Grant: Project Grant

Parkinson's disease (PD) is a common brain disorder affecting over 8 million people worldwide. It is known for its progressive motor symptoms, but they are preceded by a long period of olfactory deficits. The specific brain circuits responsible for these olfactory symptoms remain unknown, which limits its use as an early diagnostic marker for the disease. This research focuses on a brain region called the Anterior Olfactory Nucleus (AON), which is one of the first areas to be affected by the toxic protein buildups associated with PD. Our long-term goal is to understand the role of the AON in processing smells and memories, and how its disruption contributes to the early olfactory symptoms. First, we will investigate how the AON works in a healthy brain, specifically its role in processing smells and forming odor memories. Preliminary studies have shown that the AON becomes active in anticipation of a smell, and this activity is important for successful memory of that smell. Next, we will develop a new mouse model of early-stage PD by injecting PD-associated protein aggregates (a-synuclein fibrils) into the AON. This model will allow us to observe the progression of the disease and study the olfactory problems before the motor symptoms appear. Lastly, we will use this new mouse model to investigate how the disease pathology disrupts the AON's ability to represent and remember smells. This will be achieved using advanced imaging techniques to monitor changes in neural activity over time and to see how they correlate with behavioral impairments in smell and memory. Our work has the potential to identify new early biomarkers for PD, enabling earlier diagnosis and intervention. Furthermore, the research will create preclinical platforms to test treatments aimed at slowing or halting disease progression. Ultimately, this study will provide critical insights into general principles underlying early olfactory dysfunction across diverse neurodegenerative conditions.