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. My study was the first one to demonstrate that orexin gene transfer into the brains of narcoleptic mice blocks cataplexy. Indeed, orexin gene transfer into some neuron populations in the central nervous system 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 using 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 amygdala (CeA and BLA) to the dorsolateral pons (vlPAG/LC/LPT) triggers cataplexy by inhibiting the pontine circuit responsible for maintaining muscle tone. My published preliminary data supports this hypothesis because insertion of the orexin gene into amygdala neurons blocks both spontaneous and emotion-induced cataplexy. The primary goal of this project is to restrict expression of light sensitive opsins to amygdala-GABA neurons projecting to the dorsolateral pons (vlPAG/LC/LPT). We have strong preliminary data showing 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. The exploratory R21 project is a perfect vehicle to create new tools to correct circuits.
Specific neural circuits control specific behaviors. When these circuits fail, for instance, as a result of neurodegeneration of critical neurons, then it leads to abnormal behavior. An important objective of neuroscience is to identify these circuits and to correct them when they fail. We will focus on the circuit responsible for maintaining muscle tone. This circuit fails when orexin neurons die. We will repair this circuit with neuronal tracing and optogenetics.
|Liu, Meng; Blanco-Centurion, Carlos; Shiromani, Priyattam J (2017) Rewiring brain circuits to block cataplexy in murine models of narcolepsy. Curr Opin Neurobiol 44:110-115|