Role of [corrected] nigrostriatal dopamine system in learning to perform sequential motor tasks in a predictive manner.

Neurons in the primate striatum and the substantia nigra pars compacta change their firing patterns during sensory-motor learning. To study the consequences of nigrostriatal dopamine depletion for learning and memory of motor sequences, we used a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to deplete dopamine unilaterally in the striatum of macaque monkeys either before or after training them on sequential push-button motor tasks. We compared the monkeys' performance with the arms ipsilateral and contralateral to dopamine depletion. During training and retraining on the tasks, we measured initial and serial movement times and reaction times for the push button movements, electromyographic patterns of arm and orofacial muscle activity during button pushing and reward licking, and saccadic eye movements during the button push sequences. With the arm ipsilateral to the side of dopamine depletion, each monkey showed progressive shortening of movement times and initial and serial reaction times, and each developed consistent strategies of hand-orofacial and hand-eye coordination in which single button push movements were linked efficiently to succeeding movements so that performance of the whole sequence became predictive. These patterns did not develop for contralateral arm performance in this monkey treated with MPTP before training. With the arm contralateral to dopamine depletion, the monkey showed significant quantitative deficits in all parameters measured except initial reaction times. Movement times and serial reaction times were longer than those for the ipsilateral arm; anticipatory saccadic eye movements were not well time-locked to individual button pushes made with the contralateral hand; and push and licking movements were not smoothly coordinated. This monkey further showed striking differences in performance when using the ipsilateral and contralateral arms in switch trial tests in which reward was delivered unexpectedly one button early. He continued to make movements to the previously rewarded button with the ipsilateral arm but showed no such automatic movements when he used his contralateral arm. For the monkey treated with MPTP after training, performance on the push-button task was skilled for both arms before dopamine depletion, but the unilateral dopamine depletion produced deficits in contralateral arm performance for all parameters measured, again excepting initial reaction times. With retraining, however, his performance with the contralateral arm improved. We conclude that the striatum and its nigrostriatal afferents function in the initial learning underlying performance of sequences of movements as single motor programs. The nigrostriatal system also operates during the retrieval of these programs once learning is accomplished, but lesions of the nigrostriatal system spare the ability to relearn the previously acquired programs.