Insights into the roles of CMK-1 and OGT-1 in interstimulus interval-dependent habituation inCaenorhabditis elegans

Abstract

Habituation is a ubiquitous form of non-associative learning observed as a decrement in responding to repeated stimulation that cannot be explained by sensory adaptation or motor fatigue. One of the defining characteristics of habituation is its sensitivity to the rate at which training stimuli are presented—animals habituate faster in response to more rapid stimulation. The molecular mechanisms underlying this interstimulus interval (ISI)-dependent characteristic of habituation remain unknown. In this article, we use behavioural neurogenetic and bioinformatic analyses in the nematode Caenorhabiditis elegans to identify the first molecules that modulate habituation in an ISI-dependent manner. We show that the Caenorhabditis elegans orthologues of Ca 2+ /calmodulin-dependent kinases CaMK1/4, CMK-1 and O-linked N-acetylglucosamine (O-GlcNAc) transferase, OGT-1, both function in primary sensory neurons to inhibit habituation at short ISIs and promote it at long ISIs. In addition, both cmk-1 and ogt-1 mutants display a rare mechanosensory hyper-responsive phenotype (i.e. larger mechanosensory responses than wild-type). Overall, our work identifies two conserved genes that function in sensory neurons to modulate habituation in an ISI-dependent manner, providing the first insights into the molecular mechanisms underlying the universally observed phenomenon that habituation has different properties when stimuli are delivered at different rates.

Habituation Is More Than Learning to Ignore: Multiple Mechanisms Serve to Facilitate Shifts in Behavioral Strategy

“…Surprisingly, epistasis analysis (see Box ) revealed that they act in parallel for habituation of response distance—the habituation impairment of double mutants was more pronounced than either single mutant . These results were demystified when we broke response distance into its two core components, response duration and response speed, and found that cmk‐1 primarily affected habituation of response speed, while ogt‐1 primarily affected response duration . These results and those described previously raise a difficult epistemological question: how many behavioral components of habituation should be measured to accurately investigate all of its underlying mechanisms?…”

“…The observation that both cmk‐1 and ogt‐1 function in the same cells of the tap‐withdrawal circuit to influence habituation of response distance in remarkably similar ways prompted us to test whether they functioned as part of a single ISI‐sensitive pathway underlying habituation. Surprisingly, epistasis analysis (see Box ) revealed that they act in parallel for habituation of response distance—the habituation impairment of double mutants was more pronounced than either single mutant . These results were demystified when we broke response distance into its two core components, response duration and response speed, and found that cmk‐1 primarily affected habituation of response speed, while ogt‐1 primarily affected response duration .…”

“…cmk‐1 functions to slow habituation at shorter 10 s ISIs (a) and promote it at longer 60 s ISI s (b). Adapted with permission …”

“…For example, what may be a long‐ISI for C. elegans may be a very short‐ISI for a relatively long‐lived mammalian species . Even within the same animal and behavioral paradigm, there is evidence that what is considered a long‐ISI will vary throughout the life span . Indeed, the ability to induce long‐term habituation and its associated changes in gene transcription may be the only definitive separation between a short‐ISI and a long‐ISI in a given short‐term habituation paradigm.…”

Acute regulation of habituation learning via posttranslational palmitoylation

“…Studies on sensory habituation in C. elegans and Aplysia, and startle habituation in zebrafish and rodents have revealed that the synapses between sensory afferents and 'command' interneurons undergo plasticity during habituation [12][13][14][15][16][17] . Furthermore, genetic screens in C. elegans and Drosophila have been instrumental in identifying genes that regulate habituation learning [18][19][20][21][22][23][24][25][26][27][28] . Thus, while a picture of habituation in invertebrates is emerging, a comprehensive view of vertebrate habituation learning is largely absent.…”