Working memory deficits following brain trauma

脑外伤后的工作记忆缺陷

基本信息

批准号：
7869541
负责人：
PRAMOD K DASH
金额：
$ 19.82万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7869541
关键词：
Abbreviations Affect Anabolism Area Binding Cause of Death Cell Line Cell membrane Cells Cognitive Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases DARPP 32 DOPA decarboxylase Data Development Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Dose Enzymes Event Functional disorder GABA Antagonists GAD67 enzyme Glutamate Decarboxylase Hippocampus (Brain)Human Information Storage Infusion procedures Injury Intracellular Second Messenger Lesion Maintenance Medial Memory impairment Metabolism Modeling Molecular Monkeys Monoamine Oxidase Monoamine Oxidase B Neuroglia Neurons Neurotransmitters Normalcy Operative Surgical Procedures PKA inhibitor Parietal Pathway interactions Patients Performance Pharmacological Treatment Phosphorylation Play Prefrontal Cortex Property Pump Rattus Receptor Activation Reporting Research Personnel Rodent Role Second Messenger Systems Shapes Short-Term Memory Signal Transduction Structure Synapses Synaptic Cleft Synaptic Receptors System Testing Tissues Traumatic Brain Injury Tyrosine Tyrosine 3-Monooxygenase Tyrosine Hydroxylase Inhibitor United States Ventral Tegmental Area Vesicle Work attenuation base caudate nucleus cholinergic design dopamine transporter dopaminergic neuron effective intervention frontal lobe gamma-Aminobutyric Acid glial cell-line derived neurotrophic factor human TYRP1 protein improved information processing inhibitor/antagonist inhibitory neuron monoamine noradrenergic presynaptic programs receptor receptor-mediated signaling research study response

项目摘要

DESCRIPTION (provided by applicant): Almost two million people sustain traumatic brain injury each year in the United States alone, with most reporting deficits in working memory. Working memory involves the "online" storage of information necessary for performing cognitive operations. The prefrontal cortex, which is required for working memory, is highly developed in humans and its function is often impaired by brain trauma. Studies performed in humans, monkeys and rodents have shown that dopamine signaling plays a critical role in working memory. Either too little or too much dopamine receptor D1 stimulation impairs working memory performance. Recently, a few studies have examined the expression of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase (TH), and the plasma membrane dopamine transporter (DAT) in rat frontal cortex following traumatic brain injury (TBI). However, very little is known about how TBI affects the normalcy of dopamine signaling in the prelimbic/infralimbic (PL/IL) cortices, structures required for working memory performance in rodents. This proposal will test the overall hypothesis that enhanced D1 receptor-mediated signaling in the PL/IL cortices is causally related to TBI-associated working memory deficits. Consequently, attenuation of dopamine synthesis or D1 receptor-activated events in these areas will alleviate these deficits.. The Specific Aims of the proposal are: 1) To determine if dopamine biosynthesis in the PL/IL cortices is increased following TBI and to assess its role in working memory deficits. 2) To determine if TBI alters tissue dopamine content, or receptor levels in the PL/IL cortices and to assess the contribution of dopamine to working memory deficits, and 3) To determine if dopamine-activated intracellular events in the PL/IL cortices ifollowing TBI contributes to working memory deficits. An understanding of the mechanisms by which TBI alters dopamine signaling is critical for the development of mechanism-based intelligent pharmacological treatments for working memory deficits for brain trauma patients.

描述（由申请人提供）：仅在美国，每年就有近 200 万人遭受创伤性脑损伤，其中大多数人报告有工作记忆缺陷。工作记忆涉及执行认知操作所需信息的“在线”存储。工作记忆所需的前额皮质在人类中高度发达，但其功能经常因脑外伤而受损。对人类、猴子和啮齿动物进行的研究表明，多巴胺信号在工作记忆中起着至关重要的作用。多巴胺受体 D1 刺激太少或太多都会损害工作记忆表现。最近，一些研究检测了创伤性脑损伤（TBI）后大鼠额叶皮质中多巴胺合成限速酶酪氨酸羟化酶（TH）和质膜多巴胺转运蛋白（DAT）的表达。然而，关于 TBI 如何影响边缘前/边缘下 (PL/IL) 皮质（啮齿动物工作记忆性能所需的结构）中多巴胺信号传导的正常性，人们知之甚少。该提案将检验总体假设，即 PL/IL 皮质中 D1 受体介导的信号传导增强与 TBI 相关的工作记忆缺陷存在因果关系。因此，这些区域中多巴胺合成或 D1 受体激活事件的减弱将缓解这些缺陷。该提案的具体目标是：1) 确定 TBI 后 PL/IL 皮质中的多巴胺生物合成是否增加，并评估其效果。工作记忆缺陷中的作用。 2) 确定 TBI 是否改变组织多巴胺含量或 PL/IL 皮质中的受体水平，并评估多巴胺对工作记忆缺陷的影响，以及 3) 确定 PL/IL 皮质中多巴胺激活的细胞内事件是否如下TBI 会导致工作记忆缺陷。了解 TBI 改变多巴胺信号传导的机制对于开发基于机制的智能药物治疗脑外伤患者工作记忆缺陷至关重要。