Catharine Rankin et al. (2003) International Worm Meeting "The effects of avr-14 on short- and long-term memory."

Nicholas Dube, Stephan Steidl, Catharine Rankin

[International Worm Meeting, 2003]

avr-14 encodes an -type subunit of a glutamate-gated chloride channel (GluCls) in Caenorhabditis elegans. avr-14 is expressed on the glutamatergic mechanosensory neurons of the tap-withdrawal response that synapse onto the command interneurons of the circuit. Because avr-14 is expressed on the touch cells it was hypothesized that it might play a role in experience-dependant plasticity in the response to tap. Worms with a mutation in avr-14 were tested for short-term and long-term habituation of the tap response. The mutation selectively affects short-term habituation for shorter interstimulus intervals (ISIs; 10s and 30s) while not affecting habituation for long ISIs (45s and 60s). These results provide support for the hypothesis that in C. elegans there are multiple ISI-dependant short-term memory systems. avr-14 worms show long-term memory for habituation training comparable to wild-type controls when given distributed training and testing with a 60s ISI. avr-14 worms, unlike wild-type controls, also show long-term memory when trained and tested with a 10s ISI. Furthermore, long-term memory for this training protocol is protein synthesis dependant, as administering heat shock in between blocks of training blocks the formation of long-term memory. This suggests that in wild-type worms the presence of avr-14 blocks the conversion from short-term to long-term memory following training with short ISIs.Thanks to Joe Dent for avr-14.

Catharine Rankin et al. (2001) International C. elegans Meeting "Early Sensory Deprivation Alters Behavior, Rate of Development and Neuroanatomy in C. elegans"

Catharine Rankin, Susan Sangha, Jacqueline Rose, Ken Norman

[International C. elegans Meeting, 2001]

A basic feature of mammalian nervous systems is that during development activity dependent processes sculpt the final patterns and strengths of synaptic connections. Changes in synapses have been reported as a result of altered early experience. Rats raised in isolation in wire cages show fewer synapses in the visual cortex than rats raised in groups in an enriched environment (Sirevaag & Greenough, 1987). Recent evidence of this same phenomenon in invertebrates suggests that this may be a basic feature of nervous systems that is conserved across phylogeny. In these experiments we investigate the effects of early experience on the nervous system and behavior of the nematode C. elegans . Our procedure involved preparing NGM plates with 1 drop of E. coli (making a circle with approximately 1 cm. diameter) and letting 4-day old adults lay either a single fertilized egg (for isolate groups) or 20-30 eggs (for colony groups). Adult worms and excess eggs were removed from the plates and all of the plates were placed on cushioning in a 20 degree incubator for four days. For behavioral experiments 4-day old isolate and colony worms were transferred to blank NGM plates and given a single tap. For egg counting experiments plates were removed from the incubator at the designated hour and the number of eggs on the plate counted (for colony plates the number of adult worms was counted and the # of eggs/worm was determined). For imaging studies 4-day old worms were mounted and photographed using a confocal microscope. We found that depriving C. elegans of sensory stimulation by raising them in isolation leads to 4-day old adults that show: 1) decreased responsiveness to a mechanical stimulus (a tap), 2) slower rates of physical development (worms raised in isolation are smaller and slower to begin laying eggs than age-matched worms raised in groups), and 3) altered morphology of synapses between the mechanosensory neurons and the interneurons of the tap withdrawal circuit. A mutant strain of worms without functional chemoreceptors ( osm-6 ) showed the effect of isolation on the adult response to tap suggesting that chemical cues did not play a role in this effect. Other behaviors such as spontaneous reversals and response to a heat probe were not altered by isolation. The anatomical differences between worms raised in isolation and worms raised in groups were seen using two different transgenic strains of worms. One strain, developed by Michael Nonet of Washington University was pmec-7 ::VAMP::GFP (this allowed assessment of the effects of isolation on the pre-synaptic mechanosensory neurons). The other strain was a glr-1 ::GFP strain (KP1477) developed by Josh Kaplan of UC Berkeley (the glr-1 receptors are on the interneurons and allow assessment of post-synaptic changes). Using these strains we have seen clear differences in the synapses of worms raised in isolation compared to worms raised in groups. These studies add to the demonstrations of plasticity in the nervous system of C. elegans . Experience during development plays a role in determining the strength of connectivity in the adult. Thus C. elegans can serve as a model system in which to investigate the molecular mechanisms of this phenomenon. Sirevaag, A.M. & Greenough, W.T. (1987). Differential rearing effects on rat visual cortex synapses. III. Neuronal and glial nuclei, boutons, dendrites, and capillaries. Brain Research, 424(2), 320-332.

