From land to ocean: One month for southern elephant seal pups to acquire aquatic skills prior to their first departure to sea.

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 challenges of their future sea life. However, very little is known about how their body condition during this period may influence the development of their behaviour and brain activities. To characterise changes in the behavioural and brain activity of weanlings prior to ocean departure, we implemented a multi-logger approach combining measurements of movements (related to behaviour), pressure (related to diving), and brain electrical activity. As pups age, the amount of time allocated to resting decreases in favour of physical activity. Most resting (9.6 ± 1.2 h/day) takes place during daytime, with periods of slow-wave sleep representing 4.9 ± 0.9 h/day during the first 2 weeks. Furthermore, an increasing proportion of physical activity transitions from land to shore. Additionally, pups in poorer condition (lean group) are more active earlier than those in better condition (corpulent group). Finally, at weaning, clear circadian activity with two peaks at dawn and dusk is observed, and this pattern remains unchanged during the 4 weeks on land. This circadian pattern matches the one observed in adults at sea, with more prey catches at dawn and dusk, raising the question of whether it is endogenous or triggered by the mother during lactation.

Blood-brain borders: a proposal to address limitations of historical blood-brain barrier terminology.

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 between the general blood circulation and the central nervous tissue. Several authors in the field find it unfortunate that the exquisitely dynamic interfaces between blood and brain continue to be viewed primarily as obstructive barriers to transport. Although the term blood-brain interface is an excellent descriptor that does not convey the idea of a barrier, it is important and preferable for the spreading of an idea beyond specialist communities to try to appeal to well-chosen metaphors. Recent evidence reviewed here indicates that blood-brain interfaces are more than selective semi-permeable membranes in that they display many dynamic processes and complex mechanisms for communication. They are thus more like 'geopolitical borders'. Furthermore, some authors working on blood-brain interface-relevant issues have started to use the word border, for example in border-associated macrophages. Therefore, we suggest adopting the term Blood-Brain Border to better communicate the flexibility of and movement across blood-brain interfaces.

Do astrocytes act as immune cells after pediatric TBI?

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 transformations for an adaptive response. The role of astrocytic responses in brain dysfunction is not fully elucidated in adult, and even less described in the developing brain. Children are vulnerable to traumatic brain injury (TBI), which represents a leading cause of death and disability in the pediatric population. Pediatric brain trauma, even with mild severity, can lead to long-term health complications, such as cognitive impairments, emotional disorders and social dysfunction later in life. To date, the underlying pathophysiology is still not fully understood. In this review, we focus on the astrocytic response in pediatric TBI and propose a potential immune role of the astrocyte in response to trauma. We discuss the contribution of astrocytes in the local inflammatory cascades and secretion of various immunomodulatory factors involved in the recruitment of local microglial cells and peripheral immune cells through cerebral blood vessels. Taken together, we propose that early changes in the astrocytic phenotype can alter normal development of the brain, with long-term consequences on neurological outcomes, as described in preclinical models and patients.

Diving behaviour of southern elephant seals: new models of behavioural and ecophysiological adjustments of oxygen store management.

Among pinnipeds, southern elephant seals (SESs, 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 mass), yet how they manage their O2 stores during their dives is not fully understood. In this study, 63 female SESs from Kerguelen Island were equipped with accelerometers and time-depth recorders to investigate changes in diving parameters through their foraging trips. Two categories of dive behaviour were identified and related to the body size of individuals, with smaller SESs performing shallower and shorter dives requiring greater mean stroke amplitude compared with larger individuals. In relation to body size, the larger seals had lower estimated oxygen consumption levels for a given buoyancy (i.e. body density) compared with smaller individuals. However, both groups were estimated to have the same oxygen consumption of 0.079±0.001 ml O2 stroke-1 kg-1 for a given dive duration and at neutral buoyancy when the cost of transport was minimal. Based on these relationships, we built two models that estimate changes in oxygen consumption according to dive duration and body density. The study highlights that replenishing body stores improves SES foraging efficiency, as indicated by increased time spent at the bottom of the ocean. Thus, prey-capture attempts increase as SES buoyancy approaches the neutral buoyancy point.

A single mild juvenile TBI in male mice leads to regional brain tissue abnormalities at 12 months of age that correlate with cognitive impairment at the middle age.

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 brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.

Neurovascular hypoxia after mild traumatic brain injury in juvenile mice correlates with heart-brain dysfunctions in adulthood.

