Investigating the role of top-down control in the regulation of food intake

Abstract

The rate of obesity has increased significantly in the past 40 years. Research has been focused on understanding feeding behaviour. However, the mechanisms that drive feeding behaviour in response to appetitive states are still poorly understood. Recent research has demonstrated that key brain regions involved in metabolic processing such as the hypothalamus receive projections from a wide variety of “higher order” brain regions. The results presented in this thesis suggest that the hypothalamus is able to be modulated by top-down regulation. The first aim of this project was to investigate the role of gastrin-releasing peptide (GRP) on food intake behaviour. Secondly, we aimed to investigate the role that the subiculum has in regulating the hypothalamus and how modulating this circuit can affect food intake. The results presented here demonstrate a newly defined neural circuit connecting Vglut1 and Vglut2 ventral subiculum (vSub) neurons to neuropeptide Y (NPY), proopiomelanocortin (POMC) and nociceptin(ppNOC) neurons in the arcuate nucleus (ARC) of the hypothalamus. Moreover, stimulation of vSub projection fibres caused an increase in food intake in Vglut2Cre and Vglut1Cre mouse models. Lastly, I also presented results that show deletion of the GRP alleles via CRISPR does not have an effect on metabolic or behavioural phenotypes. This newly discovered vSub to ARC neural circuit presented in this thesis, suggests that the hypothalamus controls food intake, but the activity of arcuate cells are able to be modulated by top-down regulation through a brain region such as the vSub.