Catharine Rankin


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Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Sytematic phenomics analysis of autism risk genes and variants (2021)

Two major challenges facing the genetics of Autism Spectrum Disorders (ASD) are the large and growing number of candidate risk genes and gene variants of unknown functional significance. The goals of this dissertation were to combine emerging methods in CRISPR-Cas9 genome engineering with machine vision phenomics to gain insight into the functions of ASD risk genes and the functional impact of specific variants. I developed a pipeline to discover the functions of ASD risk genes by obtaining strains of the genetic model organism Caenorhabditis elegans with inactivating mutations in each gene and observed the phenotypic consequences using machine vision. I quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and learning in >27,000 animals representing 135 genotypes (98 strains with mutations in different genes and 37 strains with additional alleles of a subset of these genes), allowing us to identify disruptions in habituation (a neural circuit’s plastic ability to decrease responding to repeated sensory stimuli) as a common impairment. I then clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered on CHD8•chd-7 and NLGN3•nlg-1 that underlie mechanosensory hyper-responsivity and impaired habituation learning. Next, I demonstrated how this database can facilitate experiments that determine the functional consequences of missense variants and whether phenotypic alterations are reversible. Further, I developed a broadly applicable CRSIRP-Cas9 genome editing strategy to replace C. elegans genes with human genes that allows for in vivo analysis of human genetic variation with unprecedented precision. Finally, I contributed to the development of a multi-model system pipeline for high-confidence assessment of missense variants in the ASD risk gene PTEN. This work charts the phenotypic landscape of ASD-associated genes, offers in vivo variant functional assays, and potential therapeutic targets for ASD.

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Plasticity of behaviours modulated by alcohol (2017)

In this dissertation, I investigated the ways that alcohol modulates plasticity of behaviours through studying effects of alcohol on body posture, locomotion, and a simple form of behavioral plasticity, habituation, in the genetic model organism Caenorhabditis elegans. I found that the effects of alcohol on body posture and locomotion are temporally dynamic especially for the first 30 min. Some earlier studies found alcohol facilitated habituation but others found alcohol inhibited habitation. I found that alcohol can both facilitate or inhibit habituation of the reversal response to repeated stimuli (taps) depending on the component of the reversal response assessed. Furthermore, I discovered that alcohol altered the predominant response to tap from a backward reversal to a forward acceleration. With this understanding, I examined the role of 27 genes on the alcohol induced behavioural changes characterized in Chapter 2. I found different alcohol modulated behaviors involved different sets of genes. For example, I observed that 2 genes modulated only body posture, 3 genes modulated only reversals, 1 gene modulated posture and acceleration but not reversal. I also discovered a gene not previously implicated in alcohol’s effect on behaviour: tomosyn, a negative regulator of SNARE complex. In the final study I investigated another alcohol modulated behavioural plasticity: tolerance. In C. elegans acute tolerance has been studied, however, chronic tolerance has not. I developed a chronic alcohol exposure paradigm and tested several candidate genes to determine whether they play a role in chronic tolerance to alcohol. I found that worms with a mutation in the Neuropeptide Y receptor, a gene that is involved in acute tolerance, had better chronic tolerance than wild-type worms. I then showed that mutations in genes that encode histone methyltransferases impaired chronic tolerance, which provided the first evidence relating histone methyltransferases with functional outcomes of alcohol exposure in adult animals. Together, the results from my dissertation contribute to our understanding of how alcohol alters behaviour.

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Dopamine and PDF signaling modulate habituation to repeated activation of a polymodal nociceptor in C. elegans (2015)

