CELLULAR PROCESSES OF CENTRAL AUDITORY NEURONAL DEATH

传入输入的变化可以对形态和 中枢神经系统(CNS)中神经元的代谢，甚至导致 与突触后细胞的死亡有关。特定的细胞事件 中枢神经系统神经元死亡之前的情况尚不清楚。小鸡 脑干听觉神经元为研究提供了一个模型系统 这些细胞事件。N.二阶听神经元。 巨细胞(NM)接受其唯一的兴奋性传入传入 同侧耳蜗经第八神经。单侧人工耳蜗术 孵化后的幼体在NM神经元的数量、大小、代谢、 和超微结构。摘除耳蜗术后几乎看不到这种变化 成年动物。 我们已经证明，氧化酶活性的增加和 线粒体增殖发生在大多数去传入的NM神经元中 在幼鸟去除耳蜗后的几个小时内。神经元中的线粒体 可能在去传入后死亡的表现出异常的形态，提示 他们可能在功能上有缺陷。线粒体的阻断 氯霉素的蛋白质合成增加了NM的细胞死亡。这些 观察表明，NM中线粒体的增殖可能是 参与去传入后神经元的存活。在第一组中 我们将确定实验的时间进程和变化的幅度 在去传入的NM神经元的线粒体中。我们将评估氧化 酶活性、线粒体“偶联状态”和高能水平 中间体。然后我们将使用阻止线粒体增殖的方法 用氯霉素检查这些指标在动物身上被夸大 细胞死亡。我们将改变耳蜗摘除后的时间段 给予氯霉素来确定在此期间的“关键期” 线粒体的增殖会影响神经元的存活。我们会 用甲状腺激素提高线粒体的静息水平 去传入后是否观察到较少的细胞死亡。最后，我们 将定量地检查传入输入和 神经细胞死亡的严重性。 去除易感性年龄差异的生物学基础 传入输入的频率是未知的。我们将检查形态和新陈代谢 在孵化的幼体中识别的标记，以确定它们在 成年人。如果线粒体形态或功能上的任何差异 观察到，我们将阻止成年人线粒体蛋白质的合成 能不能诱导NM神经细胞死亡。

Changes in afferent input can have profound effects on the morphology and metabolism of neurons in the central nervous system (CNS), even resulting in the death of the postsynaptic cell. The specific cellular events which precede neuronal death in the CNS are not clearly understood. Chick brainstem auditory neurons provide a model system in which to investigate these cellular events. Second-order auditory neurons in n. magnocellularis (NM) receive their only excitatory afferent input from the ipsilateral cochlea via the eighth nerve. Unilateral cochlea removal in hatchlings produces rapid changes in NM neuronal number, size, metabolism, and ultrastructure. Few such changes are seen after cochlea removal in adult animals. We have shown that an increase in oxidative enzyme activity and proliferation of mitochondria occurs in most deafferented NM neurons within hours of cochlea removal in young birds. Mitochondria in neurons likely to die after deafferentation show abnormal morphology, suggesting that they may be functionally deficient. Blockade of mitochondrial protein synthesis with chloramphenicol increases cell death in NM. These observations suggest that mitochondrial proliferation in NM may be involved in neuronal survival following deafferentation. In the first set of experiments we will determine the time course and magnitude of changes in mitochondria in deafferented NM neurons. We will assess oxidative enzyme activity, mitochondrial "coupling state", and levels of high energy intermediates. We then will use blockade of mitochondrial proliferation with chloramphenicol to examine these indices in animals with exaggerated cell death. We will vary the period after cochlea removal in which chloramphenicol is given to determine the "critical period" during which mitochondrial proliferation can affect neuronal survival. We will increase resting levels of mitochondria with thyroid hormone to see whether less cell death is observed after deafferentation. Finally, we will examine quantitatively the relationship between afferent input and the severity of neuronal cell death. The biological basis for the age difference in susceptibility to removal of afferent input is unknown. We will examine morphological and metabolic markers identified in hatchlings to determine whether they might differ in adults. If any differences in mitochondrial morphology or function are observed, we will block mitochondrial protein synthesis in adults to see whether neuronal cell death in NM can be induced.