Optical inhibition of striatal neurons promotes focal neurogenesis and neurobehavioral recovery in mice after middle cerebral artery occlusion

Abstract

Striatal neurons regulate the activity of neural progenitor cells in the subventricular zone, but the effect of striatal neuronal activity on neurogenesis after ischemic stroke is unclear. In this study, we used optogenetic tools to investigate the impact of striatal neuronal activity on the neurogenesis and functional recovery after cerebral ischemia. We transfected striatal neurons with channelrhodopsin-2 or halorhodopsin from Natronomonas so that they can be excited by 473 nm laser or inhibited by 594 nm laser, respectively. Neural inhibition but not excitation at 4-7 days after middle cerebral artery occlusion resulted in reduced atrophy volume (6.8 ± 0.7 vs 8.5 ± 1.2 mm, p < 0.05) and better performance represented by longer sustaining time on rotarod (99.3 ± 9 vs 80.1 ± 11 s, p < 0.01) and faster moving speed (7.7 ± 2 vs 5.7 ± 1.1 cm/s, p < 0.05) in open field tests. Furthermore, neural inhibition increased the number of nestin, BrdU/doublecortin and BrdU/NeuN cells ( p < 0.001) in the subventricular zone and peri-focal region, and the expression level of axon guidance factor Netrin-1 (0.39 ± 0.16 vs 0.16 ± 0.02, p < 0.05) in the peri-focal region. These data suggest that striatal neuronal activity plays an important role in regulating neurogenesis and neural-behavioral outcomes, and that inhibiting striatal neurons by optogenetics promotes the recovery after ischemic stroke in mice.

Optogenetic rewiring of thalamocortical circuits to restore function in the stroke injured brain

“…However, it should be noted that a few other groups have tested whether optogenetic stimulation can improve stroke recovery2829. Although these other studies found a beneficial effect of stimulation on recovery, there are important differences to consider.…”

Enhancing endogenous capacity to repair a stroke-damaged brain: An evolving field for stroke research

“…By contrast to the ordinary migratory pathway through the RMS, the SVZ-derived NSCs/NPCs and neuroblast can directly migrate to the peri-infarct cortex (Leker et al, 2007) and peri-infarct striatum (Arvidsson et al, 2002) along the corpus callosum (Leker et al, 2007; Li et al, 2010), astrocyte processes (Yamashita et al, 2006), and blood vessels (Thored et al, 2007; Yamashita et al, 2006). In the peri-infarct regions, the SVZ-derived NSCs/NPCs and neuroblast differentiate into neurons (Arvidsson et al, 2002; He et al, 2017; Leker et al, 2007; Thored et al, 2006; Yamashita et al, 2006). The newly formed neurons generate synaptic connections with the neighboring striatal neurons (Yamashita et al, 2006) and are functionally integrated into neural networks in the adult brain after stroke (Hou et al, 2008).…”

Optical Imaging of the Motor Cortex Following Antidromic Activation of the Corticospinal Tract after Spinal Cord Injury

“…Previous studies have shown that pluripotent endogenous neural stem cells that proliferate by damage stimulation can be isolated from the rat spinal cord (Weiss et al, 1996; Okano et al, 2007). Nestin, which is expressed during neuronal differentiation, was found to peak in ependymal cells at an adjacent injury site at 1 W SCI and to significantly decrease at 4 W post-SCI (Shibuya et al, 2002; He et al, 2017). Neuronal regeneration was visualized by labeling with NF-200 and BrdU.…”

“…The delayed activating optical signals might be resulted from reduced populations of surviving neurons and increased demyelination after SCI (Alonso-Calvino et al, 2016; Chen et al, 2016). However, improved activating optical signals 4 weeks after SCI may have reflected spontaneous recovery, such as newly formed neuronal reorganization and neuroplasticity of the remaining neuronal synapses in the adjacent injury site (Murray et al, 2011; He et al, 2017). These results were consistent with the behavior test results.…”