Brain Star Awards – Recipients for 2013

Marc Bergeron

Article

Bergeron, Marc, et al. "Chloride extrusion enhancers as novel therapeutics for neurological diseases." Nature Medicine, 19(11), November 2013, p. 1524-1528. DOI: 10.1038/nm.3356

Biosketch

In 2007, I obtained my PhD diploma from Laval University, Quebec. My research has been done at the L’Hôtel-Dieu de Québec Research Center in renal physiology and supported by doctoral scholarships from the Fonds de la Recherche en Santé du Québec and the Société Québécoise d’Hypertension Artérielle. We demonstrated important molecular and functional mechanisms regulating the K+-Cl- cotransporters, known as KCCs (Am J Physiol Renal Physiol 2003; J Biol Chem 2006; J Cell Physiol 2009). After receiving a post-doctoral scholarship from the CIHR, I moved in Switzerland to do a postdoc also in renal physiology at the University of Bern from 2007-2010. We showed an important molecular mechanism of renal proximal tubules to prevent severe hypocitraturia (kidney stones) during an immunosuppressant treatment with cyclosporin A, by decreasing the cell surface expression of the Na+-dicarboxylate cotransporter isoform 1 (J Biol Chem 2011). We also reported a new technique to purify, growth 2D crystals, and study the structure of recombinant human transporters from X. Lævis oocytes (PLoS One 2011). Since 2010, I joined the lab of Professor Yves De Koninck at the Centre de Recherche de l’Institut Universitaire en Santé Mentale de Québec for a postdoc in neuroscience, for which I received a post-doctoral scholarship from the Savoy Foundation. Recently, we reported the founding of a 1st in-class family of compounds enhancing the KCC2 plasma membrane expression for the treatment of neurological diseases (Nat Med 2013).

Significance of the Paper

From a medical point of view, this work validates KCC2 as a druggable target and Cl− modulation as a new mechanism of action for the development of therapeutics for several psychiatric and neurological diseases with impaired Cl− transport, of which the pathophysiology is poorly understood. Although the drug CLP257 cannot be commercialized due to its poor bioavailability, other CLP analogs have been shown to possess more promising therapeutic effects (data not shown in the publication). At the molecular level, we also discovered for the first time an activator specific to KCC2, without effect on NKCC1, which is another important Cl− transporter expressed in the central nervous system. For example, specific and non-specific inhibitors have already existed for both transporters. Therefore, the drug CLP257 constitutes an excellent experimental tool to stimulate KCC2 in vitro. In our work, we clearly demonstrated that one of the studied compounds, CLP257, possesses potent analgesic effects for the treatment of chronic neuropathic pain caused by a peripheral nerve injury. Moreover, because the drug CLP257 acts on Cl− transport through KCC2, this new class of compound could also be used for the treatment of several other psychiatric and neurological diseases with impaired Cl− transport (defective KCC2) such as epilepsy, motor spasticity, stress, anxiety, schizophrenia, and morphine-induced hyperalgesia.

As a result, several international groups have already requested the use of compound CLP257 for their studies. In addition, we are currently attempting to define the exact molecular mechanisms underlying the effect of CLP257 on KCC2. The results of these studies will thus substantially improve our knowledge on impaired Cl− transport pathophysiology.


Kaylena Ehgoetz Martens

Article

Ehgoetz Martens, Kaylena, et al. "Could sensory mechanisms be a core factor that underlies freezing of gait in Parkinson’s disease?" PLoSOne, 8(5), May 2013, p. e62602. DOI: 10.1371/journal.pone.0062602

Biosketch

Kaylena Ehgoetz Martens is currently a PhD student in Cognitive Neuroscience at the University of Waterloo. Her research focuses on understanding how anxiety influences movement in Parkinson’s disease. Kaylena completed her BSc in Kinesiology in 2010 at Wilfrid Laurier University, where she volunteered as an exercise coordinator for a Parkinson’s rehabilitation program offered at the Sun Life Financial Movement Disorders Research Center (MDRC). Throughout her undergraduate she began to take part in research at the centre by completing her undergraduate thesis (published in Movement Disorders)and summer research project funded by an NSERC Undergraduate Summer Research Award (published in PLOS ONE). Kaylena was also awarded a CIHR Master’s Award: Frederick Banting and Charles Best Canada Graduate Scholarship. She completed her MA in Cognitive Neuroscience at the University of Waterloo in collaboration with the MDRC which attempted to understand how underlying sensory deficits might contribute to movement impairments in PD (published in Neuropsychologia), with a specific interest in freezing of gait (published in Neuroscience). Upon completing her Master’s degree, Kaylena was recognized with the Outstanding Achievements Master’s Award. Kaylena continues to study freezing of gait along with other movement impairments using state-of-the-art techniques such as anxiety inducing virtual environments, wireless psychophysiology equipment and advanced motion capture systems. She currently holds a Doctoral Award funded by CIHR in partnership with the Parkinson Society Canada, and was recently selected as one of the CIHR/NMHA Brain Star awardees of 2014.