Habituation is a highly conserved phenomenon that remains poorly understood at the molecular level. Invertebrate model systems, like C. elegans, can be a powerful tool for understanding this fundamental process. To expand our knowledge of habituation I developed a high-throughput learning assay using real-time computer vision software for behavioral tracking and optogenetics for stimulation of a C. elegans polymodal nociceptor pair, ASHL and ASHR. These cells are especially interesting in the context of habituation because of the diversity and salience of the stimuli they detect. Photoactivation of ASH promoted backward locomotion and persistent stimulation altered the magnitude of this response in a manner consistent with the key behavioral characteristics of habituation. The decrement in reversal duration was readily reversed by a dishabituating stimulus, in this case non-localized mechanosensory input detected by the touch receptor neurons. In addition to altering the response properties, repeated ASH activation suppressed spontaneous reversals and accelerated forward movement. Food and dopamine signaling (bas-1, cat-4, cat-2, trp-4) promoted responding to persistent ASH activation and I identified the D1-like dopamine receptor, DOP-4, as the key mediator. Neuropeptide synthesis mutants (egl-3 and egl-21) displayed impaired plasticity for a variety of behavioral metrics, prompting me to perform an RNAi screen targeting neuropeptide receptors. From this screen, I implicated pigment dispersing factor (PDF) signaling in habituation of response latency and duration. Failure to avoid some stimuli detected by ASH could be fatal for C. elegans, so why do the reversal responses habituate? My data indicate that habituation is part of a strategy to promote dispersal.

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Candidate Gene and High Throughput Genetic Analysis of Habituation in Caenorhabditis Elegans (2012)

The goal of my dissertation was to identify genes that are important for habituation (a decrease in response to a repeated stimulus) with the hope of bringing us closer to understanding the cellular and molecular mechanism that mediates this basic form of learning. To accomplish this I studied habituation of the tap withdrawal response in Caenorhabditis elegans; an organism with a tractable nervous system, well characterized habituation and availability of genetic tools and resources that make it easy to investigate the mechanisms of behaviour. Two approaches were taken. The first was a candidate gene approach where I investigated mutations in genes important for dopamine neurotransmission. A previous study showed that dopamine deficient and dopamine receptor mutants have abnormal habituation and the dopamine receptor is expressed within the tap sensory neurons. Investigating this effect more closely, I found that short-term tap habituation in C. elegans was dependent on the presence of E. coli (their food) and that this food-dependent modulation of habituation was dopamine dependent. The second approach involved characterizing habituation of a large set of C. elegans strains with known mutations in genes predicted to function in the nervous system. Many of these mutants had not previously been characterized. To accomplish this task, it was necessary to improve the speed and detail with which habituation can be assayed. In collaboration with the Kerr Lab at Janelia Farm Research Campus, we developed a high throughput C. elegans behavioural tracking system called the Multi-Worm Tracker. Using this tracking system, I examined many mutants and discovered hundreds of novel phenotypic variants for habituation in C. elegans. The genes affected by these mutations can now be investigated in more detail in order to identify the role that they play in the molecular and cellular mechanism of habituation.

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The roles of CREB, CaMK1, and ageing in short and long term Tap habituation in Caenorhabditis elegans (2012)

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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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Goa-1 and g protein signalling pathway modulation of the tap withdrawal response (2023)

Previous research on Caenorhabditis elegans by Giles (2012) and McEwan (2013) identified the goa-1 gene as a possible regulator of habituation of the tap withdrawal response because mutations in goa-1 caused abnormal habituation across multiple metrics. The original goal of this thesis was to use behavioural and genetic analyses to understand where and how goa-1 functions in habituation of the tap withdrawal response. I planned to use C. elegans with green fluorescent protein (GFP) inserted into wild-type goa-1 as well as tissue-specific degron strains to perform targeted degradation of the GOA-1 protein in subsets of cells. However, when I tested habituation the goa-1::GFP strain found that habituation for the probability of response looked similar to the probability of response habituation for the goa-1 null mutant, yet had a normal, wild-type phenotype for habituation of response duration. I compared our CRISPR goa-1::GFP strain to a second goa-1::GFP strain created by a different single copy insertion technique; the behaviour of this second goa-1::GFP was the same as our goa-1::GFP strain. I tested different mutant goa-1 strains to determine their effects on the habituation phenotypes, however, none of them matched the goa-1::GFP phenotype. Because the goa-1::GFP worms showed normal habituation of response duration I created three GOA-1::GFP degradation strains with pan-neuronal, ciliated neuron, and touch neuron specific degradation. The anatomical results showed that although goa-1::GFP degradation occurred, the behaviour results were inconclusive. Finally, I performed the habituation assay on worms with mutations in genes that were known interactors with goa-1 and found that mutations in dgk-1 led to similar habituation phenotypes as goa-1::GFP worms. The most likely explanation for the goa-1::GFP abnormal habituation phenotype is that the GFP interfered with a signalling pathway that activates the diacylglycerol kinase. These data suggest that the role of goa-1 in habituation of the probability of response is mediated through dgk-1.

