Canada Brain Power

Tag: Alberta

  • Identification of the Pannexin-1 channel in the brain as a target to treat opioid withdrawal symptoms

    Identification of the Pannexin-1 channel in the brain as a target to treat opioid withdrawal symptoms

    Brain Star Award feature: Erika Harding, Nicole Burma, Charlie Hong Ting Kwok, University of Calgary, won this prize based on the excellence of the research and its potential benefits to the health of Canadians. Brain Star Awards are presented by the Canadian Association for Neuroscience (CAN) and the Canadian Institutes of Health’s Institute of Neurosciences, Mental Health and Addiction

    Opioids remain one of the most effective analgesics, with 10-15% of Canadians receiving opioid prescriptions per year. However, opioids are also highly associated with substance use disorders and overdose related deaths. Last year alone, over 7000 Canadians passed away from opioid overdose related complications. Many people who start with an opioid prescription enter a feedforward cycle of use reinforced by significant withdrawal symptoms. Patients report these symptoms as so aversive they will do anything to avoid them, and current treatments for opioid use disorder have a high degree of relapse. There is a clear need for better treatments of opioid withdrawal.

    Research done by Drs. Erika Harding, Charlie Hong Ting Kwok and Nicole Burma in the laboratory of Dr. Tuan Trang at the University of Calgary has identified a channel called Pannexin-1, present in a brain area called the Locus Coeruleus as a potential target to alleviate opioid withdrawal symptoms.

    Read the full story here: https://can-acn.org/brain-star-award-winners-erika-harding-charlie-kwok-and-nicole-burma/

    Read the original scientific publication:

    Kwok CHT*, Harding EK*, Burma NE*, Markovic T, Massaly N, van den Hoogen NJ, Stokes-Heck S, Gambeta E, Komarek K, Yoon HJ, Navis KE, McAllister BB, Canet-Pons J, Fan C, Dalgarno R, Gorobets E, Papatzimas JW, Zhang Z, Kohro Y, Anderson CL, Thompson RJ, Derksen DJ, Morón JA, Zamponi GW, Trang T. Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry. Nat Commun. 2024 Jul 24;15(1):6264. doi: 10.1038/s41467-024-50657-7. PMID: 39048565

    https://www.nature.com/articles/s41467-024-50657-7

  • Identification of CD33m as a new protective factor in Alzheimer’s Disease development.

    Identification of CD33m as a new protective factor in Alzheimer’s Disease development.

    Brain Star Award Feature: Ghazaleh Eskandari-Sedighi, University of Alberta, won this prize based on the excellence of the research and its potential benefits to the health of Canadians. Brain Star Awards are presented by the Canadian Association for Neuroscience (CAN) and the Canadian Institutes of Health’s Institute of Neurosciences, Mental Health and Addiction

    Immune cells in the brain, called microglia, are thought to be critical in Alzheimer’s disease (AD) development through numerous functions, including their ability to remove amyloid beta (Aβ), which is protein that accumulates in the brains of AD patients. In this study, Ghazaleh Eskandari-Sedighi, working in Matthew Macauley’s laboratory at the University of Alberta, focused on understanding the mechanism of action of a protein called CD33, which has been identified as one of the top-ranked drivers in the development of AD and that is predominantly found in microglia in the brain. By transferring different versions (called isoforms) of this protein in a mouse model of AD, they were able to show that these different isoforms have opposite effects on microglial cells and AD progression.

    CD33 is a receptor that modulates immune response that exists in two forms:  a long isoform CD33M (Major) and a short isoform: CD33m (minor). Understanding how CD33 isoforms differentially impact microglial cell function has been challenging due to functional divergence between CD33 from mouse and humans. In this study, the researchers introduced the human CD33 gene in a mouse model of AD, which accumulates Aβ protein. In these mice, they found that CD33 isoforms have opposing effects on the response of microglia to Aβ accumulation. The larger CD33M increases the total level of Aβ and formation of plaques with a diffuse nature, which correlates with fewer number of microglia as well as higher number of dysfunctional neurons. In contrast, CD33m gives rise to opposite outcomes; beyond decreasing total Aβ levels, CD33m skews formation of compact Aβ deposits, correlating with increased microglia and fewer dysfunctional neurons. Overall, this work reveals how CD33, as a top genetic susceptibility factor for AD, is connected to microglial cell function.

