Transneuronal Signals for Afferent Regulation

用于传入调节的跨神经元信号

• 批准号: 6333174
• 负责人: RICHARD L. HYSON
• 金额: $ 24.48万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6333174
• 关键词: BCL2 gene /protein; GABA receptor; acoustic nerve; afferent nerve; auditory pathways; biological signal transduction; brain stem; cell death; chickens; gamma aminobutyrate; gene expression; genetic regulation; glutamate receptor; neural transmission; neurons; neuroregulation; neurotransmitter receptor; ribosomes; synapses

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验对于神经系统的最佳发展很重要。 对这一观点的支持主要源于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，对于细胞生存至关重要。 该提案的总体目标是确定传入活动调节突触后神经元完整性的信号级联。 用于这些研究的模型系统是小鸡的脑干听觉系统。 耳蜗核、大细胞核 (NM) 中的神经元从同侧听神经接收唯一的兴奋性输入。消除听觉神经活动（例如，通过去除耳蜗）会导致 NM 神经元死亡和萎缩。 摘除耳蜗后一小时内即可观察到神经元代谢的活动依赖性变化，到 6 小时后，可以将神经元亚群（约 30%）确定为注定要死亡的神经元亚群。所提出的实验使用体内和体外方法来研究参与确定传入神经元最终命运（生或死）的信号级联。 将进行三方面的研究。 首先，将详细探讨基因的传入调节，已知基因可调节其他系统中的细胞死亡。 具体而言，传入神经阻滞后 6 小时，神经元亚群中的 bcl-2 表达上调。 研究将确定该基因上调所需的条件，以及 bcl-2 在调节传入神经阻滞诱导的细胞死亡中的潜在作用。 其次，控制该系统早期活动依赖性效应（核糖体完整性调节）的神经递质受体将得到更准确的定义。 这些研究将主要关注代谢型谷氨酸受体的作用。最后一组研究将探索第二种神经递质系统 GABA 的规范特征，该系统存在于脑干听觉通路中。 鸟类脑干听觉神经元对 GABA 有一种不寻常的反应，拟议的研究将确定这种反应背后的机制。 其他实验将描述该系统中相对未表征的 GABA 细胞群。