Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity.

Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172 and accelerated in mGluR5 knock-out mice compared with wild-type mice. After stroke, multisensory stimulation by enriched environments enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in enriched environment-mediated recovery. Additionally, MTEP treatment in conjunction with enriched environment housing provided an additive recovery enhancement compared to either MTEP or enriched environment alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy.

Multisensory stimulation improves functional recovery and resting-state functional connectivity in the mouse brain after stroke.

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.

Enriched housing enhances recovery of limb placement ability and reduces aggrecan-containing perineuronal nets in the rat somatosensory cortex after experimental 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.

Post-ischemic continuous infusion of erythropoeitin enhances recovery of lost memory function after global cerebral ischemia in the rat.

BACKGROUND: Erythropoietin (EPO) and its covalently modified analogs are neuroprotective in various models of brain damage and disease. We investigated the effect on brain damage and memory performance, of a continuous 3-day intravenous infusion of EPO, starting 20 min after a transient 10 minute period of global cerebral ischemia in the rat. RESULTS: We found no effect on selective neuronal damage in the CA1 region of the hippocampus, neocortical damage and damage to the striatum assessed at 7 days after ischemia. Also, no differences were observed in sensori-motor scores between EPO treated and saline treated ischemic animals. In contrast, memory performance was significantly improved in the EPO treated group. Saline treated injured animals (n = 7) failed in a test assessing recovery of spatial memory (6/6 and 5/6), while EPO treated animals had few and none failures (0/7 and 1/7). CONCLUSION: We conclude that although post-ischemic treatment with EPO is not neuroprotective in a model of cardiac arrest brain ischemia, its markedly positive effect on brain plasticity and recovery of memory function warrants consideration as treatment of cardiac arrest patients.