Limitations of the rat medial forebrain lesion model to study prefrontal cortex mediated cognitive tasks in Parkinson's disease

Abstract

Parkinson's Disease (PD) is a progressive movement disorder characterized by the loss of dopaminergic neurons in the midbrain. Besides motor impairment, PD patients exhibit non-motor symptoms that negatively impact their quality of life and often manifest prior to motor deficits. One such symptom is mild cognitive impairment (PD-MCI), which is comprised of deficits in executive function such as working memory, attention, cognitive flexibility, and spatial memory. The 6-hydroxydopamine (6-OHDA) induced unilateral medial forebrain bundle (MFB) lesion animal model successfully recapitulates PD motor impairment but is also used to assess non-motor deficits. The present study utilizes a unilateral 6-OHDA induced MFB lesion rodent model to investigate prefrontal cortex (PFC)-mediated cognitive processes that are impaired in PD patients. In a test of attentional set shifting, PD rodents demonstrated deficits in simple discrimination, but not in rule reversal or extradimensional shifts. PD rodents also exhibited deficits in a temporal order memory task but had no deficits in novel/spatial object recognition or object-in-place tasks. These results reveal limitations of the 6-OHDA induced unilateral MFB lesion model to completely recapitulate PD-MCI symptoms suggesting a need for better lesion models to study PD-MCI.