Complete protection from impending stroke following permanent middle cerebral artery occlusion in awake, behaving rats

Abstract

Using a rodent model of ischemic stroke (permanent middle cerebral artery occlusion; pMCAO), our laboratory has previously demonstrated that sensory-evoked cortical activation via mechanical single whisker stimulation treatment delivered under an anesthetized condition within 2 hours of ischemic onset confers complete protection from impending infarct. There is a limited time window for this protection: rats that received the identical treatment 3 hours following ischemic onset lost neuronal function and sustained a substantial infarct. Rats in these studies, however, were anesthetized with sodium pentobarbital or isoflurane, whereas most human stroke patients are typically awake. To optimize our animal model, the present study examined, using functional imaging, histological, and behavioral analysis, whether self-induced sensory-motor stimulation is also protective in unrestrained, behaving, rats that actively explore an enriched environment. Rats were revived from anesthesia either immediately or three hours after pMCAO – at which point they were allowed to freely explore an enriched environment. Rats that explored immediately after ischemic onset maintained normal cortical function and did not sustain infarct, even when their whiskers were clipped. Rats that were revived 3 hours post-pMCAO exhibited eliminated cortical function and sustained cortical infarct. Further, the data suggest that the level of individual active exploration could influence the outcome. Thus, early activation of the ischemic cortical area via unrestrained exploration results in protection from ischemic infarct, whereas late activation results in infarct, irrespective of level of arousal or whisker-specific stimulation.

Spatiotemporal dynamics of pial collateral blood flow following permanent middle cerebral artery occlusion in a rat model of sensory-based protection: a Doppler optical coherence tomography study

“…Such activation results in functional and structural protection from impending ischemic stroke, findings that were independently replicated in other labs. [5][6][7][8][9][10] Further, our findings [11][12][13][14][15][16][17][18] (reviewed in Refs. [19][20][21] have demonstrated that such stimulus-based protection is achievable in anesthetized rats, unrestrained behaving rats, and in old rats.…”

Brain encoding of saltatory velocity through a pulsed pneumotactile array in the lower face

“…During acute injury, some regions of the brain sustain immediate hypovolemic damage, while other areas can remain viable and capable of plastic reorganization due to collateral blood flow through pre-existing microcirculation anastomoses. It is this collateral microcirculation that seems to be key to minimizing acute damage and offset adverse outcomes throughout the prolonged period of recovery, and may be accessed by stimulation paradigms like those presented here (Shuaib et al, 2011;Lay et al, 2011Lay et al, , 2012Liebeskind, 2012;Lay and Frostig, 2014). Similarly, chronic sensorimotor recovery is highly dependent on both the activation of existing connections, and the development of new connections either through sensory, motor or combined stimulation (Moskowitz et al, 2010, Nudo andMcNeal, 2013).…”

Prevention of the collapse of pial collaterals by remote ischemic perconditioning during acute ischemic stroke

“…urethane or sodium pentobarbital). 1,[30][31][32] Nonetheless, our quantitative analyses of pial arteriole diameter using TPLSM were performed under urethane anesthesia to allow a comparison of vascular effects and degree of neuroprotection observed under isoflurane against a different anesthetic paradigm. While wakefulness and depth of anesthesia alter hemodynamics, the mechanisms of action for urethane spare many pathways involved in neurovascular coupling and recent studies support its use in studies of cerebral hemodynamics.…”