Attentional Dysfunction in Fragile X Syndrome

超出提供的空间。本项目的目的是了解脆性X综合征(FXS)注意力缺陷所涉及的神经系统，以便设计有效的治疗方法。FXS的注意力障碍特征比他们的I.Q更严重，我们假设三个不同大脑系统的缺陷相互作用，产生这些极端的注意力困难。首先，执行功能受损已被证明是FXS注意力缺陷的原因之一。其次，对感觉信息的异常处理可能会损害注意力，并导致过度唤醒，从而损害注意力。最后，下丘脑-垂体-肾上腺轴的异常可能导致觉醒和认知功能下降。我们将使用新开发和验证的五臂迷宫注意力测量。此外，还将探讨分心刺激对这项任务成绩的影响。主动回避是一项任务，我们在这项任务上发现了注意力和情绪因素的深刻影响。由于这项任务的参数可以系统地变化来确定学习问题的性质，因此这项任务将被用来确定感觉和情绪困难对认知表现的影响。HPA轴尚未在Fmr1 KO小鼠中进行研究，但患有FXS的人类在应激后恢复到基础皮质酮水平的速度比对照组更慢，这一结果可以从Eberwin和Greough的发现预测到，FMRP与糖皮质激素受体(GR)结合，导致Fmr1 KO小鼠海马区GR水平下降25%。我们将彻底检查皮质酮的每日节律，对应激的反应和恢复，在其他动物模型中，对HPA轴的GR影响一直难以预测，因此将检测大脑和肾上腺整个轴的标志物(GR、MR、CRF、ACTH、POMC皮质酮)的表达，因为这些分子在大脑中的表达可以对认知和行为产生深远的影响。所有这些目标都建立在最终目标上，当我们有了良好的注意力和认知表现的测量，并知道HPA轴的异常时，我们可以选择可能影响我们假设的三个系统的药物，这些药物与FXS的注意缺陷有关。这些药物的单独MD组合试验将确定这些系统中每个系统的相对作用，并导致对FXS中这一重要问题的联合治疗。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================