Cholecystokinin from the Entorhinal Cortex Facilitates Motor Skills Learning

內嗅皮層膽囊收縮素促進運動技能學習

Student thesis: Doctoral Thesis

View graph of relations

Author(s)

Related Research Unit(s)

Detail(s)

Awarding Institution
Supervisors/Advisors
Award date12 Jul 2021

Abstract

Cholecystokinin (CCK) from the entorhinal cortex has been determined to be an important regulator of plasticity in the neocortex. The activities of the neurons in the motor cortex were refined when mice learn novel motor skills. However, researchers have not clearly determined whether CCK participates in the refinement of the activation patterns of neurons in the motor cortex and facilitates motor skills learning.

We investigated the role of CCK in mice learning a single pellet reaching task. Knockout of CCK gene (CCK-KO) or local blockade of CCK activity by a CCK-B receptor antagonist suppressed the motor learning ability of mice by impairing the improvements in reaching and retrieval. For C57 mice, the success rate increased from 15% on day one to > 30% on day three and then plateaued until the end of the training period on day six. Accordingly, the variation in the trajectories, in terms of pairwise Hausdorff distance between trials, also decreased by 25%. For CCK-KO mice, the success rate remained at the baseline level of 15% throughout the training periods, and the variation in the trajectories was not significantly altered. For mice locally infused with a CCK-B antagonist into the motor cortex, motor learning ability was significantly suppressed. Neurons in the motor cortex showed long-term potentiation (LTP) upon high-frequency stimulation, while neurons from CCK-KO mice were defective at inducing LTP, reminding us that the motor learning deficiency of CCK-KO mice might be attributed to a lack of neuronal plasticity in the motor cortex. In vivo calcium imaging of the CCK knockout or antagonist injected mice also suggested that the reproduction and refinement of the neuronal activity pattern in the motor cortex were impaired due to the lack of CCK function. Inactivating the CCK neurons in the entorhinal cortex using chemogenetic methods significantly suppressed the motor learning ability. Additionally, the anterograde and retrograde tracking results showed that most CCK neurons projected to the superficial layer of the motor cortex, where spine generation and elimination, deemed neuronal plasticity, were observed on the apical dendrites of soma in layer 2/3 due to motor skill training. Colocalization of immunostaining signals further revealed that all CCK-positive neurons in the entorhinal cortex retrogradely labeled from the motor cortex are excitatory neurons, which merge with CamKII and are isolated from GAD67-positive neurons. An injection of CCK 4 rescued the motor learning ability of CCK-KO mice in vivo. Based on our results, CCK plays a critical role in motor skills learning by modulating the plasticity of neurons in the motor cortex, and the entorhinal cortex functions as a hub and source of CCK for motor skills learning.

    Research areas

  • Cholecystokinin, Entorhinal cortex, Motor cortex, Single pellet reaching task, Motor skills learning