Brain Star Awards - Recipients for 2009

Oliver Ayling and Thomas Harrison

Recipient

Oliver Ayling
MSc. Neuroscience, University of British Columbia
and
Thomas Harrison
Ph.D., Neuroscience, University of British Columbia

Biosketch – Oliver Ayling

Starting in September 2008 I enrolled in the Master's program for Neuroscience at UBC, where I will be looking into sensory and motor recovery in mouse models of stroke. I am very fortunate to be a grad student in the neurosciences as I attempt to understand the brain each day I come to the lab. One of the most exciting and rewarding aspects of the work I do is that it has the potential to one day, hopefully, help understand some aspect of recovery from stroke.

In 2008 I completed my Bachelor of Psychology from the University of Victoria. During my time as an undergraduate I volunteered in several research projects and the experience that got me most excited about research was a project in visual cognition with Dr. Jim Tanaka. As a native of Vancouver I moved back home after my undergraduate and began volunteering in Dr. Tim Murphy's lab before enrolling the master's program. During my time volunteering in Dr. Murphy's lab I received a Canadian Stroke Network summer studentship as well as a UBC Neuroscience department CIHR Training Program in Neurobiology and Behaviour summer studentship.

Biosketch – Thomas Harrison

Although the physical damage caused by stroke is irreversible, the brain has an impressive capacity for spontaneous functional recovery. For example, neurons whose post-synaptic targets have been destroyed can extend their axons to more distant cortical regions to maintain communication. These mechanisms allow the brain to adapt after a stroke, with surviving neurons assuming roles previously performed by stroke-affected cells.

My PhD in Dr. Tim Murphy's lab at UBC will attempt to better define the changes that occur in neural circuitry after stroke, with the ultimate goal of improving rehabilitation prospects for stroke patients. This research relies heavily on the automated motor mapping method described in the publication for which Oliver Ayling and I received the Brain Star award. Dr. Murphy has received generous support from CIHR that provides me with all of the resources necessary to carry out my work, and I am happy to say that I am limited only by time and imagination.

Prior to joining Dr. Murphy's lab, I completed an honours undergraduate thesis with Dr. Kerry Delaney at the University of Victoria, where I helped to design and prototype a wireless device for nerve stimulation and recording.

Article

Automated light-based mapping of motor cortex by photoactivation of channelrhodopsin-2 transgenic mice. Oliver GS Ayling, Thomas C Harrison, Jamie D Boyd, Alexander Goroshkov, and Timothy H Murphy. Nature Methods. 2009 Mar; 6(3):219-24.

Significance of the paper

In the paper 'Automated light-based mapping of motor cortex…' we developed a novel method was that allows the motor representations of the brain to be mapped in mice using light activation rather than penetrating electrodes. The method employs transgenic mice which express the light sensitive ion channel, channelrhodopsin-2, allowing excitation of the cortex when activated with light. This new method provides a tool that is useful for long-term study of motor systems and how they change in response to training or injury. Understanding recovery of function and how the brain reorganizes after neurological deficits, such as stroke, is important so that therapies for patients may be enhanced. One of the most common deficits after stroke is impairment of the sensory and motor systems so that individuals may have problems with common tasks important for daily function. Traditionally, to study motor cortex plasticity after deficits, the cortex is mapped using penetrating electrodes that cause neuronal damage and is also a quite laborious technique. Furthermore, it is difficult to map the same brain over a long period of time due to the invasive nature of the electrode-based method. The light-based mapping method is able to map the brain in a matter of minutes and week-to-week imaging is possible through a chronic brain window. The hope is that light based mapping will be used to study alterations of the motor cortex in mouse models of disease that lead to motor deficits, such as stroke, Parkinson's or Huntington's models.


Top of Page

Nicholas Carleton

Recipient

Nicholas Carleton
Ph.D., Psychology, University of Regina

Biosketch

I hold a Bachelor of Arts in Administration, a Bachelor of Arts (Honours) in Psychology, and a Master of Arts in Psychology from the University of Regina. My Honours thesis research was on the psychological and behavioral effects of the September 11th terrorist attacks on geographically remote viewers. Thereafter, my Masters thesis research investigated the biophysiology of chronic pain, mapping attentional biases for pain onto established neural pathways for fear.

Currently pursuing my Doctorate in Psychology, I am working with Dr. Asmundson studying chronic pain and posttraumatic stress disorder. In addition, as a research assistant in the Anxiety and Illness Behaviours Lab, I am actively involved in and piloting several investigations in pain, anxiety, and trauma. My research interests include cognitive-behavioural models and treatments for anxiety, chronic pain, fear, and PTSD. I have been awarded a CIHR Canadian Graduate Scholarship to study biological and psychological correlates of trauma and pain.

I am currently completing my predoctoral residency at the Calgary Consortium in Clinical Psychology. In the fall, I will be taking a faculty position at the University of Regina.

Article

Carleton, R. N., & Asmundson, G. J. G. (2009). The multidimensionality of fear of pain: Construct independence for the Fear of Pain Questionnaire-Short Form and the Pain Anxiety Symptoms Scale-20. The Journal of Pain, 10, 29-37.

Significance of the paper

In Canada, at least 10% of the population endures daily chronic pain at an annual cost in the hundreds of millions. Current models of chronic pain emphasize fear and anxiety as diatheses for developing and maintaining pain. Precedent anxiety disorder research distinguishes fear as a present-oriented emotive state associated with an imminent threat, but anxiety as a future-oriented emotive state, associated with anticipated threats even without an objective stimulus. In contrast, pain-related research has typically referred to pain-related fear and anxiety collectively as fear of pain. Moreover, researchers have suggested pain-related anxiety may be a manifestation of anxiety sensitivity (AS) - the tendency to fear anxiety sensations based on the belief they may have harmful consequences. The current research suggests that pain-related fear, pain-related anxiety, and AS are related but distinct constructs. Similarly, the distinction may be critical to further develop models to explain chronic pain. For example, over time, pain-related anxiety may become an over-learned response, exacerbating unnecessary avoidance behaviours and disability. Regarding pain-related anxiety as a manifestation of AS, results were inconclusive; unlike AS, pain-related anxiety does not require a catastrophic misinterpretation for the sensation of pain to be noxious. The distinct constructs of pain-related fear, anxiety, and AS may warrant independent attention, informing theory and practice for multidisciplinary teams working to treat chronic pain (e.g., psychology, medicine, dentistry). Such attention should help to tailor more effective treatments for people with chronic pain. This research is likely to reach a substantial audience, given that it was published in The Journal of Pain, a leading peer-reviewed journal (Impact Factor: 3.58).


Top of Page

Viviane Labrie

Recipient

Viviane Labrie
Ph.D., University of Toronto

Biosketch

Currently, I am post-doctoral fellow in the Krembil Family Epigenetics Laboratory at the Centre for Addiction and Mental Health in Toronto under the supervision of Dr. Art Petronis. In this lab, we specialize in the study of epigenetic mechanisms of disease. A microarray-based approach is employed to determine genome-wide changes in DNA methylation. Fine mapping techniques, such as sodium bisulfite sequencing, are also used to confirm epigenetic modifications at specific loci. The large-scale studies conducted in this laboratory benefit our understanding of the role of the epigenome in disease pathophysiology and treatment response.

