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大脑细胞周围的组织基质如何调节其活动。我们将专注于细胞外基质成分称为神经元周围网络（PNNs），以确定它们对认知行为（思维过程，注意力，记忆）和感官知觉重要的皮层区域中的局部神经元网络活动的影响。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。我们实验室最近的工作表明，PNN在局灶性损伤后正在自我修复的皮质中减少，这表明PNN的减少可能有助于大脑重新连接。然而，PNNs也保护神经元免受损伤，死后研究表明，它们在精神分裂症患者的皮层中减少。我们最近已经证明，在精神分裂症模型中，PNNs的丢失发生在大鼠的皮层中。此外，我们已经直接表明，在皮层中的PNN的digestion导致认知障碍。因此，PNN的完整性和皮层的功能之间存在明确的关系，但对PNN的变化如何影响神经元的活动知之甚少。有趣的是，皮质中的大多数PNN与对降低大脑兴奋性很重要的“抑制性”神经元相关。*** 在这里，先进的工具，使我们能够光学记录或控制与光的神经元的活动将被用来定义如何在不同的皮质区域的神经元活动与PNN的完整性在正常发育过程中，在动物消化PNN，在模型的PNN损失在发展过程中（产前感染或PNN形成的药理学抑制），或在脑损伤的模型。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。使用大脑活动的遗传编码指标，抑制性神经元的活动将与相同区域的其他类别的神经元区分开来。将记录清醒、行为（跑步、梳理、休息）动物的自发活动，以分析区域活动和分离不同神经元中的单个神经元放电模式。将使用听觉或体感刺激诱导感觉诱发的脑激活。*** 这里提出的实验将使用先进的成像工具来定义PNN在不同发育年龄或成年人受伤后的存在或不存在如何调节皮质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.