Brain Star Awards - Recipients for 2011
Nasrin Nejatbakhsh
Article
NEJATBAKHSH, Nasrin et al. “Caltubin, a Novel Molluscan Tubulin-Interacting Protein, Promotes Axonal Growth and Attenuates Axonal Degeneration of Rodent Neurons.” The Journal of Neuroscience, 31(43), October 2011, p. 15231-15244.
Biosketch
I completed my undergraduate degree in Kinesiology and Health Sciences at York University. I was fascinated by the mechanisms that govern the functions of the human body- particularly the nervous system. My PhD thesis at the University of Toronto, under the supervision of Dr. Zhong-Ping Feng, involves the study of intrinsic neuronal mechanisms in the process of CNS regeneration and neurite outgrowth. Specifically, I am interested in finding novel proteins involved in neuronal regeneration of invertebrate neurons, and testing the application of these pathways in mammalian central neurons.
Our laboratory uses Lymnaea stagnalis (pond snail) as a model to study a wide range of phenomena-including neurite outgrowth and regeneration, synapse formation and memory consolidation. One crucial advantage of this invertebrate model is that unlike adult mammalian central neurons, these animals retain the ability for robust CNS regeneration and subsequent synaptogenesis following injury. This unique characteristic has enabled us to ask some intriguing questions about intrinsic regenerative mechanisms, which led to the discovery of caltubin- a novel, pro-regenerative, invertebrate protein (J Neurosci. 2011;31(43):15231-44).
During the past several years, I have had the opportunity to travel to the Netherlands to work with my collaborators at VUA (Free University in Amsterdam). I also travelled to Sweden as part of an exchange course with the Karolinska Institute, where I visited the Nobel museum and met some of the leading experts in the field of neuronal development. Recently, I was pleased to partner up with the Firefly Foundation to create educational material for high school students, addressing the importance of brain safety from a scientific perspective.
My graduate work has been supported by an NSERC-CGS, and I have obtained both oral and poster presentation awards for my research. The remainder of my PhD will focus on elucidating the precise mechanism of action of caltubin in both invertebrate and vertebrate central neurons.
Significance of Paper
The mandate of the INMHA is to reduce the burden of brain illness through a variety of strategies, including treatment and greater knowledge. Our finding that a novel invertebrate-specific protein can have a functional role in the regenerative response of mammalian brain cells fulfills this mandate. Our research: 1) suggests a possible avenue for treatment of brain and spinal cord injuries through the introduction of proteins which already have pro-regenerative roles in other organisms, and 2) may enhance our understanding of mammalian cellular pathways involved in neuronal regeneration, through the study of proteins downstream of caltubin (i.e. tubulin). Thus, our research is well aligned with the mandate of INMHA, both in terms of a potential long-terms treatment and as a tool for greater understanding of pathways and mechanisms involved in CNS regeneration.
Sylvia Villeneuve
Article
VILLENEUVE, Sylvia, et al.“The nature of episodic memory deficits in MCI with and without vascular burden” Neuropsychologia, 49(11), September 2011, p. 3027-3035.
Biosketch
I completed a PhD in Research/Intervention Neuropsychology at the University of Montreal in November 2011. The bulk of my research was conducted at the Montreal University Institute of Geriatrics under the supervision of Dr. Belleville and in close collaboration with Dr. Gauthier. These two doctors are world leaders in the study of the neurobiological substrates of pathological aging. My doctoral thesis focused primarily on the influence of vascular health on cognition in older adults with mild cognitive impairment (MCI) (Villeneuve and Belleville, Neurobiol Aging, 2011; Villeneuve et al., Neuropsychologia, 2011; Belleville, Villeneuve et al., Rev Neuropsychol, 2010; Villeneuve et al., DGCD, 2009). I also studied the concept of cognitive reserve, the brain's ability to compensate for cerebral lesions (Villeneuve and Belleville, Psychol Neuropsychiatr Vieil, 2010). During my clinical internships, I examined the influence of stress and psychiatric symptoms on the cognition of persons with MCI. Working with two clinicians, I conducted a research project to measure the effect of a cognitive intervention on the extent and nature of cognitive deficits in persons with MCI with psychiatric symptoms (Ouellet, Melançon and Villeneuve, RQPSY, 2011). The project was funded by the Fernand Séguin Research Centre.
While studying for my PhD, I worked with Dr. Gagnon at the Hôpital Sacré-Cœur sleep clinic in Montreal on various projects for detecting MCI in Parkinson's disease, REM sleep behaviour disorder and chronic obstructive pulmonary disease (Villeneuve et al., DGCD, 2011). I also completed an internship with Dr. Gaudet, during which I studied the genetic determinants of cardiovascular and cognitive health.
I am about to start a postdoctoral fellowship at the University of California, Berkeley, under the supervision of Dr. Jagust. My goal for this fellowship is to demystify the links between amyloid deposition (an early marker of Alzheimer's disease), cerebrovascular lesions (diffuse white matter lesions and lacunes), apolipoprotein E (the main risk factor in Alzheimer's disease) and cognition.