My graduate training was completed in the laboratory of Dr. John Roder, where I gained expertise in genetics, molecular biology, pharmacology, and behavioral neuroscience. My doctoral work examined the glutamatergic theory of schizophrenia, with a goal to identify genes that may be involved in the pathophysiology of this disorder, and to determine therapeutic targets that could benefit the treatment of schizophrenic symptoms. In particular, I investigated whether perturbations in D-serine synthesis, or breakdown, in animal models could contribute to a loss of NMDAR activity that may underlie certain endophenotypes in this disorder. In my studies, I used genetic engineering techniques and pharmacology to develop novel mouse models that tested the effects of altered D-serine availability and NMDA receptor glycine site activation. These studies led to several publications in widely read journals, including Human Molecular Genetics and Neuropsychopharmacology.

To date, I have published 11 papers. Of these, 6 were first author research articles in well-known journals. My research article examining the effects of increased D-serine on extinction was selected to be on the cover of Learning and Memory (Feb 2009). In addition, I have written a review paper that was published in 2009 in a high impact journal (Neuroscience Behavioral Review). I have also contributed 2 book chapters, including one on the potential of HDAC inhibitors as a treatment approach for cognitive disorders.

My research activities have attracted several awards, including Canadian Institutes of Health Research (CIHR) Fellowships, Samuel Lunenfeld Research Institute (SLRI) Fellowships and Natural Sciences and Engineering Research Council of Canada (NSERC) Doctoral awards. I was also awarded the Siminovitch-Salter award for outstanding scholarly contributions during my graduate studies.

I have presented my work at over 30 local, national, and international meetings. I have won many travel awards for conferences such as the Society for Neuroscience meeting and Molecular and Cellular Cognition Meeting. At the 2006 International Behavioural and Neural Genetics Society conference in Vancouver, BC I received an Outstanding Young Investigator award. In addition, I enjoy teaching, as I volunteered for many years in SLRI's Sci High program, which introduces young students to science. Also, I have been a teaching assistant in histology and histopathology at the University of Toronto for 7 years and have trained several students during my research lab experience.

In the future, I intend to establish my own research group that will be devoted to studying the molecular mechanisms underlying the pathophysiology and treatment of psychiatric disorders. Overall, my scientific goal is to fuel the discovery of psychotropic treatment interventions based on a greater insight of the molecular mechanisms underlying psychiatric illnesses.

Article

Viviane Labrie, Ryutaro Fukumura, Anjali Rastogi, Laura J. Fick, Wei Wang, Paul C. Boutros, James L. kennedy, Mawahib O. Semeralul, Frankie H. Lee, Glen B. Baker, Denise D. Belsham, Steven W. Barger, Yoichi Gondo, Albert H.C. Wong and John C. Roder. Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. Human Molecular Genetics, 2009, Vol. 18, No. 17.

Significance of the paper

In this study we identify that the D-serine synthesis enzyme, serine racemase, is involved in schizophrenia pathophysiology. This has important ramifications for the development of novel therapeutic interventions. Abnormal serine racemase function has been implicated in several neurodegenerative diseases, and our animal model establishes a basis for further in-depth study of many complex psychiatric diseases. The wide target audience of the Human Molecular Genetics journal has interest in both human and animal studies. This journal is one the top-ranking journals for the study of the molecular mechanisms involved in human disease. Publication in this broad platform is a recognition of the clinical importance of our work.


Top of Page

Grant Gordon

Recipient

Grant Gordon
Ph.D., University of British Columbia

Biosketch

My medical research training began as a summer student in 1999 and 2000 in the laboratory of Dr. Brian MacIntosh where I held two consecutive NSERC studentships. It was here I began my first physiology experiments with rat atria, where I measured the strength of atria contraction and the degree of phosphorylation of contractile proteins. In September 2001 I began my graduate studies in neuroscience. I received the unique opportunity to build a lab from the ground up with newly hired faculty member, Dr. Jaideep Bains. Before touching an experiment we spent months building electrophysiology rigs. I learned a great deal about the equipment and the methodology. In the Bains laboratory we focused on studying neurons that coordinate an organism's response to stress, with a particular interest in clarifying how the molecules released at the onset of a stressful stimulus leave a lasting imprint on how 'stress-relevant' circuitry functions. Within this context, we conducted experiments that allowed us to understand the fundamental rules that govern cell to cell communication within the hypothalamus and elucidate the molecular machinery that contributes to changes in synaptic function. To investigate these questions, we employed and in vitro brain slice preparation of the hypothalamus. Brain slices preserve the brain architecture and thus are ideal for electrophysiological recordings to measure of synaptic strength and membrane excitability within a largely intact system. With this approach we made several important discoveries that include three novel forms of synaptic plasticity, one of which required an unexpected interaction between 'support cells' called astrocytes and the neurons themselves, which was published in Nature Neuroscience. This finding involved astrocytes responding to the neuromodulator noradrenaline (a critical stress molecule in the hypothalamus) by releasing the gliotransmitter ATP, which subsequently acted on neurons to increase synaptic strength. Because the brain slice is easily coupled with live-cell fluorescent imaging enabling one to visualize cell type, study cell morphology, as well as dynamic processes such as calcium signaling, membrane voltage, pH, metabolism and others parameters, I wanted to acquire imaging techniques. In particular, two-photon fluorescence microscopy is revolutionizing the way neuroscience is conducted, with a capability to visual physiological processes at the network, cellular and subcellular level in real time deep within intact tissue. The special laser light used in this technique also allows one to be able to be 'turn on' or 'turn off' single cells without affecting others through a process called 'uncaging', a very powerful and useful technique to test causality of hypotheses. Due to these attributes, towards the end of my doctorate I applied for, and received entry to, an advanced imaging course focusing on two-photon methods at the prestigious Cold Spring Harbor Laboratories for three immersive weeks. From the instructors to the invited speakers, some of the best neuroscientists in the world participated. It was invaluable, hands-on experience that allowed me to transition into a postdoctoral position at UBC with Dr. Brian MacVicar, who specializes in electrophysiology and two-photon microscopy. This position was an excellent match for my skills and previous research discoveries because Dr. MacVicar was also very interested in neuron-astrocyte interactions in the hippocampus and cortex, but with respect to how this process works to control cerebrovascular blood flow. Once in the lab I began to solidify many of the aforementioned imaging techniques into my experimental repertoire. This work, utilizing a collaboration with Dr. Graham Ellis-Davies, led us to discover a completely novel way in which astrocytes control the diameter of cerebral arterioles, which was published recently in Nature. We found that the metabolic activity in the brain tissue is a critical factor in dictating the type of influence astrocytes induce on cerebrovascular diameter. Specifically, the level of oxygen in the brain could change the metabolic state of the tissue (i.e. shift the balance between more or less glycolysis in astrocytes) and cause astrocytes to induce opposite changes to vessel diameter. When oxygen levels are high, similar to when the brain is inactive, astrocyte activation induces vasoconstriction, which would decrease blood flow. When oxygen levels are low, mimicking high activity of neurons in the brain, astrocytes cause vasodilation of arterioles. In a sense, astrocytes are tuned to the level of activity and the metabolic needs of the brain and elicit corresponding changes to cerebral blood flow to match the delivery of new energy substrates from the blood to the needs of the neurons. In subsequent work we started a collaboration with my previous supervisor Dr. Bains and continued our collaboration with Dr. Ellis-Davies and returned to the hypothalamus to further explore neuron-astrocyte interactions in this region. In this work we have presented convincing evidence that astrocytes do indeed directly communicate to neurons to influence synaptic strength in an ATP dependent manner. This was demonstrated using combined electrophysiology and two-photon imaging, in which the latter enabled us to uncage intracellular IP3 within the volume of individual astrocytes to definitively show that IP3 signaling here can initiate cross cell communication. This work was very recently accepted in Neuron.