Significance of the Paper

The current research focuses on understanding how brain dysfunction leads to severe impairments of walking in Parkinson’s disease (PD), known as freezing of gait (FOG). FOG is arguably the most debilitating symptom associated with PD, since it leads to falls, hospitalization, and eventually immobilization. Gaining a greater understanding of the underlying neurological mechanisms of FOG will translate into new treatments and prevention strategies, thereby reducing the burden on patients living with PD, and improving their quality of life. The current study focused on manipulating sensory feedback in order to identify whether sensory-perceptual deficits contribute to these arrests in walking. The most intriguing finding of this study was the link between threat, anxiety, and FOG in PD. This research was the first to study FOG in the dark, which proved to be a very useful method of eliciting FOG. While it is well known that FOG is difficult to elicit in experimental settings, our experiment recorded a record number of FOG episodes. Due to the international impact of these findings, new lines of research into FOG behaviour have been developed both here at our center and across the world.

This research publication has attracted a lot of attention within the seven months it has been released, and has had an enormous impact on the discussion of freezing of gait within the research community. This novel way of studying FOG in the dark has obliged researchers to reconsider how sensory explanations might account for many existing hypotheses surrounding the pathophysiology of freezing of gait.


Tuan Trang

Article

Trang, Tuan, et al. "Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl- homeostasis." Nature Neuroscience, 16(2), February 2013, p. 183-192. DOI: 10.1038/nn.3295

Biosketch

I began my research career as an undergraduate student at Queen’s University. Having enjoyed my time at Queen’s, I stayed on to complete a doctoral degree in pharmacology and toxicology. I studied the spinal mechanisms of opioid analgesia and developed pharmacological strategies for improving the pain-relieving actions of opioid drugs. I then pursued postdoctoral training as a CIHR fellow at the Hospital for Sick Children in Toronto. There, I expanded my area of expertise into the cellular and molecular study of chronic pain. I am currently an assistant professor at the University of Calgary in the Faculties of Veterinary Medicine and Medicine, and I am a full member of the Hotchkiss Brain Institute. My independent research program investigates the critical molecules and processes involved in pain and how these processes can go awry to produce chronic pain. A key focus of my research is on the use of opioid drugs in treating pain. My research is supported by grants from CIHR, NSERC, CFI, and the Rita Allen Foundation/American Pain Society.

Significance of the Paper

Our study tackled two major problems that limit treatment of pain with opiates: hyperalgesia and tolerance. The prevailing view is that both problems are inevitable consequences of opiate use, and that tolerance and hyperalgesia reflect a single underlying mechanism. Our findings dispel this view by uncovering that morphine hyperalgesia, but not tolerance, is mediated by microglia-to-neuron signaling. We demonstrated that microglia signal to neurons by releasing BDNF, which disrupts Cl- homeostasis to cause disinhibition in lamina I neurons. We therefore introduced a new concept – that opiates cause disinhibition as well as inhibition through distinct mechanisms. By interfering at specific nodes of this signaling pathway, we reversed morphine hyperalgesia without affecting morphine analgesia. Therefore, our findings revealed new targets for enhancing the utility of morphine in treating chronic pain.


Francesco Ferrini

Article

Ferrini, Francesco, et al. "Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl- homeostasis." Nature Neuroscience, 16(2), February 2013, p. 183-192. DOI: 10.1038/nn.3295

Biosketch

The connecting thread of my research activity is the role of inhibitory transmission in spinal nociceptive pathways. I attended the PhD program in Neuroscience at the University of Turin in Italy under the supervision of Professor Adalberto Merighi. During my PhD, I mainly focused on pre-synaptic mechanisms modulating inhibitory transmission in the spinal dorsal horn. The results of these studies demonstrated that the activation of nociceptive C fibers and the central release of excitatory neuropeptides (such as substance P) trigger an intense activation of dorsal horn inhibitory circuits. I received my PhD degree in 2007, after which I moved to Laval University in Quebec City for my postdoctoral training. In the laboratory of Professor Yves De Koninck, I investigated inhibitory synaptic plasticity in projection neurons of the spinal dorsal horn. By combining behavioral and electrophysiological data, I have demonstrated that microglia-gated alterations of chloride extrusion capacity in dorsal horn neurons underlay the development of morphine-induced hyperalgesia, one of the major side effects of morphine treatment. My postdoctoral training was funded by a fellowship from University of Turin / Regione Piemonte. I'm presently Assistant Professor at the Department of Veterinary Sciences, University of Turin in Italy. My research activity is focused on neuronal and non-neuronal spinal mechanisms underlying neuropathic pain in animal models.

Significance of the Paper

Our study tackled two major problems that limit treatment of pain with opiates: hyperalgesia and tolerance. The prevailing view is that both problems are inevitable consequences of opiate use, and that tolerance and hyperalgesia reflect a single underlying mechanism. Our findings dispel this view by uncovering that morphine hyperalgesia, but not tolerance, is mediated by microglia-to-neuron signaling. We demonstrated that microglia signal to neurons by releasing BDNF, which disrupts Cl- homeostasis to cause disinhibition in lamina I neurons. We therefore introduced a new concept – that opiates cause disinhibition as well as inhibition through distinct mechanisms. By interfering at specific nodes of this signaling pathway, we reversed morphine hyperalgesia without affecting morphine analgesia. Therefore, our findings revealed new targets for enhancing the utility of morphine in treating chronic pain.


