Ghrelin signaling regulates feeding behavior, metabolism, and memory through the vagus nerve

Abstract

Vagal afferent neuron (VAN) signaling sends information from the gut to the brain and is fundamental in the neural control of feeding behavior and metabolism. Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including hippocampus (HPC)-dependent memory. VANs, located in nodose ganglia, express receptors for various gutderived endocrine signals, however, the function of these receptors with regards to feeding behavior, metabolism, and memory control is poorly understood. We hypothesized that VANmediated processes are influenced by ghrelin, a stomach-derived orexigenic hormone, via communication to its receptor (growth hormone secretagogue receptor [GHSR]) expressed on gut-innervating VANs. To examine this hypothesis, rats received nodose ganglia injections of an adeno-associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a control AAV) for RNA interference-mediated VAN-specific GHSR knockdown. Results reveal that VAN GHSR knockdown induced various feeding and metabolic disturbances, including increased meal frequency, impaired glucose tolerance, delayed gastric emptying, and increased body weight compared to controls. Additionally, VAN-specific GHSR knockdown impaired HPCdependent episodic contextual memory and reduced HPC brain-derived neurotrophic factor expression, but did not affect anxiety-like behavior or levels of general activity. A functional role for endogenous VAN GHSR signaling was further confirmed by results revealing that VAN signaling is required for the hyperphagic effects of peripheral ghrelin, and that gut-restricted ghrelin-induced increases in VAN firing rate require intact VAN GHSR expression. Collective results reveal that VAN GHSR signaling is required for both normal feeding and metabolic function as well as HPC-dependent memory. vagus, transmit information about gastric distension, calorie content, and peptide hormone release to the brain to regulate feeding behavior and metabolism [1]. VAN-mediated transmission of nutrient, metabolic, and physiological signals to the brain are hypothesized to occur, in part, via paracrine signaling from GI-derived peptides to receptors expressed on VAN terminals innervating the GI tract [2]. However, technical limitations in targeting VAN GI peptide receptors either pharmacologically or with transgenic models have precluded advancement in understanding the physiological role of VAN-mediated paracrine signaling. For example, receptors for the orexigenic gut hormone ghrelin (growth hormone secretagogue receptor; GHSR), which is released from the stomach epithelium in response to energy restriction and in anticipation of a meal [3][4][5][6], are expressed on VANs [7-10] as well as dispersed throughout the brain [11,12]. Based on this receptor localization profile, ghrelin has been purported to act through both a VAN-mediated paracrine as well as a blood circulation-to-brain (endocrine) pathway [7,13]. However, the specific role of VAN GHSR paracrine signaling in regulating food intake and metabol...

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