Publications by authors named "Catharine H Rankin"

58 Publications

But can they learn? My accidental discovery of learning and memory in .

J Neurogenet 2020 Sep-Dec;34(3-4):251-254

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada.

I did not set out to study . My undergraduate and graduate training was in Psychology. My postdoctoral work involved studying learning and memory in 1 mm diameter juvenile . As a starting Assistant Professor when I attempted to continue my studies on Aplysia I encountered barriers to carrying out that work; at about the same time I was introduced to and decided to investigate whether they could learn and remember. My laboratory was the first to demonstrate conclusively that could learn and in the years since then my lab and many others have demonstrated that is capable of a variety of forms of learning and memory.
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http://dx.doi.org/10.1080/01677063.2020.1833009DOI Listing
January 2021

Auxin does not affect a suite of morphological or behavioral phenotypes in two wild-type strains.

MicroPubl Biol 2020 Oct 8;2020. Epub 2020 Oct 8.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada.

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http://dx.doi.org/10.17912/micropub.biology.000307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723422PMC
October 2020

Peel-1 negative selection promotes screening-free CRISPR-Cas9 genome editing in Caenorhabditis elegans.

PLoS One 2020 22;15(9):e0238950. Epub 2020 Sep 22.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

Improved genome engineering methods that enable automation of large and precise edits are essential for systematic investigations of genome function. We adapted peel-1 negative selection to an optimized Dual-Marker Selection (DMS) cassette protocol for CRISPR-Cas9 genome engineering in Caenorhabditis elegans and observed robust increases in multiple measures of efficiency that were consistent across injectors and four genomic loci. The use of Peel-1-DMS selection killed animals harboring transgenes as extrachromosomal arrays and spared genome-edited integrants, often circumventing the need for visual screening to identify genome-edited animals. To demonstrate the applicability of the approach, we created deletion alleles in the putative proteasomal subunit pbs-1 and the uncharacterized gene K04F10.3 and used machine vision to automatically characterize their phenotypic profiles, revealing homozygous essential and heterozygous behavioral phenotypes. These results provide a robust and scalable approach to rapidly generate and phenotype genome-edited animals without the need for screening or scoring by eye.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508457PMC
October 2020

The contribution of neurogenetics to understanding neurodegenerative diseases.

J Neurogenet 2020 Sep-Dec;34(3-4):527-548. Epub 2020 Aug 8.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada.

Since was first introduced as a genetic model organism by Sydney Brenner, researchers studying it have made significant contributions in numerous fields including investigations of the pathophysiology of neurodegenerative diseases. The simple anatomy, optical transparency, and short life-span of this small nematode together with the development and curation of many openly shared resources (including the entire genome, cell lineage and the neural map of the animal) allow researchers using to move their research forward rapidly in an immensely collaborative community. These resources have allowed researchers to use to study the cellular processes that may underlie human diseases. Indeed, many disease-associated genes have orthologs in allowing the effects of mutations in these genes to be studied in relevant and reproducible neuronal cell-types at single-cell resolution Here we review studies that have attempted to establish genetic models of specific human neurodegenerative diseases (ALS, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease) in and what they have contributed to understanding the molecular and genetic underpinnings of each disease. With continuous advances in genome engineering, research conducted using this small organism first established by Brenner, Sulston and their contemporaries will continue to contribute to the understanding of human nervous diseases.
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http://dx.doi.org/10.1080/01677063.2020.1803302DOI Listing
August 2020

The role of neuropeptides in learning: Insights from C. elegans.

Int J Biochem Cell Biol 2020 08 8;125:105801. Epub 2020 Jul 8.

Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute, NSW, 2522, Australia. Electronic address:

Learning is critical for survival as it provides the capacity to adapt to a changing environment. At the molecular and cellular level, learning leads to alterations within neural circuits that include synaptic rewiring and synaptic plasticity. These changes are mediated by signalling molecules known as neuromodulators. One such class of neuromodulators are neuropeptides, a diverse group of short peptides that primarily act through G protein-coupled receptors. There has been substantial progress in recent years on dissecting the role of neuropeptides in learning circuits using compact yet powerful invertebrate model systems. We will focus on insights gained using the nematode Caenorhabditis elegans, with its unparalleled genetic tractability, compact nervous system of ∼300 neurons, high level of conservation with mammalian systems and amenability to a suite of behavioural analyses. Specifically, we will summarise recent discoveries in C. elegans on the role of neuropeptides in non-associative and associative learning.
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http://dx.doi.org/10.1016/j.biocel.2020.105801DOI Listing
August 2020

Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction.

