Characterization of the resting-state brain network topology in the 6-hydroxydopamine rat model of Parkinson’s disease

Abstract

Resting-state functional MRI (rsfMRI) is an imaging technology that has recently gained attention for its ability to detect disruptions in functional brain networks in humans, including in patients with Parkinson’s disease (PD), revealing early and widespread brain network abnormalities. This methodology is now readily applicable to experimental animals offering new possibilities for cross-species translational imaging. In this context, we herein describe the application of rsfMRI to the unilaterally-lesioned 6-hydroxydopamine (6-OHDA) rat, a robust experimental model of the dopamine depletion implicated in PD. Using graph theory to analyse the rsfMRI data, we were able to provide meaningful and translatable measures of integrity, influence and segregation of the underlying functional brain architecture. Specifically, we confirm that rats share a similar functional brain network topology as observed in humans, characterised by small-worldness and modularity. Interestingly, we observed significantly reduced functional connectivity in the 6-OHDA rats, primarily in the ipsilateral (lesioned) hemisphere as evidenced by significantly lower node degree, local efficiency and clustering coefficient in the motor, orbital and sensorimotor cortices. In contrast, we found significantly, and bilaterally, increased thalamic functional connectivity in the lesioned rats. The unilateral deficits in the cortex are consistent with the unilateral nature of this model and further support the validity of the rsfMRI technique in rodents. We thereby provide a methodological framework for the investigation of brain networks in other rodent experimental models of PD, as well as of animal models in general, for cross-comparison with human data.

Sleep-State Dependent Alterations in Brain Functional Connectivity under Urethane Anesthesia in a Rat Model of Early-Stage Parkinson’s Disease

“…In addition, a few recent studies have shown FC changes occurring in rats receiving higher 6-OHDA dose producing a complete loss of striatal DA. As expected, the high degree of dopaminergic damage induced by an MFB lesion has more prominent effects on FC, as indicated by reduced FC between the striata and increased FC between the lesioned striatum and cortical areas in both hemispheres (Monnot et al, 2017), and by increased cross-hemispheric thalamic FC and a general reduction in connectivity in the ipsilateral hemisphere and especially in cortical areas (Westphal et al, 2017). These clear differences between the partial and full lesion models are most likely attributable to the different degree of nigrostriatal dopaminergic damage.…”

Alterations of the nigrostriatal pathway in a 6-OHDA rat model of Parkinson’s disease evaluated with multimodal MRI

“…These results are in line with EEG studies in 6-OHDA rats, which have also shown increased functional coupling in basal ganglia including in STR-GP connections [ 28 , 29 ]. Westphal et al [ 30 ] showed reduced FC within cortical regions, but bilaterally increased FC in subcortical regions such as the thalamus, although these results were found in a different rat model of PD (medial forebrain-lesioned 6-OHDA rats) [ 30 ]. In addition, Debeir et al [ 31 ] used the same STR-lesioned rat model and showed loss of TH(+) fibers in the GP, which could explain MRI alterations in this structure [ 31 ].…”

Current and Emerging MR Methods and Outcome in Rodent Models of Parkinson’s Disease: A Review

“…Increased FC was found between the STR and the SM and in the TH of both hemispheres in 6-OHDA rats injected in the MFB ( Monnot et al, 2017 ; Westphal et al, 2017 ). Similarly, increased FC was found between the ipsilateral STR and the GP, the contralateral M1 and the GP, and the interhemispheric STR and the GP of 6-OHDA rats injected in the STR ( Perlbarg et al, 2018 ).…”

“…Functional connectivity changes have been explored in the nigrostriatal pathway in animal models. Decreased FC was found in the interhemispheric STR and in the ipsilateral cortices of 6-OHDA rats ( Monnot et al, 2017 ; Westphal et al, 2017 ). Those animals were injected in the MFB and anesthetized with either a mixture of isoflurane and medetomidine (former study) or with medetomidine alone (latter study) during imaging.…”