Functional Aspects of Adult Hippocampal Neurogenesis

描述(申请人提供)：成年哺乳动物的海马体含有在成年期分化为神经元的前体细胞。这种现象被称为成人神经发生。这项拟议的研究针对的是成年海马区形成的神经元是否会影响行为。成年海马区是大脑中参与学习和记忆的区域。四个假设的预测将得到检验。学习假说认为，成年海马区的神经发生在海马区依赖行为的习得中起作用。因此，根据学习假说，增加神经发生的因素应该会改善学习。遗忘假说认为，新的海马神经元有助于遗忘，增加神经发生的因素将干扰对海马体依赖行为的长期保留。自我修复假说认为，新形成的神经元修复受损的海马神经元电路，并预测增加神经发生的因素将促进海马区损伤后功能的恢复。相反，损伤过程假说认为，对海马区损伤做出反应而形成的新神经元干扰了剩余完整的海马区组织的功能。因此，损伤假说预测，增加海马神经发生的因素将加剧由海马体损伤引起的行为损害。用来检验这些假说的方法将包括以大鼠为实验对象研究学习和记忆。使用选择性5-羟色胺再摄取抑制剂氟西汀和运动(车轮跑步)可以控制海马区的神经发生。神经再生将使用免疫组织化学方法，包括BrdU、Neun、GFAP和双重皮质素标记、激光共聚焦显微镜和无偏见的体视学方法进行量化。这些研究将提供关于成年海马神经发生功能的重要新信息，并评估增加神经发生速率的因素是否促进或破坏脑损伤后海马区功能的恢复。

DESCRIPTION (provided by applicant): The adult mammalian hippocampus contains precursor cells that differentiate into neurons during adulthood. This phenomenon is referred to as adult neurogenesis. The proposed studies address whether neurons that form in the adult hippocampus, a brain region involved in learning and memory, affect behavior. Predictions of four hypotheses will be tested. The learning hypothesis posits that adult hippocampal neurogenesis plays a role in the acquisition of hippocampus-dependent behavior. Thus, according to the learning hypothesis, factors that increase neurogenesis should improve learning. The forgetting hypothesis posits that new hippocampal neurons contribute to forgetting and that factors that increase neurogenesis will interfere with the long-term retention of hippocampus-dependent behavior. The self-repair hypothesis holds that newly formed neurons repair damaged hippocampal circuitry and predicts that factors that increase neurogenesis will improve recovery of function after hippocampal injury. The injury process hypothesis, in contrast, posits that new neurons that form in response to hippocampal injury interfere with the functioning of the remaining intact hippocampal tissue. Thus, the injury hypothesis predicts that factors that increase hippocampal neurogenesis will exacerbate the behavioral impairments caused by hippocampus damage. The methods used to test these hypotheses will involve studying learning and memory using rats as experimental subjects. Hippocampal neurogenesis will be controlled using the selective serotonin reuptake inhibitor, fluoxetine, and exercise (wheel running). Neurogenesis will be quantified using immunohistochemical methods including BrdU-, NeuN-, GFAP-, and doublecortin-labeling, confocal laser microscopy, and unbiased stereology methods. The proposed studies will provide important new information about the function of adult hippocampal neurogenesis and assess whether factors that increase the rate of neurogenesis enhance, or disrupt, recovery of hippocampal function after brain damage.