Eric Legallet

Responses of tonically discharging neurons in the monkey striatum to primary rewards delivered during different behavioral states

Abstract In the primate striatum, the tonically discharging neurons respond to conditioned stimuli associated with reward. We investigated whether these neurons respond to the reward itself and how changes in the behavioral context in which the reward is delivered might influence their responsiveness. A total of 286 neurons in the caudate nucleus and putamen were studied in two awake macaque monkeys while liquid reward was delivered in three behavioral situations: (1) an instrumental task, in which reward was delivered upon execution of a visually triggered arm movement; (2) a classically conditioned task, in which reward was delivered 1 s after a visual signal; (3) a free reward situation, in which reward was delivered at irregular time intervals outside of any conditioning task. The monkeys′ uncertainty about the time at which reward will be delivered was assessed by monitoring their mouth movements. A larger proportion of neurons responsive to reward was observed in the free reward situation (86%) than in the classically conditioned (57%) and instrumental tasks (37%). Among the neurons tested in all situations (n = 78), 24% responded to reward regardless of the situation and 65% in only one or two situations. Responses selective for one particular situation occurred exclusively in the free reward situation. When the reward was delivered immediately after the visual signal in the classically conditioned task, most of the neurons reduced or completely lost their responses to reward, and other neurons remained responsive. Conversely, neuronal responses invariably persisted when reward was delivered later than 1 s after the visual signal. This is the first report that tonic striatal neurons might display responses directly to primary rewards. The neuronal responses were strongly influenced by the behavioral context in which the animals received the reward. An important factor appears to be the timing of reward. These neurons might therefore contribute to a general aspect of behavioral reactivity of the subject to relevant stimuli.

Tonically active neurons in the monkey striatum do not preferentially respond to appetitive stimuli.

Abstract The tonically active neurons in the monkey striatum respond to stimuli presented during the performance of appetitively motivated behavior. To test whether these neurons are selectively responsive to the appetitive properties of stimuli, we studied their responsiveness to three different stimuli presented in an unsignalled manner to monkeys not performing any behavioral tasks: (1) an appetitive liquid, eliciting licking movements; (2) an aversive air puff directed towards the face, eliciting eyelid closure and facial movements; (3) a neutral sound, eliciting no overt behavioral reactions. The great majority of the tonic striatal neurons tested in two monkeys showed pronounced responses to the delivery of liquid (338 of 388 neurons, 87%) or the onset of the air puff stimulus (168 of 204, 82%). In contrast, few neurons (15 of 68, 22%) were modulated by the sound. The majority (80%) of the neurons tested with appetitive and aversive stimuli (n=189) responded to both types of stimulus. The characteristics of neuronal responses to the liquid were generally not similar to those described for the air puff in terms of response pattern and response duration. This suggests the existence of differences in the encoding of the affective significance of stimuli. It is concluded that tonic striatal neurons might function to differentiate stimuli that are important to the animal from those that are not, regardless of the specific motivational attributes of relevant stimuli.

Reward-related neuronal activity in the subthalamic nucleus of the monkey

The subthalamic nucleus is a key structure for motor information processing in the basal ganglia. Little is known about its involvement in other aspects of behavior such as motivation. We investigated neuronal activity in the subthalamic nucleus while a monkey performed arm-reaching movements to obtain a liquid reward. Most neurons were modulated both during the movement and reward phases of the task. The changes in activity occurring after or just before the delivery of reward consisted of either increases or decreases in firing and were not directly related to mouth movements. These findings indicate that STN neurons are involved in the detection and expectation of reward, consistent with a role for these neurons in the processing of motivational information.