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 and brain pathophysiological trajectories are not understood. METHODS: A single impact to the left somatosensory cortical area of the intact skull was performed on juvenile mice (17 days postnatal). Cerebral 3D photoacoustic imaging was used to measure the oxygen saturation (sO2 ) in the impacted area 4 h after mTBI followed by 2D and 4D echocardiography at days 7, 30, 90, and 190 post-impact. At 8 months, we performed a dobutamine stress test to evaluate cardiac function. Lastly, behavioral analyses were conducted 1 year after initial injury. RESULTS: We report a rapid and transient decrease in cerebrovascular sO2 and increased hemoglobin in the impacted left brain cortex. Cardiac analyses showed long-term diastolic dysfunction and a diminished systolic strain response under stress in the mTBI group. At the molecular level, cardiac T-p38MAPK and troponin I expression was pathologic modified post-mTBI. We found linear correlations between brain sO2 measured immediately post-mTBI and long-term cardiac strain after 8 months. We report that initial cerebrovascular hypoxia and chronic cardiac dysfunction correlated with long-term behavioral changes hinting at anxiety-like and memory maladaptation. CONCLUSION: Experimental juvenile mTBI induces time-dependent cardiac dysfunction that corresponds to the initial neurovascular sO2 dip and is associated with long-term behavioral modifications. These imaging biomarkers of the heart-brain axis could be applied to improve clinical pediatric mTBI management.

Progressive lifespan modifications in the corpus callosum following a single juvenile concussion in male mice monitored by diffusion MRI.

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 clinically relevant neuroimaging and histological measures in a model of juvenile concussion at one month post injury (mpi) who then exhibited cognitive deficits at 12mpi. For the first time, we assess corpus callosum (CC) integrity across the lifespan after a single juvenile concussion utilizing diffusion MRI (dMRI). Methods: C57Bl/6 mice were exposed to sham or two severities of closed-head concussion (Grade 1, G1, speed 2 m/sec, depth 1mm; Grade 2, G2, 3m/sec, 3mm) using an electromagnetic impactor at postnatal day 17. In vivo diffusion tensor imaging was conducted at 1, 3, 6, 12 and 18 mpi (21 directions, b=2000 mm2/sec) and processed for dMRI parametric maps: fractional anisotropy (FA), axial (AxD), radial (RD) and mean diffusivity (MD). Whole CC and regional CC data were extracted. To identify the biological basis of altered dMRI metrics, astrocyte and microglia in the CC were characterized at 1 and 12 mpi by immunohistochemistry. Results: Whole CC analysis revealed altered FA and RD trajectories following juvenile concussion. Shams exhibited a temporally linear increase in FA with age while G1/G2 mice had plateaued FA values. G2 concussed mice exhibited high variance of dMRI metrics at 12mpi, which was attributed to the heterogeneity of TBI on the anterior CC. Regional analysis of dMRI metrics at the impact site unveiled significant differences between G2 and sham mice. The dMRI findings appear to be driven, in part, by loss of astrocyte process lengths and increased circularity and decreased cell span ratios in microglia. Conclusion: For the first time, we demonstrate progressive perturbations to WM of male mice after a single juvenile concussion across the mouse lifespan. The CC alterations were dependent on concussion severity with elevated sensitivity in the anterior CC that was related to astrocyte and microglial morphology. Our findings suggest that long-term monitoring of children with juvenile concussive episodes using dMRI is warranted, focusing on vulnerable WM tracts.

Role of the non-invasive imaging techniques in monitoring and understanding the evolution of brain edema.

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 the underlying pathology (type and extent). However, this two-edema compartment model does not adequately describe the transition between cytotoxic and vasogenic edema. Hence, a third category has been proposed, termed ionic edema, that is observed in the transition between cytotoxic and vasogenic edema. Magnetic resonance neuroimaging of edema today primarily utilizes T2-weighted (T2WI) and diffusion-weighted imaging (DWI). Clinical diagnostics and translational science studies have clearly demonstrated the temporal ability of both T2WI and DWI to monitor edema content and evolution. DWI measures water mobility within the brain reflecting cytotoxic edema. T2WI at later time points when vasogenic edema develops visualizes increased water content in the brain. Clinically relevant imaging modalities, including ultrasound and positron emission tomography, are not typically used to assess edema. In sum, edema imaging is an important cornerstone of clinical diagnostics and translational studies and can guide effective therapeutics manage edema and improve patient outcomes.

Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis.

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 space volume, and astrocyte migration. Perivascular enrichment of AQP4 at the BSCB/BBB suggests a role in glymphatic function. Recently, we have demonstrated that AQP4 localization is also dynamically regulated at the subcellular level, affecting membrane water permeability. Ageing, cerebrovascular disease, traumatic CNS injury, and sleep disruption are established and emerging risk factors in developing neurodegeneration, and in animal models of each, impairment of glymphatic function is associated with changes in perivascular AQP4 localization. CNS oedema is caused by passive water influx through AQP4 in response to osmotic imbalances. We have demonstrated that reducing dynamic relocalization of AQP4 to the BSCB/BBB reduces CNS oedema and accelerates functional recovery in rodent models. Given the difficulties in developing pore-blocking AQP4 inhibitors, targeting AQP4 subcellular localization opens up new treatment avenues for CNS oedema, neurovascular and neurodegenerative diseases, and provides a framework to address fundamental questions about water homeostasis in health and disease.

