Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia

Luo, Tianyuan; Cai, Shuang; Qin, Zai-Xun; Yang, Shao-Cheng; Shu, Yang; Liu, Cheng-Xi; Zhang, Yu; Zhang, Lin; Zhou, Liang; Yu, Tian; Yu, Shouyang

doi:10.3389/fnins.2020.559077

Cited by 42 publications

(45 citation statements)

References 51 publications

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“…Simultaneously filtered at 40 Hz and digitalized at 500 Hz. An optical fiber (Newton Inc., China) integrated with an optical diverter (Doric Lenses) was used to transmit the light between the fiber photometry system and the implanted optical fiber ( Luo et al, 2018 , 2020 ; Liu et al, 2020a ; Xu et al, 2020 ). One month later, 12 mice were subjected to record changes in GCaMP signals.…”

Section: Methodsmentioning

confidence: 99%

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Lateral Habenula Glutamatergic Neurons Modulate Isoflurane Anesthesia in Mice

Liu

Zhou

et al. 2021

Front. Mol. Neurosci.

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Since their introduction in the 1840s, one of the largest mysteries of modern anesthesia are how general anesthetics create the state of reversible loss of consciousness. Increasing researchers have shown that neural pathways that regulate endogenous sleep–wake systems are also involved in general anesthesia. Recently, the Lateral Habenula (LHb) was considered as a hot spot for both natural sleep–wake and propofol-induced sedation; however, the role of the LHb and related pathways in the isoflurane-induced unconsciousness has yet to be identified. Here, using real-time calcium fiber photometry recordings in vivo, we found that isoflurane reversibly increased the activity of LHb glutamatergic neurons. Then, we selectively ablated LHb glutamatergic neurons in Vglut2-cre mice, which caused a longer induction time and less recovery time along with a decrease in delta-band power in mice under isoflurane anesthesia. Furthermore, using a chemogenetic approach to specifically activate LHb glutamatergic neurons shortened the induction time and prolonged the recovery time in mice under isoflurane anesthesia with an increase in delta-band power. In contrast, chemogenetic inhibition of LHb glutamatergic neurons was very similar to the effects of selective lesions of LHb glutamatergic neurons. Finally, optogenetic activation of LHb glutamatergic neurons or the synaptic terminals of LHb glutamatergic neurons in the rostromedial tegmental nucleus (RMTg) produced a hypnosis-promoting effect in isoflurane anesthesia with an increase in slow wave activity. Our results suggest that LHb glutamatergic neurons and pathway are vital in modulating isoflurane anesthesia.

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Section: Methodsmentioning

confidence: 99%

“…Fiber photometry data were analyzed using MATLAB 2016a (MathWorks, Cambridge, United States). The values of fluorescence change (Δ F / F ) were calculated using the following formula: ( F − F 0 )/ F 0 , where F is the test fluorescence signal and F 0 is the basal signal ( Luo et al, 2018 , 2020 ; Liu et al, 2020a ; Xu et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Lateral Habenula Glutamatergic Neurons Modulate Isoflurane Anesthesia in Mice

Liu

Zhou

et al. 2021

Front. Mol. Neurosci.

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“…It has been demonstrated that brain regions that regulate arousal become active during anesthesia recovery process ( Muindi et al, 2016 ; Luo et al, 2018 ; Luo et al, 2020 ). Additionally, the histaminergic ( Luo and Leung, 2009 ), cholinergic ( Irmak and de Lecea, 2014 ), noradrenergic ( Berridge et al, 2012 ; Fu et al, 2017 ), dopaminergic ( Eban-Rothschild et al, 2016 ; Taylor et al, 2016 ), and orexinergic pathways ( Sakurai, 2007 ) have been implicated in linking sleep-wake regulation and the emergence from GA. Our c-Fos immunostaining data reveals that LC TH neurons are active during emergence from isoflurane anesthesia.…”

Section: Discussionmentioning

confidence: 99%

Locus Coeruleus to Paraventricular Thalamus Projections Facilitate Emergence From Isoflurane Anesthesia in Mice

Yang

Zhang

et al. 2021

Front. Pharmacol.

