肠肌间神经丛的去甲肾上腺素能神经元调控肠运动的机制研究

肠运动虽然受内脏运动神经和肠神经系统双重调控，而其主要活动方式自主运动则多受肌间神经丛（MP）调控，MP的功能异常能导致多种疾病，但MP神经元的抑制性递质及其功能尚未最终阐明。我们最近观察到MP有与抑制性神经肽共存的多巴胺-β-脱羧酶（DBH）阳性去甲肾上腺素（NE）能神经元。本项目拟对MP的NE能神经元开展如下研究：⑴观察其胞体和突起的形态、递质和受体及其对肠运动的影响，按照形态和机能标准对MP神经元进行新的分类，阐明MP神经元的多样性；⑵甄别来自中枢（交感节后纤维）和局部（MP的NE能神经元）的NE能纤维支配范围和调控效应的差异；⑶MP内非NE能神经元释放的兴奋性和抑制性递质对MP内NE能神经元功能的影响；⑷NE能神经元在肠壁局部神经环路参与肠运动调控的途径和机理。本项目的结果将有助于阐明肌间神经元分类等神经解剖学基本问题和揭示肠运动的调控机制，对维护人类健康和保证生活质量作出贡献。

Enteric nervous system (ENS) is an important composition of of the peripheral nervous system and fundamentally innervates the organs in the middle part of the digestive system. It is generally accepted that the enteric movement is regulated by both ENS and visceral motor nerves, including sympathetic nerve fibers and parasympathetic nerve fibers originating from the central nervous system (CNS). The ENS is composed by neurons in both myenteric plexus (MP) and submucous plexus and nerve fiber bundles in different layers of the wall of the digestive tract. But the enteric movement is fundamentally controlled by neurons in the MP. The dysfunction of the neurons in the MP leads to many kinds of disorders and diseases caused by enteric movement disorders. However, the chemical nature and function of the MP neurons, especially their inhibitory neurotransmitters and their mechanisms underlying the regulation of enteric motility have not been completely clarified yet. In our recent preliminary immunofluorescence histochemical mapping experiments, we surprisingly observed the presence of dopamine-β-hydroxylase (DBH)-immunopositively stained noradrenaline (NE)-ergic neurons in the MP, and within these NE-ergic neurons DBH always coexists with inhibitory neuropeptides. These results were further confirmed by fluorescence in situ hybridization (FISH) and single cell PCR detection. In order to further investigate the morphological features and functions of these NE-ergic neurons in the MP, in the present project the following studies will be carried out: (1) The morphological feature of the neurons (including the diameters of the cell body and branches of the dendrites and axons) as well as the neurotransmitters and receptors contained in the neurons and their effects on enteric movement function would be detected. According to the morphological and functional criteria, the diversity of MP neurons would be disclosed and the MP neurons will be clarified into new classes. (2) The differences on the innervation and effect between exogenous (sympathetic postganglionic fibers) originated from the CNS and endogenous (NE-ergic neurons in MP) originated from local nerve plexuses of the wall of the digestive tracts on the enteric motility would be screened; (3) The effects of excitatory and inhibitory neurotransmitters released from non-NE neurons in the MP on the functional activities of NE-ergic neurons in the MP would be tested. (4) The direct and indirect pathways and mechanisms underlying their involvement in the regulation of enteric motility in the local neural circuit on the wall of the enteric duct would be investigated. Our present study project will help us to clear the basic problems of neuroanatomy, such as the classification of the neurons in the MP, and to reveal the neural regulatory mechanisms of the ENS on the enteric movement. Thus, the results will contribute to prevent and treat digestive disorders and diseases and to maintain the human health and to guarantee for their life quality.