Effects of traumatic brain injury on hippocampal network activity: age difference

创伤性脑损伤对海马网络活动的影响：年龄差异

• 批准号: 8443632
• 负责人: Susanna Rosi
• 金额: $ 23.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443632
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Animals; Area; Attention; Behavior; Behavioral; Brain; Brain Injuries; Cell Nucleus; Cells; Cellular Compartment Analysis; Cognition; Cognitive deficits; Cytoplasm; Cytoskeleton; Data; Dementia; Development; Diffuse Axonal Injury; Elderly; Environment; Environmental Risk Factor; Failure; Fluorescent in Situ Hybridization; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Healthcare Systems; Hippocampus (Brain); Image; Immediate-Early Genes; Impaired cognition; Incidence; Individual; Injury; Kinetics; Knowledge; Life; Literature; Long-Term Effects; Maps; Mediating; Medical; Memory; Memory impairment; Messenger RNA; Methods; Molecular; Mus; Neurocognitive; Neurologic; Neuronal Plasticity; Neurons; Neurotransmitters; Pathogenesis; Patients; Performance; Process; Proteins; Publishing; Quality of life; Research; Research Infrastructure; Resolution; Risk; Role; Stimulus; Synapses; Synaptic plasticity; Techniques; Testing; Time; Trauma; Traumatic Brain Injury; United States; Work; age difference; age effect; age related; base; brain metabolism; cognitive function; disability; experience; imaging modality; information processing; innovation; neuronal circuitry; prospective; protein expression; public health relevance; research study; response; social; treatment strategy

DESCRIPTION (provided by applicant): In this study we propose to use immediate-early gene (IEG) expression imaging to assess the age-related long-term effects of traumatic brain injury (TBI) on the posttranscriptional infrastructure of gene expression involved in synaptic plasticity and memory. TBI is the leading cause of neurological disability in the world; the critical changes that affect cognition take place over a long period of time the initial injury, and age is a substantial factor in both the risk of and the incidence of acquired brain injury. While the pathogenesis of TBI- related cognitive impairment is uncertain, it is likely multifaceted involving diffuse axonal injury, altered neuronal integrity, imbalances in neurotransmitters, changes on brain metabolism, hippocampal vulnerability; these pathophysiological factors might ultimately alter neuronal plasticity and cause memory deficits. The goal of this proposal is to advance our limited knowledge of the age-related changes in the cellular mechanisms controlling hippocampal neuronal plasticity and memory after TBI. Our working hypothesis is that the long term cognitive dysfunctions resulting from TBI are mediated through altered de novo synthesis of plasticity-related IEGs and consequent disruption of hippocampal network activity. Our hypothesis is based on our recent published data demonstrating that dysregulation of the plasticity-related IEG Arc (activity-regulated cytoskeleton-associated protein) expression parallels cognitive dysfunctions observed two months after TBI. The IEG Arc is expressed in response to synaptic activity and is required for engaging durable plasticity processes that underlie memory; Arc is the only known activity-induced gene that correlates both temporally and spatially with the stimulus that induced its transcription. Given its critical role on synaptic plasticity and its well defined kinetics Arc represents the best candidate to study altered synapti plasticity and to test our hypothesis. Using imaging method called catFISH (cellular compartment analysis of temporal activity with fluorescence in situ hybridization) it is possible t detect the sub-cellular localization (nucleus and cytoplasm) of Arc mRNA in response to synaptic activity in a time-dependent manner. This technique provides excellent temporal and cellular resolution and facilitates mapping of neuronal activity; furthermore, it provides an innovative way to evaluate hippocampal networks mediating contextual and spatial information processing. Based upon our data on TBI, combined with our previous findings on hippocampal network activity we are proposing to use catFISH to: 1) identify the dynamics of the post transcriptional infrastructure of gene expression involved in synaptic plasticity and memory after TBI in behaviorally characterized young and old mice; 2) determine how age at the time of TBI affects hippocampal networks mediating contextual and spatial information processing. From these studies we will establish the role and the effect of age on the progression of TBI-related cognitive impairments from a behavioral, cellular and network prospective. These types of data are currently unavailable and are essential for the development of treatments and strategies to manage TBI- mediated neurocognitive dysfunctions.

描述（由申请人提供）：在这项研究中，我们建议使用立即早期基因（IEG）表达成像来评估创伤性脑损伤（TBI）对参与突触可塑性和记忆的基因表达的转录后基础结构的年龄相关长期影响。TBI是世界上神经系统残疾的主要原因;影响认知的关键变化发生在初始损伤的很长一段时间内，年龄是获得性脑损伤风险和发病率的重要因素。虽然创伤性脑损伤相关认知障碍的发病机制尚不确定，但可能是多方面的， 弥漫性轴突损伤、神经元完整性改变、神经递质失衡、脑代谢变化、海马易损性;这些病理生理因素可能最终改变神经元可塑性并导致记忆缺陷。这个建议的目的是推进我们有限的知识，年龄相关的变化，在细胞机制控制海马神经元可塑性和记忆TBI后。我们的工作假设是，TBI导致的长期认知功能障碍是通过改变可塑性相关的IEG的从头合成和随之而来的海马网络活动的中断来介导的。我们的假设是基于我们最近发表的数据，表明可塑性相关IEG Arc（活性调节的细胞因子相关蛋白）表达的失调与TBI后两个月观察到的认知功能障碍平行。IEG Arc在响应突触活动时表达，并且是参与记忆基础的持久可塑性过程所必需的; Arc是唯一已知的与诱导其转录的刺激在时间和空间上相关的活动诱导基因。鉴于其在突触中的关键作用， 可塑性及其明确的动力学Arc代表了研究改变的突触可塑性和检验我们的假设的最佳候选者。使用称为catFISH（具有荧光原位杂交的时间活动的细胞区室分析）的成像方法，可以以时间依赖性方式检测响应于突触活动的Arc mRNA的亚细胞定位（细胞核和细胞质）。该技术提供了良好的时间和细胞分辨率，并有利于映射的神经元活动，此外，它提供了一种创新的方式来评估海马网络介导的上下文和空间信息处理。基于我们关于TBI的数据，结合我们先前关于海马网络活动的发现，我们建议使用catFISH来：1）在行为特征的年轻和年老小鼠中鉴定TBI后参与突触可塑性和记忆的基因表达的转录后基础结构的动态; 2）确定TBI时的年龄如何影响介导上下文和空间信息处理的海马网络。通过这些研究，我们将从行为、细胞和网络的角度确定年龄对TBI相关认知障碍进展的作用和影响。这些类型的数据目前不可用，并且对于开发管理TBI介导的神经认知功能障碍的治疗和策略至关重要。