Summary Our program aims to seek fundamental knowledge about the brain and nervous system regulating our sleep quality/efficiency and to use that knowledge to reduce the burden of neurological diseases (and probably many others) for all people. Quality sleep is a fundamental necessity for maintaining health and critical for optimal cognitive functioning. Although we have known this for a long time, we have little understanding of how the quality and quantity of sleep are regulated. We began to study individuals with the familial natural short sleep trait more than a decade ago and have now identified a growing list of genes/mutations carried by these individuals. While they are genetically wired to sleep fewer hours per day, they do not desire more sleep and do not seem to suffer the consequences of sleep deficiency and usually live a long and healthy life (both physically and mentally), indicating that they sleep more efficiently. Identifying genetic differences in this population provides solid evidence for the involvement of specific molecules and pathways in regulating sleep quality/efficiency pathways. These molecules offer opportunities to not only reveal the molecular mechanisms but also map brain regions and cells responsible for sleep regulation, thus gaining an understanding of the systems involved in sleep quality/efficiency regulation. We have used our short sleep mouse models and Alzheimer-like disease mouse models to demonstrate that these short sleep mutations offer protective effects against the development and the progression of AD-like pathology. This finding has the revolutionary implication that quality sleep can help prevent many diseases, including neurodegenerative disorders. My research aims to understand how sleep quality is regulated and thus know how quality sleep can be obtained. The results from this research program will have long-lasting beneficial effects on human healthy longevity.