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Introduction
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June 2008 - December 2009
January 2014 - present
January 2007 - December 2013
Publications
Publications (124)
Weaned southern elephant seals (SES) quickly transition from terrestrial to aquatic life after a 5- to 6-week post-weaning period. At sea, juveniles and adult elephant seals present extreme, continuous diving behaviour. Previous studies have highlighted the importance of the post-weaning period for weanlings to prepare for the physiological challen...
Due to the assumed plasticity of immature brain, early in life brain alterations are thought to lead to better recoveries in comparison to the mature brain. Despite clinical needs, how neuronal networks and associated behaviors are affected by early in life brain stresses, such as pediatric concussions, have been overlooked. Here we provide first e...
Many neuroscientists use the term Blood–Brain Barrier (BBB) to emphasize restrictiveness, often equating or reducing the notion of BBB properties to tight junction molecules physically sealing cerebral endothelial cells, rather than pointing out the complexity of this biological interface with respect to its selectivity and variety of exchange betw...
Introduction
The sensitivity of white matter (WM) in acute and chronic moderate-severe traumatic brain injury (TBI) has been established. In concussion syndromes, particularly in preclinical rodent models, there is lacking a comprehensive longitudinal study spanning the lifespan of the mouse. We previously reported early modifications to WM using c...
Astrocytes are in contact with the vasculature, neurons, oligodendrocytes and microglia, forming a local network with various functions critical for brain homeostasis. One of the primary responders to brain injury are astrocytes as they detect neuronal and vascular damage, change their phenotype with morphological, proteomic and transcriptomic tran...
Among pinnipeds, Southern Elephant Seals (SES, Mirounga leonina) are extreme divers that dive deeply and continuously along foraging trips to restore their body stores after fasting on land during breeding or moulting. Their replenishment of body stores influences their energy expenditure during dives and their oxygen (O2) reserves (via muscular ma...
Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the bra...
Aim:
Retrospective studies suggest that mild traumatic brain injury (mTBI) in pediatric patients may lead to an increased risk of cardiac events. However, the exact functional and temporal dynamics and the associations between heart-brain pathophysiological trajectories are not understood.
Methods:
A single impact to the left somatosensory corti...
Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the bra...
Background
Juvenile mild traumatic brain injury (jmTBI) has the potential to elicit cognitive, adaptive, and socio‐behavioral decrements. Unknown is how early life concussions can lead to enduring effects into late adulthood. Studying jmTBI progression from an early concussive event to long term deficits in adulthood is critical for outcome predict...
Translational research now occupies a prominent position in the biomedical research landscape. It is defined in the Merriam Webster dictionary as: “medical research that is concerned with facilitating the practical application of scientific discoveries to the development and implementation of new ways to prevent, diagnose, and treat disease.” Hence...
Aquaporin channels facilitate bidirectional water flow in all cells and tissues. AQP4 is highly expressed in astrocytes. In the CNS, it is enriched in astrocyte endfeet, at synapses, and at the glia limitans, where it mediates water exchange across the blood-spinal cord and blood-brain barriers (BSCB/BBB), and controls cell volume, extracellular sp...
Human brain injury elicits accumulation of water within the brain due to a variety of pathophysiological processes. As our understanding of edema emerged two temporally (and cellular) distinct processes were identified, cytotoxic and vasogenic edema. The emergence of both types of edema is reflected by the temporal evolution and is influenced by th...
Within the neurovascular unit (NVU), the blood–brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) disea...
The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equall...
Traumatic brain injury (TBI) is a heterogeneous brain injury which represents one of the leading causes of mortality and disability worldwide. Rodent TBI models are helpful to examine the cellular and molecular mechanisms after injury. Controlled cortical impact (CCI) is one of the most commonly used TBI models in rats and mice, based on its consis...
Omega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PU...
Soccer, as a contact sport, exposes players to repetitive head impacts, especially through heading the ball. The question of a long‐term brain cumulative effect remains. Our objective was to determine whether exposure to head impacts over one soccer season was associated with changes in functional brain connectivity at rest, using magnetic resonanc...
Clinical evidence suggests that a mild traumatic brain injury occurring at a juvenile age (jmTBI) may be sufficient to elicit pathophysiological modifications. However, clinical reports are not adequately integrated with experimental studies examining changes occurring post-jmTBI. Here, we used a closed head mouse model of jmTBI to monitor the cere...
