TRANSIENT EXPRESSION OF CHOLINERGIC MARKERS IN THE PVCN

PVCN 中胆碱能标记物的瞬时表达

• 批准号: 7850360
• 负责人: Barbara J Morley
• 金额: $ 19.76万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850360
• 关键词: AMPA Receptors; ARHGEF5 gene; Acetylcholine; Acetylcholinesterase; Adult; Affect; Affinity; Age; Agonist; Auditory; Auditory system; Axon; Behavior; Biochemical; Brain; Bungarotoxins; Calcium; Carrier Proteins; Cells; Child; Choline; Choline O-Acetyltransferase; Cholinergic Receptors; Cochlear nucleus; Data; Development; Diffuse; Environment; Enzymes; Event; Extracellular Space; Gene Expression; Glutamate Receptor; Glutamates; Goals; Hearing; Histocytochemistry; Image; In Situ Hybridization; Laboratories; Language Disorders; Light; Link; Literature; Long-Term Effects; Measures; Methods; Microscopic; Minor; Molecular; Mothers; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve; Nerve Tissue; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nicotinic Receptors; Octopus; Pathway interactions; Presynaptic Terminals; Proteins; Rattus; Receptor Gene; Regulation; Research Personnel; Rodent; Role; Series; Site; Slice; Smoking; Synapses; System; Testing; Toxin; Vertebral column; Vesicle; Vesicular Transport Proteins; base; cholinergic; cholinergic neuron; deafness; experience; fetal; mRNA Expression; methyllycaconitine; nanoGold; neurochemistry; neuronal cell body; neurotransmission; novel; postnatal; postsynaptic; presynaptic; programs; pup; receptor binding; receptor expression; synaptic function; synaptogenesis; uptake

The pathways and synaptic connections in the brain are established by a finely orchestrated series of neurochemical events. Although central auditory system synapses are modified by experience after the onset of hearing, synaptic connectivity is established before the eighth nerve is responsive to the external environment. There is an emerging literature indicating that some enzymes and proteins with minor roles in neurotransmission in the adult brain have major roles in guiding axons and establishing synapses during development. Acetylcholine (ACh), acetylcholinesterase (AChE) and the a7 nicotinic acetylcholine receptor (nAChR) are among the neurochemicals that regulate synaptic events, including the expression of genes obligatory for mature synapse formation in target neurons. In our laboratory, we have discovered a pathway projecting to the rodent octopus cell region of the posterior ventral cochlear nucleus (PVCN) that transiently expresses AChE and the a? nAChR during the second postnatal week. Ultrastructural studies indicate that few synaptic junctions are present by postnatal day 3, and are abundant by P5. The temporal sequence of the expression of the cholinergic markers, together with electrophysiological data from other laboratories, suggests that ACh and related enzymes and proteins are essential for the maturation of synapses. One of their functions may be to modulate glutamatergic receptor gene expression. Toxins that specifically affect cholinergic receptors, such as nicotine, concentrate in the fetal and postnatal brain in physiologically relevant concentrations. While this would not cause deafness, it could contribute to long-term language deficits. The goal of the proposed studies is to elucidate the cholinergic molecular mechanisms related to the maturation of synapses and regulation of NMDA receptor gene expression in the rodent PVCN. The overall hypothesis is that the diffuse release of ACh regulates NMDA glutamate receptor expression by regulating intracellular calcium through a? nicotinic acetylcholine receptors clustered on postsynaptic sites of PVCN octopus cells. The specific hypotheses are: (1) ACh release is nonvesicular; (2) nAChRs are clustered postsynaptically on octopus cells; ACh (3) a? nAChRs on octopus cells regulate intracellular calcium before, but not after, the onset of hearing; (4) nicotine administration will upregulate NMDA, but not AMPA, receptor gene expression; and (5) ACh, through a7 nAChRs, regulates NMDA glutamate receptor expression.

大脑中的通路和突触连接是由一系列精心编排的神经网络建立的。 神经化学事件虽然中枢听觉系统的突触在经历了 在听觉开始时，突触连接在第八神经对外界刺激做出反应之前建立。 环境有一个新兴的文献表明，一些酶和蛋白质的次要作用， 成年人大脑中的神经传递在引导轴突和建立突触中起主要作用， 发展乙酰胆碱（ACh）、乙酰胆碱酯酶（AChE）和α 7烟碱乙酰胆碱受体 （nAChR）是调节突触事件的神经化学物质之一，包括基因表达 对于靶神经元中成熟突触的形成是必需的。在我们的实验室里，我们发现了一条 投射到啮齿类动物耳蜗后腹侧核（PVCN）的章鱼细胞区， 表达乙酰胆碱酯酶和a？nAChR在产后第二周。超微结构研究表明， 到出生后第3天，几乎没有突触连接存在，到P5时大量存在。的时间顺序 胆碱能标记物的表达，以及来自其他实验室的电生理学数据， 表明ACh和相关的酶和蛋白质是突触成熟所必需的。之一 它们的功能可能是调节多巴胺能受体基因的表达。专门影响 胆碱能受体，如尼古丁，集中在胎儿和出生后的大脑中，在生理上相关的， 浓度的虽然这不会导致耳聋，但可能会导致长期的语言缺陷。的 拟开展的研究的目的是阐明胆碱能相关的分子机制， 啮齿动物PVCN中突触的成熟和NMDA受体基因表达的调节。整体 一种假说认为ACh的弥散性释放通过调节NMDA谷氨酸受体的表达， 细胞内钙通过a？烟碱型乙酰胆碱受体聚集在PVCN的突触后部位 章鱼细胞具体的假设是：（1）ACh的释放是非囊泡的;（2）nAChRs是成簇的 ACh（3）a？章鱼细胞上的nAChRs调节细胞内钙， （4）尼古丁可上调NMDA受体，但对AMPA受体无影响 （5）ACh通过α 7 nAChRs调节NMDA谷氨酸受体的表达。