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 chan ge their firing patterns during sensory-motor learning. To study the conseq uences of nigrostriatal dopamine depletion for learning and memory of motor sequences, we used a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrid ine (MPTP), to deplete dopamine unilaterally in the striatum of macaque mon keys either before or after training them on sequential push-button motor t asks. We compared the monkeys' performance with the arms ipsilateral and co ntralateral to dopamine depletion. During training and retraining on the ta sks, we measured initial and serial movement times and reaction times for t he push button movements, electromyographic patterns of arm and orofacial m uscle activity during burton pushing and reward licking, and saccadic eye m ovements during the button push sequences. With the arm ipsilateral to the side of dopamine depletion, each monkey showed progressive shortening of mo vement times and initial and serial reaction times, and each developed cons istent strategies of hand-orofacial and hand-eye coordination in which sing le button push movements were linked efficiently to succeeding movements so that performance of the whole sequence became predictive. These patterns d id not develop for contralateral arm performance in this monkey treated wit h MPTP before training. With the arm contralateral to dopamine depletion, t he monkey showed significant quantitative deficits in all parameters measur ed except initial reaction times. Movement times and serial reaction times were longer than those for the ipsilateral arm; anticipatory saccadic eye m ovements were not well time-locked to individual button pushes made with th e contralateral hand; and push and licking movements were not smoothly coor dinated. This monkey further showed striking differences in performance whe n using the ipsilateral and contralateral arms in switch trial tests in whi ch reward was delivered unexpectedly one button early. He continued to make movements to the previously rewarded button with the ipsilateral arm but s howed no such automatic movements when he used his contralateral arm. For t he monkey treated with MPTP after training, performance on the push-button task was skilled for both arms before dopamine depletion, but the unilatera l dopamine depletion produced deficits in contralateral arm performance for all parameters measured, again excepting initial reaction times. With retr aining, however, his performance with the contralateral arm improved. We co nclude that the striatum and its nigrostriatal afferents function in the in itial learning underlying performance of sequences of movements as single m otor programs. The nigrostriatal system also operates during the retrieval of these programs once learning is accomplished, but lesions of the nigrost riatal system spare the ability to relearn the previously acquired programs .