Edema is a hallmark of many brain disorders including stroke. During vasogenic edema, blood-brain barrier (BBB) permeability increases, contributing to the entry of plasma proteins followed by water. Caveolae and caveolin-1 (Cav-1) are involved in these BBB permeability changes. The expression of the aquaporin-4 (AQP4) water channel relates to brai...
Traumatic brain injury (TBI) is the principal cause of death and disability in children and young adults. Clinical and preclinical research efforts have been carried out to understand the acute, life-threatening pathophysiological events happening after TBI. In the past few years, however, it was recognized that TBI causes significant morbidity wee...
Mild-traumatic brain injury (mTBI) represents ~80% of all emergency room visits and increases the probability of developing long-term cognitive disorders in children. To date, molecular and cellular mechanisms underlying post-mTBI cognitive dysfunction are unknown. Astrogliosis has been shown to significantly alter astrocytes' properties following...
Brain edema formation contributes to secondary brain damage and unfavorable outcome following traumatic brain injury (TBI). Aquaporins (AQP), highly selective water channels, are involved in the formation of post-trauma brain edema, however, their regulation is largely unknown. Since vasopressin receptors are involved in aquaporin-mediated water tr...
Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseas...
Juvenile traumatic brain injury (jTBI) is the leading cause of death and disability for children and adolescents worldwide, but there are no pharmacological treatments available. Aquaporin 4 (AQP4), an astrocytic perivascular protein, is increased after jTBI, and inhibition of its expression with small interference RNA mitigates edema formation and...
Age and severity are significant predictors of traumatic brain injury (TBI) outcomes in the immature brain. TBI studies have segregated TBI injury into three severity groups: mild, moderate, and severe. While mild TBI is most frequent form in children and adults, there is debate over the indicators used to denote mild injury. Clinically, magnetic r...
Brain edema is a common feature of brain injuries, which leads to increased intracranial pressure (ICP) and ischemia that worsen outcome. Current management of edema focuses on reduction of ICP, but there are no treatments targeting the molecular players directly involved in edema process. The perivascular astrocyte endfeet are critical in maintain...
Complex cellular and molecular events occur in the neurovascular unit after stroke, such as blood-brain barrier (BBB) dysfunction and inflammation that contribute to neuronal death, neurological deterioration and mortality. Caveolin-1 (Cav-1) has distinct physiological functions such as caveolae formation associated with endocytosis and transcytosi...
Introduction/Background
Soccer is the most popular sport in the world, but soccer players are exposed to repetitive head impacts (RHI) when heading the ball. While heading is repeated thousands of times over a player's career, a possible brain cumulative effect might lead to neurodegenerative diseases. However, the lack of evidence explains the abs...
Traumatic brain injury (TBI) is a leading cause of hospital visits in pediatric patients and often leads to long‐term disorders even in cases of mild severity. White matter (WM) alterations are commonly observed in patients months or years after the injury assessed by magnetic resonance imaging (MRI), but little is known about WM pathophysiology ea...
Aquaporins (AQPs) facilitate water diffusion through the plasma membrane. Brain aquaporin-4 (AQP4) is present in astrocytes and has critical roles in normal and disease physiology. We previously showed that a 24.9% decrease in AQP4 expression after in vivo silencing resulted in a 45.8% decrease in tissue water mobility as interpreted from magnetic...
Aquaporins (AQPs) are water channel molecules that allow the passage of water through the lipid bilayers of cell membranes. AQP1, AQP4 and AQP9 are expressed in the central nervous system and AQP4 is well known as the target of auto-antibodies in Devic’s neuromyelitis optica. The role of AQPs in facilitating water movements suggests a link with oed...
Bioorthogonal fluorescent turn-on reactions are attractive for the sensitive real-time detection of a variety of phenomena including bioconjugation, chemical reactivity, and material assembly. Herein we describe the use of 3,4-disubstituted sydnones, a singular class of mesoionic dipoles, for highly fluorescent turn-on copper-free click cycloadditi...
Space radiation represents a significant health risk for astronauts. Ground-based animal studies indicate that space radiation affects neuronal functions such as excitability, synaptic transmission, and plasticity, and it may accelerate the onset of Alzheimer’s disease (AD). Although protons represent the main constituent in the space radiation spe...
Effects of proton radiation on survival of APP/PSEN1 TG mice up to 9 months post-irradiation.
Irradiation with protons at doses up to 1 Gy did not significantly affect mortality/survival. All survival data beyond the 9-month time point are censored since the animals were sacrificed for electrophysiology. The survival curves are not significantly di...
