My 2019 research highlights include installing my photo-manipulation – electrophysiology suite and collecting preliminary data from my lab. As well, my collaborators and I have recently had a paper accepted in the Proceeding of the National Academy of Science USA (PNAS) Journal. PNAS is a highly prestigious multi-disciplinary journal that publishes high-impact original research.
Highlights from the past year included being invited to give two guest lectures, one for the University of Alberta (“Hot Topics in Kinesiology Research”) focusing on my clinical research to evaluate and optimize exercise function after spinal cord injury (SCI) and one in Vancouver (Canadian Spinal Cord Injury Research Meeting) examining the spinal neural mechanisms integrating the neural circuitry generating movement (exercise) with the spinal neural autonomic circuitry that provides metabolic and homeostatic support for movement exercise. These invitations arose from my review of the exercise and locomotion research literature, in which I formulated and presented a “New conceptual framework for the integrated neural control of locomotor and sympathetic function: implications for exercise after SCI”. I was invited to join a national clinical practice guideline consensus group to develop best practice guidelines on a range of SCI-specific health topics, ranging from acute hospital care to exercise to prevention of secondary health complications after SCI. I was invited to join an international committee tasked with developing the first bone health guidelines for individuals with SCI for the Paralyzed Veterans of America. Finally, I was pleased to be nominated for a Tier 2 Canada Research Chair by the University of Manitoba.
During 2018-2019, my research in the field of neuronal cell death and oxidative stress has uncovered novel aspects of cell death machinery including novel aspects of lysosomal mediated damage in spinal cord injury. My lab also has discovered one of key molecular events in induction of neuronal cell death that is mediated by decreased antioxidant levels and changes in neuronal nuclei in neurodegenerative diseases. I have received a 5-year NSERC grant (2019-2024, $160,000). I have been invited to local, national and international meetings to present these data. We have initiated new interdepartmental collaborations with Dr. Sabine Mai to employ super high resolution microscopy. I have formed a university-wide team to examine epigenetic changes that are mediated in neurodegenerative diseases. This will provide the foundation needed for my next CIHR grant application in 2020. We are currently finalizing two manuscripts for submission.
During 2019 I have expanded curriculum leadership roles, and continued to be a main contributor for a range of Neurosciences related teaching in undergraduate and graduate level educational programs. Within undergraduate medical education (UGME) of the Max Rady College of Medicine, I am a Course Director and lecturer (for the Med I Foundation of Medicine course), and am the neurophysiology lead and main neurophysiology lecturer for the Med I Neurosciences courses. I also help administrate UGME curriculum by serving on the Pre-Clerkship Curriculum, Pre-Clerkship Evalation, and Academic Appeals committees for the MRCoM. At the Department level, am the Division Head of the Neurosciences and Spinal Cord Injury Division (of the Department of Physiology and Pathophysiology), am Course Director for several graduate level courses. Additionally, I am the Director of our new Post-baccalaureate Diploma in Medical Physiology and Pathophysiology program (first intake fall 2020). In keeping with my expanding roles in development and delivery of a variety of educational programs within the Rady Faculty of Health Sciences, during 2019 I was appointed as Associate Head – Education for the Department of Physiology and Pathophysiology.
I was honoured to be asked to be one of 7 speakers presenting at a symposium in Chicago, IL in October, to honour the contributions of Dr. V Reggie Edgerton, with whom I spent 2 years as a postdoc in the mid-1970’s at UCLA. Other speakers included R. Lieber from Northwestern U, R. Nichols from Emory U, Gregoire Courtin from Lausanne, Susan Harkema from Louisville, Y. Gerasimenko from UCLA, and Sten Grillner from the Karolinska in Stockholm. Since the event was held the day before the beginning of the Society for Neuroscience Meeting, many of Edgerton’s colleagues and friends from around the world attended, and many stories were shared, both scientific and not so.
The work on the project funded by MSCIRC is part of the PhD work of Mona Nazzal, and it is being done in collaboration with Dr. Urszula Slawinska of the Nencki Institute for Experimental Biology in Warsaw, Poland. We have completed three series of experiments involving the use of DREADD (Designer Receptors Exclusively Activated by a Designer Drug) technology in an attempt to excite grafted cells transfected with an excitatory DREADD using a viral vector. In each case, the presence of the DREADD enhanced locomotor activity in the presence of the designer drugs used to activate the cells. We have done a final series of experiments using a new designer drug, Compound 21, which is effective for facilitating locomotion, using the funds provided by this grant. The two abstracts, listed below, have been produced based on this work. We have harvested the tissue from these rats, and we are in the process of carrying out the immunohistochemistry in an effort to identify the DREADD positive cells in the grafts from these animals. A manuscript based on these studies will be prepared when this data is available. These experiments establish that DREADD positive neurons in the graft can be excited by Compound 21 to produce improved locomotion, confirming our hypothesis. What remains is to determine the identity of the effective cells (those that are labeled with the reporter associated with the DREADD). We expect a portion of them to be serotonergic and/or glutamatergic.
