The molecular assembly of perineuronal nets by super-resolution microscopy in ageing brains.

通过超分辨率显微镜在衰老大脑中进行神经周围网络的分子组装。

• 批准号: 2879801
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2879801
• 关键词: molecular; assembly; perineuronal; nets; super

Perineuronal nets (PNNs) are specialised extracellular matrix structures that encase specific neuron populations within the central nervous system. PNN maturation coincides with critical period closure, where we observe a significant decrease in plasticity. Current research implicates PNNs in the control of synaptic plasticity via three main mechanisms: a) creating a physical barrier to guide axon termination, b) harbouring inhibitory molecules of axon sprouting, and c) limiting receptor motility at the synapse. Hence, we believe that manipulation of PNNs may provide a novel target for plasticity manipulation in neurodegenerative diseases, like Alzheimer's Disease. Enzymatic degradation of PNNs has already been shown to retrieve juvenile levels of plasticity in animal models, however we still face challenges with target specificity, delivery, and stability of these treatments. Furthermore, we must further interrogate the mechanisms of PNN molecular assembly and the relationship of PNN molecules to the synapse in situ, in order to understand how we can manipulate PNNs for therapeutic use. Through the use of super-resolution expansion microscopy, we aim to identify the spatial relationship of PNN molecules and synapses at 15 nm resolution. We will overcome the diffraction limit of conventional optical microscopy by embedding cultured primary PNN neurons in a hydrogel, that will undergo isotropic expansion, thereby allowing us to visualise PNN structures at the molecular level. In combination with further biophysical and dynamic analysis of PNNs we aim to discover the mechanisms of molecular assembly of PNNs on the surface of neurons.

神经周围网（PNNs）是一种特殊的细胞外基质结构，在中枢神经系统中包裹着特定的神经元群。PNN的成熟与关键时期的关闭相吻合，我们观察到可塑性显著下降。目前的研究表明，pnn通过三种主要机制来控制突触可塑性：a)创建物理屏障来引导轴突终止，b)庇护轴突发芽的抑制分子，以及c)限制突触受体的运动。因此，我们相信pnn的操作可能为神经退行性疾病（如阿尔茨海默病）的可塑性操作提供了一个新的靶点。在动物模型中，酶降解PNNs已经被证明可以恢复幼年期的可塑性水平，但是我们仍然面临着这些治疗的目标特异性、递送和稳定性方面的挑战。此外，我们必须进一步研究PNN分子组装的机制以及PNN分子与原位突触的关系，以了解我们如何操纵PNN用于治疗用途。通过使用超分辨率扩展显微镜，我们的目标是在15纳米分辨率下识别PNN分子和突触的空间关系。我们将通过将培养的原代PNN神经元嵌入水凝胶中来克服传统光学显微镜的衍射限制，水凝胶将进行各向同性膨胀，从而使我们能够在分子水平上可视化PNN结构。结合对pnn的进一步生物物理和动力学分析，我们的目标是发现pnn在神经元表面的分子组装机制。