Significance of Paper
The purpose of this study was to examine the impact of vascular diseases (e.g. diabetes, cholesterol, hypertension) and cerebrovascular diseases (diffuse white matter lesions) on the nature and extent of memory impairment in MCI. Persons with MCI represent a clinical population of interest because they are at high risk of progressing to dementia. Among persons with MCI who progress to dementia, 70% progress to dementia of the Alzheimer type and more than 30% progress to vascular dementia (Solfrizzi et al., 2004). The results of our study suggest that the memory impairment profile in persons with MCI with vascular diseases is similar to that found in individuals with vascular dementia, whereas in persons with MCI without that burden, it is similar to that found in individuals with Alzheimer's disease. Persons with MCI with vascular burden predominantly display impairment of strategic memory processes, whereas persons with MCI without vascular burden show impairment of nonstrategic processes. Vascular burden therefore seems to influence the memory profile of persons with MCI and indicate a preclinical phase of vascular dementia or mixed dementia in certain individuals showing cognitive deficits. These findings are of great clinical significance. In addition to assisting with early differential diagnosis, this knowledge could be used to develop cognitive interventions for persons with MCI with and without vascular burden. Such interventions will have the benefit of being more specific and therefore possibly more effective (Bier and Belleville, 2010). The results of this research also highlight the impact of vascular diseases on brain and cognitive function in persons with MCI. These empirical data are important for promoting the treatment and prevention of these diseases.
Clotilde Leblond-Lecrux
Article
LECRUX, Clotilde, et al. “Pyramidal Neurons Are "Neurogenic Hubs" in the Neurovascular Coupling Response to Whisker Stimulation”. The Journal of Neuroscience. 31(27), July 2011, p.9836-9847.
Biosketch
After studying biochemistry, I have been focusing throughout my Master's, PhD and postdoctoral terms on the field of neurosciences. I pursued my PhD on the physiopathology of cerebral ischemia in Caen, France and in Glasgow, UK. I have investigated the effects of chronic hypertension on the ischemic brain and published in 2 papers in Stroke in 2007 and 2008. The first term of my postdoctoral training focused on the mechanisms of neurovascular coupling in Dr. Hamel's group is one of the best groups worldwide in this field. My project aimed to identify the specific pathways driving the CBF response to sensory stimulation (Lecrux et al, J Neurosci, 2011) and cholinergic input (Lecrux et al, JCBFM, 2012). My current research project includes an in vivo electrophysiology approach, in order to investigate the neuronal activity associated with the evoked CBF changes. I am working with Dr Amir Shmuel who has set-up in his lab state-of-the-art equipment for an integrative investigation of in vivo electrical and hemodynamic signals. My goal is to continue working on elucidating the mechanisms of neurovascular coupling and its modulation which are still poorly known. A better understanding of these mechanisms is crucial for different applications, such as the interpretation of functional imaging techniques, which are powerful tools for research in animal and human patients, and for diagnosis and monitoring of physiopathology of several diseases.
Significance of Paper
Our paper "Pyramidal neurons as "neurogenic hubs" in the neurovascular coupling response to whisker stimulation" describes an original and innovative work focused on mechanistic regulation of local cerebral blood flow by specific neuronal networks in the barrel cortex. We have developed a unique methodological approach that allows identification of the cellular regulators of neuronal activity-induced cerebral blood increases. We have combined measurement of c-Fos upregulation during sensory stimulation with in vivo recording of neuronal activity under pharmacological manipulations and concurrent measurements of evoked cerebral blood flow responses.
According to the goals of the INMHA, our research contributes to a better understanding of the physiology of the brain. Furthermore, these data are the results of a multifaceted approach from the molecular level, to the cellular and in vivo levels. This wide range of techniques and expertises had allow us to provide an unique insight into the mechanisms of neurovascular coupling.
The importance of our paper was highlighted by its selection in the "This week in the journal" section of the Journal of Neuroscience.
Igal Ifergan
Article
IFERGAN, Igal, et al. “Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on alpha4 integrin.” Brain, 134(12), 2011, p. 3560-3577.
Biosketch
I completed my Bachelor's Degree in Biology at Université de Montréal in 2000. I started my post-graduate studies in the laboratory of Dr. Michel Roger at Université de Montéal studying the polymorphism of the human gene MDR-1 in relationship with HIV-1 infection. I completed my master in 2003.
In 2004, I started my PhD under Dr. Alexandre Prat supervision. The work of Dr. Prat is focused on multiple sclerosis (MS). MS is an inflammatory disorder of the central nervous system (CNS). This disease is characterized by multifocal areas of immune cell infiltration leading to oligodendrocyte death, demyelination and axonal damage.
During my PhD, I demonstrated that a subset of CD14+ monocytes migrate across the inflamed human blood-brain barrier (BBB) and differentiate into dendritic cells (DCs), under the influence adhesion molecules and cytokines released by the BBB. These DCs then promote the proliferation and expansion of distinct populations of Th1 and Th17 CD4+ T cells, cells that contribute to damage in MS and in its animal model, experimental autoimmune encephalomyelitis. I also examined the phenotype of CD8+ T lymphocytes in the CNS of MS patients and the role of alpha4 integrin in recruitment of effector memory CD8+ T cells during neuroinflammation in order to understand the emergence of CNS viral infections in Natalizumab treated MS patients.
For my post-doc training, I am planning to continue my studies on MS, in an effort to increase our knowledge of this devastating disease.
Significance of the paper
Our manuscript provides novel important data on CD8+ T lymphocytes in neuroinflammation. Immune cell transmigration across the blood-brain barrier (BBB) represents a critical step for initiation of central nervous system (CNS)-directed immune reactions. Therefore, a better understanding of the mechanisms involved in the transmigration of specific leukocyte subsets is critically needed to develop therapies aiming to reduce CNS-targeted inflammation, without affecting CD8-mediated immune surveillance.
Massieh Moayedi
Article
MOAYEDI, Massieh, et al. “Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder.” Neuroimage 55(1), 2011, p. 277-286.
