Cognitive Dysfunction after TBI: Role of alpha7 nAChrs

中枢神经系统的创伤引发急性和继发性生化和代谢变化的级联反应，经常导致持续的神经功能障碍状态。了解中枢神经系统损伤后发生的神经化学变化对于制定预防和/或修复创伤有害影响的治疗策略至关重要。外伤性脑损伤（TBI）后常见的持续性记忆缺陷的神经生物学基础尚不清楚，尽管许多研究表明中枢神经系统胆碱能系统的缺陷起着突出的作用。然而，以往的研究大多集中在毒蕈碱，而不是尼古丁胆碱能受体的机制。这是令人惊讶的，因为尼古丁受体系统的缺陷一再与阿尔茨海默病和帕金森病等神经退行性疾病的认知缺陷有关。我们的初步研究清楚地表明，皮质挫伤（CCI）导致海马和皮质α - 7烟碱受体（nAChr）表达显著和广泛的缺陷。所提出的研究的工作假设是中枢神经系统α - 7 nAChr的改变对头部创伤诱导的认知功能障碍有重要作用。此外，我们预测α - 7神经元烟碱受体的药理学调节将具有脑损伤大鼠的神经保护和认知增强特性。本提案的具体目标将评估：1)脑损伤后α 7蛋白和信息表达变化的时间过程2)脑损伤急性期尼古丁受体拮抗剂的神经保护作用3)脑损伤延迟期急性（或慢性）给予尼古丁和选择性α 7激动剂的认知增强特性4)脑损伤对听觉感觉门控缺陷的影响5)尼古丁和其他选择性α 7激动剂治疗后感觉门控的恢复。

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.