Nat Commun 2020 04 29;11(1):2073. Epub 2020 Apr 29.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada.

Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PTEN hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occur across the protein, resulting in partial-to-complete loss-of-function (LoF), which is well correlated across models. However, assays are selectively sensitive to variants located in substrate binding and catalytic domains, which exhibit complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.
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http://dx.doi.org/10.1038/s41467-020-15943-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190743PMC
April 2020

Introduction to the presidential symposium at the International Congress of Neuroethology, ICN 2018 in Brisbane, Australia.

J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2020 05 18;206(3):309-312. Epub 2020 Apr 18.

Department of Psychology and DM Centre for Brain Health, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.

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http://dx.doi.org/10.1007/s00359-020-01419-5DOI Listing
May 2020

Habituation in high-throughput genetic model organisms as a tool to investigate the mechanisms of neurodevelopmental disorders.

Neurobiol Learn Mem 2020 05 5;171:107208. Epub 2020 Mar 5.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada; Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia V6T 1Z4, Canada. Electronic address:

Alterations in habituation, a highly conserved form of non-associative learning, are suspected to contribute to a range of the complex behavioural phenotypes present in multiple neurodevelopmental disorders. While progress has been made in understanding the genetics of these disorders through the application of next-generation sequencing and related technologies, the pathogenicity of genetic variants and causes of learning and memory impairments can be difficult to determine from sequencing data alone. High-throughput genetic model organisms such as the roundworm Caenorhabditis elegans, fruit fly Drosophila melanogaster, and zebrafish Danio rerio offer low-cost and efficient methods to investigate the functions of identified neurodevelopmental disorder risk genes and the functional consequences of specific disorder-associated variants. Here, we review ways assessing habituation has been used in the genotype-first approach to first validate neurodevelopmental disorder candidate genes and now to systematically characterize large candidate gene lists. We then discuss exciting ways habituation, in combination with other techniques, can be used as a tool to assess the pathogenicity of putative genes and genetic variants, uncover and confirm molecular networks, and identify potential therapeutic avenues.
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http://dx.doi.org/10.1016/j.nlm.2020.107208DOI Listing
May 2020

Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation.

Proc Natl Acad Sci U S A 2020 01 21;117(1):656-667. Epub 2019 Nov 21.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada;

A major challenge facing the genetics of autism spectrum disorders (ASDs) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we used to systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system, we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 135 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of genotype-phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered on and that underlie mechanosensory hyperresponsivity and impaired habituation learning. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 in mutant rescued their sensory and learning impairments. Testing the rescuing ability of conserved ASD-associated neuroligin variants revealed varied partial loss of function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin-inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. 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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http://dx.doi.org/10.1073/pnas.1912049116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968627PMC
January 2020

Is There a Shared Etiology of Olfactory Impairments in Normal Aging and Neurodegenerative Disease?

J Alzheimers Dis 2020 ;73(1):1-21

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.

As we age, our olfactory function declines. In addition to occurring in normal aging, more rapid decrement of olfactory decline has been associated with several neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). It has been argued that since olfactory deficits occur less frequently or are absent in diseases such as progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy, olfactory deficits can be used for differential diagnoses of AD and PD. The purpose of this review is to provide a survey of current knowledge about the molecular bases and differential patterns of olfactory deficits present in normal aging, AD, and PD. As substantial research has been conducted in this area, the majority of the content of this review focuses on articles published in the past decade. We hypothesize that olfactory deficits in normal aging, AD, and PD may have different underlying causes, and propose the use of model organisms with small, tractable nervous systems and/or easy to manipulate genomes to further investigate the cellular mechanisms responsible for these deficits.
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http://dx.doi.org/10.3233/JAD-190636DOI Listing
January 2020

Synaptic vesicle fusion is modulated through feedback inhibition by dopamine auto-receptors.

