CHOLINERGIC MECHANISMS AND RECEPTORS IN CEREBRAL CORTEX

描述（改编自申请人摘要）：认知障碍 在美国是一个严重的健康问题 流行病学研究 表明患病率超过1%，预计这一问题将进一步恶化 随着美国人口的老龄化。 尽管这件事很严重 问题，这种情况的药物治疗仍然非常 有限公司 基础和临床研究早已认识到以下方面的重要性： 维持认知功能的胆碱能机制。 确实 有几条证据支持这样的观点， 大脑皮层是认知障碍的一个致病因素。 因此， 了解皮层中的Achergic机制， 有助于寻找有效的药物治疗， 这个条件。 这个项目的长期目标是阐明细胞和 乙酰胆碱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 通过mAChRs介导的反应在PFC，一个协会区。 期间 在过去的资助周期中，我们使用了电生理技术， 体外大鼠脑片鉴定和表征一种新的阳离子电流 这似乎是Achergic调节的主要目标之一， 这一区域 在本申请中，我们提出扩展这些研究： (1)通过检测细胞内钙（Ca 2+）在激活中的作用， （2）确定所涉及的mAChR亚型;（3） 识别激活该电流的信令机制;以及 (4)确定该电流是否也被其它电流激活。 神经递质除了乙酰胆碱。 这些研究应该扩展我们的 了解mAChRs的细胞和分子机制， 调节大鼠PFC中神经元的兴奋性。 寻找新的和有效的治疗Achergic功能障碍， 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.