Lateral Habenula Glutamatergic Neurons Modulate Isoflurane Anesthesia in Mice

Abstract

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.

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

“…The average calcium activity of LHb is significantly increased during isoflurane anesthesia maintenance and begins to decline during RORR. Calcium signals of glutamatergic neurons in LHb show no change during the induction stage [ 54 ]. These interesting findings suggest that the glutamatergic neurons may play distinct roles in general anesthesia and the sleep–wake cycle.…”

“…These unique phenomena suggest that different anesthetics may target specific neural pathways during the induction period, based on their specific pharmacological structures and physicochemical features. Furthermore, chemogenetic regulation of LHb glutamatergic neurons similarly shows that they contribute to the recovery time but not the induction time of general anesthesia [ 54 ]. In the cholinergic system, chemogenetic activation of BF cholinergic neurons affects both the induction time and the recovery time when using either isoflurane or propofol anesthesia, thereby attenuating the efficacy of general anesthesia [ 50 ].…”

“…Again, these results demonstrate that the hypothalamic preoptic area plays a crucial role in maintaining general anesthesia. After optogenetic activation of the LHb containing glutamatergic neurons [ 54 ] and VTA-LHA GABAergic projections, behavioral studies have shown that LORR significantly declines and RORR statistically increases. Optical inhibition of VTA-LHA GABAergic projections induces the opposite effects in both the EEG and behavioral outcomes [ 79 ].…”

Dopaminergic Projections From the Ventral Tegmental Area to the Nucleus Accumbens Modulate Sevoflurane Anesthesia in Mice

“…Fiber photometry data were analyzed using MATLAB 2019a (MathWorks, Cambridge, UK). The values of the fluorescence change (∆F/F) were calculated using the following formula: (F − F0)/F0, where F is the test fluorescence signal and F0 is the average fluorescence intensity before stimulation (Liu et al, 2021).…”

Paradoxical excitation of lateral habenula neurons by propofol involves enhanced presynaptic release of glutamate

“…Recently, studies have shown that GAs, such as propofol [14,15], and isoflurane [16], have a pronounced effect on the lateral habenula (LHb), an epithalamic structure which has been implicated in various psychiatric disorders such as substance abuse disorder, sleep disorder, and most notably depression [17]. The LHb serves as a critical interface between forebrain, as well as limbic regions, and monoaminergic structures by receiving dense inputs via the stria medullaris from areas such as medial prefrontal cortex and globus pallidus (rodent homolog is the entopeduncular nucleus).…”