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The role of tyramine and octopamine on short-term habituation in Caenorhabditis elegans (2021)

The goal of this thesis is to identify the potential contributions of two largely unstudied monoamines, tyramine and octopamine, in the context of tap habituation; a behavior who’s underlying circuitry heavily expresses genes encoding precursors and receptors for both these neurotransmitters. To pursue this goal I compared habituation of the tap withdrawal response in Caenorhabditis elegans - a model organism with a fully mapped connectome and proteome, and thoroughly characterized habituation - between wild type worms and worms that were null in tyramine and/or octopamine across different timepoints in young adulthood. I discovered that these gene products contribute to only isolated components of this behavior in an age-dependent manner. Although the impacts of these genes was interesting, the study of worms null in both of these precursors failed to find the striking differences in tap habituation that have been studied in animals expressing mutations in dopamine neurotransmission with much less representation in the neural circuitry responsible for this behavior. With some phenotypes identified by these mutations, their contributions to the biological underpinnings unique to each response-component can now be investigated in more detail.

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Behavioural and genetic dissociation of faciliatatory processes in Caenorhabditis elegans (2018)

The simplest forms of learning are non-associative learning. In non-associative learning, both sensitization and dishabituation cause an increase in the behavioural response. A strong and/or surprising stimulus can enhance a naïve response above the baseline in sensitization, or facilitate a previously decremented response in dishabituation. While a lot has been done to unravel the cellular and molecular mechanisms for sensitization, the mechanism(s) for dishabituation remains elusive. Sensitization and dishabituation were considered as the same facilitatory process for decades, but recent evidence suggests that they may be two separate processes. The focus of this thesis was to investigate whether sensitization and dishabituation are the same or two different processes. In this research, sensitization and dishabituation of the response to optogenetic stimulation of ASH nociceptor neurons by a mechanosensory tap stimulus were characterized and compared in a series of behavioural paradigms in C. elegans. It was found that sensitization and dishabituation were produced in four ASH response components with different time-dependent dynamics. Using a candidate gene approach, the effects of several genes on sensitization and dishabituation of the ASH response were examined. It was found that genes played differential roles in mediating the two facilitatory processes; genes that were critical for sensitization did not affect dishabituation. Taken together, these findings strongly suggest that sensitization and dishabituation are two facilitatory processes mediated by distinct genetic and molecular pathways. This research deepens our understanding of the complex mechanisms of “simple” forms of learning.

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Investigating the role of Alzheimer's disease-associated presenilin mutations in olfactory deficits (2018)

Although olfactory dysfunction is one of the hallmark symptoms in Alzheimer’s disease (AD) prior to the onset of cognitive impairments, little is known about the causes of this dysfunction. The nematode Caenorhabditis elegans is an ideal model for system-level genetic understanding of sensory neural circuits and behavior. Many cases of familial AD are linked to mutations of the presenilin (PS) genes. These genes are homologues with sel-12 genes in C. elegans. The purpose of this project was to examine the association between PS1 and olfactory deficits in order to investigate the cellular mechanism of these dementia-linked deficits. To gain a better understanding of the relationship between presenilin 1 (PS1) mutations in AD and olfactory deficits, chemotaxis experiments (with the attractant diacetyl, and the aversive octanol) were conducted on worms with a mutation in sel-12. I found that adult sel-12 mutant worms had a significantly decreased sensitivity to both odorants compared to wild-type worms. Extrachromosomal array expression of human wild-type PS1 into C. elegans rescued olfactory defects, confirming functional homology between the C. elegans and human gene. However, a PS1 mutant from an Alzheimer’s family was unable to rescue olfactory deficits. Moreover, C. elegans sel-12 mutant worms presented olfactory deficits throughout their lifespan, and the deficit increased with age, similar to the neurodegenerative progression of AD. Based on these data, I concluded that a mutation in the C. elegans homologue of PS1 is associated with decreased olfactory function, and this deficit was rescued by wild-type human PS1 gene. I suggest that altered functioning of the Notch pathway may be involved in these chemosensory deficits. Additionally, to localize the neuron(s) where wild-type sel-12 function is required for normal olfaction, sel-12 and PS1 rescues were conducted in specific sensory neurons, namely the ASH and the AWA neurons responsible for detecting octanol and diacetyl, respectively. Further, an examination of the morphology of the ASH neurons showed increased neurodegeneration over time in sel-12 mutant worms, demonstrating an association with the observed behavioral deficits.

