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.
Kelz and Mashour bring the reader up to date on our current understanding of how anesthetics work at the molecular, circuit, and network levels.They emphasize that a broad range of organisms, including plants and even single-celled ornanisms, are susceptible to anesthesia and propose a universal defintion of the anesthetized state.
Anesthesia: Synaptic power failure van Swinderen, Bruno; Kelz, Max B.
CB/Current biology,
07/2022, Letnik:
32, Številka:
14
Journal Article
Recenzirano
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One of the greatest unresolved mysteries in medicine relates to the molecular and neuronal mechanisms through which general anesthetics abolish perception. A new study in mice with mutations ...affecting mitochondrial complex 1 suggests that anesthetic-disruption of cellular energetics impairs endocytosis to alter synaptic function.
One of the greatest unresolved mysteries in medicine relates to the molecular and neuronal mechanisms through which general anesthetics abolish perception. A new study in mice with mutations affecting mitochondrial complex 1 suggests that anesthetic-disruption of cellular energetics impairs endocytosis to alter synaptic function.
Anaesthetic induction occurs at higher plasma drug concentrations than emergence in animal studies. Some studies find evidence for such anaesthetic hysteresis in humans, whereas others do not. ...Traditional thinking attributes hysteresis to drug equilibration between plasma and the effect site. Indeed, a key difference between human studies showing anaesthetic hysteresis and those that do not is in how effect-site equilibration was modelled. However, the effect-site is a theoretical compartment in which drug concentration cannot be measured experimentally. Thus, it is not clear whether drug equilibration models with experimentally intractable compartments are sufficiently constrained to unequivocally establish evidence for the presence or absence of anaesthetic hysteresis.
We constructed several models. One lacked hysteresis beyond effect-site equilibration. In another, neuronal dynamics contributed to hysteresis. We attempted to distinguish between these two systems using drug equilibration models.
Our modelling studies showed that one can always construct an effect-site equilibration model such that hysteresis collapses. So long as the concentration in the effect-site cannot be measured directly, the correct effect-site equilibration model and the one that erroneously collapses hysteresis are experimentally indistinguishable. We also found that hysteresis can naturally arise even in a simple network of neurones independently of drug equilibration.
Effect-site equilibration models can readily collapse hysteresis. However, this does not imply that hysteresis is solely attributable to the kinetics of drug equilibration.
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.
Endogenous sleep and general anesthesia are distinct states that share similar traits. Of particular interest to neuroscience is the loss of consciousness that accompanies both states. Multiple lines ...of evidence demonstrate that general anesthetics can co-opt the neural circuits regulating arousal to produce unconsciousness. However, controversy remains as to whether the neural circuits and, more specifically, the same neurons shaping sleep and wakefulness actually do influence the anesthetic state in vivo. Hypothalamic preoptic area (POA) neurons are intimately involved in modulating spontaneous and anesthetic-induced changes in arousal. Nevertheless, recent work suggests that POA GABAergic or glutamatergic neurons capable of regulating endogenous sleep fail to influence the onset or dissipation of anesthesia. We hypothesized that the POA’s broad neuronal diversity could mask convergent roles of a subset of neurons in regulating both arousal and anesthesia. Contrary to a previously published report, we show that chemogenetic activation of POA Tac1 neurons obliterates both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, strongly consolidating the waking state for hours, even during a period of elevated sleep drive. Moreover, chemogenetic activation of Tac1 POA neurons stabilizes the wake state against both isoflurane- and sevoflurane-induced unconsciousness. Tac1-activated mice display a partial resistance to entering isoflurane anesthesia and a more pronounced ability to exit both isoflurane- and sevoflurane-induced unconscious states. We conclude that POA Tac1 neurons can potently reinforce arousal both against endogenous and drug-induced unconscious states. POA Tac1 neurons thus add causal support for the involvement of arousal-regulating systems in the state of general anesthesia.
•Activation of POA Tac1 neurons promoted and stabilized wake over NREM and REM sleep•Wakefulness caused by POA Tac1 activation is not due to increased anxiety•POA Tac1 activation enhanced emergence from isoflurane and sevoflurane anesthesia•The same neurons modulating endogenous arousal may sculpt states of anesthesia
The degree to which the same neurons modulate arousal in both sleep and anesthesia is unclear. Reitz et al. describe a population of Tac1-expressing POA neurons that, when activated, reinforce arousal against both natural sleep and anesthetic-induced unconsciousness, confirming that neurons modulating endogenous arousal shape states of anesthesia.
Building on their known ability to influence sleep and arousal, Li and colleagues show that modulating the activity of glutamatergic pedunculopontine tegmental neurones also alters ...sevoflurane-induced hypnosis. This finding adds support for the shared sleep-anaesthesia circuit hypothesis. However, the expanding recognition of many neuronal clusters capable of modulating anaesthetic hypnosis raises the question of how disparate and anatomically distant sites ultimately interact to coordinate global changes in the state of the brain. Understanding how these individual sites work in concert to disrupt cognition and behaviour is the next challenge for anaesthetic mechanisms research.
Abstract
Sensory processing is distributed among many brain regions that interact via feedforward and feedback signaling. Neuronal oscillations have been shown to mediate intercortical feedforward ...and feedback interactions. Yet, the macroscopic structure of the multitude of such oscillations remains unclear. Here, we show that simple visual stimuli reliably evoke two traveling waves with spatial wavelengths that cover much of the cerebral hemisphere in awake mice. 30-50 Hz feedforward waves arise in primary visual cortex (V1) and propagate rostrally, while 3-6 Hz feedback waves originate in the association cortex and flow caudally. The phase of the feedback wave modulates the amplitude of the feedforward wave and synchronizes firing between V1 and parietal cortex. Altogether, these results provide direct experimental evidence that visual evoked traveling waves percolate through the cerebral cortex and coordinate neuronal activity across broadly distributed networks mediating visual processing.
The brain can become transiently disconnected from the environment while maintaining vivid, internally generated experiences. This so-called 'dissociated state' can occur in pathological conditions ...and under the influence of psychedelics or the anesthetic ketamine (KET). The cellular and circuit mechanisms producing the dissociative state remain poorly understood. We show in mice that KET causes spontaneously active neurons to become suppressed while previously silent neurons become spontaneously activated. This switch occurs in all cortical layers and different cortical regions, is induced by both systemic and cortical application of KET and is mediated by suppression of parvalbumin and somatostatin interneuron activity and inhibition of NMDA receptors and HCN channels. Combined, our results reveal two largely non-overlapping cortical neuronal populations-one engaged in wakefulness, the other contributing to the KET-induced brain state-and may lay the foundation for understanding how the brain might become disconnected from the surrounding environment while maintaining internal subjective experiences.
Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in ...a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice.