Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction.

The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration remain poorly understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor ß (TGFß) signalling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective TGFß receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory TGFß signalling are associated with severe, potentially life-threatening outcomes following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of TGFß signalling may be a novel strategy in treating mild traumatic brain injury.

Critical period regulation across multiple timescales.

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.

Underfeeding Alters Brain Tissue Synthesis Rate in a Rat Brain Injury Model.

Brain injuries (BI) are highly disruptive, often having long lasting effects. Inadequate standard of care (SOC) energy support in the hospital leads to dietary energy deficiencies in BI patients. However, it is unclear how underfeeding (UF) affects protein synthesis post-BI. Therefore, in a rat model, we addressed the issue of UF on the protein fractional synthesis rate (fSR) post-BI. Compared to ad libitum (AL)-fed animals, we found that UF decreased protein synthesis in hind-limb skeletal muscle and cortical mitochondrial and structural proteins (p ≤ 0.05). BI significantly increased protein synthesis in the left and right cortices (p ≤ 0.05), but suppressed protein synthesis in the cerebellum (p ≤ 0.05) as compared to non-injured sham animals. Compared to underfeeding alone, UF in conjunction with BI (UF+BI) caused increased protein synthesis rates in mitochondrial, cytosolic, and whole-tissue proteins of the cortical brain regions. The increased rates of protein synthesis found in the UF+BI group were mitigated by AL feeding, demonstrating that caloric adequacy alleviates the effects of BI on protein dynamics in cortical and cerebellar brain regions. This research provides evidence that underfeeding has a negative impact on brain healing post-BI and that protein reserves in uninjured tissues are mobilized to support cortical tissue repair following BI.

Blood-Brain Barrier Dysfunction and Astrocyte Senescence as Reciprocal Drivers of Neuropathology in Aging.

As the most abundant cell types in the brain, astrocytes form a tissue-wide signaling network that is responsible for maintaining brain homeostasis and regulating various brain activities. Here, we review some of the essential functions that astrocytes perform in supporting neurons, modulating the immune response, and regulating and maintaining the blood-brain barrier (BBB). Given their importance in brain health, it follows that astrocyte dysfunction has detrimental effects. Indeed, dysfunctional astrocytes are implicated in age-related neuropathology and participate in the onset and progression of neurodegenerative diseases. Here, we review two mechanisms by which astrocytes mediate neuropathology in the aging brain. First, age-associated blood-brain barrier dysfunction (BBBD) causes the hyperactivation of TGFß signaling in astrocytes, which elicits a pro-inflammatory and epileptogenic phenotype. Over time, BBBD-associated astrocyte dysfunction results in hippocampal and cortical neural hyperexcitability and cognitive deficits. Second, senescent astrocytes accumulate in the brain with age and exhibit a decreased functional capacity and the secretion of senescent-associated secretory phenotype (SASP) factors, which contribute to neuroinflammation and neurotoxicity. Both BBBD and senescence progressively increase during aging and are associated with increased risk of neurodegenerative disease, but the relationship between the two has not yet been established. Thus, we discuss the potential relationship between BBBD, TGFß hyperactivation, and senescence with respect to astrocytes in the context of aging and disease and identify future areas of investigation in the field.

Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players.

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Brainstem and Cortical Spreading Depolarization in a Closed Head Injury Rat Model.

Traumatic brain injury (TBI) is the leading cause of death in young individuals, and is a major health concern that often leads to long-lasting complications. However, the electrophysiological events that occur immediately after traumatic brain injury, and may underlie impact outcomes, have not been fully elucidated. To investigate the electrophysiological events that immediately follow traumatic brain injury, a weight-drop model of traumatic brain injury was used in rats pre-implanted with epidural and intracerebral electrodes. Electrophysiological (near-direct current) recordings and simultaneous alternating current recordings of brain activity were started within seconds following impact. Cortical spreading depolarization (SD) and SD-induced spreading depression occurred in approximately 50% of mild and severe impacts. SD was recorded within three minutes after injury in either one or both brain hemispheres. Electrographic seizures were rare. While both TBI- and electrically induced SDs resulted in elevated oxidative stress, TBI-exposed brains showed a reduced antioxidant defense. In severe TBI, brainstem SD could be recorded in addition to cortical SD, but this did not lead to the death of the animals. Severe impact, however, led to immediate death in 24% of animals, and was electrocorticographically characterized by non-spreading depression (NSD) of activity followed by terminal SD in both cortex and brainstem.

Blood-brain barrier dysfunction in canine epileptic seizures detected by dynamic contrast-enhanced magnetic resonance imaging.