Lisa Julian

Article

Julian, Lisa, et al. "Opposing regulation of Sox2 by cell-cycle effectors E2f3a and E2f3b in neural stem cells." Cell Stem Cell, 12(4), April 2013, p. 440-452. DOI: 10.1016/j.stem.2013.02.001

Biosketch

My research career began at the University of Western Ontario, where I completed BSc and MSc degrees in Biochemistry. My MSc training was performed under the supervision of Dr. Fred Dick, where our research focused on the mechanisms by which the classical pRB/E2F tumour suppressor pathway contributes to cancer development. Interested in merging my training in cancer biology with a long-time interest in neuroscience, I decided to move to Ottawa to pursue my PhD studies with Dr. Ruth Slack, an expert on the role of the pRB/E2F pathway in brain development and neurogenesis. I received my PhD in the summer of 2013 from the University of Ottawa. In my PhD work I focused on mechanisms regulating neural stem cell fate decisions, and discovered that the cell cycle regulators E2f3a and E2f3b work together to control expression of the pluripotency factor Sox2, thereby ensuring the correct balance between neural stem cell maintenance and neurogenesis. I am currently a postdoctoral fellow at the Ottawa Hospital Research Institute in Dr. Bill Stanford’s lab. My research goals are focused on understanding fate decisions that control the generation, maintenance and potential of neural and neural crest stem cells, and to build humanized models of diseases that originate within the neural or neural crest lineages.

Significance of the Paper

In this manuscript we link the pRB/E2F tumor suppressor pathway with regulation of the pluripotency gene Sox2, and show that this interaction is essential for the proper control of stem cell fate decisions in the brain. Our study has provided the first direct evidence that the canonical cell cycle regulatory pathway can impact stem cell function by controlling the expression of pluripotency genes, as opposed to simply regulating cell cycle dynamics. This has major implications for understanding stem cell biology, development and cancer. Specifically, we have demonstrated that two isoforms of the E2f3 transcription factor regulate Sox2 expression in an antagonistic manner, and this regulation controls the balance between neural stem cell self-renewal and differentiation in the developing neocortex and adult brain. Previous studies have demonstrated that the cell cycle machinery affects stem cell fate decisions in multiple cell types; however, little is known regarding the underlying mechanism. Our study fills this gap by demonstrating a surprisingly cell cycle-independent regulatory mechanism in neural stem cells, and suggests that a similar mechanism may underlie cell fate regulation by the cell cycle pathway in other stem cell populations. Furthermore, our study has provided the first direct evidence that the cell cycle machinery impacts mammalian behaviour and cognition, and identifies promising therapeutic targets for the modulation of neuronal networks to treat cortical dysfunction.

Stuart Trenholm

Article

Trenholm, Stuart, et al. "Lag normalization in an electrically coupled neural network." Nature Neuroscience, 16(2), February 2013, p. 154-156. DOI: 10.1038/nn.3308

Biosketch

After obtaining a Bachelor’s degree from the University of Victoria, I migrated eastward for graduate school at Dalhousie University in Halifax. During my Master’s degree, I began studying the visual system. I subsequently started a PhD at Dalhousie, while continuing to work on the visual system. Half way through my PhD, my supervisor decided to move universities and ended up pulling me back out west, back to the University of Victoria. Having completed my PhD, and a round trip of Canada, I decided to take a postdoctoral position in Basel, Switzerland, where I currently reside.

Significance of the Paper

This paper appeared in the high-impact neuroscience journal Nature Neuroscience. The paper was important for several reasons. First, using state-of-the-art technology, I was able to show a specific functional role for gap junctions in neural signaling. Gap junctions are incredibly common cellular components whose role in neural circuits is vastly underappreciated. Second, this paper revealed a novel computational principle - that a simple neural circuit could compensate for the varying velocities of moving objects and reliably encode their exact location in space. One example of the influence of this paper is that I was able to publish a more detailed follow paper later in the year in the prestigious Journal of Neuroscience. Finally, while this paper is still fairly new, it has already had an impact outside of visual neuroscience. In particular, my publication has preceded two other recent papers in influential journals that studied similar phenomenon to lag normalization in the weakly electric fish (Clarke et al., 2013, PNAS) and in the zebra fish olfactory system (Zhu et al., 2013, Nature Neuroscience).


Michel Thibodeau

Article

Thibodeau, Michel, et al. "Anxiety disorders are independently associated with suicide ideation and attempts: Propensity score matching in two epidemiological samples." Depression and Anxiety, 30(10), October 2013, p. 947-954. DOI: 10.1002/da.22203

Biosketch

I am from Tabusintac, a small bilingual community in northeastern New Brunswick. I received a Bachelor of Arts with Honours in Psychology in 2009 from the University of New Brunswick and a Master of Arts degree in Clinical Psychology from the University of Regina in 2011. I am currently pursuing a PhD in Clinical Psychology from the University of Regina under the supervision of Dr. Gordon Asmundson. My research focuses on anxiety-based mental disorders, medical conditions that share a close relationship with anxiety (e.g. chronic pain), and research methods. I hope to complete my PhD in fall 2015 and to continue my research informing evidence-based treatments for mental disorders.

Significance of the Paper

Researchers, using epidemiological data, have concluded that suicidal behavior in individuals with anxiety disorders is attributable to co-occurring depression. I perceive these findings as unintuitive since anxiety disorders inherently cause suffering, which presumably increases risk of ending that suffering by means of suicide, regardless of depression. My coauthors and I argue that the lack of evidence for this hypothesis stems from the use of traditional statistical adjustments. We used propensity score matching, a modern statistical technique, to address this hypothesis in two epidemiological surveys. Our methods yielded findings that diverged markedly from previous research. Specifically, all anxiety disorders were associated with suicidal ideation and attempts independently of other salient risk factors such as depression. These novel findings have implications that inform health policies and the training of health professionals. Specifically, our findings suggest that individuals with anxiety disorders, regardless of depressive symptomatology, should be screened for suicidal ideation. Similarly, treating anxiety disorder symptoms may lead to a reduction in suicidal ideation. This offers a new direction for suicide treatments, which have historically focused on depressive symptoms. Moreover, our use of propensity score matching is a first in this field and informs research. Traditional analyses have led to erroneous perceptions of how anxiety impacts risk of suicide, which may have misguided research and misinformed clinicians. Overall, our paper is the first to demonstrate that anxiety disorders are uniquely associated with risk of suicide beyond depression and other risk factors, a finding that warrants consideration in both research and clinical settings.


