Immunohistochemical characterisation of dopaminergic and cholinergic alterations in the prefrontal cortex and hippocampus of MPTP-treated marmosets.

Abstract

Motor symptoms traditionally characterise Parkinson's disease (PD), but cognitive dysfunctions have recently emerged as significant non-motor features. While dopamine deficiency in the substantia nigra primarily causes PD, recent evidence indicates disruptions in neurochemical pathways beyond the nigrostriatal system also contribute to cognitive dysfunction. This preclinical study examines the roles of dopamine and acetylcholine (ACh) within the hippocampus and prefrontal cortex (PFC), assessing how their combined reduction manifests as neurochemical alterations in brain regions relevant to cognitive function in PD. Ten adult marmosets were used; five were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model Parkinsonian pathology, and five served as healthy controls. Immunohistochemistry (IHC) quantified critical changes using ImageJ software. Results indicated MPTP significantly reduced neuron count, fibre length and optical density (OD) in both regions. Specifically, tyrosine hydroxylase (TH)-positive neurons decreased by 66.2% in the hippocampus and 48.7% in the PFC, while choline acetyltransferase (ChAT)-positive neurons decreased by 47.6% and 39.5%, respectively. Fibre length and OD similarly decreased by more than 55% in both regions. These uniform neurochemical alterations provide insights into the multifactorial neurochemical pathology observed in brain regions associated with cognitive dysfunction in PD. Although behavioural assessments were not conducted, the observed histopathological alterations in this model correspond with established neural substrates implicated in PD-related cognitive dysfunction. These findings underscore the need for targeted therapeutic strategies that address the complex, multi-neurotransmitter basis of the neurochemical pathology associated with cognitive dysfunction in PD.