Genetic dissections of the cerebellar circuitry involved in classical eyeblink conditioning

Converging lines of evidence from rabbits, rats, and humans demonstrate the critical involvement of the cerebellum in classical eyeblink conditioning. The studies presented in this thesis focus on the relative contribution of the cerebellar cortex versus deep nuclei (specifically the interpositus nucleus) by using various mutant mice in eyeblink conditioning.; In experiment 1, the general experimental methods were established by conducting eyeblink conditioning in two strains of mice, the BALB/c and C57BL/6 strains. Conditioned responses, sensitization, and conditioned inhibition were compared between the two strains. The results suggest that classical eyeblink conditioning is feasible in mice.; In experiment 2, the relative importance of the cerebellar cortex versus the interpositus nucleus was examined in Purkinje cell degeneration ( pcd) mice. Eyeblink conditioning was impaired in pcd mice, nevertheless, they did acquire a subnormal level of conditioned responses. The marginal learning in pcd mice was then completely abolished with IP-lesions. Thus, both the cerebellar cortex and deep nuclei are important for normal eyeblink conditioning.; In experiment 3, eyeblink conditioning was assessed in waggler mutant mice, in which BDNF expression was selectively absent from cerebellar granule cells due to an autosomal recessive mutation. The waggler mouse was severely impaired in learning. Electrophysiology studies revealed impaired granule cell synaptic development in waggler mutants, mainly the absence of AMPA receptor mediated synaptic currents at the mossy fiber-granule cell synapse. The results suggest that the mossy fiber projections to cerebellar granule cells play important roles in acquisition of conditioned eyelid responses.; Included in the discussion part of this thesis are also the results of eyeblink studies in GFAP (glial fibrillary acidic protein) and PKC- g (protein kinase C- g subunit) gene knockout mice. The results from these studies suggest that cerebellar long-term depression is a potential candidate of neural mechanisms underlying the learning and memory of conditioned eyeblink responses.