Dr. Zhou’s Research

The Roles and Applications of Orexin/Hypocretin System in Anesthesia

The proposed project will study the role of the orexin system in general anesthesia, testing the hypothesis that the orexin system mitigates the anesthesia-associated neurotoxicity in the developing brain. Thousands of orexinergic neurons in the hypothalamus project broadly throughout the central nervous system and play an essential role in both sleep and general anesthesia. The orexin system distinguishes itself from other sleep-wake systems involving signaling mediated by glutamate, acetylcholine, dopamine, noradrenaline, histamine, serotonin and GABA, in that it is a peptidergic system with its main role in arousal control. Orexins facilitate anesthesia emergence and increase sympathetic output. This proposal is motivated partly by reports that prolonged or multiple exposures to anesthesia cause neurodegeneration in the developing brain, including inhibition of synaptogenesis. In light of the roles of orexins in stimulating synaptogenesis and facilitating anesthesia emergence, I hypothesize that activation of the orexin system may mitigate the neurotoxicity of anesthesia. In Aim 1 I plan to test this hypothesis at cellular level and animal level. At cellular level, I can directly apply orexins to primary neuron cultures exposed to anesthetics to test the effect. At animal level, instead of stereotaxically injecting orexin peptides into the local brain region, I will use the DREADD, a chemical-genetic tool, which allows us to manipulate specific neural circuit activities in a more systemic way. Additionally the activation of orexinergic neurons by the DREADD receptor is more physiological since the orexinergic neurons also release neurotransmitters other than orexins, including glutamate and dynorphin. With all the beneficial effects from the orexin system, in Aim 2, I plan to initiate a pilot small molecular screen in collaboration with the SMDC at UCSF for orexin receptor agonists in the hope of developing new perioperative drugs.