PHARMACOLOGICAL CORRELATES OF AGING IN BRAIN CELL GRAFTS

项目4将利用产生的隔离电路的独特优势 通过中枢神经元移植策略研究脑缺血再灌注损伤的细胞神经生物学 衰老。该项目将检查中环与年龄相关的变化 去甲肾上腺素能和胆碱能环路，使用单眼和双眼 嫁接。中枢神经系统突触前和突触后机制的变化 去甲肾上腺素能回路将使用活体计时电流法进行评估 和电生理方法；相关的形态学和 还将进行生化测量。我们将重点关注轨迹 蓝斑、小脑和海马体。内在决定因素与外部决定因素 将通过检查异时性来测试与年龄相关的改变 同种异体移植物，2)同种异体移植物，3)热量移植物 受限主机。中央带蒂蓝斑二次和三次移植 和外围指标将被用来研究年龄相关的变化 中枢去甲肾上腺素能神经元的可塑性。推定营养的影响 影响这种可塑性的因素，如NT-3，也将被检验。这个 另一种推定的营养因子GDNF的作用将在 内侧隔核胆碱能单核和双核移植 海马体。最后，与FREE的毒性作用有关的假设 自由基，以及这种毒性效应可能被自由基逆转 清道夫，将通过将移植物暴露在常压氧气和 然后系统地或通过眼球注射自旋陷阱化合物。

Project 4 will exploit the unique advantages of isolated circuits generated by central neuron grafting strategies to study the cellular neurobiology of aging. The project will examine age-related changes in central noradrenergic and cholinergic circuits, using single and double in oculo grafts. Changes in presynaptic and postsynaptic mechanisms in central noradrenergic circuits will be evaluated using in vivo chronoamperometric and electrophysiological approaches; correlative morphological and biochemical measurements will also be carried out. We will focus on locus coeruleus, cerebellum and hippocampus. Intrinsic vs extrinsic determinants of age related alterations will be tested by examining 1) heterochronic syngeneic grafts, 2) allogenic grafts and 3) grafts to calorically restricted hosts. Double and triple grafts of locus coeruleus with central and peripheral targets will be used to study age-related changes in plasticity of central noradrenergic neurons. Effects of putative trophic factors, such as NT-3, on such plasticity will also be examined. The actions of another putative trophic factor, GDNF, will be studied on cholinergic single and double grafts of medial septal nucleus and hippocampus. Finally, hypotheses relating to the toxic effects of free radicals, and possible reversal of such toxic effects by free radical scavengers, will be tested by exposing grafts to normabaric oxygenation and then injecting spin-trap compounds systemically or in oculo.