FUNCTIONS AND TRANSNEURONAL REGULATION OF OLFACTORY BULB DOPAMINE NEURONS

嗅球多巴胺神经元的功能和跨神经元调节

• 批准号: 6238158
• 负责人: Michael Thomas Shipley
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6238158
• 关键词: axon; cell cell interaction; chemoreceptors; developmental genetics; developmental neurobiology; dopamine; dopamine receptor; electrophysiology; embryo /fetus cell /tissue; gene expression; genetically modified animals; in situ hybridization; laboratory mouse; laboratory rat; microdialysis; nervous system transplantation; neurogenesis; neurotransmitter transport; neurotrophic factors; olfactory lobe; olfactory nerve; receptor expression; synapses; tissue /cell culture; voltage /patch clamp

One of the most striking examples of a "trophic" dependence of the olfactory bulb on the epithelium is the downregulation of dopamine (DA) in bulb juxtaglomerular neurons following deafferentation or nares occlusion. Work in the last funding period extended this phenomenon of "transneuronal regulation of transmitter phenotype" to two new peptides (CCK & CRF) and two new classes of neurons (other tufted cells & mitral cells), thus indicating that it is a general phenomenon. In the last funding period we discovered that the olfactory receptor neurons (ORNs) are both afferent to and the target of the DA cells which act via DA D2 receptors on the terminals of ORNs. This leads to the hypothesis that DA presynaptically regulates olfactory nerve terminals. Preliminary electrophysiological data support this hypothesis. Electrophysiological experiments using a newly developed rat olfactory bulb slice preparation and in vivo recordings will test the novel hypothesis that the DA neurons function to presynaptically regulate the excitability of olfactory nerve terminals. If this hypothesis is correct it will be important to learn how DA release is regulated. In vivo microdialysis experiments will test the hypothesis that activity in the olfactory nerve modulates the tonic release of DA. Previous studies suggest that the dependence of DA on the olfactory nerve is due either to [a] loss of an afferent trophic factor or [b] loss of afferent activity onto the DA cells. The finding that the DA cells "target" the ORN terminals suggests the hypothesis that target- derived trophic factors maintain the DA phenotype. This "target hypothesis" will be tested in a series of tissue culture and neural transplantation experIments. Nares occlusion experiments have been taken as evidence that afferent neural activity drives the DA phenotype. However, there is now strong evidence that increased neural activity causes a rapid increase in the expression of target derived trophic factors. Thus, reducing neural activity in the olfactory nerve by nasal occlusion could reduce target derived trophic factor. Tissue culture experiments with Pixley will be done to dissociate neural activity from trophic effects to determine which factor controls the DA phenotype. Together, these experiments will: [1] test novel hypotheses about the functions of one of the largest populations of neurons in the olfactory bulb, and [2] identify the mechanism(s) of transneuronal regulation of the DA phenotype; this will provide evidence for trophic functions of the olfactory nerve.

最引人注目的例子之一就是对 上皮细胞上的嗅球是多巴胺(DA)的下调 去传入或鼻孔后球旁球神经元的分布 遮挡。上一个资助期的工作延长了这一现象 两种新多肽的“跨神经元递质表型调节” (CCK和CRF)和两类新的神经元(其他簇状细胞和二尖瓣 细胞)，从而表明这是一种普遍现象。在最后一次 资助期我们发现嗅觉感受器神经元(Ons) 既是通过DA D2活动的DA细胞的传入，也是DA细胞的靶 Orns终末的受体。这导致了一种假设，即DA 突触前调节嗅神经末梢。初步 电生理数据支持这一假说。电生理学 新研制的大鼠嗅球切片制剂的实验研究 活体记录将检验这一新的假设，即DA神经元 突触前调节嗅神经兴奋性的功能 终点站。如果这一假设是正确的，那么学习 多巴胺的释放是如何被调控的。体内微透析实验将测试 嗅神经活动调节紧张感的假说 释放检察官。以往的研究表明，DA对 嗅神经要么是由于失去了一种传入营养因子 或[b]DA细胞传入活动的丧失。这一发现表明 DA细胞以ORN终末为靶标提出了一个假设，即靶标- 衍生的营养因子保持DA表型。这个“目标” 假说“将在一系列组织培养和神经实验中得到验证 移植实验。已经进行了Nares遮挡实验 作为传入神经活动驱动DA表型的证据。 然而，现在有强有力的证据表明，神经活动的增加 导致目标衍生营养因子的表达迅速增加 各种因素。因此，鼻腔注射可减少嗅神经的神经活动。 闭塞可降低靶来源的营养因子。组织培养 皮克斯利的实验将分离神经活动和 营养效应，以确定哪个因素控制DA表型。 总而言之，这些实验将：[1]测试关于 嗅觉中最大的神经元群之一的功能 和[2]确定跨神经元调节的机制(S)。 DA表型；这将为该菌的营养功能提供证据 嗅觉神经。