The gastric hunger signal, ghrelin, influences feeding behavior via activation of the growth hormone secretagogue receptor (GHSR). GHSR's are abundantly expressed in cells in the ventral hippocampus (VHPC) where they function to regulate food intake. In this study, we used a GHSR-IRES-Cre mouse to examine whether feeding behaviors driven by GHSR cells in the VHPC are influenced by vulnerability to dietary obesity. Both males and females were exposed to 8 weeks of a high fat diet (HFD)-the top and bottom quartiles of weight gainers from each respective sex were designated as diet-induced obese (DIO) and diet resistant (DR), respectively.These mice received targeted injections of an excitatory (hM3Dq) or inhibitory DREADD (hM4Di) virus. This enabled chemogenetic control of GHSR-expressing cells in the VHPC as mice engaged in consumption of lab chow or HFD. Only DR female mice displayed the expected increase in food intake when tested with lab chow following DREADD stimulation, indicating that female mice that are resistant to dietary obesity maintain typical function for GHSR's in VHPC. Surprisingly, in males, DREADD stimulation decreased meal intake, which for chow occurred in DIO mice, whereas for HFD testing this was observed in DR mice. On the other hand, DREADD inhibition attenuated chow intake only in female mice.In the final series of studies, I used licking microstructure to examine the pre-ingestive (e.g., orosensory, palatability) and post-ingestive (e.g., gastrointestinal negative feedback) variables that regulate GHSR-dependent food intake. Multiple findings were revealed, including that the increased consumption of food in female mice following GHSR stimulation reflects a reduction in gastrointestinal negative feedback. Overall, my findings stress the need to implement a rigorous examination of a host of variables with refined analyses of meal intake to determine a role for how feeding signals in the brain impact ingestive behavior.
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