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acquisition. These results suggest that the memory trace of CR is localized in the interpositus
nucleus. Infusion of a NMDA receptor antagonist or a transcription inhibitor into the
interpositus nucleus also impairs acquisition of CR, but does not affect acquired CR,
suggesting that the synaptic plasticity plays a role in acquisition of CR. Consistent with this
view, significant increase in the number of excitatory synapses in the interpositus nucleus is
observed following the eyeblink conditioning [122]. Taken together, these results suggest that
LTP at mossy fiber - interpositus nucleus plays a critical role in the memory formation for the
eyeblink CR.
Figure 4. The neural circuits involved in the regulation of eyeblink conditioning. Filled circles and
arrows show somata and axons of excitatory neurons. An open circle and a line ended with a bar
indicate a soma and axon of an inhibitory neuron (Purkinje cell, PC). Broken circles marked with
asterisks indicate synapses implicated in the memory formation. AN: auditory nuclei, CF: climbing
fiber, GC: granule cell, IO: inferior olivary nuclei, IPN: interpositus nucleus, MF: mossy fiber, MN:
motor nuclei, PC: Purkinje cell, PF: parallel fiber, PN: pontine nuclei, RN: red nucleus, TN: trigeminal
nucleus. CR: conditioned response, CS: conditioned stimulus, UR: unconditioned response, US:
unconditioned stimulus.
How is the cerebellar cortex involved in the eyeblink conditioning? Large lesion of the
cerebellar cortex does not abolish the acquired CR, but decreases the latency and amplitude of
CR in a well-trained animal. Thus, memory of CR seems not to be stored in the cerebellar
cortex. In contrast, a Purkinje cell degeneration (
pcd
) mutant mouse without the cortical
output shows significant deficits in the acquisition of CR, although CR is slowly acquired
depending on the interpositus nucleus [123,124]. Mutant mice with impaired LTD at parallel
fiber - Purkinje cell synapses such as PLCβ4 or δ2 knockout mice also show the impaired
eyeblink conditioning [58,125]. In addition, a significant decrease in the AMPA binding to
cerebellar cortical slices is observed after the eyeblink conditioning [126]. These results
suggest that LTD at parallel fiber - Purkinje cell synapse is involved in the eyeblink
conditioning. The LTD would decrease the inhibitory outputs from a Purkinje cell, which
should in turn increase excitability of neurons in the interpositus nucleus and contribute to the
CR expression [120,127]. After repetitive CS - US pairings, the firing rate of a Purkinje cell
decreases before the US onset, implying that CR is reflected in the cortical output [128].
However, in the genetically manipulated mice in which cerebellar granule cell outputs can be
blocked by administration of a drug, Purkinje cells show very low firing rates and the CR
