How does the brain emerge from anesthesia and regain consciousness

Herein, we first discuss advancements in our understanding of the mechanisms involved in the induction of anesthesia. This includes the fundamentals of anesthesia as shaped by three influential theories: the non-specific lipid theory, the specific protein target theory, and the neural circuit theory. We then discuss the traditional identification of purely passive recovery from anesthesia due to the elimination of anesthetics from the body and brain. This is followed by a recent study that has revealed a common mechanism based on the brain's intrinsic ability to actively reboot consciousness from anesthesia. Finally, a novel theory of how the brain emerges from anesthesia and regains consciousness is presented. Advancements in understanding the mechanisms whereby the brain loses or regains consciousness after anesthesia. General anesthesia was first used on patients in the 1840s for clinical surgery. Since then, the reversible loss of consciousness (LOC) induced by anesthesia is still unclear and has been a complex and elusive subject of scientific challenge and debate. Anesthesia-induced LOC has been used as a model to investigate the neurobiological basis of anesthesia and, more recently, the general principles of brain function, including the nature of consciousness. The mechanism of anesthesia has been shaped by three influential theories: the non-specific lipid, specific protein target, and neural circuit theories. These hypotheses provide explanations from different perspectives and levels of how general anesthetics induce anesthesia. There are different pharmacological targets for diverse anesthetics to induce anesthesia. As an overarching principle, it is logical to propose that anesthetics disrupt neural activity and the integrity and function of neural circuits responsible for signal transmission and conscious perception/subjective experience by binding to specific molecular targets or through membrane-mediated targets.[1–5] However, there are still significant knowledge gaps in our understanding of the process of inhibition of neuronal activity, disruption or blocking of information transmission induced by various anesthetics, and LOC in the brain. For instance, some reagents that act as blockers/antagonists of the γ-aminobutyric acid type A (GABAARs) and N-methyl-d-aspartate (NMDARs) receptors were initially believed to induce LOC. However, this is not the case.[1] It is hypothesized that the recovery of consciousness and cognitive function from anesthesia is purely a passive process, in contrast to recovery from anesthesia, which depends on the elimination of the anesthetic from the body or brain. However, this hypothesis lacks solid experimental support and does not explain the long delay in the emergence and full recovery of cognitive function from anesthesia, which have been major challenges in clinical practice. Over the past 20 years, extensive evidence from animal model studies have shown that artificial manipulation of certain cortical and subcortical nuclei along with arousal pathways can either reverse or deepen anesthesia and accelerate or delay its emergence. The glutamatergic, GABAergic, cholinergic, noradrenergic, dopaminergic, or orexigenic efferent circuitries in certain nuclei, e.g., the prefrontal cortex, basal forebrain, locus coeruleus, ventral tegmental area, etc., may play important roles in LOC emergence.[1,6–8] These studies demonstrated that the anesthesia recovery is a dynamic and controllable process. However, the intrinsic ability of the brain to emerge from LOC, was not considered until a recently published study.[9] This study demonstrated that the brain is the subject of the paradox and plays a decisive role in regaining consciousness. Molecular mechanisms involved in the “active reboot” of the brain to consciousness after anesthesia. Under anesthesia, in addition to behavioral manifestations, such as the LOC and various forms of neural reflexes, the brain undergoes significant changes at the molecular and cellular levels. During anesthesia-induced LOC and its subsequent recovery, power play occurs between the brain’s function and anesthesia which is proposed by the apparent contradictions, these effects can be characterized as a complex dynamic. The contradictory proposals are as follows, anesthesia is the external force leading to LOC and the intrinsic ability of the brain is the internal cause of regaining consciousness. Typically, the internal cause of a pair of contradictions is the dominant force that determines the final outcome. Does the brain have an intrinsic ability to emerge from anesthesia and regain LOC? A recent study provided evidence showing a common mechanism for active rebooting of consciousness from anesthesia.[9] When the brain is forced into a minimum responsive state (MRS) by diverse anesthetics, the rapid downregulation of K+/Cl− cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) of the thalamus serves as a mechanism whereby the brain emerges from anesthesia and regains consciousness. Ubiquitin proteasomal degradation is responsible for KCC2 downregulation, which is driven by the ubiquitin ligase Fbxl4. KCC2 phosphorylation at Thr1007 promotes the interaction between KCC2 and Fbxl4. KCC2 downregulation leads to GABAAR-mediated disinhibition, enabling the accelerated recovery of VPM neuronal excitability and emergence of consciousness from anesthetic inhibition. This study demonstrated that ubiquitin degradation of KCC2 in the VPM is an important intermediate step en route to the emergence of consciousness from anesthesia. The key points of this mechanism for the active reboot of consciousness from anesthesia[9] include the following: first, the molecular process of emergence from anesthesia based on KCC2 downregulation is distinct from and occurs much earlier than behavioral recovery observed after anesthesia discontinuation. This recovery process occurs almost simultaneously and in parallel with anesthesia induction, beginning when the brain is forced into a MRS and continuing during MRS until the brain exits from this state. Second, this recovery process is not the reverse process of an anesthetic-induced action. The rapid downregulation of KCC2 in the VPM serves as a mechanism whereby the brain regains consciousness. KCC2, a neuron-specific isoform of the K+/Cl− cotransporter, transports Cl− out of the cell.