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: 6104343
• 负责人: Michael Thomas Shipley
• 金额: $ 21.03万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6104343
• 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.

“营养”依赖性最引人注目的例子之一 上皮上的嗅球是多巴胺的下调（DA） 在鳞茎上的神经元或鼻孔后置型神经元或鼻孔中 阻塞。在上一个资金期间工作延长了这种现象 两种新肽的“透射发射器表型的跨神经元调节” （CCK和CRF）和两个新类神经元（其他簇状细胞和二尖瓣 细胞），因此表明它是一种普遍现象。在最后 资金期我们发现嗅觉受体神经元（ORNS） 通过DA D2起作用的DA细胞的传播和靶标 ORN末端的受体。这导致了以下假设 突触前调节嗅觉神经末端。 初步的 电生理数据支持这一假设。电生理学 使用新开发的大鼠嗅球切片制备的实验 体内记录将检验DA神经元的新假设 功能以调节嗅觉神经的兴奋性 终端。如果这个假设是正确的，那么学习将很重要 如何调节DA释放。体内微透析实验将测试 嗅觉神经的活性调节滋补的假说 发行DA。先前的研究表明，DA对 嗅觉神经要么是由于[A]的传入营养因子丧失 或[B]传入活性丧失到DA细胞上。发现 DA细胞“靶” ORN末端表明了一个假设，即目标 - 衍生的营养因子保持DA表型。这个“目标 假设将在一系列组织培养和神经中进行测试 移植实验。纳雷斯闭塞实验已进行 作为传入神经活动驱动DA表型的证据。 但是，现在有强有力的证据表明神经活动增加 导致目标衍生营养的表达迅速增加 因素。因此，通过鼻神经减少嗅觉神经的神经活动 闭塞可以减少目标衍生的营养因子。组织培养 将进行Pixley的实验，以使神经活动与 营养效应以确定哪个因素控制DA表型。 这些实验将在一起：[1]测试有关该实验的新假设 嗅觉中最大的神经元种群之一的功能 灯泡和[2]确定了跨神经元调节的机制 DA表型；这将提供证据证明 嗅觉神经。