    Read the full story here: https://can-acn.org/brain-star-award-winnerghazaleh-eskandari-sedighi/

    Scientific publication: Eskandari-Sedighi, G., Crichton, M., Zia, S. et al. Alzheimer’s disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice. Mol Neurodegeneration 19, 42 (2024).

    https://doi.org/10.1186/s13024-024-00734-8

  • Uncovering the role of cilia in astrocyte development and function

    Uncovering the role of cilia in astrocyte development and function

    Brain Star Award feature: Lizheng Wang, University of Calgary, won this prize based on the excellence of the research and its potential benefits to the health of Canadians. Brain Star Awards are presented by the Canadian Association for Neuroscience (CAN) and the Canadian Institutes of Health’s Institute of Neurosciences, Mental Health and Addiction

    Astrocytes are a type of cells that act as crucial regulators of nearly all aspects of the brain. Different types of astrocytes exist; however, little is known about how different subtypes of astrocytes are created during development to differentially support their local neural circuits. Lizheng Wang, working in the laboratory of Jiami Guo at the University of Calgary, has discovered that a structure called the primary cilia acts as a small signaling antennae to transmit local cues and drive the region-specific diversification of astrocytes within the developing brain, and plays important roles in brain development.

    Discovered over 100 years ago, primary cilia are only beginning to be appreciated for their significance in the brain. Researchers have recently demonstrated that primary cilia of neurons are indispensable in regulating major neuronal development and functions, while the presence and function of cilia in astrocytes remained unexplored. This study shows that perturbation of astrocytic cilia leads to disruption of neuronal development and connections in the brain. Mice with primary ciliary deficient astrocytes show behavioral deficits in sensorimotor function, sociability, learning and memory.

    Read the full story here

  • Identifying a gene critical for vision

    Identifying a gene critical for vision

    A gene spanning cilia function is critical for vision

    Cilia are organelles present in most eukaryotic cells and are categorized into discrete groups: motile cilia (such as those found on spermatozoa) are required for locomotion and fluid dynamics whereas non-motile cilia (like those found in photoreceptors of the eye) are required for cell signalling. Paul William Chrystal, post-doctoral fellow at the University of Alberta, led a study that demonstrated that CFAP20 breaks this dichotomy by functioning in BOTH motile and non-motile cilia. They also identified CFAP20 as a novel cause of childhood blindness in humans, increasing the list of therapeutic targets for patients with the disease.

    Paul William Chrystal won a CAN-CIHR-INMHA Brain Star award for these discoveries.

    CFAP20 protein functions at the cilium inner junction (IJ), and is critical for connecting the component A- and B-microtubules together. The IJ is important in both motile and non-motile cilia function. When disrupted in zebrafish, cfap20 mutants displayed defective heart patterning and spine development (linked to motile cilia), and progressive retinal dystrophy and vision loss (linked to non-motile cilia). Mutations in the worm (C. elegans) Cfap-20 gene caused learning deficits resulting from dysfunction of non-motile cilia on sensory neurons. The researchers then showed that Cfap-20 loss caused an “open-seam” phenotype where the IJ was not connected, and the tubules were splayed apart. In the photoreceptor cells this led to shedding of parts of the cell and eventual cell death. These results show that CFAP20 bridges the two disparate cilia categories, and plays many important roles in cells of various organisms.