Synapse 2020 01 23;74(1):e22131. Epub 2019 Sep 23.

Department of Biological Sciences, Delaware State University, Dover, Delaware.

Mechanisms of synaptic vesicular fusion and neurotransmitter clearance are highly controlled processes whose finely-tuned regulation is critical for neural function. This modulation has been suggested to involve pre-synaptic auto-receptors; however, their underlying mechanisms of action remain unclear. Previous studies with the well-defined C. elegans nervous system have used functional imaging to implicate acid sensing ion channels (ASIC-1) to describe synaptic vesicle fusion dynamics within its eight dopaminergic neurons. Implementing a similar imaging approach with a pH-sensitive fluorescent reporter and fluorescence resonance after photobleaching (FRAP), we analyzed dynamic imaging data collected from individual synaptic termini in live animals. We present evidence that constitutive fusion of neurotransmitter vesicles on dopaminergic synaptic termini is modulated through DOP-2 auto-receptors via a negative feedback loop. Integrating our previous results showing the role of ASIC-1 in a positive feedback loop, we also put forth an updated model for synaptic vesicle fusion in which, along with DAT-1 and ASIC-1, the dopamine auto-receptor DOP-2 lies at a modulatory hub at dopaminergic synapses. Our findings are of potential broader significance as similar mechanisms are likely to be used by auto-receptors for other small molecule neurotransmitters across species.
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http://dx.doi.org/10.1002/syn.22131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336876PMC
January 2020

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

Bioessays 2019 09 19;41(9):e1900077. Epub 2019 Aug 19.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.

Recent work indicates that there are distinct response habituation mechanisms that can be recruited by different stimulation rates and that can underlie different components (e.g., the duration or speed) of a single behavioral response. These findings raise the question: why is "the simplest form of learning" so complicated mechanistically? Beyond evolutionary selection for robustness of plasticity in learning to ignore, it is proposed in this article that multiple mechanisms of habituation have evolved to streamline shifts in ongoing behavioral strategy. Then, speculations are offered regarding the implications of this reconceptualization of habituation for approaching the analysis of mechanisms of more complex forms of learning and memory.
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http://dx.doi.org/10.1002/bies.201900077DOI Listing
September 2019

EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling.

Elife 2019 02 27;8. Epub 2019 Feb 27.

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.

Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy.
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http://dx.doi.org/10.7554/eLife.37271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392500PMC
February 2019

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

Proc Biol Sci 2018 11 14;285(1891). Epub 2018 Nov 14.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5

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 to identify the first molecules that modulate habituation in an ISI-dependent manner. We show that the orthologues of Ca/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 and 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.
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http://dx.doi.org/10.1098/rspb.2018.2084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6253365PMC
November 2018

High-Throughput Analysis of Behavior Under the Control of Optogenetics in Caenorhabditis elegans.

Curr Protoc Neurosci 2019 01 2;86(1):e57. Epub 2018 Nov 2.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

In this unit, we describe an inexpensive and versatile method for optogenetic stimulation of a large population of genetically engineered Caenorhabditis elegans worms while quantitatively analyzing behavior. A custom light-emitting diode light source is used to deliver blue-light stimuli, causing direct depolarization of neurons expressing the light-gated cation channel Channelrhodopsin-2, which in turn evokes behavioral responses. The behavioral responses are recorded by a high-throughput machine vision-based tracking system, the Multi-Worm Tracker, for detailed analysis. This approach allows researchers to bypass technical obstacles to simultaneously deliver uniform stimuli to a large number of freely behaving animals and investigate the neural underpinnings of behavior. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpns.57DOI Listing
January 2019

CRISPR-Cas9 human gene replacement and phenomic characterization in to understand the functional conservation of human genes and decipher variants of uncertain significance.

