Combining animal and human imaging to understand inhibitory mechanisms for learning and brain plasticity

PhD project strategic theme: Understanding the rules of life

The brain has the important task to select and execute the most meaningful behaviour vital for survival. It does so by selectively integrating relevant sensory information while also filtering out noise. GABA, the main inhibitory neurotransmitter, has been suggested to play a crucial role in shaping the activity of principal neurons to facilitate plasticity and learning. However, the computational mechanisms through which cortical GABAergic interneurons facilitate experience-dependent plasticity are poorly understood. We are therefore interested in understanding the role of suppressive mechanisms in two contrasting types of visual behavioural tasks - the detection of visual features embedded in noise, and the discrimination between similar visual features. First, we will develop behavioural paradigms to allow us to directly investigate the neural processes involved in perceptual learning. Visual perceptual learning is a form of learning where repeated exposure to task-relevant visual stimuli results in substantial improvements in visual detection and discrimination. We will adapt the visual tasks to allow the testing of both mice and humans with the aim that the study will help bridge the gap between animal and human models of brain plasticity and perceptual learning. We will then experimentally alter GABA levels and examine the impact this has on the behavioural performance of each task. To elevate GABA levels in humans, participants will receive an oral dose of Baclofen, a GABAB receptor agonist. In mice, we will optogenetically control the activity of parvalbumin-positive GABAergic interneurons. Finally, we will combine animal and human imaging methodologies to quantify GABA levels in both species. In humans, we will use magnetic resonance spectroscopy (MRS) to measure how GABA concentration changes across the visual cortex and other areas involved in visual decision-making while subjects perform the two visual tasks. While MRS is a powerful tool enabling the direct study of inhibitory mechanism in the human visual cortex, it reflects the neural activity at population level and has a relatively low temporal resolution. Therefore, imaging studies in mice will help us probe the cortical circuits involved at a single-cell level. For example, we will use optogenetic cell-type specific manipulation combined with two photon calcium imaging to simultaneously control and image the activity of excitatory pyramidal cells and the major classes of inhibitory GABAergic interneurons. This cross-species approach will allow us to test the hypothesis that learning has opposite effects on levels of inhibition in the visual cortex for visual detection and discrimination tasks (learning-related decreases versus increases in cortical inhibition). We anticipate that the project will have important implications for translational research and applications, for example to help understand learning deficits in neurodevelopmental disorders.