    In conjunction, this group identified CFAP20 variants as a novel cause of blindness in humans. Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy, with visual deficit often starting in childhood. Sufferers experience tunnel vision and early-onset blindness. Human sequencing identified 8 patients, from 4 families, with RP and CFAP20 variants predicted to be disease-causing. By introducing the human CFAP20 variants into their mutant zebrafish, Chrystal et al. showed that patient variants retained different levels of functionality, and this correlated with patient disease severity. The researchers also propose CFAP20 as a putative cause of other disorders involving cilia (infertility, mental disability, epilepsy which were all found in this patient cohort) arising from more damaging CFAP20 mutations. Functional testing demonstrated that some mutations were more damaging to function than others and could explain the variable levels of symptoms observed between patients. Additionally, functional testing has provided evidence that reintroducing the wildtype CFAP20 sequence can reverse symptoms, the strategy used in human gene therapy.

    This work discovered a novel disease mechanism for retinitis pigmentosa originating at the inner junction, and could implicate other proteins that function at the IJ. While RP is the most common form of inherited retinal dystrophy, only one therapeutic currently exists, Luxturna, a gene-specific therapy to mutations in a gene called RPE65. This paper shows that CFAP20 is a novel cause of RP, adding to the molecular genetic underpinnings of the condition. Furthermore, these studies have provided 4 families with a genetic diagnosis that will allow for subsequent genetic counselling and intervention.

    This project was a hugely collaborative effort, with thirty listed authors. A major strength of this project was the establishment of both national (University of Alberta, Simon Fraser University, University of Calgary) and international (University College London, Moorfields Hospital) collaboration. These collaborations allowed for the researchers to combine human genetics and clinical reporting, C. elegans and zebrafish disease modelling, and a mammalian cell culture model that strengthened the conclusions. While these groups had no previous history of collaboration, they have now developed strong working relationships and hope to collaborate again in the future.

    About Paul William Chrystal

    Paul William Chrystal completed his PhD in developmental genetics at Newcastle University, UK before moving to Edmonton, Canada for postdoctoral studies. He led this study in the laboratory of Dr. W. Ted Allison at the University of Alberta, completing the zebrafish disease modelling, and contributing to analysis, and manuscript preparation. Dr. Chrystal is passionate about understanding the genetics of inherited retinal diseases and translating this knowledge into patient therapeutics. He currently works at the University of Toronto, Canada as a postdoctoral fellow testing gene therapy approaches for preservation of sight in Usher’s syndrome.

    Sources of funding

    This project was funded by the Canadian Institutes of Health Research (CIHR; grants PJT-156042 and MOP-142243), CIHR Rare Disease Models & Mechanisms award (M-UBC-27R00211), and the Natural Sciences and Engineering Research Council of Canada (NSERC; grant RGPIN-2019-04825). Student grants provided by NSERC, Alberta Innovates and CIHR. The UK team were supported by Fight For Sight UK (5045/46), National Institute of Health Research Biomedical Research Centre (NIHRBRC), NIHR-BRC Moorfields Eye Charity (Stephen and Elizabeth Archer in memory of Marion Woods), Wellcome Trust (206619/Z/17/Z), Science Foundation Ireland in partnership with BBSRC (16/BBSRC/3394), and Imperial Health Charity. Additional support provided by Olive Young Fund, University Hospital Foundation, Women and Children’s Health Research Institute Innovation Grant (WCHRI 2846), and the Michael Smith Foundation for Health Research.

    Scientific publication

    Paul W. Chrystal, Nils J. Lambacher, Lance P. Doucette, James Bellingham, Elena R. Schiff, Nicole C.L. Noel, Chunmei Li,  Sofia Tsiropoulou, Geoffrey A. Casey, Yi Zhai, Nathan J. Nadolski, Mohammed H. Majumder, Julia Tagoe, Fabiana D’Esposito, Maria Francesca Cordeiro, Susan Downes, Jill Clayton-Smith, Jamie Ellingford, Genomics England Research Consortium, Omar A. Mahroo, Jennifer C. Hocking, Michael E. Cheetham, Andrew Webster, Gert Jansen, Oliver E. Blacque, W. Ted Allison, Ping Yee Billie Au, Ian M. MacDonald, Gavin Arno, Michel R. Leroux.
    “The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision“. Nat Commun (2022), 13,

    https://www.nature.com/articles/s41467-022-33820-w

  • The latest weapon against Alzheimer’s disease could be as simple as touch

    The latest weapon against Alzheimer’s disease could be as simple as touch

    A study by a team of University of Lethbridge neuroscientists has shown that tactile stimulation shows much promise as a non-invasive method of slowing the onset of dementia in aging mice and could be an additional therapeutic intervention for people with Alzheimer’s disease.