The Role of Striatal Tonically Active Neurons in Reward Prediction Error Signaling during Instrumental Task Performance

The detection of differences between predictions and actual outcomes is important for associative learning and for selecting actions according to their potential future reward. There are reports that tonically active neurons (TANs) in the primate striatum may carry information about errors in the prediction of rewards. However, this property seems to be expressed in classical conditioning tasks but not during performance of an instrumental task. To address this issue, we recorded the activity of TANs in the putamen of two monkeys performing an instrumental task in which probabilistic rewarding outcomes were contingent on an action in block-design experiments. Behavioral evidence suggests that animals adjusted their performance according to the level of probability for reward on each trial block. We found that the TAN response to reward was stronger as the reward probability decreased; this effect was especially prominent on the late component of the pause–rebound pattern of typical response seen in these neurons. The responsiveness to reward omission was also increased with increasing reward probability, whereas there were no detectable effects on responses to the stimulus that triggered the movement. Overall, the modulation of TAN responses by reward probability appeared relatively weak compared with that observed previously in a probabilistic classical conditioning task using the same block design. These data indicate that instrumental conditioning was less effective at demonstrating prediction error signaling in TANs. We conclude that the sensitivity of the TAN system to reward probability depends on the specific learning situation in which animals experienced the stimulus–reward associations.

Neglect of contralateral visual stimuli in monkeys with unilateral striatal dopamine depletion

Unilateral lesions of the nigrostriatal dopaminergic system were induced by injecting 6-hydroxydopamine into the substantia nigra of three monkeys trained to initiate arm movements in response to stimuli randomly presented at various locations in their immediate visual space. This procedure resulted in partial reduction of dopamine content, as compared to intact side, in both the putamen and caudate nucleus, with the exception of the putamen in one monkey. A concomitant reduction in the level of dihydroxyphenylacetic acid was observed, but less systematically than the dopamine decrease in the same striatal regions. All monkeys displayed a predominant contralateral arm hypokinesia consisting of a slowness in initiating movements, little or not affected by the hemispace of presentation of the trigger stimulus. Conversely, when the monkeys responded with the arm ipsilateral to the lesion, the movement was initiated more slowly when the trigger stimulus was presented to the hemispace contralateral to the striatal dopaminergic depletion as compared to the ipsilateral hemispace. The results suggest that the visual neglect is more conspicuous when monkeys performed with the arm ipsilateral to the damaged nigrostriatal system. This neglect may be described as a disorder in the ease with which stimuli presented to the side contralateral to the impaired dopaminergic transmission are able to elicit behavioral responses, possibly as the result of a lack of selective attention or defective movement initiation.

Responses of tonically discharging neurons in monkey striatum to visual stimuli presented under passive conditions and during task performance.

To test whether the responsiveness of tonically discharging neurons from monkey striatum is dependent on the motor or rewarding features of the conditioned stimuli, we studied the responses of these neurons to visual stimuli presented under two behavioral conditions: during an operant task in which the stimulus triggered a movement to obtain a reward, and in a non-performing state in which the stimulus was consistently followed by a reward outside of a task. Most of the neurons tested (110/158) responded to the stimuli presented in both conditions, while a relatively small number of neurons (35/158) showed selective responses in one or other of the conditions. A gradual disappearance of neuronal responses occurred in the passive state when presenting a stimulus which was never followed by reward. These results provide evidence that tonic striatal neurons may be involved in detecting stimuli predicting reward, regardless of the behavioral contingency of those stimuli.

Spatio-temporal and kinematic analysis of pointing movements performed by cerebellar patients with limb ataxia.

Abstract Three patients with cerebellar limb ataxia and three age-matched controls performed arm-pointing movements towards a visual stimulus during an experimental procedure using a double-step paradigm in a three-dimensional space. Four types of trajectories were defined: P1, single-step pointing movement towards the visual stimulus in the initial position S1; P2, double-step pointing movement towards S1; P3, double-step straight pointing movement towards the second position S2; and P4, double-step pointing movement towards S2 with an initial direction towards S1. We found that the cerebellar patients, as well as the controls, were able to modify their motor programs, but with impaired timing, severe anomalies in the direction and amplitude of the changed movement trajectories and alteration of the precision of the pointing movements.

