Functional Analysis of Nonmotor Symptoms from Regions Innervating the Locus Coeruleus in a Mouse Gut-Brain Alpha-Synuclein PFF Model
Abstract
If someone asked, What are the symptoms associated with Parkinsons disease?, the first thoughts that come to mind are the tremors and loss of motor control. This is the observed physical manifestation that has become synonymous with Parkinsons disease. However, this is merely one of many symptoms suffered by these individuals. The truth is there are several psychiatric symptoms that are not only present but precede the tremors and motor dysfunction by many years. These symptoms include anxiety, depression, loss of REM sleep, loss of memory, and even delusions and hallucinations. The current theory of what causes Parkinsons disease is that a protein called alpha-synuclein aggregates within the neurons of the brain forming structures called Lewy bodies. These Lewy bodies disrupt the normal function of the neurons and eventually result in their death. It is thought that the alpha-synuclein protein is inhaled or otherwise ingested and travels from the gut to the brain where it slowly migrates throughout the brain, affecting the different areas. One of the brain regions affected early in the disease progression is the locus coeruleus, the part of the brain responsible for the fight or flight response. But this small part of the brain does so much more. It is involved in anxiety, depression, REM sleep, and even in forming everyday working memory. In this proposal, we will investigate how the alpha-synuclein protein affects the function of the locus coeruleus using a mouse model that recapitulates the spread of alpha-synuclein pathology. We propose a series of experiments to ascertain how the toxic alpha-synuclein affects normal neural circuit function giving insight into the disease process that leads to the psychiatric symptoms in Parkinsons disease. This proposal is in direct alignment with the Focus Area of this Program Announcement, Mechanisms of cognitive and psychiatric symptoms of Parkinsons disease. The ultimate goal of this proposal is to identify regions of the brain that communicate with the locus coeruleus and are affected by the aggregation of this toxic protein. By determining the functional role that these regions play and how alpha-synuclein aggregation affects this function, it is our hope that through this identification we will be able to develop targeted therapies to mitigate the devastating symptoms of Parkinsons disease. These therapies may utilize existing FDA-approved medications but be administered as a combination treatment based on the affected brain regions. These treatments would be more readily available than the development of new pharmaceuticals, decreasing the Bench-to-Bedside time to as little as five to seven years. The Principal Investigator is fully committed to understanding and developing treatments for Parkinsons disease. The proposed research and development plan represent an underrepresented area of Parkinsons disease research and will be the focus of the principal investigators research goals. To foster success, the principal investigator has enlisted the advice and entered into collaborations with both basic scientists and clinicians specializing in neuroscience, psychobiology, neurology, and psychiatry. It is our goal that within our lifetime we will see the end of Parkinsons disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910701
Entities
People
- Adam Behensky
Organizations
- Johns Hopkins University
- United States Army