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.

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 equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

Changes in resting-state functional brain connectivity associated with head impacts over one men's semi-professional soccer season.

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 resonance imaging (MRI). In this prospective cohort study, 10 semi-professional men soccer players, aged 18-25 years, and 20 age-matched men athletes without a concussion history and who do not practice any contact sport were recruited in Bordeaux (France). Exposure to head impacts per soccer player during competitive games over one season was measured using video analysis. Resting-state functional magnetic resonance imaging data were acquired for both groups at two times, before and after the season. With a seed-based analysis, resting-state networks that have been intimately associated with aspects of cognitive functioning were investigated. The results showed a mean head impacts of 42 (±33) per soccer player over the season, mainly intentional head-to-ball impacts and no concussion. No head impact was found among the other athletes. The number of head impacts between the two MRI acquisitions before and after the season was associated with increased connectivity within the default mode network and the cortico-cerebellar network. In conclusion, our findings suggest that the brain functioning changes over one soccer season in association with exposure to repetitive head impacts.

Contusion Rodent Model of Traumatic Brain Injury: Controlled Cortical Impact.

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 consistency of injury and ease of implementation. Here, we describe a CCI protocol to induce a moderate contusion to the somatosensory motor cortex. We provide additional protocols for monitoring animals after CCI induction.

Caveolin-1 Regulates Perivascular Aquaporin-4 Expression After Cerebral Ischemia.

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 brain swelling, however, its regulation is poorly understood. Here we tested whether Cav-1 regulates AQP4 expression in the perivascular region after brain ischemia in mice. We showed that Cav-1 knockout mice had enhanced hemispheric swelling and decreased perivascular AQP4 expression in perilesional and contralateral cortical regions compared to wild-type. Glial fibrillary acidic protein-positive astrocytes displayed less branching and ramification in Cav-1 knockout mice compared to wild-type animals. There was a positive correlation between the area of perivascular AQP4-immunolabelling and branch length of Glial fibrillary acidic protein-positive astrocytes in wild-type mice, not seen in Cav-1 knockout mice. In summary, we show for the first time that loss of Cav-1 results in decreased AQP4 expression and impaired perivascular AQP4 covering after cerebral ischemia associated with altered reactive astrocyte morphology and enhanced brain swelling. Therapeutic approaches targeting Cav-1 may provide new opportunities for improving stroke outcome. SIGNIFICANCE STATEMENT: Severe brain edema worsens outcome in stroke patients. Available treatments for stroke-related edema are not efficient and molecular and cellular mechanisms are poorly understood. Cellular water channels, aquaporins (AQPs), are mainly expressed in astrocytes in the brain and play a key role in water movements and cerebral edema, while endothelial caveolins have been suggested to play a role in vasogenic edema. Here we used an integrative approach to study possible interaction between AQP4 and caveolin-1 (Cav-1) after stroke. Absence of Cav-1 was associated with perivascular changes in AQP4 expression and enhanced brain swelling at 3 days after cerebral ischemia. The present work indicates a direct or indirect effect of Cav-1 on perivascular AQP4, which may lead to novel edema therapy.

Early cerebrovascular and long-term neurological modifications ensue following juvenile mild traumatic brain injury in male mice.

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 brain changes occurring post-jmTBI. We monitored the cerebrovascular modifications and assessed the long-term behavioral and electrographic changes resulting from experimental jmTBI. In vivo photoacoustic imaging demonstrated a decrease of cerebrovascular oxygen saturation levels in the impacted area hours post-jmTBI. Three days post-jmTBI oxygenation returned to pre-jmTBI levels, stabilizing at 7 and 30 days after the injury. At the functional level, cortical arterioles displayed no NMDA vasodilation response, while vasoconstriction induced by thromboxane receptor agonist was enhanced at 1 day post-jmTBI. Arterioles showed abnormal NMDA vasodilation at 3 days post-jmTBI, returning to normality at 7 days post injury. Histology showed changes in vessel diameters from 1 to 30 days post-jmTBI. Neurological evaluation indicated signs of anxiety-like behavior up to 30 days post-jmTBI. EEG recordings performed at the cortical site of impact 30 days post-jmTBI did not indicate seizures activity, although it revealed a reduction of gamma waves as compared to age matched sham. Histology showed decrease of neuronal filament staining. In conclusion, experimental jmTBI triggers an early cerebrovascular hypo­oxygenation in vivo and faulty vascular reactivity. The exact topographical coherence and the direct casualty between early cerebrovascular changes and the observed long-term neurological modifications remain to be investigated. A potential translational value for cerebro-vascular oxygen monitoring in jmTBI is discussed.

