Modulation of Central Vagal Afferent Endings in the Control of Food Intake

Carlos Arturo Campos

The nucleus of the solitary tract (NTS) of the caudal hindbrain integrates an array of viscerosensory information, including gastrointestinal signals conveyed by vagal afferent fibers that mediate the process of satiation. The NTS also receives afferents from within the brain itself, including melanocortinergic inputs that participate in long-term energy homeostasis, in part by modulating gastrointestinal signals in the NTS where melanocortin-4 receptors (MC4R) are expressed. Previous results indicate that N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the NTS play an important role in control of food intake, but the mechanisms by which NMDAR interact with specific controls of food intake are not known. The aim of work presented in this dissertation was to identify NMDAR-dependent mechanisms and neural substrates that contribute to the processing of satiation signals using immunohistochemical, pharmacological, behavioral, and electrophysiological approaches in rats. In Chapters One and Two, we identified NMDAR-dependent, ERK1/2-catalyzed synapsin I phosphorylation in NTS vagal afferent endings as a mechanism necessary for reduction of food intake by the archetypical gastrointestinal peptide, cholecystokinin. In Chapters Three and Four, we found that NTS MC4R activation increases NMDAR-dependent, PKA-catalyzed synapsin I phosphorylation in vagal afferent endings. Similarly, reduction of food intake following MC4R activation required NMDAR activation, and destruction of central vagal afferent endings attenuated MC4R-induced reduction of food intake and synapsin I phosphorylation. Accordingly, we inferred that NMDAR-mediated activation of vagal afferent endings contributes to melanocortinergic modulation of food intake. Previous reports indicated that reduction of food intake following hypothalamic leptin receptor activation is dependent on NTS MC4R activation. In Chapter Five, we found that reduction of food intake evoked by hypothalamic leptin administration is attenuated by NTS injection of an NMDAR antagonist, supporting a role for NTS NMDAR participation in leptin-induced reduction of food intake. Collectively, these results indicate that NMDARs in the NTS play an essential role in control of food intake by peptide signals acting on peripheral vagal afferents and in the NTS itself. In addition, our results suggest that phosphorylation of synaptic proteins in vagal afferent endings is a mechanism through which NMDARs modulate control of food intake.

Modulation of Central Vagal Afferent Endings in the Control of Food Intake

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