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

(PQ 9) 颅脑辐射后注意力和执行功能缺陷的突触基础

基本信息

批准号：
9763496
负责人：
DAVID R GROSSHANS
金额：
$ 48.13万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763496
关键词：
Acute Adult Adverse effects Age Animal Model Animals Area Attention Attentional deficit Behavioral Brain Brain Neoplasms Cells Cessation of life Childhood Brain Neoplasm Clinic Clinical Clinical Research Clinical Trials Cognitive Cognitive deficits Cranial Irradiation Data Development Electrophysiology (science)Epigenetic Process Functional disorder Glutamate Receptor Glutamates Goals Hippocampus (Brain)Image Impaired cognition Impulsivity Intervention Knowledge Laboratories Laboratory Study Left Life Measurement Measures Memantine Memory Memory impairment Mission Molecular N-Methylaspartate National Cancer Institute Neurons Neurotransmitters Nitric Oxide Oxidative Stress Patients Phase III Clinical Trials Prefrontal Cortex Prevention Preventive treatment Public Health Quality of life Radiation Radiation therapy Reaction Time Research Research Support Resistance Resources Role Signal Transduction Structure Survivors Synapses Synaptic plasticity Techniques Testing Therapeutic Thinness Time Toxic effect Transgenic Animals Treatment Side Effects cancer rehabilitation cancer therapy clinical investigation design excitotoxicity executive function frontal lobe functional outcomes improved in vivo inhibitor/antagonist irradiation neurocognitive test neurogenesis neuron loss novel novel therapeutics postnatal precursor cell preservation prevent processing speed protective effect radiation effect radiation-induced cognitive dysfunction real-time images synaptic function tumor

项目摘要

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.

近几十年来，成人和儿童脑肿瘤的治愈率有所提高。不幸的是，许多幸存者现在终生承受着治疗本身带来的副作用。放射治疗尤其损害大脑并导致长期认知缺陷。大多数实验室和临床调查的重点是辐射对记忆的负面影响。海马体，大脑在出生后神经发生发生的记忆形成中重要的结构一直是唯一的焦点。虽然记忆力非常重要，但注意力和执行功能的缺陷也可能同样使人衰弱对于患者。其他大脑区域，包括额叶皮层，控制着这些功能和辐射对人体的影响。这些非神经源性大脑区域被忽视了。移动到海马体之外的区域令人兴奋的新初步数据表明，神经元在不发生神经发生的大脑中额叶皮层也容易受到辐射引起的功能障碍的影响。这挑战了普遍持有的观念关于辐射引起的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引起的认知能力下降的基本方面。到确定此类机制，我们将使用独特的资源，包括同步成像和辐射突触活动的电生理记录以及持久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，我们将检查辐射后急性谷氨酸毒性的作用，探索突触功能如何变化额叶皮层并确定导致长期持续突触功能障碍的机制。我们将实现以下目标； (1)定义谷氨酸毒性和氧化应激在前额叶的作用辐射后皮质，（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改变联系起来，（3）确定表观遗传机制在辐射后突触结构和功能的长期持续变化。早期和晚期的知识所涉及的机制将有助于开发更有效的预防性治疗方法，甚至逆转先前存在的辐射引起的缺陷。