Article

Brain metabolism dictates the polarity of astrocyte control of arterioles, Gordon, G.R., Choi, H.B., Rungta, R.L. Ellis-Davies, G.C.R. and MacVicar, B.A., Nature, 456(7223):745-749, 2008.

Significance of the paper

We have made a seminal discovery in the control of cerebral blood flow (CBF) by astrocytes. The manuscript describing this finding has recently been published as an article in Nature, which is the most prestigious scientific publication. We found that the amount of oxygen in the brain determines the type of vessel response triggered by astrocyte calcium signals. When oxygen is high, astrocyte activation causes vasoconstriction of nearby arterioles, which would reduce CBF. When oxygen is low, which occurs when the brain is very active or possibly during pathological conditions where the oxygen supply is compromised, astrocytes induce vasodilation, which would increase CBF. While it has been previously appreciated that oxygen levels can change dynamically in the brain, that oxygen itself is an important variable in controlling the type of astrocyte influence on vessel diameter was very surprising. This discovery will have important implications for treating abnormalities in the regulation of cerebral blood flow that occur in some dementias and after stroke. The finding also provides new insight into the mechanisms of how the brain is intrinsically capable of regulating is own blood supply, which is very important for the interpretation of functional magnetic resonance imaging data, a technique that is widely used in humans to ascertain brain function in both normal and pathological states. Finally, these data resolve a discrepancy in the literature, in which astrocytes have been observed to induce both vasoconstrictions and vasodilations, without knowledge of what underlies such variability. Our results show that oxygen and the metabolic state of the brain tissue determines the effect of astrocyte activation on CBF.


Top of Page

Brent Kuzmiski

Recipient

Brent Kuzmiski
Ph.D., University of Calgary

Biosketch

I completed my undergraduate degree in Life Sciences at Queen's University in 1998. I then moved to the University of Calgary where I worked in the lab of Dr. Brian MacVicar and received my PhD in 2004. During my PhD I investigated how muscarinic acetylcholine receptors modulate hippocampal neuron excitability and contribute to seizure generation. Currently, I am a postdoctoral fellow in the labs of Dr. Jaideep Bains and Quentin Pittman. My current research focuses on understanding how challenges to homeostasis lead to long-term changes in the neural circuitry in the hypothalamus. I discovered that multiple forms of synaptic plasticity work together to ensure that an effective response to a life-threatening challenge, such as severe blood loss, is followed by an immediate recovery of these neural circuits to pre-challenge conditions. This work set of synaptic rules to help us understand how homeostatic setpoints are re-set in vivo and demonstrate that synaptic plasticity is essential for maintaining stability in a nervous system constantly bombarded by inputs from the outside world.

Article

Kuzmiski et al. Metaplasticity of hypothalamic synapses following in vivo challenge, Neuron 62, 839-849.

Significance of the paper

Homeostasis, the body’s own mechanism of regulating and maintaining internal balance is necessary for survival. Precisely how the brain pulls off this tricky balancing act has not been well appreciated. By examining neural circuits that regulate fluid volume, we have demonstrated that multiple forms of synaptic plasticity work together to ensure that an effective response to a life-threatening challenge is followed by an immediate recovery of theses neural circuits to pre-challenge conditions.


Top of Page

Brent Kuzmiski

Recipient

Kelsey Collimore
Ph.D., Clinical Psychology, University of Regina

Biosketch

Kelsey Collimore is a doctoral student in Clinical Psychology at the University of Regina and a trainee with The Traumatic Stress Group. She received her Bachelor of Health Sciences (Honours) from McMaster University in 2004, and her M.A. in Clinical Psychology from the University of Regina in 2007. Kelsey worked as a research assistant at the Rotman Research Institute at Baycrest Centre for Geriatric Care in 2004-2005, and has worked as a research assistant in the Anxiety and Illness Behaviours Laboratory at the University of Regina since 2005. She has published nine articles (two as first author) and five book chapters (regarding the anxiety disorders, health anxiety, and fear of pain), and has given several oral and poster presentations at academic conferences. Kelsey received a CIHR Canada Graduate Scholarship Master's Award (2006-2007) and is the recipient of a CIHR Doctoral Research Award. In 2009, she was awarded a Career Development Travel Award from the Anxiety Disorders Association of America. Her clinical and research interests include anxiety and related conditions, anxiety disorder co-morbidity, and cognitive-behavioural treatments of anxiety disorders. In the fall, Kelsey will be starting her predoctoral internship at the Centre for Addiction and Mental Health in Toronto, Ontario.

Article

Collimore, K. C., Asmundson, G. J. G., Taylor, S., & Jang, K. L. (2009). Socially related fears following exposure to trauma: Environmental and genetic influences. Journal of Anxiety Disorders, 23, 240-246.

Significance of the paper

The relationship between traumatic events and psychopathology has received considerable empirical attention (e.g., O'Donnell, Creamer, & Pattison, 2004, O'Donnell, Bryant, Creamer, & Carty, 2007); however the heterogeneity of responses to trauma continues to stimulate advances in trauma research. Although traumatic event exposure is necessary for the development of Posttraumatic Stress Disorder [and is specified as a criterion in the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2000)], traumatic events have also been shown to increase the risk for many other emotional disorders (Kessler, Davis, & Kendler, 1997), including Social Anxiety Disorder (SAD; Zayfert, DeViva, & Hofmann, 2005). Although a growing body of research suggests that socially related fears and posttraumatic stress symptoms frequently co-occur, few studies have examined the mechanisms underlying this co-occurrence. The results of this study have clinical implications regarding co-occurring symptoms of socially related fears and PTSD. These findings suggest that the type of trauma experienced (whether assaultive or nonassaultive trauma) does not impact socially related fears; however, persons with significant PTSD symptoms may be at greater risk for the development of socially related fears. Accordingly, among persons with PTSD, it may be particularly important to assess for elevated levels of socially related fears. Future research may further inform our understanding of these co-occurring conditions and ultimately lead to advances in treating persons suffering from co-occurring SAD and PTSD symptoms.


Top of Page

Jason Gallivan

Recipient

Jason Gallivan
Ph.D., University of Western Ontario

Biosketch

I received my Honour's B.Sc. in Biology from the University of Western Ontario (UWO). During two years of my undergrad I worked for Dr. David Cechetto, who was examining the effects of anti-inflammatory agents on a rodent model of Alzheimer's Disease. I assisted his lab with data collection and analyses (microscopy, statistical analyses, gel electrophoresis and rat surgeries).

I received my M.Sc. and current PhD training at UWO in the Neuroscience program studying under Dr. Jody Culham. I use functional magnetic resonance imaging (fMRI) to examine brain activation within areas of parietal and frontal cortex involved in hand and arm actions. Our lab conducts unique experiments where subjects can directly view objects and perform real hand actions in the scanner (like reaching or grasping). This makes our experimental tasks quite natural compared to the standard neuroimaging practice of requiring subjects to view objects/displays through mirrors (which require additional transformations in the brain) and make no hand/arm movements. Indeed, limb movements within the scanner create several challenges because they perturb the magnetic field causing artifacts in the data. Our more natural experiments require the use of special hardwares (open face coils, arm braces, reaching platforms) and softwares (preprocessing algorithms) to address these problems. I have also recently acquired experience designing and analyzing kinematic behavioural experiments in which we track participant's and patient's arm trajectories with infrared emitting markers while they complete reaching, pointing and grasping tasks. The goal of our neuroimaging and behavioural research is to understand how the sensorimotor system plans and executes goal directed actions as well as provide anatomical explanations for the behavioural deficits found in parietal lobe patients.

