The somatostatin pathway projected from basal forebrain to the lateral habenula promotes isoflurane anesthesia recovery

The basal forebrain (BF) acts as a pivotal relay station in the transmission of arousal signals, projecting to both cortical and subcortical structures. Among its downstream targets is the lateral habenula (LHb), which recent research has implicated in the modulation of sleep rhythms and in mediating the loss of consciousness associated with anesthetic agents. In our study, we utilized optogenetic manipulation to selectively modulate the BF VGluT2/SOM neuron projection pathway to the LHb, thereby examining its impact on behavioral and electroencephalographic responses to isoflurane anesthesia. Our results demonstrated that in healthy adult male mice, the activation of the BF SOM -LHb projection pathway significantly prolonged the induction time of anesthesia and shortened recovery time, consequently diminishing the anesthetic potency of isoflurane and reducing EEG δ power. In contrast, the inhibition of this pathway yielded the inverse effects. Notably, modulation of the BF VGluT2 -LHb projection pathway did not significantly affect the induction or recovery times of isoflurane anesthesia. Employing optogenetics in conjunction with calcium signal recording, we elucidated that the arousing effect of the BF SOM -LHb pathway is attributable to the enhanced inhibitory action of BF SOM neurons on LHb Glu neurons. This discovery sheds new light on the neural circuits involved in the loss and recovery of consciousness induced by anesthetic drugs, potentially informing future therapeutic strategies. Significance Statement The basal forebrain (BF), a key node in the ascending reticular activating system, plays a critical role in maintaining cortical rhythms associated with arousal and cognition. It projects to the lateral habenula (LHb), that is rich in glutamatergic neurons and is implicated in the promotion of anesthesia effects. Current research on the projection pathways linking the BF and LHb in the context of consciousness loss induced by general anesthesia is limited. Our study uncovers the BF SOM -LHb pathway as a key facilitator of recovery from isoflurane anesthesia, while the BF VGluT2 -LHb pathway shows no significant influence. This insight into the neural mechanisms of anesthesia could lead to strategies for improving the control of anesthesia emergence.