Identifying a new circuit that controls feeding behavior: leptin and serotonin interactions.

University Of South Carolina At Columbia, Columbia SC

Investigators

Abstract

Non-technical Abstract Feeding is an essential activity for the maintenance of life, and its regulation is associated with multiple brain mechanisms that work together to ensure that animals eat appropriately. The complexity of these interactions has presented challenges to our efforts to fully appreciate the neural basis of food intake. However, before we can understand that complexity we must first identify the individual brain circuits that regulate food intake. The main goal of this project is therefore to use advanced genetic and anatomical approaches to identify a novel circuit that contributes to the control of feeding behavior. Identifying this circuit will ultimately allow us to determine how it works together with other feeding circuits that we already know more about to regulate a complex behavior critical for animal survival. In achieving that goal the work will not only increase our understanding of fundamental principles associated with how the brain regulates behavior, but may also lead to unexpected insights into feeding disorders and the chronic medical conditions associated with them that create considerable economic and social burdens, nationally and globally. In addition, this project includes a Summer Internship Program that will provide an integrated research experience for undergraduate students, particularly students who will be recruited from populations that are under-represented in science and medicine. These research experiences will provide such students with experiential learning opportunities that will create a foundation for future success in biomedical or basic research science. Technical Abstract Many studies agree that leptin controls food intake through activation of hypothalamic leptin receptors (LepRs). In addition, recent reports have examined the participation of extra-hypothalamic LepRs. In this regard, we have identified neurons in the rat raphe nuclei that are activated by leptin. Intra raphe administration of leptin increases pSTAT3 expression in discrete serotonergic neurons and suppresses food intake. Using optogenetic approaches, we were able to inhibit feeding behavior when the raphe neurons responsive to leptin were photo-stimulated, and we showed that intra-raphe leptin increases hypothalamic 5-HT levels.zpur overarching hypothesis is therefore that, in addition to direct hypothalamic actions, leptin powerfully regulates food intake by activating LepRs located in the raphe nuclei, thus stimulating 5-HT release in the hypothalamic nuclei where 5-HT exerts anorectic effect. The current project will test this hypothesis by studying the functional anatomical serotonergic connections between the raphe and the hypothalamic nuclei, measuring in vivo 5-HT release in the hypothalamic nuclei that receive serotonergic terminals following optogenetic stimulation of leptin responsive neurons of the raphe nuclei; and identifying the phenotype of the hypothalamic neurons that are activated by leptin-stimulated serotonin release. The idea that leptin is acting at multiple target sites including serotonergic neurons in the raphe will advance our understanding of the regulation of feeding behavior. This research will also be used to provide in-depth research opportunities for students from a nearby liberal arts college, particularly students from under-represented populations.