DESCRIPTION (provided by applicant): Recent advances in viral-mediated gene transfer have produced an exciting new toolset for neuroscience research. In particular, many studies in the last 10 years have used microinjection of viral vectors to insert genetic material into brain neurons in vivo. However, typically these viral manipulations have not been directed at a specific cell type, but rather viral infection has been targeted at all cells within the injection site. In addition, there have been almost no studies using such technology to explicitly modulate firing activity of neurons. We propose here to take advantage of cell-type specific viral expression technology coupled with new designer receptors to overcome these limitations. The goal of this collaborative proposal is to develop and validate a method to insert designer receptors into orexin neurons in brain in vivo, so that impulse activity in this important cell group can be selectively controlled by systemically administered compounds that are otherwise pharmacologically inert. Orexins have recently been found to be important in reward and addiction, as well as in arousal. Future applications of this new technology would include regulation of activity in orexin neurons selectively to better delineate their role in addiction. In addition, selective manipulation of impulse activity in cell- type specific neurons can be applied widely to other neurons, and will be a valuable new tool in behavioral and electrophysiological analyses of neural function. PUBLIC HEALTH RELEVANCE The proposed research is relevant to human health because it will develop new tools for more selective and specific manipulation of genes in brain neurons. These new tools not only will be important for basic research into the functions of specific brain neurons with consequences for new therapeutic development, but will also lead the way for new clinical approaches in gene therapy for a large number of disorders of the nervous system. Given the roles of the orexin system in addiction and in sleep disorders, the specific method proposed will lead to new ways to control orexin neuron activity for treating addiction or sleep disorders such as narcolepsy.

RELEVANCE The proposed research is relevant to human health because it will develop new tools for more selective and specific manipulation of genes in brain neurons. These new tools not only will be important for basic research into the functions of specific brain neurons with consequences for new therapeutic development, but will also lead the way for new clinical approaches in gene therapy for a large number of disorders of the nervous system. Given the roles of the orexin system in addiction and in sleep disorders, the specific method proposed will lead to new ways to control orexin neuron activity for treating addiction or sleep disorders such as narcolepsy.