(PQ 9) Synaptic basis of deficits in attention and executive function following cranial radiation

近几十年来，成人和儿童脑瘤的治愈率有所提高。不幸的是，许多人 幸存者现在生活在治疗本身的终生副作用中。放射治疗尤其是 损害大脑，并导致长期的认知缺陷。实验室和临床上的大多数 研究的重点是辐射对记忆的负面影响。海马体，一个大脑 在记忆形成中非常重要的结构，在出生后发生神经发生的地方，一直是唯一的焦点。 虽然记忆力非常重要，但注意力和执行功能的缺陷可能同样会使人衰弱 对病人来说。其他大脑区域，包括额叶皮质，控制着这些功能和辐射对 这些非神经性脑区一直被忽视。从海马体转移到海马区 在没有发生神经发生的大脑中，令人兴奋的新的初步数据表明，前脑中的神经元 额叶皮质也容易受到辐射引起的功能障碍的影响。这挑战了人们普遍持有的观念。 关于辐射导致认知功能障碍的分子和细胞机制。 这些发现有可能解释辐射导致的认知能力下降的基本方面。至 确定这样的机制，我们将使用独特的资源，包括同时成像和 辐射对突触活动的电生理记录以及对持续性的体内评估 转基因动物突触可塑性和树突结构的改变。在本提案中，我们将 研究辐射后急性谷氨酸毒性的作用，探索突触功能如何变化 并确定导致长期突触功能障碍的机制。我们会 实现以下目标：(1)确定谷氨酸毒性和氧化应激在前额叶中的作用 辐射后的大脑皮层，(2)建立辐射引起的注意力和执行缺陷的动物模型 并将这些与突触功能的变化联系起来，(3)确定表观遗传机制在 辐射后突触结构和功能的长期变化。对早期和晚期的认识 所涉及的机制将允许开发更有效的预防性治疗，甚至 逆转先前存在的辐射引起的缺陷。

In recent decades, the cure rates for adult and childhood brain tumors have improved. Unfortunately, many survivors now live with life-long side effects from the treatment itself. Radiation therapy is particularly damaging to the brain and results in long-term cognitive deficits. The majority of both laboratory and clinical investigation has focused on the negative effects of radiation on memory. The hippocampus, a brain structure important in memory formation where postnatal neurogenesis occurs, has been the sole focus. While memory is of great importance, deficits in attention and executive function may be equally debilitating for patients. Other brain areas, including the frontal cortex, control these functions and radiation effects on these non-neurogenic brain areas have been ignored. Moving outside the hippocampus to areas of the brain where neurogenesis does not occur, exciting new preliminary data indicate that neurons in the pre- frontal cortex are also susceptible to radiation-induced dysfunction. This challenges commonly held notions regarding the molecular and cellular mechanisms that underlie radiation-induced cognitive dysfunction. Such findings have the potential to explain fundamental aspects of radiation-induced cognitive decline. To identify such mechanisms we will use unique resources including simultaneous imaging and electrophysiological recordings of synaptic activity with radiation as well as in vivo assessments of persistent alterations in synaptic plasticity and dendritic structure in transgenic animals. In this proposal we will examine the role of acute glutamate toxicity following radiation, explore how synaptic function changes in the frontal cortex and determine the mechanisms leading to long lasting synaptic dysfunction. We will conduct the following aims; (1) define the role of glutamate toxicity and oxidative stress in the prefrontal cortex following radiation, (2) establish an animal model of radiation-induced attention and executive deficits and correlate these with alterations in synaptic function, (3) identify the role of epigenetic mechanisms in long lasting changes in synaptic structure and function following radiation. Knowledge of the early and late mechanisms involved will allow for the development of more effective preventative treatments or even reversal of pre-existing radiation-induced deficits.