Anesthesia in mice activates discrete populations of neurons throughout the brain

Abstract

The brain undergoes rapid, dramatic, and reversible transitioning between states of wakefulness and unconsciousness during natural sleep and in pathological conditions such as hypoxia, hypotension, and concussion. Transitioning can also be induced pharmacologically using general anesthetic agents. The effect is selective. Mobility, sensory perception, memory formation, and awareness are lost while numerous housekeeping functions persist. How is selective transitioning accomplished? Classically a handful of brainstem and diencephalic "arousal nuclei" have been implicated in driving brain-state transitions on the grounds that their net activity systematically varies with brain state. Here we used transgenic targeted recombination in active populations mice to label neurons active during wakefulness with one reporter and neurons active during pentobarbital-induced general anesthesia with a second, contrasting reporter. We found 'wake-on' and 'anesthesia-on' neurons in widely distributed regions-of-interest, but rarely encountered neurons labeled with both reporters. Nearly all labeled neurons were either wake-on or anesthesia-on. Thus, anesthesia-on neurons are not unique to the few nuclei discovered to date whose activity appears to increase during anesthesia. Rather neuronal populations selectively active during anesthesia are located throughout the brain where they likely play a causative role in transitioning between wakefulness and anesthesia. The widespread neuronal suppression reported in prior comparisons of the awake and anesthetized brain in animal models and noninvasive imaging in humans reflects only net differences. It misses the ubiquitous presence of neurons whose activity increases during anesthesia. The balance in recruitment of anesthesia-on versus wake-on neuronal populations throughout the brain may be a key driver of regional and global vigilance states.

Isoflurane Rapidly Modifies Synaptic and Cytoskeletal Phosphoproteomes of the Supraoptic Nucleus of the Hypothalamus and the Cortex

“…The SON has recently been identified as a neuroendocrine substrate essential to mediate the effects of diverse general anaesthetics and sleep [6]. We explored phosphoproteome changes in the SON in response to isoflurane treatment and compared the findings in the SON with those obtained in the CC, a brain region that does not respond to anaesthesia by increasing Fos [7], and the PP, an essential part of the hypothalamo-neurohypophysial system.…”

“…These include the preoptic area, which is considered a sleep-promoting area, and the basal forebrain, lateral hypothalamic area, ventral tegmental area, and locus coeruleus those are brain regions involved in mediating sleep-arousal and anaesthesia-arousal transitions [1]. Remarkably, recent studies have identified an ensemble of neuroendocrine cells in the supraoptic nucleus (SON) of the hypothalamus persistently activated by GA [6, 7]. In elegant studies, Jiang-Xie et al [6] demonstrated that GA diminishes the expression of the immediate early gene Fos , commonly used as a marker for activated neurones, throughout the entire brain except for a subset of neurones in the SON that were persistently and commonly activated by several types of general anaesthetics.…”

“…Since it has been demonstrated that several anaesthetics, including isoflurane, propofol, ketamine with xylazine, and dexmedetomidine, activate the same neuronal population in the SON as isoflurane, we focused on isoflurane-mediated effects. We have compared the phosphorylation changes in the SON with the cingulate cortex (CC), a brain region without changes in FOS expression in response to anaesthetics [7], and the neurointermediate lobe (NIL) of the pituitary, consisting of the pituitary intermediate lobe as well as the posterior lobe, which is the hypothalamic-neurohypophysial system structure from where OXT and AVP are secreted to the systemic circulation. While no changes in phosphorylation were recorded in the NIL, we found that phosphorylated proteins in the SON and CC in response to GA are mainly involved in cytoskeleton remodelling and the synaptic vesicle cycle, although the proteins involved and/or the phosphorylation sites significantly differ between both structures.…”

Thiamine‐dependent regulation of mammalian brain pyridoxal kinase in vitro and in vivo

“…After physiological monitoring, the animals were decapitated using a guillotine (OpenScience, Moscow, Russia), as described previously (Aleshin, Graf, et al, 2021). This method of euthanasia was chosen as the most suitable for our studies on the brains of adult animals in view of strong interactions of anesthetics with the metabolic changes underlying the state of wakefulness, such as neurotransmitter levels, and with action of neuroprotectants (Leary et al, 2020; Müller et al, 2011; Yatziv et al, 2021). The method followed existing recommendations (Leary et al, 2020) and was approved by the Bioethics Committee of Lomonosov Moscow State University.…”

Noninvasive Electrophysiology: Emerging Prospects in Aquatic Neurotoxicity Testing

“…Importantly, the above-mentioned study analyzed LFP activity in the absence of anesthetics. , This issue is pertinent for neurotoxicology since anesthetics and analgesics can confound interpretations of electrophysiological recordings in anesthetized animals. Specifically, there is a ubiquitous presence of neurons whose activity increases during anesthesia throughout the brain . The balance in recruitment of anesthesia-on versus wake-on neuronal populations throughout the brain may be a key driver of regional and global vigilance states.…”