Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia

Abstract

Mechanisms driving emergence from general anesthesia are not well understood. The noradrenergic brain nucleus locus coeruleus (LC) modulates arousal and may have effects on general anesthetic state. Using virally delivered designer receptors to specifically control LC norepinephrine (NE) neurons, we investigated the causal relationship between LC-NE activity and general anesthetic state under isoflurane. Selective activation of LC-NE neurons produced cortical electroencephalography (EEG) activation under continuous deep isoflurane anesthesia. Specifically, LC-NE activation reduced burst suppression in EEG and drove a rightward shift in peak EEG frequency with reduced δ EEG power and increased θ EEG power, measures of cortical arousal. LC-NE activation also accelerated behavioral emergence from deep isoflurane anesthesia; this was prevented with β or α1 noradrenergic antagonists. Moreover, these adrenoreceptor antagonists alone were sufficient to markedly potentiate anesthetic duration when delivered centrally or peripherally. Induction of anesthesia also was retarded by LC-NE activation. Our results demonstrate that the LC-NE system strongly modulates the anesthetic state, and that changes in LC-NE neurotransmission alone can affect the emergence from isoflurane general anesthesia. Taken together, these findings extend our understanding of mechanisms underlying general anesthesia and cortical arousal, and have significant implications for optimizing the clinical safety and management of general anesthesia. DREADD | RASSLA nesthetic agents are critical tools in modern medicine. General anesthesia is akin to a drug-induced transient coma-like state (1). Emergence from general anesthesia is currently a passive process in which the anesthetic agent is discontinued and the patient monitored for spontaneous recovery of physiological and behavioral signs of consciousness, which is a variable and unpredictable process in patient populations (1). There are no drugs available for actively reversing general anesthesia should procedural or safety considerations necessitate rapid emergence. Understanding the neural substrates involved in emergence can identify targets for reversing general anesthesia and reveal mechanisms involved in cortical arousal.Histaminergic, cholinergic, dopaminergic, and orexinergic/hypocertinergic pathways have been implicated in the emergence from general anesthesia (2-4). These pathways are important in arousal networks that regulate sleep and waking, among other actions. The locus coeruleus (LC)-norepinephrine (NE) brain system is a key arousal node (5); however, the function of LC-NE neurons in anesthetic emergence has been relatively understudied (6-8).The pontine nucleus LC projects NE fibers throughout the CNS and is the primary source of NE to the cerebral cortex, among other areas (9). The LC receives arousal influences via inputs from orexinergic and histaminergic neurons, as well as an indirect circadian input from suprachiasmatic nucleus via dorsomedial hypothalamus (5), and in turn regu...

Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context

“…S6). Together with previous studies demonstrating electrophysiological and behavioral characterization using the DREADDs system to manipulate LC neurons (30,31), our results validate the effectiveness of DREADDs in silencing LC activity. We monitored Ca 2+ activity in CA3 cells over 3 d in an experimental design in which mice explored a novel context A for 30 min for two consecutive days and then explored a second novel context B on the following day, in the order A1/A2/B (Fig.…”

Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia

“…A variety of experimental approaches have been used to study the neural circuits that underlie anesthetic-induced unconsciousness and recovery of consciousness in rodents, including designer receptors exclusively activated by designer drugs (DREADDs) (35), genetic manipulations (36), local and systemic drug administration (10,(37)(38)(39), microdialysis (40,41), targeted brain lesions (42,43), and electrical stimulation (34). Optogenetics is a novel tool that provides distinct advantages over previous techniques used to study anesthetic-induced unconsciousness and recovery of consciousness in rodents.…”

Designer receptors: therapeutic adjuncts to cell replacement therapy in Parkinson’s disease

“…Cholinergic and noradrenergic neurons are prime candidates to target for improving nonmotor dysfunction in PD (15,16). Indeed, DREADDs were recently shown to be effective for functional modulation of locus coeruleus noradrenergic neurons, resulting in significant behavioral effects (10). With a dual-targeting approach, the same ligand could positively modulate both transplanted neurons and residual neurons in another affected system to broaden therapeutic efficacy.…”

“…DREADDs couple only weakly to the arrestin pathway (9), meaning that DREADDs are rarely internalized or undergo desensitization and thus may be useful for chronic therapy. Indeed, the DREADD ligand CNO is orally bioavailable and rapidly activates DREADDexpressing neural populations for sustained time periods after systemic delivery (8,10), increasing potential clinical utility.…”