A Guide to the Generation of a 6-Hydroxydopamine Mouse Model of Parkinson’s Disease for the Study of Non-Motor Symptoms

Abstract

In Parkinson’s disease (PD), a large number of symptoms affecting the peripheral and central nervous system precede, develop in parallel to, the cardinal motor symptoms of the disease. The study of these conditions, which are often refractory to and may even be exacerbated by standard dopamine replacement therapies, relies on the availability of appropriate animal models. Previous work in rodents showed that injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in discrete brain regions reproduces several non-motor comorbidities commonly associated with PD, including cognitive deficits, depression, anxiety, as well as disruption of olfactory discrimination and circadian rhythm. However, the use of 6-OHDA is frequently associated with significant post-surgical mortality. Here, we describe the generation of a mouse model of PD based on bilateral injection of 6-OHDA in the dorsal striatum. We show that the survival rates of males and females subjected to this lesion differ significantly, with a much higher mortality among males, and provide a protocol of enhanced pre- and post-operative care, which nearly eliminates animal loss. We also briefly discuss the utility of this model for the study of non-motor comorbidities of PD.

Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response

“…Contrarily to this significant effect on the SST, the FST showed similar latency to immobility between control and lesioned animals (data not shown), and a subtle decrease in the immobility time of 6-OHDA lesioned animals ( Figure 2 c). This result is not in line with previous reports using bilateral striatal lesions in mice, which showed an increase in the immobility time for 6-OHDA-lesion animals—considered as a measure of behavioral despair [ 19 , 25 ]. However, FST could also be interpreted as a measure of learned-helplessness, a depressive-like paradigm that has been shown to be affected in unilateral intrastriatal 6-OHDA lesions in rats [ 42 ].…”

“…Finally, in contrast to bilateral 6-OHDA administration, unilateral lesions avoid profound impairments in feeding, drinking and animals’ general health. In our study, the survival rate was greater than 70%, a value that could be further increased using enhanced post-operative care in future studies [ 25 ].…”

“…Post-operative mortality is generally high in 6-OHDA mice models, and animals can suffer from a variety of complications ( Table S3 ) [ 11 , 25 ]. However, this can be overcome by continuous health assessment and intensive post-operative care after lesion surgery.…”

Rat models of major neurodegenerative disorders

“…While the lesions produced resemble cell loss in humans, unilateral lesions are mostly used in experimental settings, inducing cell loss in one hemisphere only. These lesions are mostly produced in rats, as mice are more prone to weight loss and post-lesion mortality which can be circumvented by modification of the injection sites and improved post-surgical surveillance [302][303][304] .…”

Propolis induces cardiac metabolism changes in 6-hydroxydopamine animal model: A dietary intervention as a potential cardioprotective approach in Parkinson’s disease

“…Intracerebral injection of the neurotoxin 6-OHDA is widely used in PD research due to consistent results in predictable degeneration of dopaminergic neurons. The 6-OHDA model also mimics several non-motor features of disease often detected in patients, including cardiovascular manifestations ( Silva et al, 2015 ; Rodrigues et al, 2019 ; Gonçalves et al, 2020 ; Masini et al, 2021 ) thus, providing an important platform for assessing potential therapeutic interventions.…”