Disturbances in the daily sleep-wake cycle are a common feature experienced by individuals with neurodegenerative disorders. They have difficulty sleeping at night and staying awake during the day. These disturbances have a major impact on their quality of life as well as on the family members who care for them. Huntington's disease (HD) is the most common genetically determined neurodegenerative disease and we have documented that circadian rhythms are disrupted early in the disease progression in three distinct mouse models of HD. Using a mouse model of HD which expresses the human mutation (BACHD), we have successfully improved the behavioral and some of the autonomic deficits using a protocol that limits the daily food intake into a 6-hr window during the animal's active phase, and is thus named: time restricted feeding (TRF). This feeding/fasting cycle improved behaviorally defined sleep in the BACHD model when applied early in disease progression. To our knowledge, this is the first demonstration that TRF can improve sleep parameters in mice although earlier work has shown that a similar schedule can improve behavioral sleep patterns in Drosophila. A critical gap in our knowledge is whether TRF specifically alters the temporal pattern of sleep stages, sleep homeostasis or cortical up/down states reflecting slow wave activity. This proposal will employ electrophysiological and optical approaches to close this gap and determine if such treatments can be usefully employed in HD. Given the shared pathology including the formation of protein aggregates and cell death, treatment strategies that prove to be effective in HD are likely to be broadly beneficial in the management of neurodegenerative diseases.

Many Huntington's disease patients exhibit disturbances in their daily sleep-wake cycle as part of their daily life. Using mouse models, we have found that we can improve sleep behavior as well as autonomic function and motor performance by controlling the timing of feeding. We now want to use EEG and optical measurements of cortical activity to explore the mechanisms underlying this treatment to move toward the development of new interventions designed to manage the disease.