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Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness.

ABSTRACT: A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, na and unc79. Although loss of function mutations in these genes can increase or decrease sensitivity to anesthesia induction, surprisingly, they all collapse neural inertia. These effects are genetically selective: neural inertia is not perturbed by loss-of-function mutations in all genes required for the sleep/wake cycle. These effects are also anatomically selective: sss acts in different neurons to influence arousal-promoting and arousal-suppressing processes underlying neural inertia. Supporting the idea that anesthesia and sleep share some, but not all, genetic and anatomical arousal-regulating pathways, we demonstrate that increasing homeostatic sleep drive widens the neural inertial barrier. We propose that processes selectively contributing to sleep homeostasis and neural inertia may be impaired in pathophysiological conditions such as coma and persistent vegetative states.

SUBMITTER: Joiner WJ

PROVIDER: S-EPMC3764144 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness.

Joiner William J WJ Friedman Eliot B EB Hung Hsiao-Tung HT Koh Kyunghee K Sowcik Mallory M Sehgal Amita A Kelz Max B MB

PLoS genetics 20130905 9

A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, ...[more]

PMID: 24039590

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Project description:Background:The dystonias include a clinically and etiologically very diverse group of disorders. There are both degenerative and non-degenerative subtypes resulting from genetic or acquired causes. Traditionally, all dystonias have been viewed as disorders of the basal ganglia. However, there has been increasing appreciation for involvement of other brain regions including the cerebellum, thalamus, midbrain, and cortex. Much of the early evidence for these other brain regions has come from studies of animals, but multiple recent studies have been done with humans, in an effort to confirm or refute involvement of these other regions. The purpose of this article is to review the new evidence from animals and humans regarding the motor network model, and to address the issues important to translational neuroscience. Methods:The English literature was reviewed for articles relating to the neuroanatomical basis for various types of dystonia in both animals and humans. Results:There is evidence from both animals and humans that multiple brain regions play an important role in various types of dystonia. The most direct evidence for specific brain regions comes from animal studies using pharmacological, lesion, or genetic methods. In these studies, experimental manipulations of specific brain regions provide direct evidence for involvement of the basal ganglia, cerebellum, thalamus and other regions. Additional evidence also comes from human studies using neuropathological, neuroimaging, non-invasive brain stimulation, and surgical interventions. In these studies, the evidence is less conclusive, because discriminating the regions that cause dystonia from those that reflect secondary responses to abnormal movements is more challenging. Discussion:Overall, the evidence from both animals and humans suggests that different regions may play important roles in different subtypes of dystonia. The evidence so far provides strong support for the motor network model. There are obvious challenges, but also advantages, of attempting to translate knowledge gained from animals into a more complete understanding of human dystonia and novel therapeutic strategies.

Dataset Information

Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness.

Publications

Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness.

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