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，该病的治疗选择仍然有限。 临床和实验研究表明胆碱能缺陷 在认知障碍的发病机制中起着重要作用。 因此，胆碱能系统为理性的 开发新的治疗方法。不幸的是，在 这一方向目前受阻于对 大脑皮层的胆碱能机制。因此，从长远来看 这项提议的目标是开发一种细胞和分子 对乙酰胆碱调节机制的认识 联合皮质中神经元的兴奋性。 以前的研究已经使用电生理方法来研究 神经功能的胆碱能调节。这些人主要集中在 在海马体上，他们发现了多种钾 被M受体抑制的电流。在研究过程中 然而，过去几年的情况表明， 海马体不能直接转座到皮质，尤其是 大脑皮层的关联区。因为这些领域在 作为高级认知功能的中介，迫切需要 探讨胆碱能受体的调节机制 这些区域的神经元兴奋性。 为了解决该问题，本申请建议调查 大鼠前额叶皮质的胆碱能机制。 特别是，它试图识别和刻画一个新的毒枭 调节钙激活的内向电流存在于该区域。 在完成这一目标后，它建议检验以下假设 不同的受体亚型和转导机制参与 这一区域胆碱能反应的信号。最后，它 结论是建议评估这些受体在 调节胆碱能神经传递。 这些实验应该会加深我们对细胞和 乙酰胆碱调节皮质功能的分子机制。 因此，他们应该为旨在开发新的和 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.