Article

Jason P. Gallivan, Cristiana Cavina-Pratesi, and Jody C. Culham Is That within Reach? fMRI Reveals That the Human Superior Parieto-Occipital Cortex Encodes Objects Reachable by the Hand. J. Neurosci., Apr 2009; 29: 4381 - 4391

Significance of the paper

In this paper we show using functional magnetic resonance imaging that a brain region implicated in reaching actions, the superior parieto-occipital cortex (SPOC), also selectively encodes reachable vs. unreachable 3D objects during viewing. We take these visual responses in SPOC to suggest that the brain encodes the potential to act on an object (i.e., for the purposes of reach planning). This finding is highly relevant to other neuroimaging and neurophysiological studies in humans and macaques which have also found visual responses within action-related areas of parietal cortex. Moreover, previous studies in parietal lobe patients with extinction and neglect have shown deficits selective for near space, however 1) these patients typically have large brain lesions making it difficult to determine what areas within parietal cortex are affected (especially true given the close proximity of reaching areas in parietal cortex) and 2) these patient results are based on small sample sizes (sometimes n=1) which make the results difficult to generalize to the neurologically intact population as a whole. Our consistent finding across several subjects and two separate imaging experiments suggests an anatomical basis for some of these near space deficits. In addition, some patients with damage to frontal cortex, which receives heavy projections from reach areas in parietal cortex, are unable to inhibit actions to objects located within reachable space (called alien hand syndrome). Combined with our findings, these patient results suggest an inhibitory role of the frontal cortex for potential actions.


Top of Page

Ana Mingorance-Le Meur

Recipient

Ana Mingorance-Le Meur
Ph.D., University of British Columbia

Biosketch

I am a cellular neurobiologist with a background in brain development and regeneration. The main theme connecting my graduate, postdoctoral and current research has been the study of the cellular mechanisms that allow or prevent neurons to grow and to regenerate after injury. My ultimate goal is to find strategies able to promote neuronal plasticity for the treatment of neurological disorders.

I started my journey in Spain, with an undergraduate in Biology from the University of La Laguna followed by a PhD in Neuroscience from the University of Barcelona. During my graduate work under the supervision of Dr. José Antonio del Río, I investigated the role of glial cells in preventing neuronal growth and regeneration. My thesis helped understanding how myelin-associated proteins limit the regeneration of cortical connections. We also described how some of those same molecules are present in the immature nervous system where they actually help regulating brain development.

For my post-doctoral research, I switched my attention from the glial factors that restrict neuronal growth to the neuronal changes that could explain why neuronal plasticity decreases as the brain maturates. In other words, in elucidating the internal regulators of neuronal plasticity. The goal of this project was to "rejuvenate" neurons and therefore enhance brain capacity to self-repair. For this project, I received fellowships from the European organization EMBO and the Canadian Michael Smith Foundation from Health Research, and had the pleasure of working with Dr. Tim O'Connor, my mentor at the University of British Columbia.

The resulting findings are described in the EMBO Journal publication for which we received this Brain Star Award. We discovered that neurons don't actually lose their plastic or protrusive ability as the brain maturates, but instead they activate an internal mechanism of repression. By turning off this internal repression we could in fact restore their apparently lost plasticity, and therefore in some sense "rejuvenate" those neurons. This was not only a conceptual advance, but also an important accomplishment from a translational perspective as the pathway we described has numerous points where neuronal plasticity and brain self-repair could potentially be induced.

Following my postdoctoral training, I now work in industry identifying new molecular targets for drug discovery and contributing to the development of treatments for a variety of neurological disorders.

Article

Mingorance-Le Meur, A. and O’Connor, TP (2009) Neurite consolidation involves constant repression of protrusive activity. EMBO Journal 28(3):248-60 (February 4 2009, issue).

Significance of the paper

The mature central nervous system has a very limited capacity to repair itself after injury or disease, often leading to lifelong disabilities. Two key questions in neurobiology are why the brain has such limited plasticity, and how we could enhance it. There has been extensive research on how external inhibitors, present in the mature central nervous system, cooperate to restrict neurite plasticity – the discovered an unsuspected mechanism by which neurons control (and actually repress) their capacity to sprout in a cell-autonomous manner.

The main accomplishment of this research is the significant conceptual advance it provides, revealing that neurite plasticity is internally regulated by the neuron and that protrusive potential is not lost in mature neurons but repressed. From a translational perspective, the pathway we have described has numerous potential points where neurite plasticity can be induced, and so drugs acting on this pathway – including some already being tested for neuroprotection – may be of therapeutic benefit for neurological diseases. I believe this work opens a new avenue for researching neurite plasticity regulation and exploring its involvement in normal and pathological brain function.


Top of Page

Hong-Shuo Sun

Recipient

Hong-Shuo Sun
Post Doctoral Fellow, University of Toronto

Biosketch

Hong-Shuo Sun obtained his Ph.D. degree in 2004 for work on neuroprotection of KATP channels in cerebral ischemia under the supervision of Dr. Robert J. French who is a well known biophysicist of ion channels in the University of Calgary. During his PhD program, he held the first Focus on Stroke Doctoral Research Award (jointly funded by CIHR, HSFC, CSN, etc). Using the Kir6.2 KATP channel knockout mice (obtained from international collaboration with Drs. Seino and Miki in Kobe, Japan), he confirmed that Kir6.2 KATP channels are important for neuroprotection for both hippocampal and neocortical neurons from cerebral ischemia in both in-vitro and in-vivo. KATP channel modulators may prove to be clinically useful in a neuroprotective agent, in the future, as part of a combination therapy for stroke management.

His works have been published in J Neuro-physiol and Neurosci. He also has previous medical training (Cardiologist), and a Master of Science degree in Pharmacology from the University of Alberta. Currently, he has been a postdoctoral fellow for the last 3 years in two Canadian leading stroke research laboratories under the supervision of Dr. Michael Tymianski and Dr. John F. MacDonald in Toronto Western Hospital Research Institute of UHN and Department of Physiology at the University of Toronto. His work has been focused on investigating the cellular and molecular mechanisms of ischemic brain injury, and on in-vivo therapeutics for stroke. Dr. Sun has also held a 4th Focus on Stroke Fellowship funded jointly by CIHR, HSFC and CSN from 2005 to 2007.

During his postdoctoral training, Dr. Sun has made significant progress in his capacity to become a very inventive and productive independent researcher, who is able to elaborate, formulate, perform, evaluate, and compose his own research work and projects. He has succeeded an exceptionally challenging series of experiments and projects in which he independently built new biomedical instrumentation, developed and optimized new techniques. He also established his own national and international collaborations and networks with investigators from across Canada, USA, UK and Japan. Besides, he also serves in numerous national and local trainee committees.

Article

Sun HS, Jackson MF, Martin LJ, Jansen K, Teves L, Cui H, Kiyonaka S, Mori Y, Jones M, Forder JP, GoldeTE, Orser BA, MacDonald JF & Tymianski M. Suppression of Hippocampal TRPM7 Protein Prevents Delayed Neuronal Death in Brain Ischemia. Nature Neuroscience. October 2009, 12(10): 1300-1307 (featured in News & Views pp1215).

Significance of the paper

This publication established the important role of TRPM7 channels in hallmarked delayed neuronal cell death in global cerebral ischemia and stroke, which may have implications and significance in many other major neurological and neurodegenerative disorders, such as Alzheimer's, Huntington's and Parkinson's diseases. In addition, our findings will help formulating potential means, including genetic and pharmacological, to reduce ischemic brain damage for many CSN neurological conditions. TRPM7 is widely expressed in many tissues and systems, such as in the heart and kidney. It is likely that TRPM7 channels are involved in ischemia of other tissues including myocardial and renal ischemia and, given their roles in delayed neuronal cell death, they may also be involved in other neurodegenerative diseases such as Alzheimer's and Parkinson's. Thus, our work may have profound significance to many fields of study outside of stroke research.

