Unilateral striatal 6-hydroxydopamine lesion in female mice induces nigrostriatal degeneration with motor, gastrointestinal and skeletal dysfunction

Parkinson's disease (PD) research has historically under-represented females, limiting understanding of the involved pathological mechanisms and its systemic consequences. Women with PD are highly susceptible to fracture risk, although it is unclear whether this is linked to dopaminergic neurodegeneration or simply a correlation. A unilateral 6-hydroxydopamine (6-OHDA) lesion was administered to the striatum of adult female C57BL/6 mice. Motor and non-motor behaviours were assessed 3 weeks post-lesion, with tissue collected at 5 weeks. Neurochemical effects were evaluated using Western blot densitometry and immunohistochemistry, while downstream skeletal outcomes were assessed using microcomputed tomography and mechanical testing. The 6-OHDA lesion resulted in significant loss of dopaminergic markers throughout the nigrostriatal pathway and produced pronounced motor impairments, including reduced coordination, locomotion, and speed. Non-motor phenotyping revealed deficits in spatial working memory, olfaction, and delayed defecation, accompanied by region-specific alterations of dopaminergic marker expression within associated brain regions. In the contralateral prefrontal cortex, there was an upregulation of dopaminergic markers; this asymmetry may indicate an intersection between nigrostriatal and mesocortical dopaminergic pathways. In addition to these central effects, significant deterioration of appendicular bone microarchitecture and reduced biomechanical strength were observed following 6-OHDA injury, indicating rapid skeletal vulnerability secondary to dopaminergic neurodegeneration and motor dysfunction. Collectively, these findings establish a reproducible female 6-OHDA model that captures several multidimensional manifestations of PD, including reduced skeletal composition. This work supports the utility of similar experimental designs for investigating disease mechanisms and evaluating interventions relevant to PD, particularly in females.