Browsing by Subject "Serotonin"
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Item Familiar Food-Induced Feeding Activation in C. Elegans(2011-08-10) Song, Bo-mi; Avery, LeonThe growing epidemic of obesity and eating disorders demands the study of regulatory mechanisms of food intake. Studying mutants whose food intake is altered under various conditions has greatly advanced our understanding of the mechanism. However, it is still largely unknown by which mechanisms perception of food activates food intake. The simple anatomy, genetic tractability, and well-characterized and quantifiable feeding behavior and evolutionary conservation of feeding regulators make C. elegans an attractive model system for the study. Food intake in C. elegans requires two muscle motions, pharyngeal pumping and isthmus peristalsis, and the frequencies of the two feeding motions dramatically increase in response to food as in other organisms. I attempted to understand the mechanism underlying food-induced feeding activation by studying the mechanism and the physiological context of action of serotonin, an endogenous activator of pharyngeal pumping. Here I show that like food, serotonin increases overall feeding by activating both feeding motions. Serotonin activates the two feeding motions by activating two distinct neural pathways. A 5-HT7 receptor activated the two motions mainly by acting in the two distinct pharyngeal motor neurons that are essential for food-induced feeding activation. Moreover, the results support that the serotonin receptor activated the two distinct neurons mainly by activating two distinct downstream G protein signaling pathways. Despite the separate regulation, isthmus peristalsis was coupled to the preceding pharyngeal pump. The separate regulation with coupling of the two feeding motions may have evolved to support efficient feeding by allowing control of the ratio of the frequencies of the two muscle motions according to density of food and by preventing futile isthmus peristalsis. Then, which aspect of food triggers the serotonin signal that increases food intake? I found that recognition of familiar food selectively triggers the serotonin signal. Worms selectively consume particular bacteria more actively after experience and the behavioral plasticity requires serotonin signaling. By dissecting the mechanism, I found that recognition of familiar food triggers serotonin release from a pair of chemosensory neurons. The released serotonin acts as an endocrine signal to increase pharyngeal pumping rate by activating the pharyngeal motor neuron that directly triggers pharyngeal pumping. The results suggest that worms form a memory of previously experienced food and that the memory controls food intake. Consistently, the familiar-food induced feeding was strongly dependent on duration of exposure to food to learn but not developmental timing of exposure or nutritional status. Furthermore, worms could remember the previously experienced food at least for several hours. My study provides insight into how feeding organ operates to increase food intake in response to food and how a particular aspect of food controls the process to increase food intake in C. elegans. Studying familiar food-induced feeding activation may help us understand the mechanisms underlying perception of different food and encoding, retention and retrieval of the memory of familiar food.Item Interplay Between Tryptophan Metabolites and the Virulence Factors of Enteric Pathogens(2020-08-01T05:00:00.000Z) Kumar, Aman; Winter, Sebastian E.; Sperandio, Vanessa; Conrad, Nicholas; Tu, BenjaminThe human gut consists of a complex milieu of several small molecules that helps in shaping its overall chemistry and biogeography. Trillions of bacteria, collectively known as the gut microbiota, colonize this landscape and occupy a specific niche. Small molecules derived from diet, gut microbial metabolism, and host metabolic activity have an impact on dictating the underlying gut microbiome composition. Gut bacterial populations effectively sense these molecular signatures and modulate gene expression to colonize this niche. An invading intestinal pathogen, to effectively colonize the gut, must sense and respond to the molecular signatures in the gut, which leads to effective colonization and infection. Diet is the principal source of energy by the intake of three main nutrients: carbohydrates, proteins, and fats. Tryptophan is an essential amino acid taken from the diet and plays an important role in protein biosynthesis. Tryptophan is also metabolized to different small molecules and its metabolic products are known to be present in high concentrations in the body. Upon ingestion, tryptophan is readily available in the luminal environment of the gut. Abundant levels of tryptophan are also absorbed by intestinal epithelial cells and is made available in different cellular compartments for normal physiological processes. Tryptophan present in the gut lumen can be further metabolized to numerous small molecules by the action of the gut microbial metabolic activity. Indole is one of the most abundant tryptophan-derived metabolites present in the gut and is absorbed by the host epithelial cells. The host can also metabolize tryptophan to various small molecules including serotonin that is made available in the gut lumen upon release from the host cells. Bacteria in the gut sense these bacterial and host-derived small molecules to colonize and maintain their niche. Similarly, an invading food-borne pathogen such as Enterohemorrhagic Escherichia coli (EHEC), which causes gastroenteritis by primarily colonizing the human colon, sense these small molecules and respond in a way that is conducive for its colonization and virulence gene expression. The role of these highly abundant tryptophan-derived small molecules in dictating the infectivity of an enteric pathogen remains unknown. Because the concentrations of these small molecules naturally present in the body are in the range of the drug concentrations that are used to treat certain diseases, it is possible to repurpose the information gained from these studies to treat intestinal infections. In the present study, we focused on two highly abundant tryptophan-derived small molecules present in the gut. Indole is derived from bacterial metabolism while serotonin is present via the action of host metabolism of tryptophan. Indole and serotonin are structurally similar and therefore may have similar effects against a pathogen in vivo. Indeed, we identified that both indole and serotonin decrease the virulence of the human pathogen Enterohemorrhagic E. coli (EHEC) and the mouse pathogen Citrobacter rodentium. We used multiple strategies including genetic manipulation, pharmacological inhibitors, and knock-out murine models to show that both indole and serotonin are inhibitory signals for virulence gene expression in EHEC and C. rodentium. We further investigated the mechanism used by these pathogens to sense these signals. We identified the first bacterial receptor for both indole and serotonin, and showed that these signals are sensed by a bacterial membrane bound histidine kinase CpxA. Upon sensing indole or serotonin, CpxA dephosphorylates itself and the transcription factor CpxR. In its phosphorylated state, CpxR directly activates expression of the virulence genes, its dephosphorylation prevents its action, decreasing expression of these genes. Together, our studies highlight the importance of sensing small molecules and understanding the gut biogeography by invading pathogens to successfully colonize the gut.Item [UT Southwestern Medical Center News](2010-11-11) Shear, Kristen HollandItem [UT Southwestern Medical Center News](2006-07-19) Despres, Cliff