[10] Normal expression of KCC2 is essential for the maintenance of inhibitory GABAAR responses. This rapid downregulation of KCC2 under anesthesia impairs the function of KCC2 and reduces GABAAR-mediated inhibition. Third, rapid KCC2 downregulation during anesthesia is mediated by ubiquitin-proteasomal degradation, but not by the previously recognized mechanisms of NMDAR–Ca2+–calpain and brain-derived neurotrophic factor (BDNF)–tropomyosin receptor kinase B (TrkB) activation.[11–15] Activity-dependent KCC2 downregulation via NMDAR-Ca2+–calpain and BDNF–TrkB activation occurs in the context of increased neuronal excitability; however, during anesthesia, KCC2 downregulation occurs in the context of decreased neuronal excitability. Fourth, KCC2 degradation is independent of the highlighted anesthetic targets. KCC2-Thr1007 phosphorylation causes ubiquitin degradation in KCC2. Although we considered that ketamine produces anesthesia by acting on NMDARs and propofol; pentobarbital and isoflurane produce anesthesia by acting on GABAARs, KCC2-Thr1007 phosphorylation increases by ketamine, propofol, pentobarbital, or isoflurane does not occur via NMDAR or GABAAR activity. Changes in EGABA levels induced by ketamine, propofol, pentobarbital, and isoflurane occurred independently of NMDAR and GABAAR. Propofol, pentobarbital, and isoflurane are believed to induce anesthesia by activating GABAARs. However, propofol induced KCC2-phosphorylation at Thr1007 in HEK293 cells overexpressing KCC2 (wild-type [WT] and mutant), whereas there was no evidence that GABAAR was expressed in HEK293 cells. This supports the notion that increased phosphorylation of KCC2-Thr1007 induced by propofol, pentobarbital, isoflurane, and ketamine occurs independent of their anesthetic target proteins, GABAARs, and NMDARs.[9] Finally, after the brain successfully exits from the MRS driven by the ubiquitin degradation of KCC2, a KCC2 downregulation-independent recovery process continues. This later recovery may depend on the clearance of anesthetics from the body; the reversal of neural activity patterns in anesthetic-related nuclei; and changes in protein targets, neurotransmitter systems, neural circuits, arousal systems, and other unknown mechanisms.[1] Novel theory for the recovery of consciousness after anesthesia. Based on the progress of recent studies, previous assumptions, and inferences about the recovery of consciousness after anesthesia, the following analogy has been conceptualized; the VPM neurons serve as “power generators” in the brain that are connected by neural networks, or “power lines” whereby neurons exchange neural signals. Anesthesia disrupts this important neural activity and produces a “power outage”. Ubiquitin-proteasomal degradation of KCC2 serves as a “reboot” mechanism within the VPM neuron “power generators” to restore the function of neural “power lines” that are essential for thalamocortical signal transmission and cortical activation. Thus, the force balance between the VPM neuron “power generators” and inhibitory force of anesthetics determines if the brain can successfully emerge from anesthesia and regain consciousness. The VPM neuron “power generators” restore the function of neural “power lines” and allow the emergence of consciousness. We would propose that without the effective work of the “reboot” mechanism within the “power generators”, the brain could not regain consciousness even after the termination and removal of anesthetics. Conversely, if an anesthetic is sustained at high enough concentrations, the brain’s intrinsic “power generators” could not successfully restore the anesthesia-interrupted “power lines”, regardless of the speed and intensity at which the “power generators” worked. Artificial manipulation of certain anesthesia-inhibited nuclei and arousal systems may help to restore certain “power lines” and could therefore synergistically interact with VPM neuron “power generators” to restore all necessary neural “power lines”, resulting in the emergence of consciousness from an unconsciousness state. This concept is illustrated in Figure 1. Finally, while this hypothesis is significantly innovative, further research is necessary to provide a more solid and reliable basis.Figure 1: An illustrative diagram showing the molecular basis for the LOC induced by the anesthetics and active emergence of consciousness driven by the ubiquitin-proteasomal degradation of KCC2 in the VPM of the thalamus. LOC: Loss of consciousness; MRS: Mini­mum responsive state; VPM: Ventral posteromedial nucleus; KCC2: K+/Cl− cotransporter 2.Acknowledgments We thank William Song at the University of Pennsylvania Perelman Medical School for his thoughtful comments and suggestions. Funding This work was partly supported by a grant from the National Natural Science Foundation of China (No. 82350710225). Conflicts of interest None.