Vedrana Cvetkovska

Article

CVETKOVSKA, Vedrana, et al. "Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting." Nature Neuroscience, 16(6), June 2013, p. 677-682. DOI: 10.1038/nn.3396

Biosketch

I obtained my undergraduate degree in Biochemistry in 2009 at McGill University. I stayed at McGill for my graduate studies in Neuroscience and joined the laboratory of Dr. Brian Chen as his first graduate student. In Dr. Chen’s lab I embarked on a project investigating the molecular mechanisms that regulate precise connectivity and neural circuit assembly. The precision with which neural circuits self-assemble during development is astonishing, yet we still know very little about how neurons can distinguish correct from incorrect synaptic partners. To study this process we use the fruit fly Drosophila melanogaster as a model organism. We developed a method that allows us to study synaptic targeting through combined structural and functional analysis of single identifiable sensory neurons (Kays, Cvetkovska & Chen, Nature Protocols, 2014). We used this method to demonstrate that dysregulated expression of Down syndrome cell adhesion molecule impairs precise connectivity and circuit function and could be underlying neural circuit miswiring in Down syndrome and Fragile X syndrome (Cvetkovska et al., Nature Neuroscience, 2013). For my accomplishments I’ve been awarded several awards from the Integrated Program in Neuroscience at McGill, the McGill Faculty of Medicine, Fonds de Recherche du Québec, and a generous contribution from the Sievers family (Ann and Richard Sievers Award). In addition to my research, I have been involved in teaching molecular biology at the undergraduate level, as well as mentoring undergraduate and CEGEP students in the lab. I am currently finishing my PhD after five fruitful years, and I am looking forward to continuing my research in neurodevelopment as a postdoctoral fellow under the mentorship of Dr. Ann Marie Craig at the University of British Columbia.

Significance of the Paper

It is generally thought that miswiring of neuronal circuits leads to cognitive impairment in intellectual disabilities. Our study provides evidence that elevated levels of Down Syndrome Cell Adhesion Molecule (Dscam) could be a common molecular mechanism leading to neuronal miswiring in two of the most common forms of intellectual disability, Down syndrome and Fragile X syndrome. Both disorders are characterized by elevated protein levels and our study identifies Dscam protein as a molecule responsible for impaired synaptic targeting and behavior in Drosophila that have three copies of the Dscam gene, similar to the Down syndrome case, and in models of Fragile X syndrome. To our knowledge, this is the first study to show that overexpression of a single molecule is responsible for neural wiring phenotypes observed in two different forms of intellectual disability. We believe that maintaining the correct levels of Dscam is crucial for proper brain development and circuit formation, and dysregulation of Dscam levels may contribute to other neural developmental disorders such as Autism Spectrum Disorders and Rett Syndrome. Our finding identifies Dscam as an important target in the future for helping to manage some of the disability associated with different and complex disorders.


Agustin Cerani

Article

Cerani, Agustin, et al. "Neuron-derived Semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via Neuropilin-1." Cell Metabolism, 18(4), October 2013, p. 505-518. DOI: 10.1016/j.cmet.2013.09.003

Biosketch

I was born in Buenos Aires, Argentina, and immigrated to Canada in 2004. In Vancouver, B.C., I pursued my undergraduate studies in Biological Sciences at Simon Fraser University (SFU). At SFU, I obtained my first research experience under the supervision of Dr. Gordon Rintoul and developed a great interest in the field of neuroscience while studying mitochondrial dynamics in neurons and astrocytes in the context of stroke. In 2010, I moved to Montreal and joined Dr. Przemyslaw Sapieha’s new laboratory at Hôpital Maisonneuve-Rosemont (HMR) in order to pursue a Master’s at the Department of Biochemistry and Molecular Medicine in the University of Montreal. In Dr. Sapieha’s lab, I studied the interaction of neurons and vessels in the pathophysiology of diabetic retinopathy.

Currently, I am continuing to investigate the neurovascular interaction in diabetes as it is associated to diabetes-related central nervous system disorders. This intriguing and exciting field has inspired me to pursue a career in science as an independent researcher, which would ultimately allow me to become involved in the development of therapeutics to counter this major cause of loss of sight.

Significance of the Paper

Currently available treatments for DR, the leading cause of loss of vision in the working-age population, present non-negligible side effects such as cataract formation with intra-vitreal use of corticosteroid or reduced visual field with laser-based photocoagulation. Similarly, newer anti-VEGF therapies can lead to thromboembolic events, neuronal toxicity, and atrophy when used as frequent long-term regimens given that VEGF serves a vaso- and neuro-protective role in the retina. These therapeutic limitations highlight the need for novel pharmacological interventions.

