Facilitation of Behavioral and Cortical Emergence from Isoflurane Anesthesia by GABAergic Neurons in Basal Forebrain

Abstract

General anesthesia shares many similarities with natural sleep in behavior and electroencephalogram (EEG) patterns. The latest evidence suggests that general anesthesia and sleep–wake behavior may share overlapping neural substrates. The GABAergic neurons in the basal forebrain (BF) have recently been demonstrated to play a key role in controlling wakefulness. It was hypothesized that BF GABAergic neurons may participate in the regulation of general anesthesia. Here, usingin vivofiber photometry, we found that the activity of BF GABAergic neurons was generally inhibited during isoflurane anesthesia, having obviously decreased during the induction of anesthesia and being gradually restored during the emergence from anesthesia, in Vgat-Cre mice of both sexes. Activation of BF GABAergic neurons with chemogenetic and optogenetic approaches decreased sensitivity to isoflurane, delayed induction, and accelerated emergence from isoflurane anesthesia. Optogenetic activation of BF GABAergic neurons decreased EEG delta power and the burst suppression ratio (BSR) during 0.8% and 1.4% isoflurane anesthesia, respectively. Similar to the effects of activating BF GABAergic cell bodies, photostimulation of BF GABAergic terminals in the thalamic reticular nucleus (TRN) also strongly promoted cortical activation and behavioral emergence from isoflurane anesthesia. Collectively, these results showed that the GABAergic BF is a key neural substrate for general anesthesia regulation that facilitates behavioral and cortical emergence from general anesthesia via the GABAergic BF-TRN pathway. Our findings may provide a new target for attenuating the depth of anesthesia and accelerating emergence from general anesthesia.Statement of Significance:The basal forebrain (BF) is a key brain region controlling sleep–wake behavior. Activation of GABAergic neurons in the BF potently promotes behavioral arousal and cortical activity. Recently, many sleep–wake-related brain structures have been reported to participate in the regulation of general anesthesia. However, it is still unclear what role BF GABAergic neurons play in general anesthesia. In this study, we aim to reveal the role of BF GABAergic neurons in behavioral and cortical emergence from isoflurane anesthesia and elucidate the underlying neural pathways. Understanding the specific role of BF GABAergic neurons in isoflurane anesthesia would improve our understanding of the mechanisms of general anesthesia and may provide a new strategy of accelerating emergence from general anesthesia.

Recent advances in neural mechanism of general anesthesia induced unconsciousness: insights from optogenetics and chemogenetics

“…Activation of the basal forebrain GABAergic neurons with chemogenetics and optogenetics decreased sensitivity to isoflurane, prolonged the induction time, and accelerated emergence from isoflurane anesthesia. Optogenetic activation of the basal forebrain GABAergic neurons decreased delta power and the burst suppression ratio during 0.8% and 1.4% isoflurane anesthesia ( Cai et al, 2023 ). In addition, chemogenetic activation of astrocytes in the basal forebrain had a significantly shortened isoflurane induction time, prolonged emergence time, and augmented delta power of EEG during anesthesia maintenance and recovery periods ( Lin et al, 2023 ).…”

“…Furthermore, optogenetic activation of the basal forebrain GABAergic terminals in the thalamic reticular nucleus (TRN) also strongly promoted cortical activation and behavioral emergence from isoflurane anesthesia. EEG spectral analysis showed that optogenetic activation induced a notable decline in delta power and theta power, an increase in alpha power and beta power ( Cai et al, 2023 ). Collectively, these results showed that the basal forebrain plays a pivotal role in facilitating behavioral and cortical emergence from general anesthesia.…”

GABAergic neurons of anterior thalamic reticular nucleus regulate states of consciousness in propofol‐ and isoflurane‐mediated general anesthesia

“…25,26,31 Brief optogenetic stimulation of TRN neurons induces spindles in the cortex, 32 whereas the alpha oscillations (8)(9)(10)(11)(12) in the cortex is identified as a characteristic of propofol-induced anesthesia, [33][34][35][36][37] which indicated the involvement of TRN in GA regulation. Furthermore, manipulation of the basal forebrain (BF)-TRN or the locus coeruleus (LC)-TRN pathway affected the progress of isoflurane-or propofol-mediated GA. 38,39 The TRN is anatomically divided into several sectors distributed along the plane of the nucleus, and each sector forms distinct neural circuits which are composed of the specific cortical afferents and the thalamic target of TRN neurons. 40 The anterior sector of the TRN (aTRN) receives the projections from the prefrontal cortex (PFC) 41 and sends mainly outputs to the thalamic nonspecific nuclei, such as the thalamic mediodorsal nucleus (MD) and the VPM 40 to play a part the regulation of the corticothalamic and thalamocortical activities.…”

“…Brief optogenetic stimulation of TRN neurons induces spindles in the cortex, 32 whereas the alpha oscillations (8–12 Hz) in the cortex is identified as a characteristic of propofol‐induced anesthesia, 33–37 which indicated the involvement of TRN in GA regulation. Furthermore, manipulation of the basal forebrain (BF)‐TRN or the locus coeruleus (LC)‐TRN pathway affected the progress of isoflurane‐ or propofol‐mediated GA 38,39 . The TRN is anatomically divided into several sectors distributed along the plane of the nucleus, and each sector forms distinct neural circuits which are composed of the specific cortical afferents and the thalamic target of TRN neurons 40 .…”