NEUROGENESIS AND COGNITION IN IRRADIATED YOUNG MICE

在儿童中，脑辐射暴露发生在治疗颅内恶性肿瘤、预防白血病治疗和骨髓移植全身暴露的过程中。这些患者脑部照射的一个主要不良反应是认知功能障碍，涉及学习和记忆障碍，年龄较小的儿童尤其敏感。这种变化的发病机制还不是很清楚，但人们假设内侧颞叶记忆系统的主要组成部分--海马体参与其中。海马体功能障碍会降低空间学习和记忆能力以及充分探索环境的能力，所有这些都很容易在小鼠身上进行评估。海马齿状回的颗粒细胞参与空间记忆，辐射引起的颗粒细胞层的细胞枯竭与认知障碍有关。我们最近发现，负责产生颗粒细胞的海马区增殖的神经前体细胞对X射线特别敏感。我们假设，在幼年动物中，辐射诱导的神经前体细胞的丢失将导致特定的海马区依赖的认知功能的损害，并且影响早期辐射反应的药物可以改善前体细胞的丢失和随后的认知缺陷。这项提议的总体目标是建立一个小鼠模型来检验这一假说。有4个具体目标支持我们的目标：1)确定辐射诱导小鼠海马齿状回颗粒下增殖区(SGZ)细胞凋亡的剂量反应随动物年龄的变化；2)确定辐射诱导幼年动物SGZ前体细胞增殖的减少是否与X射线照射后认知障碍的严重程度有关；3)确定抑制辐射诱导幼年动物SGZ前体细胞增殖所需的cspace抑制剂z-VAD-fmk的剂量和给药时间表；4)确定抑制SGZ前体细胞凋亡是否改善了辐射诱导的认知缺陷。

In children, radiation exposure of the brain occurs during the treatment of intracranial malignancies, prophylactic therapy for leukemia and in whole body exposures for bone marrow transplantation. A major adverse effect of brain irradiation in these patients is cognitive dysfunction, involving learning and memory impairments, and younger children are particularly sensitive. The pathogenesis of such changes is not well understood, but it has been hypothesized that the hippocampus a major component of the medial temporal lobe memory system, is involved. Disturbances in hippocampal functioning reduce spatial learning and memory performance and the ability to explore the environment adequately, all of which are easily assessed in mice. The granule cells of the dentate gyrus of the hippocampus are involved in spatial memory, and radiation-induced cellular depletion of the granule cell layer has been implicated in cognitive deficits. We have recently shown that proliferating neural precursor cells of the hippocampus, which are responsible for producing granule cells, are particularly sensitive to x-rays. We hypothesize that radiation-induced loss of neural precursor cells in young animals will result in impairments in specific hippocampus-dependent cognitive functions, and that precursor cell loss and subsequent cognitive deficits can be ameliorated by agents that affect early radiation response. The overall objective of this proposal is to establish a mouse model to test this hypothesis. There are 4 specific aims in support of our objective: 1) Determine the dose response for radiation-induced apoptosis in the dentate subgranular proliferative zone (SGZ) of the mouse hippocampus as a function of animal age; 2) Determine if radiation-induced reduction of proliferating SGZ precursors in young animals is related to the severity of cognitive deficits after x- irradiation; 3) Determine the dose and administration schedule of the caspace inhibitor z-VAD-fmk required to inhibit radiation-induced apoptosis in proliferating SGZ precursor cells in young animals; and 4) Determine if inhibition of apoptosis in SGZ precursor cells ameliorates radiation-induced cognitive deficits in young animals.