Eyeblink conditioning in mutant mice

Unrestricted Eyeblink conditioning has been used extensively in rabbits to study the role of the cerebellum in motor learning and memory for many years. The well-organized anatomy of the cerebellum allows a mapping of the circuitry essential for eyeblink conditioning. The convergent inputs of parallel and climbing fibers at the Purkinje cells and mossy and climbing fiber collaterals at the interpositus nuclei provide 2 simultaneous coincidence detection pathways for conditioned stimuli (CS) and unconditioned stimuli (US). Different synaptic plasticities are found in these 2 pathways in the cerebellar cortex and deep cerebellum, establishing the cerebellum as a motor learning machine. Before diving into the fascinating world of mutant/transgenic mice, one has to make sure that the mice and rabbits share similar eyeblink circuitry in the cerebellum. It has been repeatedly shown in rabbits that lesioning of the interpositus nuclei abolishes previously acquired conditioned eyeblink responses (CRs). Similarly, bilateral lesioning of the interpositus nuclei after acquiring eyeblink conditioning also abolishes CRs in C57BL/6 mice. The results suggest that the motor memory trace is mediated at the interpositus nuclei in the deep cerebellum.; The advent of genetically engineered mice makes it possible to study the functions of different genes involving cerebellar-dependent motor learning and memory. Tissue- or cell type-specific mutants/transgenics, such as mice with pcp/L7 promoters, prove that the cerebellum is necessary for motor learning and memory. The use of CaMKIV KO and CRD-NRG-1 heterozygous mutant mice in eyeblink conditioning sheds light on how the interpositus nuclei mediates motor memory; moreover, the use of HCN1 KO, CaMKIV KO, PMCA2 KO, and CRD-NRG-1 heterozygous mutant mice provides insight into how the cerebellar cortex modulates motor learning, such as the temporal properties of CRs. Finally, the offspring from PolyI:C-injected pregnant mice offer a putative model for studying autism.