Stroke causes direct structural damage to local brain networks and indirect functional damage to distant brain regions. Neuroplasticity after stroke involves molecular changes within perilesional tissue that can be influenced by regions functionally connected to the site of injury. Spontaneous functional recovery can be enhanced by rehabilitative strategies, which provides experience-driven cell signaling in the brain that enhances plasticity. Functional neuroimaging in humans and rodents has shown that spontaneous recovery of sensorimotor function after stroke is associated with changes in resting-state functional connectivity (RS-FC) within and across brain networks. At the molecular level, GABAergic inhibitory interneurons can modulate brain plasticity in peri-infarct and remote brain regions. Among this cell-type, a decrease in parvalbumin (PV)-immunoreactivity has been associated with improved behavioral outcome. Subjecting rodents to multisensory stimulation through exposure to an enriched environment (EE) enhances brain plasticity and recovery of function after stroke. Yet, how multisensory stimulation relates to RS-FC has not been determined. In this study, we investigated the effect of EE on recovery of RS-FC and behavior in mice after stroke, and if EE-related changes in RS-FC were associated with levels of PV-expressing neurons. Photothrombotic stroke was induced in the sensorimotor cortex. Beginning 2 days after stroke, mice were housed in either standard environment (STD) or EE for 12 days. Housing in EE significantly improved lost tactile-proprioceptive function compared to mice housed in STD environment. RS-FC in the mouse was measured by optical intrinsic signal imaging 14 days after stroke or sham surgery. Stroke induced a marked reduction in RS-FC within several perilesional and remote brain regions. EE partially restored interhemispheric homotopic RS-FC between spared motor regions, particularly posterior secondary motor. Compared to mice housed in STD cages, EE exposure lead to increased RS-FC between posterior secondary motor regions and contralesional posterior parietal and retrosplenial regions. The increased regional RS-FC observed in EE mice after stroke was significantly correlated with decreased PV-immunoreactivity in the contralesional posterior motor region. In conclusion, experimental stroke and subsequent housing in EE induces dynamic changes in RS-FC in the mouse brain. Multisensory stimulation associated with EE enhances RS-FC among distinct brain regions relevant for recovery of sensorimotor function and controlled movements that may involve PV/GABA interneurons. Our results indicate that targeting neural circuitry involving spared motor regions across hemispheres by neuromodulation and multimodal sensory stimulation could improve rehabilitation after stroke.

Stroke causes life long disabilities where few therapeutic options are available. Using electrical and magnetic stimulation of the brain and physical rehabilitation, recovery of brain function can be enhanced even late after stroke. Animal models support this notion, and housing rodents in an enriched environment (EE) several days after experimental stroke stimulates lost brain function by multisensory mechanisms. We studied the dynamics of functional recovery of rats with a lesion to the fore and hind limb motor areas induced by photothrombosis (PT), and with subsequent housing in either standard (STD) or EE. In this model, skilled motor function is not significantly enhanced by enriched housing, while the speed of recovery of sensori-motor function substantially improves over the 9-week study period. In particular, this stroke lesion completely obliterates the fore and hind limb placing ability when visual and whisker guidance is prevented, a deficit that persists for up to 9 weeks of recovery, but that is markedly restored within 2 weeks by enriched housing. Enriched housing after stroke also leads to a significant loss of perineuronal net (PNN) immunoreactivity; detection of aggrecan protein backbone with AB1031 antibody was decreased by 13–22%, and labelling of a glycan moiety of aggrecan with Cat-315 antibody was reduced by 25–30% in the peri-infarct area and in the somatosensory cortex, respectively. The majority of these cells are parvalbumin/GABA inhibitory interneurons that are important in sensori-information processing. We conclude that damage to the fore and hind limb motor areas provides a model of loss of limb placing response without visual guidance, a deficit also seen in more than 50% of stroke patients. This loss is amenable to recovery induced by multiple sensory stimulation and correlates with a decrease in aggrecan-containing PNNs around inhibitory interneurons. Modulating the PNN structure after ischemic damage may provide new therapies enhancing tactile/proprioceptive function after stroke.

Following stroke, complete cellular death in the ischemic brain area may ensue, with remaining brain areas undergoing tissue remodelling to various degrees. Experience-dependent brain plasticity exerted through an enriched environment (EE) promotes remodelling after central nervous system injury, such as stroke. Post-stroke tissue reorganization is modulated by growth inhibitory molecules differentially expressed within the ischemic hemisphere, like chondroitin sulfate proteoglycans found in perineuronal nets (PNNs). PNNs in the neocortex predominantly enwrap parvalbumin-containing GABAergic (PV/GABA) neurons, important in sensori-information processing. Here, we investigate how extracellular matrix (ECM) proteases and their inhibitors may participate in the regulation of PNN integrity during stroke recovery. Rats were subjected to photothrombotic stroke in the motor cortex, and functional deficits were assessed at 7 days of recovery. Sham and stroked rats were housed in either standard or EE conditions for 5 days, and infarct volumes were calculated. PNNs were visualized by immunohistochemistry and counted in the somatosensory cortex of both hemispheres. mRNA expression levels of ECM proteases and protease inhibitors were assessed by RT-qPCR and their activity analyzed by gel zymography. PNNs and protease activity were also studied in brains from stroke patients where similar results were observed. EE starting 2 days after stroke and continuing for 5 days stimulated behavioral recovery of limb-placement ability without affecting infarct size. EE promoted a decrease of PNNs around PV/GABA neurons and a concomitant modulation of the proteolytic activity and mRNA expression of ECM proteases and protease inhibitors in the somatosensory cortex. This study provides molecular targets for novel therapies that could support rehabilitation of stroke patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-017-0461-2) contains supplementary material, which is available to authorized users.

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