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Short-term memory for tap-habituation in the roundworm C. elegans: response-components & genetic dissection (2018)

Habituation is a simple form of learning that manifests as a decrease in an innate response to a repeated stimulus that is not associated with important events. In this thesis, habituation-memory was studied using the tap-reversal response emitted by the roundworm C. elegans in response to a non-localized tap-stimulus. Delivery of 30 tap-stimuli produced a decline in the probability, duration, and speed of the reversal-response (i.e., learning). When stimulation was ceased for 10-minutes each of these response-components recovered partially but not completely, as evidenced by differences between training and test sessions (i.e., memory). Each of the components (probability, duration and speed) of the tap-reversal response showed different profiles of habituation-learning and habituation-memory in wild-type worms, with one not being predictive of the other. A genetic screen supported these findings and identified mutant strains that were deficient in habituation-memory for one component of the response but not the others. It was also shown that simply because a mutant strain showed more habituation-learning did not necessarily predict that it would show more habituation-memory. This suggested that different biological underpinnings likely underlie A) the persistence of habituation from stimulus-to-stimulus within a session of stimuli and B) the persistence of habituation from one session of stimuli to another. The genetic screen also identified mutant strains which supported a genetic dissociation of initial response-difference from overall average response-difference. This suggested that considering the phase of test-session is important for measuring memory. Finally, it was shown that the habituation-memory deficits shown by one mutant strain (pde-4) were selective to the frequency of training used and did not show deficits at all training frequencies. Together, these data suggest that habituation-memory is multidimensional and that considering both the components and time-scales of the response is important.

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Behavioral Investigation of Normal and Mutant Human Presenilin Functions in Caenorhabditis Elegans (2015)

Presenilins are well known as sites of mutations responsible for early-onset Alzheimer's disease. The normal functions of presenilins and the mechanisms by which presenilins cause Alzheimer disease are not yet known. Conservation of cellular and molecular functions between the C.elegans and human genes makes it a powerful experimental model organism to investigate cellular mechanisms of Alzheimer's disease and neurodegenerative disorders in general. Mutations in the C.elegans presenilin1homologue, sel-12, decrease Notch signaling activity, which results in an egg-laying deficit in these animals. It has been well established that pathogenic PS1 mutations impair Notch signaling; however, in the first part of this thesis we showed that a recently discovered PS1Δs₁₆₉ human mutation rescued the egg-laying deficit associated with Lin12/Notch pathway, suggesting that in this pathogenic PS1 mutation Notch processing remained intact. In the second part of this thesis the behavioural phenotypes of a mutation in the C.elegans presenilin homologue, sel-12, were studied. Our results revealed that a mutation in the sel-12 gene causes chemotaxis deficits toward volatile and water-soluble stimuli in sel-12 mutant animals. Reintroducing the sel-12 or the wild-type human presenilin gene decreased those behavioural phenotypes, indicating that the observed chemotaxis deficits were dependent on sel-12 activity. However, rescuing with the human PS1C₄₁₀Y mutation, which has a severe effect on Notch processing, did not ameliorate the chemotaxis deficit; in contrast, rescuing with PS1Δs₁₆₉ rescued both volatile and water-soluble chemotaxis impairments suggesting that the chemotaxis deficit causing by sel-12 mutation depends on the Notch pathway.

