Dissecting the role of neural inputs in the regulation of AgRP neurons

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Project Abstract: Proper regulation of food intake is essential for survival to prevent over- or under-feeding. Sensory signals generated by the detection and consumption of food can modulate food intake. External sensory cues such as the sight and smell of food and food cues can potentiate feeding, while internal sensory information from nutrients and distension in the gastrointestinal tract can inhibit feeding. Yet how the brain integrates these two streams of information to modulate feeding behavior is unclear. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) are a useful entry point into this question. ARCAgRP neurons are both necessary and sufficient for feeding behavior, and they have been shown to integrate these two types of sensory signals across two different time scales: rapid inhibition in response to the sight and smell of food, and slower inhibition during intragastric delivery of food. However, the sources of these signals that modulate ARCAgRP activity in response to sensory information are poorly understood. I propose here to address this question by systematically testing two known neural inputs to ARCAgRP neurons: 1. Pituitary adenylate-cyclase activating peptide expressing neurons in the paraventricular nucleus of the hypothalamus (PVHPACAP), and 2. Leptin receptor expressing neurons in the dorsomedial hypothalamus (DMHLepR). I will examine the exact types of information each of these inputs represents, as well as the necessity of two of these inputs in modulating AgRP neurons in response to sensory information. Additionally, I will investigate a potential mechanism by which nutritional state alters the response of DMHLepR neurons to food presentation. Together these results would reveal how a critical neural feeding center is regulated, as well as illuminate potential mechanisms by which sensory signal integration could become disrupted in maladaptive feeding behaviors such as obesity.