Extracellular matrix regulation of neuronal structure, function, and plasticity

在接下来的五年里，我的研究小组将研究围绕脑细胞的组织基质如何调节其活动。我们将重点研究称为神经周围神经网络(PNNS)的细胞外基质成分，以确定它们对大脑皮层区域局部神经元网络活动的影响，这些区域对认知行为(思维过程、注意力、记忆)和感觉知觉至关重要。值得注意的是，PNNS调节大脑在发育过程中适当连接自身的能力。我们实验室最近的研究表明，在局灶性损伤后自我修复的皮质中，PNN减少，这表明PNN的减少可能有助于大脑的重新连接。然而，PNNS也保护神经元免受损害，尸检研究表明，精神分裂症患者的大脑皮质中PNNS减少。我们最近证明，在精神分裂症模型中，大鼠的大脑皮层发生了PNNS的丢失。此外，我们已经直接证明，大脑皮质中PNNS的消化会导致认知障碍。因此，PNN的完整性和皮质功能之间存在明显的关系，但关于PNN的变化如何影响神经元的活动，人们知之甚少。有趣的是，大脑皮层中的大多数PNN与“抑制性”神经元有关，这些神经元对降低大脑的兴奋性很重要。

Over the next five years, my research group will investigate how the tissue matrix that surrounds the cells of the brain regulate its activity. We will focus on extracellular matrix components called perineuronal nets (PNNs) to determine their influence on the activity of local neuronal networks in regions of the cortex important for cognitive behaviours (thought processes, attention, memory) and sensory perception. Notably, PNNs regulate the ability of the brain to appropriately wire itself during development. Recent work from our lab suggests that PNNs are reduced in cortex that is repairing itself after a focal injury, suggesting a reduction of PNNs may help the brain rewire. However, PNNs also protect neurons from damage and postmortem studies have shown that they are reduced in the cortex of individuals with schizophrenia. We have recently demonstrated that a loss of PNNs occurs in the cortex of rats in a model of schizophrenia. Moreover, we have directly shown that digestions of PNNs in the cortex leads to cognitive impairment. As such, there is a clear relationship between PNN integrity and the function of the cortex, but little is known about how changes in PNNs affect the activity of neurons. Interestingly, the majority of PNNs in the cortex are associated with “inhibitory” neurons important for reducing brain excitability.