Lake Evelyn M R, Bazzigaluppi Paolo, Mester James, Thomason Lynsie A M, Janik Rafal, Brown Mary, McLaurin JoAnne, Carlen Peter L, Corbett Dale, Stanisz Greg J, Stefanovic Bojana
Department of Medical Biophysics, University of Toronto, ON, Canada.
Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada; Neurobiology, Toronto Western Research Institute, Toronto, ON, Canada.
Neuroimage. 2017 Feb 1;146:869-882. doi: 10.1016/j.neuroimage.2016.09.016. Epub 2016 Sep 21.
Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia and macrophages, with neuronal loss and inflammation extending beyond the peri-lesional cortex. These findings highlight the complex relationship between neurophysiological state and behaviour and provide evidence of highly dynamic functional changes in the peri-infarct zone weeks following the ischemic insult, suggesting an extended temporal window for therapeutic interventions.
在中风幸存者和中风临床前模型中均观察到局灶性脑缺血后的脑可塑性。内源性神经血管适应目前尚未完全了解，但其增强可能会改善长期功能结局。我们采用纵向磁共振成像、颅内阵列电生理学、蒙托亚阶梯测试和免疫荧光技术，除了在缺血性损伤进展的亚急性期检测前肢熟练抓握能力外，还检测脑血管、神经元和神经胶质细胞的功能。通过将内皮素-1（ET-1）直接注射到成年Sprague-Dawley大鼠的右侧感觉运动皮层，诱发局灶性缺血性中风（约100立方毫米或占全脑体积的20%），导致左前肢抓握能力持续受损。中风后7天，病灶周围皮层的静息灌注和对高碳酸血症的血管反应性分别升高了约60%和80%。与此同时，局部场电位（LFP）对周围体感刺激的正常拓扑模式被消除，自发LFP活动的平均功率相对于对侧病灶皮层衰减了约50%，表明梗死灶周围区域的初始反应减弱。中风后21天，病灶周围血流恢复，但病灶周围血管反应性仍然升高。与此同时，LFP反应幅度随着与ET-1注射部位距离的增加而增加，表明从病灶核心到周边存在功能重塑。自发神经元活动的偏侧化进一步支持了这一观点：到第21天，自发LFP活动的同侧病灶平均功率几乎是对侧病灶皮层的两倍。在观察期内，病灶周围皮层血管密度增加，同时伴有神经元丢失、星形胶质细胞活化以及小胶质细胞和巨噬细胞的募集和活化，神经元丢失和炎症超出病灶周围皮层。这些发现突出了神经生理状态与行为之间的复杂关系，并为缺血性损伤后数周梗死灶周围区域高度动态的功能变化提供了证据，提示治疗干预存在延长的时间窗。
