The basal ganglia are neural structures within the motor and cognitive control circuits in the mammalian forebrain and are interconnected with the neocortex by multiple loops. Dysfunction in these parallel loops caused by damage to the striatum results in major defects in voluntary movement, exemplified in Parkinson's disease and Huntington's disease. These parallel loops have a distributed modular architecture resembling local expert architectures of computational learning models. During sensorimotor learning, such distributed networks may be coordinated by widely spaced striatal interneurons that acquire response properties on the basis of experienced reward.

The basal ganglia have been implicated in motor planning and motor learning. In the study reported here, we directly tested for response plasticity in striatal neurons of macaque monkeys undergoing Pavlovian conditioning. To focus the study, we recorded from the tonically active neurons (TANs) of the striatum, which are known to respond to conditioned sensory stimuli that signal reward delivery and elicit behavioral reactions. The activities of 858 TANs were recorded extracellularly from the striatum in alert behaving macaque monkeys before, during, and after the acquisition of a classical conditioning task. Two monkeys were trained to lick reward juice delivered on a spoon simultaneously with the presentation of a click. Almost no licks were triggered by the cues at the start of training, but by the fifth day more than 90% of licks were triggered, and values were near 100% for the remainder of the 3 week training period. In the striatum, only a small number of TANs responded to the clicks at the start before conditioning (about 17%). During training, the numbers of responding TANs gradually increased, so that by the end of training more than 50-70% of the TANs recorded (51.3-73.5%) became responsive to the clicks. The responses consisted of a pause in firing that occurred approximately 90 msec after the click and that was in some cells preceded by a brief activation and in most cells was followed by a rebound excitation. Prolonged recordings from single TANs (n = 6) showed that individual TANs can acquire a conditioned response within at least as short a time as 10 min. TANs retained such responsiveness after overtraining, and also after a 4 week intermission in training. When the monkey was trained to receive rewards in relation to a new conditioning stimulus, TANs were capable of switching their sensory response to the new stimulus. Histological reconstruction showed that the TANs that became responsive were broadly distributed in the region of striatum explored, which included the dorsal half to two-thirds of the caudate nucleus and putamen over a large anteroposterior span. We conclude that, during the acquisition of a sensorimotor association, TANs widely distributed through the striatum become responsive to sensory stimuli that induce conditioned behavior. This distributed change in activity could serve to modulate the activity of surrounding projection neurons in the striatum engaged in mediating learned behavior.

Dysfunction of the nigrostriatal dopamine system results in marked disorders of movement such as occur in Parkinson's disease. Functions of this dopamine-containing projection system were examined in monkeys trained in a classical conditioning task, and the effects of striatal dopamine depletion were tested. Unilateral dopamine loss substantially reduced the acquired sensory responsiveness of striatal neurons monitored electrophysiologically. This effect was ipsilateral and selective, and could be reversed by apomorphine. These results suggest that the primate nigrostriatal system modulates expression of neuronal response plasticity in the striatum during sensorimotor learning.

1. Tonically active neurons (TANs) in the primate striatum develop transient responses to sensory conditioning stimuli during behavioral training in classical conditioning tasks. In this study we examined the temporal characteristics of such TAN responses and mapped the sites of TANs responding to auditory and visual conditioned stimuli in the striatum in macaque monkeys. We further mapped the locations of TANs recorded acutely in the squirrel monkey striatum in relation to the neurochemically distinguished striosome and matrix compartments of the striatum, and made quantitative comparisons between the densities and compartmental distributions of TANs and those of four major types of striatal interneuron identified by histochemical and immunohistochemical staining. 2. We made recordings from 858 TANs at different sites in the striatum in two behaving macaque monkeys at different times during training with auditory (click) and visual (light-emitting diode flash) conditioning stimuli. TANs distributed across large parts of the striatum developed responses to the conditioning stimuli. The responses comprised a decrement of tonic firing (pause) followed by a rebound excitation. Measurements were made of the onsets, offsets, and durations of the pauses of individual TANs and of the interspike intervals (ISIs) of the same cells. 3. The mean duration of the pause responses (268.3 ms) was greater than the mean ISI of the same neurons (181 ms), suggesting that the pause represents an active suppression of TAN firing. The coefficient of variation (CV) for the pause responses was 0.28, compared with a CV of 0.63 for the same cells' ISIs. The population CV for the pauses was 0.16, compared with a population CV of 0.20 for the ISIs. These data, together with temporal analysis of the responses and population histograms, suggest that the pauses became temporally aligned across large parts of the striatum after learning. Analyses of variance (ANOVAs) were carried out to determine whether there were differences in the onset and offset latencies of the pause response or in the durations of the pause responses for TANs at different sites. These analyses suggested that, with rare exceptions, there was no difference in the timing of the TAN responses across large (> 10 mm3) parts of the striatum. 4. Comparisons of TAN responses in different regions of the striatum showed that, for responses to a given modality of conditioned stimulus, there were no significant differences in pause offset times for TANs recorded in the caudate nucleus or putamen, or for TANs recorded in more anterior or more posterior parts of these nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)

The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease. During sensorimotor learning, the arrival of a conditioned stimulus reporting a reward evokes a pause response in the firing of the tonically active cholinergic interneurons in targeted areas of the striatum, whereas the same stimulus triggers an increase in the firing frequency of the dopaminergic neurons in the substantia nigra pars compacta. The pause response of the cholinergic interneurons begins with an initial depolarizing phase followed by a pause in spike firing and ensuing rebound excitation. The timing of the pause phase coincides well with the surge in dopaminergic firing, indicating that a dramatic rise in dopamine (DA) release occurs while nicotinic receptors remain unbound by acetylcholine. The pause response begins with dopamine D5 receptor-dependent synaptic plasticity in the cholinergic neurons and an increased GABAergic IPSP, which is followed by a long pause in firing through D2 and D5 receptor-dependent modulation of ion channels. Inactivation of muscarinic receptors on the projection neurons eventually yields endocannabinoidmediated, dopamine-dependent long-term depression in the medium spiny projection neurons. Breakdown of acetylcholine-dopamine balance hampers proper functioning of the cortico-basal ganglia-thalamocortical loop circuits. In Parkinson's disease, dopamine depletion blocks autoinhibition of acetylcholine release through muscarinic autoreceptors, leading to excessive acetylcholine release which eventually prunes spines of the indirectpathway projection neurons of the striatum and thus interrupts information transfer from motor command centers in the cerebral cortex. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S148-S157.