Exercise reverses learning deficits induced by hippocampal injury by promoting neurogenesis

Lavinia N Codd,Daniel G Blackmore,Perry F Bartlett,Jana Vukovic

doi:10.1038/s41598-020-76176-1

Lavinia N Codd, Daniel G Blackmore + Show 2 more

Open Access

https://doi.org/10.1038/s41598-020-76176-1

Copy DOI

Journal: Scientific Reports	Publication Date: Nov 6, 2020
Citations: 14	License type: open-access

Affiliation: University of Queensland

Abstract

Hippocampal atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke. To determine whether cognitive decline can be ameliorated by exercise-induced neurogenesis, C57BL/6 mice in which a unilateral hippocampal injury had been induced by injecting the vasoconstrictor endothelin-1 into their right hippocampus, were run voluntarily for 21 days on a running-wheel. We found the severe deficits in spatial learning, as detected by active place-avoidance task, following injury were almost completely restored in animals that ran whereas those that did not run showed no improvement. We show the increase in neurogenesis found in both the injured and contralateral hippocampi following running was responsible for the restoration of learning since bilateral ablation of newborn doublecortin (DCX)-positive neurons abrogated the cognitive improvement, whereas unilateral ablations of DCX-positive neurons did not prevent recovery, demonstrating that elevated neurogenesis in either the damaged or intact hippocampus is sufficient to reverse hippocampal injury-induced deficits.

Highlights

Hippocampal atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke
Prior to intrahippocampal ET-1 or PBS injection the performance of all animal groups significantly improved over the 5 days of testing as indicated by a reduction in shocks received (Fig. 1f, block APA1; F = 14.6, DFn = 4, DFd = 148, p < 0.0001; Bonferroni post hoc comparisons: ET-1 Injury p = 0.0034, Vehicle No Injury p = 0.0009, Naïve p = 0.0001) and there were no differences between the groups (F = 0.1668, DFn = 2, DFd = 37, p = 0.8470)
We investigated the impact of unilateral ablation of DCX-positive neurons on the final day of running, in either the ET-1-injected (Fig. 8b) or the contralateral vehicle-injected hippocampus (Fig. 8c). DCXDTR animals that received intrahippocampal injection of diphtheria toxin (DT) on the final day of running could not learn the shock-zone location when testing commenced 2 weeks after unilateral ET-1 hippocampal injury (APA3) and there was no significant difference in the number of shocks they received compared with wild-type ET-1 Injury + No Run mice

Summary

Introduction

Hippocampal atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke. The short survival period and motor deficits that result from the recommended and commonly used middle cerebral artery occlusion (MCAO) rodent stroke model[22,23] confound the accurate, long-term assessment of strategies to enhance recovery of hippocampal-dependent learning following ischemic injury. To address this issue, we developed a mouse model of unilateral hippocampal injury that results in a measurable learning deficit, but with prolonged survival and no motor impairment. We report that voluntary exercise after unilateral hippocampal injury leads to increased bilateral hippocampal neurogenesis and recovery in learning deficits, and that unilateral increased neurogenesis is sufficient for this recovery, regardless of whether this occurs in the injured or uninjured hippocampus

Methods

Results

Conclusion