Neurological disorders are recognized by the World Health Organization as ?one of the greatest threats to public health.? Parkinson's disease (PD) in particular is estimated to afflict nearly 10 million people worldwide, 1 million of whom reside in the US. Recent evidence suggests a causal role for the microbiota in promoting motor behaviorial abnormalities and alpha-synuclein pathology in animal models of PD, but the precise mechanisms that mediate these effects remain elusive. In addition, the vagus nerve has been extensively hypothesized to play a role in the spread of amyloid pathology from the enteric nervous system to the central nervous system during development of PD, but there has been no interrogation to date into the consequences of microbiome-induced alterations in vagal activity on the development of PD symptoms. These fundamental gaps in knowledge surrounding precisely how the microbiome modulates PD symptoms motivates my research on uncovering interactions between microbes and vagal activity in a PD mouse model. I hypothesize that vagal chemosensation of microbially-modulated metabolites contributes to the development of PD-related symptoms. The proposed research has the potential to inform novel therapeutic targets for early intervention or diagnosis of PD, and aligns directly with the NINDS mission to ?seek fundamental knowledge about the brain and nervous system to reduce the burden of neurological disease.? My preliminary data support the central hypothesis that the microbiome modulates vagal fiber activity in vivo, and that alterations in vagal activity result from active sensation of bacterial stimuli occurring on short time scales. Further, results from my experiments indicate that vagal fiber activity is elevated in a PD mouse model, supporting a role for vagal hyperactivity as a contributing factor to the development of PD-related behaviors. In light of these data, I hypothesize that functional alterations in vagal afferent signaling to the CNS arise from dysregulated microbial signals in the intestinal lumen and that microbiome-induced vagal hyperactivity contributes to the development of PD symptoms. I propose to test these hypotheses through the following aims.
Aim 1 : Identify select microbially-mediated metabolites that regulate vagal neuronal activity;
Aim 2 : Determine the role of mcirobiota-driven alterations in vagal activity in the development of PD-related symptoms. Findings from these aims will reveal novel insights into the molecular and cellular signaling mechanisms underlying microbiota-gut-brain communication at homeostasis and during the progression of PD symptoms.
Alterations in the gut microbiome and in vagal activity are increasingly implicated in the pathogenesis of PD (PD). My proposed research will uncover fundamental mechanisms underlying vagal afferent chemosenstion of microbially-modulated metabolites in the small intestinal lumen, as well as the distinct ligand-receptor pathways involved. The research will further determine how microbiome-mediated alterations in vagal activity during the prodromal phase of a PD mouse model contributes to the development of PD symptoms.