    January is Alzheimer’s Awareness Month and the Alzheimer Society encourages everyone to learn more about dementia and its impact on Canadians. Alzheimer’s disease (AD) is the most common form of dementia and represents a global health crisis.

    Current treatment options only serve to slow the progression of the disease, not to cure or prevent it. That’s why researchers at the Canadian Centre for Behavioural Neuroscience are working hard to increase knowledge about what happens in the brain with AD and find more therapeutic treatments. A recent study by Drs. Bryan Kolb, Majid Mohajerani and their team points the way to a possible easily accessible treatment for AD in humans. Working with a mouse model of AD, the researchers found that tactile stimulation (TS) in the form of light massaging slowed the onset of AD.

    Read the full story on the University of Lethbridge website

  • Exoskeleton robot helps researchers shed new light on learning and stroke recovery

    Exoskeleton robot helps researchers shed new light on learning and stroke recovery

    UCalgary clinical trial maps how we learn motor skills, and the results could be a game-changer for stroke rehabilitation.

    This morning, you probably reached out of bed to turn off your alarm clock, and later brushed your teeth or buttoned a shirt. Those movements are routine; mundane, even. You are long past the point of wondering how you learned to do any of those things and don’t give a second thought to the complexity of what happened in your brain so that your arm could lift your cup of coffee. (more…)

  • Watch University of Calgary’s Lecture of a Lifetime 2022 with Dr. Samuel Weiss

    Watch University of Calgary’s Lecture of a Lifetime 2022 with Dr. Samuel Weiss

    Sustaining a career that includes making two major scientific discoveries, winning a Gairdner Award, founding the Hotchkiss Brain Institute, and a foray into health policy requires fuel — lots of it — and Dr. Samuel Weiss, PhD’83, knows how to find it.

    From being dragged back to school by his mom for the third year of his undergrad in 1977, to being encouraged to bring his knowledge and expertise to Ottawa last year by Canada’s minister of mental health and addictions, Weiss says there was one driving force at play in every stage of his career: Inspiration.

    (more…)

  • UCalgary researchers use computer modelling to simulate impact of Alzheimer’s on the brain

    UCalgary researchers use computer modelling to simulate impact of Alzheimer’s on the brain

    New way to model neural disease could lead to better understanding

    Author: Shea Coburn, Hotchkiss Brain Institute

    A deep neural network is a computerized brain-inspired machine learning model, which uses many layers of simulated neurons to mimic the function of the cerebral cortex. Each layer in the network creates more complex activity, which simulates the way information is processed in the human brain. These networks can be designed to replicate structures in the brain, allowing researchers and scientists to model specific brain functions more easily.

    University of Calgary researchers have taken a new approach to using these networks for modelling of the human brain. Most studies, to date, have used deep neural networks to look at healthy brain function. These investigators wanted to know if these models could be applied to better understand brain function in a diseased brain. In this case, looking at posterior cortical atrophy (PCA), an atypical form of Alzheimer’s disease affecting the visual cortex.

    “Using these artificial networks to model dementia could enable an improved understanding of the disease,” says Dr. Nils Forkert, PhD, an associate professor in the Cumming School of Medicine and principal investigator. “It allows us to have one well-established reference model that can be damaged in many different ways versus having to image hundreds of patients with different neurodegeneration patterns to obtain similar information.”

    In the findings published in Frontiers in Neuroinformatics, Forkert, along with Dr. Anup Tuladhar, PhD, Dr. Zahinoor Ismail, MD, and PhD student Jasmine A. Moore used a standard neural network for automatic object recognition in images, titled VGG19, to simulate a brain with dementia symptoms. The researchers progressively damaged connections between neurons in the network, to mimic neurodegeneration in the visual system of the human brain.

    Read the full story on the University of Calgary website