In light of these therapeutic restrictions, Sema3A could represent an attractive target for treatment since its physiological function in the eye is mostly limited to development and it is associated with apoptosis and cytoskeletal remodeling, which are important features of ischemic and proliferative retinopathies such as DR. Thus, early Sema3A neutralization would protect vascular barrier function and simultaneously allow VEGF to elicit its physiological restorative and pro-survival effects. Alternatively and most importantly, in later stages of retinopathy when BRB function is affected by elevated levels of VEGF and Sema3A, coupled neutralization of these proteins could be achieved by using neuropilin-1 as a bivalent trap due to its ability to bind both molecules.

Besides the innovative practical applications of our discovery, the presented study provides the first evidence of a neuron-derived factor involved in the pathophysiology of diabetic retinopathy. Such evidence supports a role for neurovascular crosstalk in the etiology of vascular/ischemic retinopathies, and could provide insight into the etiology of other conditions where vascular barrier function is compromised, such as stroke and cancer.


Jillian Stobart

Article

Stobart, Jillian, et al. "Astrocyte-induced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase." Proceedings of the National Academy of Sciences of the United States of America, 110(8), February 2013, p. 3149-3154. DOI: 10.1073/pnas.1215929110

Biosketch

I first became interested in neuroscience when I studied prion diseases at the National Microbiology Lab in Winnipeg as an undergraduate co-op student from 2004 to 2005. This work helped me realize my passion for research and interest in glial cells and led to my PhD in the glial biology research group of Dr. Chris Anderson at the University of Manitoba in 2006. My graduate work focused on astrocyte D-serine and NMDA receptors in neurovascular coupling and has generated several peer-reviewed publications. Throughout my PhD, I have been an active member of the Canadian Association for Neuroscience and the Society for Neuroscience, which has facilitated my attendance at numerous conferences where I have received several travel and poster awards. I was also invited to give an oral presentation at the Manitoba Neuroscience Network conference in 2011 and at the Canadian Student Health Research Forum in 2014 as part of the E.L. Drewry Memorial award for research excellence. I have been very fortunate to be fully supported throughout my PhD by fellowships and awards from CIHR, the Manitoba Health Research Council, the University of Manitoba, and the Alzheimer’s Society of Manitoba. I completed my PhD in October 2012 and I am continuing to study astrocytes during neurovascular coupling in vivo as a post-doctoral fellow in the group of Dr. Bruno Weber at the University of Zurich.

Significance of the Paper

Neuronal energy demand is met with increased blood flow in a process known as functional hyperemia, involving signaling between neurons, astrocytes and blood vessels. The cellular mechanisms underlining functional hyperemia are not clear, and likely multiple pathways and events are involved. Our paper describes exciting new evidence that astrocytes release D-serine, which increases blood flow by activating NMDA receptors. We also found that eNOS influenced dilation by suppressing levels of vasoconstrictor arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid. This is the first time D-serine and eNOS have been shown to directly mediate neurovascular coupling, and these timely and highly relevant findings complement and elevate the current knowledge of the role of astrocytes in blood flow control.

These results also contribute to our understanding of brain physiology and the functional relationship between neurons, astrocytes, and brain arteries. Therefore, this paper is potentially relevant to a broad range of neuroscientists and vascular biologists and may facilitate new ideas and avenues of research. Neurovascular coupling is known to be dysfunctional in disorders such as Alzheimer’s disease and stroke, so this work is also relevant to disease and future therapy design.


Lingling Lu

Article

Lu, Lingling, et al. "Astrocyte-induced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase." Proceedings of the National Academy of Sciences of the United States of America, 110(8), February 2013, p. 3149-3154. DOI: 10.1073/pnas.1215929110

Biosketch

I completed my Master’s and PhD in Neuropharmacology Research at Shenyang Pharmaceutical University in China and the University of Meijo in Japan from 2004 to 2010. My previous study focused on the neurobehavioral and cognitive dysfunction of neuronal NMDA receptors in schizophrenia animal models. I came to Canada to start my postdoctoral studies in Dr. Chris Anderson’s lab at the University of Manitoba and St. Boniface Hospital Research Centre, beginning in 2010. My current research is looking for the astrocytes-related cerebrovascular effects of the endothelial NMDA receptors. This study enriches my understanding of the NMDA receptors and leads me to a new field in neurovascular coupling. Under the supervision of Dr. Chris Anderson and in collaboration with Dr. Jillian Stobart, we successfully published the PNAS paper in 2013. This research helped me acquire many advanced techniques including the two-photon imaging system, and led me to understand a novel mechanism of regulating hyperemia, of which dysfunction has relevance with multiple diseases. Throughout my postdoctoral fellowship, I received a two-year postdoctoral fellowship award for the years 2012 to 2014, which is supported by the Manitoba Health Research Council.

Significance of the Paper

Neuronal energy demand is met with increased blood flow in a process known as functional hyperemia, involving signaling between neurons, astrocytes and blood vessels. The cellular mechanisms underlining functional hyperemia are not clear, and likely multiple pathways and events are involved. Our paper describes exciting new evidence that astrocytes release D-serine, which increases blood flow by activating NMDA receptors. We also found that endothelial Nitric Oxide Synthase (eNOS) influenced dilation by suppressing levels of vasoconstrictor arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid. This is the first time D-serine and eNOS have been shown to directly mediate neurovascular coupling, and these timely and highly relevant findings complement and elevate the current knowledge of the role of astrocytes in blood flow control. These results also contribute to our understanding of brain physiology and the functional relationship between neurons, astrocytes, and brain arteries. Therefore, this paper is potentially relevant to a broad range of neuroscientists and vascular biologists and may facilitate new ideas and avenues of research. Neurovascular coupling is known to be dysfunctional in disorders such as Alzheimer’s disease and stroke, so this work is also relevant to disease and future therapy design.