Peripheral Blood and Salivary Biomarkers of Blood-Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts.

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) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.

Vasopressin V1a Receptors Regulate Cerebral Aquaporin 1 after Traumatic Brain Injury.

Brain edema formation contributes to secondary brain damage and unfavorable outcome after 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. Because vasopressin receptors are involved in AQP-mediated water transport in the kidney and inhibition of V1a receptors reduces post-trauma brain edema formation, we hypothesize that cerebral AQPs may be regulated by V1a receptors. Cerebral Aqp1 and Aqp4 messenger ribonucleic acid (mRNA) and AQP1 and AQP4 protein levels were quantified in wild-type and V1a receptor knockout (V1a-/-) mice before and 15 min, 1, 3, 6, 12, or 24 h after experimental TBI by controlled cortical impact. In non-traumatized mice, we found AQP1 and AQP4 expression in cortical neurons and astrocytes, respectively. Experimental TBI had no effect on Aqp4 mRNA or AQP4 protein expression, but increased Aqp1 mRNA (p < 0.05) and AQP1 protein expression (p < 0.05) in both hemispheres. The Aqp1 mRNA and AQP1 protein regulation was blunted in V1a receptor knockout mice. The V1a receptors regulate cerebral AQP1 expression after experimental TBI, thereby unraveling the molecular mechanism by which these receptors may mediate brain edema formation after TBI.

Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis.

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 transcytosis as well as in signaling pathways. Cav-1 has been proposed to be involved in BBB dysfunction after brain injury; however, its precise role is poorly understood. The goal of this study was to characterize the expression and effect of Cav-1 deletion on outcome in the first week in a transient Middle Cerebral Artery Occlusion stroke model. We found increased Cav-1 expression in new blood vessels in the lesion and in reactive astrocytes in the peri-lesion areas. In Cav-1 KO mice, the lesion volume was larger and the behavioral outcome worse than in WT mice. Cav-1 KO mice exhibited reduced neovascularization and modified astrogliosis, without formation of a proper glial scar around the lesion at three days post injury, coinciding with aggravated outcomes. Altogether, these results point towards a potential protective role of endogenous Cav-1 in the first days after ischemia by promoting neovascularization, astrogliosis and scar formation.

Aquaporins in brain edema.

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 maintaining brain homeostasis with ionic and water exchange; in this context, aquaporins (AQPs), astrocyte water channels, have emerged as privileged targets for edema modulation. However, AQPs can facilitate either accumulation or drainage of water, depending on the osmotic gradients between extra-intracellular space; and thus inhibition of AQPs leads to different outcomes depending on specific tissue characteristics and time post-injury. Most of this knowledge has been gathered from the study of AQP4, the best characterized AQP and the one that has the biggest impact on water movement. In addition to the level of expression, the ratio of AQP4 isoforms (m1, m23 or mz), the spatial distribution of AQP4 into orthogonal arrays of particles, and the interaction of AQP4 with neighboring ionic channels and gap junctions could directly impact edema formation. Although there are no specific AQP4 pharmacological blockers, the development of AQP4 siRNA offers a promising therapeutic tool. Given the complex dynamics of AQP4, therapies targeting AQP4 should carefully take into account the particular features of the injury (e.g., hemorrhagic vs. non-hemorrhagic) and different times after injury (e.g., phase of edema formation vs. resolution).

Noninvasive magnetic resonance imaging stratifies injury severity in a rodent model of male juvenile traumatic brain injury.

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 resonance imaging (MRI) and computed tomography (CT) are used to diagnose the TBI severity when medically warranted. Herein, we induced mild, moderate, and severe TBI in juvenile rats (jTBI) using the controlled cortical impact model. We characterized the temporal and spatial injury after graded jTBI in vivo using high-field MRI at 0.25 (6 hr), 1 and 3 days post-injury (dpi) with comparative histology. Susceptibility-weighted imaging (SWI) for blood and T2-weighted imaging (T2WI) for edema were quantified over the 0.25-3 dpi. Edema volumes increased linearly with severity at 0.25 dpi that slowly continued to decrease over the 3 dpi. In contrast, blood volumes did not decrease over time. Mild TBI had the least amount of blood visible on SWI. Fluoro-jade B (FJB) staining for cell death confirmed increased cellular death with increasing severity and increased FJB + cells in the corpus callosum (CC). Interestingly, the strongest correlation was observed for cell death and the presence of extravascular blood. A clear understanding of acute brain injury (jTBI) and how blood/edema contribute to mild, moderate, and severe jTBI is needed prior to embarking on therapeutic interventions. Noninvasive imaging should be used in mild jTBI to verify lack of overt injury.