The journal of Nature Neuroscience, a very reputable and high impact journal, was chosen for our publication since it will reach a broad audience in medical research and as well as targeted readers in fields of neuroscience, mental health and aging. Stroke is a leading cause of morbidity and mortality in industrialized countries with the prevalence expected to triple by 2050 and disabilities in afflicted survivors have a significant socioeconomic impact to our society and health care spendings. Whereas few clinical treatments exist for acute stroke, ischemic mechanisms are beginning to be better understood. We tried to generate neuroscientists' interests in combating ischemic stroke and developing potential treatment strategy for stroke, which may have applicability to other forms of CNS injuries, such as neurodegeneratice diseases, hemorrhagic stroke and neurotrauma. As TRPM7 is widely expressed in many other systems, it may have strong impact and influence for many other medical researchers in other fields.


Top of Page

Carl Ernst

Recipient

Carl Ernst
Ph.D., McGill University

Biosketch

My main scientific interests revolve around three main questions: 1) How does genetic variation impact disease phenotype, particularly psychopathology? 2) To what extent do epigenetic modifiers alter the expression of complex phenotypes? And, 3) Can novel strategies be developed to study the function of epigenetic changes and genetic background in relation to non-monogenic disorders?

To address these questions, I completed an MSc in Neuroscience at UBC in 2004 and a PhD at McGill in 2009, where my work focused on understanding gene expression changes in brain and the mechanisms that underlie these alterations. I'm currently a postdoc at Harvard, where I'm trying to address the research questions laid out above.

As part of the developmental genome anatomy project (dgap.harvard.edu), I map translocation breakpoints in subjects with psychiatric disease and a chromosomal anomaly. The hope is to identify genes specifically related to disease and to study these genes in cell systems and mouse models. To better understand how genes are related to disease I am developing high-throughput assays to assess short-hairpin RNA knock down of 100's of genes related to autism. Finally, I am reprogramming different cell types (induced pluripotency) to generate neurons. This technology should allow for the generation of neurons after the isolation of easily accessible cells from patients with a disease of interest. Reprogramming these cells could allow for the study of patient-specific genetic and epigenetic backgrounds in neurons.

Article

Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related Kinase B in the Frontal Cortex of Suicide Completers. Carl Ernst, MSc; Vesselina Deleva, MSc; Xiaoming Deng, MD; Adolfo Sequeira, PhD; Amanda Pomarenski, BSc; Tim Klempan, PhD; Neil Ernst, MSc; Remi Quirion, PhD; Alain Gratton, PhD; Moshe Szyf, PhD; Gustavo Turecki, MD, PhD. Arch Gen Psychiatry. 2009;66(1):22-32.

Significance of the paper

Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. We assessed the level of an astrocyte-specific variant of TrkB (TrkB.T1), an important neurotrophic factor receptor, in brains of people with major depression that died by suicide.

In brains of people who committed suicide we found a decrease in TrkB.T1 compared to the levels of TrkB.T1 of control subjects. To explain our findings we assessed epigenetic mechanisms of transcription regulation. We found that people who commit suicide had more methyl groups attached to important regions of DNA than control subjects. Methyl groups can be added or removed from DNA and could possibly be regulated by non-heritable life events. Increased methylation is thought be a molecular mechanism for transcriptional repression.

These findings suggest that astrocytes may play an important role in mood and/or suicidal behavior and that the addition of chemical groups to particular regions of DNA may affect the transcription of mood-related genes.


Top of Page

Keith Fenrich

Recipient

Keith Fenrich
Ph.D, Queen’s University

Biosketch

In 2003 I completed my BSc in pharmacology from the University of Alberta. In the last year of my degree at the U of A I worked with Drs. Tessa Gordon and Vivian Mushahwar. Under their guidance I developed an interest in the study of nervous system regeneration following traumatic injury. In 2003, Dr. Gordon and I wrote and published a review article on regenerative processes in the peripheral and central mammalian nervous systems. At this time I was worked in the lab of Dr. Mushahwar performing experiments on spinal regeneration in rats following contusion injuries.

Very soon after the completion of my undergrad, I began my graduate training in the lab of Dr. P. Ken Rose at Queen's University. My first project focused on neuronal polarity following spinal cord injury. Specifically, we found that some axotomized spinal interneurons sprout new axons from distal dendrites following a spinal cord injury in the adult mammals. We then examined whether axotomized spinal interneurons are capable of spontaneous functional regeneration following spinal cord injury in the adult mammal. We found that cut spinal commissural interneurons can regenerate through spinal midline transection sites containing dense deposits chondroitin sulfate proteoglycans, which are typically inhibitory to regenerating axons. In addition we also showed that these regenerated axons conduct action potentials and form functional synaptic connections with neurons across from the lesion site. The final projects of my PhD research focused on the cellular and molecular mechanisms used by axotomized spinal interneurons to regenerate though spinal cord injury sites. I successfully defended by PhD thesis in November of 2009. Currently I am a continuing my research on spinal interneuron regeneration as a post-doctoral researcher in the Rose lab.

Recently, I accepted a post-doctoral position with Drs. Geneviève Rougon and Franck Debarbieux at the Developmental Biology Institute of Marseilles-Luminy (France), where I will be studying the roles of VEGF on axonal regeneration and angiogenesis following spinal cord injury using fluorescent transgenic mice and in vivo two-photon imaging techniques.

Article

Fenrich, K.K and Rose, P.K. Spinal interneuron axons spontaneously... (2009) J Neurosci. 29(39) 12145-58

Significance of the paper

Contrary to the commonly held belief that adult mammalian CNS axons cannot spontaneously regenerate following injury, the results from our study show that cut spinal interneuron axons of the adult feline can regenerate in the absence of therapeutic interventions and in close proximity to potent growth inhibiting molecules. In addition, our data shows that these regenerated axons form functional monosynaptic connections with motoneurons across from the lesion. To the best of our knowledge, this is the first study to directly examine the regenerative capacity of spinal interneurons. Taken together, we have uncovered a new role for spinal interneurons that emphasizes their importance in forming new connections following spinal cord injury. Given the novelty of this discovery, we believe that our findings are of immediate importance to all those who study spinal cord injury and CNS regeneration.

In addition, the significance of our results extends beyond the amelioration of deficits caused by spinal cord injury. Axonal damage also occurs following head trauma, stroke, and in neurodegenerative diseases (ex. Alzheimer's and Parkinson's). Current therapies for these conditions are often designed to promote regeneration of injured axons. Elucidation of the mechanisms that allow spinal interneuron axons to regenerate may prove useful for understanding regeneration failure in these conditions and developing regenerative therapies for these conditions.

Furthermore, the mechanisms responsible for axon growth, guidance, and synaptogenesis are also fundamental to our understanding how neuronal circuits are constructed during development. Our study suggests that spinal interneurons may be a useful model to study these phenomenons in adult animals, and determine whether adult regeneration is regulated by the same mechanisms used during development.

Considering the novelty of our findings, and the important implications they have to others research fields, we believe that this paper is of great value to a broad range of neuroscientists. As such we chose to submit our paper to The Journal of Neuroscience. This journal is highly regarded in the neuroscience community, has a high impact, and has a very large readership. To further increase the status of our paper, it was featured as part of an editorial highlight in its publication issue.


