Cognitive Flexibility Deficits Following 6-OHDA Lesions of the Rat Dorsomedial Striatum

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder marked by severe motor deficits and reduced striatal dopamine levels. PD patients also commonly exhibit cognitive flexibility impairments, e.g., probabilistic reversal learning deficits that limit daily living. However, less is known about how decreased striatal dopamine signaling affects cognitive flexibility. Past studies indicate that the rat dorsomedial striatum is a striatal subregion that supports cognitive flexibility. Because PD patients exhibit probabilistic reversal learning deficits, the present experiment investigated whether the neurotoxin 6-hydroxydopamine (6-OHDA) injected into the dorsomedial striatum of male Long-Evans rats affects the acquisition and/or reversal learning of a spatial discrimination using a probabilistic learning procedure (80/20). Behavioral testing was conducted in a cross maze that occurred across two consecutive days. Rats with 6-OHDA lesions were not impaired on acquisition, but were impaired in reversal learning compared to that of sham controls. In reversal learning, dorsomedial striatal dopamine depletion led to initial perseveration of the previously correct choice pattern, as well as an impairment in maintaining the new choice pattern after initially selected (regressive errors). A 6-OHDA lesion in the dorsomedial striatum also significantly increased 'lose-shift' probabilities in reversal learning suggesting that reduced dopamine signaling in this striatal area increased sensitivity to negative feedback ultimately impairing the maintenance of a new response pattern. Overall, the findings suggest that dopamine reduction in this striatal subregion can serve as a useful model to test novel treatments for ameliorating cognitive flexibility deficits in PD.

Keywords: Parkinson’s disease; basal ganglia; dopamine; perseveration; reversal learning.