Electric Stimulation of Neurogenesis Improves Behavioral Recovery After Focal Ischemia in Aged Rats.

Adrian Tudor Balseanu,Dirk M Hermann,Leonard-Radu Pinosanu,Daniela Glavan,Mark Slevin,Aurel Popa-Wagner,Monica Grigore

doi:10.3389/fnins.2020.00732

Abstract

The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. Despite remarkable advances in cell therapy for stroke, stem cell-based tissue replacement has not been achieved yet stimulating the search for alternative strategies for brain self-repair using the neurogenic zones of the brain, the dentate gyrus and the subventricular zone (SVZ). However, during aging, the potential of the hippocampus and the SVZ to generate new neuronal precursors, declines. We hypothesized that electrically stimulation of endogenous neurogenesis in aged rats could increase the odds of brain self-repair and improve behavioral recuperation after focal ischemia. Following stroke in aged animals, the rats were subjected to two sessions of electrical non-convulsive stimulation using ear-clip electrodes, at 7- and 24 days after MCAO. Animal were sacrificed after 48 days. We report that electrical stimulation (ES) stimulation of post-stroke aged rats led to an improved functional recovery of spatial long-term memory (T-maze) but not on the rotating pole or the inclined plane, both tests requiring complex sensorimotor skills. Surprisingly, ES had a detrimental effect on the asymmetric sensorimotor deficit. Histologically, there was a robust increase in the number of doublecortin-positive cells in the dentate gyrus and SVZ of the infarcted hemisphere and the presence of a considerable number of neurons expressing tubulin beta III in the infarcted area. Among the gene that were unique to ES, we noted increases in the expression of seizure related 6 homolog like which is one of the physiological substrate of the β-secretase BACE1 involved in the pathophysiology of the Alzheimer’s disease and Igfbp3 and BDNF receptor mRNAs which has been shown to have a neuroprotective effect after cerebral ischemia. However, ES was associated with a long-term down regulation of cortical gene expression after stroke in aged rats suggesting that gene expression in the peri-infarcted cortical area may not be related to electrical stimulation induced-neurogenesis in the subventricular zone and hippocampus.

Highlights

The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia
In this study we report that electrical stimulation (ES) of post-stroke aged rats led to a considerable increase in the number of Tubulin beta III in the infarcted area and a robust increase in newly born DCX cells in the dentate gyrus and subventricular zone (SVZ) of the infarcted hemisphere
ES had a detrimental effect on the asymmetric sensorimotor deficit

Summary

Introduction

The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. In animal models, brain tissue replacement does not occur after focal ischemia stimulating the search for alternative strategies for brain repair and behavioral recuperation after stroke. The newly born cells were shown to be able to migrate from the SVZ to the stroke-damaged striatum, develop and differentiate into the phenotype of the neurons damaged by ischemic lesion (Arvidsson et al, 2002; Yamashita et al, 2006). For focal cortical stroke, the migration of neuronal precursors from the SVZ to the peri-infarcted area does occur to a lesser extent (Shimada et al, 2010)

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