Motor sequence learning in primate: Role of the D2 receptor in movement chunking during consolidation

Abstract

Motor learning disturbances have been shown in diseases involving dopamine insufficiency such as Parkinson’s disease and schizophrenic patients under antipsychotic drug treatment. In non-human primates, motor learning deficits have also been observed following systemic administration of raclopride, a selective D2-receptor antagonist. These deficits were characterized by persistent fluctuations of performance from trial to trial, and were described as difficulties in consolidating movements following a learning period. Moreover, it has been suggested that these raclopride-induced fluctuations can result from impediments in grouping separate movements into one fluent sequence. In the present study, we explore the hypothesis that such fluctuations during movement consolidation can be prevented through the use of sumanirole – a highly selective D2 agonist – if administered before raclopride. Two monkeys were trained to execute a well known sequence of movements, which was later recalled under three pharmacological conditions: (1) no drug, (2) raclopride, and (3) sumanirole + raclopride. The same three pharmacological conditions were repeated with the two monkeys, trained this time to learn new sequences of movements. Results show that raclopride has no deleterious effect on the well known sequence, nor the sumanirole + raclopride co-administration. However, results on the new sequence to be learned revealed continuous fluctuations of performances in the raclopride condition, but not in the sumanirole + raclopride condition. These fluctuations occurred concurrently with a difficulty in merging separate movement components, known as a “chunking deficit”. D2 receptors seem therefore to be involved in the consolidation of new motor skills, and this might involve the chunking of separate movements into integrated motor sequences.

Introduction

Activities of daily living such as reaching and grasping an object, writing a letter, or playing golf, always involve sequences of movements grouped together that constitute complex actions. However, the functional and physiological processes underlying such combinations of isolated movements into smooth and coherent motor sequences remain poorly understood. The synergy and kinematic properties of the motor sequence are thought to be progressively learned through practice, until error-based readjustments become minimal [9]. The motor skill is then considered as optimally performed.

Two stages have been commonly identified in the learning process of a motor sequence: a first stage in which rapid improvement takes place within very few trials, and a second stage involving slower but progressive improvement from trial to trial, or from a testing session to another [17], [30]. Following this second stage, the motor skill is thought to be consolidated because its optimal performance remains stable, whatever the delay or the interference between each occurrence. This consolidated phase was found to be compromised following the anatomical or pharmacological disturbance of the central dopaminergic systems, in both humans and animals [2], [3], [16], [24], [27], [38]

Recently, Levesque et al. [22] described persistent fluctuations of motor performance in primates following the administration of raclopride, a selective dopamine D₂ receptor (D₂R) antagonist. Although these fluctuations were present throughout learning, they were more particularly evident during the late learning stages, for many weeks, when performances should have been stabilized. However, raclopride did not affect motor sequences that were already consolidated, that is stable before the administration of the drug. Qualitative analyses revealed that the raclopride-induced fluctuations occurred in concomitance with a specific difficulty monkeys had in grouping separate movements into integrated and fluent motor sequences [22].

Graybiel et al. [13] referred to the chunking hypothesis to explain the grouping of movements that takes place during motor sequence learning. This hypothesis, raised first by Miller [27] about episodic memory, may be summarized as the grouping of discrete items into meaningful or categorical chunks, in order to facilitate their retention. The view that such a functional mechanism is also involved in movement learning is concordant with results obtained in rats and primates showing cell activity in the striatum, involved in the re-organization of single movements into integrated sequences [2], [3], [16], [24].

Currently, there is no study showing the systematic induction and reversal of chunking disturbances during movement sequence learning. The present study aimed at further showing the Dopamine dependent mechanism in such a chunking process during motor learning. Two experiments have been conducted in primates for this purpose: one assessing the effects of a systemic injection of a D₂R antagonist, and the second assessing the effects of an injection of D₂R agonist prior to the D₂R antagonist. According to previous studies [22], fluctuations of performance and chunking disturbances are expected with raclopride, especially during the late learning stage, that is during the consolidation process. In the present study, the pre-administration of sumanirole, a selective D₂R agonist, is expected, however, to prevent such a raclopride-induced deleterious effect.