Top of Page

Kevin Eade

Recipient

Kevin Eade

Biosketch

I began my research training as an undergraduate in Dr Patricia Schulte's lab at the University of British Columbia (UBC). My project was focused on transcriptional regulation of heat shock proteins under varying stress conditions in tidepool sculpins. Here I was given my own independent project where I learned basic molecular biology techniques and worked largely unsupervised. Although this project was primarily physiologically based, it led to my current interests in transcriptional regulation.

Following graduation I began work on my Ph.D. thesis with Dr. Douglas Allan at the Life Science Centre at UBC. My decision to work in this lab weighed heavily upon my interest to understand the molecular and genetic processes of transcriptional regulation in mature neurons. Ultimately I aim to further our understanding of how the process of aging leads to the development of degenerative neurological diseases.

As the first graduate student in Dr Allan's lab, I was faced with the unique challenge of developing my research project, along with all the molecular, genetic, and imaging techniques required to achieve my publication, without the aid of an established research group. This experience has allowed me to achieve greater independence in my research and encouraged me to explore new and innovative fields. Although Dr Allan is a new investigator, our lab environment well funded and contains our own fully-featured upright Olympus Fluoview FV1000 confocal microscope, to which I have immediate and constant access. My training environment is highly interactive and intellectually stimulating to facilitate my development as an independent researcher.

Article

Neuronal Phenotype in the Mature Nervous System Is Maintained by Persistent Retrograde Bone Morphogenetic Protein Signaling. K.T. Eade and D.W. Allan. Journal of Neuroscience. 29(12):3852–3864. (2009)

Significance of the paper

Maintenance of neuronal phenotype is critical to nervous system function. Understanding the transcriptional mechanisms that underlie cellular differentiation and maintenance of neuronal function is an important goal in the field of neurobiology pertinent to congenital and degenerative diseases. Although we have a basic understanding of the differentiation of neuronal phenotype in the developing nervous system, our understanding of the mechanisms that maintain the differentiated state of mature neurons in adults is very rudimentary. Our publication is the first to provide direct evidence for long-standing hypothesis regarding the role of target contact in maintaining neuronal phenotype.

Neuronal differentiation during development entails the induction of a cell-specific profile of terminal differentiation genes (TDGs, such as neuropeptides, neurotransmitter biosynthetic enzymes, ion channels etc) that determine neuronal function and phenotype. In 1988, a pioneering discovery by Story Landis indicated, in rodents, that neuronal phenotype is directed by retrograde signals secreted from the target cells that the neurons innervate. This mechanism for induction of neuronal phenotype has been found to be common to many neuronal subtypes in vertebrates. However, it was not known if the maintenance of neuronal phenotype in the adult nervous system requires persistent retrograde signaling from target cells.

Our lab's work had previously shown that target-dependent induction of neuronal phenotype is a conserved mechanism in the Drosophila nervous system. In my publication, we tested whether target-dependent signaling is subsequently required to maintain neuronal gene phenotype in adult Drosophila neurons. In order to do this, we took advantage of a genetic technology unique to Drosophila that enables precise temporal control of transgene expression in small subsets of specific neurons. Our results provided the first definitive proof that target-derived signaling is required, on a persistent basis, to maintain the expression of target-dependent TDGs in neurons in the adult nervous system, for any model organism. These findings have profound implications for our understanding of neurodegenerative diseases. Disorders such as Alzheimer's disease, motor neuron disease, schizophrenia and polyglutamine expansion disorders have all been linked to defects in axonal trafficking, neuronal loss or synaptic dysfunction. Our data now provides the experimentally-verified rationale that this likely directly disrupts the normal expression of TDGs in mammalian neurons, providing a novel mechanism for neuronal dysfunction in disease.

We chose the Journal of Neuroscience for publication of our work due to the broad readership that we wished to reach, notably researchers and clinicians in the fields of vertebrate developmental neurobiology, as well as aging and neurodegeneration. Our goal to reach a wide audience was aided by the editor's decision to highlight our publication in the "This week in the journal" section, showing confidence that our work is of particular interest to the entire readership of the Journal of Neuroscience.


Top of Page

Carrie Cuttler

Recipient

Carrie Cuttler
Ph.D., Psychiatry, University of British Columbia

Biosketch

My diverse research interests are united by a focus on prospective memory, which is our ability to remember to perform delayed intentions. This ability is required for the successful execution of many daily activities including taking medications on schedule, attending appointments and turning the stove off after use. My research targets distinct populations likely to display deficits in prospective memory (e.g., compulsive checkers, pregnant women, chronic marijuana users), allowing me to assess the complex interplay of factors contributing to the functioning of prospective memory and to better understand how prospective memory deficits contribute to dysfunctional behaviours such as compulsive checking.

In 2008 I completed my PhD in Cognitive Psychology at the University of British Columbia (UBC). My dissertation research with Dr. Peter Graf focused on the mechanisms that contribute to checking compulsions. My work identified prospective memory deficits specific to sub-clinical compulsive checkers, and I proposed the hypothesis that compulsive checkers' increased frequency of experiencing prospective memory failures may trigger the intrusive doubts that tasks were not complete and that those in turn instigate the compulsion to check. For my dissertation work, I received a dissertation award from the Canadian Psychological Association. My graduate work was supported by a Graduate Entrance Scholarship and an Elizabeth Young Lacey Scholarship from UBC, a Post Graduate Scholarship and a Canadian Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC), as well as a Junior Graduate Scholarship and a Senior Graduate Scholarship from the Michael Smith Foundation for Health Research (MSFHR). My pre-graduate and graduate research experiences have resulted in a total of 11 journal publications and over 50 conference presentations.

I am currently working as a Postdoctoral Fellow in the Department of Psychiatry at UBC with Dr. Steven Taylor. The research I am conducting focuses on further examining and extending my findings of prospective memory deficits in sub-clinical compulsive checkers to a clinical population of patients with Obsessive Compulsive Disorder. I am currently supported by a Postdoctoral Fellowship from the MSFHR. My postdoctoral training has resulted in the publication of a book chapter and over 10 conference presentations.

In addition to my Postdoctoral Fellowship I am currently completing a 2 year position as a Curriculum Development Specialist and Lecturer in the Department of Psychology at UBC. In these roles I have been responsible for developing practical laboratory components for the department's undergraduate courses in research methods and statistics as well as for teaching these courses. My work as a Curriculum Development Specialist has resulted in the publication of two laboratory guides.

Article

Cuttler, C., & Graf, P. (2009). Checking-in on the memory deficit and meta-memory deficit theories of compulsive checking. Clinical Psychology Review, 29, 393-409.

Significance of the paper

Various versions of the memory deficit and meta-memory deficit theories of checking compulsions have circulated in the literature for over a century. While previous reviewers have made the critical first step of determining whether memory and meta-memory deficits are present in individuals with checking compulsions, my paper is the first to critically examine whether there is evidence that memory deficits and/or meta-memory deficits are unique to individuals with checking compulsions.

My paper has implication for the broader context of the field of mental health in that it delivers an important methodological reminder, namely, that valid insights into Axis I disorders can only be achieved by investigations that involve properly selected control groups. Even though the memory deficit and meta-memory deficit theories of checking compulsions have motivated a myriad of empirical investigations, only a remarkably small subset of those investigations have used the proper control groups required for determining whether memory deficits are unique to the compulsive checkers (as opposed to being a common feature of OCD or anxiety disorders more generally). By combining the results from this small subset of investigations, my paper reveals that deficits in retrospective memory are not specific to checkers and therefore that they do not have the power to explain the compulsion to check. In addition, on the basis of preliminary evidence from investigations concerned with prospective memory, I showed that prospective memory deficits are specific to checkers and thus may hold the key to a better understanding of the compulsion to check.

