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Prefrontal cortical GABAergic inhibition and cognition

前额皮质 GABA 能抑制和认知

基本信息

批准号：
2275703
负责人：
金额：
--
依托单位：
University of Nottingham
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-2275703
关键词：
Prefrontal cortical GABAergic inhibition cognition

项目摘要

The project aims to examine the role of prefrontal cortical GABAergic inhibition in clinically relevant cognitive functions. The student will combine intracerebral drug microinfusions and pharmacogenetic methods, to manipulate regional GABA and interneuron function, with behavioural and electrophysiological methods in rats. Reduced cortical GABAergic inhibition, so-called neural disinhibition, characterises many neuropsychiatric disorders with cognitive deficits, including age-related cognitive decline and schizophrenia. In rats, neural disinhibition in medial prefrontal cortex and hippocampus, by local microinfusion of GABA antagonists, impairs some clinically relevant cognitive functions of the disinhibited region (including prefrontal attention and hippocampal memory) and of projection sites (e.g., disruption of prefrontal attention by hippocampal disinhibition). This supports that GABAergic inhibition is required for some cognitive functions of cortical regions ('local' effects) and their projection sites ('distal' effects), and may be a promising target to treat cognitive deficits. However, the role of GABA in many clinically relevant cognitive functions, and the role of GABAergic interneurons - the locus of dysfunction in disorders - remain to be clarified. This project has two main aims: 1) To characterise further the role of medial prefrontal GABA in clinically relevant aspects of behavioural and cognitive flexibility, which have been linked to the prefrontal cortex and can be studied across species using translational behavioural assays. 2) To complement drug microinfusion studies and examine directly cognitive functions of inhibitory GABA interneurons, by manipulating these neurons using pharmacogenetic DREADD technology.

该项目旨在研究前额叶皮层GABA能抑制在临床相关认知功能中的作用。学生将结合联合收割机脑内药物微量输注和药物遗传学的方法，操纵区域GABA和中间神经元的功能，在大鼠的行为和电生理方法。皮质GABA能抑制减少，即所谓的神经去抑制，是许多具有认知缺陷的神经精神障碍的特征，包括与年龄相关的认知衰退和精神分裂症。在大鼠中，通过GABA拮抗剂的局部微输注，内侧前额叶皮层和海马中的神经去抑制损害了去抑制区域（包括前额叶注意力和海马记忆）和投射部位（例如，海马去抑制引起的前额叶注意力的破坏）。这支持了GABA能抑制是皮质区域（“局部”效应）及其投射部位（“远端”效应）的某些认知功能所需的，并且可能是治疗认知缺陷的一个有希望的靶点。然而，GABA在许多临床相关的认知功能中的作用，以及GABA能中间神经元（疾病中功能障碍的部位）的作用仍有待澄清。该项目有两个主要目标：1）进一步证实内侧前额叶GABA在行为和认知灵活性的临床相关方面的作用，这与前额叶皮层有关，可以使用翻译行为测定法跨物种进行研究。2)补充药物微输注研究，并通过使用药物遗传学DREADD技术操纵这些神经元直接检查抑制性GABA中间神经元的认知功能。