TRANSIENT EXPRESSION OF CHOLINERGIC MARKERS IN THE PVCN

PVCN 中胆碱能标记物的瞬时表达

• 批准号: 7035598
• 负责人: Barbara J Morley
• 金额: $ 27.54万
• 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/7035598
• 关键词: AMPA receptors; NMDA receptors; acetylcholine; acetylcholinesterase; auditory cortex; calcium flux; cochlear nerve; developmental neurobiology; electron microscopy; gene expression; hearing; histochemistry /cytochemistry; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; neurotransmitter transport; nicotine; nicotinic receptors; protein localization; receptor expression; synapses; synaptogenesis

DESCRIPTION (provided by applicant): 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 a7 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) a7 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.

描述（由申请人提供）：大脑中的途径和突触连接是由精心策划的一系列神经化学事件建立的。尽管中央听觉系统的突触是通过听力开始后经验修改的，但在第八神经对外部环境响应之前，建立了突触连通性。有新兴文献表明，在成人大脑中，在神经传递中具有较小作用的某些酶和蛋白质在引导轴突和在发育过程中建立突触具有重要作用。乙酰胆碱（ACH），乙酰胆碱酯酶（ACHE）和A7烟碱乙酰胆碱受体（NACHR）是调节突触事件的神经化学物质之一，包括在靶神经元中成熟突触形成的基因表达。在我们的实验室中，我们发现了一条途径，该途径向后腹侧耳蜗核（PVCN）的啮齿动物章鱼细胞区域投射，该途径会瞬时表达ACHE和A？在第二个后周内NACHR。超微结构研究表明，在产后第3天之前，很少有突触连接，并且P5大量。胆碱能标记的表达的时间序列以及其他实验室的电生理数据表明，ACH及相关酶和蛋白质对于突触的成熟至关重要。他们的功能之一可能是调节谷氨酸能受体基因表达。特异性影响胆碱能受体的毒素（例如尼古丁）集中在生理相关浓度的胎儿和产后大脑中。尽管这不会引起耳聋，但它可能导致长期语言缺陷。拟议的研究的目的是阐明与突触成熟和NMDA受体基因表达在啮齿动物PVCN中的成熟和调节有关的胆碱能分子机制。总体假设是，通过通过在PVCN章鱼后的突触后部位聚集在a7烟碱乙酰胆碱受体中，通过调节细胞内钙的细胞内钙来调节NMDA谷氨酸受体表达。特定的假设是：（1）ACH释放是无抗性的； （2）NACHR在章鱼细胞上簇后簇聚集； ACH（3）章鱼细胞上的A7 NACHRS在听力发作之前（但不是之后）调节细胞内钙； （4）尼古丁给药将上调NMDA，但不会上调AMPA受体基因表达； （5）通过A7 NACHRS调节NMDA谷氨酸受体表达。