GLUT3 Gene Expression is Critical for Embryonic Growth, Brain Development and Survival

PubMed Central

Carayannopoulos, Mary O.; Xiong, Fuxia; Jensen, Penny; Rios-Galdamez, Yesenia; Huang, Haigen; Lin, Shuo; Devaskar, Sherin U.

2015-01-01

Glucose is the primary energy source for eukaryotic cells and the predominant substrate for the brain. GLUT3 is essential for trans-placental glucose transport and highly expressed in the mammalian brain. To further elucidate the role of GLUT3 in embryonic development, we utilized the vertebrate whole animal model system of Danio rerio as a tractable system for defining the cellular and molecular mechanisms altered by impaired glucose transport and metabolism related to perturbed expression of GLUT3. The comparable orthologue of human GLUT3 was identified and the expression of this gene abrogated during early embryonic development. In a dose-dependent manner embryonic brain development was disrupted resulting in a phenotype of aberrant brain organogenesis, associated with embryonic growth restriction and increased cellular apoptosis. Rescue of the morphant phenotype was achieved by providing exogenous GLUT3 mRNA. We conclude that GLUT3 is critically important for brain organogenesis and embryonic growth. Disruption of GLUT3 is responsible for the phenotypic spectrum of embryonic growth restriction to demise and neural apoptosis with microcephaly. PMID:24529979

DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY ALTERS THE AMPLITUDE OF THE ACOUSTIC STARTLE RESPONSE IN RATS

EPA Science Inventory

Purpose: The thyroid hormone (TH) system is one of the targets of endocrine disrupting chemicals. Since TH is essential for proper brain development, disruption by exposure to chemicals during development can result in adverse neurological outcomes. Previous studies revealed th...

Neurotoxicity of Thyroid Disrupting Contaminants

EPA Science Inventory

Thyroid hormones playa critical role in the normal development ofthe mammalian brain. Thyroid disrupting chemicals (TDCs) are environmental contaminants that alter the structure or function ofthe thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeost...

The Effects of Low-Dose Bisphenol A and Bisphenol F on Neural Differentiation of a Fetal Brain-Derived Neural Progenitor Cell Line.

PubMed

Fujiwara, Yuki; Miyazaki, Wataru; Koibuchi, Noriyuki; Katoh, Takahiko

2018-01-01

Environmental chemicals are known to disrupt the endocrine system in humans and to have adverse effects on several organs including the developing brain. Recent studies indicate that exposure to environmental chemicals during gestation can interfere with neuronal differentiation, subsequently affecting normal brain development in newborns. Xenoestrogen, bisphenol A (BPA), which is widely used in plastic products, is one such chemical. Adverse effects of exposure to BPA during pre- and postnatal periods include the disruption of brain function. However, the effect of BPA on neural differentiation remains unclear. In this study, we explored the effects of BPA or bisphenol F (BPF), an alternative compound for BPA, on neural differentiation using ReNcell, a human fetus-derived neural progenitor cell line. Maintenance in growth factor-free medium initiated the differentiation of ReNcell to neuronal cells including neurons, astrocytes, and oligodendrocytes. We exposed the cells to BPA or BPF for 3 days from the period of initiation and performed real-time PCR for neural markers such as β III-tubulin and glial fibrillary acidic protein (GFAP), and Olig2. The β III-tubulin mRNA level decreased in response to BPA, but not BPF, exposure. We also observed that the number of β III-tubulin-positive cells in the BPA-exposed group was less than that of the control group. On the other hand, there were no changes in the MAP2 mRNA level. These results indicate that BPA disrupts neural differentiation in human-derived neural progenitor cells, potentially disrupting brain development.

Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS.

PubMed

Pai, Vaibhav P; Lemire, Joan M; Chen, Ying; Lin, Gufa; Levin, Michael

2015-01-01

Bioelectric signals, particularly transmembrane voltage potentials (Vmem), play an important role in large-scale patterning during embryonic development. Endogenous bioelectric gradients across tissues function as instructive factors during eye, brain, and other morphogenetic processes. An important and still poorly-understood aspect is the control of cell behaviors by the voltage states of distant cell groups. Here, experimental alteration of endogenous Vmem was induced in Xenopus laevis embryos by misexpression of well-characterized ion channel mRNAs, a strategy often used to identify functional roles of Vmem gradients during embryonic development and regeneration. Immunofluorescence analysis (for activated caspase 3 and phosphor-histone H3P) on embryonic sections was used to characterize apoptosis and proliferation. Disrupting local bioelectric signals (within the developing neural tube region) increased caspase 3 and decreased H3P in the brain, resulting in brain mispatterning. Disrupting remote (ventral, non-neural region) bioelectric signals decreased caspase 3 and highly increased H3P within the brain, with normal brain patterning. Disrupting both the local and distant bioelectric signals produced antagonistic effects on caspase 3 and H3P. Thus, two components of bioelectric signals regulate apoptosis-proliferation balance within the developing brain and spinal cord: local (developing neural tube region) and distant (ventral non-neural region). Together, the local and long-range bioelectric signals create a binary control system capable of fine-tuning apoptosis and proliferation with the brain and spinal cord to achieve correct pattern and size control. Our data suggest a roadmap for utilizing bioelectric state as a diagnostic modality and convenient intervention parameter for birth defects and degenerative disease states of the CNS.

PROGRESS AND PROBLEMS IN THE APPLICATION OF FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION

PubMed Central

Vykhodtseva, Natalia; McDannold, Nathan; Hynynen, Kullervo

2008-01-01

Advances in neuroscience have resulted in the development of new diagnostic and therapeutic agents for potential use in the central nervous system (CNS). However, the ability to deliver the majority of these agents to the brain is limited by the blood–brain barrier (BBB), a specialized structure of the blood vessel wall that hampers transport and diffusion from the blood to the brain. Many CNS disorders could be treated with drugs, enzymes, genes, or large-molecule biotechnological products such as recombinant proteins, if they could cross the BBB. This article reviews the problems of the BBB presence in treating the vast majority of CNS diseases and the efforts to circumvent the BBB through the design of new drugs and the development of more sophisticated delivery methods. Recent advances in the development of noninvasive, targeted drug delivery by MRI-guided ultrasound-induced BBB disruption are also summarized. PMID:18511095

Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link

PubMed Central

Velázquez-Moctezuma, J.

2016-01-01

Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins. PMID:27738642

Infant Neurosensory Development: Considerations for Infant Child Care

ERIC Educational Resources Information Center

Marshall, Jennifer

2011-01-01

Infant brain development is a dynamic process dependent upon endogenous and exogenous stimulation and a supportive environment. A critical period of brain and neurosensory development occurs during the third trimester and into the "fourth" trimester (first three months of life). Disruption, damage, or deprivation in the infant's social and…

Osmotic blood-brain barrier disruption. Computerized tomographic monitoring of chemotherapeutic agent delivery.

PubMed Central

Neuwelt, E A; Maravilla, K R; Frenkel, E P; Rapaport, S I; Hill, S A; Barnett, P A

1979-01-01

The present study describes a canine model of transient reversible blood-brain barrier disruption with hyperosmolar mannitol infusion into the internal carotid artery. Studies in this model show that osmotic blood-brain barrier disruption before intracarotid infusion of methotrexate results in markedly elevated (therapeutic) levels of drug in the ipsilateral cerebral hemisphere. Levels in the cerebrospinal fluid correlate poorly and inconsistently with brain levels. Computerized tomograms in this canine model provide a noninvasive monitor of the degree, time-course, and localization of osmotic blood-brain barrier disruption. Images PMID:457877

Thyroid insufficiency in developing rat brain: A genomic analysis.

EPA Science Inventory

Thyroid Insufficiency in the Developing Rat Brain: A Genomic Analysis. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption (ED) is an area of major concern in environmental neurotoxicity. Severe deficits in thyroid hormone (TH) levels have bee...

Developmental Thyroid Hormone Insufficiency Induces Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study

EPA Science Inventory

Thyroid hormones (TH) are essential for brain development, but animal models of well-defined and sensitive downstream apical neurotoxic outcomes associated with developmental TH disruption are lacking. A structural anomaly, a cortical heterotopia, in the brains of hypothyroid rat...

CHEMICALS THAT DISRUPT THE THYROID AXIS: COLLABORATION BETWEEN ORD AND STAR GRANT RECIPIENTS.

EPA Science Inventory

For effective regulation, the EPA must determine the potential adverse consequences of mild disturbances of the thyroid axis on brain development. Severe hypothyroidism has long been known to lead to profound alterations in brain development and mental retardation. However, the s...

THYROID HORMONE INSUFFICIENCY DURING BRAIN DEVELOPMENT REDUCES PARVALBUMIN IMMUNOREACTIVITY AND INHIBITORY FUNCTION IN THE HIPPOCAMPUS.

EPA Science Inventory

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

Loss of aPKCλ in Differentiated Neurons Disrupts the Polarity Complex but Does Not Induce Obvious Neuronal Loss or Disorientation in Mouse Brains

PubMed Central

Yamanaka, Tomoyuki; Tosaki, Asako; Kurosawa, Masaru; Akimoto, Kazunori; Hirose, Tomonori; Ohno, Shigeo; Hattori, Nobutaka; Nukina, Nobuyuki

2013-01-01

Cell polarity plays a critical role in neuronal differentiation during development of the central nervous system (CNS). Recent studies have established the significance of atypical protein kinase C (aPKC) and its interacting partners, which include PAR-3, PAR-6 and Lgl, in regulating cell polarization during neuronal differentiation. However, their roles in neuronal maintenance after CNS development remain unclear. Here we performed conditional deletion of aPKCλ, a major aPKC isoform in the brain, in differentiated neurons of mice by camk2a-cre or synapsinI-cre mediated gene targeting. We found significant reduction of aPKCλ and total aPKCs in the adult mouse brains. The aPKCλ deletion also reduced PAR-6β, possibly by its destabilization, whereas expression of other related proteins such as PAR-3 and Lgl-1 was unaffected. Biochemical analyses suggested that a significant fraction of aPKCλ formed a protein complex with PAR-6β and Lgl-1 in the brain lysates, which was disrupted by the aPKCλ deletion. Notably, the aPKCλ deletion mice did not show apparent cell loss/degeneration in the brain. In addition, neuronal orientation/distribution seemed to be unaffected. Thus, despite the polarity complex disruption, neuronal deletion of aPKCλ does not induce obvious cell loss or disorientation in mouse brains after cell differentiation. PMID:24391875

Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Substrate-Docking Site in the Developing Brain Causes Microcephaly with Abnormal Brain Morphogenesis Independently of Akt, Leading to Impaired Cognition and Disruptive Behaviors

PubMed Central

Cordón-Barris, Lluís; Pascual-Guiral, Sònia; Yang, Shaobin; Giménez-Llort, Lydia; Lope-Piedrafita, Silvia; Niemeyer, Carlota; Claro, Enrique; Lizcano, Jose M.

2016-01-01

The phosphoinositide (PI) 3-kinase/Akt signaling pathway plays essential roles during neuronal development. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) coordinates the PI 3-kinase signals by activating 23 kinases of the AGC family, including Akt. Phosphorylation of a conserved docking site in the substrate is a requisite for PDK1 to recognize, phosphorylate, and activate most of these kinases, with the exception of Akt. We exploited this differential mechanism of regulation by generating neuron-specific conditional knock-in mice expressing a mutant form of PDK1, L155E, in which the substrate-docking site binding motif, termed the PIF pocket, was disrupted. As a consequence, activation of all the PDK1 substrates tested except Akt was abolished. The mice exhibited microcephaly, altered cortical layering, and reduced circuitry, leading to cognitive deficits and exacerbated disruptive behavior combined with diminished motivation. The abnormal patterning of the adult brain arises from the reduced ability of the embryonic neurons to polarize and extend their axons, highlighting the essential roles that the PDK1 signaling beyond Akt plays in mediating the neuronal responses that regulate brain development. PMID:27644329

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer

PubMed Central

Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood–brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future. PMID:26488496

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer.

PubMed

Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood-brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future.

Distortions and disconnections: disrupted brain connectivity in autism.

PubMed

Wass, Sam

2011-02-01

The past few years have seen considerable interest in findings of abnormal brain connectivity in the autism spectrum disorders (ASD). We review recent work from neuroimaging and other sources, and argue that there is considerable convergent evidence suggesting that connectivity is disrupted in ASD. We point to evidence both of local over-connectivity and of long-distance under-connectivity, and describe some non-uniformities in this picture, most notably that disruptions appear more severe in later-developing cortical regions. We conclude by discussing a number of extant questions. Firstly, we consider whether aberrant connectivity should be seen as part of the primary pathogenesis of autism, or whether disrupted connectivity in ASD emerges over time. Secondly, we consider how the patterns of disrupted connectivity found in ASD might relate to those being found in a range of other disorders. Copyright © 2010 Elsevier Inc. All rights reserved.

THYROID INSUFFICIENCY AND GENE EXPRESSION IN DEVELOPING RAT BRAIN: A DOSE RESPONSE STUDY.

EPA Science Inventory

Thyroid Insufficiency and Gene Expression in Developing Rat Brain: A Dose Response Study. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption is an area of major concern in environmental neurotoxicity. Deficits in thyroid hormone (TH) levels h...

THYROID HORMONE INSUFFICIENCY AND BRAIN DEVELOPMENT -- DETERMINATION OF NEUROTOXICITY AT LOW LEVELS OF HORMONE DISRUPTION.

EPA Science Inventory

Thyroid hormone (TH) deficiencies during development produce deleterious effects on brain structure and function. The degree to which TH must be perturbed to induce neurotoxicity remains unclear. The present study was conducted as part of a Cooperative Agreement between US EPA, U...

The Biology of Trauma: Implications for Treatment

ERIC Educational Resources Information Center

Solomon, Eldra P.; Heide, Kathleen M.

2005-01-01

During the past 20 years, the development of brain imaging techniques and new biochemical approaches has led to increased understanding of the biological effects of psychological trauma. New hypotheses have been generated about brain development and the roots of antisocial behavior. We now understand that psychological trauma disrupts homeostasis…

The Major Histocompatibility Complex and Autism Spectrum Disorder

PubMed Central

Needleman, Leigh A.; McAllister, A. Kimberley

2015-01-01

Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune- related genes and immune responses to environmental stimuli. Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function. Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD. PMID:22760919

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

PubMed

Liu, Yu-Cheng; Lee, Yu-Da; Wang, Hwai-Lee; Liao, Kate Hsiurong; Chen, Kuen-Bao; Poon, Kin-Shing; Pan, Yu-Ling; Lai, Ted Weita

2017-01-01

Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison to the inhibitors of the neuronal death signaling cascade; these, in fact, can attenuate the infarct volume measured at 24 h post-ischemia when administered at 6 h in our same stroke model.

Local brain connectivity across development in autism spectrum disorder: A cross-sectional investigation.

PubMed

Dajani, Dina R; Uddin, Lucina Q

2016-01-01

There is a general consensus that autism spectrum disorder (ASD) is accompanied by alterations in brain connectivity. Much of the neuroimaging work has focused on assessing long-range connectivity disruptions in ASD. However, evidence from both animal models and postmortem examination of the human brain suggests that local connections may also be disrupted in individuals with the disorder. Here, we investigated how regional homogeneity (ReHo), a measure of similarity of a voxel's timeseries to its nearest neighbors, varies across age in individuals with ASD and typically developing (TD) individuals using a cross-sectional design. Resting-state fMRI data obtained from a publicly available database were analyzed to determine group differences in ReHo between three age cohorts: children, adolescents, and adults. In typical development, ReHo across the entire brain was higher in children than in adolescents and adults. In contrast, children with ASD exhibited marginally lower ReHo than TD children, while adolescents and adults with ASD exhibited similar levels of local connectivity as age-matched neurotypical individuals. During all developmental stages, individuals with ASD exhibited lower local connectivity in sensory processing brain regions and higher local connectivity in complex information processing regions. Further, higher local connectivity in ASD corresponded to more severe ASD symptomatology. These results demonstrate that local connectivity is disrupted in ASD across development, with the most pronounced differences occurring in childhood. Developmental changes in ReHo do not mirror findings from fMRI studies of long-range connectivity in ASD, pointing to a need for more nuanced accounts of brain connectivity alterations in the disorder. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Advanced Microscopic Imaging Methods to Investigate Cortical Development and the Etiology of Mental Retardation

ERIC Educational Resources Information Center

Haydar, Tarik F.

