A14 neurons in mediating neuromedin-S effect on feeding

Obesity is a significant problem of our days: more than 13% of people worldwide are classified as obese, mainly resulting from sustained overeating. The global level of the problem pressures the health system by increasing comorbid disease risks. For balancing caloric consumption, strict physiological mechanisms regulate food intake through the hormonal release from body peripheral tissues, mainly, stomach, fat tissue, and pancreas. These substances, act on the hypothalamus, the brain region that regulates appetite and satiety together with controlling other basic physiological functions. Despite the enormous progress during the last 25 years in understanding basic mechanisms of brain regulation of food consumption, the circuits involved in complex feeding behavior are not yet well defined. Particularly, our understanding of how the activity of neurons mediating hunger is blended with locomotor activity and how it is interrelated with the daily rhythms of food consumption. Emerging evidence from us and others supports the existence of cell type(s) that previously avoided close attention and are involved in the regulation of feeding. Surprisingly, among them are the neuromedin-S+ producing cells from the suprachiasmatic nucleus (SCN) of the hypothalamus, the cells that serve as an internal brain clock and regulate day-rhythm activity. Meantime, neuromedin S itself was discovered as a novel anorexigenic hormone thar strongly supresses feeding. However, the circuit modality via which neuromedin S exerts its effect on feeding is not known. In our recent works, we were able to address the action of neruomedin-S producing cells on specific cell population in the hypothalamus A14 dopamine neurons. These dopamine neurons reproducibly respond to neuromedin S in different physiological experiments. Our past and preliminary work gave impetus to the central hypothesis of this application that A14 neurons are essential players in orchestration of feeding behavior. We will test the idea that the A14 dopamine neuronal activation is controlled by neuromedin S (Aim 1), suppresses feeding (Aim 1,2) and stimulates locomotor activity. These opposing effects might explain why mice lacking receptors to neuromedin S in the paraventricular and periventricular zones of the hypothalamus, have altered food intake and increased body weight.