Decoding the control of food intake Insights from the habenula and hypothalamus

This thesis focused on the habenula and hypothalamus, two brain regions important for reward in general and food intake specifically, and their role in regulating (palatable) food intake. We first described a free-choice high-fat high-sugar diet (fcHFHSD) commonly used in our laboratory as a tool to gain mechanistic insights into the relevant brain circuits in the development of obesity. Next, we studied two populations of lateral hypothalamic (LH) neurons, the GABAergic and glutamatergic neurons, and their responses to sucrose drinking and how this was affected by the consumption of a fcHFHSD. Next, we focussed on the (lateral) habenula (LHb) and described that blocking all glutamatergic input to the LHb did not acutely affect palatable feeding, but had a more slow, modulatory effect. This could be driven by specific inputs to the LHb, of which we reported one projection from the central amygdala (CeA) dopamine receptor 1 (Drd1) expressing neurons. When chemogenetically manipulated, this specific CeADrd1+ connection did alter feeding behavior in a satiety state-dependent manner. Finally, to add translational knowledge, we used functional magnetic resonance imaging (fMRI) to study the resting state functional connectivity (rsFC) of the habenula in humans. We reported an interaction effect between BMI and hemoglobin A1c (HbA1c) for the habenula-ventral tegmental area (VTA) connection’s rsFC, suggesting an additional role for the habenula in glucose regulation. In conclusion, in this thesis, we described experiments that contributed to our knowledge of the habenula and hypothalamus and their control over food intake in the context of obesity development.