2005-01-01

Studies on human patients and animal models of disease have shown that disruptions in prenatal and early postnatal brain development are a root cause of mental retardation. Since proper brain development is achieved by a strict spatiotemporal control of neurogenesis, cell migration, and patterning of synapses, abnormalities in one or more of these…

Disrupted global metastability and static and dynamic brain connectivity across individuals in the Alzheimer’s disease continuum

NASA Astrophysics Data System (ADS)

Córdova-Palomera, Aldo; Kaufmann, Tobias; Persson, Karin; Alnæs, Dag; Doan, Nhat Trung; Moberget, Torgeir; Lund, Martina Jonette; Barca, Maria Lage; Engvig, Andreas; Brækhus, Anne; Engedal, Knut; Andreassen, Ole A.; Selbæk, Geir; Westlye, Lars T.

2017-01-01

As findings on the neuropathological and behavioral components of Alzheimer’s disease (AD) continue to accrue, converging evidence suggests that macroscale brain functional disruptions may mediate their association. Recent developments on theoretical neuroscience indicate that instantaneous patterns of brain connectivity and metastability may be a key mechanism in neural communication underlying cognitive performance. However, the potential significance of these patterns across the AD spectrum remains virtually unexplored. We assessed the clinical sensitivity of static and dynamic functional brain disruptions across the AD spectrum using resting-state fMRI in a sample consisting of AD patients (n = 80) and subjects with either mild (n = 44) or subjective (n = 26) cognitive impairment (MCI, SCI). Spatial maps constituting the nodes in the functional brain network and their associated time-series were estimated using spatial group independent component analysis and dual regression, and whole-brain oscillatory activity was analyzed both globally (metastability) and locally (static and dynamic connectivity). Instantaneous phase metrics showed functional coupling alterations in AD compared to MCI and SCI, both static (putamen, dorsal and default-mode) and dynamic (temporal, frontal-superior and default-mode), along with decreased global metastability. The results suggest that brains of AD patients display altered oscillatory patterns, in agreement with theoretical premises on cognitive dynamics.

Rat model of blood-brain barrier disruption to allow targeted neurovascular therapeutics.

PubMed

Martin, Jacob A; Maris, Alexander S; Ehtesham, Moneeb; Singer, Robert J

2012-11-30

Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier(1). The barrier selectively excludes molecules from crossing between the blood and the brain based upon their size and charge. This function can impede the delivery of therapeutics for neurological disorders. A number of chemotherapeutic drugs, for example, will not effectively cross the blood-brain barrier to reach tumor cells(2). Thus, improving the delivery of drugs across the blood-brain barrier is an area of interest. The most prevalent methods for enhancing the delivery of drugs to the brain are direct cerebral infusion and blood-brain barrier disruption(3). Direct intracerebral infusion guarantees that therapies reach the brain; however, this method has a limited ability to disperse the drug(4). Blood-brain barrier disruption (BBBD) allows drugs to flow directly from the circulatory system into the brain and thus more effectively reach dispersed tumor cells. Three methods of barrier disruption include osmotic barrier disruption, pharmacological barrier disruption, and focused ultrasound with microbubbles. Osmotic disruption, pioneered by Neuwelt, uses a hypertonic solution of 25% mannitol that dehydrates the cells of the blood-brain barrier causing them to shrink and disrupt their tight junctions. Barrier disruption can also be accomplished pharmacologically with vasoactive compounds such as histamine(5) and bradykinin(6). This method, however, is selective primarily for the brain-tumor barrier(7). Additionally, RMP-7, an analog of the peptide bradykinin, was found to be inferior when compared head-to-head with osmotic BBBD with 25% mannitol(8). Another method, focused ultrasound (FUS) in conjunction with microbubble ultrasound contrast agents, has also been shown to reversibly open the blood-brain barrier(9). In comparison to FUS, though, 25% mannitol has a longer history of safety in human patients that makes it a proven tool for translational research(10-12). In order to accomplish BBBD, mannitol must be delivered at a high rate directly into the brain's arterial circulation. In humans, an endovascular catheter is guided to the brain where rapid, direct flow can be accomplished. This protocol models human BBBD as closely as possible. Following a cut-down to the bifurcation of the common carotid artery, a catheter is inserted retrograde into the ECA and used to deliver mannitol directly into the internal carotid artery (ICA) circulation. Propofol and N2O anesthesia are used for their ability to maximize the effectiveness of barrier disruption(13). If executed properly, this procedure has the ability to safely, effectively, and reversibly open the blood-brain barrier and improve the delivery of drugs that do not ordinarily reach the brain (8,13,14).

Structural Abnormalities and Learning Impairments Induced by Low Level Thyroid Hormone Insufficiency: A Cross-Fostering Study

EPA Science Inventory

Severe reductions in thyroid hormones (TH) during development alter brain structure and impair learning. Uncertainty surrounds both the impact oflower levels of TH disruption and the sensitivity of available metrics to detect neurodevelopmental deficits of this disruption. We ha...

Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit.

PubMed

Banks, William A; Gray, Alicia M; Erickson, Michelle A; Salameh, Therese S; Damodarasamy, Mamatha; Sheibani, Nader; Meabon, James S; Wing, Emily E; Morofuji, Yoichi; Cook, David G; Reed, May J

2015-11-25

Disruption of the blood-brain barrier (BBB) occurs in many diseases and is often mediated by inflammatory and neuroimmune mechanisms. Inflammation is well established as a cause of BBB disruption, but many mechanistic questions remain. We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in mice. BBB disruption was measured using (14)C-sucrose and radioactively labeled albumin. Brain cytokine responses were measured using multiplex technology and dependence on cyclooxygenase (COX) and oxidative stress determined by treatments with indomethacin and N-acetylcysteine. Astrocyte and microglia/macrophage responses were measured using brain immunohistochemistry. In vitro studies used Transwell cultures of primary brain endothelial cells co- or tri-cultured with astrocytes and pericytes to measure effects of LPS on transendothelial electrical resistance (TEER), cellular distribution of tight junction proteins, and permeability to (14)C-sucrose and radioactive albumin. In comparison to LPS-induced weight loss, the BBB was relatively resistant to LPS-induced disruption. Disruption occurred only with the highest dose of LPS and was most evident in the frontal cortex, thalamus, pons-medulla, and cerebellum with no disruption in the hypothalamus. The in vitro and in vivo patterns of LPS-induced disruption as measured with (14)C-sucrose, radioactive albumin, and TEER suggested involvement of both paracellular and transcytotic pathways. Disruption as measured with albumin and (14)C-sucrose, but not TEER, was blocked by indomethacin. N-acetylcysteine did not affect disruption. In vivo, the measures of neuroinflammation induced by LPS were mainly not reversed by indomethacin. In vitro, the effects on LPS and indomethacin were not altered when brain endothelial cells (BECs) were cultured with astrocytes or pericytes. The BBB is relatively resistant to LPS-induced disruption with some brain regions more vulnerable than others. LPS-induced disruption appears is to be dependent on COX but not on oxidative stress. Based on in vivo and in vitro measures of neuroinflammation, it appears that astrocytes, microglia/macrophages, and pericytes play little role in the LPS-mediated disruption of the BBB.

IDENTIFICATION OF NEURAL BIOMARKERS OF ALTERED SEXUAL DIFFERENTIATION FOLLOWING GESTATIONAL EXPOSURE***

EPA Science Inventory

Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

Identification of neural biomarkers of altered sexual differentiation following gestational exposure

EPA Science Inventory

Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) during...

Identification of neural biomarkers of altered sexual differentiation following gestational exposure###

EPA Science Inventory

Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

Interleukin 2 Activates Brain Microvascular Endothelial Cells Resulting in Destabilization of Adherens Junctions.

PubMed

Wylezinski, Lukasz S; Hawiger, Jacek

2016-10-28

The pleiotropic cytokine interleukin 2 (IL2) disrupts the blood-brain barrier and alters brain microcirculation, underlying vascular leak syndrome that complicates cancer immunotherapy with IL2. The microvascular effects of IL2 also play a role in the development of multiple sclerosis and other chronic neurological disorders. The mechanism of IL2-induced disruption of brain microcirculation has not been determined previously. We found that both human and murine brain microvascular endothelial cells express constituents of the IL2 receptor complex. Then we established that signaling through this receptor complex leads to activation of the transcription factor, nuclear factor κB, resulting in expression of proinflammatory interleukin 6 and monocyte chemoattractant protein 1. We also discovered that IL2 induces disruption of adherens junctions, concomitant with cytoskeletal reorganization, ultimately leading to increased endothelial cell permeability. IL2-induced phosphorylation of vascular endothelial cadherin (VE-cadherin), a constituent of adherens junctions, leads to dissociation of its stabilizing adaptor partners, p120-catenin and β-catenin. Increased phosphorylation of VE-cadherin was also accompanied by a reduction of Src homology 2 domain-containing protein-tyrosine phosphatase 2, known to maintain vascular barrier function. These results unravel the mechanism of deleterious effects induced by IL2 on brain microvascular endothelial cells and may inform the development of new measures to improve IL2 cancer immunotherapy, as well as treatments for autoimmune diseases affecting the central nervous system. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Blood-brain barrier disruption induced by diagnostic ultrasound combined with microbubbles in mice.

PubMed

Zhao, Bingxia; Chen, Yihan; Liu, Jinfeng; Zhang, Li; Wang, Jing; Yang, Yali; Lv, Qing; Xie, Mingxing

2018-01-12

To investigate the effects of the microbubble (MB) dose, mechanism index (MI) and sonication duration on blood-brain barrier (BBB) disruption induced by diagnostic ultrasound combined with MBs as well as to investigate the potential molecular mechanism. The extent of BBB disruption increased with MB dose, MI and sonication duration. A relatively larger extent of BBB disruption associated with minimal tissue damage was achieved by an appropriate MB dose and ultrasound exposure parameters with diagnostic ultrasound. Decreased expression of ZO-1, occludin and claudin-5 were correlated with disruption of the BBB, as confirmed by paracellular passage of the tracer lanthanum nitrate into the brain parenchyma after BBB disruption. These findings indicated that this technique is a promising tool for promoting brain delivery of diagnostic and therapeutic agents in the diagnosis and treatment of brain diseases. The extent of BBB disruption was qualitatively assessed by Evans blue (EB) staining and quantitatively analyzed by an EB extravasation measurement. A histological examination was performed to evaluate tissue damage. Expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5 was determined by western blotting analysis and immunohistofluorescence. Transmission electron microscopy was performed to observe ultrastructure changes of TJs after BBB disruption.

Sleep disruption and the sequelae associated with traumatic brain injury.

PubMed

Lucke-Wold, Brandon P; Smith, Kelly E; Nguyen, Linda; Turner, Ryan C; Logsdon, Aric F; Jackson, Garrett J; Huber, Jason D; Rosen, Charles L; Miller, Diane B

2015-08-01

Sleep disruption, which includes a loss of sleep as well as poor quality fragmented sleep, frequently follows traumatic brain injury (TBI) impacting a large number of patients each year in the United States. Fragmented and/or disrupted sleep can worsen neuropsychiatric, behavioral, and physical symptoms of TBI. Additionally, sleep disruption impairs recovery and can lead to cognitive decline. The most common sleep disruption following TBI is insomnia, which is difficulty staying asleep. The consequences of disrupted sleep following injury range from deranged metabolomics and blood brain barrier compromise to altered neuroplasticity and degeneration. There are several theories for why sleep is necessary (e.g., glymphatic clearance and metabolic regulation) and these may help explain how sleep disruption contributes to degeneration within the brain. Experimental data indicate disrupted sleep allows hyperphosphorylated tau and amyloid β plaques to accumulate. As sleep disruption may act as a cellular stressor, target areas warranting further scientific investigation include the increase in endoplasmic reticulum and oxidative stress following acute periods of sleep deprivation. Potential treatment options for restoring the normal sleep cycle include melatonin derivatives and cognitive behavioral therapy. Published by Elsevier Ltd.

Sleep disruption and the sequelae associated with traumatic brain injury

PubMed Central

Lucke-Wold, Brandon P.; Smith, Kelly E.; Nguyen, Linda; Turner, Ryan C.; Logsdon, Aric F.; Jackson, Garrett J.; Huber, Jason D.; Rosen, Charles L.; Miller, Diane B.

2016-01-01

Sleep disruption, which includes a loss of sleep as well as poor quality fragmented sleep, frequently follows traumatic brain injury (TBI) impacting a large number of patients each year in the United States. Fragmented and/or disrupted sleep can worsen neuropsychiatric, behavioral, and physical symptoms of TBI. Additionally, sleep disruption impairs recovery and can lead to cognitive decline. The most common sleep disruption following TBI is insomnia, which is difficulty staying asleep. The consequences of disrupted sleep following injury range from deranged metabolomics and blood brain barrier compromise to altered neuroplasticity and degeneration. There are several theories for why sleep is necessary (e.g., glymphatic clearance and metabolic regulation) and these may help explain how sleep disruption contributes to degeneration within the brain. Experimental data indicate disrupted sleep allows hyperphosphorylated tau and amyloid β plaques to accumulate. As sleep disruption may act as a cellular stressor, target areas warranting further scientific investigation include the increase in endoplasmic reticulum and oxidative stress following acute periods of sleep deprivation. Potential treatment options for restoring the normal sleep cycle include melatonin derivatives and cognitive behavioral therapy. PMID:25956251

Lysophosphatidic acid receptor, LPA6, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy.

PubMed

Masago, Kayo; Kihara, Yasuyuki; Yanagida, Keisuke; Hamano, Fumie; Nakagawa, Shinsuke; Niwa, Masami; Shimizu, Takao

2018-07-02

Cerebral edema is a life-threatening neurological condition characterized by brain swelling due to the accumulation of excess fluid both intracellularly and extracellularly. Fulminant hepatic failure (FHF) develops cerebral edema by disrupting blood-brain barrier (BBB). However, the mechanisms by which mediator induces brain edema in FHF remain to be elucidated. Here, we assessed a linkage between brain edema and lysophosphatidic acid (LPA) signaling by utilizing an animal model of FHF and in vitro BBB model. Azoxymethane-treated mice developed FHF and hepatic encephalopathy, associated with higher autotaxin (ATX) activities in serum than controls. Using in vitro BBB model, LPA disrupted the structural integrity of tight junction proteins including claudin-5, occludin, and ZO-1. Furthermore, LPA decreased transendothelial electrical resistances in in vitro BBB model, and induced cell contraction in brain endothelial monolayer cultures, both being inhibited by a Rho-associated protein kinase inhibitor, Y-27632. The brain capillary endothelial cells predominantly expressed LPA 6 mRNA, whose knockdown blocked the LPA-induced endothelial cell contraction. Taken together, the up-regulation of serum ATX in hepatic encephalopathy may activate the LPA-LPA 6 -G 12/13 -Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema. Copyright © 2018 Elsevier Inc. All rights reserved.

Neuroimaging of the Injured Pediatric Brain: Methods and New Lessons.

PubMed

Dennis, Emily L; Babikian, Talin; Giza, Christopher C; Thompson, Paul M; Asarnow, Robert F

2018-02-01

Traumatic brain injury (TBI) is a significant public health problem in the United States, especially for children and adolescents. Current epidemiological data estimate over 600,000 patients younger than 20 years are treated for TBI in emergency rooms annually. While many patients experience a full recovery, for others there can be long-lasting cognitive, neurological, psychological, and behavioral disruptions. TBI in youth can disrupt ongoing brain development and create added family stress during a formative period. The neuroimaging methods used to assess brain injury improve each year, providing researchers a more detailed characterization of the injury and recovery process. In this review, we cover current imaging methods used to quantify brain disruption post-injury, including structural magnetic resonance imaging (MRI), diffusion MRI, functional MRI, resting state fMRI, and magnetic resonance spectroscopy (MRS), with brief coverage of other methods, including electroencephalography (EEG), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). We include studies focusing on pediatric moderate-severe TBI from 2 months post-injury and beyond. While the morbidity of pediatric TBI is considerable, continuing advances in imaging methods have the potential to identify new treatment targets that can lead to significant improvements in outcome.

Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs

PubMed Central

Michinaga, Shotaro; Koyama, Yutaka

2015-01-01

Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available. Thus, the development of novel anti-edema drugs is required. The pathogenesis of brain edema is classified as vasogenic or cytotoxic edema. Vasogenic edema is defined as extracellular accumulation of fluid resulting from disruption of the blood-brain barrier (BBB) and extravasations of serum proteins, while cytotoxic edema is characterized by cell swelling caused by intracellular accumulation of fluid. Various experimental animal models are often used to investigate mechanisms underlying brain edema. Many soluble factors and functional molecules have been confirmed to induce BBB disruption or cell swelling and drugs targeted to these factors are expected to have anti-edema effects. In this review, we discuss the mechanisms and involvement of factors that induce brain edema formation, and the possibility of anti-edema drugs targeting them. PMID:25941935

Blood-brain barrier disruption induced by diagnostic ultrasound combined with microbubbles in mice

PubMed Central

Liu, Jinfeng; Zhang, Li; Wang, Jing; Yang, Yali; Lv, Qing; Xie, Mingxing

2018-01-01

Objective To investigate the effects of the microbubble (MB) dose, mechanism index (MI) and sonication duration on blood-brain barrier (BBB) disruption induced by diagnostic ultrasound combined with MBs as well as to investigate the potential molecular mechanism. Results The extent of BBB disruption increased with MB dose, MI and sonication duration. A relatively larger extent of BBB disruption associated with minimal tissue damage was achieved by an appropriate MB dose and ultrasound exposure parameters with diagnostic ultrasound. Decreased expression of ZO-1, occludin and claudin-5 were correlated with disruption of the BBB, as confirmed by paracellular passage of the tracer lanthanum nitrate into the brain parenchyma after BBB disruption. Conclusions These findings indicated that this technique is a promising tool for promoting brain delivery of diagnostic and therapeutic agents in the diagnosis and treatment of brain diseases. Methods The extent of BBB disruption was qualitatively assessed by Evans blue (EB) staining and quantitatively analyzed by an EB extravasation measurement. A histological examination was performed to evaluate tissue damage. Expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5 was determined by western blotting analysis and immunohistofluorescence. Transmission electron microscopy was performed to observe ultrastructure changes of TJs after BBB disruption. PMID:29435150

Adolescent Brain Development and Underage Drinking in the United States: Identifying Risks of Alcohol Use in College Populations

PubMed Central

Silveri, Marisa M.

2015-01-01

Alcohol use typically is initiated during adolescence, an age period that overlaps with critical structural and functional maturation of the brain. Brain maturation and associated improvements in decision-making continue into the second decade of life, reaching plateaus within the period referred to as “emerging adulthood” (18–24 years). Emerging adulthood is the typical age span of the traditionally aged college student, which includes the age (21 years) when alcohol consumption becomes legal in the United States. This review highlights neurobiological evidence indicating the vulnerabilities of the emerging adult brain to alcohol effects. This review also identifies that reduced sensitivity to alcohol sedation and increased sensitivity to alcohol-related disruptions in memory, positive family history of alcoholism effects on brain structure and function, and emerging co-morbid psychiatric conditions serve as unique vulnerabilities that increase the risks associated with underage alcohol use. These vulnerabilities likely contribute to excessive and unsupervised drinking in college students. Discouraging alcohol consumption until neurobiological adulthood is reached is important for minimizing alcohol-related disruptions in brain development and decision-making capacity, and reducing the negative behavioral consequences associated with underage alcohol use. PMID:22894728

Minocycline Attenuates Iron-Induced Brain Injury.

PubMed

Zhao, Fan; Xi, Guohua; Liu, Wenqaun; Keep, Richard F; Hua, Ya

2016-01-01

Iron plays an important role in brain injury after intracerebral hemorrhage (ICH). Our previous study found minocycline reduces iron overload after ICH. The present study examined the effects of minocycline on the subacute brain injury induced by iron. Rats had an intracaudate injection of 50 μl of saline, iron, or iron + minocycline. All the animals were euthanized at day 3. Rat brains were used for immunohistochemistry (n = 5-6 per each group) and Western blotting assay (n = 4). Brain swelling, blood-brain barrier (BBB) disruption, and iron-handling proteins were measured. We found that intracerebral injection of iron resulted in brain swelling, BBB disruption, and brain iron-handling protein upregulation (p < 0.05). The co-injection of minocycline with iron significantly reduced iron-induced brain swelling (n = 5, p < 0.01). Albumin, a marker of BBB disruption, was measured by Western blot analysis. Minocycline significantly decreased albumin protein levels in the ipsilateral basal ganglia (p < 0.01). Iron-handling protein levels in the brain, including ceruloplasmin and transferrin, were reduced in the minocycline co-injected animals. In conclusion, the present study suggests that minocycline attenuates brain swelling and BBB disruption via an iron-chelation mechanism.

Recovery of Neurological Function Despite Immediate Sleep Disruption Following Diffuse Brain Injury in the Mouse: Clinical Relevance to Medically Untreated Concussion

PubMed Central

Rowe, Rachel K.; Harrison, Jordan L.; O'Hara, Bruce F.; Lifshitz, Jonathan

2014-01-01

Study Objective: We investigated the relationship between immediate disruption of posttraumatic sleep and functional outcome in the diffuse brain-injured mouse. Design: Adult male C57BL/6 mice were subjected to moderate midline fluid percussion injury (n = 65; 1.4 atm; 6-10 min righting reflex time) or sham injury (n = 44). Cohorts received either intentional sleep disruption (minimally stressful gentle handling) or no sleep disruption for 6 h following injury. Following disruption, serum corticosterone levels (enzyme-linked immunosorbent assay) and posttraumatic sleep (noninvasive piezoelectric sleep cages) were measured. For 1-7 days postinjury, sensorimotor outcome was assessed by Rotarod and a modified Neurological Severity Score (NSS). Cognitive function was measured using Novel Object Recognition (NOR) and Morris water maze (MWM) in the first week postinjury. Setting: Neurotrauma research laboratory. Measurements and Results: Disrupting posttraumatic sleep for 6 h did not affect serum corticosterone levels or functional outcome. In the hour following the first dark onset, sleep-disrupted mice exhibited a significant increase in sleep; however, this increase was not sustained and there was no rebound of lost sleep. Regardless of sleep disruption, mice showed a time-dependent improvement in Rotarod performance, with brain-injured mice having significantly shorter latencies on day 7 compared to sham. Further, brain-injured mice, regardless of sleep disruption, had significantly higher NSS scores postinjury compared with sham. Cognitive behavioral testing showed no group differences among any treatment group measured by MWM and NOR. Conclusion: Short-duration disruption of posttraumatic sleep did not affect functional outcome, measured by motor and cognitive performance. These data raise uncertainty about posttraumatic sleep as a mechanism of recovery from diffuse brain injury. Citation: Rowe RK; Harrison JL; O'Hara BF; Lifshitz J. Recovery of neurological function despite immediate sleep disruption following diffuse brain injury in the mouse: clinical relevance to medically untreated concussion. SLEEP 2014;37(4):743-752. PMID:24899763

Reinforcement of the Brain's Rich-Club Architecture Following Early Neurodevelopmental Disruption Caused by Very Preterm Birth

PubMed Central

Karolis, Vyacheslav R.; Froudist-Walsh, Sean; Brittain, Philip J.; Kroll, Jasmin; Ball, Gareth; Edwards, A. David; Dell'Acqua, Flavio; Williams, Steven C.; Murray, Robin M.; Nosarti, Chiara

2016-01-01

The second half of pregnancy is a crucial period for the development of structural brain connectivity, and an abrupt interruption of the typical processes of development during this phase caused by the very preterm birth (<33 weeks of gestation) is likely to result in long-lasting consequences. We used structural and diffusion imaging data to reconstruct the brain structural connectome in very preterm-born adults. We assessed its rich-club organization and modularity as 2 characteristics reflecting the capacity to support global and local information exchange, respectively. Our results suggest that the establishment of global connectivity patterns is prioritized over peripheral connectivity following early neurodevelopmental disruption. The very preterm brain exhibited a stronger rich-club architecture than the control brain, despite possessing a relative paucity of white matter resources. Using a simulated lesion approach, we also investigated whether putative structural reorganization takes place in the very preterm brain in order to compensate for its anatomical constraints. We found that connections between the basal ganglia and (pre-) motor regions, as well as connections between subcortical regions, assumed an altered role in the structural connectivity of the very preterm brain, and that such alterations had functional implications for information flow, rule learning, and verbal IQ. PMID:26742566

Intra-Arterial Delivery of AAV Vectors to the Mouse Brain After Mannitol Mediated Blood Brain Barrier Disruption

PubMed Central

Santillan, Alejandro; Sondhi, Dolan; Dyke, Jonathan P.; Crystal, Ronald G.; Gobin, Y. Pierre; Ballon, Douglas J.

2014-01-01

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration. PMID:25270115

Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

PubMed

Huppert, Jula; Closhen, Dorothea; Croxford, Andrew; White, Robin; Kulig, Paulina; Pietrowski, Eweline; Bechmann, Ingo; Becher, Burkhard; Luhmann, Heiko J; Waisman, Ari; Kuhlmann, Christoph R W

2010-04-01

Recently T-helper 17 (Th17) cells were demonstrated to disrupt the blood-brain barrier (BBB) by the action of IL-17A. The aim of the present study was to examine the mechanisms that underlie IL-17A-induced BBB breakdown. Barrier integrity was analyzed in the murine brain endothelial cell line bEnd.3 by measuring the electrical resistance values using electrical call impedance sensing technology. Furthermore, in-cell Western blots, fluorescence imaging, and monocyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. IL-17A induced NADPH oxidase- or xanthine oxidase-dependent reactive oxygen species (ROS) production. The resulting oxidative stress activated the endothelial contractile machinery, which was accompanied by a down-regulation of the tight junction molecule occludin. Blocking either ROS formation or myosin light chain phosphorylation or applying IL-17A-neutralizing antibodies prevented IL-17A-induced BBB disruption. Treatment of mice with EAE using ML-7, an inhibitor of the myosin light chain kinase, resulted in less BBB disruption at the spinal cord and less infiltration of lymphocytes via the BBB and subsequently reduced the clinical characteristics of EAE. These observations indicate that IL-17A accounts for a crucial step in the development of EAE by impairing the integrity of the BBB, involving augmented production of ROS.-Huppert, J., Closhen, D., Croxford, A., White, R., Kulig, P., Pietrowski, E., Bechmann, I., Becher, B., Luhmann, H. J., Waisman, A., Kuhlmann, C. R. W. Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

How schizophrenia develops: cognitive and brain mechanisms underlying onset of psychosis

PubMed Central

Cannon, Tyrone D.

2015-01-01

Identifying cognitive and neural mechanisms involved in the development of schizophrenia requires longitudinal observation of individuals prior to onset. Here recent studies of prodromal individuals who progress to full psychosis are briefly reviewed in relation to models of schizophrenia pathophysiology. Together, this body of work suggests that disruption in brain connectivity, driven primarily by a progressive reduction in dendritic spines on cortical pyramidal neurons, may represent a key triggering mechanism. The earliest disruptions appear to be in circuits involved in referencing experiences according to time, place, and agency, which may result in a failure to recognize particular cognitions as self-generated or to constrain interpretations of the meaning of events based on prior experiences, providing the scaffolding for faulty reality testing. PMID:26493362

Insulin Action in Brain Regulates Systemic Metabolism and Brain Function

PubMed Central

Kleinridders, André; Ferris, Heather A.; Cai, Weikang

2014-01-01

Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases. PMID:24931034

Progressively Disrupted Brain Functional Connectivity Network in Subcortical Ischemic Vascular Cognitive Impairment Patients.

PubMed

Sang, Linqiong; Chen, Lin; Wang, Li; Zhang, Jingna; Zhang, Ye; Li, Pengyue; Li, Chuanming; Qiu, Mingguo

2018-01-01

Cognitive impairment caused by subcortical ischemic vascular disease (SIVD) has been elucidated by many neuroimaging studies. However, little is known regarding the changes in brain functional connectivity networks in relation to the severity of cognitive impairment in SIVD. In the present study, 20 subcortical ischemic vascular cognitive impairment no dementia patients (SIVCIND) and 20 dementia patients (SIVaD) were enrolled; additionally, 19 normal controls were recruited. Each participant underwent a resting-state functional MRI scan. Whole-brain functional networks were analyzed with graph theory and network-based statistics (NBS) to study the functional organization of networks and find alterations in functional connectivity among brain regions. After adjustments for age, gender, and duration of formal education, there were significant group differences for two network functional organization indices, global efficiency and local efficiency, which decreased (NC > SIVCIND > SIVaD) as cognitive impairment worsened. Between-group differences in functional connectivity (NBS corrected, p  < 0.01) mainly involved the orbitofrontal, parietal, and temporal cortices, as well as the basal ganglia. The brain connectivity network was progressively disrupted as cognitive impairment worsened, with an increased number of decreased connections between brain regions. We also observed more reductions in nodal efficiency in the prefrontal and temporal cortices for SIVaD than for SIVCIND. These findings indicated a progressively disrupted pattern of the brain functional connectivity network with increased cognitive impairment and showed promise for the development of reliable biomarkers of network metric changes related to cognitive impairment caused by SIVD.

Quantitative assessment of cerebral glucose metabolic rates after blood-brain barrier disruption induced by focused ultrasound using FDG-MicroPET.

PubMed

Yang, Feng-Yi; Chang, Wen-Yuan; Chen, Jyh-Cheng; Lee, Lin-Chien; Hung, Yi-Shun

2014-04-15

The goal of this study was to evaluate the pharmacokinetics of (18)F-2-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the expression of glucose transporter 1 (GLUT1) protein after blood-brain barrier (BBB) disruption of normal rat brains by focused ultrasound (FUS). After delivery of an intravenous bolus of ~37 MBq (1 mCi) (18)F-FDG, dynamic positron emission tomography scans were performed on rats with normal brains and those whose BBBs had been disrupted by FUS. Arterial blood sampling was collected throughout the scanning procedure. A 2-tissue compartmental model was used to estimate (18)F-FDG kinetic parameters in brain tissues. The rate constants Ki, K1, and k3 were assumed to characterize the uptake, transport, and hexokinase activity, respectively, of (18)F-FDG. The uptake of (18)F-FDG in brains significantly decreased immediately after the blood-brain barrier was disrupted. At the same time, the derived values of Ki, K1, and k3 for the sonicated brains were significantly lower than those for the control brains. In agreement with the reduction in glucose, Western blot analyses confirmed that focused ultrasound exposure significantly reduced the expression of GLUT1 protein in the brains. Furthermore, the effect of focused ultrasound on glucose uptake was transient and reversible 24h after sonication. Our results indicate that focused ultrasound may inhibit GLUT1 expression to decrease the glucose uptake in brain tissue during the period of BBB disruption. Copyright © 2013 Elsevier Inc. All rights reserved.

Seizure Control and Memory Impairment Are Related to Disrupted Brain Functional Integration in Temporal Lobe Epilepsy.

