314-OR: Mechanisms of AgRP Neuron-Induced Hunger

Neural circuits express a remarkable diversity of neuropeptides, yet the specific function of most of these peptides remains unclear. Agouti-Related Peptide (AgRP) neurons in the arcuate nucleus are critical for the regulation of energy balance. These cells are activated by food deprivation and their activity promotes food seeking and consumption. When food is discovered, AgRP neurons are inhibited within seconds, yet their potentiation of feeding persists for tens of minutes. The mechanisms underlying this sustained hunger drive remain unknown. I will describe data showing that Neuropeptide Y (NPY) is uniquely required for the long-lasting effects of AgRP neurons on feeding behavior. We systematically blocked the ability of AgRP neurons to signal through AgRP, NPY, and GABA, and then stimulated these cells using an optogenetic paradigm that mimics their natural regulation. We found that genetic deletion of NPY abolished optically stimulated food intake and lever-pressing for food, whereas inactivation of AgRP or GABA signaling had no effect. Re-expression of NPY selectively in AgRP neurons rescued these deficits. These findings reveal that NPY plays a critical role in enabling AgRP neurons to drive feeding behavior, due its unique ability to sustain hunger in the interval between food discovery and consumption.