NEUROGENESIS AND COGNITION IN IRRADIATED YOUNG MICE

在儿童中，脑部辐射暴露发生在颅内恶性肿瘤的治疗、白血病的预防性治疗和骨髓移植的全身照射中。脑辐照对这些患者的主要不良影响是认知功能障碍，包括学习和记忆障碍，年龄较小的儿童尤其敏感。这种变化的发病机制尚不清楚，但据推测，海马是内侧颞叶记忆系统的主要组成部分。海马体功能的紊乱会降低空间学习和记忆的表现以及充分探索环境的能力，这些都很容易在小鼠身上得到评估。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耗竭与认知缺陷有关。我们最近的研究表明，负责产生颗粒细胞的海马体中增殖的神经前体细胞对x射线特别敏感。我们假设，辐射引起的幼龄动物神经前体细胞的丧失会导致特定海马依赖的认知功能受损，而影响早期辐射反应的药物可以改善前体细胞的丧失和随后的认知缺陷。本提案的总体目标是建立一个小鼠模型来验证这一假设。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亚颗粒增殖区（SGZ）凋亡的剂量反应与动物年龄的关系；2)确定放射诱导的幼龄动物SGZ前体增殖减少是否与x射线照射后认知缺陷的严重程度有关；3)确定caspace抑制剂z-VAD-fmk抑制幼年动物辐射诱导的SGZ前体细胞增殖凋亡所需的剂量和给药计划；4)确定抑制SGZ前体细胞凋亡是否能改善幼年动物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.