Catharine Rankin et al. (2007) International Worm Meeting "A Mutation in CREB Disrupts Long-Term Memory For Habituation and Blocks Memory Associated Changes in Glutamate Receptor Subunit Expression."

Tiffany Timbers, Catharine Rankin

[International Worm Meeting, 2007]

Catharine H Rankin et al. (2002) West Coast Worm Meeting "Analysis of learning, short-term and long-term memory in the presenilin mutant strains sel-12 and hop-1"

Jacqueline K Rose, Catharine H Rankin

[West Coast Worm Meeting, 2002]

Alzheimer's disease is a prevalent neurodegenerative disorder with symptoms that include decreased memory ability and cognitive decline eventually leading to dementia and finally death. Presenilin 1 and Presenilin 2 are human genes associated with the occurrence of Alzheimer's disease. Presenilin genes have also been discovered in the nematode Caenorhabditis elegans: sel-12 and hop-1. In the worm, these presenilins are associated with the LIN-12/Notch signaling pathway through the Notch receptors LIN-12 and GLP-1. sel-12 (Levitan and Greenwald, 1995) is ubiquitously expressed and results in an egl phenotype which can be rescued by human PS1 and PS2 constructs (Levitan et al., 1996). hop-1 (homolog of presenilin) was discovered using reverse genetics techniques by searching the C. elegans genome sequence database and looking for genes with a similar amino acid sequence to sel-12 (Li and Greenwald, 1997). hop-1 constructs rescue the egl phenotype of the sel-12 mutations providing evidence that hop-1 is a presenilin gene. The hop-1 mutant strain is a deletion mutation and does not show the egl phenotype noted with sel-12 gene mutation suggesting that hop-1 may be functionally redundant to sel-12. Only in the hop-1;sel-12 double mutant is a novel phenotype noted, e.g., a distorted morphology phenotype. At this time, behavioral analysis of the presenilin mutant worms has focused on thermotaxis: worms with sel-12 ;hop-1 mutations are unable to migrate to their "home temperature" when placed on a temperature gradient (Wittenburg et al., 2000). This deficit in thermotaxis was rescued by insertion of a sel-12 transgene.

McEwan, Andrea et al. (2011) International Worm Meeting "Candidate screen for mutants defective in long-term memory of habituation."

McEwan, Andrea, Rankin, Catharine

[International Worm Meeting, 2011]

Neurodegenerative-dependent memory loss is becoming increasingly relevant in today's aging population. The mechanisms that underlie memory are complex and, as yet, not fully understood. C.elegans offers a unique opportunity to study the biochemical pathways central to learning and memory. C.elegans has a simple, fully mapped nervous system and demonstrates several types of memory, including long-term memory for habituation. In the past, researchers have shied away from behavioural screens for long-term memory for habituation because of the labor intensive and time consuming methods used for data collection and analyses. Recently, a fully automated system called the multi-worm tracker has been developed and used to investigate genes involved in short-term habituation. The multi-worm tracker is able to record and analyze the movement of individual worms within a population in real time, greatly increasing the efficiency of behavioural studies. We have established a new protocol for investigating long-term memory for habituation on the multi-worm tracker and plan to perform a high-throughput candidate screen for mutants that fail to show long-term memory of habituation to mechanosensory stimulation. A screen for long-term memory for habituation could potentially identify novel players involved in aspects of memory, including genes involved in memory formation and memory storage.