Biosketch
I completed my Bachelor's degree in Biology (Honours) at the University of Ottawa in 2007. I then began my graduate studies at the Institute of Medical Science at the University of Toronto (U of T), under the supervision of Dr. Karen Davis at the Toronto Western Research Institute. My thesis examines structural abnormalities in the brains of patients with temporomandibular disorder (TMD), a prevalent chronic pain disorder. My research focuses on fundamental scientific questions in a clinical population, which requires an interdisciplinary approach. The U of T and the University Health Network provide a unique and training environment, where I work alongside experts in several fields, such as brain imaging, pain, psychology, statistics, dentistry, physics, amongst other fields related to my research. This translational research interface of basic and clinical science allows me to pose questions not only relevant to relevant to the TMD patients, but also understanding basic pain mechanisms.
My membership to the U of T's Centre for the Study of Pain and the Collaborative Program in Neuroscience have provided the opportunity to exchange ideas with my peers, and has sparked several collaborations. I am currently working with several groups on projects investigating epilepsy, movement disorders and autism. To complement my graduate training, I have been a trainee member of two CIHR Strategic Training Initiatives in Health Research (STIHR): Cell signaling in mucosal inflammation and pain and Pain: Molecules to Community. These have provided forums to develop new ideas and form new questions informed by experts within my field and through interdisciplinary exchange.
I am an active member of the Society for Neuroscience, the Organization for Human Brain Mapping, and the International Association for the Study of Pain. These affiliations allowed me to present my work at conferences. I have also published two critical literature reviews and three original articles in peer-reviewed journals. I have presented my work at two prominent laboratories in England, which resulted in a postdoctoral fellowship offer at the University College London. Also, I have attended a number of short-courses in brain imaging software offered at international conferences to develop and enhance my skills and knowledge base.
I value my participation in campus life as much as my own research. I have had the pleasure of teaching undergraduate and graduate level courses in Neuroscience. As Life Science Academic Don at Trinity College, I have mentored students across several disciplines. I have also given several lectures at U of T to make my findings more accessible to the public.
I firmly believe that collaboration, interdisciplinary exchange and dialogue with the community provide a trainee in Neuroscience with the required perspective to pose relevant, substantial and informed questions, and will enhance the quality of research. Throughout my training, I have built strong connections and actively engaged different communities to learn from their experience.
Significance of the paper
Our study is in line with a mandate of Institute of Neurosciences, Mental Health and Addiction. Our paper is the first study to examine structural gray matter abnormalities in patients with idiopathic temporomandibular disorder (TMD), a prevalent chronic pain population. Because TMD pain can be idiopathic, there are few effective treatment options. Furthermore, as TMD is a functional pain disorder, patients often encounter challenges in obtaining treatment. The purpose of our study was to demonstrate that there are brain abnormalities associated with TMD, and to identify central contributions to TMD. To do so, we used novel brain imaging techniques and analysis methods to assess the structure of brain gray matter in patients with TMD, compared to controls. We found that patients with TMD had increased gray matter thickness in sensory, cognitive and modulatory regions of the brain, which suggests activity-induced plasticity due to increased nociceptive processing. Finally, we reported that neuroticism (a stable personality trait) contributes to TMD pathophysiology, indicating that personality characteristics may also be a predisposing factor to the development of TMD. Our findings provide novel evidence about central components contributing to TMD pain: some structural abnormalities are pain-driven, whereas other pre-existing abnormalities may predispose patients to developing TMD. By understanding how brain structure is affected by pain, we can increase our understanding of chronic pain and identify novel therapeutic targets In sum, our paper studies chronic pain – a sensory disorder, associated with perceptive, cognitive, and motor abnormalities – and the neural substrate of these abnormalities in the brain.
Bahareh Ajami
Article
AJAMI, Bhareh, et al. “Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool Nature Neuroscience, (14)9, September 2011, p. 1142-1149. DOI: 10.1038/nn.2887.
Biosketch
My education has been an interesting and rather unusual journey. In 1999, I graduated as an engineer from Tehran University in Iran as the first ranked student. I completed my Bachelor's degree thesis in design of food factories. Being specialized in food science, I decided to continue my education in biotechnology and food science. In 2002, I started my Master's degree at the University of Sydney, Australia, in molecular biotechnology program. At that time, I became fascinated by cell and molecular biology that changed my career path. Furthermore, I realized that my interest resided in the field of neurosciences; therefore, I decided to pursue my Master's degree thesis in stem cells and neurological disorders.
My Master's degree thesis was focused on the neural generating potential of mesenchymal stem cells for the treatment of lysosomal storage disorders, such as Krabbe disease. In 2003, I graduated my Master's degree with distinction and moved to Canada. In January 2006, I started my PhD with Dr. Fabio Rossi. Since then, I have been studying the homeostasis of myeloid cells in in Central Nervous System (CNS) and their role in neuroinflammatory disease. The first part of my study was published in Nature Neuroscience journal in 2007. I was the recipient of brain star award and the 2008 Marlene Reimer Brain Star of the Year award for this paper. This study has substantially changed the view and understanding of the role and capacity of resident microglia as a self-renewing population in health and subset of neurological diseases.
Following this study, I investigated the role of myeloid cells in murine model of Multiple Sclerosis (MS) disease, an autoimmune disease that affects the brain and spinal cord. In September 2011, I published the second first author paper as a PhD student in Nature Neuroscience journal based on this study. This paper identifies blood-derived monocytes responsible for the progress of the disease in the animal model of Multiple Sclerosis (MS) suggesting a strong correlation between monocyte infiltration and progression to the paralytic stage. Conversely, blocking the infiltration of inflammatory cells prevented the disease progress. Furthermore, we found that recruited monocytes vanish, thus not ultimately contributing to the resident microglial pool in the CNS.
