RIKEN BSI News No. 38 (Jan. 2008)

Language: English ยป Japanese

Special Feature

Soichi Nagao

Mechanism of Motor Memory in the Brain

Dr. Soichi Nagao, Head,
Laboratory for Motor Leaning Control,
Neuronal Circuit Mechanisms Research Group


Introduction

Most of our movements depend on the skillful utilization of what our brains have learned and memorized over the course of our lives. The indispensable role played by the cerebellum was first identified more than ninety years ago by lesion effects on experimental animals and clinical studies on patients with cerebellar disorders. Around 1970, Drs. Marr, Ito (Special Advisor, RIKEN BSI) and Albus independently proposed that "optimal motion is learned within the cerebellar circuitry utilizing error signals that is produced during actual motion and mediated to the cerebellar cortex". Furthermore, Ito et al. (1982) discovered that the synapses on the cerebellar Purkinje cells have a plasticity that is called "long-term depression (LTD). For more than thirty years, this Marr-Ito-Albus hypothesis has been thoroughly examined and challenged. Representative controversial view against it is that the cerebellum contains the information required for motor learning but the learning itself occurs at its output destinations such as the cerebellar and vestibular nuclei (Miles and Lisberger, 1981). Our laboratory has investigated the implications of this issue over many years and now proposes that motor memory shifts transsynaptically.


Inter-Synaptic Shifting of Trace of Motor Learning

Our findings resulted from studies performed jointly with Dr. Shutoh (currently of the School of Comprehensive Human Sciences, Graduate Univ. of Tsukuba) in which we developed a learning paradigm of long-term adaptation of the horizontal optokinetic response (HOKR) of mice. When we watch the scenery from the window of a train, our eyeballs move with the moving landscape keeping the image sharp, not blurry. This action is called HOKR. We can simulate this behavior in the laboratory, by moving checkered-patterned screen in front of a mouse in a sine-wave direction. The HOKR effect shifts the eyes of the mouse in the same sine-wave form. If the screen is moved too rapidly, the eyes of the mouse cannot follow its movement because the efficiency of HOKR (the HOKR gain) is low at the beginning. However, the HOKR gain will improve with training and then the mouse's eyes will be able to follow the screen movement. When we returned the mouse to a dark cage after its initial training and tested the HOKR again on the next day, all gain increase disappeared. However, when we repeated the 1-hour training every day for a week, HOKR gain increase lasted for several weeks. This is a long-term learning effect. In addition, we also found that the learning effect obtained by the training of a day is extinguished immediately when the cerebellum is anesthetized, but long-term training is not affected at all. Hence, short-term motor memory after a day of training is retained in the cerebellum, but long-term memory is stored elsewhere. We also confirmed electrophysiologically that memory trace obtained from motor learning is actually present at the output destinations of the cerebellum after one week of learning. Based on our results, we concluded that the cerebellum initially obtains motor memory but this memory then shifts to the vestibular nuclei trans-synaptically as learning progresses and remains there. These findings extend the original Marr-Ito-Albus theory, and add the cerebellar cortical-nuclear circuitry as the storage mechanism of motor memory. The transfer of the memory trace probably was the source of controversy. In addition, in a joint study with Dr. Itohara, Head of the Laboratory for Behavioral Genetics, we found that LTD plays an important role in the transfer of memory to the vestibular nuclei.


Future Topics

With very simple behavioral experiments using mice, we were able to put an end to almost four decades of controversy about function of the cerebellum, and propose that memory acquired in the cerebellum shifts transsynaptically for long-term retention-thus challenging conventional wisdom in brain science. We have also confirmed that the transfer of the trace of motor learning occurs in the primates. At present, our laboratory is looking for the mechanism for the memory trace transfer in motor learning morphologically, genetically, and electrophysiologically. A transfer of the memory trace in the neural circuit has already been suggested for the declarative memory system in which the hippocampus plays the main role, but the essential processes are not yet known. The transfer of the memory trace seems important for memory retention, and finding the mechanism that enables that process will yield some important clues that will help solve the mystery of memory.


Shutoh F, Ohki M, Kitazawa S, Itohara S, Nagao S.: Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation. Neuroscience 139, 767-777 (2006).


Fig. 1: Mouse Horizontal Optokinetic Response (HOKR) Measuring System:
A cold mirror is placed in front of a mouse and the eye is irradiated with IR laser. A TV camera system monitors eye movement by tracking the position of the pupil center. When the check-pattern screen placed around the mouse is moved in a sine wave direction, HOKR was induced causing the eye of the mouse to move in the sine-wave shape. The HOKR gain can be quantified by comparing the eye movement (E) and the screen movement (S).


Fig. 2: Long-term Adaptation Paradigm of HOKR:
[A] One hour of training per day produces motor learning in the mouse HOKR and increases the HOKR gain (ratio between eye movements and screen movements). The HOKR gain is reset when the mouse is housed in a dark cage after the training but when one-hour daily training continues for one week, long-term motor learning is produced and the HOKR gain before the training of every day increases gradually. When the training is stopped and the mouse is housed under normal conditions, the HOKR gain that has increased by the long-term motor leaning is reset in about 2 weeks.
[B] The effect of cerebellum inactivation in long-term motion learning: When 1-hour training is continued for 4 days, long-term motor memory is produced, and HOKR gain increased (left graph shows the average gains for 6 mice, right shows a typical case). When we injected local anesthetic (lidocaine chloride) to both sides of the cerebellum immediately after the training of the 4th day, the increase in the HOKR gain caused by the day's training (the difference in height between the red and gray bars) was extinguished but the increase in gains caused by the trainings on the previous 3 days (the difference in height between the gray and white bars) was not affected.


Fig.3: Transfer of Motor Memory Trace from Cerebellum to Vestibular Nuclei:
The motor memory of HOKR is initially acquired by the cerebellum as short-term memory (STM). When learning is sustained for longer term, memory shifts to the vestibular nuclei (VN), which is an output destination of the cerebellum (FL), and then fixed as long-term memory (LTM) in the VN. Long-term depression (LTD) of parallel fiber (pf)-Purkinje cell synapses by climbing fiber (cf) inputs play an important role in the fixation (LTM) of motor memory as well as its acquisition (STM).
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