PHARMACOLOGICAL CORRELATES OF AGING IN BRAIN CELL GRAFTS

项目4将利用隔离电路的独特优势， 通过中枢神经元移植策略来研究 衰老 该项目将研究中环与年龄有关的变化， 去甲肾上腺素能和胆碱能回路，在oculo中使用单和双回路 移植物 中枢突触前和突触后机制的变化 去甲肾上腺素能回路将使用体内计时电流法进行评价 和电生理方法;相关的形态学和 并进行生化测试。 我们将专注于轨迹 蓝斑、小脑和海马。 内在与外在决定因素 年龄相关的变化将通过检查1）异时性 同系移植物，2）同种异体移植物和3）移植到热量 受限主机 蓝斑双和三移植，中央 外周靶点将用于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。 假定营养的影响 因素，如NT-3，对这种可塑性也将被检查。 的 另一种假定的营养因子GDNF的作用将在 内侧隔核胆碱能单、双移植物， 海马体。 最后，关于自由基的毒性作用的假设 自由基，以及自由基可能逆转这种毒性作用 清除剂，将通过将移植物暴露于常压氧合来测试， 然后全身或眼内注射自旋捕获化合物。

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.