Exploring the Mechanisms of Bidirectional Plasticity From Temporal Feature Stimuli in Cerebellar Motor Learning: A Ca ²⁺ -Mediated Simulation

The cerebellum plays a vital role in motor learning. The delay eyeblink conditioning is a standard protocol for studying cerebellar function from both computational and experimental perspectives. Ca<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2+</sup>-mediated bidirectional plastic changes between parallel fibers and Purkinje cells are regarded as the most important modulation that can dominate cerebellar motor learning. However, the mechanism of such modulation is unclear and difficult to uncover with experimental methods <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vivo</i>. In this study, we propose a biologically plausible learning rule for parallel fibers-Purkinje cells (PFs-PCs) bidirectional synaptic plasticity based on the inositol 1,4,5-trisphosphate (IP<sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub>)-βCaMKII-AMPAR cascade mediated by Ca<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2+</sup>. We simulate the process of AMPA receptor phosphorylation and dephosphorylation which are influenced by the concentration of regenerative Ca<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2+</sup> and IP<sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> mediated by the coactivation of parallel fiber and climbing fiber to Purkinje cell. Using this model, Purkinje cells can not only learn the responses of single interstimulus interval (ISI), sequential double ISIs, and two sessions of different ISIs, but also show excitatory responses after short ISI afferents, consistent with our observation. In addition, the conditioned response maxima of the simulation results all appear before the expected unconditioned stimulus input, which confirms the biological experimental findings. These results suggest that PF-PC plasticity based on the IP<sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub>-Ca<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2+</sup>-AMPAR cascade may be the key to revealing unknown mechanisms of cerebellar motor learning and our model can reproduce subtle details of the motor learning process of delay eyeblink conditioning.