MOTOR IMPAIRMENTS AND NEUROCHEMICAL CHANGES AFTER UNILATERAL 6-HYDROXYDOPAMINE LESION OF THE NIGROSTRIATAL DOPAMINERGIC SYSTEM IN MONKEYS

Unilateral lesions of the nigrostriatal dopaminergic system were induced in five monkeys by intranigral injections of the neurotoxin 6-hydroxydopamine. Following the lesion, all monkeys showed a transient reluctance in using the contralateral forelimb, accompanied, in two monkeys by semi-flexed posture of the disabled forelimb. Three of the monkeys that had been conditioned to perform a visually triggered goal-directed arm movement, showed an increase in latency and duration of contralateral arm movements. Task performance recovered spontaneously to preoperative levels within four months in two monkeys despite significant reductions of endogenous dopamine and dihydroxyphenylacetic acid contents in the caudate nucleus, putamen and globus pallidus ipsilateral to the neurotoxic nigral injection. The third monkey exhibited a persistent increase in movement latency associated with a near complete loss of dopamine in both the putamen and the caudate nucleus. In all cases, an increase the dihydroxyphenyl-acetic acid to dopamine ratio was detected in the striatum and pallidum suggesting a compensatory increase in dopamine turnover in remaining intact dopaminergic nerve terminals. The level of serotonin was changed in all monkeys consisting of either a decrease or an increase, depending on the striatopallidal regions studied. Changes in choline acetyltransferase and glutamic acid decarboxylase activities in the same regions were only seen in some cases. The present results show that 6-hydroxydopamine-induced partial unilateral lesion of nigral dopaminergic neurons produced predominantly contralateral hypokinesia, accompanied by reductions of dopamine content in the ipsilateral striatum and pallidum. The use of this locally applied neurotoxin appears to be a suitable method for investigating neurophysiological mechanisms underlying hypokinesia since deficits in both initiating and executing movements can be expressed independently of other behavioral symptoms. The results show more persistent deficits in starting movements than in their execution and thus suggest that motor initiation is more dependent upon the functional integrity of the nigrostriatal dopamine system than movement completion.

Motor impairment after unilateral electrolytic lesions of the substantia nigra in baboons: Behavioral data with quantitative and kinematic analysis of a pointing movement

Unilateral electrolytic lesions of the substantia nigra (SN) were carried out stereotaxically on 4 baboons which had been previously trained to perform a visually guided pointing movement. For a few days after operation, all animals exhibited a behavioral impairment affecting the contralateral body half and consisting of dystonic flexed posture and akinesia. The animals were thus unable to perform the pointing task with the contralateral hand. After a delay which depended on the extent of the SN lesion, the animals began to make the pointing movement again. Postoperative changes were then observed only on the side opposite the SN lesion. These consisted of an increase in the latency and particularly the duration of the movement without any change in the accuracy. The kinematic analysis of the hand trajectory showed that the contralateral increase in the movement duration corresponded to a regular decrease in the velocities. Study of the recovery over 120 days after SN lesion showed a progressive improvement which was faster with regard to movement duration than to movement latency. These data clearly point to the functional role of the SN in the initiation and particularly in the execution of movement. Quantitative and kinematic analysis of this pointing movement makes it possible to detect and quantify very closely the changes in movement program and execution induced by a SN lesion. This experimental model will be useful for pharmacological in vivo studies allowing a more specific assessment of the functional role of the neurotransmitters involved in SN dysfunction.

The Use of Advance Information for Motor Preparation in Parkinson's Disease: Effects of Cueing and Compatibility between Warning and Imperative Stimuli

The ability of 13 Parkinsonian patients and 11 age-matched control subjects to process and use two components of the information given prior to a voluntary movement was studied using reaction time (RT) tasks. This advance information about the direction of a pointing movement was given using a double stimulation paradigm with an auditory warning signal (WS) which occurred prior to a visual imperative signal (IS). The first component of the information was given by the WS at the beginning of each trial, and the second component was the WS-IS compatibility during series of trials. The subjects were tested with three RT paradigms: a cued simple (CS) task, a cued choice (NC) task, and a priming choice (P) task. The results show that the normal subjects used both the lateral cue and the WS-IS compatibility to shorten their RTs, whereas the Parkinsonian patients were able to use the lateral warning signal, but their ability to use the degree of compatibility stimuli was impaired. These data suggest that when dealing with lateral cues in a RT task, Parkinsonian patients have no difficulty in identifying a stimulus and selecting the appropriate response, but that this is no longer so in the case of stimulus compatibility. This impairment may be due to attentional disorders involving a dysfunction affecting the medial premotor system, which includes the basal ganglia and may be responsible for the feedforward movement control deficits associated with Parkinsons disease.