François Binet

Article

Binet, François, et al. "Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1α degradation of Netrin-1." Cell Metabolism, 17(3), March 2013, p. 353-371. DOI: 10.1016/j.cmet.2013.02.003

Biosketch

My PhD training, done in the lab of Denis Girard at the INRS-Institut Armand-Frappier in Laval involved characterization of the mechanism of action of arsenic trioxide, a chemotherapeutic drug, on the neutrophil biology. I uncovered new proteins involved in the neutrophil response to arsenic trioxide, namely annexin-1 and the HSP89a as well as describing its pro-inflammatory effect in vitro. I also demonstrated that the ER stress pathways, until then uncharacterized in this cell type, could be activated following arsenic trioxide treatment and be responsible for its effect on the neutrophil. I then pursued my scientific formation as a postdoctoral researcher in the lab of Mike Sapieha at the Maisonneuve-Rosemont Research Center. There, I studied the potential role of neuronal guidance cues, namely semaphorin 3A and netrin-1, as targets for reparative angiogenesis in the retina. My work also led to the discovery of a crucial association between ER stress pathways and the formation of pathological vascular tufts that are characteristics of proliferative retinopathies (diabetic retinopathy and retinopathy of prematurity). Part of my work also focused on age-related macular degeneration and GPR91, the receptor for succinate. We found a surprising phenotype in the GPR91-/- KO mice that share many features of AMD, including outer retinal lesions, Bruch’s membrane thickening and accumulation of microglia in the sub-retinal space.

Significance of the Paper

In addition to describing netrin-1 as a new target for treatment of proliferative retinopathies, this paper shows that modulation of the ER stress pathways, more precisely IRE1α can circumvent formation of neovascular tufts formation and improve revascularization of the retina. The IRE1α endoribonuclease activity was demonstrated to be responsible for degradation of netrin-1 mRNA under conditions of hypoxia. Down-regulation of IRE1α by lentiviral injections of shRNA restored the level of netrin-1 and sped up the therapeutic angiogenesis in the central vaso-obliterated zones of the retina. Therefore, we detailed a new pathway through to the molecular level explaining how IRE1α can influence angiogenesis by controlling specific vascular guidance cue. This is the first report showing a direct effect of IRE1α endonuclease activity on netrin-1 mRNA. These results also show that netrin-1 controls the activity of cells from the immune system, more precisely macrophages and microglia. We propose that netrin-1 is a pro-angiogenic effector by acting indirectly through enhancement of VEGF expression from macrophages and microglial cells. These data offer a new perspective on this field of research since conflicting results have been shown for netrin-1 activity on the vasculature (pro- and anti-angiogenic). We believe that restoring netrin-1 level could be beneficial to other diseases, such as stroke, where ischemic conditions prevail.


Jaclyn Wamsteeker Cusulin

Article

Wamsteeker Cusulin, Jaclyn, et al. "Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses." Nature Neuroscience, 16(5), May 2013, p. 596-605. DOI: 10.1038/nn.3374

Biosketch

I am interested in how stressful experiences recruit and shape brain circuits to impact physical and mental function. I completed a Bachelor’s of Health Sciences (Honours, First class) at the University of Calgary in 2007. After spending time as a research assistant at Lund University, Sweden, I began as a PhD student in under the supervision of Dr. Jaideep Bains at the Hotchkiss Brain Institute, Calgary in 2008. My research, forming part of the PhD thesis I defended in late 2013, focused on how synaptic signaling in neuroendocrine neurons the hypothalamus subserves homeostatic regulation of stress hormones. In April, 2014, I joined the lab of Dr. Andreas Lüthi and am carrying out postdoctoral training at the Friedrich Miescher Institute in Basel, Switzerland.

Significance of the Paper

Exposure to stress, a real or perceived survival threat, recruits the neuroendocrine stress-axis culminating in the release of hormones called glucocorticoids (GCs). Homeostatic regulation of GCs by stress-axis neurons in the hypothalamus of the brain is essential for normal mental function and dysregulation in this system is strongly implicated in mental disorders including major depression. Despite this, neural mechanisms for stress adaptation are not well understood. My paper, published in Nature Neuroscience, provides new evidence that GCs self-limit by acting as circuit-breakers for information transfer at hypothalamic synapses. Through electrophysiological recordings of synaptic communication in rat brain slices, I observed that GCs released during stress gate synaptic plasticity through distinct alterations to stress-axis neuron signaling cascades. This plasticity is caused by activity-dependent release of opioid peptides from neuronal dendrites which act at afferent terminals to shut down incoming transmission. My paper provides a compelling candidate mechanism for adaptive stress-axis control and novel insight about how neurons utilize peptides in signaling. These findings enrich current understanding of how experiences can bi-directionally shape neural circuits during distinct temporal windows.


