Neuropeptide VF in Fatigue Behavior
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease estimated to occur in up to one million U.S. residents. While more likely to affect women than men, ME/CFS is observed in all ethnic populations and among all vocations, including those serving in the military. Our understanding of ME/CFS remains poor. In particular, we do not understand why individuals with this syndrome complain of profound fatigue. Often individuals will describe the fatigue as similar to that experienced during infection with a virus such as COVID19, influenza A, or infectious mononucleosis. Hence, one attractive idea is that in ME/CFS, the body functions as it would in a sick person, but without the actual sickness. Most research on ME/CFS has focused on the role of peripheral immune system. While the immune system is likely involved in the development of this disorder, the main organ that malfunctions in ME/CFS is the brain. Yet, heretofore, there has been a paucity of investigations of the brain mechanisms of fatigue in ME/CFS. This grant proposal aims to fill this gap in our knowledge. We will investigate a candidate brain mechanism of a fatigue. We will study a chemical called NPVF, which belongs to a class of chemicals called neuropeptides. As the name suggests, neuropeptides are small proteins (called peptides) expressed in neurons (nerve cells). Our motivation for studying NPVF initiated from studies done in very simple animals, including worms, flies, and fish. These studies found that neuropeptides similar to NPVF caused animals to reduce their movement, stop eating, and fall asleep during sickness. Other studies done in mice, rats, chickens, and sheep also support a role for NPVF during sickness. Remarkably, NPVF is found in just a very small location deep in the brain, in an area previously implicated in sickness behavior. To study NPVF function in fatigue, we will use the laboratory mouse. Mice offer powerful tools for genetic manipulation, and, because they are mammals (like humans), are widely considered the most appropriate animal to use for testing ideas directly relevant to humans. We already generated genetically modified mouse strains, which will allow us to study the function of NPVF neurons in fatigue behavior. The first goal of our project will be to see whether activating NPVF neurons results in fatigue behavior and sleep. Conversely, we will test whether silencing NPVF neurons attenuates sickness behavior. We will also test whether NPVF neurons are activated during sickness and whether the NPVF itself is released in response to sickness. We are proposing to use the CDMRP PRMRP Discovery Award mechanism to fund this project. This mechanism serves to fund high-risk science that also offers the possibility of high reward. Since this project studies a new mechanism for fatigue and is not based on published data, the proposed research represents far more than an incremental advance upon published data.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210069
Entities
People
- David M Raizen
Organizations
- United States Army
- University of Pennsylvania