OBJECTIVE: Dogs with spontaneous or acquired epilepsy exhibit resemblance in etiology and disease course to humans, potentially offering a translational model of the human disease. Blood-brain barrier dysfunction (BBBD) has been shown to partake in epileptogenesis in experimental models of epilepsy. To test the hypothesis that BBBD can be detected in dogs with naturally occurring seizures, we developed a linear dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis algorithm that was validated in clinical cases of seizing dogs and experimental epileptic rats. METHODS: Forty-six dogs with naturally occurring seizures of different etiologies and 12 induced epilepsy rats were imaged using DCE-MRI. Six healthy dogs and 12 naive rats served as control. DCE-MRI was analyzed by linear-dynamic method. BBBD scores were calculated in whole brain and in specific brain regions. Immunofluorescence analysis for transforming growth factor beta (TGF-ß) pathway proteins was performed on the piriform cortex of epileptic dogs. RESULTS: We found BBBD in 37% of dogs with seizures. A significantly higher cerebrospinal fluid to serum albumin ratio was found in dogs with BBBD relative to dogs with intact blood-brain barrier (BBB). A significant difference was found between epileptic and control rats when BBBD scores were calculated for the piriform cortex at 48 hours and 1 month after status epilepticus. Mean BBBD score of the piriform lobe in idiopathic epilepsy (IE) dogs was significantly higher compared to control. Immunohistochemistry results suggested active TGF-ß signaling and neuroinflammation in the piriform cortex of dogs with IE, showing increased levels of serum albumin colocalized with glial acidic fibrillary protein and pSMAD2 in an area where BBBD had been detected by linear DCE-MRI. SIGNIFICANCE: Detection of BBBD in dogs with naturally occurring epilepsy provides the ground for future studies for evaluation of novel treatment targeting the disrupted BBB. The involvement of the piriform lobe seen using our linear DCE-MRI protocol and algorithm emphasizes the possibility of using dogs as a translational model for the human disease.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.

Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis.

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.

Neuroinflammatory targets and treatments for epilepsy validated in experimental models.

A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New antiseizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, antiepileptogenesis, and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries.

A potential role for glia-derived extracellular matrix remodeling in postinjury epilepsy.

Head trauma and vascular injuries are known risk factors for acquired epilepsy. The sequence of events that lead from the initial injury to the development of epilepsy involves complex plastic changes and circuit rewiring. In-depth, comprehensive understanding of the epileptogenic process is critical for the identification of disease-modifying targets. Here we review the complex interactions of cellular and extracellular components that may promote epileptogenesis, with an emphasis on the role of astrocytes. Emerging evidence demonstrates that astrocytes promptly respond to brain damage and play a critical role in the development of postinjury epilepsy. Astrocytes have been shown to regulate extracellular matrix (ECM) remodeling, which can affect plasticity and stability of synapses and, in turn, contribute to the epileptogenic process. From these separate lines of evidence, we present a hypothesis suggesting a possible role for astrocyte-regulated remodeling of ECM and perineuronal nets, a specialized ECM structure around fast-spiking inhibitory interneurons, in the development and progression of posttraumatic epilepsies. © 2016 Wiley Periodicals, Inc.

Albumin induces excitatory synaptogenesis through astrocytic TGF-ß/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction.

Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-ß) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-ß-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-ß inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-ß-pathway as a potential strategy for the prevention of PIE.

Losartan prevents acquired epilepsy via TGF-ß signaling suppression.

OBJECTIVE: Acquired epilepsy is frequently associated with structural lesions after trauma, stroke, and infections. Although seizures are often difficult to treat, there is no clinically applicable strategy to prevent the development of epilepsy in patients at risk. We have recently shown that vascular injury is associated with activation of albumin-mediated transforming growth factor ß (TGF-ß) signaling, and followed by local inflammatory response and epileptiform activity ex vivo. Here we investigated albumin-mediated TGF-ß signaling and tested the efficacy of blocking the TGF-ß pathway in preventing epilepsy. METHODS: We addressed the role of TGF-ß signaling in epileptogenesis in 2 different rat models of vascular injury, combining in vitro and in vivo biochemical assays, gene expression, and magnetic resonance and direct optical imaging for blood-brain barrier permeability and vascular reactivity. Long-term electrocorticographic recordings were acquired in freely behaving animals. RESULTS: We demonstrate that serum-derived albumin preferentially induces activation of the activin receptor-like kinase 5 pathway of TGF-ß receptor I in astrocytes. We further show that the angiotensin II type 1 receptor antagonist, losartan, previously identified as a blocker of peripheral TGF-ß signaling, effectively blocks albumin-induced TGF-ß activation in the brain. Most importantly, losartan prevents the development of delayed recurrent spontaneous seizures, an effect that persists weeks after drug withdrawal. INTERPRETATION: TGF-ß signaling, activated in astrocytes by serum-derived albumin, is involved in epileptogenesis. We propose losartan, a drug approved by the US Food and Drug Administration, as an efficient antiepileptogenic therapy for epilepsy associated with vascular injury.

Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus.

Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

Glucocorticoid Regulation of Reproduction.

It is well accepted that stress, measured by increased glucocorticoid secretion, leads to profound reproductive dysfunction. In times of stress, glucocorticoids activate many parts of the fight or flight response, mobilizing energy and enhancing survival, while inhibiting metabolic processes that are not necessary for survival in the moment. This includes reproduction, an energetically costly procedure that is very finely regulated. In the short term, this is meant to be beneficial, so that the organism does not waste precious energy needed for survival. However, long-term inhibition can lead to persistent reproductive dysfunction, even if no longer stressed. This response is mediated by the increased levels of circulating glucocorticoids, which orchestrate complex inhibition of the entire reproductive axis. Stress and glucocorticoids exhibits both central and peripheral inhibition of the reproductive hormonal axis. While this has long been recognized as an issue, understanding the complex signaling mechanism behind this inhibition remains somewhat of a mystery. What makes this especially difficult is attempting to differentiate the many parts of both of these hormonal axes, and new neuropeptide discoveries in the last decade in the reproductive field have added even more complexity to an already complicated system. Glucocorticoids (GCs) and other hormones within the hypothalamic-pituitary-adrenal (HPA) axis (as well as contributors in the sympathetic system) can modulate the hypothalamic-pituitary-gonadal (HPG) axis at all levels-GCs can inhibit release of GnRH from the hypothalamus, inhibit gonadotropin synthesis and release in the pituitary, and inhibit testosterone synthesis and release from the gonads, while also influencing gametogenesis and sexual behavior. This chapter is not an exhaustive review of all the known literature, however is aimed at giving a brief look at both the central and peripheral effects of glucocorticoids on the reproductive function.

Glucocorticoids and the Brain: Neural Mechanisms Regulating the Stress Response.

In this chapter, we describe the central role of the brain in the glucocorticoid mediated stress response. We describe the mechanisms by which the brain gauges the severity of stress, mechanisms of hypothalamic-pituitary-adrenal axis (HPA) regulation, and how various sub-systems of the brain respond to glucocorticoid (GC) signaling to regulate stress behavior. In particular, we focus on the hippocampus, pre-frontal cortex, and amygdala, where GCs can induce a series of changes. Finally, we briefly discuss an apparent paradox in GC signaling: while exposure to glucocorticoids promotes the survival of an organism during acute stress, these same hormones in chronic excess can also cause damage and promote illness.

From spreading depolarization to blood-brain barrier dysfunction: navigating traumatic brain injury for novel diagnosis and therapy.

Considerable strides in medical interventions during the acute phase of traumatic brain injury (TBI) have brought improved overall survival rates. However, following TBI, people often face ongoing, persistent and debilitating long-term complications. Here, we review the recent literature to propose possible mechanisms that lead from TBI to long-term complications, focusing particularly on the involvement of a compromised blood-brain barrier (BBB). We discuss evidence for the role of spreading depolarization as a key pathological mechanism associated with microvascular dysfunction and the transformation of astrocytes to an inflammatory phenotype. Finally, we summarize new predictive and diagnostic biomarkers and explore potential therapeutic targets for treating long-term complications of TBI.

Cortical plasticity is associated with blood-brain barrier modulation.

Brain microvessels possess the unique properties of a blood-brain barrier (BBB), tightly regulating the passage of molecules from the blood to the brain neuropil and vice versa. In models of brain injury, BBB dysfunction and the associated leakage of serum albumin to the neuropil have been shown to induce pathological plasticity, neuronal hyper-excitability, and seizures. The effect of neuronal activity on BBB function and whether it plays a role in plasticity in the healthy brain remain unclear. Here we show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and BBB-mapping MRI in human subjects, we show that prolonged stimulation of the limb induces a focal increase in BBB permeability in the corresponding somatosensory cortex that is associated with long-term synaptic plasticity. We further show that the increased microvascular permeability depends on neuronal activity and involves caveolae-mediated transcytosis and transforming growth factor ß signaling. Our results reveal a role of BBB modulation in cortical plasticity in the healthy brain, highlighting the importance of neurovascular interactions for sensory experience and learning.