PubMed

Park, Chang-Hyun; Choi, Yun Seo; Jung, A-Reum; Chung, Hwa-Kyoung; Kim, Hyeon Jin; Yoo, Jeong Hyun; Lee, Hyang Woon

2017-01-01

Brain functional integration can be disrupted in patients with temporal lobe epilepsy (TLE), but the clinical relevance of this disruption is not completely understood. The authors hypothesized that disrupted functional integration over brain regions remote from, as well as adjacent to, the seizure focus could be related to clinical severity in terms of seizure control and memory impairment. Using resting-state functional MRI data acquired from 48 TLE patients and 45 healthy controls, the authors mapped functional brain networks and assessed changes in a network parameter of brain functional integration, efficiency, to examine the distribution of disrupted functional integration within and between brain regions. The authors assessed whether the extent of altered efficiency was influenced by seizure control status and whether the degree of altered efficiency was associated with the severity of memory impairment. Alterations in the efficiency were observed primarily near the subcortical region ipsilateral to the seizure focus in TLE patients. The extent of regional involvement was greater in patients with poor seizure control: it reached the frontal, temporal, occipital, and insular cortices in TLE patients with poor seizure control, whereas it was limited to the limbic and parietal cortices in TLE patients with good seizure control. Furthermore, TLE patients with poor seizure control experienced more severe memory impairment, and this was associated with lower efficiency in the brain regions with altered efficiency. These findings indicate that the distribution of disrupted brain functional integration is clinically relevant, as it is associated with seizure control status and comorbid memory impairment.

Cerebral amyloid angiopathy, blood-brain barrier disruption and amyloid accumulation in SAMP8 mice.

PubMed

del Valle, Jaume; Duran-Vilaregut, Joaquim; Manich, Gemma; Pallàs, Mercè; Camins, Antoni; Vilaplana, Jordi; Pelegrí, Carme

2011-01-01

Cerebrovascular dysfunction and β-amyloid peptide deposition on the walls of cerebral blood vessels might be an early event in the development of Alzheimer's disease. Here we studied the time course of amyloid deposition in blood vessels and blood-brain barrier (BBB) disruption in the CA1 subzone of the hippocampus of SAMP8 mice and the association between these two variables. We also studied the association between the amyloid deposition in blood vessels and the recently described amyloid clusters in the parenchyma, as well as the association of these clusters with vessels in which the BBB is disrupted. SAMP8 mice showed greater amyloid deposition in blood vessels than age-matched ICR-CD1 control mice. Moreover, at 12 months of age the number of vessels with a disrupted BBB had increased in both strains, especially SAMP8 animals. At this age, all the vessels with amyloid deposition showed BBB disruption, but several capillaries with an altered BBB showed no amyloid on their walls. Moreover, amyloid clusters showed no spatial association with vessels with amyloid deposition, nor with vessels in which the BBB had been disrupted. Finally, we can conclude that vascular amyloid deposition seems to induce BBB alterations, but BBB disruption may also be due to other factors. Copyright © 2011 S. Karger AG, Basel.

Recovery of neurological function despite immediate sleep disruption following diffuse brain injury in the mouse: clinical relevance to medically untreated concussion.

PubMed

Rowe, Rachel K; Harrison, Jordan L; O'Hara, Bruce F; Lifshitz, Jonathan

2014-04-01

We investigated the relationship between immediate disruption of posttraumatic sleep and functional outcome in the diffuse brain-injured mouse. Adult male C57BL/6 mice were subjected to moderate midline fluid percussion injury (n = 65; 1.4 atm; 6-10 min righting reflex time) or sham injury (n = 44). Cohorts received either intentional sleep disruption (minimally stressful gentle handling) or no sleep disruption for 6 h following injury. Following disruption, serum corticosterone levels (enzyme-linked immunosorbent assay) and posttraumatic sleep (noninvasive piezoelectric sleep cages) were measured. For 1-7 days postinjury, sensorimotor outcome was assessed by Rotarod and a modified Neurological Severity Score (NSS). Cognitive function was measured using Novel Object Recognition (NOR) and Morris water maze (MWM) in the first week postinjury. Neurotrauma research laboratory. Disrupting posttraumatic sleep for 6 h did not affect serum corticosterone levels or functional outcome. In the hour following the first dark onset, sleep-disrupted mice exhibited a significant increase in sleep; however, this increase was not sustained and there was no rebound of lost sleep. Regardless of sleep disruption, mice showed a time-dependent improvement in Rotarod performance, with brain-injured mice having significantly shorter latencies on day 7 compared to sham. Further, brain-injured mice, regardless of sleep disruption, had significantly higher NSS scores postinjury compared with sham. Cognitive behavioral testing showed no group differences among any treatment group measured by MWM and NOR. Short-duration disruption of posttraumatic sleep did not affect functional outcome, measured by motor and cognitive performance. These data raise uncertainty about posttraumatic sleep as a mechanism of recovery from diffuse brain injury.

Disruptions of brain structural network in end-stage renal disease patients with long-term hemodialysis and normal-appearing brain tissues.

PubMed

Chou, Ming-Chung; Ko, Chih-Hung; Chang, Jer-Ming; Hsieh, Tsyh-Jyi

2018-05-04

End-stage renal disease (ESRD) patients on hemodialysis were demonstrated to exhibit silent and invisible white-matter alterations which would likely lead to disruptions of brain structural networks. Therefore, the purpose of this study was to investigate the disruptions of brain structural network in ESRD patients. Thiry-three ESRD patients with normal-appearing brain tissues and 29 age- and gender-matched healthy controls were enrolled in this study and underwent both cognitive ability screening instrument (CASI) assessment and diffusion tensor imaging (DTI) acquisition. Brain structural connectivity network was constructed using probabilistic tractography with automatic anatomical labeling template. Graph-theory analysis was performed to detect the alterations of node-strength, node-degree, node-local efficiency, and node-clustering coefficient in ESRD patients. Correlational analysis was performed to understand the relationship between network measures, CASI score, and dialysis duration. Structural connectivity, node-strength, node-degree, and node-local efficiency were significantly decreased, whereas node-clustering coefficient was significantly increased in ESRD patients as compared with healthy controls. The disrupted local structural networks were generally associated with common neurological complications of ESRD patients, but the correlational analysis did not reveal significant correlation between network measures, CASI score, and dialysis duration. Graph-theory analysis was helpful to investigate disruptions of brain structural network in ESRD patients with normal-appearing brain tissues. Copyright © 2018. Published by Elsevier Masson SAS.

Effects of Anesthetics on Brain Circuit Formation

PubMed Central

Wagner, Meredith; Ryu, Yun Kyoung; Smith, Sarah C.; Mintz, C. David

2014-01-01

The results of several retrospective clinical studies suggest that exposure to anesthetic agents early in life is correlated with subsequent learning and behavioral disorders. While ongoing prospective clinical trials may help to clarify this association, they remain confounded by numerous factors. Thus, some of the most compelling data supporting the hypothesis that a relatively short anesthetic exposure can lead to a long-lasting change in brain function are derived from animal models. The mechanism by which such changes could occur remains incompletely understood. Early studies identified anesthetic-induced neuronal apoptosis as a possible mechanism of injury, and more recent work suggests that anesthetics may interfere with several critical processes in brain development. The function of the mature brain requires the presence of circuits, established during development, that perform the computations underlying learning and cognition. In this review we examine the mechanisms by which anesthetics could disrupt brain circuit formation, including effects on neuronal survival and neurogenesis, neurite growth and guidance, formation of synapses, and function of supporting cells. There is evidence that anesthetics can disrupt aspects of all of these processes, and further research is required to elucidate which are most relevant to pediatric anesthetic neurotoxicity. PMID:25144504

PERINATAL EXPOSURE TO POLYCHLORINATED BIPHENYLS AROCLOR 1016 OR 1254 DID NOT ALTER BRAIN CATECHOLAMINES NOR DELAYED ALTERNATION PERFORMANCE IN LONG EVANS RATS

EPA Science Inventory

Several reports have indicated that polychlorinated biphenyls (PCB) altered development of biogenic amine systems in the brain, impaired behavioral performances and disrupted maturation of the thyroid axis. The current study examines whether these developmental effects of PCB ar...

Thyroid Hormone-Dependent Formation of a Subcortical Band Heterotopia (SBH) in the Neonatal Brain is not Exacerbated Under Conditions of Low Dietary Iron (FeD)

EPA Science Inventory

Although the critical role of thyroid hormone (TH) in brain development is well established - severe deficiency producing significant neurological dysfunction - there is a paucity of data on neurological impairments that accompany modest degrees of TH disruption. Quantitative m...

Rich club network analysis shows distinct patterns of disruption in frontotemporal dementia and Alzheimer’s disease

PubMed Central

Daianu, Madelaine; Jahanshad, Neda; Villalon-Reina, Julio E.; Mendez, Mario F.; Bartzokis, George; Jimenez, Elvira E.; Joshi, Aditi; Barsuglia, Joseph; Thompson, Paul M.

2015-01-01

Diffusion imaging and brain connectivity analyses can reveal the underlying organizational patterns of the human brain, described as complex networks of densely interlinked regions. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants – 15 patients with behavioral variant frontotemporal (bvFTD) dementia, 19 with early-onset Alzheimer’s disease (EOAD), and 30 healthy elderly controls. Based on whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We examined how bvFTD and EOAD disrupt the weighted ‘rich club’ – a network property where high-degree network nodes are more interconnected than expected by chance. bvFTD disrupts both the nodal and global organization of the network in both low- and high-degree regions of the brain. EOAD targets the global connectivity of the brain, mainly affecting the fiber density of high-degree (highly connected) regions that form the rich club network. These rich club analyses suggest distinct patterns of disruptions among different forms of dementia. PMID:26161050

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and CNS Homeostasis

PubMed Central

Tran, Khiem A.; Zhang, Xianming; Predescu, Dan; Huang, Xiaojia; Machado, Roberto F.; Göthert, Joachim R.; Malik, Asrar B.; Valyi-Nagy, Tibor; Zhao, You-Yang

2015-01-01

Background The blood-brain barrier (BBB) formed by brain endothelial cells (ECs) interconnected by tight junctions (TJs) is essential for the homeostasis of the central nervous system (CNS). Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results Using a mouse model with tamoxifen-inducible EC-restricted disruption of ctnnb1 (iCKO), here we show that endothelial β-catenin signaling is essential for maintaining BBB integrity and CNS homeostasis in adult. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and CNS inflammation, and all died postictal. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of specific TJ proteins Claudin-1 and -3 in adult brain ECs. The clinical relevance of the data is indicated by the observation of decreased expression of Claudin-1 and nuclear β-catenin in brain ECs of hemorrhagic lesions of hemorrhagic stroke patients. Conclusion These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity and CNS inflammation. PMID:26538583

Reduced Cortical Activity Impairs Development and Plasticity after Neonatal Hypoxia Ischemia

PubMed Central

Ranasinghe, Sumudu; Or, Grace; Wang, Eric Y.; Ievins, Aiva; McLean, Merritt A.; Niell, Cristopher M.; Chau, Vann; Wong, Peter K. H.; Glass, Hannah C.; Sullivan, Joseph

2015-01-01

Survivors of preterm birth are at high risk of pervasive cognitive and learning impairments, suggesting disrupted early brain development. The limits of viability for preterm birth encompass the third trimester of pregnancy, a “precritical period” of activity-dependent development characterized by the onset of spontaneous and evoked patterned electrical activity that drives neuronal maturation and formation of cortical circuits. Reduced background activity on electroencephalogram (EEG) is a sensitive marker of brain injury in human preterm infants that predicts poor neurodevelopmental outcome. We studied a rodent model of very early hypoxic–ischemic brain injury to investigate effects of injury on both general background and specific patterns of cortical activity measured with EEG. EEG background activity is depressed transiently after moderate hypoxia–ischemia with associated loss of spindle bursts. Depressed activity, in turn, is associated with delayed expression of glutamate receptor subunits and transporters. Cortical pyramidal neurons show reduced dendrite development and spine formation. Complementing previous observations in this model of impaired visual cortical plasticity, we find reduced somatosensory whisker barrel plasticity. Finally, EEG recordings from human premature newborns with brain injury demonstrate similar depressed background activity and loss of bursts in the spindle frequency band. Together, these findings suggest that abnormal development after early brain injury may result in part from disruption of specific forms of brain activity necessary for activity-dependent circuit development. SIGNIFICANCE STATEMENT Preterm birth and term birth asphyxia result in brain injury from inadequate oxygen delivery and constitute a major and growing worldwide health problem. Poor outcomes are noted in a majority of very premature (<25 weeks gestation) newborns, resulting in death or life-long morbidity with motor, sensory, learning, behavioral, and language disabilities that limit academic achievement and well-being. Limited progress has been made to develop therapies that improve neurologic outcomes. The overall objective of this study is to understand the effect of early brain injury on activity-dependent brain development and cortical plasticity to develop new treatments that will optimize repair and recovery after brain injury. PMID:26311776

Blood-Brain Barrier Breakdown Following Traumatic Brain Injury: A Possible Role in Posttraumatic Epilepsy

PubMed Central

Tomkins, Oren; Feintuch, Akiva; Benifla, Moni; Cohen, Avi; Friedman, Alon; Shelef, Ilan

2011-01-01

Recent animal experiments indicate a critical role for opening of the blood-brain barrier (BBB) in the pathogenesis of post-traumatic epilepsy (PTE). This study aimed to investigate the frequency, extent, and functional correlates of BBB disruption in epileptic patients following mild traumatic brain injury (TBI). Thirty-seven TBI patients were included in this study, 19 of whom suffered from PTE. All underwent electroencephalographic (EEG) recordings and brain magnetic resonance imaging (bMRI). bMRIs were evaluated for BBB disruption using novel quantitative techniques. Cortical dysfunction was localized using standardized low-resolution brain electromagnetic tomography (sLORETA). TBI patients displayed significant EEG slowing compared to controls with no significant differences between PTE and nonepileptic patients. BBB disruption was found in 82.4% of PTE compared to 25% of non-epileptic patients (P = .001) and could be observed even years following the trauma. The volume of cerebral cortex with BBB disruption was significantly larger in PTE patients (P = .001). Slow wave EEG activity was localized to the same region of BBB disruption in 70% of patients and correlated to the volume of BBB disrupted cortex. We finally present a patient suffering from early cortical dysfunction and BBB breakdown with a gradual and parallel resolution of both pathologies. Our findings demonstrate that BBB pathology is frequently found following mild TBI. Lasting BBB breakdown is found with increased frequency and extent in PTE patients. Based on recent animal studies and the colocalization found between the region of disrupted BBB and abnormal EEG activity, we suggest a role for a vascular lesion in the pathogenesis of PTE. PMID:21436875

PPAR agonist-mediated protection against HIV Tat-induced cerebrovascular toxicity is enhanced in MMP-9-deficient mice

PubMed Central

Huang, Wen; Chen, Lei; Zhang, Bei; Park, Minseon; Toborek, Michal

2014-01-01

The strategies to protect against the disrupted blood–brain barrier (BBB) in HIV-1 infection are not well developed. Therefore, we investigated the potential of peroxisome proliferator-activated receptor (PPAR) agonists to prevent enhanced BBB permeability induced by HIV-1-specific protein Tat. Exposure to Tat via the internal carotid artery (ICA) disrupted permeability across the BBB; however, this effect was attenuated in mice treated with fenofibrate (PPARα agonist) or rosiglitazone (PPARγ agonist). In contrast, exposure to GW9662 (PPARγ antagonist) exacerbated Tat-induced disruption of the BBB integrity. Increased BBB permeability was associated with decreased tight junction (TJ) protein expression and activation of ERK1/2 and Akt in brain microvessels; these effects were attenuated by cotreatment with fenofibrate but not with rosiglitazone. Importantly, both PPAR agonists also protected against Tat-induced astrogliosis and neuronal loss. Because disruption of TJ integrity has been linked to matrix metalloproteinase (MMP) activity, we also evaluated Tat-induced effects in MMP-9-deficient mice. Tat-induced cerebrovascular toxicity, astrogliosis, and neuronal loss were less pronounced in MMP-9-deficient mice as compared with wild-type controls and were further attenuated by PPAR agonists. These results indicate that enhancing PPAR activity combined with targeting MMPs may provide effective therapeutic strategies in brain infection by HIV-1. PMID:24424383

The developmental disruptions of serotonin signaling may involved in autism during early brain development.