- Nazzal M., Armstrong K, Cabaj A, Majczynski H, Slawinska U., Jordan L, Achieving the proper balance between DREADD ligand effects on the hM3D(Gq) receptor and direct effects on serotonin receptors – a key for locomotor recovery in paraplegic rats. Canadian Health Science Research Forum, Winnipeg-Canada, 2018
- Nazzal M., Armstrong K, Cabaj A, Majczynski H, Slawinska U., Jordan L, Improved locomotor recovery with chemogenetic activation of grafted serotonergic neurons in paraplegic rats. Manitoba Neuroscience Network Meeting, Winnipeg-Canada, 2018.
Work is also advancing in the area of chemogenetic and optogenetic activation of serotonergic cells transfected with DREADS in vivo, to determine the specific role these cells normally paly in the intact animal. Mona Nazzal and Katrina Armstrong are the students working on these projects. The following presentations of this data have taken place. This work is funded in part from a joint CIHR grant with Dr. Katinka Stecina. Manuscripts describing these results are in preparation.
- Armstrong, S. Bhavya, M. Nazzal, X.Chen, U. Slawinska, K. Stecina, L.M. Jordan. Serotonergic neurons involved in the excitation of spinal neurons. SFN 2019 (Abstract)
- Armstrong, S. Bhavya, M. Nazzal, X. Chen, U. Slawinska, L.M. Jordan. Downregulation of 5-HT7 receptors in adult rats and selective serotonergic neuron excitation changes hindlimb activity during fictive locomotion. MNN 2019 (Abstract)
A third project addressing the plasticity of afferent pathways that facilitate locomotion is nearing completion. We are scheduled to do six more experiments to address this issue. Achieving an understanding of the afferent fibers responsible for this facilitation of locomotion will be valuable information for designing rehabilitation strategies for injured patients.
We had a productive year at all fronts in 2019. We published several high impact articles in top-tier journals such as Progress in Neurobiology, GLIA and Journal of Neuroinflammation. I was also involved in several national and international leadership activities. I was invited to serve in the Advisory Board of the International Neurotrauma Society (INTS) and the Executive Committee of the international Women in Multiple Sclerosis (iWiMS) (and Chair of Governance Subcommittee), while continued to serve in the Board of Directors of the Canadian Association for Neuroscience (CAN). I also served on the Organizing and Scientific Advisory Committee of the 3rdAmerica School of Neuroimmunology that was held in Montreal in September 2019. I was invited to chair two sessions of the Interim Symposium on the Nervous System of European ERA-NET NEURON in Bonn, Germany. I continued my participation in the review board of operating grants and fellowships for the New York State Department of Health and the Spinal Cord Injury Research Board (SCIRB), Consortia of ‘External Insults to the Nervous System of European ERA-NET NEURON and the CIHR Cellular and Molecular Neuroscience panel (NSB), the Canada Foundation for Innovation (CFI) review panels. I was also invited to serve on the Health Sciences Panel of the Ontario Research Fund, Research Excellence program, Ontario Ministry of Economic Development, Job Creation and Trade in Toronto, the Biomedical Operating Grants Review Panel and endMS Summer School Review Committee of the Multiple Sclerosis Society of Canada. Additionally, I provide mentorship for a group of junior researchers (graduate students and postdoctoral fellows) for the endMS National Training Program (SPRINT). This is to enhance MS research in Canada by increasing the skills and intent among trainees in MS research area. I work with three trainees from other institutions for one year. I also continued my role as the Associate Editor for the Frontiers in Neurology and BMC Neuroscience journals. At U of M, I joined the Graduate Program Committee of the Department of Physiology and Pathophysiology, I served on the 2019 Children’s Hospital Research Institute of Manitoba, Operating Grant Review Panel and Faculty Search Committee, Department of Physiology and Pathophysiology.
Members of Dr. Nagy’s group continue to delve into the nature of electrical synapses formed by gap junctions composed of connexin36 in the central nervous system. They have studied the deployment of these synapses in a number of neuronal networks, including most recently their presence among unmyelinated primary afferent sensory fibers. With respect to delineation of the macromolecular structural organization of gap junctions that create electrical synapses, they have extended knowledge by showing association of several adherens junction proteins with these synapses. Further, they have reported evidence that connexin36 interacts with a protein (LNX E3 ubiquitin ligase) that may mediate degradation of this connexin. Summaries of their recent progress has been presented with Nagy’s collaborators in three major reviews focused on electrical synapses in the CNS.
Nothing to report in 2019.
This was an active, fast-spaced year in the labs. In the animal labs, the ongoing projects have brought us exciting results. The pioneering works of my Ph.D. student with the designer receptors is just coming to new heights now after many hours of additional control experiments. The great job of our most recently graduated MSc student, Andre Coleman, has also lead to exciting developments in the autonomic research we started about two years ago. Lots of great publications are expected as a result of these projects. The human lab has also seen a lot of progress this last year – we completed training on the use of all equipment and software systems. We are collecting pilot data for “real research” projects – thanks to the generous support from a new URGP grant. For the first time, our senior PhD students demonstrated some of the human research techniques of the new labs to high school students during the Discovery Day organized by the Canadian Medical Hall of Fame. Participating in several invited talks and also in the “Innovational Research Incentives Scheme” of The Dutch Research Council as an external reviewer has provided me a great opportunity to learn about cutting-edge work on the neural control of sensory and motor function.