Brainstem Esophageal-Gastric Reflexes

描述（申请人提供）：接受性松弛反射[RRR]被认为是协调摄食行为和胃功能的最重要的迷走反射机制之一。在经典的反射描述中，食道的扩张，当进食时发生，导致迷走神经介导的放松和运动的抑制。这种反射可以在实验中被激发出来，并被认为允许胃等压接受摄入。然而，最近的报告显示，在进食期间和之后，RRR一定在某种程度上被暂停，甚至“倒转”，因为在这些时候胃的转运实际上比禁食时更快。我们自己的研究表明，在禁食一夜的大鼠中，食道膨胀导致（正如预期的）强大的胃松弛。相反，我们对喂养大鼠的观察表明，食道膨胀诱导胃张力显著增加。这种由食道膨胀引起的与进食相关的胃张力增加在几个小时后逐渐恢复到“纯粹的”胃松弛。这种重要的迷走神经控制反射功能的戏剧性变化为我们的总体假设提供了基础：迷走-迷走胃肠道控制反射的神经回路是高度动态的，并受摄食状态相关因素的调节。我们以前已经表明，外在因素，特别是胃肠道激素，直接和显著地调节肠道的迷走反射控制。然而，Gl激素重组对内脏传入输入的反射反应的具体机制尚不清楚。我们提出肠道激素的一个子集，特别是CCK和GLP-1，作用于迷走背复合体的神经元，改变孤立核突触前儿茶酚胺受体的可用性[NTS]。我们进一步提出，这种受体群体的转变对背迷走神经复合体的反射神经传递模式有显著影响。我们将结合神经胃肠病学、神经生理学和免疫组织化学方法来检验这些建议。这些关于迷走-迷走反射的摄食状态转换调节机制的研究结果也有助于解释代谢和激素参数的变化如何将脑干中摄食程序生成回路从“摄食”状态切换到“不摄食”状态。

DESCRIPTION (provided by applicant): The receptive relaxation reflex [RRR] is acknowledged as one of the most important vagal reflex mechanisms coordinating feeding behavior with gastric function. In the classic description of the reflex, distension of the esophagus, as occurs while feeding, causes a vagally-mediated relaxation and suppression of motility. This reflex can be elicited experimentally and is assumed to allow the stomach to accept ingesta isobarically. More recent reports show, however, that the RRR must be some how suspended, or even "inverted" during and after feeding since gastric transit is actually more rapid at these times than during fasting. Our own studies show that in rats fasted overnight, esophageal distention causes (as expected) a powerful gastric relaxation. Conversely, our observations in fed rats show that esophageal distention induces a significant increase in gastric tone. This feeding-related increase in gastric tone induced by esophageal distention gradually reverts back to a "pure" gastric relaxation after few hours. This dramatic change in the function of such an essential vagal control reflex provides the basis for our overarching hypothesis: Neural circuits underlying vago-vagal gastrointestinal control reflexes are highly dynamic and regulated by factors associated with feeding status. We have previously shown that extrinsic factors, especially gastrointestinal hormones, directly and dramatically modulate vago-vagal reflex control of the gut. However, the specific mechanisms by which Gl hormones can reorganize a reflex response to a visceral afferent input are not well understood. We propose that a subset of gut hormones, in particular, CCK and GLP-1, act on neurons in the dorsal vagal complex to alter the availability of presynaptic catcholamine receptors in the solitary nucleus [NTS]. We propose further that this shift in receptor population has a dramatic effect on reflex neurotransmission patterns in the dorsal vagal complex. We will apply a combination of neurogastroenterological, neurophysiological and immunohistochemical methods to test these proposals. Results from these studies on mechanisms regulating the feeding-state-related switching of vago-vagal reflexes could also help explain how changes in metabolic and hormonal parameters can act to switch ingestion program generation circuits in the brainstem from a "feeding" to "not feeding" state.