Throughout my Master's degree and PhD studies, I have been the recipient of many prestigious awards and scholarships. In Australia, I was the recipient of the National Health and Medical Research Council (NH&MRC) award and Multiple Sclerosis Postgraduate Research Scholarship by MS Australia. In Canada, I was awarded the three-year doctoral scholarships from Michael Smith Foundation for Medical Research (MSFHR) and Canadian Institute of Health Research (CIHR) – ALS.
As the next step in my scientific career, I will be working as a CIHR postdoctoral fellow at Stanford University in the laboratory of Dr. Steinman continuing to work on Multiple Sclerosis disease. In the future, I have a keen interest to continue researching pathologies
Significance of the paper
Our paper is strongly aligned with the mandate and vision of INMHA. This research identifies blood-derived monocytes responsible for the progress of Experimental autoimmune encephalomyelitis (EAE), the animal model for Multiple Sclerosis disease to paralytic stage.
In this study we used an innovate approach which used parabiosis model that sutured two pairs of mice together leading to a shared circulation in combination with irradiation. This model allowed us for the first time to distinguish between blood-derived macrophages and Central Nervous System (CNS) resident microglia in the complete absence of colonizing the CNS parenchyma with infiltrating cell, therefore enabling us to correlate the infiltration of cells to the CNS with disease kinetics.
This discovery may prove invaluable for tailoring therapeutic strategies for patients that have already been diagnosed with Multiple Sclerosis by targeting the cells that are responsible for the disease progress. Furthermore, this research has uncovered a very fundamental neurobiology question, which is the extent of contribution of blood-derived myeloid cells to microgolia population. In this paper we revealed that, in neuroinflammatory disease, even when myeloid cells enter the CNS and participate in disease progress, they do not contribute to the microglia population, the resident myeloid cells of the CNS.
Simon Girard
Article
GIRARD, Simon, et al. “Increased exonic de novo mutation rate in individuals with schizophrenia” Girard et al., Nature Genetics, (43)9, p. 860-863, DOI:10.1038/ng.886.
Biosketch
Simon did his undergraduate studies in Quebec City, at Laval Université, where he completed a BSc in bioinformatics. He then moved to Montréal for his master degree at Université de Montréal. At the time, his main topic was genetic analysis of Restless Leg Syndrome, with a particular focus on the identification of CNVs associated with the disease. After completing his master degree, he started a PhD in molecular biology in Dr. Guy Rouleau's laboratory at the CHUM research center. He is cosupervised by Dr. Marie-Pierre Dubé, director of the Pharmacogenomic center at Université de Montréal. The main focus of his thesis is to understand the genetic aetiology of schizophrenia, but he is also very interested in many other brain diseases, such as Tourette, Obsessive-Compulsive Disorder, Parkinson's disease and sleep disorders. He is very interested in studying the role of new genetic mechanisms, notably the implication of de novo mutations, in psychiatric and neurological disorders. Finally, he is also very enthralled by the project of a genetic characterization of the French-Canadian population using the new high-throughput sequencing technologies.
Significance of the paper
This project fits in perfectly with the mandate of the INMHA. The identification of a new genetic mechanism responsible for the transmission of schizophrenia, as well as the identification of a number of candidate genes, suggests that it may be possible, in the very near future, to use sequencing to refine the diagnosis of the disease. The identification of candidate genes also helps identify new targets for the development of new therapeutic approaches. All of this is aimed at reducing the burden of schizophrenia.
Ruben Martins, MD
Article
MARTINS, Ruben et al. “Changes in Regional and Temporal Patterns of Activity Associated with Aging during the Performance of a Lexical Set-Shifting Task”, Cerebral Cortex, (online publication August 24, 2011).
Biosketch
Since January 2009, I'm completing a Doctorate in Biomedical sciences at the Université de Montreal under the supervision of Dr. Oury Monchi. My main goal is to explore how normal aging affects the brain activity related with executive and language processes using functional neuroimaging. I'm also a resident in psychiatry at McGill University since 2010, and graduated earlier that year with a M.D. from the Université de Montréal.
From 2007 to 2009, I was enrolled as a (M.D.)-M.Sc. candidate at the Université de Montreal. I did not graduate from my master's degree, but instead went directly into the PhD program. Most of my research was performed during the summer and was financed by the COPSE (summer scholarship - Université de Montréal).
I also graduated with a Bachelor's Degree in Science from McGill University in 2006. While an undergrad, I did some research in Dr Pollack's laboratory (neurobiology). I looked at differences between flight-capable and flight-incapable morphs of a wing-dimorphic cricket species regarding ultrasound sensitivity. The study had both a behavioral and physiological component (recording of neuronal activity). I was financed by the NSERC Undergrad Student Research Assistant Award.
Significance of Paper
This paper is of great significance since it is the first, to our knowledge, to show that older individuals use, at the same time, several age-related "compensatory mechanisms" (namely "neural compensation", "neural reserve", and, most interestingly, "load-shift") to maintain high executive functions. It is also the first article (since Velanova et al. 2007) to show that older individuals tend to operate on information sequentially and delay some executive processes.
Therefore, this paper offers a good understanding of how the brain adapts to normal age-related neuronal loss in order to maintain performance. As a result, we strongly believe that it may very well become an obligatory reference for all future studies dealing with age-related cognitive decline. Moreover, these findings are also relevant for researchers studying cognitive impairment and clinicians (psychologists, physicians, etc) dealing with the elderly or individuals suffering from cognitive deficits.