PubMed

Yang, C-J; Tan, H-P; Du, Y-J

2014-05-16

Autism is a developmental disorder defined by the presence of a triad of communication, social and stereo typical behavioral characteristics with onset before 3years of age. In spite of the fact that there are potential environmental factors for autistic behavior, the dysfunction of serotonin during early development of the brain could be playing a role in this prevalence rise. Serotonin can modulate a number of developmental events, including cell division, neuronal migration, cell differentiation and synaptogenesis. Hyperserotonemia during fetal development results in the loss of serotonin terminals through negative feedback. The increased serotonin causes a decrease of oxytocin in the paraventricular nucleus of the hypothalamus and an increase in calcitonin gene-related peptide (CGRP) in the central nucleus of the amygdale, which are associated with social interactions and vital in autism. However, hyposerotonemia may be also relevant to the development of sensory as well as motor and cognitive faculties. And the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. This review briefly summarized the developmental disruptions of serotonin signaling involved in the pathogenesis of autism during early development of the brain. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Invasion of Peripheral Immune Cells into Brain Parenchyma after Cardiac Arrest and Resuscitation.

PubMed

Zhang, Can; Brandon, Nicole R; Koper, Kerryann; Tang, Pei; Xu, Yan; Dou, Huanyu

2018-06-01

Although a direct link has long been suspected between systemic immune responses and neuronal injuries after stroke, it is unclear which immune cells play an important role. A question remains as to whether the blood brain barrier (BBB) is transiently disrupted after circulatory arrest to allow peripheral immune cells to enter brain parenchyma. Here, we developed a clinically relevant cardiac arrest and resuscitation model in mice to investigate the BBB integrity using noninvasive magnetic resonance imaging. Changes in immune signals in the brain and periphery were assayed by immunohistochemistry and flow cytometry. Quantitative variance maps from T1-weighted difference images before and after blood-pool contrast clearance revealed BBB disruptions immediately after resuscitation and one day after reperfusion. Time profiles of hippocampal CA1 neuronal injuries correlated with the morphological changes of microglia activation. Cytotoxic T cells, CD11b + CD11c + dendritic cells, and CD11b + CD45 +hi monocytes and macrophages were significantly increased in the brain three days after cardiac arrest and resuscitation, suggesting direct infiltration of these cells following the BBB disruption. Importantly, these immune cell changes were coupled with a parallel increase in the same subset of immune cell populations in the bone marrow and blood. We conclude that neurovascular breakdown during the initial reperfusion phase contributes to the systemic immune cell invasion and subsequent neuropathogenesis affecting the long-term outcome after cardiac arrest and resuscitation.

PROVIDING A BETTER UNDERSTANDING OF THE SCIENCE UNDERLYING THE EFFECTS, EXPOSURE, ASSESSMENT, AND MANAGEMENT OF EDCS: DOES MILD HYPOTHYROIDISM INDUCED BY ENVIRONMENTAL CONTAMINANTS IRREVERSIBLY ALTER CNS FUNCTION IN THE JUVENILE AND ADULT ANIMAL?

EPA Science Inventory

SUMMARY: The NTD research project on Endocrine-Disrupting Chemicals (EDC) is focused on the effects of thyroid hormone (TH) deficiencies on the developing brain and is one component of a larger NHEERL research program evaluating androgen, estrogen, and thyroid-disrupting chemical...

Blockade of AT1 Receptors Protects the Blood–Brain Barrier and Improves Cognition in Dahl Salt-Sensitive Hypertensive Rats

PubMed Central

Pelisch, Nicolas; Hosomi, Naohisa; Ueno, Masaki; Nakano, Daisuke; Hitomi, Hirofumi; Mogi, Masaki; Shimada, Kenji; Kobori, Hiroyuki; Horiuchi, Masatsugu; Sakamoto, Haruhiko; Matsumoto, Masayasu; Kohno, Masakazu; Nishiyama, Akira

2011-01-01

BACKGROUND The present study tested the hypothesis that inappropriate activation of the brain renin–angiotensin system (RAS) contributes to the pathogenesis of blood–brain barrier (BBB) disruption and cognitive impairment during development of salt-dependent hypertension. Effects of an angiotensin II (AngII) type-1 receptor blocker (ARB), at a dose that did not reduce blood pressure, were also examined. METHODS Dahl salt-sensitive (DSS) rats at 6 weeks of age were assigned to three groups: low-salt diet (DSS/L; 0.3% NaCl), high-salt diet (DSS/H; 8% NaCl), and high-salt diet treated with ARB, olmesartan at 1 mg/kg. RESULTS DSS/H rats exhibited hypertension, leakage from brain microvessels in the hippocampus, and impaired cognitive functions, which were associated with increased brain AngII levels, as well as decreased mRNA levels of tight junctions (TJs) and collagen-IV in the hippocampus. In DSS/H rats, olmesartan treatment, at a dose that did not alter blood pressure, restored the cognitive decline, and ameliorated leakage from brain microvessels. Olmesartan also decreased brain AngII levels and restored mRNA expression of TJs and collagen-IV in DSS/H rats. CONCLUSIONS These results suggest that during development of salt-dependent hypertension, activation of the brain RAS contributes to BBB disruption and cognitive impairment. Treatment with an ARB could elicit neuroprotective effects in cognitive disorders by preventing BBB permeability, which is independent of blood pressure changes. PMID:21164491

Early brain injury alters the blood-brain barrier phenotype in parallel with β-amyloid and cognitive changes in adulthood.

PubMed

Pop, Viorela; Sorensen, Dane W; Kamper, Joel E; Ajao, David O; Murphy, M Paul; Head, Elizabeth; Hartman, Richard E; Badaut, Jérôme

2013-02-01

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 processes by examining long-term alterations of BBB proteins, β-amyloid (Aβ) neuropathology, and cognitive changes. A controlled cortical impact was delivered to the parietal cortex of male rats at postnatal day 17, with behavioral studies and brain tissue evaluation at 60 days post-injury (dpi). Immunoglobulin G extravasation was unchanged, and jTBI animals had higher levels of tight-junction protein claudin 5 versus shams, suggesting the absence of BBB disruption. However, decreased P-glycoprotein (P-gp) on cortical blood vessels indicates modifications of BBB properties. In parallel, we observed higher levels of endogenous rodent Aβ in several brain regions of the jTBI group versus shams. In addition at 60 dpi, jTBI animals displayed systematic search strategies rather than relying on spatial memory during the water maze. Together, these alterations to the BBB phenotype after jTBI may contribute to the accumulation of toxic products, which in turn may induce cognitive differences and ultimately accelerate brain aging.

Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion.

PubMed

Lin, Mingyan; Pedrosa, Erika; Hrabovsky, Anastasia; Chen, Jian; Puliafito, Benjamin R; Gilbert, Stephanie R; Zheng, Deyou; Lachman, Herbert M

2016-11-15

Individuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in early differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients. Eight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subjected to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. Lastly, we related our findings from in vitro neuronal cultures to brain development by mapping differentially expressed genes to BrainSpan transcriptomes. We observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value < 0.05, 36 of which reached a false discovery rate < 0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p < 0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples. By leveraging transcriptome profiles of normal human brain tissues across human development into adulthood, we showed that the differentially expressed genes converge on a sub-network mediated by CDC45 and the cell cycle, which would be disrupted by the 22q11.2 deletion during embryonic brain development, and another sub-network modulated by PRODH, which could contribute to disruption of brain function during adolescence. This study has provided evidence for disruption of potential molecular events in SZ patient with 22q11.2 deletion and related our findings from in vitro neuronal cultures to functional perturbations that can occur during brain development in SZ.

Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.

PubMed

Wardill, Hannah R; Mander, Kimberley A; Van Sebille, Ysabella Z A; Gibson, Rachel J; Logan, Richard M; Bowen, Joanne M; Sonis, Stephen T

2016-12-15

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity. © 2016 UICC.

Epigenetic impacts of endocrine disruptors in the brain☆

PubMed Central

Walker, Deena M.; Gore, Andrea C.

2017-01-01

The acquisition of reproductive competence is organized and activated by steroid hormones acting upon the hypothalamus during critical windows of development. This review describes the potential role of epigenetic processes, particularly DNA methylation, in the regulation of sexual differentiation of the hypothalamus by hormones. We examine disruption of these processes by endocrine-disrupting chemicals (EDCs) in an age-, sex-, and region-specific manner, focusing on how perinatal EDCs act through epigenetic mechanisms to reprogram DNA methylation and sex steroid hormone receptor expression throughout life. These receptors are necessary for brain sexual differentiation and their altered expression may underlie disrupted reproductive physiology and behavior. Finally, we review the literature on histone modifications and non-coding RNA involvement in brain sexual differentiation and their perturbation by EDCs. By putting these data into a sex and developmental context we conclude that perinatal EDC exposure alters the developmental trajectory of reproductive neuroendocrine systems in a sex-specific manner. PMID:27663243

Developmental Thyroid Hormone Disruption: Prevalence, Environmental Contaminants and Neurodevelopmental Consequences

EPA Science Inventory

Thyroid hormones (TH) are critical for growth and development and particularly brain development. There are numerous environmental agents that lead to marginal reductions of circulating TH. Although it is clear that severe developmental hypothyroidism is profoundly detrimental to...

The Rich Get Richer: Brain Injury Elicits Hyperconnectivity in Core Subnetworks

PubMed Central

Hillary, Frank G.; Rajtmajer, Sarah M.; Roman, Cristina A.; Medaglia, John D.; Slocomb-Dluzen, Julia E.; Calhoun, Vincent D.; Good, David C.; Wylie, Glenn R.

2014-01-01

There remains much unknown about how large-scale neural networks accommodate neurological disruption, such as moderate and severe traumatic brain injury (TBI). A primary goal in this study was to examine the alterations in network topology occurring during the first year of recovery following TBI. To do so we examined 21 individuals with moderate and severe TBI at 3 and 6 months after resolution of posttraumatic amnesia and 15 age- and education-matched healthy adults using functional MRI and graph theoretical analyses. There were two central hypotheses in this study: 1) physical disruption results in increased functional connectivity, or hyperconnectivity, and 2) hyperconnectivity occurs in regions typically observed to be the most highly connected cortical hubs, or the “rich club”. The current findings generally support the hyperconnectivity hypothesis showing that during the first year of recovery after TBI, neural networks show increased connectivity, and this change is disproportionately represented in brain regions belonging to the brain's core subnetworks. The selective increases in connectivity observed here are consistent with the preferential attachment model underlying scale-free network development. This study is the largest of its kind and provides the unique opportunity to examine how neural systems adapt to significant neurological disruption during the first year after injury. PMID:25121760

The rich get richer: brain injury elicits hyperconnectivity in core subnetworks.

PubMed

Hillary, Frank G; Rajtmajer, Sarah M; Roman, Cristina A; Medaglia, John D; Slocomb-Dluzen, Julia E; Calhoun, Vincent D; Good, David C; Wylie, Glenn R

2014-01-01

There remains much unknown about how large-scale neural networks accommodate neurological disruption, such as moderate and severe traumatic brain injury (TBI). A primary goal in this study was to examine the alterations in network topology occurring during the first year of recovery following TBI. To do so we examined 21 individuals with moderate and severe TBI at 3 and 6 months after resolution of posttraumatic amnesia and 15 age- and education-matched healthy adults using functional MRI and graph theoretical analyses. There were two central hypotheses in this study: 1) physical disruption results in increased functional connectivity, or hyperconnectivity, and 2) hyperconnectivity occurs in regions typically observed to be the most highly connected cortical hubs, or the "rich club". The current findings generally support the hyperconnectivity hypothesis showing that during the first year of recovery after TBI, neural networks show increased connectivity, and this change is disproportionately represented in brain regions belonging to the brain's core subnetworks. The selective increases in connectivity observed here are consistent with the preferential attachment model underlying scale-free network development. This study is the largest of its kind and provides the unique opportunity to examine how neural systems adapt to significant neurological disruption during the first year after injury.

Toward a conceptual framework for early brain and behavior development in autism

PubMed Central

Piven, J; Elison, J T; Zylka, M J

2017-01-01

Studies of infant siblings of older autistic probands, who are at elevated risk for autism, have demonstrated that the defining features of autism are not present in the first year of life but emerge late in the first and into the second year. A recent longitudinal neuroimaging study of high-risk siblings revealed a specific pattern of brain development in infants later diagnosed with autism, characterized by cortical surface area hyper-expansion in the first year followed by brain volume overgrowth in the second year that is associated with the emergence of autistic social deficits. Together with new observations from genetically defined autism risk alleles and rodent model, these findings suggest a conceptual framework for the early, post-natal development of autism. This framework postulates that an increase in the proliferation of neural progenitor cells and hyper-expansion of cortical surface area in the first year, occurring during a pre-symptomatic period characterized by disrupted sensorimotor and attentional experience, leads to altered experience-dependent neuronal development and decreased elimination of neuronal processes. This process is linked to brain volume overgrowth and disruption of the refinement of neural circuit connections and is associated with the emergence of autistic social deficits in the second year of life. A better understanding of the timing of developmental brain and behavior mechanisms in autism during infancy, a period which precedes the emergence of the defining features of this disorder, will likely have important implications for designing rational approaches to early intervention. PMID:28937691

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis.

PubMed

Tran, Khiem A; Zhang, Xianming; Predescu, Dan; Huang, Xiaojia; Machado, Roberto F; Göthert, Joachim R; Malik, Asrar B; Valyi-Nagy, Tibor; Zhao, You-Yang

2016-01-12

The blood-brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Using a mouse model with tamoxifen-inducible endothelial cell-restricted disruption of ctnnb1 (iCKO), we show here that endothelial β-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear β-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients. These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation. © 2015 American Heart Association, Inc.

L-NAME reduces infarction, neurological deficit and blood-brain barrier disruption following cerebral ischemia in mice.

PubMed

Ding-Zhou, Li; Marchand-Verrecchia, Catherine; Croci, Nicole; Plotkine, Michel; Margaill, Isabelle

2002-12-20

The role of nitric oxide (NO) in the development of post-ischemic cerebral infarction has been extensively examined, but fewer studies have investigated its role in other outcomes. In the present study, we first determined the temporal evolution of infarct volume, NO production, neurological deficit and blood-brain barrier disruption in a model of transient focal cerebral ischemia in mice. We then examined the effect of the nonselective NO-synthase inhibitor N(omega)-nitro-L-arginine-methylester (L-NAME). L-NAME given at 3 mg/kg 3 h after ischemia reduced by 20% the infarct volume and abolished the increase in brain NO production evaluated by its metabolites (nitrites/nitrates) 48 h after ischemia. L-NAME with this protocol also reduced the neurological deficit evaluated by the grip test and decreased by 65% the extravasation of Evans blue, an index of blood-brain barrier breakdown. These protective activities of L-NAME suggest that NO has multiple deleterious effects in cerebral ischemia.

Cocaine-Induced Neurodevelopmental Deficits and Underlying Mechanisms

PubMed Central

Martin, Melissa M.; Graham, Devon L.; McCarthy, Deirdre M.; Bhide, Pradeep G.; Stanwood, Gregg D.

2017-01-01

Exposure to drugs early in life has complex and long-lasting implications for brain structure and function. This review summarizes work to date on the immediate and long-term effects of prenatal exposure to cocaine. In utero cocaine exposure produces disruptions in brain monoamines, particularly dopamine, during sensitive periods of brain development, and leads to permanent changes in specific brain circuits, molecules, and behavior. Here, we integrate clinical studies and significance with mechanistic preclinical studies, to define our current knowledge base and identify gaps for future investigation. PMID:27345015

Attenuating Ischemic Disruption of K+ Homeostasis in the Cortex of Hypoxic-Ischemic Neonatal Rats: DOR Activation vs. Acupuncture Treatment.

