias, circadian rhythm sleepwake disorders, central disorders of hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders. Sleep-wake disorders can have far-reaching consequences on physical, mental, and social well-being and health and, thus, need be treated with effective and rational therapies. Apart from behavioral (e.g., cognitive behavioral therapy for insomnia), physiological (e.g., chronotherapy with bright light), and mechanical (e.g., continuous positive airway pressure treatment of obstructive sleep apnea) interventions, pharmacological treatments often are the first-line clinical option to improve disturbed sleep and wake states. Nevertheless, not all patients respond to pharmacotherapy in uniform and beneficial fashion, partly due to genetic differences. The improved understanding of the neurochemical mechanisms regulating sleep and wakefulness and the mode of action of sleep-wake therapeutics has provided a conceptual framework, to search for functional genetic variants modifying individual drug response phenotypes. This article will summarize the currently known genetic polymorphisms that modulate drug sensitivity and exposure, to partly determine individual responses to sleep-wake pharmacotherapy. In addition, a pharmacogenetic strategy will be outlined how based upon classical and opto-/chemogenetic strategies in animals, as well as human genetic associations, circuit mechanisms regulating sleep-wake functions in humans can be identified. As such, experimental human sleep-wake pharmacogenetics forms a bridge spanning basic research and clinical medicine and constitutes an essential step for the search and development of novel sleep-wake targets and therapeutics.

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Pharmacosynthetic Deconstruction of Sleep-Wake Circuits in the Brain

Cited by 7 publications

References 221 publications

The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox

The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox

The Biology of General Anesthesia from Paramecium to Primate

Clinical and Experimental Human Sleep-Wake Pharmacogenetics

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