Winzenried Eric T, Neyens Drew M, Calkins Rowan, Appleyard Suzanne M
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States.
Am J Physiol Regul Integr Comp Physiol. 2025 Jan 1;328(1):R121-R132. doi: 10.1152/ajpregu.00280.2023. Epub 2024 Nov 7.
Vagal sensory afferents carrying information from the gastrointestinal tract (GI) terminate in the nucleus of the solitary tract (NTS). Different subpopulations of NTS neurons then relay this information throughout the brain. Cholecystokinin (CCK) is a satiety peptide that activates vagal afferents in the GI. However, CCK is also expressed by neurons in the NTS, and activation of these neurons decreases food intake. What is less clear is how these NTS CCK neurons are activated by vagal afferents and what type of information they integrate about meal size and content. To address this, we identified NTS-CCK neurons by crossing CCK-IRES-Cre mice with floxed-Rosa-tdtomato mice and made a horizontal brain slice containing vagal afferents in the solitary tract (ST). Voltage clamp recordings of NTS-CCK neurons show that activation of the ST evokes excitatory postsynaptic currents (EPSCs) mediated by both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and -methyl-d-aspartate (NMDA) receptors. Analysis of these EPSCs revealed that 80% of NTS-CCK neurons receive direct, monosynaptic inputs, with many also receiving indirect, or polysynaptic, inputs. NTS-CCK neurons are sensitive to the transient receptor potential vanilloid type 1 agonist capsaicin, suggesting that they are downstream of C-fibers. In addition, both CCK and a 5 hydroxytryptamine 3 receptor (5-HT3R) agonist increased spontaneous EPSC (sEPSC) frequency in NTS-CCK neurons, with 69% of NTS-CCK neurons sensitive to CCK and 42% to the 5-HT3 receptor agonist, as well as 45% sensitive to both and 10% to neither. Taken together with previous studies, this suggests that NTS-CCK neurons are driven primarily by vagal afferents that are sensitive to CCK and are only weakly driven by those sensitive to serotonin. Nucleus of the solitary tract (NTS) cholecystokinin (CCK) expressing neurons are directly activated by glutamate released from vagal afferents. They are downstream of primarily C-type CCK-sensitive afferents, with a small proportion also downstream of serotonin-sensitive afferents. These findings suggest that NTS-CCK neurons integrate signals from the gut about ingestion of fats and proteins as well as stretch of the stomach, which they then relay to other brain regions important for the control of food intake.
携带来自胃肠道（GI）信息的迷走感觉传入神经在孤束核（NTS）终止。然后，NTS神经元的不同亚群将这些信息传递到整个大脑。胆囊收缩素（CCK）是一种饱足肽，可激活胃肠道中的迷走传入神经。然而，NTS中的神经元也表达CCK，这些神经元的激活会减少食物摄入量。目前尚不清楚的是，这些NTS CCK神经元是如何被迷走传入神经激活的，以及它们整合了哪些关于进餐量和内容的信息类型。为了解决这个问题，我们通过将CCK-IRES-Cre小鼠与floxed-Rosa-tdtomato小鼠杂交来鉴定NTS-CCK神经元，并制作了一个包含孤束（ST）中迷走传入神经的水平脑片。对NTS-CCK神经元的电压钳记录表明，ST的激活会诱发由α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和N-甲基-D-天冬氨酸（NMDA）受体介导的兴奋性突触后电流（EPSC）。对这些EPSC的分析表明，80%的NTS-CCK神经元接受直接的单突触输入，许多神经元还接受间接或多突触输入。NTS-CCK神经元对瞬时受体电位香草酸受体1激动剂辣椒素敏感，这表明它们位于C纤维的下游。此外，CCK和5-羟色胺3受体（5-HT3R）激动剂均增加了NTS-CCK神经元的自发性EPSC（sEPSC）频率，69%的NTS-CCK神经元对CCK敏感，42%对5-HT3受体激动剂敏感，45%对两者均敏感，10%对两者均不敏感。结合先前的研究，这表明NTS-CCK神经元主要由对CCK敏感的迷走传入神经驱动，仅由对血清素敏感的迷走传入神经微弱驱动。孤束核（NTS）中表达胆囊收缩素（CCK）的神经元被迷走传入神经释放的谷氨酸直接激活。它们主要位于对CCK敏感的C型传入神经的下游，一小部分也位于对血清素敏感传入神经的下游。这些发现表明，NTS-CCK神经元整合来自肠道的关于脂肪和蛋白质摄入以及胃扩张的信号，然后将其传递到对食物摄入控制很重要的其他脑区。