PubMed

Chao, Dongman; Wang, Qinyu; Balboni, Gianfranco; Ding, Guanghong; Xia, Ying

2016-12-01

Perinatal hypoxic-ischemic (HI) brain injury results in death or profound long-term neurologic disability in both children and adults. However, there is no effective pharmacological therapy due to a poor understanding of HI events, especially the initial triggers for hypoxic-ischemic injury such as disrupted ionic homeostasis and the lack of effective intervention strategy. In the present study, we showed that neonatal brains undergo a developmental increase in the disruption of K + homeostasis during simulated ischemia, oxygen-glucose deprivation (OGD) and neonatal HI cortex has a triple phasic response (earlier attenuation, later enhancement, and then recovery) of disrupted K + homeostasis to OGD. This response partially involves the activity of the δ-opioid receptor (DOR) since the earlier attenuation of ischemic disruption of K + homeostasis could be blocked by DOR antagonism, while the later enhancement was reversed by DOR activation. Similar to DOR activation, acupuncture, a strategy to promote DOR activity, could partially reverse the later enhanced ischemic disruption of K + homeostasis in the neonatal cortex. Since maintaining cellular K + homeostasis and inhibiting excessive K + fluxes in the early phase of hypoxic-ischemic insults may be of therapeutic benefit in the treatment of ischemic brain injury and related neurodegenerative conditions, and since many neurons and other cells can be rescued during the "window of opportunity" after HI insults, our first findings regarding the role of acupuncture and DOR in attenuating ischemic disruption of K + homeostasis in the neonatal HI brain suggest a potential intervention therapy in the treatment of neonatal brain injury, especially hypoxic-ischemic encephalopathy.

Reduced integration and improved segregation of functional brain networks in Alzheimer’s disease

NASA Astrophysics Data System (ADS)

Kabbara, A.; Eid, H.; El Falou, W.; Khalil, M.; Wendling, F.; Hassan, M.

2018-04-01

Objective. Emerging evidence shows that cognitive deficits in Alzheimer’s disease (AD) are associated with disruptions in brain functional connectivity. Thus, the identification of alterations in AD functional networks has become a topic of increasing interest. However, to what extent AD induces disruption of the balance of local and global information processing in the human brain remains elusive. The main objective of this study is to explore the dynamic topological changes of AD networks in terms of brain network segregation and integration. Approach. We used electroencephalography (EEG) data recorded from 20 participants (10 AD patients and 10 healthy controls) during resting state. Functional brain networks were reconstructed using EEG source connectivity computed in different frequency bands. Graph theoretical analyses were performed assess differences between both groups. Main results. Results revealed that AD networks, compared to networks of age-matched healthy controls, are characterized by lower global information processing (integration) and higher local information processing (segregation). Results showed also significant correlation between the alterations in the AD patients’ functional brain networks and their cognitive scores. Significance. These findings may contribute to the development of EEG network-based test that could strengthen results obtained from currently-used neurophysiological tests in neurodegenerative diseases.

Reduced integration and improved segregation of functional brain networks in Alzheimer's disease.

PubMed

Kabbara, A; Eid, H; El Falou, W; Khalil, M; Wendling, F; Hassan, M

2018-04-01

Emerging evidence shows that cognitive deficits in Alzheimer's disease (AD) are associated with disruptions in brain functional connectivity. Thus, the identification of alterations in AD functional networks has become a topic of increasing interest. However, to what extent AD induces disruption of the balance of local and global information processing in the human brain remains elusive. The main objective of this study is to explore the dynamic topological changes of AD networks in terms of brain network segregation and integration. We used electroencephalography (EEG) data recorded from 20 participants (10 AD patients and 10 healthy controls) during resting state. Functional brain networks were reconstructed using EEG source connectivity computed in different frequency bands. Graph theoretical analyses were performed assess differences between both groups. Results revealed that AD networks, compared to networks of age-matched healthy controls, are characterized by lower global information processing (integration) and higher local information processing (segregation). Results showed also significant correlation between the alterations in the AD patients' functional brain networks and their cognitive scores. These findings may contribute to the development of EEG network-based test that could strengthen results obtained from currently-used neurophysiological tests in neurodegenerative diseases.

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism.

PubMed

Ferris, Heather A; Perry, Rachel J; Moreira, Gabriela V; Shulman, Gerald I; Horton, Jay D; Kahn, C Ronald

2017-01-31

Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

PubMed Central

Ferris, Heather A.; Perry, Rachel J.; Moreira, Gabriela V.; Shulman, Gerald I.; Horton, Jay D.; Kahn, C. Ronald

2017-01-01

Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function. PMID:28096339

Sleep in adolescence: physiology, cognition and mental health

PubMed Central

Tarokh, Leila; Saletin, Jared M.; Carskadon, Mary A.

2016-01-01

Sleep is a core behavior of adolescents, consuming up to a third or more of each day. As part of this special issue on the adolescent brain, we review changes to sleep behaviors and sleep physiology during adolescence with a particular focus on the sleeping brain. We posit that brain activity during sleep may provide a unique window onto adolescent cortical maturation and compliment waking measures. In addition, we review how sleep actively supports waking cognitive functioning in adolescence. Though this review is focused on sleep in healthy adolescents, the striking comorbidity of sleep disruption with nearly all psychiatric and developmental disorders (for reviews see 1,2) further highlights the importance of understanding the determinants and consequences of adolescent sleep for the developing brain. Figure 1 illustrates the overarching themes of our review, linking brain development, sleep development, and behavioral outcomes. PMID:27531236

Is the ferret a suitable species for studying perinatal brain injury?

PubMed Central

Empie, Kristen; Rangarajan, Vijayeta; Juul, Sandra E.

2016-01-01

Complications of prematurity often disrupt normal brain development and/or cause direct damage to the developing brain, resulting in poor neurodevelopmental outcomes. Physiologically relevant animal models of perinatal brain injury can advance our understanding of these influences and thereby provide opportunities to develop therapies and improve long-term outcomes. While there are advantages to currently available small animal models, there are also significant drawbacks that have limited translation of research findings to humans. Large animal models such as newborn pig, sheep and nonhuman primates have complex brain development more similar to humans, but these animals are expensive, and developmental testing of sheep and piglets is limited. Ferrets (Mustela putorius furo) are born lissencephalic and undergo postnatal cortical folding to form complex gyrencephalic brains. This review examines whether ferrets might provide a novel intermediate animal model of neonatal brain disease that has the benefit of a gyrified, altricial brain in a small animal. It summarizes attributes of ferret brain growth and development that make it an appealing animal in which to model perinatal brain injury. We postulate that because of their innate characteristics, ferrets have great potential in neonatal neurodevelopmental studies. PMID:26102988

Bisphenol S (BPS) Alters Maternal Behavior and Brain in Mice Exposed During Pregnancy/Lactation and Their Daughters

PubMed Central

Catanese, Mary C.

2017-01-01

Estrogenic endocrine disrupting chemicals have been shown to disrupt maternal behavior in rodents. We investigated the effects of an emerging xenoestrogen, bisphenol S (BPS), on maternal behavior and brain in CD-1 mice exposed during pregnancy and lactation (F0 generation) and in female offspring exposed during gestation and perinatal development (F1 generation). We observed different effects in F0 and F1 dams for a number of components of maternal behavior, including time on the nest, time spent on nest building, latency to retrieve pups, and latency to retrieve the entire litter. We also characterized expression of estrogen receptor α in the medial preoptic area (MPOA) and quantified tyrosine hydroxylase immunoreactive cells in the ventral tegmental area, 2 brain regions critical for maternal care. BPS-treated females in the F0 generation had a statistically significant increase in estrogen receptor α expression in the caudal subregion of the central MPOA in a dose-dependent manner. In contrast, there were no statistically significant effects of BPS on the MPOA in F1 dams or the ventral tegmental area in either generation. This work demonstrates that BPS affects maternal behavior and brain with outcomes depending on generation, dose, and postpartum period. Many studies examining effects of endocrine disrupting chemicals view the mother as a means by which offspring can be exposed during critical periods of development. Here, we demonstrate that pregnancy and lactation are vulnerable periods for the mother. We also show that developmental BPS exposure alters maternal behavior later in adulthood. Both findings have potential public health implications. PMID:28005399

Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

NASA Astrophysics Data System (ADS)

Cho, Hongseok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-Ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

2016-08-01

Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway

PubMed Central

Lim, Sanghee; Kwak, Minhye; Gray, Christy D.; Xu, Michael; Choi, Jun H.; Junn, Sue; Kim, Jieun; Xu, Jing; Schaefer, Michele; Johns, Roger A.; Song, Hongjun; Ming, Guo-Li; Mintz, C. David

2017-01-01

Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition. PMID:28683067

Disorganized Cortical Patches Suggest Prenatal Origin of Autism

MedlinePlus

... 2014 Disorganized cortical patches suggest prenatal origin of autism NIH-funded study shows disrupted cell layering process ... study suggests that brain irregularities in children with autism can be traced back to prenatal development. “While ...

A Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Glia

PubMed Central

Bilbo, Staci D.; Smith, Susan H.; Schwarz, Jaclyn M.

2011-01-01

Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual‘s risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or “re-programming” of this crucial process by external events (e.g, stress, infection). An impact on glia, which in turn alters neural development, has the capacity to profoundly impact cognitive and mental health function at all stages of life. PMID:21822589

The Emerging Relationship Between Interstitial Fluid-Cerebrospinal Fluid Exchange, Amyloid-β, and Sleep.

PubMed

Boespflug, Erin L; Iliff, Jeffrey J

2018-02-15

Amyloid-β (Aβ) plaques are a key histopathological hallmark of Alzheimer's disease (AD), and soluble Aβ species are believed to play an important role in the clinical development of this disease. Emerging biomarker data demonstrate that Aβ plaque deposition begins decades before the onset of clinical symptoms, suggesting that understanding the biological determinants of the earliest steps in the development of AD pathology may provide key opportunities for AD treatment and prevention. Although a clinical association between sleep disruption and AD has long been appreciated, emerging clinical studies and insights from the basic neurosciences have shed important new light on how sleep and Aβ homeostasis may be connected in the setting of AD. Aβ, like many interstitial solutes, is cleared in part through the exchange of brain interstitial fluid and cerebrospinal fluid along a brain-wide network of perivascular pathways recently termed the glymphatic system. Glymphatic function is primarily a feature of the sleeping brain, rather than the waking brain, and is slowed in the aging and posttraumatic brain. These changes may underlie the diurnal fluctuations in interstitial and cerebrospinal fluid Aβ levels observed in both the rodent and the human. These and other emerging studies suggest that age-related sleep disruption may be one key factor that renders the aging brain vulnerable to Aβ deposition and the development of AD. If this is true, sleep may represent a key modifiable risk factor or therapeutic target in the preclinical phases of AD. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Brain and retinal ferroportin 1 dysregulation in polycythaemia mice.

PubMed

Iacovelli, Jared; Mlodnicka, Agnieska E; Veldman, Peter; Ying, Gui-Shuang; Dunaief, Joshua L; Schumacher, Armin

2009-09-15

Disruption of iron homeostasis within the central nervous system (CNS) can lead to profound abnormalities during both development and aging in mammals. The radiation-induced polycythaemia (Pcm) mutation, a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), disrupts transcriptional and post-transcriptional regulation of this pivotal iron transporter. This regulatory mutation induces dynamic alterations in peripheral iron homeostasis such that newborn homozygous Pcm mice exhibit iron deficiency anemia with increased duodenal Fpn1 expression while adult homozygotes display decreased Fpn1 expression and anemia despite organismal iron overload. Herein we report the impact of the Pcm microdeletion on iron homeostasis in two compartments of the central nervous system: brain and retina. At birth, Pcm homozygotes show a marked decrease in brain iron content and reduced levels of Fpn1 expression. Upregulation of transferrin receptor 1 (TfR1) in brain microvasculature appears to mediate the compensatory iron uptake during postnatal development and iron content in Pcm brain is restored to wild-type levels by 7 weeks of age. Similarly, changes in expression are transient and expression of Fpn1 and TfR1 is indistinguishable between Pcm homozygotes and wild-type by 12 weeks of age. Strikingly, the adult Pcm brain is effectively protected from the peripheral iron overload and maintains normal iron content. In contrast to Fpn1 downregulation in perinatal brain, the retina of Pcm homozygotes reveals increased levels of Fpn1 expression. While retinal morphology appears normal at birth and during early postnatal development, adult Pcm mice demonstrate a marked, age-dependent loss of photoreceptors. This phenotype demonstrates the importance of iron homeostasis in retinal health.

Brain and retinal ferroportin 1 dysregulation in polycythaemia mice

PubMed Central

Iacovelli, Jared; Mlodnicka, Agnieska E.; Veldman, Peter; Ying, Gui-Shuang; Dunaief, Joshua L.; Schumacher, Armin

2009-01-01

Disruption of iron homeostatsis within the central nervous system (CNS) can lead to profound abnormalities during both development and aging in mammals. The radiation-induced polycythaemia (Pcm) mutation, a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), disrupts transcriptional and post-transcriptional regulation of this pivotal iron transporter. This regulatory mutation induces dynamic alterations in peripheral iron homeostatis such that newborn homozygous Pcm mice exhibit iron deficiency anemia with increased duodenal Fpn1 expression while adult homozygotes display decreased Fpn1 expression and anemia despite organismal iron overload. Herein we report the impact of the Pcm microdeletion on iron homeostasis in two compartments of the the central nervous system: brain and retina. At birth, Pcm homozygotes show a marked decrease in brain iron content and reduced levels of Fpn1 expression. Upregulation of transferrin receptor 1 (TfR1) in brain microvasculature appears to mediate the compensatory iron uptake during postnatal development and iron content in Pcm brain is restored to wildtype levels by 7 weeks of age. Similarly, changes in expression are transient and expression of Fpn1 and TfR1 is indistinguishable between Pcm homozygotes and wildtype by 12 weeks of age. Strikingly, the adult Pcm brain is effectively protected from the peripheral iron overload and maintains normal iron content. In contrast to Fpn1 downregulation in perinatal brain, the retina of Pcm homozygotes reveals increased levels of Fpn1 expression. While retinal morphology appears normal at birth and during early postnatal development, adult Pcm mice demonstrate a marked, age-dependent loss of photoreceptors. This phenotype demonstrates the importance of iron homeostasis in retinal health. PMID:19596281

Alterations in the Vaginal Microbiome by Maternal Stress Are Associated With Metabolic Reprogramming of the Offspring Gut and Brain.

PubMed

Jašarević, Eldin; Howerton, Christopher L; Howard, Christopher D; Bale, Tracy L

2015-09-01

The neonate is exposed to the maternal vaginal microbiota during parturition, providing the primary source for normal gut colonization, host immune maturation, and metabolism. These early interactions between the host and microbiota occur during a critical window of neurodevelopment, suggesting early life as an important period of cross talk between the developing gut and brain. Because perturbations in the prenatal environment such as maternal stress increase neurodevelopmental disease risk, disruptions to the vaginal ecosystem could be a contributing factor in significant and long-term consequences for the offspring. Therefore, to examine the hypothesis that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota and on the developing brain, we used genomic, proteomic and metabolomic technologies to examine outcomes in our mouse model of early prenatal stress. Multivariate modeling identified broad proteomic changes to the maternal vaginal environment that influence offspring microbiota composition and metabolic processes essential for normal neurodevelopment. Maternal stress altered proteins related to vaginal immunity and abundance of Lactobacillus, the prominent taxa in the maternal vagina. Loss of maternal vaginal Lactobacillus resulted in decreased transmission of this bacterium to offspring. Further, altered microbiota composition in the neonate gut corresponded with changes in metabolite profiles involved in energy balance, and with region- and sex-specific disruptions of amino acid profiles in the developing brain. Taken together, these results identify the vaginal microbiota as a novel factor by which maternal stress may contribute to reprogramming of the developing brain that may predispose individuals to neurodevelopmental disorders.

