In VivoVoltage-Sensitive Dye Imaging in Adult Mice Reveals That Somatosensory Maps Lost to Stroke Are Replaced over Weeks by New Structural and Functional Circuits with Prolonged Modes of Activation within Both the Peri-Infarct Zone and Distant Sites

Abstract

After brain damage such as stroke, topographically organized sensory and motor cortical representations remap onto adjacent surviving tissues. It is conceivable that cortical remapping is accomplished by changes in the temporal precision of sensory processing and regional connectivity in the cortex. To understand how the adult cortex remaps and processes sensory signals during stroke recovery, we performed in vivo imaging of sensory-evoked changes in membrane potential, as well as multiphoton imaging of dendrite structure and tract tracing. In control mice, forelimb stimulation evoked a brief depolarization in forelimb cortex that quickly propagated to, and dissipated within, adjacent motor/hindlimb areas (Ͻ100 ms). One week after forelimb cortex stroke, the cortex was virtually unresponsive to tactile forelimb stimulation. After 8 weeks recovery, forelimb-evoked depolarizations reemerged with a characteristic pattern in which responses began within surviving portions of forelimb cortex (Ͻ20 ms after stimulation) and then spread horizontally into neighboring peri-infarct motor/hindlimb areas in which depolarization persisted 300 -400% longer than controls. These uncharacteristically prolonged responses were not limited to the remapped peri-infarct zone and included distant posteromedial retrosplenial cortex, millimeters from the stroke. Structurally, the remapped peri-infarct area selectively exhibited high levels of dendritic spine turnover, shared more connections with retrosplenial cortex and striatum, and lost inputs from lateral somatosensory cortical regions. Our findings demonstrate that sensory remapping during stroke recovery is accompanied by the development of prolonged sensory responses and new structural circuits in both the peri-infarct zone as well as more distant sites.

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

“…In the days to weeks after stroke, the peri-infarct cortex loses its initial response to afferent inputs and then gradually regains this response, with new locations of sensory or motor body maps [52,53]. This process of an initial loss of sensory, motor, or language representation in peri-infarct and connected areas is seen in humans and in animal models of stroke [54][55][56].…”

“…The best recovery in human stroke occurs when motor, sensory, or language function is re-mapped into peri-infarct and connected regions [54,55]. This process of remapping occurs with widespread changes in the location and temporal flow of neuronal excitability, visualized with voltage-sensitive dye responses with optical imaging [52,53]. There is an initial downscaling of peri-infarct responsiveness in neurons in the first week after stroke, and then a differential return of neuronal activation within peri-infarct cortex [57].…”

“…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.…”

“…Small-to-medium-sized strokes occur in a brain hemisphere in which there is substantial remaining tissue adjacent to the stroke site. In experimental studies in rodent and nonhuman primate with these types of strokes, neurons from robust new connections in peri-infarct cortex, such as from motor cortex to somatosensory, premotor, prefrontal, and association areas [39,52,69,96]. These mediate motor recovery [36,39].…”

“…Multipotent neural progenitors (which can give rise to glia and neurons) divide to produce more rapidly proliferating cells (termed transit amplifying cells), which then give rise to immature neurons (termed neuroblasts). In the rodent brain, neuroblasts from the SVZ migrate to the olfactory bulb [52,103]. In the human brain, this migration to the olfactory bulb may be reduced, and neuroblasts may migrate into the basal ganglia [104].…”