Department of Neural and Behavioral Sciences, Penn State College of Medicine , Hershey, Pennsylvania.
Department of Cellular and Molecular Physiology, Penn State College of Medicine , Hershey, Pennsylvania.
Am J Physiol Gastrointest Liver Physiol. 2019 Jul 1;317(1):G40-G50. doi: 10.1152/ajpgi.00079.2019. Epub 2019 May 1.
Perinatal high-fat diet (pHFD) exposure increases the inhibition of dorsal motor nucleus of the vagus (DMV) neurons, potentially contributing to the dysregulation of gastric functions. The aim of this study was to test the hypothesis that pHFD increases the inhibition of DMV neurons by disrupting GABA receptor subunit development. In vivo gastric recordings were made from adult anesthetized Sprague-Dawley rats fed a control or pHFD (14 or 60% kcal from fat, respectively) from embryonic (E13) to postnatal (P42), and response to brainstem microinjection of benzodiazepines was assessed. Whole cell patch clamp recordings from DMV neurons assessed the functional expression of GABA α subunits, whereas mRNA and protein expression were measured via qPCR and Western blotting, respectively. pHFD decreased basal antrum and corpus motility, whereas brainstem microinjection of L838,417 (positive allosteric modulator of α subunit-containing GABA receptors) produced a larger decrease in gastric tone and motility. GABAergic miniature inhibitory postsynaptic currents in pHFD DMV neurons were responsive to L838,417 throughout development, unlike control DMV neurons, which were responsive only at early postnatal timepoints. Brainstem mRNA and protein expression of the GABA α and subunits, however, did not differ between control and pHFD rats. This study suggests that pHFD exposure arrests the development of synaptic GABA α receptor subunits on DMV neurons and that functional synaptic expression is maintained into adulthood, although cellular localization may differ. The tonic activation of slower GABA α subunit-containing receptors implies that such developmental changes may contribute to the observed decreased gastric motility. Vagal neurocircuits involved in the control of gastric functions, satiation, and food intake are subject to significant developmental regulation postnatally, with immature GABA receptors expressing slower α-subunits, whereas mature GABA receptor express faster α-subunits. After perinatal high-fat diet exposure, this developmental regulation of dorsal motor nucleus of the vagus (DMV) neurons is disrupted, increasing their tonic GABAergic inhibition, decreasing efferent output, and potentially decreasing gastric motility.
围产期高脂肪饮食（pHFD）暴露会增加背侧运动核迷走神经（DMV）神经元的抑制，可能导致胃功能失调。本研究旨在测试以下假设：pHFD 通过破坏 GABA 受体亚基的发育来增加 DMV 神经元的抑制。从胚胎期（E13）到出生后（P42），对接受对照或 pHFD（分别来自脂肪的 14%或 60%卡路里）喂养的成年麻醉 Sprague-Dawley 大鼠进行胃内记录，并评估脑干微注射苯二氮䓬的反应。从 DMV 神经元进行全细胞膜片钳记录评估 GABAα 亚基的功能表达，而通过 qPCR 和 Western blot 分别测量 mRNA 和蛋白表达。pHFD 降低基础胃窦和胃体运动，而脑干微注射 L838,417（包含 GABA 受体的α 亚基的正变构调节剂）则导致胃张力和运动更大的降低。pHFD DMV 神经元中的 GABA 能微小抑制性突触后电流对 L838,417 的反应贯穿整个发育过程，而对照 DMV 神经元仅在出生后早期时间点有反应。然而，GABAα和β亚基的脑干部位 mRNA 和蛋白表达在对照和 pHFD 大鼠之间没有差异。这项研究表明，pHFD 暴露会阻止 DMV 神经元上 GABAα 受体亚基的突触发育，并且尽管细胞定位可能不同，但功能性突触表达会维持到成年期。较慢的 GABAα 受体包含的受体的紧张性激活表明，这种发育变化可能导致观察到的胃动力降低。参与胃功能、饱腹感和摄食控制的迷走神经回路在出生后经历显著的发育调节，不成熟的 GABA 受体表达较慢的α亚基，而成熟的 GABA 受体表达较快的α亚基。在围产期高脂肪饮食暴露后，DMV 神经元的这种发育调节被打乱，增加了它们的紧张性 GABA 能抑制，减少了传出输出，并可能减少了胃动力。
