Activation of noradrenergic terminals in the reticular thalamus delays arousal from propofol anesthesia in mice

Zhang, Yu; Fu, Bao; Liu, Chengxi; Yu, Shouyang; Luo, Tianyuan; Zhang, Lin; Zhou, Wenjing; Yu, Tian

doi:10.1096/fj.201802164rr

Cited by 29 publications

(18 citation statements)

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“…GABAergic TRN neurons have been proven to provide critical contributions to the initiation of unconsciousness in both physiological and pathological states (Fuentealba and Steriade, 2005;Gottschalk and Miotke, 2009). In addition, our previous study found that changing noradrenergic inputs to TRN can modulate the unconsciousness time of general anesthesia (Zhang et al, 2019).…”

Section: Introductionmentioning

confidence: 88%

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Liu

Zhang

et al. 2020

Front. Neurosci.

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Electrical synapses between neurons exhibit a high degree of plasticity, which makes critical contributions to neuronal communication. The GABAergic parvalbuminexpressing (PV+) neurons in the thalamic reticular nucleus (TRN) interact with each other through electrical and chemical synapses. Plasticity of electrical synaptic transmission in TRN plays a key role in regulating thalamocortical and corticothalamic circuits and even the formation of consciousness. We here examined the effects of propofol, a commonly used general anesthetic agent, on the strength of electrical synapses between TRN PV+ neurons by fluorescence-guided patch-clamp recording and pharmacological methods. Results show that 100 µM propofol reduced the electrical synaptic strength between TRN PV+ neurons. Notably, the propofol-induced depression of electrical synaptic strength between TRN PV+ neurons was diminished by saclofen (10 µM, antagonist of GABA B receptors), but not blocked by gabazine (10 µM, antagonist of GABA A receptors). Application of baclofen (10 µM, agonist of GABA B receptors), similar to propofol, also reduced the electrical synaptic strength between TRN PV+ neurons. Moreover, the propofol-induced depression of electrical synaptic strength between TRN PV+ neurons was abolished by 9-CPA (100 µM, specific adenylyl cyclase inhibitor), and by KT5720 (1 µM, selective inhibitor of PKA). Our findings indicate that propofol acts on metabotropic GABA B receptors, resulting in a depression of electrical synaptic transmission of coupled TRN PV+ neurons, which is mediated by the adenylyl cyclase-cAMP-PKA signaling pathway. Our findings also imply that propofol may change the thalamocortical communication via inducing depression of electrical synaptic strength in the TRN.

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Section: Introductionmentioning

confidence: 88%

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Liu

Zhang

et al. 2020

Front. Neurosci.

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“…Chemogenetic inhibition generally followed our previous study (Zhang et al, 2019). AAV vectors containing the Gi-coupled inhibitory human M4 muscarinic receptor (rAAV-hSyn-hM4D(Gi)-EGFP, BrainVTA Co., Ltd., WuHan, China) were injected in the target area and allowed 4 weeks for sufficient virus expression.…”

Section: Chemogenetic Inhibition Of Ventral Tegmental Area or Locus Coeruleus Neuron And Behavioral Testmentioning

confidence: 99%

Neurons in the Locus Coeruleus Modulate the Hedonic Effects of Sub-Anesthetic Dose of Propofol

Chen

Yan

et al. 2021

Front. Neurosci.

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Propofol is a worldwide-used intravenous general anesthetic with ideal effects, but hedonic effects of propofol have been reported and cause addictive issue. There is little known about the neurobiological mechanism of hedonic effects of propofol. Increasing researches have shown that the dopaminergic nervous system of the ventral tegmental area (VTA) and the noradrenergic system of locus coeruleus (LC) play a crucial role in hedonic experiences, which are putative sites for mediating the hedonic effects of propofol. In the present study, rat hedonic response scale and place conditioning paradigm were employed to examine the euphoric effects of propofol. In vivo GCaMP-based (AVV-hSyn-GCaMP6s) fiber photometry calcium imaging was used to monitor the real-time neuronal activity in VTA and LC area in rats exhibiting propofol-induced euphoric behaviors. Then DREADDs (designer receptors exclusively activated by designer drugs) modulation using rAAV-hSyn-hM4D(Gi)-EGFP was performed to confirm the neuronal substrate that mediates the euphoric effects of propofol. The score of hedonic facial responses was significantly increased in the 4 mg/kg group compared with that of the 0 mg/kg group. The locomotor activity in the propofol-paired compartment was significantly increased at the 4 mg/kg dose compared with that of the saline-paired group. When compared with the 0 mg/kg group, the place preference increased in the 4 mg/kg group. Administration of 4 mg/kg of propofol triggers reliable increases in GcaMP fluorescence. However, in the VTA GcaMP-expressing rats, administration of 4 mg/kg of propofol did not induce any change of GcaMP signals. The facial score and the place preference, which increased by 4 mg/kg propofol were abolished by chemogenetic inhibition of the neuronal activity in the LC area. Our results suggest that LC noradrenergic neurons, not VTA dopaminergic neurons, are directly involved in the hedonic effects of sub-anesthetic dose of propofol.

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“…In this serial study, the data are presented as mean ± SEM. Sample size calculations of every step were based on our previous studies (Luo T. et al, 2018;Zhang et al, 2019). The changes in neuronal calcium signals of different anesthesia stages were analyzed using paired Student's t-tests.…”

Section: Data and Statistical Analysismentioning

confidence: 99%

Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia

et al. 2020

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Cholinergic neurons in the basal forebrain (BF) have long been considered to be the key neurons in the regulation of cortical and behavioral arousal, and cholinergic activation in the downstream region of the BF can arouse anesthetized rats. However, whether the activation of BF cholinergic neurons can induce behavior and electroencephalogram (EEG) recovery from anesthesia is unclear. In this study, based on a transgenic mouse line expressing ChAT-IRES-Cre, we applied a fiber photometry system combined with GCaMPs expression in the BF and found that both isoflurane and propofol inhibit the activity of BF cholinergic neurons, which is closely related to the consciousness transition. We further revealed that genetic lesion of BF cholinergic neurons was associated with a markedly increased potency of anesthetics, while designer receptor exclusively activated by designer drugs (DREADD)-activated BF cholinergic neurons was responsible for slower induction and faster recovery of anesthesia. We also documented a significant increase in δ power bands (1-4 Hz) and a decrease in β (12-25 Hz) power bands in BF cholinergic lesioned mice, while there was a clearly noticeable decline in EEG δ power of activated BF cholinergic neurons. Moreover, sensitivity to anesthetics was reduced after optical stimulation of BF cholinergic cells, yet it failed to restore wakelike behavior in constantly anesthetized mice. Our results indicate a functional role of BF cholinergic neurons in the regulation of general anesthesia. Inhibition of BF cholinergic neurons mediates the formation of unconsciousness induced by general anesthetics, and their activation promotes recovery from the anesthesia state.

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Activation of noradrenergic terminals in the reticular thalamus delays arousal from propofol anesthesia in mice

Cited by 29 publications

References 50 publications

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Neurons in the Locus Coeruleus Modulate the Hedonic Effects of Sub-Anesthetic Dose of Propofol

Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia

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