NEURAL CONTROL OF GASTROINTESTINAL ACTIVITY

胃肠活动的神经控制

• 批准号: 2262497
• 负责人: MICHAEL D GERSHON
• 金额: $ 31.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2262497
• 关键词: autonomic reflex; calcium channel; chromaffin cells; cyclic AMP; gastrointestinal motility /pressure; guinea pigs; hormone regulation /control mechanism; interneurons; laboratory mouse; membrane transport proteins; myenteric plexus; neural information processing; neuroendocrine system; neurotransmitter transport; phosphatidylinositols; protein kinase C; secretion; serotonin; serotonin receptor; voltage gated channel

The most unique feature of the enteric nervous system (ENS) is its ability to mediate reflexes int he absence of input from the CNS. One such reflex, which is manifested by isolated segments of gut in vitro, is the peristaltic reflex, a descending propulsive wave of oral contraction and anal relaxation evoked by increases in intraluminal pressure. The ability of the ENS to function autonomously is reflected in a complex internal organization and structure that is more similar to the CNS than to peripheral nerve. Progress has been made in functionally identifying final common excitatory and inhibitory enteric motor neurons to smooth muscle and glands. More recently, we identified intrinsic primary afferent neurons in submucosal ganglia. These neurons project to the myenteric plexus and are excited when mechanical stimuli re applied to the mucosa. This excitation is blocked by antagonists of a subtype of 5-HT receptor (5-HT1p) that we have identified in the bowel and demonstrated, with an anti-idiotypic antibody, to be expressed by the sensory neurons. Since pressure induces enterochromaffin (EC) cells to secrete 5-HT, these data support the hypothesis that pressure or distortion provokes EC cell 5-HT secretion, which activates the mucosal processes of the intrinsic sensory neurons that initiate the peristaltic reflex. We now propose to define the enteric microcircuit responsible for this reflex ant to analyze the role played by 5-HT in its initiation and propagation. Specific questions will be: (1) How does pressure cause the secretion of mucosal 5-HT to activate the peristaltic reflex? (We will study stimulus-secretion coupling in EC cells and the role of the 5-HT transporter [which we recently discovered in crypt epithelial cells] in terminating the mucosal action of 5-H.) (2) Which cells int he myenteric plexus constitute a microcircuit with input from intrinsic sensory neurons and output to smooth muscle? (We will trace the circuit with a recombinant strain of pseudorabies virus that expresses beta-galactosidase.) (3) Do serotonergic interneurons play a critical role in the propagation of the peristaltic reflex? (Serotonergic neurons will be selectively lesioned with 5,7-dihydroxytryptamine and neuronal 5-HT will be selectively depleted with tryptamine; neither agent affects EC cells.) (4) How are the effects of the 5-HT 1p receptor mediated? We will identify which isozymes of PKC are in myenteric neurons then determine whether; (1) they are activated by 5-HT; (ii) 5-HT increases hydrolysis of phosphoinositides; (iii) 5-HT- responsive enteric neurons contain type 2 adenyl cyclase, the form activated by PKC; (iv) activation of PKC increases cAMP; (v) down regulation of PKC modifies the effect of 5-HT on cAMP; (vi) PKC is the critical mediator of 5-HT1p-mediated effects in enteric neurons. These studies will thus identify both the neuronal circuits that mediate the peristaltic reflex and the roles played in it by 5-HY and the 5-HT1p receptor. A better understanding of enteric reflex pathways should help in developing means of treating the extremely common, often disabling, but presently untreatable functional diseases of the bowel. In addition, the undesirable GI side effects of psychoactive drugs that affect 5-HT may be better understand and, if anticipated, avoided.

肠神经系统（ENS）最独特的特征是 能够介导反射的能力，他没有来自中枢神经系统的输入。 一种反射，由肠道孤立的段表现出来 体外是蠕动反射，是下降的推进波 口服收缩和肛门放松因增加而引起 腔内压力。 ENS运作的能力 自主反映在复杂的内部组织中 与CNS更相似的结构，而不是周围神经。 在功能上确定最终常见方面已经取得了进展 兴奋性和抑制性肠运动神经元对平滑肌 和腺体。 最近，我们确定了固有的主要 粘膜神经节中的传入神经元。 这些神经元将 脑丛丛，当机械刺激恢复时会感到兴奋 应用于粘膜。 这种激发被拮抗剂阻塞 我们已经确定的5-HT受体（5-HT1P）的亚型 肠和抗IDiotypic抗体证明是 由感觉神经元表示。 由于压力会引起 肠球毒蛋白（EC）细胞分泌5-HT，这些数据支持 压力或失真会激发EC细胞5-HT的假设 分泌，激活固有的粘膜过程 启动蠕动反射的感觉神经元。 我们现在 建议定义负责此的肠微电路 反射蚂蚁分析5-HT在其启动中所扮演的作用 传播。 具体问题将是：（1）压力如何 导致粘膜5-HT的分泌激活蠕动 反射？ （我们将研究EC细胞和 5-HT转运蛋白的作用[我们最近在 隐窝上皮细胞]在终止粘膜作用5-h时。 （2）哪些细胞在肌丛中构成微电路 固有感觉神经元的输入和输出到平滑 肌肉？ （我们将用重组应变的电路跟踪 表达β-半乳糖苷酶的假病毒。）（3）do 血清素能中间神经元在传播中起关键作用 蠕动反射？ （血清素能神经元将是 有选择地用5,7-二羟色胺和神经元5-HT病变 可以选择性地用色胺耗尽；没有代理都会影响 EC细胞。）（4）5-HT 1P受体的影响如何 介导？ 我们将确定哪些PKC的同工酶位于肌肉中 然后神经元确定是否； （1）它们被5-HT激活； （ii）5-HT增加磷酸肌醇的水解； （iii）5-ht- 响应式肠神经元包含2型腺基环化酶，形式 由PKC激活； （iv）PKC的激活增加了营地； （v）下降 PKC的调节会改变5-HT对营地的影响； （vi）PKC是 5-HT1P介导的肠中的关键介体 神经元。 因此，这些研究将识别神经元 介导蠕动反射和扮演角色的电路 在5-HY和5-HT1P受体中。 更好地理解 肠形反射途径应有助于开发治疗的手段 极为常见的，通常是残疾，但目前无法治疗 肠的功能性疾病。 另外，不良的gi 影响5-HT的精神活性药物的副作用可能更好 理解并避免了，如果预期的话。