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Locus coeruleus (LC) sends widespread outputs to many brain regions to modulate diverse functions, including sleep/wake states, attention, and the general anesthetic state. The paraventricular thalamus (PVT) is a critical thalamic area for arousal and receives dense tyrosine-hydroxylase (TH) inputs from the LC. Although anesthesia and sleep may share a common pathway, it is important to understand the processes underlying emergence from anesthesia. In this study, we hypothesize that LC TH neurons and the TH:LC-PVT circuit may be involved in regulating emergence from anesthesia. Only male mice are used in this study. Here, using c-Fos as a marker of neural activity, we identify LC TH expressing neurons are active during anesthesia emergence. Remarkably, chemogenetic activation of LC TH neurons shortens emergence time from anesthesia and promotes cortical arousal. Moreover, enhanced c-Fos expression is observed in the PVT after LC TH neurons activation. Optogenetic activation of the TH:LC-PVT projections accelerates emergence from anesthesia, whereas, chemogenetic inhibition of the TH:LC-PVT circuit prolongs time to wakefulness. Furthermore, optogenetic activation of the TH:LC-PVT projections produces electrophysiological evidence of arousal. Together, these results demonstrate that activation of the TH:LC-PVT projections is helpful in facilitating the transition from isoflurane anesthesia to an arousal state, which may provide a new strategy in shortening the emergence time after general anesthesia.

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“…Neuroinflammation may trigger cognitive dysfunction after surgery via synaptic dysfunction, neuronal cell death, and microglial priming (Lyman et al, 2014); Aβ accumulation and neuroinflammation mutually enhance neurotoxicity (Yamamoto et al, 2007;Wan et al, 2010). General anesthesia per se (induced by inhaled anesthetics) increased Aβ production and aggregation, and tau accumulation (Run et al, 2009;Perucho et al, 2010), and inhibited the activities of cholinergic neurons in preclinical studies (Luo et al, 2020). However, clinical studies found no evidence that general anesthesia increased POCD, compared to non-general anesthesia (neuraxial, regional and local anesthesia; Mason et al, 2010;Silbert et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Surgery Performed Under Propofol Anesthesia Induces Cognitive Impairment and Amyloid Pathology in ApoE4 Knock-In Mouse Model

Kim

Jung

Lee

et al. 2021

Front. Aging Neurosci.

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Background: Postoperative cognitive dysfunction (POCD) following anesthesia and surgery is a common and severe complication, especially in elderly patients. A pre-existing cognitive impairment may impart susceptibility to further cognitive dysfunction; the mechanism remains unclear. We hypothesized that the specific impacts of anesthesia and surgery on individuals with preclinical Alzheimer’s disease (AD) may render them more susceptible to an increase in the risk of cognitive impairment. The aim of this study was to compare the cognitive impairment between normal adult mice and those with preclinical AD after propofol anesthesia and surgery.Methods: We performed abdominal surgery in cognitively pre-symptomatic, 5-month-old male mice with sporadic AD (apolipoprotein E4 allele, ApoE4-KI) and age-matched (C57BL/6J) controls. Propofol anesthesia (170 mg/kg) was induced via retro-orbital injection over 2 h. Morris water maze (MWM) and Y-maze tests were conducted 2 days before and 2, 4, and 7 days after surgery. The mean escape latencies and spontaneous alternation percentages were the major outcomes. Neuronal apoptosis in hippocampal sections was evaluated using the terminal dUTP nick-end labeling (TUNEL) assay. Hippocampal amyloid beta (Aβ) levels were assessed via quantitative immunohistochemistry (IHC).Results: The control mice exhibited increased mean escape latencies of MWM at postoperative 2 and 4, but not at day 7; ApoE4-KI mice exhibited such increases at postoperative days 2, 4 and 7. Significant differences between ApoE4-KI and control mice in terms of the mean escape latencies were evident at days 2 and 7 (both P < 0.05). However, performance on a non-hippocampal memory tasks (Y-maze test) did not differ. More TUNEL-positive neurons were evident in the hippocampal CA3 region of ApoE4-KI mice at postoperative days 2 and 4, but not at day 7 compared to the control group (both P < 0.05). IHC revealed significantly elevated Aβ deposition in the hippocampal CA3 region of ApoE4-KI mice at postoperative days 4 and 7 compared to control mice (both P < 0.05).Conclusions: Propofol anesthesia followed by surgery induced persistent changes in cognition, and pathological hippocampal changes in pre-symptomatic, but vulnerable AD mice. It would be appropriate to explore whether preclinical AD patients are more vulnerable to POCD development.

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Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia

Cited by 42 publications

References 51 publications

Lateral Habenula Glutamatergic Neurons Modulate Isoflurane Anesthesia in Mice

Lateral Habenula Glutamatergic Neurons Modulate Isoflurane Anesthesia in Mice

Locus Coeruleus to Paraventricular Thalamus Projections Facilitate Emergence From Isoflurane Anesthesia in Mice

Surgery Performed Under Propofol Anesthesia Induces Cognitive Impairment and Amyloid Pathology in ApoE4 Knock-In Mouse Model

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