Gene Transfer for Cataplexy of Narcolepsy

摘要

Abstract I am a new young investigator with a proven publication record who is using new tools to correct specific circuits in the sleep disorder, narcolepsy. This disorder is linked to a specific loss of neurons containing the neuropeptide orexin, also known as hypocretin. Mine was the first study to demonstrate that orexin gene transfer into the brains of narcoleptic mice blocks cataplexy. Indeed, orexin gene transfer into some neuron populations in the CNS has proven to be ineffective indicating that only specific surrogate neurons can repair narcoleptic behavior. This project will continue to focus on cataplexy, an important distinguishing symptom of narcolepsy. Cataplexy is a sudden loss of muscle tone during waking and it is often triggered by strong emotions, including both positive (e.g. laughter, humor) and negative (e.g. anger, fear or sudden surprise) emotions. It is not known how emotions trigger cataplexy. I seek to identify this circuit by combining orexin gene transfer, optogenetics and novel brain circuit mapping tools that restrict expression of specific genes to phenotype and projection-specific neurons. The overall hypothesis driving the aims is that during strong emotions GABA input from the central nucleus of the amygdala (CeA) to the dorsolateral pons (vlPAG/LC/LPT) triggers cataplexy by inhibiting the pontine circuit responsible for maintaining muscle tone. Preliminary data supports this hypothesis because optogenetic inhibition or insertion of orexin into the CeA amygdala neurons projecting to the vlPAG/LC/LPT decreases emotion- induced cataplexy. Five aims are proposed to test the overall hypothesis. The proposed aims are mutually supporting, hypothesis driven, with clear objectives and definite endpoints. Extensive preliminary data show support for the hypothesis and feasibility of the approach. At the end of the funding period the project will have identified a meaningful neural circuit. This will have a significant impact in the development of potential therapies, including pharmacological agents, that can be selectively directed to this circuit.