The immediate audience for my paper is the community of researchers and clinicians who are concerned with the understanding and treatment of OCD. For this audience, my paper provides compelling evidence against the tenability of the traditional versions of the memory deficit and meta-memory deficit theories. Moreover, it delivers the novel message that the tendency to engage in compulsive checking is uniquely linked to deficits in prospective memory. By framing checking compulsions as a compensatory strategy for dealing with a prospective memory deficit, my paper has the potential to remove some of the stigma associated with compulsive checking. Concomitantly, it may inspire the development of treatment interventions that are more effective and better tolerated by patients, for example, by augmenting current treatment practices with assessments for prospective memory deficits and training in prospective memory improvement strategies. To reach my target audience I chose to publish this paper in Clinical Psychology Review. This journal is recognized as the second top journal in the field of Clinical Psychology, as evidenced by its impact factor of 6.76.


Top of Page

Henry Martin and Changiz Taghibiglou

Recipient

Henry Martin
Ph.D., Molecular Neuroscience, University of British Columbia
and
Changiz Taghibiglou
Ph.D, University of British Columbia

Biosketch - Henry Martin

My initial research training was gained during a MRes at Imperial College (UK) in biochemistry where I first picked up basic molecular biology techniques with Dr. Murray Selkirk and Dr. Deborah Smith investigating molecular parasitology. It was during this program I also studied basic electrophysiology with Dr. Brian Robertson. I completed my PhD in molecular neuroscience with Dr. Jeremy Henley at the University of Bristol studying the effects of bPIX on hippocampal synaptic structure and physiology. During this training I gained significant experience with confocal microscopy. I have spent the last 4 years with Dr. Yu Tian Wang studying the mechanisms of NMDA receptor mediated excitotoxicity as a post-doctoral trainee.

Biosketch - Changiz Taghibiglou

I received my Ph.D in Lipid Biochemistry from University of Toronto. Then I joined to the laboratory of Prof. Yu Tian Wang at the Brain research Centre (UBC) to do my post-doctoral fellowship where I was awarded both CIHR and MSFHR PDF awards. During my PDF training I investigated neuronal lipid rafts and receptor trafficking (Neuropharmacology 2009), SREBP1 lipid transcription factor stroke (Nature Medicine 2009). As a PDF, I also collaborated with Prof. Graham Collingridge (U of Bristol, UK) on role of GSK3 beta and synaptic plasticity (Neuron 2007). . At the present, I am working with Prof. Neil Cashman to study the role of SREBP1 in ALS and other neurodegenerative diseases.

Article

Role of NMDA receptor-dependent activation of SREBP1 in excitotoxicity and ischemic neuronal injuries. Changiz Taghibiglou, Henry G S Martin, Ted Weita Lai, Taesup Cho, Shiv Prasad, Luba Kojic, Jie Lu, Yitao Liu, Edmund Lo, Shu Zhang, Julia Z Z Wu, Yu Ping Li, Yan Hua Wen, Joon-Hyuk Imm, Max S Cynader & Yu Tian Wang (2009) Nature Medicine 15 (12) 1399 - 1406).

Significance of the paper

The transcription factor SREBP1 is critically involved in the regulation of fatty acid metabolism yet its function in the lipid rich environment of the brain is poorly understood. The discovery of SREBP1 as a causative agent in neuronal loss is unprecedented and opens exciting avenues of research linking changes in fatty acid and neuronal loss. We selected Nature Medicine for publication due to the important in vivo outcome of our novel therapeutic Indip and the desire to educate clinicians about an import developing field in stroke treatment. We anticipate significant cross over to other neurological disorders, such as Huntington's, due to the shared mechanism of NMDA receptor dependent excitotoxicity also seen in stroke.


Top of Page

Derek Dunfield

Recipient

Derek Dunfield
Ph.D., Neuroscience, University of British Columbia

Biosketch

Derek Dunfield is a PhD student at the University of British Columbia researching brain development and activity induced neural network plasticity under the supervision of Dr. Kurt Haas. Derek is a NSERC Canadian Graduate Scholar, Michael Smith Foundation for Health Research Senior Research Trainee, and British Columbia Innovation Council Graduate Scholar. He holds a Master of Science in Physics from Queen's University. His previous research experience includes the study and commercialization of novel biomaterials for bone replacement. Derek has seven peer reviewed articles published or in press. Derek independently conceived, designed, executed, and analyzed all research for the publication submitted herein. He also drafted the manuscript and all figures.

Article

Dunfield, D., and Haas, K. (2009) Metaplasticity Governs Natural Experience-Driven Plasticity of Nascent Embryonic Brain Circuits. Neuron 64, 240-250.

Significance of the paper

The degree that Nature (our genes) or Nurture (our environment) influences brain development remains unanswered, yet is central to modern philosophy and has critical implications ranging from early child rearing practices to origins of common and devastating neurological disorders. In this paper, I demonstrate that different patterns of sensory stimuli produce long lasting increases or decreases brain circuit function, and that the degree of these changes is predisposed by recent brain activity. These results clearly support a strong role for Nurture in the developing brain.

In this paper, I combined a number of innovative techniques to non-invasively measure functional neuronal plasticity induced by natural experience in the awake, intact brain. Specifically, I used visual stimuli and calcium imaging to elicit and record responses from 100's of central neurons simultaneously with single cell resolution in the embryonic Xenopus laevis visual system.

I demonstrate that specific visual training paradigms can preferentially shift population responses toward potentiation or depression. This research significantly advances traditional methods of studying plasticity, which typically involve non-physiological electrical stimulation of rodent hippocampal brain slices. My research is the first to make connections between single cell plasticity (such as potentiation and depression of neuronal responses) and network plasticity (including changes in correlated firing and population responses). For example, I demonstrated that sub-networks of neurons potentiated by visual training also undergo training-induced enhanced correlated firing.

In further experiments, my research illustrated, for the first time, that functional plasticity of individual developing neurons is dependent on their historic firing rate in an NMDA-receptor dependent manor. This is the first evidence of metaplasticity (the influence of a neuron's previous history on its current plasticity) during normal embryonic brain development. In support of the impact of this research, Neuron featured my work in a separate article in the same issue (Wang and Tao, 2009) and a method to replicate my protocol is currently in press at Nature Protocols (Dunfield and Haas, in press).

The results of this study significantly advance our understanding of how sensory experience interacts with intrinsic brain properties to optimize development of brain circuit function. Implications of this study have the potential to promote new clinical therapies for epilepsy, amblyopia, or other neurological disorders where sensory experience could be used to modify subsequent brain function or rescue plasticity. The prevalence of metaplasticity in early brain development may also lead to optimization of techniques to promote early learning. Neuron was chosen to publish this research because of its broad neuroscience audience.


Top of Page

Alexander McGirr

Recipient

Alexander McGirr
M.D., Undergraduate Medical Program, University of Toronto

Biosketch

I have been involved in research since my undergraduate degree at McGill University where I was involved in studies of adolescent depression under the supervision of Dr. John Abela. Following this, I worked for a year as a research assistant with the McGill Group for Suicide Studies studying endophenotypes of suicide. This lead to a masters degree under the supervision of Dr. Gustavo Turecki. In the fall of 2008, I began my studies in medicine at the University of Toronto. Projects there have involved the molecular basis for schizophrenia under the supervision of Dr. John Roder. My long term career objectives are as a clinician scientist studying the underlying mechanisms of behaviour and mental health.