ENDOCRINE DISRUPTORS AS A THREAT TO NEUROLOGICAL FUNCTION

PubMed Central

Weiss, Bernard

2011-01-01

Endocrine disruption is a concept and principle whose origins can be traced to the beginnings of the environmental movement in the 1960s. It began with puzzlement about and the flaring of research on the decline of wildlife, particularly avian species. The proposed causes accented pesticides, especially persistent organochlorines such as DDT. Its scope gradually widened beyond pesticides, and, as endocrine disruption offered an explanation for the wildlife phenomena, it seemed to explain, as well, changes in fertility and disorders of male reproduction such as testicular cancer. Once disturbed gonadal hormone function became the most likely explanation, it provoked other questions. The most challenging arose because of how critical gonadal hormones are to brain function, especially as determinants of brain sexual differentiation. Pursuit of such connections has generated a robust literature embracing a broad swath of chemical classes. How endocrine disrupting chemicals influence the adult and aging brain is a question, so far mostly ignored because of the emphasis on early development, that warrants vigorous investigation. Gonadal hormones are crucial to optimal brain function during maturity and even senescence. They are pivotal to the processes of neurogenesis. They exert protective actions against neurodegenerative disorders such as dementia and support smoothly functioning cognitive activities. The limited research conducted so far on endocrine disruptors, aging, and neurogenesis argues that they should be overlooked no longer. PMID:21474148

Growth and development of the brain and impact on cognitive outcomes.

PubMed

Hüppi, Petra S

2010-01-01

Understanding human brain development from the fetal life to adulthood is of great clinical importance as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral maturation. The developing brain is particularly prone to being affected by endogenous and exogenous events through the fetal and early postnatal life. The concept of 'developmental plasticity or disruption of the developmental program' summarizes these events. Increases in white matter, which speed up communication between brain cells, growing complexity of neuronal networks suggested by gray and white matter changes, and environmentally sensitive plasticity are all essential aspects in a child's ability to mentalize and maintain the adaptive flexibility necessary for achieving high sociocognitive functioning. Advancement in neuroimaging has opened up new ways for examining the developing human brain in vivo, the study of the effects of early antenatal, perinatal and neonatal events on later structural and functional brain development resulting in developmental disabilities or developmental resilience. In this review, methods of quantitative assessment of human brain development, such as 3D-MRI with image segmentation, diffusion tensor imaging to assess connectivity and functional MRI to visualize brain function will be presented. Copyright (c) 2010 S. Karger AG, Basel.

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases.

PubMed

Preciados, Mark; Yoo, Changwon; Roy, Deodutta

2016-12-13

During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer's Disease (AD), Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD- APOE , APP , ATP5A1 , CALM1 , CASP3 , GSK3B , IL1B , MAPT , PSEN2 and TNF- underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2 , DPYSL2 , EIF2S1 , ENO1 , MAPT , and PAXIP1 . These genes are also responsive to the following EEDs: ethinyl estradiol ( APBB2 , DPYSL2 , EIF2S1 , ENO1 , MAPT , and PAXIP1 ), BPA ( APBB2 , EIF2S1 , ENO1 , MAPT , and PAXIP1 ), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate ( DPYSL2 and MAPT ). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes- APLP1 , APP , GRIN1 , GRIN2B , MAPT , PSEN2 , PEN2 , and IDE -are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders.

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor

PubMed Central

Shaltiel-Karyo, Ronit; Frenkel-Pinter, Moran; Rockenstein, Edward; Patrick, Christina; Levy-Sakin, Michal; Schiller, Abigail; Egoz-Matia, Nirit; Masliah, Eliezer; Segal, Daniel; Gazit, Ehud

2013-01-01

The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease. PMID:23637226

A blood-brain barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD).

PubMed

Shaltiel-Karyo, Ronit; Frenkel-Pinter, Moran; Rockenstein, Edward; Patrick, Christina; Levy-Sakin, Michal; Schiller, Abigail; Egoz-Matia, Nirit; Masliah, Eliezer; Segal, Daniel; Gazit, Ehud

2013-06-14

The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease.

Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound.

PubMed

Kobus, Thiele; Vykhodtseva, Natalia; Pilatou, Magdalini; Zhang, Yongzhi; McDannold, Nathan

2016-02-01

The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Systemic Prenatal Insults Disrupt Telencephalon Development

PubMed Central

Robinson, Shenandoah

2006-01-01

Infants born prematurely are prone to chronic neurologic deficits including cerebral palsy (CP), epilepsy, cognitive delay, behavioral problems, and neurosensory impairments. In affected children, imaging and neuropathological findings demonstrate significant damage to white matter. The extent of cortical damage has been less obvious. Advances in the understanding of telencephalon development provide insights into how systemic intrauterine insults affect the developing white matter, subplate and cortex, and lead to multiple neurologic impairments. In addition to white matter oligodendrocytes and axons, other elements at risk for perinatal brain injury include subplate neurons, GABAergic neurons migrating through white matter and subplate, and afferents of maturing neurotransmitter systems. Common insults including hypoxia-ischemia and infection often affect the developing brain differently than the mature brain, and insults precipitate a cascade of damage to multiple neural lineages. Insights from development can identify potential targets for therapies to repair the damaged neonatal brain before it has matured. PMID:16061421

Effects of deferoxamine on blood-brain barrier disruption after subarachnoid hemorrhage.

PubMed

Li, Yanjiang; Yang, Heng; Ni, Wei; Gu, Yuxiang

2017-01-01

Blood brain barrier (BBB) disruption is a key mechanism of subarachnoid hemorrhage (SAH)-induced brain injury. This study examined the mechanism of iron-induced BBB disruption after SAH and investigated the potential therapeutic effect of iron chelation on SAH. Male adult Sprague-Dawley rats had an endovascular perforation of left internal carotid artery bifurcation or sham operation. The rats were treated with deferoxamine (DFX) or vehicle (100mg/kg) for a maximum of 7 days. Brain edema, BBB leakage, behavioral and cognitive impairment were examined. In SAH rat, the peak time of brain edema and BBB impairment in the cortex was at day 3 after SAH. SAH resulted in a significant increase in ferritin expression in the cortex. The ferritin positive cells were colocalized with endothelial cells, pericytes, astrocytes, microglia and neurons. Compared with vehicle, DFX caused less ferritin upregulation, brain water content, BBB impairment, behavioral and cognitive deficits in SAH rats. The results suggest iron overload could be a therapeutic target for SAH induced BBB damage.

Cortical Volume and Developmental Instability Are Independent Predictors of General Intellectual Ability

ERIC Educational Resources Information Center

Thoma, Robert J.; Yeo, Ronald A.; Gangestad, Steven W.; Halgren, Eric; Sanchez, Natalie M.; Lewine, Jeffrey D.

2005-01-01

Measures of developmental instability (DI) reflect developmental disruptions due to genetic and environmental perturbations during normal development. DI might be expected to influence the developmental course of brain development and hence intelligence, and several studies indicate this to be the case. The factors that mediate this relationship…

The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood–brain barrier disruption: Implications for multiple sclerosis treatment

PubMed Central

Bourrié, Bernard; Bribes, Estelle; Esclangon, Martine; Garcia, Laurent; Marchand, Jean; Thomas, Corinne; Maffrand, Jean-Pierre; Casellas, Pierre

1999-01-01

Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is a widely used animal model for multiple sclerosis (MS) and, as in MS, clinical signs of EAE are associated with blood–brain barrier (BBB) disruption. SR 57746A, a nonpeptide drug without classical immunosuppressive properties, efficiently protected the BBB and impaired intrathecal IgG synthesis (two conventional markers of MS exacerbation) and consequently suppressed EAE clinical signs. This compound inhibited EAE-induced spinal cord mononuclear cell invasion and normalized tumor necrosis factor α and IFN-γ mRNA expression within the spinal cord. These data suggested that pharmacological intervention aimed at inhibiting proinflammatory cytokine expression within the central nervous system provided protection against BBB disruption, the first clinical sign of EAE and probably the key point of acute MS attacks. This finding could lead to the development of a new class of compounds for oral therapy of MS, as a supplement to immunosuppressive agents. PMID:10536012

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse.

PubMed

Kimura, Eiki; Kubo, Ken-Ichiro; Endo, Toshihiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

2017-01-01

The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain. We transfected constitutively active (CA)-AhR, AhR, or control vector plasmids into neurons via in utero electroporation on gestational day 14 and analyzed neuronal positioning in the hippocampal CA1 region of offspring on postnatal day 14. CA-AhR transfection affected neuronal positioning, whereas no change was observed in AhR-transfected or control hippocampus. These results suggest that constitutively activated AhR signaling disrupts neuronal migration during hippocampal development. Further studies are needed to investigate whether such developmental disruption in the hippocampus leads to the abnormal cognition and behavior of rodent offspring upon maternal exposure to AhR xenobiotic ligands.

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

PubMed Central

Basu-Roy, Upal; Ty, Maureen; Alique, Matilde; Fernandez-Arias, Cristina; Movila, Alexandru; Gomes, Pollyanna; Edagha, Innocent; Wassmer, Samuel C.; Walther, Thomas

2016-01-01

Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum–infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter–endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin–induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC–induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised. PMID:27643439

Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease.

PubMed

Cabezas, Ricardo; Avila, Marcos; Gonzalez, Janneth; El-Bachá, Ramon Santos; Báez, Eliana; García-Segura, Luis Miguel; Jurado Coronel, Juan Camilo; Capani, Francisco; Cardona-Gomez, Gloria Patricia; Barreto, George E

2014-01-01

The blood-brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson's Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson's disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.

Computational Modeling of Thyroid Hormone Regulated Neurodevelopment for Chemical Prioritization (SOT)

EPA Science Inventory

Thyroid hormones (TH) are critical for normal brain development. Environmental chemicals may disrupt TH homeostasis through a variety of physiological systems including membrane transporters, serum transporters, synthesis and catabolic enzymes, and nuclear receptors. Current comp...

Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT).

PubMed

Åslund, Andreas K O; Snipstad, Sofie; Healey, Andrew; Kvåle, Svein; Torp, Sverre H; Sontum, Per C; Davies, Catharina de Lange; van Wamel, Annemieke

2017-01-01

The blood-brain barrier (BBB) is a major obstacle in drug delivery for diseases of the brain, and today there is no standardized route to surpass it. One technique to locally and transiently disrupt the BBB, is focused ultrasound in combination with gas-filled microbubbles. However, the microbubbles used are typically developed for ultrasound imaging, not BBB disruption. Here we describe efficient opening of the BBB using the promising novel Acoustic Cluster Therapy (ACT), that recently has been used in combination with Abraxane® to successfully treat subcutaneous tumors of human prostate adenocarcinoma in mice. ACT is based on the conjugation of microbubbles to liquid oil microdroplets through electrostatic interactions. Upon activation in an ultrasound field, the microdroplet phase transfers to form a larger bubble that transiently lodges in the microvasculature. Further insonation induces volume oscillations of the activated bubble, which in turn induce biomechanical effects that increase the permeability of the BBB. ACT was able to safely and temporarily permeabilize the BBB, using an acoustic power 5-10 times lower than applied for conventional microbubbles, and successfully deliver small and large molecules into the brain.

Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques.

PubMed

McDannold, Nathan; Arvanitis, Costas D; Vykhodtseva, Natalia; Livingstone, Margaret S

2012-07-15

The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method.

Dynamic analysis of the blood-brain barrier disruption in experimental stroke using time domain in vivo fluorescence imaging.

PubMed

Abulrob, Abedelnasser; Brunette, Eric; Slinn, Jacqueline; Baumann, Ewa; Stanimirovic, Danica

2008-01-01

The blood-brain barrier (BBB) disruption following cerebral ischemia can be exploited to deliver imaging agents and therapeutics into the brain. The aim of this study was (a) to establish novel in vivo optical imaging methods for longitudinal assessment of the BBB disruption and (b) to assess size selectivity and temporal patterns of the BBB disruption after a transient focal ischemia. The BBB permeability was assessed using in vivo time domain near-infrared optical imaging after contrast enhancement with either free Cy5.5 (1 kDa) or Cy5.5 conjugated with bovine serum albumin (BSA) (67 kDa) in mice subjected to either 60- or 20-minute transient middle cerebral artery occlusion (MCAO) and various times of reperfusion (up to 14 days). In vivo imaging observations were corroborated by ex vivo brain imaging and microscopic analyses of fluorescent tracer extravasation. The in vivo optical contrast enhancement with Cy5.5 was spatially larger than that observed with BSA-Cy5.5. Longitudinal studies after a transient 20-minute MCAO suggested a bilateral BBB disruption, more pronounced in the ipsilateral hemisphere, peaking at day 7 and resolving at day 14 after ischemia. The area differential between the BBB disruption for small and large molecules could potentially be useful as a surrogate imaging marker for assessing perinfarct tissues to which neuroprotective therapies of appropriate sizes could be delivered.

Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer’s Disease

PubMed Central

Bellanti, Francesco; Iannelli, Giuseppina; Blonda, Maria; Tamborra, Rosanna; Villani, Rosanna; Romano, Adele; Calcagnini, Silvio; Mazzoccoli, Gianluigi; Vinciguerra, Manlio; Gaetani, Silvana; Giudetti, Anna Maria; Vendemiale, Gianluigi; Cassano, Tommaso; Serviddio, Gaetano

2017-01-01

A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer’s disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis. PMID:28671110

Distortions and Disconnections: Disrupted Brain Connectivity in Autism

ERIC Educational Resources Information Center

Wass, Sam

2011-01-01

The past few years have seen considerable interest in findings of abnormal brain connectivity in the autism spectrum disorders (ASD). We review recent work from neuroimaging and other sources, and argue that there is considerable convergent evidence suggesting that connectivity is disrupted in ASD. We point to evidence both of local…

[Circadian rhythm disruption and human development].

PubMed

Kohyama, Jun

2013-12-01

Ontogenetic developments of rest-activity, sleep-wakefulness, temperature and several hormone rhythms in humans were reviewed. The reported effects of environment on these alterations were also summarized. Then, disorders or conditions which often encounter during early stage of life and reveal circadian rhythm disruptions were described. These disorders or conditions included severe brain damage, visual disturbance, developmental disorders(autistic spectrum disorder and attention deficit/hyperactivity disorder), Rett syndrome, Angelman syndrome, Smith-Magenis syndrome, epilepsy, Yonaki, and inadequate sleep hygiene. Finally, it was emphasized that we should pay special attention on the development of youngsters who showed sleep disturbance during early stage of life with special reference to the later occurrence of developmental disorders.

Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy.

PubMed

Ho, Kwok M; Honeybul, Stephen; Yip, Cheng B; Silbert, Benjamin I

2014-09-01

The authors assessed the risk factors and outcomes associated with blood-brain barrier (BBB) disruption in patients with severe, nonpenetrating, traumatic brain injury (TBI) requiring decompressive craniectomy. At 2 major neurotrauma centers in Western Australia, a retrospective cohort study was conducted among 97 adult neurotrauma patients who required an external ventricular drain (EVD) and decompressive craniectomy during 2004-2012. Glasgow Outcome Scale scores were used to assess neurological outcomes. Logistic regression was used to identify factors associated with BBB disruption, defined by a ratio of total CSF protein concentrations to total plasma protein concentration > 0.007 in the earliest CSF specimen collected after TBI. Of the 252 patients who required decompressive craniectomy, 97 (39%) required an EVD to control intracranial pressure, and biochemical evidence of BBB disruption was observed in 43 (44%). Presence of disruption was associated with more severe TBI (median predicted risk for unfavorable outcome 75% vs 63%, respectively; p = 0.001) and with worse outcomes at 6, 12, and 18 months than was absence of BBB disruption (72% vs 37% unfavorable outcomes, respectively; p = 0.015). The only risk factor significantly associated with increased risk for BBB disruption was presence of nonevacuated intracerebral hematoma (> 1 cm diameter) (OR 3.03, 95% CI 1.23-7.50; p = 0.016). Although BBB disruption was associated with more severe TBI and worse long-term outcomes, when combined with the prognostic information contained in the Corticosteroid Randomization after Significant Head Injury (CRASH) prognostic model, it did not seem to add significant prognostic value (area under the receiver operating characteristic curve 0.855 vs 0.864, respectively; p = 0.453). Biochemical evidence of BBB disruption after severe nonpenetrating TBI was common, especially among patients with large intracerebral hematomas. Disruption of the BBB was associated with more severe TBI and worse long-term outcomes, but when combined with the prognostic information contained in the CRASH prognostic model, this information did not add significant prognostic value.

Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease.