Dis Model Mech 2018 11 26;11(12). Epub 2018 Nov 26.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada

Our ability to sequence genomes has vastly surpassed our ability to interpret the genetic variation we discover. This presents a major challenge in the clinical setting, where the recent application of whole-exome and whole-genome sequencing has uncovered thousands of genetic variants of uncertain significance. Here, we present a strategy for targeted human gene replacement and phenomic characterization, based on CRISPR-Cas9 genome engineering in the genetic model organism , that will facilitate assessment of the functional conservation of human genes and structure-function analysis of disease-associated variants with unprecedented precision. We validate our strategy by demonstrating that direct single-copy replacement of the ortholog () with the critical human disease-associated gene phosphatase and tensin homolog () is sufficient to rescue multiple phenotypic abnormalities caused by complete deletion of , including complex chemosensory and mechanosensory impairments. In addition, we used our strategy to generate animals harboring a single copy of the known pathogenic lipid phosphatase inactive PTEN variant (PTEN-G129E), and showed that our automated phenotypic assays could accurately and efficiently classify this missense variant as loss of function. The integrated nature of the human transgenes allows for analysis of both homozygous and heterozygous variants and greatly facilitates high-throughput precision medicine drug screens. By combining genome engineering with rapid and automated phenotypic characterization, our strategy streamlines the identification of novel conserved gene functions in complex sensory and learning phenotypes that can be used as functional assays to decipher variants of uncertain significance.
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http://dx.doi.org/10.1242/dmm.036517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307914PMC
November 2018

An Afferent Neuropeptide System Transmits Mechanosensory Signals Triggering Sensitization and Arousal in C. elegans.

Neuron 2018 09 23;99(6):1233-1246.e6. Epub 2018 Aug 23.

Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, Cambridgeshire, CB2 0QH, UK. Electronic address:

Sensitization is a simple form of behavioral plasticity by which an initial stimulus, often signaling danger, leads to increased responsiveness to subsequent stimuli. Cross-modal sensitization is an important feature of arousal in many organisms, yet its molecular and neural mechanisms are incompletely understood. Here we show that in C. elegans, aversive mechanical stimuli lead to both enhanced locomotor activity and sensitization of aversive chemosensory pathways. Both locomotor arousal and cross-modal sensitization depend on the release of FLP-20 neuropeptides from primary mechanosensory neurons and on their receptor FRPR-3. Surprisingly, the critical site of action of FRPR-3 for both sensory and locomotor arousal is RID, a single neuroendocrine cell specialized for the release of neuropeptides that responds to mechanical stimuli in a FLP-20-dependent manner. Thus, FLP-20 peptides function as an afferent arousal signal that conveys mechanosensory information to central neurons that modulate arousal and other behavioral states.
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http://dx.doi.org/10.1016/j.neuron.2018.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162336PMC
September 2018

Habituation as an adaptive shift in response strategy mediated by neuropeptides.

NPJ Sci Learn 2017 18;2. Epub 2017 Aug 18.

1Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC Canada V6T 2B5.

Habituation is a non-associative form of learning characterized by a decremented response to repeated stimulation. It is typically framed as a process of selective attention, allowing animals to ignore irrelevant stimuli in order to free up limited cognitive resources. However, habituation can also occur to threatening and toxic stimuli, suggesting that habituation may serve other functions. Here we took advantage of a high-throughput learning assay to investigate habituation to noxious stimuli. Using real-time computer vision software for automated behavioral tracking and optogenetics for controlled activation of a polymodal nociceptor, ASH, we found that neuropeptides mediated habituation and performed an RNAi screen to identify candidate receptors. Through subsequent mutant analysis and cell-type-specific gene expression, we found that pigment-dispersing factor (PDF) neuropeptides function redundantly to promote habituation via PDFR-1-mediated cAMP signaling in both neurons and muscles. Behavioral analysis during learning acquisition suggests that response habituation and sensitization of locomotion are parts of a shifting behavioral strategy orchestrated by pigment dispersing factor signaling to promote dispersal away from repeated aversive stimuli.
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http://dx.doi.org/10.1038/s41539-017-0011-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161508PMC
August 2017

Habituation is altered in neuropsychiatric disorders-A comprehensive review with recommendations for experimental design and analysis.

Neurosci Biobehav Rev 2017 Sep 1;80:286-305. Epub 2017 Jun 1.

Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia, V6T 1Z4, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Rm F221, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5, Canada. Electronic address:

Abnormalities in the simplest form of learning, habituation, have been reported in a variety of neuropsychiatric disorders as etiologically diverse as Autism Spectrum Disorder, Fragile X syndrome, Schizophrenia, Parkinson's Disease, Huntington's Disease, Attention Deficit Hyperactivity Disorder, Tourette's Syndrome, and Migraine. Here we provide the first comprehensive review of what is known about alterations in this form of non-associative learning in each disorder. Across several disorders, abnormal habituation is predictive of symptom severity, highlighting the clinical significance of habituation and its importance to normal cognitive function. Abnormal habituation is discussed within the greater framework of learning theory and how it may relate to disease phenotype either as a cause, symptom, or therapy. Important considerations for the design and interpretation of habituation experiments are outlined with the hope that these will aid both clinicians and basic researchers investigating how this simple form of learning is altered in disease.
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http://dx.doi.org/10.1016/j.neubiorev.2017.05.028DOI Listing
September 2017

Dopamine receptor DOP-4 modulates habituation to repetitive photoactivation of a C. elegans polymodal nociceptor.

Learn Mem 2016 10 15;23(10):495-503. Epub 2016 Sep 15.

DM Centre for Brain Health, University of British Columbia, Vancouver V6T 2B5, Canada Department of Psychology, University of British Columbia, Vancouver V6T 1Z4, Canada

Habituation is a highly conserved phenomenon that remains poorly understood at the molecular level. Invertebrate model systems, like Caenorhabditis elegans, can be a powerful tool for investigating this fundamental process. Here we established a high-throughput learning assay that used real-time computer vision software for behavioral tracking and optogenetics for stimulation of the C. elegans polymodal nociceptor, ASH. Photoactivation of ASH with ChR2 elicited backward locomotion and repetitive stimulation altered aspects of the response in a manner consistent with habituation. Recording photocurrents in ASH, we observed no evidence for light adaptation of ChR2. Furthermore, we ruled out fatigue by demonstrating that sensory input from the touch cells could dishabituate the ASH avoidance circuit. Food and dopamine signaling slowed habituation downstream from ASH excitation via D1-like dopamine receptor, DOP-4. This assay allows for large-scale genetic and drug screens investigating mechanisms of nociception modulation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026203PMC
http://dx.doi.org/10.1101/lm.041830.116DOI Listing
October 2016

Accumulation of Laminin Monomers in Drosophila Glia Leads to Glial Endoplasmic Reticulum Stress and Disrupted Larval Locomotion.

J Neurosci 2016 Jan;36(4):1151-64

Departments of Zoology and Neuroscience Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Unlabelled: The nervous system is surrounded by an extracellular matrix composed of large glycoproteins, including perlecan, collagens, and laminins. Glial cells in many organisms secrete laminin, a large heterotrimeric protein consisting of an α, β, and γ subunit. Prior studies have found that loss of laminin subunits from vertebrate Schwann cells causes loss of myelination and neuropathies, results attributed to loss of laminin-receptor signaling. We demonstrate that loss of the laminin γ subunit (LanB2) in the peripheral glia of Drosophila melanogaster results in the disruption of glial morphology due to disruption of laminin secretion. Specifically, knockdown of LanB2 in peripheral glia results in accumulation of the β subunit (LanB1), leading to distended endoplasmic reticulum (ER), ER stress, and glial swelling. The physiological consequences of disruption of laminin secretion in glia included decreased larval locomotion and ultimately lethality. Loss of the γ subunit from wrapping glia resulted in a disruption in the glial ensheathment of axons but surprisingly did not affect animal locomotion. We found that Tango1, a protein thought to exclusively mediate collagen secretion, is also important for laminin secretion in glia via a collagen-independent mechanism. However loss of secretion of the laminin trimer does not disrupt animal locomotion. Rather, it is the loss of one subunit that leads to deleterious consequences through the accumulation of the remaining subunits.

Significance Statement: This research presents a new perspective on how mutations in the extracellular matrix protein laminin cause severe consequences in glial wrapping and function. Glial-specific loss of the β or γ laminin subunit disrupted glia morphology and led to ER expansion and stress due to retention of other subunits. The retention of the unpaired laminin subunit was key to the glial disruption as loss of Tango1 blocked secretion of the complete laminin trimer but did not lead to glial or locomotion defects. The effects were observed in the perineurial glia that envelope the peripheral and central nervous systems, providing evidence for the importance of this class of glia in supporting nervous system function.
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http://dx.doi.org/10.1523/JNEUROSCI.1797-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604820PMC
January 2016

Developmental Function of the PHR Protein RPM-1 Is Required for Learning in Caenorhabditis elegans.

