Functional role of CGRP as an efferent neurotransmitter

CGRP 作为传出神经递质的功能作用

• 批准号: 6988862
• 负责人: COLLEEN G. LE PRELL
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988862
• 关键词: Functional; role; CGRP; efferent; neurotransmitter

DESCRIPTION (provided by applicant): There is growing evidence that the lateral olivocochlear (LOC) pathway modulates auditory nerve (AN) activity. We contributed to this body of work by selectively lesioning LOC innervation at its origin (Le Prell et al. 2003), or its termination (Le Prell et al. 2004). Our studies, as well as earlier investigations in which both LOC and medial olivocochlear (MOC) pathways were disrupted (Liberman 1990; Walsh et al. 1998; Zheng et al. 1999), suggest the net effect of LOC innervation is enhancement of spontaneous and sound-driven auditory nerve fiber (ANF) activity. Depression of AN activity after LOC disruption has been attributed to loss of one or more excitatory transmitters. Recently, Maison et al. (2003) presented evidence that calcitonin-gene-related peptide (CGRP) could modulate the excitatory LOC effects observed in the above investigations. The finding that alphaCGRP-null mice have depressed amplitude of the sound-evoked auditory brainstem response (ABR, see Maison et al. 2003) may reflect direct enhancement of driven AN activity by CGRP. However, changes in driven activity might also be a consequence of changes in spontaneous activity. In the amphibian lateral line, CGRP increases spontaneous activity (Adams et al. 1987; Sewell & Starr 1991; Bailey & Sewell 2000a; 2000b). If CGRP similarly enhances spontaneous activity of ANFs, one might predict enhanced sound-driven ANF activity as ANFs with higher spontaneous rates of firing have lower thresholds and higher driven firing rates. To distinguish among competing hypotheses, and determine the extent to which CGRP effects are similar in the amphibian and mammalian systems, it is essential that we identify the effects of CGRP agonists and antagonists on spontaneous and driven activity in the mammalian cochlea. This investigation specifically addresses several important issues using single unit and whole nerve potentials. First, it directly addresses the prediction that activation (or blockade) of CGRP receptors modulates spontaneous and sound-evoked ANF activity (Specific Aim 1). Second, these experiments will identify functional changes in temporal resolution and changes in response to signals in noise, providing important new data on the role of CGRP in LOC function. Additional experiments (Specific Aim 2) will identify the extent to which changes induced by CGRP manipulation mimic the effects of disrupting all (or most) of the LOC system using MPTP (a dopaminergic neurotoxin that we have used previously to disrupt LOC innervation, see Le Prell et al. 2004).

描述（由申请人提供）：越来越多的证据表明，侧面橄榄石（LOC）途径调节了听觉神经（AN）活动。我们通过在其起源（Le Prell等，2003）或终止（Le Prell等，2004）中选择性地将LOC神经支配选择性地促进了这项工作。我们的研究以及较早的研究，其中LOC和内侧橄榄石（MOC）途径都受到破坏（Liberman 1990； Walsh等，1998； Zheng等，1999），表明LOC神经的净效应是增强自发性和sound驱动的听觉Never Nerver Fiber（ANF）活性。 LOC中断后的活动抑郁归因于一个或多个兴奋性发射器的丧失。最近，Maison等。 （2003年）提供了证据表明，降钙素 - 基因相关肽（CGRP）可以调节上述研究中观察到的兴奋性LOC效应。 Alphacgrp-null小鼠的发现，声音诱发的听觉脑干响应的幅度降低了（ABR，参见Maison等人，2003年）可能反映了CGRP驱动的活动的直接增强。但是，驱动活动的变化也可能是自发活动变化的结果。在两栖动物的侧线中，CGRP增加了自发活动（Adams等，1987； Sewell＆Starr 1991； Bailey＆Sewell 2000a; 2000b）。如果CGRP类似地增强了ANF的自发活动，则可能会预测，随着自发发射速率较高的ANF的增强的ANF活动具有较低的阈值和较高的驱动射击速率。为了区分竞争假设，并确定两栖动物和哺乳动物系统中CGRP效应相似的程度，我们必须确定CGRP激动剂和拮抗剂对哺乳动物的自发和驱动活性的影响。这项调查专门解决了使用单个单元和整个神经电位的几个重要问题。首先，它直接解决了CGRP受体的激活（或阻断）调节自发和声音诱发的ANF活动的预测（特定AIM 1）。其次，这些实验将确定时间分辨率的功能变化以及响应噪声信号的变化，从而为CGRP在LOC函数中的作用提供重要的新数据。其他实验（特定目标2）将确定CGRP操纵引起的变化模仿使用MPTP破坏所有（或大多数）LOC系统的影响（多巴胺能神经毒素我们先前使用以破坏LOC神经的伤害，请参见Le Prell等，2004年）。