Investigating the Enteroendocrine - Brain Axis: Ghrelin Cell and ECL Cell Physiology and Ghrelin Action on Mood and Complex Eating

The mechanisms and neurochemical pathways through which the orexigenic peptide hormone ghrelin act to regulate homeostatic feeding is fairly well documented. However, less understood are the mechanisms and brain regions that mediate ghrelin's effects on mood and complex eating behaviors. At the cellular level, little is known about the ghrelin cell's transcriptional profile, its secretory products other than ghrelin, and its relationship to other gastric endocrine cells, such as the histamine producing enterochromaffin-like cell. My doctoral research encompasses multiple aspects of the ghrelin system, from physiological assessments of the ghrelin cell to evaluations of ghrelin action on cue-potentiated feeding and stress-induced depressive-like behavior. Ghrelin has antidepressant effects, which become obvious following chronic stress. In the first part of my thesis, I found that this effect was mediated by neurogenesis. I observed that chronic stress reduces neurogenesis more severely in the ventral dentate gyrus of Ghsr-null mice, suggesting ghrelin provides a level of neuroprotection in the stress environment. Administration of anti-apoptotic P7C3-related compounds not only blocked stress-induced reductions in neurogenesis, but also minimized the severity of depressive-like behavior in mice. Focal hippocampal irradiation prevented the anti-depressant efficacy of P7C3-related compounds, indicating that P7C3 regulates mood directly through neurogenesis. In the second part of my thesis, I designed a novel protocol for studying cue-potentiated feeding behaviors in mice. Absence of ghrelin signaling in Ghsr-null mice, or administration of a ghrelin receptor antagonist in wild-type mice, disrupted the development of normal cue-food associations. Additionally, I discovered Ghsr expression in the basolateral amygdala (BLA), and BLA neuronal activation in response to a food-associated positive cue significantly correlated with amount of food intake. Thus, ghrelin signaling in the BLA may be responsible for its mediation of cue-potentiated feeding behaviors. The third part of my thesis examined the ghrelin cell transcriptome for potential secretory proteins and revealed significant expression of Rbp4, Ttr, and Nucb2, along with RBP4 protein secretion. Lastly, I characterized a novel HDC-Cre mouse model that may be advantageous in future studies to determine potential interactions between histaminergic and ghrelin signaling pathways. The full range of these discoveries advances our comprehensive understanding of ghrelin.