Attentional Dysfunction in Fragile X Syndrome

这个项目的目标是了解脆性X的注意缺陷所涉及的神经系统 综合征(FXS)，以便能够设计出有效的治疗方法。注意障碍的特征 FX比他们的I.Q更严重，我们假设有三个不同的缺陷 大脑系统的相互作用会产生这些极端的注意力困难。第一，执行功能受损 Ha被证明是FXS注意力缺陷的原因之一。第二，感觉的异常加工 信息可能会损害注意力，还会导致过度兴奋，从而损害注意力。最后， 下丘脑-垂体-肾上腺轴的异常可能与觉醒和认知障碍有关 功能。我们将使用新开发和验证的五臂迷宫注意力测量。的效果 此外，还将探讨影响这项任务表现的干扰因素。主动回避是我们要完成的一项任务 已经发现了注意力和情绪因素的深刻影响。因为此任务的参数可以改变 为了系统地确定学习问题的性质，将使用此任务来确定影响 感觉和情绪障碍对认知表现的影响。中还没有研究过HPA轴 Fmr1 KO小鼠，但患有FXS的人在应激后恢复基础皮质酮水平的速度更慢 而不是对照组，这一结果可以从Eberwin和Greough的发现中预测到，FMRP 与糖皮质激素受体(GR)结合，导致海马区GR水平下降25% Fmr1 KO小鼠。我们将彻底检查皮质酮的每日节律、反应 在其他动物模型中，应激对HPA轴的GR效应降低 很难预测，所以大脑和肾上腺的标志物表达为整个脑轴(GR、MR、CRF、ACTH、 POMC皮质酮)将被检测，因为这些分子在大脑中的表达可以有深远的影响 对认知和行为的影响。当我们有了好的措施时，所有这些目标都会形成最终的目标 注意和认知表现，并知道HPA轴的异常，我们可以选择药物 可能会影响我们假设涉及FXS注意力缺陷的三个系统。个体 MD对这些药物的联合测试将确定这些系统中每个系统的相对作用，并导致 对FXS中这一重要问题的-，-组合治疗。

The objective of this project is to understand the neural systems involved in the attention deficits in fragile X syndrome (FXS), so that effective treatments can be devised. The attention impairment characteristic of FXS are more severe than would be expected for their'I.Q, We hypothesize that defects in three different brain systems interact to produce these extreme attention difficulties. First, impairment of executive function ha been shown to contribute to attention deficits in FXS. Second, abnormal processing of sensory information likely impairs attention as well as leading to over arousal that impairs attention. Finally, abnormalities in the hypothalamic pituitary adrenal axis likely contribute to arousal and lower cognitive function. We will use the newly developed and validated 5-arm maze attention measure. Effects of distracting stimuli on performance on this task will also be explored. Active avoidance is a task on whichWe have found profound effects of attentional and emotional factors. As parameters of this task can be varied systematically to determine the nature of the learning problem, this task will be used to determine the impact of the sensory and emotional difficulties on cognitive performance. The HPA axis has not been studied in the Fmr1 KO mouse, but humans with FXS return to basal corticosterone levels more slowly after stress than do controls, a result that would be predicted by the finding from Eberwine and Greenough that FMRP binds to the glucocorticoid receptor (GR), resulting in a 25% decrease in GR levels Inthe hippocampus in the Fmr1 KO mouse. We will conduct a thorough examination of the corticosterone daily rhythm, response to and recovery from stress, In other animal models of reduced GR effects on the HPA axis have been difficult to predict, so brain and adrenal expression of markers for the entire axis (GR, MR, CRF, ACTH, POMC corticosterone) will be examined, as expression of these molecules in the brain can have profound effects upon cognition and behavior. All of these aims build to the final aim, When we have good measures of attention and cognitive performance and know the abnormalities in the HPA axis, we can select drugs likely to impact the three systems we hypothesize to be involved in the attention deficits in FXS. Individual md combination tests of these drugs will determine the relative roles of each of these systems, and lead to ¿-,-combination treatments for this Important problem In FXS.