Tabrez J. Siddiqui

Article

Siddiqui, Tabrez J, et al. "An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells." Neuron, 79(4), August 2013, p. 680-695. DOI: 10.1016/j.neuron.2013.06.029

Biosketch

Tabrez J. Siddiqui obtained his Master’s in Science at the International Max Planck Research School in Molecular Biology in Goettingen, Germany and his PhD at the Max Planck Institute for Biophysical Chemistry working with Dr. Reinhard Jahn. For his postdoctoral training, he joined the laboratory of Dr. Ann Marie Craig at the Brain Research Centre, University of British Columbia. His primary research interests are in elucidating the molecular mechanisms of neuronal synapse development and function. He has uncovered several interactions critical for excitatory synapse organization and generated several knock-out mouse models for novel synaptogenic molecules, which may be useful animal models for psychiatric disorders including autism and schizophrenia. In the near future, he hopes to establish an independent laboratory and implement a rigorous research program to study the biochemical, molecular and cellular mechanisms of synapse development, specificity, function, and plasticity, with an eye to determining how synaptic dysfunction underlies psychiatric and neurodevelopmental disorders. Dr. Siddiqui has received several awards and fellowships including a Pfizer award, EMBO and Michael Smith foundation postdoctoral fellowships, McGeer Prize for Basic Science, CIHR’s Brain Star Award, and most recently Brain and Behavior Foundation’s NARSAD Young Investigator Award.

Significance of the Paper

This study has significantly enhanced the molecular understanding of the organization of excitatory synapses. In a previous study, I have shown that LRRTM-1 and -2 and the neuroligin family of synapse organizers bind to neurexins in a distinct and differential binding code to mediate excitatory synapse development. Here, I have shown that functionally and structurally related LRRTM4 mediates excitatory synapse development by trans-synaptically binding to HSPGs. This study is significant from a structural viewpoint as two different members of the same family of proteins execute similar functions while binding to distinct partners. This study has also identified a role for HSPGs in mediating excitatory presynaptic differentiation, thus placing the HSPGs as a third family of presynaptic inducers, in addition to neurexins and Receptor Protein Tyrosine Phosphatases. While most of the synaptic adhesion proteins studied so far mediate synapse development ubiquitously in the brain, LRRTM4 is a rare example of a synapse organizer mediating synapse development in a cell-type specific manner, thus opening possibilities of synapse adhesion molecules in mediating distinct circuit wiring. As both LRRTM4 and HSPGs are highly linked to autism, this study may reveal signaling pathways disrupted in psychiatric disorders and indicate that aberrant synapse development, organization and function may be a common pathogenesis of psychiatric disorders.


Tomas Ros

Article

Ros, Tomas, et al. "Mind over chatter: Plastic up-regulation of the fMRI salience network directly after EEG neurofeedback." NeuroImage, 65, January 2013, p. 324-335. DOI: 10.1016/j.neuroimage.2012.09.046

Biosketch

I started research on electroencephalogram neurofeedback during my PhD in the laboratory of Professor John Gruzelier at the University of London, United Kingdom. During that time, I demonstrated the beneficial effect neurofeedback can have on motor learning, including surgical skills (Ros et al, BMC Neuroscience 2009). There I also completed the first study harnessing transcranial magnetic stimulation to probe for the plastic effects of neurofeedback, showing that cortical excitability changes may manifest directly after a training session (Ros et al, European Journal of Neuroscience 2010). For my postdoctoral studies, I joined the Psychiatry Department at the University of Western Ontario, working with Professor Ruth Lanius, a specialist in neuroimaging and post-traumatic stress disorder (PTSD). Given my long-standing interest in meditation and its benefits on mental health, we were excited to uncover a neurofeedback protocol that positively correlated with reductions in mind-wandering, along with enhanced functional connectivity in a key cognitive control network (Ros et al, NeuroImage 2013). This led to the first translational study investigating the impact of this protocol in patients with PTSD, revealing a positive effect on well-being and a plastic modulation of salience/default-mode networks (Kluetsch et al, Acta Scandinavica Psychiatrica 2014). I have now received a postdoctoral fellowship at the Laboratory for Neurology and Neuroimaging of Cognition, headed by Professor Patrik Vuilleumier at the University of Geneva, investigating the promising application of neurofeedback for attentional/affective disorders, and its neurobiological mechanisms. Given the brain’s astonishing plasticity, my hope is that this research could eventually inform a remarkably safe, non-invasive, and more natural approach for directing neuroplastic change.

Significance of the Paper

This is the first study to show that neurofeedback can be successfully used to boost connectivity specifically within a key brain functional network (salience network) subserving cognitive control, whose abnormal coupling pervades a wide range of brain disorders (e.g. ADHD, addiction, depression, and schizophrenia). This protocol has directly led to research in a psychiatric population and appears to have a positive impact in PTSD patients: modulating default-mode and salience network connectivity, and significantly increasing levels of calmness. By using a sham-control group, it also originally demonstrates that attentional focus can be influenced with such training; insofar subjects that had the greatest neurofeedback-related EEG changes had greatest decreases in mind-wandering. This suggests a promising basis for treating disorders characterized by excessive levels of thought intrusion or task-unrelated thoughts (e.g. depression, ADHD).


