Cholinergic-Induced Specific Oscillations in the Medial Prefrontal Cortex to Reverse Propofol Anesthesia

Abstract

General anesthesia is a drug-induced reversible state comprised of altered states of consciousness, amnesia, analgesia, and immobility. The medial frontal cortex (mPFC) has been discovered to modulate the level of consciousness through cholinergic and glutamatergic pathways. The optogenetic tools combined with in vivo electrophysiological recording were used to study the neural oscillatory modulation mechanisms in mPFC underlying the loss of consciousness (LOC) and emergence. We found that optogenetic activation of both cholinergic and glutamatergic neurons in the basal forebrain (BF) reversed the hypnotic effect of propofol and accelerated the emergence from propofol-induced unconsciousness. The cholinergic light-activation during propofol anesthesia increased the power in the β (12–20 Hz) and low γ (20–30 Hz) bands. Conversely, glutamatergic activation increased the power at less specific broad (1–150 Hz) bands. The cholinergic-induced alteration to specific power bands after LOC had opposite effects to that of propofol. These results suggested that the cholinergic system might act on more specific cortical neural circuits related to propofol anesthesia.

Inactivation of Prefrontal Cortex Attenuates Behavioral Arousal Induced by Stimulation of Basal Forebrain During Sevoflurane Anesthesia

“…Although data from this study and previous reports 18 , 19 provide compelling evidence that the basal forebrain is an arousal-promoting area, we cannot discount the possibility that—rather than being a source of arousal, per se—the basal forebrain may be a point of convergence for the arousal-promoting influence of other subcortical nuclei and/or that the basal forebrain may be activating other brain regions to promote behavioral arousal. For example, selective activation of orexinergic terminals in basal forebrain was shown to accelerate the emergence from isoflurane anesthesia, 36 and orexin administration in basal forebrain has been shown to increase cortical acetylcholine and facilitate recovery from anesthesia.…”

“…Luo et al 18 showed that genetic lesions of basal forebrain cholinergic neurons delayed the emergence from isoflurane and propofol anesthesia, while chemogenetic stimulation of basal forebrain cholinergic neurons had an opposite effect. In a similar and more recent study, Wang et al 19 demonstrated that optogenetic stimulation of cholinergic and glutamatergic neurons in basal forebrain accelerated the emergence from propofol anesthesia. Although the results from these 2 studies and our findings from the current study converge, it is important to note that, unlike facilitating passive emergence from anesthesia as was done in past studies, we were able to actively reverse the state of general anesthesia (in the continued presence of sevoflurane) and provide the most robust evidence for a direct role of basal forebrain cholinergic neurons in promoting behavioral arousal and emergence from anesthesia.…”

“…However, there is no direct evidence for an interplay between PFC and basal forebrain in behavioral arousal. Furthermore, although recent studies showed a role for basal forebrain cholinergic neurons in passive emergence from anesthesia, 18 , 19 a direct role of cholinergic basal forebrain neurons in reversing the state of anesthesia has not been demonstrated.…”

Deep brain stimulation of the thalamus restores signatures of consciousness in a nonhuman primate model

“…Our findings suggest that DBS of CT might help restore not only arousal but also awareness in patients with disorders of consciousness, as previously investigated in some patients ( 37 , 43 ). While previous studies demonstrated that direct modulation of other cortical ( 62 ) and subcortical ( 63 – 65 ) brain areas could reverse the anesthesia-induced loss of consciousness in rodent models, there was no evidence that it could also restore conscious access. Nevertheless, a clear limitation of our experiment is that it relies on a primate model of loss of consciousness due to anesthetic agents ( 18 , 45 , 46 ).…”

The role of the basal forebrain in general anesthesia

“…To determine how to modulate the propofol process by changing glutamatergic neuron activity, local field potentials and cortical EEG were used to analyze the relationship between glutamatergic neuron and propofol. Wang found that cortical EEG and field potential during propofol anesthesia changed from a low‐frequency, high‐amplitude slow‐oscillating pattern to an active high‐frequency, low‐amplitude pattern as a result of glutamatergic neuron activation in the BF 41 . All of these transmitter and electrophysiological studies suggest that glutamatergic neurons in BF play a role in the regulation of anesthesia.…”