BM performance of the APP/PSEN1 TG and WT mice 3 and 6 months post-irradiation.
(A) Performance on each of the 5 blocks. (B) Performance averaged over the blocks. Genotype effects were observed on all three tests (see analyses below). No significant radiation-induced changes were observed across time-points on any test for the TG mice. Data represe...
Full profile I-O curves in slices from APP/PSEN1 TG and WT mice 9 months post-irradiation.
(A) Presynaptic fiber volley (pV) amplitudes: Radiation exposure did not significantly affect pV amplitudes either in TG or in WT mice. Presynaptic excitability was significantly elevated in TG controls when compared to WT controls. Inset: Original trace and...
LTP in CA1 and CA3 neurons in slices from APP/PSEN1 TG and WT mice 6 and 9 months post-irradiation.
LTP of the fEPSP was induced by high frequency (100 Hz; 2 trains 20 s apart) in CA1 and CA3 neurons by presynaptic stimulation (at time “0”) of Schaffer collaterals or Mossy fibers, respectively. LTP time course was not significantly affected by the...
Traumatic brain injury (TBI) is one of the leading causes of death and disability, particularly amongst the young and the elderly. The functions of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are strongly impaired after TBI, thus affecting brain homeostasis. Following the primary mechanical injury that characterizes...
Edema consists of a mix of cytotoxic and vasogenic components whose time course depends on the underlying pathology depending of the type and extent of neurological injury. Recently a third category has been proposed ionic edema, that can be observed as a transition between cytotoxic and vasogenic edema. Current neuroimaging of edema is primarily v...
The present chapter is presenting the knowledge gathered for the mechanisms involved in brain edema formation in traumatic brain injury (TBI) preclinical models. The classical subdivision of brain edema formation into cytotoxic and vasogenic edema has been recently revised with a better definition of the time-, space-dependent course of brain edema...
Advances in understanding the molecular mechanisms of cerebral edema formation are leading to a fundamental transition, away from the era of osmotherapeutics and steroids to an era of molecularly targeted therapies. Challenges remain. There is an active debate regarding the source(s) of edema fluid, with the classic theory involving endothelium now...
In this chapter, we describe the role of water channel proteins, aquaporins (AQPs), in brain edema formation. The recent knowledge on the three main AQPs expressed in the brain (AQP1, AQP4, and AQP9) is summarized; however, AQP4 is the most studied in the central nervous system. Thus, AQPs, and in particular AQP4, have important roles both in the f...
Brain Edema: From Molecular Mechanisms to Clinical Practice brings together the most widely recognized experts in experimental and clinical brain edema research to review the current knowledge gathered on the molecular and cellular pathophysiology and clinical management of brain edema. This timely book also discusses future directions of research...
Traumatic brain injury (TBI) is the leading cause of death and disability in children. Indeed, the acute mechanical injury often evolves to a chronic brain disorder with long-term cognitive, emotional and social dysfunction even in the case of mild TBI. Contrary to the commonly held idea that children show better recovery from injuries than adults,...
Here we assess the potential functional role of increased aquaporin 9 (APQ9) in astrocytes. Increased AQP9 expression was achieved in primary astrocyte cultures by transfection of a plasmid-containing green fluorescent protein fused to either wild-type or mutated human AQP9. Increased AQP9 expression and phosphorylation at Ser222 were associated wi...
Traumatic brain injuries (TBI) often involve vascular dysfunction that leads to long-term alterations in physiological and cognitive functions of the brain. Indeed, all the cells that form blood vessels and that are involved in maintaining their proper function can be altered by TBI. This Review focuses on the different types of cerebrovascular dys...
A hallmark of stroke is water accumulation (edema) resulting from dysregulation of osmotic homeostasis. Brain edema contributes to tissue demise and may lead to increased intracranial pressure and lethal herniation. Currently, there are only limited treatments to prevent edema formation following stroke. Aquaporin 4 (AQP4), a brain water channel, h...
We review the recent advances in the understanding of the roles of choroid plexus (CP), cerebrospinal (CSF), and interstitial fluids (ISF) in neurodegenerative diseases. For several years research in this field has been focusing on neuronal dysfunctions. Recently, there has been a new interest in considering the neuron as part of a larger system al...
Patients enrolled in clinical trials for traumatic brain injury (TBI) may present with heterogeneous features over a range of injury severity, such as diffuse axonal injury, ischemia, edema, hemorrhage, oxidative damage, mitochondrial and metabolic dysfunction, excitotoxicity, inflammation, and other pathophysiological processes. To determine wheth...
