Department of Integrative Medical Biology (IMB), Physiology section, Umeå University, Umeå, Sweden.
Department of Neuroscience and Brain Technologies (NBT), Italian Institute of Technology (IIT), Genova, Italy.
J Physiol. 2018 May 15;596(10):1949-1964. doi: 10.1113/JP275690. Epub 2018 Apr 17.
Recovery from the potentially devastating consequences of stroke depends largely upon plastic changes occurring in the lesion periphery and its inputs. In a focal model of stroke in mouse somatosensory cortex, we found that the recovery of sensory responsiveness occurs at the level of synaptic inputs, without gross changes of the intrinsic electrical excitability of neurons, and also that recovered responses had longer than normal latencies. Under normal conditions, one somatosensory cortex inhibits the responsiveness of the other located in the opposite hemisphere (interhemispheric inhibition) via activation of GABA receptors. In stroke-recovered animals, the powerful interhemispheric inhibition normally present in controls is lost in the lesion periphery. By contrast, contralateral hemisphere activation selective contributes to the recovery of sensory responsiveness after stroke.
Recovery after stroke is mediated by plastic changes largely occurring in the lesion periphery. However, little is known about the microcircuit changes underlying recovery, the extent to which perilesional plasticity occurs at synaptic input vs. spike output level, and the connectivity behind such synaptic plasticity. We combined intrinsic imaging with extracellular and intracellular recordings and pharmacological inactivation in a focal stroke in mouse somatosensory cortex (S1). In vivo whole-cell recordings in hindlimb S1 (hS1) showed synaptic responses also to forelimb stimulation in controls, and such responses were abolished by stroke in the neighbouring forelimb area (fS1), suggesting that, under normal conditions, they originate via horizontal connections from the neighbouring fS1. Synaptic and spike responses to forelimb stimulation in hS1 recovered to quasi-normal levels 2 weeks after stroke, without changes in intrinsic excitability and hindlimb-evoked spike responses. Recovered synaptic responses had longer latencies, suggesting a long-range origin of the recovery, prompting us to investigate the role of callosal inputs in the recovery process. Contralesional S1 silencing unmasked significantly larger responses to both limbs in controls, a phenomenon that was not observed when GABA receptors were antagonized in the recorded area. Conversely, such GABA -mediated interhemispheric inhibition was not detectable after stroke: callosal input silencing failed to change hindlimb responses, whereas it robustly reduced recovered forelimb responses. Thus, recovery of subthreshold responsiveness in the stroke periphery is accompanied by a loss of interhemispheric inhibition and this is a result of pathway-specific facilitatory action on the affected sensory response from the contralateral cortex.
从中风可能造成的破坏性后果中恢复在很大程度上取决于病灶周边和其输入部位的可塑性变化。在小鼠体感皮层的局灶性中风模型中，我们发现感觉反应的恢复发生在突触输入水平，神经元的固有电兴奋性没有明显变化，并且恢复后的反应潜伏期也比正常情况下长。在正常情况下，一个体感皮层通过激活 GABA 受体抑制位于对侧半球的另一个体感皮层的反应（半球间抑制）。在中风恢复的动物中，正常情况下存在于对照组中的强大的半球间抑制在病灶周边丧失。相比之下，对侧半球的激活选择性地有助于中风后的感觉反应恢复。
中风后的恢复是由主要发生在病灶周边的可塑性变化介导的。然而，对于恢复所涉及的微电路变化、病灶周边的可塑性在突触输入与尖峰输出水平上发生的程度以及这种突触可塑性背后的连接情况知之甚少。我们在小鼠体感皮层（S1）的局灶性中风中结合了内源性成像、细胞外和细胞内记录以及药理学失活。在活体后腿体感皮层（hS1）的全细胞膜片钳记录显示，在对照组中也可以对前腿进行刺激产生突触反应，而这种反应在前腿体感皮层（fS1）的相邻区域中风后被消除，这表明在正常情况下，它们通过来自相邻 fS1 的水平连接产生。中风后 2 周，hS1 对前腿刺激的突触和尖峰反应恢复到接近正常水平，而固有兴奋性和后腿诱发的尖峰反应没有变化。恢复后的突触反应潜伏期较长，提示恢复的起源较远，促使我们研究胼胝体输入在恢复过程中的作用。对侧体感皮层的沉默使对照组中对双腿的反应明显增大，而在记录区域中拮抗 GABA 受体时则没有观察到这种现象。相反，中风后不能检测到 GABA 介导的半球间抑制：胼胝体输入的沉默不能改变后腿的反应，而它却能强烈地减少恢复后的前腿反应。因此，中风病灶周边的亚阈值反应恢复伴随着半球间抑制的丧失，这是由于对侧皮层对受影响的感觉反应的特定通路的促进作用。
