Learning new sequential stepping patterns requires striatal plasticity during the earliest phase of acquisition

Abstract

Animals including humans execute motor behavior to reach their goals. For this purpose, they must choose correct strategies according to environmental conditions and shape many parameters of their movements, including their serial order and timing. To investigate the neurobiology underlying such skills, we used a multi-sensor equipped, motor-driven running wheel with adjustable sequences of foothold pegs on which mice ran to obtain water reward. When the peg patterns changed from a familiar pattern to a new pattern, the mice had to learn and implement new locomotor strategies in order to receive reward. We found that the accuracy of stepping and the achievement of water reward improved with the new learning after changes in the peg-pattern, and c-Fos expression levels assayed after the first post-switch session were high in both dorsolateral striatum and motor cortex, relative to post-switch plateau levels. Combined in situ hybridization and immunohistochemistry of striatal sections demonstrated that both enkephalin-positive (indirect pathway) neurons and substance P-positive (direct pathway) neurons were recruited specifically after the pattern switches, as were interneurons expressing neuronal nitric oxide synthase. When we blocked N-methyl-D-aspartate (NMDA) receptors in the dorsolateral striatum by injecting the NMDA receptor antagonist, D-2-amino-5-phosphonopentanoic acid (AP5), we found delays in early post-switch improvement in performance. These findings suggest that the dorsolateral striatum is activated on detecting shifts in environment to adapt motor behavior to the new context via NMDA-dependent plasticity, and that this plasticity may underlie forming and breaking skills and habits as well as to behavioral difficulties in clinical disorders.

Dopaminergic modulation of striatal function and Parkinson’s disease

“…Furthermore, the functional significance of NO-LTD is unclear. A recent study shows that the NO-synthesizing plateau and low threshold spike interneurons (PLTSIs) are recruited (in addition to iSPNs and dSPNs) in learning of new sequential stepping patterns (Nakamura et al 2017), suggesting that NO-LTD may be essential for certain types of striatum-dependent learning.…”

Mutations in CalDAG-GEFI Lead to Striatal Signaling Deficits and Psychomotor Symptoms in Multiple Species Including Human

“…This striking finding indicates that there is abnormal plasticity in corticostriatal or thalamostriatal circuits, or other intrinsic basal ganglia circuits impacting striatal function (Mallet et al, 2012) possibly related to the delayed sensorimotor learning that we found in the CDGI mutant mice. NMDA receptor function in the dorsolateral (sensorimotor) striatum, which is particularly enriched for CDGI expression, is essential for normal learning on the wheelrunning assay that we used (Nakamura et al, 2017). Thus, the NMDA signaling abnormalities in the striatum of CDGI mutants might directly underlie their slowed learning in this task.…”

“…The CDGI knockout mice showed no deficits in the allocentric maze task, or in assays of amygdaloid complex function ( Figure S3). We next tested the knockout mice on a sensitive peg-wheel running assay of striatal learning (Kitsukawa et al, 2011;Nakamura et al, 2017) in which the arrangement of the wheel's left and right footstep pegs could be changed to test the ability of the mice to learn different running patterns ( Figures 2B and S3). Learning was measured as reduced variance in the timing of paw-placement on the pegs.…”

“…(B) KO mice showed delayed learning in a motor sequence task. Mice were trained in a running wheel with unevenly spaced foot-rungs, and learning was measured as a reduction in the variance of paw placement on a designated rung (Nakamura et al, 2017). Intact KOs and controls learned at equivalent rates; after whisker-cutting, KOs showed delayed re-acquisition.…”

“…The whiskers of all mice were then cut off, and the mice were given 2 days in their home cage followed by re-testing for 8 days with irregularly-spaced rung pattern 1. The variance of paw-touch to the 12 th rung across training was calculated (Nakamura et al, 2017).…”