Dataset Information

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice.

ABSTRACT:

Introduction

Despite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound's long-term therapeutic effects.

Materials and methods

In the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA injection of 4 and 8 μg and lasting until 56 days post-lesion. Apomorphine-induced rotational test and rotarod test were also performed on Day 23 and 43 post-lesion, respectively. Immunohistochemistry for dopaminergic neurons stained by tyrosine hydroxylase (TH) was also performed.

Results

Our results showed that both the 4 and 8 μg 6-OHDA lesion groups exhibited forelimb use asymmetry with a preference for the ipsilateral (injection) side on Day 3 and until Day 21 post-lesion, but did not show forelimb asymmetry on Day 28 to 56 post-lesion. The 8 μg 6-OHDA lesion group still exhibited forelimb asymmetry on Day 28 and 42 post-lesion, but not on Day 56. The gait analysis showed that the contralateral front and hind step cycles increased from Day 3 to 42 post-lesion and recovered on Day 56 post-lesion. In addition, our results displayed a dose-dependent reduction in TH⁺ cells and TH⁺ fibers, as well as dose-dependent apomorphine-induced rotations. In the rotarod test, the 8 μg 6-OHDA lesion group, but not the 4 μg group, decreased the latency to fall on the rotarod on Day 43 post-lesion.

Conclusion

In summary, unilateral striatal 6-OHDA injections of 4 and 8 μg induced spontaneous motor impairment in mice, which partially recovered starting on Day 28 post-lesion. Forced motor deficits were observed in the 8 g 6-OHDA lesion group, which remained stable on Day 43 post-lesion. In addition, the rotarod test and apomorphine-induced rotational test can distinguish between lesions of different extents and are useful tools for the assessment of functional recovery in studies screening novel potential therapies.

SUBMITTER: Sun X

PROVIDER: S-EPMC9730519 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice.

Sun Xiuping X Li Xianglei X Zhang Ling L Zhang Yu Y Qi Xiaolong X Wang Siyuan S Qin Chuan C

Frontiers in behavioral neuroscience 20221124

<h4>Introduction</h4>Despite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound's long-term therapeutic effects.<h4>Materials and methods</h4>In the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA inject ...[more]

PMID: 36505729

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Project description:We hypothesized that the study of gene expression at 1, 2, 4, 6 and 16 weeks in the substantia nigra (SN) after intrastriatal 6-OHDA in the Sprague-Dawley rat (rattus norvegicus) would identify cellular responses during the degenerative process that could be axoprotective. Specifically, we hypothesized that genes expressed within the SN that followed a profile of being highly upregulated early after the lesion (during active axonal degeneration) and then progressively declined to baseline over 16 weeks as DA neurons died are indicative of potential protective responses to the striatal 6-OHDA insult. Utilizing a κ-means cluster analysis strategy, we demonstrated that one such cluster followed this hypothesized expression pattern over time, and that this cluster contained several interrelated transcripts that are classified as regeneration-associated genes (RAGs) including Atf3, Sprr1a, Ecel1, Gadd45a, Gpnmb, Sox11, Mmp19, Srgap1, Rab15,Lifr, Trib3, Tgfb1, and Sema3c. All exemplar transcripts tested from this cluster (Sprr1a, Ecel1, Gadd45a, Atf3 and Sox11) were validated by qPCR and a smaller subset (Sprr1a, Gadd45a and Sox11) were shown to be exclusively localized to SN DA neurons using a dual label approach with RNAScope in situ hybridization and immunohistochemistry. Upregulation of RAGs is typically associated with the response to axonal injury in the peripheral nerves and was not previously reported as part of the axodegenerative process for DA neurons of the SN. Interestingly, as part of this cluster, other transcripts were identified based on their expression pattern but without a RAG provenance in the literature. These "RAG-like" transcripts need further characterization to determine if they possess similar functions to or interact with known RAG transcripts. Ultimately, it is hoped that some of the newly identified axodegeneration-reactive transcripts could be exploited as axoprotective therapies in PD and other neurodegenerative diseases.

Project description:Brain lesion characteristics (timing, location, and extent) and the type of corticospinal tract (CST) wiring have been proposed as determinants of upper limb (UL) motor function in unilateral cerebral palsy (uCP), yet an investigation of the relative combined impact of these factors on both motor and sensory functions is still lacking. Here, we first investigated whether structural brain lesion characteristics could predict the underlying CST wiring and we explored the role of CST wiring and brain lesion characteristics to predict UL motor and sensory functions in uCP. Fifty-two participants with uCP (mean age (SD): 11 y and 3 m (3 y and 10 m)) underwent a single-pulse Transcranial Magnetic Stimulation session to determine CST wiring between the motor cortex and the more affected hand (n = 17 contralateral, n = 19 ipsilateral, and n = 16 bilateral) and an MRI to determine lesion timing (n = 34 periventricular (PV) lesion, n = 18 corticosubcortical (CSC) lesion), location, and extent. Lesion location and extent were evaluated with a semiquantitative scale. A standardized protocol included UL motor (grip strength, unimanual capacity, and bimanual performance) and sensory measures. A combination of lesion locations (damage to the PLIC and frontal lobe) significantly contributed to differentiate between the CST wiring groups, reclassifying the participants in their original group with 57% of accuracy. Motor and sensory functions were influenced by each of the investigated neurological factors. However, multiple regression analyses showed that motor function was predicted by the CST wiring (more preserved in individuals with contralateral CST (p < 0.01)), lesion extent, and damage to the basal ganglia and thalamus. Sensory function was predicted by the combination of a large and later lesion and an ipsilateral or bilateral CST wiring, which led to increased sensory deficits (p < 0.05). These novel insights contribute to a better understanding of the underlying pathophysiology of UL function and may be useful to delineate individualized treatment strategies.

Dataset Information

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice.

Introduction

Materials and methods

Results

Conclusion

Publications

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice.

Similar Datasets

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