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Transneuronal Signals for Afferent Regulation

用于传入调节的跨神经元信号

基本信息

批准号：
7033926
负责人：
RICHARD L. HYSON
金额：
$ 19.46万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-01 至 2007-05-31
项目状态：
已结题

项目摘要

It is generally accepted that early experience is important for optimal development of the nervous system. Support for this notion stems largely from studies showing that sensory deprivation results in neuronal atrophy. During development, afferent input regulates the metabolic activity of postsynaptic neurons and is crucial for cell survival. The general aims of this proposal are to identify the signaling cascades by which afferent activity regulates the integrity of postsynaptic neurons. The model system used for these studies is the brain stem auditory system of the chick. Neurons in the cochlear nucleus, nucleus magnocellularis (NM), receive their sole excitatory input from the ipsilateral auditory nerve. Eliminating auditory nerve activity (e.g., by cochlea removal) results in death and atrophy of NM neurons. Activity-dependent changes in neuronal metabolism are observed within an hour after cochlea removal, and by 6 hrs, a subpopulation of neurons (approx. 30 percent) can be identified as those destined to die. The proposed experiments use both in vivo and in vitro methods to investigate the signaling cascades involved in determining the ultimate fate (life or death) of deafferented neurons. Three lines of research will be pursued. First, afferent regulation of genes, which are known to regulate cell death in other systems, will be explored in detail. Specifically, bcl-2 expression is up-regulated in a subpopulation of neurons by 6 hrs after deafferentation. Studies will determine the conditions necessary for the up-regulation of this gene, and the potential role of bcl-2 in regulating deafferentation-induced cell death. Second, the neurotransmitter receptors controlling an early activity- dependent effect in this system, the regulation of ribosomal integrity, will be more accurately defined. These studies will primarily focus on the role of metabotropic glutamate receptors. A final set of studies will explore normative features of a second neurotransmitter system, GABA, which is present in the brain stem auditory pathways. Avian brain stem auditory neurons have an unusual response to GABA, and the proposed studies will determine the mechanisms underlying this response. Additional experiments will describe a relatively uncharacterized population of GABAergic cells in this system.

人们普遍认为，早期经历对神经系统的最佳发育很重要。对这一观点的支持主要来自于一些研究，这些研究表明感觉剥夺会导致神经元萎缩。在发育过程中，传入输入调节突触后神经元的代谢活动，对细胞存活至关重要。这一建议的总体目标是确定信号级联通过传入活动调节突触后神经元的完整性。这些研究使用的模型系统是小鸡的脑干听觉系统。耳蜗大细胞核（NM）内的神经元接收来自同侧听神经的唯一兴奋输入。消除听神经活动（例如，通过耳蜗切除）导致NM神经元死亡和萎缩。在耳蜗切除后1小时内观察到神经元代谢的活动依赖性变化，到6小时时，一个亚群的神经元(约为1。30%)可以确定为那些注定要死去的人。本实验采用体内和体外两种方法来研究决定失传入神经元最终命运（生或死）的信号级联。将进行三项研究。首先，基因的传入调控，这是已知的调节细胞死亡在其他系统中，将被详细探讨。具体来说，bcl-2在神经元亚群中在去神经分化后6小时表达上调。研究将确定该基因上调的必要条件，以及bcl-2在调节脱神经分化诱导的细胞死亡中的潜在作用。其次，在该系统中控制早期活性依赖效应的神经递质受体，即对核糖体完整性的调节，将得到更准确的定义。这些研究将主要集中在代谢性谷氨酸受体的作用上。最后一组研究将探索第二种神经递质系统的规范特征，GABA，它存在于脑干听觉通路中。鸟类脑干听觉神经元对GABA有不同寻常的反应，提出的研究将确定这种反应的机制。额外的实验将描述一个相对未表征的群体gaba能细胞在这个系统中。