TRANSIENT EXPRESSION OF CHOLINERGIC MARKERS IN THE PVCN

PVCN 中胆碱能标记物的瞬时表达

• 批准号: 7320265
• 负责人: Barbara J Morley
• 金额: $ 26.39万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-06 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320265
• 关键词: 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 Agents; Cholinergic Receptors; Chromosome Pairing; 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; Localized; 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; Purpose; Rattus; Receptor Gene; Regulation; Research Personnel; Rodent; Role; Series; Site; Slice; Smoke; Synapses; System; Testing; Toxin; Vertebral column; Vesicle; Vesicular Transport Proteins; Week; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; cholinergic; cholinergic neuron; day; 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策划的 神经化学事件。尽管中枢听觉系统突触在经历了 听力开始时，突触连接在第八神经对外部做出反应之前建立 环境。有一个新兴的文献表明，一些酶和蛋白质在 成人大脑中的神经传递在引导轴突和建立突触方面发挥着重要作用 发展。乙酰胆碱 (ACh)、乙酰胆碱酯酶 (AChE) 和 a7 烟碱乙酰胆碱受体 (nAChR) 是调节突触事件（包括基因表达）的神经化学物质之一 目标神经元中成熟突触形成所必需的。在我们的实验室，我们发现了一条途径 投射到啮齿动物章鱼后腹侧耳蜗核（PVCN）的细胞区域，短暂地 表示 AChE 和 a? nAChR 在产后第二周。超微结构研究表明 出生后第 3 天出现的突触连接很少，而到 P5 时突触连接非常丰富。的时间顺序 胆碱能标记物的表达以及其他实验室的电生理数据， 表明乙酰胆碱和相关酶和蛋白质对于突触的成熟至关重要。之一 它们的功能可能是调节谷氨酸能受体基因表达。专门影响的毒素 胆碱能受体，如尼古丁，以生理相关的方式集中在胎儿和出生后的大脑中 浓度。虽然这不会导致耳聋，但可能会导致长期的语言障碍。这 拟议研究的目标是阐明与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 假设 ACh 的弥散释放通过调节 NMDA 谷氨酸受体表达 细胞内钙通过?烟碱乙酰胆碱受体聚集在 PVCN 的突触后位点 章鱼细胞。具体假设是：（1）ACh释放是非囊泡的； (2) nAChRs聚集 章鱼细胞突触后；乙酰胆碱 (3) a?章鱼细胞上的 nAChR 调节细胞内钙， 但不是在听力开始之后； (4) 尼古丁给药会上调 NMDA，但不会上调 AMPA 受体 基因表达； (5)ACh通过a7 nAChRs调节NMDA谷氨酸受体的表达。