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The roles of CREB, CaMK1 and ageing in short- and long-term tap habituation in Caenorhabditis elegans Timbers, Tiffany-Anne

Abstract

Changes in synaptic connections and neural excitability are thought to mechanistically underlie learning and memory. This dissertation further extends our understanding of the processes governing learning and memory through experimental studies of short- and long-term habituation to mechanical (tap) stimuli in the nematode Caenorhabditis elegans. I investigated the role of the C. elegans CREB homologue, crh-1, in response to tap habituation. crh-1 mutants performed smaller reversals in response to tap than did wild-type worms and did not show long-term habituation; however, short-term habituation was normal. Expressing CRH-1 in a subset of interneurons of the tap withdrawal circuit rescued the long-term habituation defects observed in crh-1 mutants: demonstrating for the first time that CREB is required for long-term habituation and that the reversal interneurons are the locus of plasticity for long-term tap habituation in C. elegans. To test whether CaMK1 functioned in learning in vivo I tested if strains of C. elegans with mutations in the CaMK1 homologue, cmk-1, and its upstream activating kinase, CaMKK, (ckk-1 in C. elegans) could habituate to tap. cmk-1 but not ckk-1 mutants performed larger reversals in response to tap and did not habituate as deeply as wild-type worms. This is the first demonstration that CAMK1 is required for learning. An analysis of 46 worm strains with mutations in genes predicted by the literature and/or bioinformatics to be targets of phosphorylation by CaMK1 identified 4 strains that ranged from partial to full phenocopy of mutations in cmk-1, suggesting that they may function in the same pathway as CaMK1 in learning. I also performed a large parametric behavioural study of tap habituation over a range of intensities in ageing worms. As worms age from 72 to 120 hrs post-egg lay response probability habituation increased. These age-related changes were reflected by the worms’ decreasing capacity to show behavioural discrimination of stimulus intensity as they aged. Optogenetics experiments suggested that the age-dependent changes occur upstream of depolarization of the mechanosensory neurons. These findings increase our knowledge of the mechanisms that govern habituation and open new doors for further research in this area.

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