Comparative Whole-Brain Mapping of Isoflurane and Ketamine-Activated Nuclei and Functional Networks

Abstract

Ketamine (KET) and isoflurane (ISO) are two widely used general anesthetics, yet their distinct and shared neurophysiological mechanisms remain elusive. In this study, we conducted a comparative analysis of KET and ISO effects on c-Fos expression across the brain, utilizing principal component analysis (PCA) and c-Fos-based functional network analysis to evaluate the responses of individual brain regions to each anesthetic. Our findings demonstrate that KET significantly activates cortical and subcortical arousal-promoting nuclei, with the somatosensory cortex (SS) serving as a hub node, corroborating the top-down general anesthesia theory for dissociative anesthesia. In contrast, ISO activates the nuclei in the hypothalamus and brain-stem, with the locus coeruleus (LC) as a hub node, implying a bottom-up mechanism for anesthetic-induced unconsciousness. Notably, the coactivation of sleep-wakefulness regulation, analgesia-related, neuroendocrine-related nuclei (e.g., prelimbic area (PL) and infralimbic areas (ILA), and the anterior paraventricular nucleus (aPVT), Edinger-Westphal nucleus (EW), locus coeruleus (LC), parabrachial nucleus (PB), solitary tract nucleus (NTS)) by both anesthetics underscores shared features such as unconsciousness, analgesia, and autonomic regulation, irrespective of their specific molecular targets. In conclusion, our results emphasize the distinct actions of KET and ISO while also uncovering the commonly activated brain regions, thus contributing to the advancement of our understanding of the mechanisms under-lying general anesthesia.