Objective: The aim of our study is to address the impact of a moderate nigrostriatal DA lesion induced by 6-hydroxydopamine (6-OHDA) injection into the dorsomedial striatum (DMS) on behavioral flexibility and inhibitory control skills in mice.

Background: Primary motor symptoms of Parkinson’s disease (PD) result from degeneration of nigrostriatal dopaminergic (DA) neurons. However, cognitive symptoms such as executive control and behavioural flexibility deficits often affect PD patients early in the disease. Whether altered DA signaling in the DMS contribute to such non-motor symptoms remains an open question.

Method: Mice with 6-OHDA lesion in the DMS were submitted to operant reversal learning tasks to assess behavioral flexibility performances. To further assess aspects of proactive inhibition control related to preparation and initiation of motor action, lesioned mice were tested in a cued response inhibition task in which they needed to withhold a nose-poke response during presentation of a visual cue of variable durations.

Results: DMS dopamine denervation induced behavioural flexibility deficits in the reversal learning task of a two-step sequence of actions (central followed by lateral nose-poke), but not in a simple reversal learning task (one lateral nose-poke). Lesioned mice were unable to rapidly shift their pattern of response under changing task contingencies and increased perseverative responses in the first sessions after reversal.  They also produced premature responses in the rewarded side omitting the first central response. Lesioned mice, trained in the cued response inhibition task, were unable to withhold a prepotent response during the variable response inhibition period and made more omisisons during the response period.

Conclusion: Overall, bilateral DA denervation of the dorsomedial striatum of mice impairs flexible behaviour and induces proactive inhibition deficits. Flexibility disorders observed in PD patients may thus directly result from their inability to restrain an action that is not appropriate. These findings suggest that impulsivity observed in PD patients could result from nigrostriatal DA depletion early in the disease and not only from DA replacement therapy as commonly observed. These early deficits may help to detect potential susceptibility to side-effects of pharmacological treatment of PD patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impaired-behavioral-proactive-inhibitory-control-and-flexibility-in-a-mouse-model-of-early-parkinsons-disease/