CHOLINERGIC MECHANISMS AND RECEPTORS IN CEREBRAL CORTEX

认知障碍是美国一个重要的公共卫生问题。 然而，其治疗的治疗选择仍然有限。 临床和实验研究表明，胆碱能缺乏 在认知障碍的发病机制中起重要作用。 因此，胆碱能系统提供了一个很好的目标， 开发新的治疗方法。 不幸的是， 这一方向目前受到对以下问题的有限理解的阻碍： 大脑皮层的胆碱能机制 因此，从长远来看， 该提案的目标是开发一种细胞和分子 了解乙酰胆碱调节 联合皮层神经元兴奋性。 以前的研究已经使用电生理方法来调查 胆碱能调节神经元功能。 这些主要集中在 他们在海马体上发现了各种钾离子 被毒蕈碱受体抑制的电流。 研究期间， 然而，过去几年的情况表明， 海马不能直接转座到皮层， 皮层的联合区。 由于这些领域在 调节更高的认知功能，迫切需要 研究胆碱能受体调节 神经元的兴奋性。 为了解决这个问题，本申请提出研究 大鼠前额叶皮层的胆碱能机制。 特别是，它试图确定和表征一种新的毒蕈碱 调节的钙激活内向电流存在于该区域。 在完成这一目标之后，它提议检验以下假设： 不同的受体亚型和转导机制参与 这个区域的胆碱能反应信号。 最后 最后，建议评估这些受体的作用， 介导胆碱能神经传递。 这些实验将进一步加深我们对细胞和 乙酰胆碱调节皮质功能的分子机制。 因此，它们应当为旨在发展新的和 治疗疾病的有效治疗策略 与认知障碍有关

Cognitive impairment is an important public health concern in the United States yet therapeutic options for its treatment remain limited. Clinical and experimental studies indicate that a cholinergic deficit plays an important role in the pathogenesis of cognitive impairment. Thus cholinergic systems offer a good target for the rational development of novel therapeutic approaches. Unfortunately efforts in this direction are currently hampered by a limited understanding of cholinergic mechanisms in the cerebral cortex. Therefore the long term goal of this proposal is to develop a cellular and molecular understanding of the mechanisms by which acetylcholine regulates neuronal excitability in association cortex. Previous studies have used electrophysiological methods to investigate cholinergic regulation of neuronal function. These have focused mostly on hippocampus where they have identified a variety of potassium currents that are inhibited by muscarinic receptors. Studies during the last few years however suggest that the information obtained in hippocampus is not directly transposable to cortex and especially association regions of cortex. Since these areas are important in mediating higher cognitive function, there is a pressing need to investigate the mechanisms by which cholinergic receptors regulate neuronal excitability in these regions. To address this problem the present application proposes to investigate cholinergic mechanisms in rat prefrontal cortex, an associative area. In particular it seeks to identify and characterize a novel muscarinic regulated calcium-activated inward current present in this region. Following completion of this aim it proposes to test the hypothesis that different receptors subtypes and transduction mechanisms participate in the signalling of cholinergic responses in this region. Finally, it concludes by proposing to assess the role of these receptors in mediating cholinergic neurotransmission. These experiments should further our understanding of the cellular and molecular mechanisms by which acetylcholine regulates cortical function. As such they should contribute to efforts aimed at developing novel and effective therapeutic strategies for the treatment of diseases associated with cognitive impairment.