The Neuronal Activation of Deep Cerebellar Nuclei Is Essential for Environmental Enrichment-Induced Post-Stroke Motor Recovery.

Chuan-Jie Wang,Jun-Fa Wu,Ming-Yue Li,Qi-Li Shi,Qun Zhang,Wen-Yuan Wang,Xin Wang,Yi Wu

doi:10.14336/ad.2018.1220

Abstract

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. We reasoned that the cerebellum may be an important player in post-stroke rehabilitation. Because the neurons in the deep cerebellar nuclei (DCN) represent virtually all of the output from the cerebellum, in this study, using environmental enrichment (EE) to promote rehabilitation, we investigated the influence of the optogenetic neuronal modulation of DCN on EE-induced rehabilitation. We found that neuronal inhibition of the DCN almost completely blocked motor recovery in EE treated mice, but the stroke mice with neuronal activation of the DCN achieved a similar recovery level as those in the EE treated group. No difference was observed in anxiety-like behavior. Moreover, Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq. This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. We further verified this using the 5-HT2A receptor antagonist, MDL100907, to inhibit the function of 5-HT2A receptor in the DCN. This treatment resulted in impaired recovery in EE treated mice, who performed at a level as poor as the stroke-only group. Thus, this work contributes to an understanding of the importance of the DCN activation in EE-induced post-stroke rehabilitation. Attempts to clarify the mechanism of 5-HT2A receptor-mediated signaling in the DCN may also lead to the creation of a pharmacological mimetic of the benefits of EE-induced rehabilitation.

Highlights

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery
As EE started from the 7th day post-stroke onwards, better performance was observed in the Photothrombotic stroke (PT)+EE group compared to the PT group on both the 14th (p=0.004) and 21st (p
We demonstrated that the ability of EE to promote post-stroke motor function was definitively dependent on the deep cerebellar nuclei (DCN) activation

Summary

Introduction

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. Chronic modulation of activity in the lateral cerebellar nucleus has been found to result in better post-stroke motor recovery in rodents [6] Taken together, these observations indicate the cerebellum may be involved in the process of poststroke recovery, and neuromodulation of the deep cerebellar nuclei (DCN), which comprise the sole output pathway of the cerebellum, appears to be a promising approach for stroke rehabilitation. As previous studies have indicated that EE leads to an improvement in motor function in both cerebellar injury and Rett syndrome [9], the involvement of the cerebellum in EE-induced post-stroke recovery is deserving of further investigation

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