Traumatic brain injury (TBI) is one of the major causes of death and disability in pediatrics, and results in a complex cascade of events including the disruption of the blood-brain barrier (BBB). A controlled-cortical impact on post-natal 17 day-old rats induced BBB disruption by IgG extravasation from 1 to 3 days after injury and returned to norm...
In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Ab) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI mode...
The classical neurovascular unit (NVU), composed primarily of endothelium, astrocytes, and neurons, could be expanded to include smooth muscle and perivascular nerves present in both the up- and downstream feeding blood vessels (arteries and veins). The extended NVU, which can be defined as the vascular neural network (VNN), may represent a new phy...
The revised 'expanded' neurovascular unit (eNVU) is a physiological and functional unit encompassing endothelial cells, pericytes, smooth muscle cells, astrocytes and neurons. Ischemic stroke and traumatic brain injury are acute brain injuries directly affecting the eNVU with secondary damage, such as blood-brain barrier (BBB) disruption, edema for...
Traumatic brain injury (TBI) refers to physical trauma to the brain that can lead to motor and cognitive dysfunctions. TBI is particularly serious in infants and young children, often leading to long-term functional impairments. Although clinical research is useful for quantifying and observing the effects of these injuries, few studies have empiri...
Ever since the discovery of small interfering ribonucleic acid (siRNA) a little over a decade ago, it has been highly sought after for its potential as a therapeutic agent for many diseases. In this review, we discuss the promising possibility of siRNA to be used as a drug to treat acute brain injuries such as stroke and traumatic brain injury. Fir...
Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development...
Introduction: Aquaporin-4 (AQP4) is an abundant aquaporin in brain that has been hypothesized to play a central role in edema formation. Furthermore, AQP4 downregulation has been correlated with connexin 43 (Cx43) downregulation, a gap junction protein important for ion and water transport through astrocyte networks. AQP4 deletion in mice was shown...
Neuroinflammation is a common pathological event observed in many different brain diseases, frequently associated with blood--brain barrier (BBB) dysfunction and followed by cerebral edema. Neuroinflammation is characterized with microglia activation and astrogliosis, which is a hypertrophy of the astrocytes. Astrocytes express aquaporin 4, the wat...
Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood-brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these...
The concept of the neurovascular unit as the key brain component affected by stroke is controversial, because current definitions of this entity neglect mechanisms that control perfusion and reperfusion of arteries and arterioles upstream of the cerebral microcirculation. Indeed, although definitions vary, many researchers consider the neurovascula...
Aquaglyceroporin-9 (AQP9) facilitates diffusion of water and energy substrates such as glycerol and monocarboxylates. AQP9 is present in plasma membrane and mitochondria of astrocytes and catecholaminergic neurons, suggesting that it plays a role in the energetic status of these cells. Using specific small interference RNA directed against AQP9 in...
The neurovascular/gliovascular unit has recently gained increased attention in cerebral ischemic research, especially regarding the cellular and molecular changes that occur in astrocytes and endothelial cells. In this paper we summarize the recent knowledge of these changes in association with edema formation, interactions with the basal lamina, a...
Traumatic brain injury (TBI) is one of the leading causes of death and disability in children and adolescents. The neuropathological sequelae that result from TBI are a complex cascade of events including edema formation, which occurs more frequently in the pediatric than the adult population. This developmental difference in the response to injury...
Aging and atherosclerosis are well-recognized risk factors for cardiac and neurovascular diseases. The Apolipoprotein E deficient (ApoE−/−) mouse on a high-fat diet is a classical model of atherosclerosis, characterized by the presence of atherosclerotic plaques in extracranial vessels but not in cerebral arteries. Increase in arginase activity was...
Traumatic brain injury (TBI) affects many infants and children, and results in enduring motor and cognitive impairments with accompanying changes in white matter tracts, yet few experimental studies in rodent juvenile models of TBI (jTBI) have examined the timeline and nature of these deficits, histologically and functionally. We used a single cont...
The complex nature of the cause and evolution of traumatic brain injury (TBI) and the wide variety of lesions that occur have made it difficult to develop animal models that accurately reflect the clinical picture. This is particularly true when comparing children with adults. Over the past two decades various experimental approaches have been purs...
Traumatic brain injury (TBI) affects all age groups in a population and is an injury generating scientific interest not only as an acute event, but also as a complex brain disease with several underlying neurobehavioral and neuropathological characteristics. We review early and long-term alterations after juvenile and adult TBI with a focus on chan...
