Cognitive Dysfunction after TBI: Role of alpha7 nAChrs

TBI 后的认知功能障碍：α7 nAChrs 的作用

• 批准号: 6624070
• 负责人: JAMES R PAULY
• 金额: $ 26.45万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624070
• 关键词: auditory feedback; autoradiography; behavior test; brain injury; chemoprevention; cognition disorders; disease /disorder model; histochemistry /cytochemistry; in situ hybridization; inhibitor /antagonist; laboratory rat; mental disorder prevention; messenger RNA; neurochemistry; neuropharmacology; neuroprotectants; nicotinic receptors; protein structure function; receptor binding; receptor expression; sensory feedback; stereotaxic techniques; trauma

Trauma to the CNS initiates acute and secondary cascades of biochemical and metabolic changes often results in a state of persistent neurological dysfunction. Understanding the neurochemical alterations that occur following damage to the CNS is critical for the development of therapeutic strategies that can prevent and/or remediate the detrimental effects of trauma. The neurobiological basis for the protracted memory deficit that commonly occurs following traumatic brain injury (TBI) is not clearly understood although a number of studies have suggested that deficits in the CNS cholinergic system play a prominent role. However, most of the previous studies have focused on muscarinic, rather than nicotinic cholinergic receptor mechanisms. This is surprising since deficits in the nicotinic receptor system have been repeatedly associated with the cognitive deficit that occurs to neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. Our initial studies clearly demonstrate that a cortical contusion injury (CCI) causes significant and widespread defects in hippocampal and cortical alpha 7 nicotinic receptor (nAChr) expression. The working hypothesis of the proposed studies is that changes in the CNS alpha7 nAChr's contribute significantly to head trauma- induced cognitive dysfunction. Furthermore, we predict that pharmacological modulation of alpha7 neuronal nicotinic receptors will have neuroprotective and cognitive-enhancing properties in head-injured rats. The Specific Aims of this proposal will evaluate: 1) the time course of changes in alpha7 protein and message expression following TBI 2) neuroprotective actions of nicotinic receptor antagonists administered in the acute phase of TBI, 3) cognitive enhancing properties of nicotine and selective alpha7 agonists administered acutely (or chronically) in the delayed phase of TBI 4) the effects of TBI on deficits in auditory sensory gating and 5) restoration of sensory gating following treatment with nicotine and other selective alpha7 agonists.

中枢神经系统的创伤引发了生化和代谢变化的急性和次要级联反应通常会导致持续的神经功能障碍。 了解在CNS损害后发生的神经化学改变对于可以预防和/或补救创伤的有害影响的治疗策略的发展至关重要。尽管许多研究表明，CNS胆碱能系统的缺陷起着重要作用，但尚未清楚地理解脑损伤（TBI）通常发生的旷日持久记忆缺乏的神经生物学基础。 但是，以前的大多数研究都集中在毒蕈碱，而不是烟碱胆碱能受体机制上。 这是令人惊讶的，因为烟碱受体系统中的缺陷与神经退行性疾病（例如阿尔茨海默氏病和帕金森氏病）的认知不足反复相关。 我们的初步研究清楚地表明，皮质挫伤损伤（CCI）在海马和皮质α7烟碱受体（NACHR）表达中引起明显和广泛的缺陷。 提出的研究的工作假设是，CNS alpha7 NACHR的变化对头部创伤引起的认知功能障碍有显着贡献。 此外，我们预测，α7神经元烟碱受体的药理调节将在头部受伤的大鼠中具有神经保护性和认知增强特性。 该提案的具体目的将评估：1）TBI后α7蛋白质和消息表达变化的时间过程2）在TBI的急性阶段施用的烟碱受体拮抗剂的神经保护作用，3）3）烟碱和选择性alpha7 a andersed a andecter and and prestistive Alpha7 aponist的认知性增强特性（或在延迟）中（或延迟）。尼古丁和其他选择性α7激动剂治疗后，听觉感觉门控的缺陷和5）恢复感觉门控。