In the United States today aberrant food intake and body weight regulation is prevalent and is manifested by extremes that include obesity and anorexia nervosa. The central nervous system tightly regulates food intake and body weight. Central circuits which utilize serotonin (5HT) exert powerful behavioral effects to decrease body weight. However the mechanism(s) of action of serotonin in regulating feeding and body weight are not understood. Recent studies have established leptin as a fundamental in the regulation of energy balance and neuroendocrine function. Administration of both leptin and serotonergic agonists inhibit food intake. However, it is unknown if leptin and serotonin systems interact within the CNS. Our preliminary findings suggest that leptin engages serotonergic neurons in the dorsal raphe nucleus. We hypothesize that the action of serotonergic systems on feeding converge on leptin-regulated systems as a final common output mechanism and will test these ideas in our specific aims. We will also extend that knowledge to the human brain which will provide fundamental information regarding the mechanisms by which food intake is regulated aberrantly in obesity and in eating disorders such as anorexia nervosa. In this proposal, we outline experiments designed to characterize the neuroanatomic mechanisms by which leptin and serotonin systems interact to regulate food intake. First, we will identify and characterize the chemical identity of hypothalamic neurons that express 5-HT2C and 5-HT1B receptors as these receptors are thought to modulate food intake and body weight. We will use dual label in situ hybridization for 5-HT2C and 5-HT1B mRNA coupled with ISHH for neuropeptides known to regulate food intake. Next, using retrograde tracing and in situ hybridization of 5-HT2C and 5-HT1B receptor mRNA, we will determine if hypothalamic neurons that innervate key autonomic regulatory sites receive serotonergic innervation and express 5-HT1B and 2C receptor mRNA. Third, using retrograde tracing and in situ hybridization for immediate early genes we will determine the CNS sites innervated by leptin-responsive neurons in the dorsal raphe nucleus. Finally, using retrograde tracing and immunohistochemistry for Fos following fenfluramine administration, we will determine the chemical identity and CNS sites innervated by serotonin-activated neurons that regulate food intake.
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