G3 (Bethesda) 2015 Oct 13;5(12):2745-57. Epub 2015 Oct 13.

Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458

The PAM/Highwire/RPM-1 (PHR) proteins are signaling hubs that function as important regulators of neural development. Loss of function in Caenorhabditis elegans rpm-1 and Drosophila Highwire results in failed axon termination, inappropriate axon targeting, and abnormal synapse formation. Despite broad expression in the nervous system and relatively dramatic defects in synapse formation and axon development, very mild abnormalities in behavior have been found in animals lacking PHR protein function. Therefore, we hypothesized that large defects in behavior might only be detected in scenarios in which evoked, prolonged circuit function is required, or in which behavioral plasticity occurs. Using quantitative approaches in C. elegans, we found that rpm-1 loss-of-function mutants have relatively mild abnormalities in exploratory locomotion, but have large defects in evoked responses to harsh touch and learning associated with tap habituation. We explored the nature of the severe habituation defects in rpm-1 mutants further. To address what part of the habituation circuit was impaired in rpm-1 mutants, we performed rescue analysis with promoters for different neurons. Our findings indicate that RPM-1 function in the mechanosensory neurons affects habituation. Transgenic expression of RPM-1 in adult animals failed to rescue habituation defects, consistent with developmental defects in rpm-1 mutants resulting in impaired habituation. Genetic analysis showed that other regulators of neuronal development that function in the rpm-1 pathway (including glo-4, fsn-1, and dlk-1) also affected habituation. Overall, our findings suggest that developmental defects in rpm-1 mutants manifest most prominently in behaviors that require protracted or plastic circuit function, such as learning.
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http://dx.doi.org/10.1534/g3.115.021410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683646PMC
October 2015

Finding a worm's internal compass.

Elife 2015 Aug 5;4. Epub 2015 Aug 5.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada.

A pair of neurons is required for nematodes to be able to navigate using the Earth's magnetic field.
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http://dx.doi.org/10.7554/eLife.09666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525074PMC
August 2015

Cross-referencing online activity with the connectome to identify a neglected but well-connected neuron.

Curr Biol 2015 May;25(10):R405-6

Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5 Canada; Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia, V6T 1Z4 Canada. Electronic address:

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http://dx.doi.org/10.1016/j.cub.2015.03.043DOI Listing
May 2015

Casting a genome-wide net for learning mutants.

Neuron 2015 Mar;85(6):1147-8

Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada; Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4, Canada. Electronic address:

Wolman et al. (2015) report a forward genetic screen in zebrafish that implicated pregnancy-associated plasma protein-aa in habituation of the acoustic startle response. PAPP-AA is expressed in the underlying circuit, including Mauthner cells, and regulates habituation via IGF signaling.
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http://dx.doi.org/10.1016/j.neuron.2015.03.016DOI Listing
March 2015

Habituation mechanisms and their importance for cognitive function.

Front Integr Neurosci 2014 8;8:97. Epub 2015 Jan 8.

Department of Psychology, University of British Columbia Vancouver, BC, Canada ; Brain Research Centre, University of British Columbia Vancouver, BC, Canada.

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http://dx.doi.org/10.3389/fnint.2014.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288050PMC
January 2015

A review of transgenerational epigenetics for RNAi, longevity, germline maintenance and olfactory imprinting in Caenorhabditis elegans.

J Exp Biol 2015 Jan;218(Pt 1):41-9

Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, BC, Canada, V6T 2B5

Inheritance of acquired characteristics without changes in DNA sequence has been called transgenerational epigenetics. This review looks at studies that used the model system Caenorhabditis elegans to uncover mechanisms of transgenerational epigenetics in studies of RNA interference, studies of longevity, studies of germline continuity and a study on olfactory imprinting. In each case, researchers have uncovered critical roles for small RNAs and for Argonaute proteins. They have revealed several different genetic pathways that mediate RNA silencing of foreign RNA for a few or for many generations, as well as identifying a related pathway responsible for recognized self-generated RNAs. Together, these studies have greatly advanced our understanding of trangenerational epigenetics.
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http://dx.doi.org/10.1242/jeb.108340DOI Listing
January 2015

Assaying mechanosensation.

