Histological Correlates of Neuroanatomical Changes in a Rat Model of Levodopa-Induced Dyskinesia Based on Voxel-Based Morphometry.

Xiaoqian Zhang,Xuebing Cao,Yu Xu,Xiaomei Yang,Yan Xu,Yi Wu,Weiqi Zeng,Yuhao Yuan,Jialing Wang,Xiaoman Yang,Chi Cheng,Hao Lei,Wei Chen

doi:10.3389/fnagi.2021.759934

Abstract

Long-term therapy with levodopa (L-DOPA) in patients with Parkinson’s disease (PD) often triggers motor complications termed as L-DOPA-induced dyskinesia (LID). However, few studies have explored the pathogenesis of LID from the perspective of neuroanatomy. This study aimed to investigate macroscopic structural changes in a rat model of LID and the underlying histological mechanisms. First, we established the hemiparkinsonism rat model through stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, followed by administration of saline (PD) or L-DOPA to induce LID. Magnetic resonance imaging (MRI) and behavioral evaluations were performed at different time points. Histological analysis was conducted to assess the correlations between MRI signal changes and cellular contributors. Voxel-based morphometry (VBM) analysis revealed progressive bilateral volume reduction in the cortical and subcortical areas in PD rats compared with the sham rats. These changes were partially reversed by chronic L-DOPA administration; moreover, there was a significant volume increase mainly in the dorsolateral striatum, substantia nigra, and piriform cortex of the lesioned side compared with that of PD rats. At the striatal cellular level, glial fibrillary acidic protein-positive (GFAP+) astrocytes were significantly increased in the lesioned dorsolateral striatum of PD rats compared with the intact side and the sham group. Prolonged L-DOPA treatment further increased GFAP levels. Neither 6-OHDA damage nor L-DOPA treatment influenced the striatal expression of vascular endothelial growth factor (VEGF). Additionally, there was a considerable increase in synapse-associated proteins (SYP, PSD95, and SAP97) in the lesioned striatum of LID rats relative to the PD rats. Golgi-Cox staining analysis of the dendritic spine morphology revealed an increased density of dendritic spines after chronic L-DOPA treatment. Taken together, our findings suggest that striatal volume changes in LID rats involve astrocyte activation, enrichment of synaptic ultrastructure and signaling proteins in the ipsilateral striatum. Meanwhile, the data highlight the enormous potential of structural MRI, especially VBM analysis, in determining the morphological phenotype of rodent models of LID.

Highlights

Levodopa (L-DOPA)-induced dyskinesia (LID) is a common motor complication of chronic L-DOPA treatment in patients with Parkinson’s disease (PD) (Iravani and Jenner, 2011)
After acute challenging with apomorphine (0.05 mg/kg, s.c.), 27 out of 40 (67.5%) 6-OHDA-injected rats presented with >200 contralateral rotations, which was considered as the completely damaged PD model
Many attempts in functional neuroimaging and some results have been achieved (Cerasa et al, 2015; Herz et al, 2015), dyskinesia interferes with signal acquisition in experimental animals and limits the utility of functional magnetic resonance imaging (fMRI), which provides us an opportunity to address this issue from an anatomical perspective

Summary

Introduction

Levodopa (L-DOPA)-induced dyskinesia (LID) is a common motor complication of chronic L-DOPA treatment in patients with Parkinson’s disease (PD) (Iravani and Jenner, 2011). Electrophysiological and neuropathological studies have suggested that LID results from long-term adaptive brain plasticity (Belujon et al, 2010; Ohlin et al, 2011; Zheng et al, 2020), which could be attributed to neuroanatomical remodeling at the level of cells (Bortolanza et al, 2015; Mulas et al, 2016; Fletcher et al, 2020), spine and synapses (Zhang et al, 2013; Suarez et al, 2016; Fieblinger et al, 2018), or blood vessels (Lindgren et al, 2009; Ohlin et al, 2011; Booth et al, 2021) It remains unclear whether these cellular contributors cause macroscopic structural changes in the brain volume of LID. Combining well-validated animal models of LID with advanced non-invasive and accessible structural MRI methods (Duty and Jenner, 2011; Fletcher et al, 2020) could overcome this limitation and allow direct integration of different research areas, accelerate the clinical translation of basic findings, and facilitate explanation of MRI phenomena in dyskinetic patients (Finlay et al, 2014)

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