Leptin signaling within the nucleus of the solitary tract (NTS) contributes to the control of food intake, and injections of leptin into the NTS reduce meal size and increase the efficacy of vagus-mediated satiation signals. Leptin receptors (LepRs) are expressed by vagal afferents as well as by a population of NTS neurons. However, the electrophysiological properties of LepR-expressing NTS neurons have not been well characterized, and it is unclear how leptin might act on these neurons to reduce food intake. To address this question, we recorded from LepR-expressing neurons in horizontal brain slices containing the NTS from male and female LepR-Cre X Rosa-tdTomato mice. We found that the vast majority of NTS LepR neurons received monosynaptic innervation from vagal afferent fibers and LepR neurons exhibited large synaptic NMDA receptor (NMDAR)-mediated currents compared with non-LepR neurons. During high-frequency stimulation of vagal afferents, leptin increased the size of NMDAR-mediated currents, but not AMPAR-mediated currents. Leptin also increased the size of evoked EPSPs and the ability of low-intensity solitary tract stimulation to evoke action potentials in LepR neurons. These effects of leptin were blocked by bath applying a competitive NMDAR antagonist (DCPP-ene) or by an NMDAR channel blocker applied through the recording pipette (MK-801). Last, feeding studies using male rats demonstrate that intra-NTS injections of DCPP-ene attenuate reduction of overnight food intake following intra-NTS leptin injection. Our results suggest that leptin acts in the NTS to reduce food intake by increasing NMDAR-mediated currents, thus enhancing NTS sensitivity to vagal inputs.

SIGNIFICANCE STATEMENT Leptin is a hormone that critically impacts food intake and energy homeostasis. The nucleus of the solitary tract (NTS) is activated by vagal afferents from the gastrointestinal tract, which promotes termination of a meal. Injection of leptin into the NTS inhibits food intake, while knockdown of leptin receptors (LepRs) in NTS neurons increases food intake. However, little was known about how leptin acts in the NTS neurons to inhibit food intake. We found that leptin increases the sensitivity of LepR-expressing neurons to vagal inputs by increasing NMDA receptor-mediated synaptic currents and that NTS NMDAR activation contributes to leptin-induced reduction of food intake. These findings suggest a novel mechanism by which leptin, acting in the NTS, could potentiate gastrointestinal satiation signals.

孤束（NTS）核内的瘦素信号传导有助于控制食物摄入，向NTS中注射瘦素可减少进餐量并提高迷走神经介导的饱食信号的功效。迷走神经传入以及一群NTS神经元表达瘦素受体（LepRs）。然而，尚未充分表征表达LepR的NTS神经元的电生理特性，并且尚不清楚瘦素如何作用于这些神经元以减少食物摄入。为了解决这个问题，我们在水平大脑切片中从表达LepR的神经元中记录下来，该切片中包含来自雄性和雌性LepR-Cre X Rosa-tdTomato小鼠的NTS。我们发现，绝大多数NTS LepR神经元从迷走神经传入纤维接受单突触神经支配，与非LepR神经元相比，LepR神经元表现出大的突触NMDA受体（NMDAR）介导的电流。在高频刺激迷走神经传入期间，瘦素增加了NMDAR介导的电流的大小，但没有增加AMPAR介导的电流的大小。瘦素还增加了诱发的EPSP的大小，并增强了低强度孤立道刺激的LepR神经元动作电位的能力。通过使用竞争性NMDAR拮抗剂（DCPP-ene）进行沐浴或通过记录移液管施加的NMDAR通道阻断剂（MK-801）来阻断瘦素的这些作用。持续，使用雄性大鼠进食的研究表明，NTS内注射瘦素后，NTPP内注射的DCPP-ene可以减少过夜进食的减少。我们的结果表明，瘦素在NTS中起作用，通过增加NMDAR介导的电流来减少食物摄入，从而增强NTS对迷走神经输入的敏感性。

重要声明瘦素是一种会严重影响食物摄入和能量稳态的激素。孤立道（NTS）的核被胃肠道的迷走神经传入激活，从而促进进餐。将瘦素注射到NTS中会抑制食物摄入，而敲低NTS神经元中的瘦素受体（LepRs）则会增加食物摄入。然而，关于瘦素如何在NTS神经元中抑制食物摄取的了解甚少。我们发现瘦素通过增加NMDA受体介导的突触电流来增加表达LepR的神经元对迷走神经输入的敏感性，并且NTS NMDAR激活有助于瘦素诱导的食物摄入减少。这些发现提示瘦素在NTS中发挥作用，可以增强胃肠道饱合信号。