WormBook 2014 Jul 31. Epub 2014 Jul 31.

Department of Biological Sciences, Columbia University, New York NY, USA.

C. elegans detect and respond to diverse mechanical stimuli using neuronal circuitry that has been defined by decades of work by C. elegans researchers. In this WormMethods chapter, we review and comment on the techniques currently used to assess mechanosensory response. This methods review is intended both as an introduction for those new to the field and a convenient compendium for the expert. A brief discussion of commonly used mechanosensory assays is provided, along with a discussion of the neural circuits involved, consideration of critical protocol details, and references to the primary literature.
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http://dx.doi.org/10.1895/wormbook.1.172.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448936PMC
July 2014

Mechanisms of plasticity in a Caenorhabditis elegans mechanosensory circuit.

Front Physiol 2013 23;4:88. Epub 2013 Aug 23.

Brain Research Centre, University of British Columbia Vancouver, BC, Canada.

Despite having a small nervous system (302 neurons) and relatively short lifespan (14-21 days), the nematode Caenorhabditis elegans has a substantial ability to change its behavior in response to experience. The behavior discussed here is the tap withdrawal response, whereby the worm crawls backwards a brief distance in response to a non-localized mechanosensory stimulus from a tap to the side of the Petri plate within which it lives. The neural circuit that underlies this behavior is primarily made up of five sensory neurons and four pairs of interneurons. In this review we describe two classes of mechanosensory plasticity: adult learning and memory and experience dependent changes during development. As worms develop through young adult and adult stages there is a shift toward deeper habituation of response probability that is likely the result of changes in sensitivity to stimulus intensity. Adult worms show short- intermediate- and long-term habituation as well as context dependent habituation. Short-term habituation requires glutamate signaling and auto-phosphorylation of voltage-dependent potassium channels and is modulated by dopamine signaling in the mechanosensory neurons. Long-term memory (LTM) for habituation is mediated by down-regulation of expression of an AMPA-type glutamate receptor subunit. Intermediate memory involves an increase in release of an inhibitory neuropeptide. Depriving larval worms of mechanosensory stimulation early in development leads to fewer synaptic vesicles in the mechanosensory neurons and lower levels of an AMPA-type glutamate receptor subunit in the interneurons. Overall, the mechanosensory system of C. elegans shows a great deal of experience dependent plasticity both during development and as an adult. The simplest form of learning, habituation, is not so simple and is mediated and/or modulated by a number of different processes, some of which we are beginning to understand.
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http://dx.doi.org/10.3389/fphys.2013.00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750945PMC
August 2013

The FMRFamide-related neuropeptide FLP-20 is required in the mechanosensory neurons during memory for massed training in C. elegans.

Learn Mem 2013 Jan 16;20(2):103-8. Epub 2013 Jan 16.

Department of Biology, City College of the City University of New York, NY 10031, USA.

Lasting memories are likely to result from a lasting change in neurotransmission. In the nematode Caenorhabditis elegans, spaced training with a tap stimulus induces habituation to the tap that lasts for >24 h and is dependent on glutamate transmission, postsynaptic AMPA receptors, and CREB. Here we describe a distinct, presynaptic mechanism for a shorter lasting memory for tap habituation induced by massed training. We report that a FMRFamide-related peptide (FMRF = Phe-Met-Arg-Phe-NH(2)), FLP-20, is critical for memory lasting 12 h following massed training, but is not required for other forms of memory. Massed training correlated with a flp-20-dependent increase in synaptobrevin tagged with green fluorescent protein in the presynaptic terminals of the PLM mechanosensory neurons that followed the timeline of the memory trace. We also demonstrated that flp-20 is required specifically in the mechanosensory neurons for memory 12 h after massed training. These findings show that within the same species and form of learning, memory is induced by distinct mechanisms to create a lasting alteration in neurotransmission that is dependent upon the temporal pattern of training: memory of spaced training results from postsynaptic changes in the interneurons of the neural circuit, whereas memory of massed training results from presynaptic changes in the mechanosensory neurons of the neural circuit.
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http://dx.doi.org/10.1101/lm.028993.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549060PMC
January 2013