Mark Ferro

Article

Ferro, Mark, et al. "Self-concept among youth with a chronic illness: A meta-analytic review." Health Psychology, 32(8), August 2013, p. 839-848. DOI: 10.1037/a0031861

Biosketch

I completed my PhD in Epidemiology and Biostatistics at Western University funded by the CIHR Banting and Best Doctoral Award. My doctoral thesis examined the influence of maternal depression and the family environment on the health-related quality of life children newly diagnosed with epilepsy under the supervisor of Dr. Kathy Speechley. Based on this work, I was the recipient of a Young Investigator Award from the American Epilepsy Society in 2009, Trainee of the Year from the Children's Health Research Institute for 2011, and the Fellow Research Award from the Canadian League Against Epilepsy in 2012. Upon completion of my PhD, I began postdoctoral training under the mentorship of Dr. Michael Boyle in the Department of Psychiatry and Behavioural Neurosciences and the Offord Centre for Child Studies at McMaster University. Initially funded by the Michael G. DeGroote Fellowship Award, I was the recipient of a Banting Postdoctoral Fellowship from the Government of Canada. During my postdoctoral training, I have expanded my program of research to investigate the mental health of children and adolescents with chronic physical illnesses. Using a variety of methodological and analytical techniques applied to both population and clinical samples, I am developing a stress process model that links chronic physical illness, family environment factors, child self-concept, and mental health problems in children. This program of research has implications for the health care of children and adolescents with co-morbid physical and mental health problems - identifying targets for intervention in which to reduce or prevent the onset of mental health problems in youth with chronic physical illness; emphasizing the adoption and evaluation of approaches to family-centred care; as well as focusing on the transition of care from pediatric to adult health services. In 2014, I was appointed Assistant Professor in the Departments of Psychiatry and Behavioural Neurosciences and Pediatrics at McMaster University. I am currently a PI or co-investigator on five CIHR-funded studies totaling $7.6M and have published 29 peer-reviewed articles (23 since 2011) in leading journals including Neurology, Schizophrenia Research, Epilepsia, Health Psychology, and Journal of Pediatric Psychology.

Significance of the Paper

This manuscript was published in Health Psychology which has the highest impact of all health psychology journals. The results have substantive and methodological implications. Substantively, results suggested that youth with chronic illness (YwCI) have compromised self-concept compared to healthy controls. This is a key finding, since previous evidence shows that self-concept is modifiable and is antecedent to more serious mental health problems. This research represents an improvement over previous work and extends the knowledge base by 1) assessing the quality of included studies; 2) extending the scope of the review and the chronic illnesses examined; 3) analyzing moderating variables to better understand how study design impacts effect sizes. It supports the notion that adopting non-categorical approaches to chronic illness is valid; as a group, YwCI have lower self-concept, likely the result of a shared experience of adversity. Methodologically, the research has implications for understanding the relationship between chronic illness and self-concept specifically, and in the conduct of meta-analysis. For example, the positive illusory bias may underestimate effect sizes and has implications for any self-reported measures of mental health. Also, the use of normative data appears to also underestimate effect sizes and researchers should be cognizant of how control groups may influence effect sizes in meta-analyses. This meta-analysis has led to the publication of two additional articles and one in review by Dr. Ferro that examines the psychometric properties of self-concept measures and how self-concept changes over time in YwCI.


Ruifeng Cao

Article

Cao, Ruifeng, et al. "Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling." Neuron, 79(4), August 2013, p. 712-724. DOI: 10.1016/j.neuron.2013.06.026

Biosketch

I received an MD at the Fourth Military Medical University in China in 2002 and a PhD at the Ohio State University in 2010. I currently work as a postdoctoral fellow in Dr. Nahum Sonenberg's laboratory at McGill University. My graduate work focused on the molecular signaling pathways that couple external light signals to the internal biological clock and regulate circadian rhythms in mammals. I discovered a light- and clock-regulated mTOR signaling (a signaling pathway that controls protein synthesis) in the suprachiasmatic nucleus, the locus of master circadian clock in mammals. During my postdoctoral studies, I continued to study the roles of 4E-BPs, which are pivotal downstream targets of mTOR signaling in the circadian clock. We have recently studied how a fundamental process of protein synthesis is controlled within the master clock by 4E-BP1. We have discovered that 4E-BP1 is a repressor protein of the SCN clock and that by removing this protein the brain clock function was improved. A better understanding the molecular mechanisms of biological clocks may contribute to the development of time-managing drugs and shed light on future treatments for disorders triggered by circadian clock dysfunctions. The project was funded by the Canadian Institutes of Health Research (CIHR) and the Fonds de Recherche du Québec- Santé (FRSQ). I am also an active member of the Society for Neuroscience, the Society for Research on Biological Rhythms (SRBR), and Canadian Society for Chronobiology (CSC). These affiliations have allowed me to present my work at international conferences.

Significance of the Paper

The rotation of the earth generates day and night. It also confers daily rhythms to all living beings. In the modern society, trans-time zone travel, graveyard shifts, extensive use of night light and night owl life styles all become health hazards that frequently disrupt our circadian clock in the brain. According to a study at Université Laval, sleep disorders affect 40% of adult Canadians. Also, accumulating evidence demonstrates that disruption of circadian clock function is linked to a number of diseases such as cancer, diabetes and cardiovascular diseases which commonly affect Canadians. Thus, to treat the circadian abnormalities, we have to study the fundamental biological mechanisms that control our internal clocks. Our study has discovered that the functions of the brain clock can be boosted by decreasing the activity of a specific repressor protein, 4E-BP1. It provides a novel way to improve internal clock function. A stronger clock function may help improve many physiological processes such as ageing. In addition, a better understanding the molecular mechanisms of biological clocks may contribute to the development of time-managing drugs and shed light on future treatments for disorders triggered by circadian clock dysfunctions, including jet lag, shift work disorders, and chronic conditions such as depression and Parkinson’s disease. The significance of the publication is evidenced by the number of media reports on our work.

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