It should also be noted that our paper has not only been popular in the scientific world, but in the media as well. Several newspapers (both in print and web format), radio-shows, TV-shows and blogs have presented and summarized our main findings. This large interest appears to show that these findings may very well have an impact that goes beyond the field of neuroscience and contribute to how the general population views and conceptualizes aging and cognition.
Hideto Takahashi, MD, PhD
Article
TAKAHASHI H. et al. “Postsynaptic TrkC and Presynaptic PTPσ function as a Bidirectional Excitatory Synaptic Organizing Complex.”, (2011) Neuron, 69(2) p. 287-303.
Biosketch
I completed my M.D. in 1997 and my Ph.D. in neuroscience in 2003 at Gunma University School of Medicine in Japan. During my Ph.D., under the supervision of Prof. Tomoaki Shirao, I addressed the molecular functions and regulatory basis for the actin-binding protein drebrin, a protein responsible for regulating structure and dynamics of dendritic spines in neurons (Takahashi H. et al. J. Neurosci. 2003, 23:6586-95, Takahashi H. et al. J. Neurochem. 2006, 97:110-115, Takahashi H. et al. J Cell Sci. 2009, 122:1211-9). In my Ph.D. training, I mastered extensive cell-biological, biochemical and imaging techniques, from low-density hippocampal neuronal culture to FRAP live imaging.
I subsequently moved to the University of British Columbia in 2007. Under the leadership of Prof. Alaa El-Husseini, I studied a novel palmitoylated form of cdc42 using my previous cell-biological techniques (Kang R et al. Nature 2008, 456:904-9.). Tragically, Prof. El-Husseini passed away in December 2007. I subsequently joined the lab of Prof. Ann Marie Craig. Here I started a functional, unbiased expression screen for synapse organizing genes, based on a bioactivity assay previously used in studying the Neuroligin-Neurexin complex, and eventually identified several novel synapse organizing genes. I have been focusing my work on the neurotrophin receptor TrkC/receptor-type protein tyrosine phosphatase PTPσ trans-synaptic interaction, identified through the unbiased expression screen (Takahashi H. et al. Neuron 2011, 69:287-303.) In addition, I have been working with the Slitrk family, identified as synaptic organizers by using a candidate screen based on bioinformatics (Linhoff MW. et al. Neuron 2009, 61:734-49). This work has been supported by a NARSAD Young Investigator Award 2010.
In 2011, I presented my above works as a symposium speaker at the International Society for Neurochemistry/European Society for Neurochemistry Biennial Meeting and the Japan Neuroscience Annual Meeting. Further, I gave talks at seminars at the University of British Columbia, RIKEN-BSI and University of Tokyo. I was also involved in teaching graduate students in the Graduate Program in Neuroscience at the University of British Columbia.
Eventually, I aim to have my own laboratory and build an innovative neuroscience research program that creatively introduces unique cell-biological techniques into in vivo models to develop novel therapeutic strategies for ameliorating neuropsychiatric disorders.
Significance of Paper
In this paper, I identified the neurotrophin receptor TrkC as a synaptogenic adhesion molecule responsible for excitatory synapse development through an unbiased neuron-fibroblast coculture screen. Furthermore, I identified the receptor-type tyrosine phosphatase PTPσ as the high-affinity presynaptic receptor of TrkC. The TrkC-PTPσ trans-synaptic interaction mediates bidirectional glutamatergic synaptic assembly: postsynaptic TrkC triggers presynaptic assembly via binding axonal PTPσ, and presynaptic PTPσ triggers postsynaptic assembly via binding dendritic TrkC. These findings assign a crucial function to the previously uncharacterized TrkC cell adhesion domains and non-catalytic isoforms, and perhaps accounting for the widespread expression of TrkC in the brain. The identity of TrkC's synaptic partner is also unexpected because the major previously identified roles of PTPσ are in axon growth and regeneration. Despite the TrkC synaptogenic function not requiring kinase activity or neurotrophin-3 binding, the fact that these partners are a neurotrophin-regulated postsynaptic tyrosine kinase and a presynaptic tyrosine phosphatase suggests a wealth of possibilities for future studies on interplay of tyrosine phosphorylation and dephosphorylation, as well as potential regulation by neurotrophin-3. My paper also suggests that the dysfunction of synaptic organizing complexes may underlie the basic pathogenesis of neuropsychiatric disorders, given the disease-associations of the TrkC NTRK3 gene. Thus, my findings lead to our greater understanding of the molecular mechanisms of synapse development, and will make significant scientific impacts on not only neuroscience but also cell and developmental biology, neurogenetics, and psychiatric medicine.
Jodi Edwards
Article
EDWARDS, Jodi, et al. “Changes in Intracortical Excitability After Transient Ischemic Attack Are Associated with ABCD2 Score”, Stroke, 42(3), 2011, p. 728-733.
