Sleep Molecular Laboratory

Dr. Meng Liu - Orexin Gene Transfer

Soon after the discovery that narcolepsy is a neurodegenerative sleep disorder our lab began to devise ways to repair the circuit.  Initial approach was to graft orexin neurons into the brain in a manner similar to that employed by researchers in Parkinson’s disease.  However, we quickly realized that only 1-5% of the grafted neurons survived (Arias et al., 2004) and that more neurons would be required to influence sleep behavior.  Therefore, we undertook the strategy of gene transfer.  Dr. Meng Liu in the lab inserted the gene for orexin into an inactivated herpes simplex-1 virus (supplied by Dr. Rachael Neve) and did the preliminary experiments demonstrating that the virus transferred the gene for orexin into neurons and also made the gene product.  Then the gene was delivered to the brains of mice that lacked the gene, i.e., orexin knockout mice.  In these mice the neurons in the targeted brain region began to make the peptide and also released it into the cerebrospinal fluid.  Most importantly, when the gene was transfered into the orexin knockout mice their narcoleptic behavior was significantly reduced (by 60%)(see Liu et al., 2008).

Orexin immunoreactive neurons in the brain of an orexin knockout mouse given the orexin gene transfer.  Note that the orexin peptide is present in the processes.

We have now improved the efficacy of the virus so that the gene can be expressed for a month or longer (see photo) (Liu et al., J Neuroscience, 2011).  

Our most recent publication identified an hitherto unknown group of neurons in the brain that regulate cataplexy.  These neurons are located in the Zona Incerta, receive input from the amygdala and project to the Locus Coeruleus.  Interestingly, electrical stimulation of the zona incerta controls the tremor in patients with Parkinson’s disease.