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

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.

Cognitive flexibility impairment and reduced frontal cortex BDNF expression in the ouabain model of mania.

Central infusion of the Na+/K+-ATPase inhibitor, ouabain in rats serves as an animal model of mania because it leads to hyperactivity, as well as reproduces ion dysregulation and reduced brain-derived neurotrophic factor (BDNF) levels similar to that observed in bipolar disorder. Bipolar disorder is also associated with cognitive inflexibility and working memory deficits. It is unknown whether ouabain treatment in rats leads to similar cognitive flexibility and working memory deficits. The present study examined the effects of an intracerebral ventricular infusion of ouabain in rats on spontaneous alternation, probabilistic reversal learning and BDNF expression levels in the frontal cortex. Ouabain treatment significantly increased locomotor activity, but did not affect alternation performance in a Y-maze. Ouabain treatment selectively impaired reversal learning in a spatial discrimination task using an 80/20 probabilistic reinforcement procedure. The reversal learning deficit in ouabain-treated rats resulted from an impaired ability to maintain a new choice pattern (increased regressive errors). Ouabain treatment also decreased sensitivity to negative feedback during the initial phase of reversal learning. Expression of BDNF mRNA and protein levels was downregulated in the frontal cortex which also negatively correlated with regressive errors. These findings suggest that the ouabain model of mania may be useful in understanding the neuropathophysiology that contributes to cognitive flexibility deficits and test potential treatments to alleviate cognitive deficits in bipolar disorder.