Biosketch
My research experience to date has focused on the use of brain imaging techniques to investigate cognitive function and recovery after acute ischemic stroke. Throughout my undergraduate and master's degrees I was involved in a number of studies investigating cognitive processing that led to several publications, including 3 first authored manuscripts. One of these studies, published in Cognitive Brain Research, involved the use of functional magnetic resonance imaging (fMRI) to assess language recognition in healthy individuals and was my first experience with the acquisition and analysis of brain imaging data. Upon the completion of my master's degree in 2003, I joined the Functional Brain Imaging Research Group at the Seaman Family MR Research Centre with the University of Calgary as a Research Associate. In this position, I gained further experience with the use and analysis of fMRI and expanded my research into patient populations, including stroke, epilepsy, and ADHD. I contributed to several more peer-reviewed original publications in journals such as Journal of Cognitive Neuroscience, an invited review on cognitive recovery after stroke, and several conference presentations. In 2006, I took a Research Associate position with the Functional Imaging Group within the Montreal Neurological Institute at McGill University in Montreal. As a Research Associate with this group, I continued to apply my skills with fMRI brain imaging techniques and also gained experience in the administration of neuropsychological assessments in clinical populations. In 2007, I decided to pursue a PhD in Clinical Epidemiology with a focus on Stroke Prevention and Diagnostic Imaging at the University of British Columbia in Vancouver.
My current PhD research employs brain stimulation techniques to identify individuals at high risk of having a stroke after they have had a mini-stroke, or Transient Ischemic Attack (TIA). Specifically, during my PhD, I have trained in the use of Transcranial Magnetic Stimulation (TMS), which measures the excitability of cortical neurons. With this technique, I have conducted two first-authored studies, including the manuscript submitted for this award. This paper was the first study to investigate the utility of TMS as a diagnostic tool for the identification of individuals at high risk of stroke after a TIA. I presented these data as a symposia presentation at the International Congress for Clinical Neuroepidemiology in Munich, Germany and this paper was published in the journal Stroke, one of the highest impact neurology journals specializing in stroke research. In addition, this study led to a successfully funded CIHR operating grant to follow-up this research longitudinally, of which I am a Co-Investigator. This fall, I will join the research team at Sunnybrook Research Institute in Toronto as a post-doctoral fellow in the lab of Dr. Sandra Black. The focus of my post-doctoral research will be to use multi-modal brain imaging techniques, including amyloid PET imaging, to examine associations between amyloid deposition and cognitive impairment in individuals with cerebral small vessel disease and TIA.
Significance of the paper
This study is immediately relevant to the field of neuroscience, as it provides important insights into the impact of transient ischemia on the brain. It was previously thought that transient ischemic attack (TIA) had no lasting effect on the brain beyond the resolution of clinical symptoms. However, results from this study confirm that intracortical excitability in the motor system is affected up to 2 weeks post event. In addition, this study showed that these effects were correlated with clinical markers of stroke risk after a TIA. Thus, these findings provide critical new evidence for intracortical changes that occur after TIA and demonstrate the potential utility of transcranial magnetic stimulation to detect these effects. Beyond neuroscience, the significance of this study extends to the field of clinical neurology and has potential applications for TIA diagnosis and assessment, in the identification of individuals at high risk of stroke after TIA. It was for these reasons that the journal Stroke was chose for publication of this study, as it is one of the highest-ranking and high impact journals in stroke neurology, with a wide readership of neurologists, clinicians and basic neuroscientists.
Jason Gallivan
Article
GALLIVAN, Jason, et al. “Decoding Action Intentions from Preparatory Brain Activity in Human Parieto-Frontal Networks”, The Journal of Neuroscience, 31(26), June 2011, p. 9599-9610.
Biosketch
I received my Masters and PhD degrees in Neuroscience at the University of Western Ontario studying under Dr. Jody Culham. The focus of my PhD work was directed towards understanding how and where in the human brain intentions for action are coded. To investigate these types of research questions our lab uses functional magnetic resonance imaging (fMRI) and unique experimental tasks where subjects, while in the scanner, directly view three-dimensional objects and perform real actions toward those objects (e.g., reaching, grasping, eye movements, and related functions). Much of my PhD work shows that the mere intention of an individual to perform specific hand and eye movements can be successfully decoded from their brain activity patterns several seconds prior to them actually initiating the movement. Expanding upon this previous work, I have recently begun post-doctoral studies with Dr. Randy Flanagan in the Centre for Neuroscience Studies at Queen's University. My current focus is to map and characterize the planning-related brain signals that lead to more complex behaviours like object manipulation and movement sequencing. Our work hopes to elucidate several cases of sensorimotor dysfunction and assist the development of brain-machine interfaces, cognitively-driven devices which may eventually enable the reconstruction of desired actions in movement-impaired patient populations.
Significance of the Paper
In order to understand the many cognitive disorders of the brain and mind (e.g., neurological and mental disease states) it is first important to understand the neural underpinnings of normal cognitive brain function (i.e., how the human brain is supposed to function). My research maps and characterizes normal brain function with human fMRI and uses advanced analytical techniques in order to elucidate how the brain represents high-level goals and intentions -- the types of cognitive states often disturbed in mental and neurological disorders. To examine how the brain encodes these higher-level cognitive processes I study the cortical mechanisms that guide the planning of arm, hand and eye movements, the simple everyday motor actions that form the building blocks of a more complex repertoire of human behaviours. The overarching aim of this research program is to provide a detailed understanding, at the level of populations of neurons, as to how and where in the human brain intentions and decisions are coded. As a consequence, we hope to assist the development of cognitive neural prosthetics or brain-machine interfaces, cognitively-driven devices which may eventually enable the reconstruction of desired actions and behaviours in movement-impaired patient populations.
Vivek Swarup
Article
SWARUP, Vivek, et al. “Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor B–mediated pathogenic pathways”, The Journal of Experimental Medicine, 208(12), November 2011, p. 2429-2447.
