Prefrontal cortical GABAergic inhibition and cognition

该项目旨在研究前额皮质gaba能抑制在临床相关认知功能中的作用。该学生将结合脑内药物微输注和药物遗传学方法，在大鼠中操作区域GABA和中间神经元功能，并结合行为和电生理方法。皮层gaba能抑制减少，即所谓的神经去抑制，是许多伴有认知缺陷的神经精神疾病的特征，包括与年龄相关的认知能力下降和精神分裂症。在大鼠中，局部微量输注GABA拮抗剂对内侧前额叶皮层和海马的神经去抑制会损害去抑制区（包括前额叶注意和海马记忆）和投射部位（如海马去抑制对前额叶注意的破坏）的一些临床相关认知功能。这支持了gaba能抑制是某些皮质区域认知功能（“局部”效应）及其投射部位（“远端”效应）所必需的，并且可能是治疗认知缺陷的有希望的靶点。然而，GABA在许多临床相关认知功能中的作用，以及GABA能中间神经元的作用-障碍中的功能障碍位点-仍有待阐明。该项目有两个主要目的：1)进一步表征内侧前额叶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，可以使用转化行为分析跨物种研究。2)补充药物微输注研究，通过使用药物遗传学的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。

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.