Prefrontal cortical GABAergic inhibition and cognition

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.