Grant: Project Grant

Alzheimer's disease is characterized by pathological hallmarks in the brain but, differences in brain function can be observed years prior to cognitive impairments. One of the earliest brain regions to exhibit changes in activity is the retrosplenial cortex. However, little is known about the subsequent pathological changes in this region. This is an important knowledge gap because the retrosplenial cortex is critically important for the types of memory that are disrupted in Alzheimer's disease. The retrosplenial cortex is also critical for maintaining communication between brain regions. Disruptions in the Retrosplenial cortex can have profound and distributed impacts on brain function. The Retrosplenial cortex is an attractive target for slowing Alzheimer's disease progression given that its activity is disrupted very early in Alzheimer's disease and intact connectivity of the retrosplenial cortex is a hallmark of healthy cognitive aging. However, a better understanding of the cellular and circuit dysfunctions in this region is a prerequisite. Our preliminary data in Alzheimer's model mice (and brain tissue from Alzheimer's patients) suggest that a particular subset of neurons in the retrosplenial cortex are impaired, resulting in disrupted retrosplenial cortex activity and memory impairments. This is significant due to the early disruption in activity in this region in Alzheimer's disease. The proposal will examine changes in the activity of neurons in the retrosplenial cortex, how this leads to impaired memory and whether targeting this disruption can slow or prevent memory impairments. We will use a mouse model of Alzheimer's disease to determine how activity in this region is altered over the progression of AD pathology. Then, we will modulate activity in this region to slow the progression of cellular and cognitive dysfunction. The results will provide critical insight into the progressive impairments that underlie the development of Alzheimer's disease.