Neural circuit mapping af orexigenic systems

Abstract

Orexigenic systems in the brain process appetite and/or hunger information and ultimately coordinate feeding responses. These brain circuits are critical for survival and originally evolved to ensure that we consume sufficient amounts of diverse nutrients to survive future famines. External and internal signals, such as food availability and energy state, converge on the orexigenic brain systems. Imbalances or faulty processing of these inputs can result in disordered eating behaviour. Examples are hormonal imbalances of satiety or hunger signals and aberrant responses to food-predicting cues in certain brain areas in people suffering from obesity on one hand of the body weight spectrum and anorexia nervosa on the other. Eating disorders impact on health and hence, place a huge financial burden on society. Currently, we lack effective treatments for the full spectrum of eating disorders. To impact, we need better non-invasive and effective treatments. The first step towards this goal is to better identify the brain targets, genes and mechanisms driving feeding behaviours. With this ultimate goal in mind, we explored the role of different orexigenic systems in feeding behaviour and aimed to identify the neuronal substrates involved.

Firstly, we found that olfactory food cues increase food intake and food seeking in rats. The cue engaged the hunger-signalling ghrelin system and activated a diverse population of cells in the arcuate nucleus of the hypothalamus, an important hub in the feeding circuitry. Secondly, we showed that Ghsr-IRES-Cre mice are a model for deficient ghrelin signalling (evidenced by the absence of ghrelin-induced food intake and decreased Ghsr mRNA expression in these mice) and that disrupted Ghsr expression rendered compromised growth and metabolic response to fasting. Thirdly, chemogenetic activation of a ghrelin-responsive ensemble in the arcuate nucleus was sufficient to drive feeding-related behaviours (food intake, food motivation, food choice) and condition a place aversion in mice. Finally, we found that the lateral hypothalamus was potently activated in the activity-based anorexia (ABA) mouse model (in which mice are severely energy depleted), including cells expressing orexin. Inhibition of orexin signalling using the clinically approved dual orexin receptor antagonist suvorexant suppressed food anticipatory running wheel activity.

Altogether, the work presented in this thesis shows that the arcuate nucleus plays an important role in processing hunger and appetite signals. Our data highlight the importance of this brain area in relaying sensory (food cues) and hormonal (peripheral ghrelin) inputs, ultimately driving feeding-related behaviours and conveying ghrelin’s negative valence. We also found that the orexigenic ghrelin signalling system plays a pivotal role in growth and in the metabolic response to a fast. Finally, data from our ABA experiment in mice suggest that suvorexant could potentially be used in anorexia nervosa patients to reduce orexin signalling and herewith aiding them to reduce hyperactivity and promote recovery.