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

使用新型配体剖析神经调节剂腺苷对神经回路的控制

基本信息

批准号：
2265915
负责人：
金额：
--
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2265915
关键词：
Use novel ligands dissect control

项目摘要

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.

大脑中控制特定行为的神经回路由一组神经元组成，这些神经元由经典的快速、兴奋性和抑制性突触相连。然而，这类电路中一个经常被忽视的组成部分是扩散性神经调节剂，它可以改变电路的功能。这种神经调节剂是嘌呤腺苷，它在神经活动期间由神经元和胶质细胞释放，然后通过激活A1受体提供一个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的膜电位超极化(通过开放K+通道)，降低其放电动作电位的可能性。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开来。然而，我们已经开发了新的A1受体配体，这些配体显示出受体信号偏向，这使得我们能够剖析A1受体激活的多种影响。本项目的目的是利用这些新的配体作为工具，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、新皮质和丘脑皮质回路。这个项目旨在了解在疾病状态下可能会受到损害的正常大脑功能的基本机制。