CELLULAR PROCESSES OF CENTRAL AUDITORY NEURONAL DEATH

传入输入的变化可以对形态学和组织学产生深远的影响。 中枢神经系统（CNS）中神经元的代谢，甚至导致 突触后细胞的死亡。 特定的细胞事件， 中枢神经系统中神经元死亡之前的机制尚不清楚。 小妞 脑干听觉神经元提供了一个模型系统， 这些细胞活动。 n.二级听神经元。 大细胞（NM）接受他们唯一的兴奋性传入输入从 通过第八神经进入同侧耳蜗。 单侧耳蜗切除术 孵化的幼鱼在NM神经元数量、大小、代谢 和超微结构。 在耳蜗切除后很少看到这种变化， 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神经元 在幼鸟耳蜗被移除后的几小时内。 神经元线粒体 可能在传入神经阻滞后死亡，显示异常形态，表明 他们可能有功能缺陷。 线粒体阻滞 氯霉素的蛋白质合成增加了NM中的细胞死亡。 这些 观察结果表明，NM中的线粒体增殖可能是 参与了传入神经阻滞后神经元的存活。 在第一盘 我们将通过实验来确定变化的时间进程和幅度 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”和高能量水平 中间体的 然后我们会用阻断线粒体增殖的方法 与氯霉素检查这些指数的动物夸大 细胞死亡 我们将改变耳蜗切除后的时间， 氯霉素是用来确定“关键时期”的， 线粒体增殖可影响神经元存活。 我们将 增加线粒体与甲状腺激素的静息水平， 在去传入神经后是否观察到较少的细胞死亡。 最后我们 将定量研究传入输入和 神经细胞死亡的严重程度。 去除敏感性年龄差异的生物学基础 传入的输入是未知的。 我们将检查形态学和代谢 在孵化出的幼龟中识别出的标记，以确定它们是否在 成年人了 如果线粒体形态或功能的任何差异， 观察，我们将阻止成年人的线粒体蛋白质合成， 是否可以诱导NM中的神经元细胞死亡。

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.