Neurogenesis ablation exacerbates dopaminergic dysfunction and fine motor deficits induced by 6-OHDA in rats

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Abstract Adult neurogenesis is increasingly recognised as a potential modulator of Parkinson’s disease (PD) pathology, yet its interaction with dopaminergic degeneration remains poorly understood. Here, we investigated how ablation of adult neurogenesis influences dopaminergic vulnerability and associated motor outcomes using a combined rat model of conditional neurogenesis ablation (GFAP‑Tk) and dopaminergic lesion (6-hydroxydopamine (6-OHDA)). Both neurogenesis suppression and dopaminergic lesions reduced hippocampal and subventricular zone (SVZ) proliferation. While dopaminergic lesion decreased Ki-67-positive cell density, it did not significantly alter neuroblast prevalence. In animals with impaired neurogenesis, tyrosine hydroxylase (TH) immunoreactivity was increased in the ventral hippocampus. In contrast, in the anterior amygdaloid area, only the combined manipulation reduced TH-positive fiber density, indicating region-specific monoaminergic adaptations. Further analyses of the SVZ revealed subregion-specific reduction in proliferation, with preservation of Ki67-positive cells in the lateral SVZ, suggesting potential shifts in progenitor fate and migration following injury. Importantly, these cellular alterations were accompanied by pronounced fine motor impairments in animals subjected to both neurogenesis ablation and dopaminergic lesion. Together, these findings indicate that reduced neurogenesis exacerbates dopaminergic dysfunction and associated motor deficits, highlighting a bidirectional interaction that may influence PD progression. Targeting this interplay may offer novel therapeutic targets to preserve neural plasticity and improve functional outcomes.

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