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

博士项目战略主题：理解生活规则大脑肩负着选择和执行对生存至关重要的最有意义的行为的重要任务。它通过有选择地整合相关的感官信息，同时过滤掉噪音来做到这一点。GABA是主要的抑制性神经递质，被认为在塑造主神经元的活动以促进可塑性和学习方面发挥着至关重要的作用。然而，皮质GABA能中间神经元促进经验依赖性可塑性的计算机制却知之甚少。因此，我们有兴趣了解抑制机制在两种不同类型的视觉行为任务中的作用--检测嵌入噪声的视觉特征，以及区分相似的视觉特征。首先，我们将开发行为范式，使我们能够直接研究知觉学习中涉及的神经过程。视觉知觉学习是一种学习形式，反复暴露于与任务相关的视觉刺激会导致视觉检测和辨别能力的显著改善。我们将调整视觉任务，以允许对老鼠和人类进行测试，目的是这项研究将有助于弥合动物和人类大脑可塑性和知觉学习模型之间的差距。然后，我们将通过实验改变GABA水平，并检查这对每项任务的行为表现的影响。为了提高人体内的GABA水平，参与者将接受口服剂量的巴氯芬，一种GABAB受体激动剂。在小鼠中，我们将通过光基因控制小白蛋白阳性的GABA能中间神经元的活动。最后，我们将结合动物和人类的成像方法来量化这两个物种的GABA水平。在人类身上，我们将使用磁共振波谱(MRS)来测量当受试者执行两项视觉任务时，视觉皮质和其他参与视觉决策的区域的GABA浓度是如何变化的。虽然MRS是直接研究人类视皮层抑制机制的有力工具，但它反映了种群水平的神经活动，具有相对较低的时间分辨率。因此，对小鼠的成像研究将有助于我们在单细胞水平上探索涉及的大脑皮层回路。例如，我们将使用光遗传细胞类型的特异性操作结合双光子钙成像来同时控制和成像兴奋性锥体细胞和主要类别的抑制性GABA能中间神经元的活动。这种跨物种的方法将使我们能够检验这样一个假设，即学习对视觉检测和辨别任务中视觉皮质的抑制水平有相反的影响(与学习相关的减少与皮质抑制的增加相比)。我们预计该项目将对翻译研究和应用产生重要影响，例如帮助理解神经发育障碍的学习缺陷。

PhD project strategic theme: Understanding the rules of lifeThe 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.