The data presented here suggest that there is a substantial functional reorganization of the dorsal striatum during the acquisition and automatization of a motor skill. Long-term synaptic plasticity in the striatum has been observed with a variety of protocols in brain slices and in anesthetized animals20,21,30
. To the best of our knowledge, the data reported here, both in vivo
, in awake behaving mice, and ex vivo
, in striata taken from trained mice, constitute the first evidence of region-specific and pathway-specific long-lasting synaptic plasticity in the striatum during the acquisition and consolidation of a skill. Taken together with previous studies showing that mice that lack LTP specifically in the striatum are impaired in skill learning31
and that LTP can be induced in the striatum in vivo
by intracranial self-stimulation30
, our studies indicate that long-lasting potentiation of glutamatergic transmission in the striatum is necessary for skill learning.
A notable observation is the pronounced difference between the direction of changes observed in dorsolateral (sensorimotor) striatum and dorsomedial (associative) striatum during the different phases of skill learning. This pattern is consistent with previous work in both rats and monkeys suggesting distinct functional roles for these regions on the basis of the origin of their main cortical afferents, that is, sensorimotor versus association cortices2,3,17,18
. In the associative striatum (DMS), potentiation of synaptic strength is only observed early in training, with extended training resulting in a return of synaptic strength back to naive levels. In contrast, no substantial potentiation of synaptic strength occurs during the early learning phase in the sensorimotor striatum (DLS), but long-lasting potentiation of glutamatergic transmission develops with extended training. How this long-lasting potentiation in DLS relates to skill automatization is still not clear, especially given that it was observed in a substantial proportion of the neurons; one possibility is that it could subserve the generation of central pattern generator–type ensembles in sensorimotor cortico-thalamo-striatal circuits32
. Furthermore, it remains to be determined whether this long-lasting potentiation observed in DLS is accompanied by structural plasticity (for example, by an increase in the number of spines and synapses).
A straightforward explanation for these observations is that early on in acquisition, during the fast phase of skill learning, the inputs from associative cortices into dorsomedial striatum are preferentially strengthened, whereas the inputs into sensorimotor striatum are gradually potentiated with extended training, as shown by an increase in synaptic strength, excitability, NMDA currents and firing rate modulation during running on the rotarod. These results are consistent with recent in vivo
work showing that the coordination between cortical areas and striatal regions has a mediolateral gradient33
. These findings provide a possible mechanism to explain previous results showing that these different striatal regions are involved in controlling goal-directed actions and automatic habitual responses, respectively, and that, with extended training, the control over behavior by the goal-directed system is replaced by the habit system2,3,17,18,34–36
. Our lesion results suggest a model in which fast and slow skill learning develop in parallel in DMS and DLS, respectively, and not serially. DMS lesions seem to affect performance only early in training, but have no effect later on. However, DLS lesions affect behavior early in training and continue to affect it later on. This interpretation of our skill learning results is consistent with previous studies in operant conditioning showing that lesions of the DMS accelerate acquisition of an interval schedule of reinforcement, whereas lesions of the DLS impair it18
, and that inactivation of the DLS in habitual animals renders the behavior goal-directed again37
Although these differences in medial and lateral plasticity in the dorsal striatum in vivo
can be explained in part by differences in anatomical connectivity, the distribution of key receptors and differences in dopaminergic release and uptake may also be involved. For example, the CB1 endocannabinoid receptor, which is critical for habit formation, is more abundantly expressed in the dorsolateral striatum38
. The role of dopamine during the different phases of skill learning is also complex, not only because its mechanisms of release and reuptake show substantial regional variation39,40
, but also because it has different physiological effects on two populations of projection neurons in the striatum: D1 receptor–expressing and D2 receptor–expressing neurons26
. We found that D2-expressing striatopallidal medium spiny neurons in the dorsolateral striatum showed a preferential increase in synaptic strength in comparison with striatonigral neurons after extensive training. This is, to the best of our knowledge, the first report showing an increase in synaptic strength in striatopallidal neurons as a result of learning and is consistent with recent results that reported LTP in this class of neurons26,41
. These studies showed that the activation of A2A adenosine receptors, which are colocalized with D2 receptors, is critical for LTP in the striatopallidal pathway, whereas the activation of D1 receptors is critical for LTP in the striatonigral pathway26,41
. In addition, a notable finding from our study is the increased NMDA and AMPA currents following extended training. A recent study has shown the importance of A2A receptors in the LTP of the NMDA component of glutamatergic transmission42
; such a mechanism may well be critical for the training-induced potentiation that we observed in the DLS.
We observed that performance on the rotarod became independent of D1 receptor activation with extensive training (expressed mainly in striatonigral neurons) but still required D2 receptor activation. These findings are consistent with previous studies using a Pavlovian approach task in rats43
. We found it interesting that D1 and D2 receptors seem to be differentially expressed in the medial and lateral regions of the dorsal striatum, with D2 receptor being more prominent laterally28,29
(). In addition, D1 receptors have lower affinity for dopamine binding than D2 receptors, suggesting that D1 receptor activation requires a phasic increase in dopamine release, whereas D2 receptor activation can be achieved with tonic dopamine release44
. This suggests that during early acquisition of a new skill, when dopaminergic neurons show a phasic increase in activity in response to novel elements of the task45
, D1 receptors could be activated. With extensive training and the development of automaticity, however, phasic increases in dopaminergic activity can become less frequent45
and, consequently, the dopamine that is released would mainly activate D2 receptors. Also, given the recent data indicating that D2-expressing striatopallidal neurons have more and stronger inhibitory projections to D1-expressing striatonigral neurons than the converse46
, potentiation of glutamatergic transmission onto striatopallidal neurons could result in increased inhibition of striatonigral neurons and serve as a substrate for the competition between these different pathways in behavioral control.
Our findings may have implications for our understanding of the symptoms of Parkinson's disease. It is well-known that individuals with Parkinson's disease can perform automatized movements, but have difficulty initiating voluntary movements47,48
. The progressive loss of dopamine in Parkinson's disease may first affect D1 receptor activation (lower affinity) and affect D2 receptor activation later on. Thus, our observation that D2-expressing striatopallidal neurons are potentiated after extensive training and that automatized movements can become independent of D1 receptor activation may provide a mechanistic explanation for the relative preservation of more automatic movements in Parkinson's’ disease (see Supplementary Videos 1
In summary, we report evidence for extensive functional reorganization in the striatum during the acquisition and consolidation of a skill via region-specific and pathway-specific changes in synaptic strength. We observed that the neuronal activity in the dorsomedial and dorsolateral striata of awake behaving mice changed across the different phases of learning. These changes were accompanied by dynamic patterns of synaptic plasticity in the associative striatum (DMS) and the sensorimotor striatum (DLS) during the different phases of learning. Although synaptic strength in the DMS was greater early in training, extensive training induced long-lasting potentiation at excitatory synapses onto medium spiny neurons in the sensorimotor striatum (DLS). This potentiation in the DLS after extended training occurred predominantly in D2 receptor–expressing striatopalidal neurons at the same time that the performance of the skill became less dependent on the activation of D1 receptors, which are mainly expressed in striatonigral neurons. Together, these data provide a first glimpse into the dynamic reorganization in neural circuits as a skill is learned and automatized. These findings could shed light on why voluntary movements are more affected than automatized movements in individuals with Parkinson's disease.