Yu, Alex et al. (2021) International Worm Meeting "Charactering the roles of neuropeptides in non-associative learning"

Rankin, Catharine, Yu, Alex

[International Worm Meeting, 2021]

Non-associative forms of learning (habituation, dishabituation and sensitization) are the simplest forms of learning and are often thought as "cognitive building blocks" for higher learning. To better understand non-associative forms of plasticity and the cellular and molecular mechanisms, our work focuses on neuromodulatory signalling pathways underlying these forms of plasticity. First, we found that egl-3 and egl-21 mutants deficient of neuropeptides showed learning deficits in three forms of non-associative learning, habituation, dishabituation, and sensitization,, suggesting neuropeptides play a key role in non-associative learning. Further, we found that FLP-20/FRPR-3 signalling mediates sensitization but not dishabituation of the same response, and that the PDF neuropeptides differentially affect sensitization of response duration and response speed. These data suggest different forms of non-associative plasticity are mediated by different cellular and molecular components. We are in the process of testing mutations in a range of neuropeptide genes to examine how they influence non-associative learning. This project will generate data to better understand how neuropeptide signalling mediates different forms of non-associative plasticity.

Bortolon, Ricardo et al. (2011) International Worm Meeting "Spontaneous recovery from habituation to tap is interstimulus interval-dependent."

Rankin, Catharine H., Bortolon, Ricardo

[International Worm Meeting, 2011]

Habituation is a fundamental form of learning throughout the animal kingdom but almost nothing is known about the mediating genes and proteins. The length of time between stimuli (interstimulus interval) is known to influence the rate and degree of both habituation and spontaneous recovery from habituation and whether long term memory is formed but little research has demonstrated its effect on other defining characteristics of habituation. Using a multi-worm tracker to measure habituation and recovery of both magnitude and frequency of reversals in response to tap, a 2-second interstimulus interval results in more rapid spontaneous recovery of both the magnitude and frequency of reversals from habituation than a 10-second interstimulus interval. This provides an opportunity to screen for genes which determine the mechanisms of spontaneous recovery from habituation and which mediate interstimulus-dependent differences.

Reiss AP et al. (2021) J Neurogenet "Gaining an understanding of behavioral genetics through studies of foraging in Drosophila and learning in C. elegans."

Rankin CH, Reiss AP

[J Neurogenet, 2021]

The pursuit of understanding behavior has led to investigations of how genes, the environment, and the nervous system all work together to produce and influence behavior, giving rise to a field of research known as behavioral neurogenetics. This review focuses on the research journeys of two pioneers of aspects of behavioral neurogenetic research: Dr. Marla Sokolowski and Dr. Catharine Rankin as examples of how different approaches have been used to understand relationships between genes and behavior. Marla Sokolowski's research is centered around the discovery and analysis of <i>foraging</i>, a gene responsible for the natural behavioral polymorphism of <i>Drosophila melanogaster</i> larvae foraging behavior. Catharine Rankin's work began with demonstrating the ability to learn in <i>Caenorhabditis elegans</i> and then setting out to investigate the mechanisms underlying the &quot;simplest&quot; form of learning, habituation. Using these simple invertebrate organisms both investigators were able to perform in-depth dissections of behavior at genetic and molecular levels. By exploring their research and highlighting their findings we present ways their work has furthered our understanding of behavior and contributed to the field of behavioral neurogenetics.

Timbers, Tiffany A et al. (2009) International Worm Meeting "The Role of the Calcium/Calmodulin-dependent Protein Kinase Cascade in Mechanosensory Habituation."

