Previous research from our lab has shown that when using a rodent model of ischemic stroke (permanent middle cerebral artery occlusion), mild sensory stimulation, when delivered within two hours of ischemic onset, completely protects the cortex from impending ischemic stroke damage when assessed 24 hours post-occlusion. However, the long-term stability of this protection remains unclear. Using intrinsic signal optical imaging for assessment of cortical function, laser speckle imaging for assessment of blood flow, a battery of behavioral tests and cresyl violet for histological assessment, the present study examined whether this protection was long-lasting. When assessed 4 months post-occlusion (this length of time being equivalent to 10-15 years in humans), rats receiving sensory stimulation treatment immediately after ischemic onset exhibit normal neuronal and vascular function, and they are behaviorally and histologically equivalent to healthy controls (surgical shams). Thus, the complete neuroprotection due to cortical activation via sensory stimulation remains stable with time. These findings add support to the translational potential of this sensory stimulation-based treatment.

Despite progress in reducing ischemic stroke damage, complete protection remains elusive. Here we demonstrate that, after permanent occlusion of a major cortical artery (middle cerebral artery; MCA), single whisker stimulation can induce complete protection of the adult rat cortex, but only if administered within a critical time window. Animals that receive early treatment are histologically and behaviorally equivalent to healthy controls and have normal neuronal function. Protection of the cortex clearly requires reperfusion to the ischemic area despite permanent occlusion. Using blood flow imaging and other techniques we found evidence of reversed blood flow into MCA branches from an alternate arterial source via collateral vessels (inter-arterial connections), a potential mechanism for reperfusion. These findings suggest that the cortex is capable of extensive blood flow reorganization and more importantly that mild sensory stimulation can provide complete protection from impending stroke given early intervention. Such non-invasive, non-pharmacological intervention has clear translational potential.

Experience alters cortical networks through neural plasticity mechanisms. During a developmental critical period, the most dramatic consequence of occluding vision through one eye (monocular deprivation) is a rapid loss of excitatory synaptic inputs to parvalbumin-expressing (PV) inhibitory neurons in visual cortex. Subsequent cortical disinhibition by reduced PV cell activity allows for excitatory ocular dominance plasticity. However, the molecular mechanisms underlying critical period synaptic plasticity are unclear. Here we show that brief monocular deprivation during the critical period downregulates neuregulin-1(NRG1)/ErbB4 signaling in PV neurons, causing retraction of excitatory inputs to PV neurons. Exogenous NRG1 rapidly restores excitatory inputs onto deprived PV cells through downstream PKC-dependent activation and AMPA receptor exocytosis, thus enhancing PV neuronal inhibition to excitatory neurons. NRG1 treatment prevents the loss of deprived eye visual cortical responsiveness in vivo. Our findings reveal molecular, cellular, and circuit mechanisms of NRG1/ErbB4 in regulating the initiation of critical period visual cortical plasticity.

Experience alters cortical networks through neural plasticity mechanisms. During a developmental critical period, the most dramatic consequence of occluding vision through one eye (monocular deprivation) is a rapid loss of excitatory synaptic inputs to parvalbumin-expressing (PV) inhibitory neurons in visual cortex. Subsequent cortical disinhibition by reduced PV cell activity allows for excitatory ocular dominance plasticity. However, the molecular mechanisms underlying critical period synaptic plasticity are unclear. Here we show that brief monocular deprivation during the critical period downregulates neuregulin-1(NRG1)/ErbB4 signaling in PV neurons, causing retraction of excitatory inputs to PV neurons. Exogenous NRG1 rapidly restores excitatory inputs onto deprived PV cells through downstream PKC-dependent activation and AMPA receptor exocytosis, thus enhancing PV neuronal inhibition to excitatory neurons. NRG1 treatment prevents the loss of deprived eye visual cortical responsiveness in vivo. Our findings reveal molecular, cellular, and circuit mechanisms of NRG1/ErbB4 in regulating the initiation of critical period visual cortical plasticity.