Dopamine in the Auditory Midbrain: Changes with Deafness and Noise Trauma

听觉中脑中的多巴胺：随耳聋和噪音创伤而变化

• 批准号: 7148609
• 负责人: Avril Genene Holt
• 金额: $ 7.53万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-26 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148609
• 关键词: auditory pathways; deafness; dopamine; glutamates; glycine; mesencephalon; neurons; neurotransmitters; noise; trauma

DESCRIPTION (provided by applicant): Whether deafness occurs as a result of mechanical trauma, noise over-stimulation, or aging (presbyacusis), the mechanisms regulating central changes resulting from this deficit are poorly understood. Thus, our long- term goal is to understand the role of dopaminergic circuits, within the central auditory system and how they change following deafness. Dopamine (DA) is an inhibitory neurotransmitter that modulates the action of amino acid neurotransmitters. In the frontal cortex DA affects cognition with through facilitation of glutamatergic effects. Dopamine can also affect the release of co-localized GABA and glutamate by binding receptors at pre-synaptic sites. As a first step towards achieving our goal, the studies we have proposed in Specific Aims 1-3 use tract tracers to identify and characterize three dopaminergic pathways originating in the external cortex of the inferior colliculus (ICex), central nucleus of the inferior colliculus (ICC), and nuclei of the lateral lemniscus (NIL). To determine whether these pathways are dopaminergic, we will co-immunolabel for tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of dopamine, and tract tracers. We will also use the dopaminergic neurotoxin MPTP to confirm the presence of DA in midbrain circuits. In other systems DA is often co-localized with other neurotransmitters, therefore, we will examine whether dopaminergic neurons in these brain regions co-localize with neurotransmitters traditionally associated with auditory midbrain regions (GABA, glycine and glutamate). There are deafness related decreases in the gene expression of TH, (Holt et al., 2005) in the IC. Dopamine immunolabeled neurons have been identified in the IC and lateral lemniscus and there is a dramatic decrease in dopaminergic neurons in these brain regions following deafness (Tong et al., 2005). Our final specific aim then addresses the relationship between deafness related decreases in TH levels and changes in the production of other co-localized transmitters. Characterizing the circuitry and neurochemistry of these pathways allows for future studies that examine the function of specific dopaminergic pathways in this system. The current application paves the way for functional studies, developing the use of stereotaxic MPTP injections to lesion DA pathways. Ultimately, understanding DA pathways in the auditory system may lead to the development of novel mechanisms for modulation neuronal activity. Identifying key neurotransmitters within the central auditory system leads to understanding pathways into which they are integrated, their function, and ultimately help us devise methods to manipulate these key players to provide the best possible hearing outcomes for those with cochlear prostheses or those individuals being treated for presbyacusis.

描述（由申请人提供）：是否由于机械创伤，噪声过度刺激或老化（长期）而导致耳聋，调节由于这种赤字而导致的中心变化的机制尚不清楚。因此，我们的长期目标是了解中央听觉系统中多巴胺能电路的作用以及它们在耳聋之后的变化。多巴胺（DA）是一种抑制性神经递质，可调节氨基酸神经递质的作用。在额叶皮质中，da通过促进谷氨酸能效应来影响认知。多巴胺还可以通过突触前部位的结合受体来影响共定位的GABA和谷氨酸的释放。作为实现目标的第一步，我们在特定目标1-3中提出的研究使用道示踪剂来识别和表征三种起源于下丘比拉鲁斯外皮层（ICEX）（ICEX）的多巴胺能途径（ICEX），下丘丘（ICC）的中央核（ICC）（ICC），以及后期的Lememencus（nilil）。为了确定这些途径是否是多巴胺能，我们将共抗阳离子羟化酶（Th），多巴胺生物合成中的速率限制酶和示踪剂。我们还将使用多巴胺能神经毒素MPTP确认中脑电路中的DA存在。在其他系统中，DA通常与其他神经递质共定位，因此，我们将检查这些大脑区域的多巴胺能神经元是否与传统上与听觉中脑区域（GABA，GABA，Glycine，Glycine和Glutamate）相关的神经递质合作。 IC中Th的基因表达（Holt等，2005）的基因表达有耳聋相关。多巴胺免疫标记的神经元已在IC和外侧Lemniscus中鉴定出来，耳聋后这些大脑区域的多巴胺能神经元急剧下降（Tong等，2005）。然后，我们的最终具体目的解决了与聋哑人之间的关系降低的水平和其他共定位发射器的生产变化。表征这些途径的电路和神经化学，可以进行未来的研究，以检查该系统中特定多巴胺能途径的功能。当前的应用为功能研究铺平了道路，开发了对病变DA途径注射立体定位MPTP的使用。最终，了解听觉系统中的DA途径可能会导致开发用于调节神经元活性的新机制。在中央听觉系统中识别关键的神经递质，从而了解其融合的途径，功能，并最终帮助我们设计方法来操纵这些关键参与者，以为有人工身假的那些或为Persberbycusis治疗的人提供最佳的听力结果。