Grant: Project Grant

Brain diseases characterized by age-related progressive loss of neural tissue (neurodegeneration), like Alzheimer and Parkinson disease, often start with abnormal connectivity between brain cells and regions. Huntington disease (HD) is an inherited brain disorder with average onset in middle age and progressive impairment of movement, thinking and mood. Neurodegeneration is most severe in two brain regions -- the cortex and striatum, and the first changes occur at connections (synapses) within cortex and between cortex and striatum. Although genetic approaches to reduce the mutated protein in HD patients are in clinical trials, evidence suggests changes in synapses may not be reversed once the disease has started. Moreover, there are significant challenges for scaling up therapeutic delivery of these biological agents. There is a critical need to develop complementary therapies to normalize function of brain connections before clinical disease onset, by investigating the circuit and cellular mechanisms underlying those changes. Notably, we have discovered that HD is associated with changes in the way sensory signals (touch, sound, light) are processed in the cortex, which may contribute to the well-documented impairments in movement and aspects of cognition (attention, concentration, learning). Here, we will investigate the causes of these sensory changes, and determine their impact on simple learning tasks. Our results will guide development of therapies to restore brain connections critical for maintaining normal function longer in HD gene mutation carriers.