Biosketch
I have been involved with neuroscience research for the last 5 years. During my undergraduate studies in neuroscience at National Brain Research Centre in India, I was involved in understanding the pathogenic mechanisms of Japanese Encephalitis Virus mediated neurotoxicity and thereby determining possible therapeutic intervention for the disease. I published in several international peer reviewed journals about the mechanisms of neurotoxicity caused by the virus and possible drug treatment in cell-culture and mouse models of the disease. My basic training in cell-culture, immunoblotting, immunohistochemistry and pharmacokinetics/pharmacodynamics laid the foundation and encouraged me to join Prof. Jean-Pierre Julien's lab on Amyotrophic Lateral Sclerosis (ALS) research at the Department of Neuroscience and Psychiatry, University Laval, Quebec.
My PhD work is focused on generating and characterizing new TDP-43 transgenic mouse model of ALS. Within 3 years I generated transgenic mice encoding genomic fragments of human TDP-43. To better mimic human ALS cases, we generated transgenic mice that exhibit moderate and ubiquitous expression of TDP-43 species using genomic fragments encoding human TDP-43 wild-type or FALS-linked mutants TDP-43G348C and TDP-43A315T. These novel TDP-43 transgenic mice were published in the journal Brain (Swarup, et al Brain 2011) and develop many age-related pathological and biochemical changes reminiscent of human ALS including ubiquitinated TDP-43 positive inclusions, TDP-43 cleavage fragments, intermediate filament abnormalities, axonopathy and neuroinflammation. All three transgenic mouse models exhibited during aging impaired learning and memory capabilities as well as motor dysfunction. I developed a powerful technique for real-time imaging in vivo with the use of biophotonic TDP-43 transgenic mice carrying GFAP-luciferase reporter. In vivo imaging revealed that the behavioral defects were preceded by induction of astrogliosis, a finding consistent with a role for reactive astrocytes in ALS pathogenesis. These novel TDP-43 transgenic mice mimic several characteristics of human ALS/FTLD (fronto-temporal dementia) and they should provide valuable animal models for testing therapeutic approaches.
I have presented my work in more than 15 different national and international conferences. In addition to my scientific training, I have been an active member of Canadian Association of Neuroscience, ALS Society of Canada and Society for Neuroscience (SFN) and regularly present my work at the annual meetings. The knowledge which I have gained in my PhD will enable me to join in a post-doctoral position so that I can contribute to science for the betterment of mankind.
Significance of the Paper
Our innovative work is strongly aligned with the goals and principles of INMHA of conducting and disseminating ethically responsible research which deepens our understanding of various neurodegenerative diseases in general and ALS /FTLD-U in particular. TDP-43 aggregates are reported in various neurodegenerative diseases like Alzhiemers disease, Parkinson's disease, Paget disease and ALS/FTLD-U. Understanding TDP-43 mediated pathogenic mechanism in neurodegenerative diseases is the key in deciphering possible convergent neurotoxic mechanism. Our research has direct implication in therapy of ALS and we intend to take our discovery to clinical trials for ALS patients. Our collaborative work signifies importance in team-work linking researchers across Canada and other parts of the world for a common cause to understand the pathogenesis of the disease and to fight against it so as to make the world a better place to live in.
Helene Beaudry
Biosketch
I first started to be interested in neurosciences during my undergraduate studies (Sept 2000 to May 2004). I made three (3) training courses in Dr. Nicole Gallo-Payet's laboratory at the Université de Sherbrooke. I was interested in verifying the implication of protein kinase C in Angiontensin II-induced neuronal differentiation. I have worked with different biochemical techniques such as subcellular fractionation, kinase assays, western blot analysis (including ERK1/2 activation) and immunofluorescence. Then I started my MSc training on the same topic, which allowed me to contiunue to explore the AT2R signaling pathways in neuronal differentiation of NG108-15 cells, and my work led to 6 publications. In October 2006, I started my thesis and I wanted to continue to explore neurosciences in a more in vivo approach. I got a doctoral research award from NSERC and FRSG and I moved to Dr. Louis Gendron's laboratory (Université de Sherbrooke). I worked on role and regulation of delta opioid receptor in pain treatment using different behavioral and biochemical techniques and my results were published in 4 research articles. Recently, I received a postdoctoral fellowship to study the implication of delta opioid receptor in the onset of morphine tolerance in Dr. Jose Moron-Concepcion's laboratory at Columbia University in New York City.
Edor Kabashi
Article
KABASHI, Edor, et al. “FUS and TARDBP but Not SOD1 Interact in Genetic Models of Amyotrophic Lateral Sclerosis”.
Biosketch
After receiving my BSc. in Biology at McGill University, I started my PhD studies with Dr. Heather Durham at the Montreal Neurological Institute. During these studies I tried to understand the major mechanisms that cause motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). During these PhD studies I demonstrated that the proteasome activity and structure is disrupted in a number of ALS models, including the mutant SOD1 transgenic mice (Kabashi et al. J Neurochem 2004; 2007). During my postdoctoral training with Dr. Guy Rouleau, I identified TDP-43 mutations playing a major role in ALS patients (Kabashi et al. Nat Genet 2008; CIHR Brain Star awarded in 2008). Discovery of these mutations prompted us to develop animal models for ALS that have rapidly led to elucidation of novel pathways involved in these motor neuron diseases. I continued this groundbreaking research by generating zebrafish models for mutant TDP-43 as well as other major ALS genes, such as FUS and SOD1. Zebrafish due to their availability, transparency, and ease of genetic manipulation are proving to be excellent models to study a number of health diseases. Training with Dr. Pierre Drapeau in an internationally reputed zebrafish laboratory, we have developed over the last few years a number of transient and stable transgenic zebrafish models. These models will be extremely useful to study mechanisms of disease, to further understand genetic interactions between different ALS genes, as well as to perform chemical screens to identify and validate ALS therapeutics. In total, I have published over 20 research articles including a number of highly-cited first-author publications in journals with high impact factor (including Nature Genetics, PLoS Genetics, Annals of Neurology, Trends in Genetics, Human Molecular Genetics etc.), review papers and a number of book chapters and commentaries. I have presented my work in a number of national and international conferences where I have been awarded a number of prestigious research prizes. I have also been awarded a number of salary awards, including the Tim E. Noel fellowship and Graduate studentship from the CIHR Graduate studentship, the McGill Faculty of Medicine studentship award, The Herbert Jasper fellowship from University of Montreal and a Development Grant from the Muscular Dystrophy Association. Currently my research is supported by the Atip/Avenir of Inserm, ALS Canada, ALS Therapeutic Award from the Department of Defense, as well as funds from the Robert Packard and Frick Foundations for ALS Research.