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Behavioral Characterization of C. elegans Homologs of Parkinson's Disease Associated Genes (2014)

Parkinson’s disease (PD) is a neurodegenerative disorder of central nervous system affecting more than 10 million people globally. This disease has a strong genetic component with 14% of individuals with PD reporting a first-degree relative with the disease. While genes like PARK2 and PINK1 have been associated with familial early onset PD, LRRK2, DNAJC13, and VPS35 have been linked to idopathic PD. These genes are largely involved in the maintenance of mitochondria or in the quality control via the cellular machinery that degrades unneeded proteins. Mutations in these genes affect the function and survival of particular neurons in parts of the brain that regulate normal movement, balance, and coordination. One endophenotype of PD is abnormal habituation; habituation is a simple form of learning in which repeated stimulation causes a decrement in responding over time. By investigating how these PD associated genes are involved in habituation, we hope to better understand the underlying pathophysiology induced by these genetic differences. In this study mechanosensory habituation was examined in Caenorhabditis elegans (C.elegans; microscopic transparent roundworms) in both wild-type worms and in worms with mutations in homologues of genes implicated in PD. Each strain of mutant worms showed a unique combination of basal characteristics and habituation phenotypes that distinguished them from wild-type worms. The integrity of dopamine neurotransmission was also investigated using the SWIP assay and ON/OFF Food Habituation assay. The C. elegans homologue of the PD gene VPS35, vps-35, an essential component of the retromer complex, was found to display the characteristics of abnormal dopamine signaling and was chosen for additional testing. Experiments using channelrhodopsin confirmed a lower dopamine signaling phenotype, with overexpression and rescue strains of this mutant being created to further explore how this protein affects behavior. These experiments set the groundwork for using C. elegans as a genetic model of PD that can help us better understand this complicated neurological disorder.

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Modulation of habituation kinetics and behavioural shifts by members of the G-protein signaling pathways (2013)

Despite its apparent simplicity, the soil-dwelling nematode Caenorhabditis elegans has a surprisingly large capacity to learn and remember. Previous characterization of C. elegans genome and neuronal circuit makes this worm an ideal choice for studying behavior and the mechanisms that underlie it. Through careful behavioral and genetic studies, nematodes have been shown to form many different types of memory, including short-term non-associative memory called habituation. Habituation is the defined as the decrement in response after repeated, irrelevant stimuli. In the first part of this thesis, detailed analyses showed that as one response type, reversals, decreased other responses, accelerations, decelerations and pauses became more prevalent. An earlier large-scale screen of mutant strains of C.elegans showed that several genes related to heterotrimeric G-protein family of signaling pathways exhibited striking defects in habituation. To follow-up on those findings, in the second part of my thesis I investigated the role of heterotrimeric G-protein signaling pathway and showed that Gαi and Gαq signaling pathways share a broad role regulating habituation whereas the Gαs pathway modulates the rate of habituation. The analyses of all the behaviours nematodes preform in response to habituation training showed that heterotrimeric G-protein signaling pathways play a role in regulating the shift in behaviour during habituation training. Together these data add to our understanding of the mechanisms underlying habituation of the tap response in C. elegans.

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Chemosensory context conditioning in Caenorhabditis elegans (2010)

These studies were designed to investigate how environmental cues are associated during a non-associative learning process by studying chemosensory context conditioning for habituation in the nematode Caenorhabditis elegans. In chemosensory context conditioning for habituation animals that are trained and tested in the presence of either a taste or smell context cue show greater retention of habituation to tap stimuli when compared to animals trained and tested in different environments. This thesis is based on the work of Rankin (2000), in which taste (sodium acetate) context conditioning of habituation, extinction and latent inhibition of the cue were demonstrated. Here, I have shown context conditioning for an olfactory chemosensory cue (diacetyl) and dissociated the taste and smell pathways for this form of learning. odr-7 worms, with non-functional AWA olfactory chemosensory neuron (that detects diacetyl), showed short-term context conditioning to the taste but not to smell; the reverse was true for osm-3 worms with non-functional taste chemosensory neurons. This dissociation allows me to distinguish learning genes from genes involved in the detection of taste or smell. I also demonstrated long-term associative memory (24h) for context conditioning; context conditioning did not enhance normal long-term habituation, however, it produced memory in a training procedure that normally does not produce memory. My results showed that glr-1 (an AMPA-type ionotropic glutamate receptor subunit) and nmr-1 (an NMDA-type ionotropic glutamate receptor subunit) mutant worms did not show either short- or long-term context conditioning. To identify one site of plasticity, I showed that NMR-1 in the RIM interneurons was critical to produce short-term olfactory context conditioning. These studies lay the foundation to elucidate the cellular mechanisms of non-associative and associative learning for both short- and long-term memory, and may provide insights into how interneurons integrate information from multiple sensory systems.

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