Brainstem circuits controlling gastrointestinal function

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Project Summary/Abstract Autonomic dysfunctions, especially gastrointestinal motility disorders, occur frequently in parkinsonian patients and are often prodromic to the clinical diagnosis of Parkinson’s disease (PD). Chronic constipation and delayed gastric emptying are observed in many parkinsonian patients and are especially troublesome; the latter provides an additional unresolved complication to the absorption and appropriate therapeutic dosing regimen of L-DOPA, i.e. the main therapy used to treat PD-related motor dysfunctions. In the quest to elucidate the treatment of parkinsonian-related gastroparesis, it is necessary to understand the factors, including the environmental influences, which contribute to the etiology and development of idiopathic PD. Several epidemiological studies have associated an increased incidence of PD with pesticide or herbicide exposure and rural location/lifestyle. Similarly, studies have indicated that vegetarians who follow a diet high in plant seed lectins have a higher incidence of PD compared to non-vegetarians. Of note, some vegetable cultivars in SE Asia have enriched lectin concentrations of up to 1%. Based on our preliminary studies that indicate impaired gastric motility upon administration of subthreshold doses of lectins and the herbicide paraquat, we propose the following novel hypothesis: “lectin- mediated retrograde transport of environmental toxins disrupts the brain-gut axis through a vagally-dependent ENS-DMV-SNpc pathway” prior to the development of PD-related motor dysfunctions. To investigate this novel hypothesis, we will use a combination of in vivo optogenetic, electrophysiological, anatomical and behavioral approaches in rodents to investigate on the gastric-related neural pathways affected in parkinsonian-related gastric dysfunctions.