Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstraße 55, 45122, Essen, Germany.
Group of Optical Nanoscopy in Neuroscience, Max Planck Institute for Multidisciplinary Sciences, City Campus, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.
J Biomed Sci. 2023 Sep 1;30(1):76. doi: 10.1186/s12929-023-00971-x.
Stroke remains one of the leading causes of long-term disability worldwide, and the development of effective restorative therapies is hindered by an incomplete understanding of intrinsic brain recovery mechanisms. Growing evidence indicates that the brain extracellular matrix (ECM) has major implications for neuroplasticity. Here we explored how perineuronal nets (PNNs), the facet-like ECM layers surrounding fast-spiking interneurons, contribute to neurological recovery after focal cerebral ischemia in mice with and without induced stroke tolerance.
We investigated the structural remodeling of PNNs after stroke using 3D superresolution stimulated emission depletion (STED) and structured illumination (SR-SIM) microscopy. Superresolution imaging allowed for the precise reconstruction of PNN morphology using graphs, which are mathematical constructs designed for topological analysis. Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery (tMCAO). PNN-associated synapses and contacts with microglia/macrophages were quantified using high-resolution confocal microscopy.
PNNs undergo transient structural changes after stroke allowing for the dynamic reorganization of GABAergic input to motor cortical L5 interneurons. The coherent remodeling of PNNs and their perforating inhibitory synapses precedes the recovery of motor coordination after stroke and depends on the severity of the ischemic injury. Morphological alterations in PNNs correlate with the increased surface of contact between activated microglia/macrophages and PNN-coated neurons.
Our data indicate a novel mechanism of post stroke neuroplasticity involving the tripartite interaction between PNNs, synapses, and microglia/macrophages. We propose that prolonging PNN loosening during the post-acute period can extend the opening neuroplasticity window into the chronic stroke phase.
中风仍然是全球导致长期残疾的主要原因之一，而对内在大脑恢复机制的不完全了解阻碍了有效恢复治疗的发展。越来越多的证据表明，大脑细胞外基质（ECM）对神经可塑性有重大影响。在这里，我们探讨了围绕快速放电中间神经元的细胞周神经网（PNNs）如何在具有和不具有诱导的中风耐受的小鼠中风后对神经恢复做出贡献。
我们使用 3D 超分辨率受激发射损耗（STED）和结构照明显微镜研究中风后 PNNs 的结构重塑。超分辨率成像允许使用图形精确重建 PNN 形态，图形是为拓扑分析而设计的数学结构。通过短暂阻断大脑中动脉（tMCAO）来诱导中风。使用高分辨率共聚焦显微镜来量化 PNN 相关突触和与小胶质细胞/巨噬细胞的接触。
PNNs 在中风后经历短暂的结构变化，从而允许 GABA 能输入到运动皮层 L5 中间神经元的动态重组。PNNs 的连贯重塑及其穿透性抑制性突触先于中风后运动协调的恢复，并且依赖于缺血性损伤的严重程度。PNNs 的形态改变与激活的小胶质细胞/巨噬细胞与 PNN 包被神经元之间接触面积的增加相关。
我们的数据表明，涉及 PNNs、突触和小胶质细胞/巨噬细胞之间的三方相互作用的中风后神经可塑性的新机制。我们提出，在中风后急性期延长 PNN 松解可以将神经可塑性开放窗口扩展到慢性中风阶段。
