CHOLINERGIC MECHANISMS AND RECEPTORS IN CEREBRAL CORTEX

描述(改编自申请人的摘要)：认知障碍 在美国是一个严重的健康问题。流行病学研究 表示流行率超过1%，而且这个问题可能会恶化 随着美国人口的老龄化。尽管这件事很严重 问题是，对这种情况的药物治疗仍然非常困难 有限的。基础和临床研究早已认识到 维持认知功能的胆碱能机制。确实如此 有几条证据支持这样一种观点，即缺铁性贫血 大脑皮层是认知障碍的致病因素。因此，一个 了解大脑皮层的脑缺血机制可以大大 有助于寻找有效的药物治疗方法 这种情况。 这个项目的长期目标是阐明细胞和 ACh调节神经元兴奋性的分子机制 大脑皮层的功能。为此，我们最初将重点放在 关于联结区PFC中mAChRs介导的反应。在.期间 在过去的资助周期中，我们使用了电生理技术 大鼠体外脑片鉴定和表征一种新的阳离子电流 这似乎是印度政府监管的主要目标之一。 这个地区。在本申请中，我们建议扩展这些研究： (1)通过检测细胞内钙离子在激活过程中的作用 (2)确定涉及mAChR亚型；(3) 确定激活该电流的信号机制；以及 (4)确定该电流是否也被其他设备激活 除ACh外的神经递质。这些研究应该扩大我们的 了解mAChRs的细胞和分子机制 调节大鼠前额叶皮质神经元兴奋性。这些知识应该有助于 寻找新的有效的治疗心力衰竭的方法 一般，尤其是认知障碍。

DESCRIPTION (adapted from the applicant's abstract): Cognitive impairment is a serious health concern in the United States. Epidemiological studies indicate a prevalence of over 1%, and this problem can be expected to worsen with the aging of the U.S. population. In spite of the seriousness of this problem, pharmacotherapeutic treatment for this condition remain extremely limited. Basic and clinical studies have long recognized the importance of cholinergic mechanisms for the maintenance of cognitive functioning. Indeed several lines of evidence support the idea that an AChergic deficit in cerebral cortex is a causative element in cognitive impairment. Thus, an understanding of AChergic mechanisms in cortex could substantially contribute to the search for effective pharmacotherapeutic treatments for this condition. The long term goal of this project is to elucidate the cellular and molecular mechanisms by which ACh regulates neuronal excitability and function in the cerebral cortex. To that effect, we have initially focused on responses mediated through mAChRs in PFC, an association area. During the past funding cycle, we have used electrophysiological techniques in vitro rat brain slices to identify and characterize a novel cation current that appears to be one of the principal targets for AChergic regulation in this region. In the present application we propose to extend these studies: (1) by examining the role of intracellular calcium (Ca2+) in the activation of this current; (2) determining the mAChR subtypes involved; (3) identifying the signaling mechanism by which this current is activated; and (4) determining whether this current is also activated by other neurotransmitters besides ACh. These studies should extend our understanding of the cellular and molecular mechanisms by which mAChRs regulate neuronal excitability in rat PFC. This knowledge should contribute to the search for novel and effective treatments for AChergic dysfunction in general, and cognitive impairment in particular.