Local Hemodynamics Dictate Long-Term Dendritic Plasticity in Peri-Infarct Cortex

Abstract

Changes in dendritic spine turnover are a major mechanism of experience-dependent plasticity in the adult neocortex. Dendritic spine plasticity may also contribute to functional recovery after stroke, but in that setting its expression may be complicated by alterations in local tissue perfusion, especially around the infarct. Using adult Thy-1 GFP-M mice, we simultaneously recorded long-term spine dynamics in apical dendrites from layer 5 pyramidal cells and blood flow from surrounding capillaries with in vivo two-photon microscopy in peri-infarct cortex before and after unilateral middle cerebral artery occlusion. Blood flow in periinfarct cortex decreased significantly immediately after stroke and improved gradually over time, in a distance-dependent manner from the epicenter of the infarct. However, local tissue perfusion was never fully restored even after a 3 month recovery period. On average, surviving layer 5 pyramidal neurons experienced a ϳ20% decrease in spine density acutely after stroke but eventually recovered. The dynamics of this improvement were different depending on the degree of tissue perfusion acutely after arterial occlusion. Cells in ischemic areas closer to the infarct returned to normal spine density levels slowly by retaining spines, while cells in more remote regions with preserved blood flow recovered faster by adding more spines, eventually surpassing baseline spine density by 15%. Our data suggest that maintaining tissue perfusion in the area surrounding the infarct could hasten or augment synaptic plasticity and functional recovery after stroke.

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…These are mostly stable in the adult cortex [60,61], although they remodel in response to loss of afferent inputs or learning [62][63][64]. After stroke, there is initially a net loss of dendritic spines in peri-infarct cortex in the first week after stroke [52,65]. This occurs in regions with normal blood flow [65], indicating that this loss is due to neuronal network damage from loss of axonal connections and not due to partial ischemia in peri-infarct regions.…”

“…After stroke, there is initially a net loss of dendritic spines in peri-infarct cortex in the first week after stroke [52,65]. This occurs in regions with normal blood flow [65], indicating that this loss is due to neuronal network damage from loss of axonal connections and not due to partial ischemia in peri-infarct regions. After this loss of connections, peri-infarct cortex within 1 mm of the infarct in the mouse recovers synaptic connections back to baseline [65], whereas neurons in regions 1-2 mm away from the infarct gain synaptic connections compared with control [65], indicating these neurons form new connections after stroke.…”

“…It is important to note that animal models of stroke differ in their initiation of angiogenesis. The photothrombotic stroke model, which is used in many optogenetic studies of stroke neural repair, does not produce substantial angiogenesis [65,109]. However, other stroke models with reperfusion and the production of a periinfarct region of partial damage do induce angiogenesis [29,107,110].…”

Layer 4 Pyramidal Neurons Exhibit Robust Dendritic Spine PlasticityIn Vivoafter Input Deprivation

“…Intrinsic optical signal (IOS) imaging was performed to map the barrel field using contralateral stimulation of a bundle of whiskers and custom-written MATLAB routines, as described previously (Johnston et al, 2013).…”

“…Imaging was done under light isoflurane anesthesia (1-1.5%) with a custom-built two-photon microscope, using a Ti:Sapph laser (910 nm, Chameleon Ultra II, Coherent), as previously described , using ScanImage software (Pologruto et al, 2003). A preliminary imaging session at low-magnification was performed to identify potential candidates for dendritic imaging.…”