Serotonergic Modulation Of The Central Glp-1 System

Rosa Leon, University of Pennsylvania

Abstract

The prevalence of metabolic and stress-related disorders has been on the rise for decades and has reached epidemic proportions globally. The high degree of comorbidity between these pathological states is likely due, at least in part, to the significant overlap in neural circuitry that governs energy balance and stress-related physiological and behavioral responses. The future of pharmacotherapies aimed at treating these and other disorders relies on a more comprehensive understanding of the molecular interaction between different neuro-transmitter / -peptide systems. Of particular interest is a growing body of literature that supports an interaction between serotonin (5-HT) and the central glucagon-like peptide-1 (GLP-1) system, both of which are involved in the control of stress and energy balance. The research presented in this doctoral dissertation investigates the role of 5-HT as an endogenous modulator of the central GLP-1 system and its effects on feeding behavior and stress-induced neuronal activation. In Chapter 2, I establish that the anorectic and body weight changes induced by administration of exogenous hindbrain 5-HT are dependent on central GLP-1 receptor (GLP-1R) signaling. Second, I provide anatomical evidence of 5-HT2C and 5-HT3 receptor mRNA expression on GLP-1-producing preproglucagon (PPG) neurons in the medial nucleus tractus solitarius (NTS). Additionally, I show that hindbrain activation of these 5-HT receptors induces hypophagia in rats and that this effect is achieved via central GLP-1R signaling. Finally, a role for the 5-HT3 receptor was identified in mediating anorectic effect induced by the interoceptive stressor, lithium chloride (LiCl). Chapter 3 explores the 5-HT modulation of the central GLP-1 system in the context of acute stressors and the potential source of 5-HT driving the 5-HT/GLP-1 hindbrain interaction. 5-HT2C and 5-HT3 receptors were demonstrated to mediate the activation of NTS PPG neurons that results from exposure to LiCl and novel restraint. These acute stressors activate 5-HT activity in the Raphe magnus (RMg), a sub-nuclei of the caudal raphe (CR), as measured by increased c-Fos expression. Lastly, using a viral tracing technique I confirm that RMg neurons innervate NTS PPG neurons and that a sub-population of these PPG neurons lie in close proximity to 5-HT axons. Taken together, the results presented in this document expand the current understanding of both the central 5-HT and the GLP-1 systems. This collective body of work underscores the complexity of interactions between two different neural substrates and calls attention to the relevance such interactions play in the modulation behavioral and physiology.