Relevance
This paper represents a cornerstone for ALS research since it convincingly demonstrates that SOD1 mutations cause motor neuron degeneration through independent pathways from TDP-43 and FUS, perhaps explaining why therapeutics found to be efficient in mutant SOD1 transgenic mice had no effect in the majority of ALS patients. This paper was selected in the Faculty of 1000 (F1000), which places this work in our library of the top 2% of published articles in biology and medicine.
This research article demonstrates for the first time a genetic interaction between FUS and TDP-43, two major genes in the most common motor neuron disease, Amyotrophic Lateral Sclerosis (ALS). In 2008, I was first author in a paper that made the breakthrough discovery of TDP-43 mutations in ALS patients. Subsequently, FUS mutations were also identified in ALS patients. FUS and TDP-43 represent the most prevalent genetic cause in ALS with both these genes having structural and functional similarities. Understanding how FUS and TDP-43 mutations cause motor neuron degeneration and the mechanisms that promote sequestration of these mutant proteins in insoluble aggregates is the major challenge in ALS research and most likely will bring forward new therapeutic avenues for this disorder. To determine whether FUS and TDP-43 share common mechanisms of disease, in this research paper, we functionally characterized for the first time FUS mutations in vivo and performed multigenic interactions between the three major ALS genes, FUS, TDP-43 and SOD1 using zebrafish as a vertebrate model organism. We discovered that overexpression of WT, but not mutant FUS is able to rescue the motor phenotype derived from knockdown of TDP-43 in zebrafish. These results suggest that TDP-43 and FUS share similar pathogenic mechanisms with TDP-43 being upstream in this pathway. However mutant SOD1 does not play a role in these mechanisms either upstream or downstream. This paper represents a cornerstone for ALS research since it convincingly demonstrates that SOD1 mutations cause motor neuron degeneration through independent pathways from TDP-43 and FUS, perhaps explaining why therapeutics found to be efficient in mutant SOD1 transgenic mice had no effect in the majority of ALS patients.
Paul Metzak
Article
METZAK, Paul et al. “Decreased efficiency of task-positive and task-negative networks during working memory in schizophrenia”. Schizophrenia Bulletin,(2011)DOI: 10-1093/schbul/sbq154.
Biosketch
My interest in neuroscience was blossomed while I was completing a double major in Philosophy and Psychology from Simon Fraser University. Upon the completion of my undergraduate degree, I began work as a research assistant for Dr. Todd Woodward at Riverview Hospital, where I was given the opportunity to study the cognitive and behavioural changes that characterize mental illness. This experience furnished me with a desire to understand the alterations in brain function that give rise to the symptomatology of schizophrenia, which led me to pursue a Masters degree in Neuroscience at UBC under the supervision of Dr. Woodward. During the course of my Masters degree, I used functional magnetic resonance imaging (fMRI) to study differences in brain activity between schizophrenia patients and healthy volunteers while performing memory tasks. I am currently working on my PhD, and my project, which is also supervised by Dr. Woodward, is focused on examining the changes in brain activity related to cognitive control in schizophrenia using both fMRI and magnetoencephalography (MEG).
Significance of the Paper
The research paper I have submitted is aligned with INMHA's mandate as its principal aim was to identify neural differences in individuals suffering from schizophrenia relative to healthy controls. Specifically, this research found that, while performing a working memory task, (1) the brain is organized into two functional networks, the task positive and task negative network, that organize in three main configurations to carry out the three phases of the working memory task (encoding, maintenance and response), and (2) schizophrenia patients showed increased activity and connectivity relative to healthy controls at moderate levels of working memory load, suggesting that the performance deficits commonly found in schizophrenia patients at high working memory loads may reflect an inability to recruit additional neural activity in the face of increasing demands. This study links a commonly observed behavioural difference in schizophrenia e.g. deficits in working memory performance, to inefficiencies in functional brain networks that have been found to be present in almost every cognitive task.
This research makes an important contribution to cognitive neuroscience by demonstrating that three configurations of two functional brain networks carry out the three phases of working memory, and that that schizophrenia patients show inefficiency in the activity in these functional brain networks relative to healthy volunteers while performing working memory tasks. Given that these increases were detected in brain networks that are the basis of most fMRI results regardless of the specific cognitive task, this research is relevant to a wide range of cognitive deficits in schizophrenia. It was for this reason that we opted to publish in Schizophrenia Bulletin. Furthermore, this paper marked the first published clinical application of a multivariate statistical methodology developed by our laboratory for the analysis of fMRI data. Therefore, this research is also of interest to anyone performing fMRI experiments, particularly when applied to clinical samples, as this analysis method has advantages over many of the commonly used analysis programs.