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

Abstract

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.

Neural Substrates for the Regulation of Sleep and General Anesthesia

“…Similar to volatile anesthetics, the LC-NA system has been tested to regulate general anesthesia induced by propofol and etomidate [ 98 ]. Although LC noradrenergic projections to the midline thalamus exerted similar emergence-promoting effects [ 103 , 104 ], the intracerebral injection of NA or the activation of noradrenergic terminals in the TRN delayed recovery from the propofol anesthesia [ 105 ], indicating diverse effects mediated by different neural circuits.…”

Regulation of Neural Circuitry under General Anesthesia: New Methods and Findings

“…LC is the primary source of norepinephrine in the brain and sends abundant outputs to many subregions of the forebrain, making it a vital arousal node [ 73 ]. Chemogenetic activation of LC in rats induces cortical arousal and a noticeable decrease in time to emergence from isoflurane, but the induction time remains unchanged [ 4 , 74 ]. Furthermore, the paraventricular thalamus (PVT) is a wakefulness-promoting region that receives numerous projections from the LC [ 75 ].…”

“…Furthermore, the paraventricular thalamus (PVT) is a wakefulness-promoting region that receives numerous projections from the LC [ 75 ]. Researchers found that chemogenetic inhibition of LC-PVT projections significantly delayed emergence time from isoflurane anesthesia but had no impact on the induction phase [ 74 ]. Thus, although both dopaminergic and noradrenergic neurons belong to the class of monoaminergic neurons, there is a difference between these neurons in the process of consciousness transformation during general anesthesia.…”

Editorial: Novel Aspects of Neurotransmitters

“…In Anxiety and Depression, brain transmitters could be modulated by intestinal microbiota (Huang and Wu). The locus coeruleus (LC) tyrosine-hydroxylase (TH) neurons and the TH:LCparaventricular thalamus circuit may be involved in regulating emergence from anesthesia (Ao et al, 2021).Moroz leads us to explore, in an elegant dissertation, the evolutionary aspects of neurons origin. He presents the most relevant hypotheses on the aspects that have given rise to neuronal types, their organization, way of communication, and the mechanisms underlying these characteristics (Moroz).…”

“…In Anxiety and Depression, brain transmitters could be modulated by intestinal microbiota ( Huang and Wu ). The locus coeruleus (LC) tyrosine-hydroxylase (TH) neurons and the TH:LC-paraventricular thalamus circuit may be involved in regulating emergence from anesthesia ( Ao et al, 2021 ).…”