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包围大脑细胞的组织基质是如何调节大脑活动的。我们将专注于细胞外基质成分，称为神经周围网络（PNNs），以确定它们对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）和感觉知觉很重要。值得注意的是，pnn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，pnn在正在自我修复的皮层中减少，这表明pnn的减少可能有助于大脑的重新连接。然而，pnn也保护神经元免受损伤，死后研究表明，精神分裂症患者的皮层中pnn减少。我们最近证明，在精神分裂症模型中，pnn的丢失发生在大鼠的皮质中。此外，我们已经直接证明了皮层中pnn的消化会导致认知障碍。因此，PNN的完整性与皮层的功能之间存在明确的关系，但对于PNN的变化如何影响神经元的活动知之甚少。有趣的是，皮层中的大多数pnn与“抑制性”神经元有关，这对降低大脑兴奋性很重要。***在这里，允许我们光学记录或用光控制神经元活动的先进工具将用于定义在正常发育期间，PNN消化的动物，发育期间PNN丢失模型（产前感染或药物抑制PNN形成）或脑损伤模型中，不同皮质区域的神经元活动如何随PNN完整性而变化。使用“双光子显微镜”的重复成像将用于获得清醒和麻醉小鼠完整大脑中神经元信号的高分辨率实时记录。利用大脑活动的遗传编码指标，抑制性神经元的活动将与同一区域的其他类型的神经元区分开来。将记录醒着、有行为（跑步、梳理毛发、休息）的动物的自发活动，以便分析不同神经元的区域活动和分离单个神经元的放电模式。听觉或体感刺激可诱发感觉诱发的大脑激活。***本文提出的实验将使用先进的成像工具来确定不同发育年龄或成年后损伤后pnn的存在或缺失如何调节皮层中抑制性和兴奋性神经元的自发和诱发活动。更好地了解pnn在调节大脑兴奋性方面的功能，将有助于深入了解它们在神经发育过程中的重要性，它们在精神疾病中的作用，以及它们对脑损伤恢复的贡献。

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. *** Here, advanced tools that allow us to optically record or control with light the activity of neurons will be used to define how neuronal activity across different cortical regions varies with PNN integrity during normal development, in animals with digested PNNs, in models of PNN loss during development (prenatal infection or pharmacological inhibition of PNN formation), or in models of brain injury. Repeated imaging using “two-photon microscopy” will be used to attain high resolution, real-time recordings of neuronal signaling in intact brains of awake and anaesthetized mice. Using genetically encoded indicators of brain activity, the activity of inhibitory neurons will be differentiated from other classes of neurons in the same areas. Spontaneous activity will be recorded in awake, behaving (running, grooming, resting) animals to permit analysis of regional activity and separation of individual neuronal firing patterns in different neurons. Sensory-evoked brain activation will be induced using auditory or somatosensory stimuli. *** The experiments proposed here will use advanced imaging tools to define how the presence or absence of PNNs at different ages of development or after injury as an adult regulates spontaneous and evoked activity in inhibitory and excitatory neurons in the cortex. A better understanding of the function of PNNs in modulating brain excitability will provide insight into their importance during neurodevelopment, their role in mental illness, and their contribution to recovery from brain injury.