Oral Presentation Australian and New Zealand Obesity Society Annual Scientific Conference 2023

Chronic overconsumption of calorie-dense foods, which can be driven by both homeostatic and hedonic eating mechanisms, is known to predominantly contribute to the worldwide prevalence of obesity. Neuropeptide Y (NPY) and its receptors modulate these mechanisms in various brain regions, including the lateral habenula (LHb), a brain structure that influences rewarding behaviours by regulating dopamine and serotonin activity within the midbrain. We used specific retrograde tracing techniques and identified NPY regions involved in feeding, reward and stress, which directly innervate the LHb. By anterograde tracing techniques, we found that Y1 receptor neurons within the LHb directly innervate the dorsal raphe nucleus and ventral tegmental area, two key regions know for altering hedonic eating behaviours. Previous studies showed that hedonic eating behaviours were altered by both dopaminergic neurons within the ventral tegmental area and serotonergic neurons in the dorsal raphe nucleus. Based on the combination of these findings as well as our current tracing results, we hypothesized that NPY signalling via Y1 receptors in the LHb could influence hedonic eating behaviours by modulating dopamine and serotonin activity. To test this hypothesis, we used chemogenetic technology to specifically manipulate the activity of Y1 receptor neurons in the LHb of Npy1r^Cre/+ mice. We observed that inhibition of the LHb Y1-receptor neurons increased sucralose preference, indicating that these neurons have a role in hedonic eating behaviours by increasing the desire for palatability. In addition, chemogenetic stimulation of NPY Y1 receptor neurons in the LHb altered sucrose consumption in a way resembling and promoting compulsive eating phenotypes. Our results demonstrate the potential role of an NPY circuit involving Y1 receptor neurons in the LHb in regulating hedonic eating behaviour. This circuit could provide a novel therapeutic target for obesity treatment, especially for cases caused by excessive consumption of calorie-dense palatable foods.