Timbers, Tiffany A, Rankin, Catharine H

[International Worm Meeting, 2009]

Studies of CaMKIV, CaMKII and CaMKK in knockout mice show that these genes are critical for learning and memory. Curiously, CaMKI, a widely expressed CaMK has received little attention on its role in learning and memory. Our objective was to test the hypothesis that cmk-1 (homologous to CaMKI) is necessary for learning and/or memory. Because cmk-1 is highly homologous (and perhaps ancestral) to CaMKIV, and is widely expressed in the nervous system we predicted that animals with mutations in cmk-1 would show deficiencies in learning and/or memory. Worms strains with mutations in cmk-1, and ckk-1 (homologous to CaMKK and a known activator of cmk-1; Kimura et al. 2001) were tested for deficits in learning, short-term and long-term memory. Worms were habituated to mechanical stimuli (taps to the side of the Petri dish) using different stimulation protocols known to induce short-term, and long-term habituation. Worms with mutations in cmk-1 habituate normally when stimuli are presented at a 10s interstimulus interval (ISI), but do not habituate as deeply as wild-type animals when stimuli are presented at a 60s ISI, and cannot form long-term memory. No deficits in either short or long-term habituation were found in animals with a mutation in ckk-1. These results are similar to those of Satterlee et al. (2004) who also found that cmk-1, but not ckk-1 regulated gene expression, morphology, and functions of the AFD thermosensory neurons. This evidence suggests that a novel kinase may play the role of activating cmk-1 in the context of short-term habituation and long-term memory of habituation. To investigate whether the long-term memory deficit of the cmk-1 mutants is a result of the animals short-term habituation deficit or whether it is independently involved in both processes we created a strain that expresses the cmk-1 gene without the nuclear localization signal (NLS), restricting its expression to the cytoplasm (CaMKIV, and perhaps cmk-1 in some animals, are thought to participate in the induction of long-term memory by phosphorylating the transcription factor CREB in the nucleus). We predict that cmk-1 without the NLS will rescue the short-term habituation deficit but will be incapable of rescuing the long-term memory deficit, demonstrating that cmk-1 acts in independently in these two processes. In these studies we show, for the first time, that cmk-1 is critical for learning and memory. We also present data that support the hypothesis that cmk-1 is ancestral to mammalian CaMKIV and suggest that in species where CaMKIV does not exist, cmk-1 may function in its place.

Ardiel, Evan L. et al. (2009) International Worm Meeting "A species specific chemosensory cue can modulate body size in C. elegans."

Rankin, Catharine H., Ardiel, Evan L.

[International Worm Meeting, 2009]

Previous research on C. elegans has shown that sensory perception mutants are smaller than wild-type worms (Fujiwara et al., 2002). This suggests that sensory input from the environment regulates adult body size. But what are the relevant external cues? Work in our lab suggests that interactions with conspecifics are one source. We have found that worms reared in isolation are dwarfed compared to worms reared in colonies. Furthermore, adding another worm to the plate of an isolated worm rescues colony body size. C. briggsae are also dwarfed when reared in isolation, but the relevant conspecific cue appears to be species specific, as the presence of C. briggsae cannot rescue colony body size in an isolated C. elegans. Using sensory perception mutants with cell structure (che-2, che-3, osm-3, daf-6), signal transduction (odr-1, odr-3, tax-4, osm-9), and cell specification (ceh-36, lim-4, odr-7) defects and cell-type specific rescues, we have identified a subset of chemosensory neurons with a role in the modulation of body size in response to conspecifics. Because isolated worms exposed to the stable water-soluble or volatile chemical cues of a colony are still smaller than colony worms, we propose that a species specific contact pheromone triggers growth to a larger body size. Fujiwara, M., Segupta, P., & McIntire, S.L. (2002). Regulation of body size and behavioral state of C. elegans by sensory perception and the egl-4 cGMP-dependent protein kinase. Neuron, 366 (6), 1091-1102.