Use of novel ligands to dissect the control of neural circuits by the neuromodulator adenosine

大脑中控制特定行为的神经回路由由经典的快速兴奋性和抑制性突触连接的神经元群组成。然而，这种神经回路中一个经常被忽视的组成部分是弥漫性神经调节剂，它可以改变神经回路的功能方式。这种神经调节剂是嘌呤腺苷，在神经活动期间由神经元和胶质细胞释放，然后通过A1受体的激活提供可调节的负反馈控制机制。A1受体的激活有两个主要作用：抑制突触传递和神经元膜电位的超极化（通过打开K+通道），降低它们发射动作电位的可能性。到目前为止，A1受体激活的这两种作用还不能从药理学或遗传学上分离出来。然而，我们已经开发出新的A1受体配体，它显示出受体信号偏倚，这使我们能够分解A1受体激活的多重效应。该项目的目的是利用这些新的配体作为工具，以充分了解A1受体激活的不同成分在电路功能中的作用。特别是研究由不同形式的活动激活的海马体，新皮层和丘脑皮层回路。该项目旨在了解在疾病状态下可能受损的正常脑功能的基本机制。

Neural circuits in the brain which control specific behaviours consist of groups of neurons linked by classical fast excitatory and inhibitory synapses. However an often neglected component of such circuits are diffusive neuromodulators, which can change the way circuits function Such a neuromodulator is the purine adenosine, which is released by neurons and glia during neural activity and then via activation of A1 receptors provides a tuneable negative feedback control mechanism. Activation of A1 receptors has two major effects: inhibition of synaptic transmission and hyperpolarisation of the membrane potential of neurons (by opening K+ channels) reducing their likelihood of firing action potentials. Until now these two effects of A1 receptor activation could not be pharmacologically or genetically separated. However we have developed new A1 receptor ligands which show receptor signalling bias and these allow us dissect apart the multiple effects of A1 receptor activation. The aim of this project is to use these novel ligands as tools to fully understand the roles of the different components of A1 receptor activation in circuit function. In particular investigating hippocampal, neocortical and thalamocortical circuits which are activated by different forms of activity. This project aims to understand basic mechanisms underlying normal brain function which may become compromised in disease states.