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Abstract
Chronic consumption of high-calorie food increases food intake, leading to weight gain. Food intake is regulated via homeostatic and hedonic cues, and hedonic signals linked to reward signaling can override homeostatic cues leading to overconsumption in the absence of hunger. Human imaging data suggest that the reward pathway's hyposensitivity is linked to obesity, a deficit in reward signaling (Dopamine (DA) is the main neurotransmitter) leading to compensatory overeating. Recent evidence indicates that gut-originating signals interact with the reward pathways. Gut microbiota plays a role in obesity. Colonization of germ-free (GF) animals with either a "lean" or an "obese" microbiota recapitulated their donor phenotype, identifying the gut microbiota as a potential driver of obesity. Probiotic treatments reduce anxiety in mice; this effect is lost with vagotomy (sectioning of the vagus nerve connecting the gut to the brain). While GF animals display a marked preference for fat, the influence of microbiota composition on appetitive feeding behavior has yet to be studied. Thus, this dissertation aims to understand microbiota's influence on the reward pathway and appetitive behavior and determine whether this signal is mediated via vagus afferent neurons (VAN). I hypothesized that microbiota composition alters DA release in the nucleus accumbens (NAc) to modulate appetitive behavior and that microbiota-brain communication is mediated via VAN. For all studies, Fischer GF rats were conventionalized with a normal (ConvLF) or a high-fat (HF) type microbiota (ConvHF). Animals DA signaling was determined via microdialysis, in situ hybridization for dopamine receptors (DRD2,1) levels, and appetitive behavior using progressive ratio (PR) schedules. In chapter 2, inflammation, structure, and function of the VAN were assessed. In chapter 3, I employed a novel approach of vagal deafferentation to silence gut-origin vagal signaling to determine the role of VAN. ConvHF rats showed obesogenic phenotype, inflammation and remodeling of the VAN, reduced reward signaling (lower DOPAC, DRD2 level), and motivation (lower breakpoints) than ConvLF rats. Deafferentation of ConvHF rats rescued alterations in reward signaling. Collectively, these data suggest HF-type microbiota is sufficient to downregulate DA signaling in the reward centers and alter appetitive behavior and that VAN mediates these effects.