NPY inhibits vagal activation of NTS catecholamine neurons via presynaptic Y2 receptors in mice

Neurons in the nucleus of the solitary tract (NTS) are activated by inputs from the vagus nerve, including those from the gastrointestinal tract. This activation is relayed to central nervous system (CNS) regions critical for the control of food intake. Changes to NTS neuron activation, therefore, impact the transmission of vagal information to the brain. Injection of neuropeptide Y (NPY) and the Y2 receptor agonist PYY-(3-36) into the dorsal vagal complex (DVC) containing the NTS increases food intake. However, how NPY produces this effect is not known. Here, we use transgenic mice with enhanced green fluorescent protein (EGFP) expression driven by the tyrosine hydroxylase promoter (TH-EGFP) to identify NTS catecholamine neurons, as NPY terminals have been found in close proximity to NTS-TH neurons. We recorded from NTS TH-EGFP neurons in horizontal brain slices containing vagal afferents within the solitary tract (ST) using whole cell patch-clamp techniques. NPY inhibited ST-evoked excitatory postsynaptic currents (ST-EPSCs) in approximately two-thirds of TH-EGFP neurons. This effect was blocked by the Y2 receptor antagonist N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide hydrochloride (BIIE0246) and mimicked by the Y2 agonist PYY-(3-36). In contrast, the Y1 receptor agonist LP-NPY did not inhibit ST-EPSCs. NPY also reduced both basal and vagal-evoked action potentials in CA neurons. Finally, NPY attenuated the ability of the satiety peptide cholecystokinin (CCK) to increase glutamate release onto TH-EGFP neurons, an effect mimicked by PYY-(3-36). These results indicate that NPY inhibits both vagal- and CCK-induced activation of most NTS-TH neurons and suggest a potential mechanism for its effects to increase food intake at the level of the hindbrain.NEW & NOTEWORTHY NPY administered to the NTS stimulates food intake. However, the underlying cellular mechanisms were not well understood. Here we show that NPY inhibits vagal-evoked currents in NTS TH neurons through presynaptic Y2Rs, resulting in reduced throughput of vagal-evoked action potentials. NPY and Y2R activation also inhibited both basal and CCK-induced glutamate release, corresponding with a decrease in basal action potentials. This research identifies presynaptic Y2Rs as the major site of NPY-induced inhibition of NTS neurons.