Transneuronal Signals for Afferent Regulation

人们普遍认为，早期经验对神经系统的最佳发育很重要。对这一观点的支持很大程度上源于研究表明，感觉剥夺会导致神经元萎缩。在发育过程中，传入信息调节突触后神经元的代谢活动，对细胞生存至关重要。这一建议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雏鸡的脑干听觉系统。耳蜗核中的神经元，即大细胞核(NM)，从同侧听神经接受其唯一的兴奋性输入。消除听神经活动(例如，通过去除耳蜗)会导致NM神经元的死亡和萎缩。在去除耳蜗后的一小时内，观察到神经元代谢的活性依赖性变化，并在6小时后，观察到神经元亚群(约.30%)可以被确定为注定要死的人。拟议的实验使用体内和体外方法来研究与决定去传入神经元的最终命运(生或死)有关的信号级联。将进行三个方面的研究。首先，我们将详细探讨在其他系统中调节细胞死亡的基因的传入调节。具体地说，在去传入后6小时，bcl2在神经元亚群中的表达上调。研究将确定该基因上调所需的条件，以及bcl2在调节去传入诱导的细胞死亡中的潜在作用。其次，在这个系统中控制早期活性依赖效应的神经递质受体，即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个神经递质系统GABA的标准特征，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，拟议中的研究将确定这种反应的机制。其他实验将描述该系统中相对未描述的GABA能细胞群。

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.