Article

McGirr A, Alda M, Séguin M, Cabot S, Lesage A, Turecki G. Familial aggregation of suicide explained by cluster B traits: a three-group family study of suicide controlling for major depressive disorder. Am J Psychiatry. 2009 Oct; 166(10):1124-34. Epub 2009 Sep 15.

Significance of the paper

Our publication provides strong evidence for a heritable mechanism underlying the familial transmission of suicide. Moreover, our study is the first to demonstrate by design that the familial contribution to suicide is independent from the familial loading of psychiatric illness. The importance of our work in understanding and preventing suicide was highlighted by an editorial in the October issue of the American Journal of Psychiatry and spotlighted on the AJP website. The AJP is ranked 3rd among 94 journals in psychiatry and is the top cited psychiatric journal. As the official journal of the American Psychiatric Association, it reaches a broad readership directly involved in improving mental health outcomes and the study of neuroscience.


Top of Page

David Ng and Graham Pitcher

Recipient

David Ng
Ph.D., University of Toronto
and
Graham Pitcher
Research Fellow, University of Toronto

Biosketch - David Ng

My research experience began in the University of Toronto's high school mentorship program under the supervision of Dr. Voon Loong (Ricky) Chan and the late Dr. Eric Hani. We were interested in elucidating the genomic organiziation of Campylobacter jejuni, a leading cause of acute bacterial enterocolitis in humans. From this opportunity, I developed a keen interest in molecular microbiology and genetics, and earned a B.Sc. in molecular genetics at the University of Toronto.

For my graduate studies, under the supervision of Dr. Roderick R. McInnes, also at the University of Toronto in the Department of Molecular and Medical Genetics, I cloned and characterized a novel transmembrane protein which we named Neto1. This study blossomed into a multidisciplinary project that allowed me to develop a strong foundation in biochemistry, molecular genetics, developmental neuroscience, and introduced me to electrophysiology and cognitive behavioural neuroscience. Our studies showed that Neto1 is a synaptic protein important for the regulation NMDA-dependent synaptic plasticity. We also found that mice lacking Neto1 have cognitive dysfunction, which could be pharmacologically corrected.

Following my graduate studies, I worked with Drs. Michael W. Salter and Roderick R. McInnes for a brief tenure as a post-doc to further study the molecular biology of NMDA receptors as well as its relationship with Neto1. I am currently a Howard Hughes Research Associate, pursing post-doctoral studies in spinal cord circuitry with Dr. Thomas M. Jessell at Columbia University in New York.

Biosketch - Graham Pitcher

My research experience began as an undergraduate in McGill University's Mentorship program with Dr. J.L. Henry, where I was introduced to pharmacology, physiology, and animal behavior techniques. I later obtained my B.Sc. degree at McGill. I then joined Dr. T.J. Coderre's laboratory at the Institute Recherche Clinique de Montreal and Dr. J.L. Henry's laboratory at McGill and obtained my M.Sc. degree for my studies on spinal sensory physiology. I later completed my Ph.D. degree in Dr. Henry's laboratory for my electrophysiological studies on the function of spinal dorsal horn sensory neurons in an animal model of neuropathic pain. I am currently a Research Fellow (received CIHR funding as a CIHR Research Fellow) in Dr. M.W. Salter's laboratory at The Hospital for Sick Children pursuing studies on pain processing in the spinal dorsal horn and mechanisms underlying learning, memory, and cognitive function in the hippocampus. Part of my work, described briefly below, focused on a novel protein, Neto1, and how it is critically involved in regulating the N-methyl-D-aspartic subtype of glutamate receptor at excitatory synapses in the hippocampus. This work was done in collaboration with David Ng.

Article

Ng D, Pitcher GM, Szilard RK, Sertié A, Kanisek M, et al. (2009) Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biol 7(2): e1000041. doi:10.1371/journal.pbio.1000041

Significance of the paper

The N-methyl-D-asparate (NMDA) receptor is a major excitatory ligand-gated ion channel in the CNS that plays a critical role in synaptic plasticity, learning and memory. We discovered that Neto1 is a novel NMDAR accessory protein required for synaptic targeting of NMDARs. Mice lacking Neto1 have fewer NMDARs at excitatory synapses, impairments in NMDAR-dependent synaptic plasticity and spatial learning. Remarkably, the deficits in synaptic plasticity and learning in Neto1-null mice were rescued by a small molecule, CX546 at doses without effect in wild-type. Our studies identify Neto1 as a key regulator of NMDAR function, expression and cognitive function. Our results also demonstrate that an inherited learning defect due to dysfunction of NMDARs can be pharmacologically corrected.

Our discovery identifies an important role of Neto1 in brain function as a critical regulatory switch at excitatory synapses essential for lasting synaptic changes in neurons and raises the possibility that Neto1 might be a candidate gene for inherited synaptic disorders involving learning and memory deficits. Our study also suggests that synaptic proteins that share a molecular signature with Neto1, called the CUB-domain, may be important components of synaptic receptors across species, because several CUB-domain proteins in worms have also been found to regulate synaptic receptors. Importantly, our findings also establish the principle that inherited abnormalities of synaptic plasticity and behaviour due to NMDA receptor dysfunction can be pharmacologically corrected. We propose that such pharmacological approaches may be a possible therapeutic strategy for cognitive disorders in humans.

We submitted our paper to PLoS Biology because of its open access policy, high impact, and its publication of studies on novel discoveries on synaptic transmission and plasticity in cognitive function.


Top of Page

Mahmoud Pouladi

Recipient

Mahmoud Pouladi
Ph.D., Medical Genetics, University of British Columbia

Biosketch

Over the past 10 years, I have been involved in a range of research efforts, working in different laboratories across Canada. As a summer student and then lab technician, I assisted in an international project to sequence a mega-plasmid of a nitrogen-fixing bacterium (Rhizobium meliloti) in the lab of Dr. TM Finan at McMaster University.

Article

Pouladi MA, Graham RK, Karasinska JM, Sie Y, Santos RD, Petersén A, Hayden MR. Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin. Brain. 2009; 132(pt 4): 919-32.

Significance of the paper

Depression affects an estimated 40-50% of patients with Huntington disease (HD), and can precede the onset of motor symptoms by many years. We present evidence that depression in HD is at least partly attributable to the pathophysiological effects of the HD-causing mutation, raising the possibility that the depressive symptoms could be ameliorated by disease-modifying therapies.

To eliminate the influence of psychosocial and environmental stressors, such as the knowledge of carrying a mutation for an incurable disease, we examined depressive phenotypes in transgenic YAC128 HD mice. These mice express an expanded form of human huntingtin with 128 CAG repeats, and the resulting phenotype recapitulates many of the motor and cognitive deficits of human HD. We subjected the YAC128 mice to two well-established tests of depression, the forced swim and the sucrose intake tests. We show that the YAC128 mice exhibit a depressive phenotype, which is observed at an early stage of the disease and does not worsen over time, features that are consistent with the depression experienced by humans with HD. Also, like many cases of depression HD, the depressive phenotype in the YAC128 mice fails to respond to antidepressant treatment.

A key step in the pathogenesis of HD is the cleavage of mutant huntingtin at amino acid residue 586. We demonstrate that the depressive phenotype is rescued in transgenic mice expressing a form of huntingtin that is resistant to cleavage at this residue, providing further evidence that depression in HD has a strong neurobiological basis, and suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on depressive symptoms in HD.

Furthermore, as increased incidence of depression is also seen in patients afflicted with other neuro-degenerative disorders such as Alzheimer's and Parkinson's disease, our findings suggest that depression in these disorders may not be reactionary and is likely to have a neurobiological basis as well.