PubMed

Zinnanti, William J; Lazovic, Jelena; Griffin, Kathleen; Skvorak, Kristen J; Paul, Harbhajan S; Homanics, Gregg E; Bewley, Maria C; Cheng, Keith C; Lanoue, Kathryn F; Flanagan, John M

2009-04-01

Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branched-chain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress.

Bisphenol S (BPS) Alters Maternal Behavior and Brain in Mice Exposed During Pregnancy/Lactation and Their Daughters.

PubMed

Catanese, Mary C; Vandenberg, Laura N

2017-03-01

Estrogenic endocrine disrupting chemicals have been shown to disrupt maternal behavior in rodents. We investigated the effects of an emerging xenoestrogen, bisphenol S (BPS), on maternal behavior and brain in CD-1 mice exposed during pregnancy and lactation (F0 generation) and in female offspring exposed during gestation and perinatal development (F1 generation). We observed different effects in F0 and F1 dams for a number of components of maternal behavior, including time on the nest, time spent on nest building, latency to retrieve pups, and latency to retrieve the entire litter. We also characterized expression of estrogen receptor α in the medial preoptic area (MPOA) and quantified tyrosine hydroxylase immunoreactive cells in the ventral tegmental area, 2 brain regions critical for maternal care. BPS-treated females in the F0 generation had a statistically significant increase in estrogen receptor α expression in the caudal subregion of the central MPOA in a dose-dependent manner. In contrast, there were no statistically significant effects of BPS on the MPOA in F1 dams or the ventral tegmental area in either generation. This work demonstrates that BPS affects maternal behavior and brain with outcomes depending on generation, dose, and postpartum period. Many studies examining effects of endocrine disrupting chemicals view the mother as a means by which offspring can be exposed during critical periods of development. Here, we demonstrate that pregnancy and lactation are vulnerable periods for the mother. We also show that developmental BPS exposure alters maternal behavior later in adulthood. Both findings have potential public health implications. Copyright © 2017 by the Endocrine Society.

The maternal brain and its plasticity in humans

PubMed Central

Kim, Pilyoung; Strathearn, Lane; Swain, James E.

2015-01-01

Early mother-infant relationships play important roles in infants’ optimal development. New mothers undergo neurobiological changes that support developing mother-infant relationships regardless of great individual differences in those relationships. In this article, we review the neural plasticity in human mothers’ brains based on functional magnetic resonance imaging (fMRI) studies. First, we review the neural circuits that are involved in establishing and maintaining mother-infant relationships. Second, we discuss early postpartum factors (e.g., birth and feeding methods, hormones, and parental sensitivity) that are associated with individual differences in maternal brain neuroplasticity. Third, we discuss abnormal changes in the maternal brain related to psychopathology (i.e., postpartum depression, posttraumatic stress disorder, substance abuse) and potential brain remodeling associated with interventions. Last, we highlight potentially important future research directions to better understand normative changes in the maternal brain and risks for abnormal changes that may disrupt early mother-infant relationships. PMID:26268151

Blood-brain barrier disruption and vascular damage induced by ultrasound bursts combined with microbubbles can be influenced by choice of anesthesia protocol

PubMed Central

McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia

2011-01-01

Numerous animal studies have demonstrated that ultrasound bursts combined with a microbubble-based ultrasound contrast agent can temporarily disrupt the blood-brain barrier (BBB) with little or no other apparent effects to the brain. As the BBB is a primary limitation to the use of most drugs in the brain, this method could enable a noninvasive means for targeted drug delivery in the brain. This work investigated whether BBB disruption and vessel damage when overexposure occurs can be influenced by choice of anesthesia protocol, which have different vasoactive effects. Four locations were sonicated transcranially in each brain of 16 rats using an unfocused 532 kHz piston transducer. Burst sonications (10 ms bursts applied at 1 Hz for 60 s) were combined with intravenous Definity (10 μl/kg) injections. BBB disruption was evaluated using contrast-enhanced MRI. Half of the animals were anesthetized with i.p. ketamine and xylazine, and the other half with inhaled isoflurane and oxygen. Over the range of exposure levels tested, MRI contrast enhancement was significantly higher (P<0.05) for animals anesthetized with ketamine/xylazine. Furthermore, the threshold for extensive erythrocyte extravasation was lower with ketamine/xylazine. These results suggest that BBB disruption and/or vascular damage can be affected by vascular or other factors that are influenced by different anesthesia protocol. These experiments may also have been influenced by the recently reported findings that the circulation time for perfluorocarbon microbubbles is substantially reduced when oxygen is used as the carrier gas. PMID:21645965

Facilitation of Drug Transport across the Blood-Brain Barrier with Ultrasound and Microbubbles.

PubMed

Meairs, Stephen

2015-08-31

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood-brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer's disease is presented.

An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome.

PubMed

Gilbert, Mary E; Hedge, Joan M; Valentín-Blasini, Liza; Blount, Benjamin C; Kannan, Kurunthachalam; Tietge, Joseph; Zoeller, R Thomas; Crofton, Kevin M; Jarrett, Jeffrey M; Fisher, Jeffrey W

2013-03-01

Thyroid hormones (THs) are essential for brain development, and iodine is required for TH synthesis. Environmental chemicals that perturb the thyroid axis result in modest reductions in TH, yet there is a paucity of data on the extent of neurological impairments associated with low-level TH disruption. This study examined the dose-response characteristics of marginal iodine deficiency (ID) on parameters of thyroid function and neurodevelopment. Diets deficient in iodine were prepared by adding 975, 200, 125, 25, or 0 µg/kg potassium iodate to the base casein diet to produce five nominal iodine levels ranging from ample (Diet 1: 1000 μg iodine/kg chow, D1) to deficient (Diet 5: 25 µg iodine/kg chow, D5). Female Long Evans rats were maintained on these diets beginning 7 weeks prior to breeding until the end of lactation. Dams were sacrificed on gestational days 16 and 20, or when pups were weaned on postnatal day (PN) 21. Fetal tissue was harvested from the dams, and pups were sacrificed on PN14 and PN21. Blood, thyroid gland, and brain were collected for analysis of iodine, TH, and TH precursors and metabolites. Serum and thyroid gland iodine and TH were reduced in animals receiving two diets that were most deficient in iodine. T4 was reduced in the fetal brain but was not altered in the neonatal brain. Neurobehavior, assessed by acoustic startle, water maze learning, and fear conditioning, was unchanged in adult offspring, but excitatory synaptic transmission was impaired in the dentate gyrus in animals receiving two diets that were most deficient in iodine. A 15% reduction in cortical T4 in the fetal brain was sufficient to induce permanent reductions in synaptic function in adults. These findings have implications for regulation of TH-disrupting chemicals and suggest that standard behavioral assays do not readily detect neurotoxicity induced by modest developmental TH disruption.

Disrupted Functional Connectivity with Dopaminergic Midbrain in Cocaine Abusers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomasi, D.; Tomasi, D.; Volkow, N.D.

Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task. We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and thismore » was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.« less

The interleukins-1 alpha, -1 beta, and -2 do not acutely disrupt the murine blood-brain barrier.

PubMed

Banks, W A; Kastin, A J

1992-05-01

Previous studies have suggested that some of the central nervous system (CNS) effects of interleukin-2 (IL-2) and perhaps other cytokines might be mediated through disruption of the blood-brain barrier (BBB). We investigated the ability of human IL-2 and, in selected studies, human IL-1 alpha and human IL-1 beta to disrupt the BBB to radioiodinated bovine serum albumin (RISA) after intravenous (i.v.) and intracerebroventricular (i.c.v.) injection. No disruption of the BBB occurred for up to 2 h after the i.v. injection of 2 micrograms/mouse of IL-2 (10(5) U/kg of body weight), 2 micrograms of IL-1 alpha (10(7) U/kg), or 2 micrograms of IL-1 beta (10(7) U/kg). This dose of i.v. IL-2 also did not affect BBB permeability to RISA in the brain to blood direction. Damage to the BBB induced by hypertension elicited by i.v. epinephrine was not enhanced or prolonged by IL-2. When given directly into the CNS by the i.c.v. route, 100 ng of IL-2 (2.2 x 10(5) U/kg of brain), 100 ng of IL-1 alpha (2.2 x 10(7) U/kg of brain), or 100 ng of IL-1 beta (2.2 x 10(7) U/kg of brain) had no effect on BBB integrity in either the blood to brain or the brain to blood direction. We conclude that the effects of IL-1 alpha, IL-1 beta, and IL-2 on the CNS, as studied under these conditions, are not due to disruption of the BBB but are mediated by other mechanisms including the ability of some interleukins to cross the BBB by a saturable transport system described previously.

Building a scientific framework for studying hormonal effects on behavior and on the development of the sexually dimorphic nervous system

EPA Science Inventory

There has been increasing concern that low-dose exposure to hormonally active chemicals disrupts sexual differentiation of the brain and peripheral nervous system. There also has been active drug development research on the therapeutic potential of hormone therapy on behaviors. T...

Cyclosporine A alleviated matrix metalloproteinase 9 associated blood-brain barrier disruption after subarachnoid hemorrhage in mice.

PubMed

Pan, Pengyu; Zhang, Xuan; Li, Qiang; Zhao, Hengli; Qu, Jie; Zhang, John H; Liu, Xin; Feng, Hua; Chen, Yujie

2017-05-10

The aim of this study was to investigate whether Cyclosporine A (CsA) attenuates early brain injury by alleviating matrix metalloproteinase 9 (MMP-9) associated blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). A standard intravascular perforation model was used to produce the experimental SAH in C57B6J mice. Dosages of 5mg/kg, 10mg/kg and 15mg/kg CsA were evaluated for effects on neurological score, brain water content, Evans blue extravasation and fluorescence, P-p65, MMP-9 and BBB components' alterations after SAH. We found that CsA 15mg/kg is effective in attenuating BBB disruption, lowering edema, and improving neurological outcomes. In addition, Collagen IV, ZO-1, Occludin and Claudin 5 expressions in ipsilateral/left hemisphere were downregulated after SAH, but increased after CsA treatment. Our results suggest that CsA exert a neuroprotective role in SAH pathophysiology, possibly by alleviating MMP-9 associated BBB disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

Perinatal Asphyxia and Brain Development: Mitochondrial Damage Without Anatomical or Cellular Losses.

PubMed

Lima, Jean Pierre Mendes; Rayêe, Danielle; Silva-Rodrigues, Thaia; Pereira, Paula Ribeiro Paes; Mendonca, Ana Paula Miranda; Rodrigues-Ferreira, Clara; Szczupak, Diego; Fonseca, Anna; Oliveira, Marcus F; Lima, Flavia Regina Souza; Lent, Roberto; Galina, Antonio; Uziel, Daniela

2018-03-26

Perinatal asphyxia remains a significant cause of neonatal mortality and is associated with long-term neurodegenerative disorders. In the present study, we evaluated cellular and subcellular damages to brain development in a model of mild perinatal asphyxia. Survival rate in the experimental group was 67%. One hour after the insult, intraperitoneally injected Evans blue could be detected in the fetuses' brains, indicating disruption of the blood-brain barrier. Although brain mass and absolute cell numbers (neurons and non-neurons) were not reduced after perinatal asphyxia immediately and in late brain development, subcellular alterations were detected. Cortical oxygen consumption increased immediately after asphyxia, and remained high up to 7 days, returning to normal levels after 14 days. We observed an increased resistance to mitochondrial membrane permeability transition, and calcium buffering capacity in asphyxiated animals from birth to 14 days after the insult. In contrast to ex vivo data, mitochondrial oxygen consumption in primary cell cultures of neurons and astrocytes was not altered after 1% hypoxia. Taken together, our results demonstrate that although newborns were viable and apparently healthy, brain development is subcellularly altered by perinatal asphyxia. Our findings place the neonate brain mitochondria as a potential target for therapeutic protective interventions.

Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover.

PubMed

Dere, Ekrem; De Souza-Silva, Maria A; Topic, Bianca; Spieler, Richard E; Haas, Helmut L; Huston, Joseph P

2003-01-01

The brain's histaminergic system has been implicated in hippocampal synaptic plasticity, learning, and memory, as well as brain reward and reinforcement. Our past pharmacological and lesion studies indicated that the brain's histamine system exerts inhibitory effects on the brain's reinforcement respective reward system reciprocal to mesolimbic dopamine systems, thereby modulating learning and memory performance. Given the close functional relationship between brain reinforcement and memory processes, the total disruption of brain histamine synthesis via genetic disruption of its synthesizing enzyme, histidine decarboxylase (HDC), in the mouse might have differential effects on learning dependent on the task-inherent reinforcement contingencies. Here, we investigated the effects of an HDC gene disruption in the mouse in a nonreinforced object exploration task and a negatively reinforced water-maze task as well as on neo- and ventro-striatal dopamine systems known to be involved in brain reward and reinforcement. Histidine decarboxylase knockout (HDC-KO) mice had higher dihydrophenylacetic acid concentrations and a higher dihydrophenylacetic acid/dopamine ratio in the neostriatum. In the ventral striatum, dihydrophenylacetic acid/dopamine and 3-methoxytyramine/dopamine ratios were higher in HDC-KO mice. Furthermore, the HDC-KO mice showed improved water-maze performance during both hidden and cued platform tasks, but deficient object discrimination based on temporal relationships. Our data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.

Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model

NASA Astrophysics Data System (ADS)

Wang, Po-Hsun; Liu, Hao-Li; Hsu, Po-Hung; Lin, Chia-Yu; Chris Wang, Churng-Ren; Chen, Pin-Yuan; Wei, Kuo-Chen; Yen, Tzu-Chen; Li, Meng-Lin

2012-06-01

In this study, we develop a novel photoacoustic imaging technique based on gold nanorods (AuNRs) for quantitatively monitoring focused-ultrasound (FUS) induced blood-brain barrier (BBB) opening in a rat model in vivo. This study takes advantage of the strong near-infrared absorption (peak at ~800 nm) of AuNRs and the extravasation tendency from BBB opening foci due to their nano-scale size to passively label the BBB disruption area. Experimental results show that AuNR contrast-enhanced photoacoustic microscopy (PAM) successfully reveals the spatial distribution and temporal response of BBB disruption area in the rat brains. The quantitative measurement of contrast enhancement has potential to estimate the local concentration of AuNRs and even the dosage of therapeutic molecules when AuNRs are further used as nano-carrier for drug delivery or photothermal therapy. The photoacoustic results also provide complementary information to MRI, being helpful to discover more details about FUS induced BBB opening in small animal models.

Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain.

PubMed

Takeuchi, Akihide; Iida, Kei; Tsubota, Toshiaki; Hosokawa, Motoyasu; Denawa, Masatsugu; Brown, J B; Ninomiya, Kensuke; Ito, Mikako; Kimura, Hiroshi; Abe, Takaya; Kiyonari, Hiroshi; Ohno, Kinji; Hagiwara, Masatoshi

2018-05-01

Genes specifically expressed in neurons contain members with extended long introns. Longer genes present a problem with respect to fulfilment of gene length transcription, and evidence suggests that dysregulation of long genes is a mechanism underlying neurodegenerative and psychiatric disorders. Here, we report the discovery that RNA-binding protein Sfpq is a critical factor for maintaining transcriptional elongation of long genes. We demonstrate that Sfpq co-transcriptionally binds to long introns and is required for sustaining long-gene transcription by RNA polymerase II through mediating the interaction of cyclin-dependent kinase 9 with the elongation complex. Phenotypically, Sfpq disruption caused neuronal apoptosis in developing mouse brains. Expression analysis of Sfpq-regulated genes revealed specific downregulation of developmentally essential neuronal genes longer than 100 kb in Sfpq-disrupted brains; those genes are enriched in associations with neurodegenerative and psychiatric diseases. The identified molecular machinery yields directions for targeted investigations of the association between long-gene transcriptopathy and neuronal diseases. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Fetal Alcohol Spectrum Disorders: An Overview from the Glia Perspective.

PubMed

Wilhelm, Clare J; Guizzetti, Marina

2015-01-01

Alcohol consumption during pregnancy can produce a variety of central nervous system (CNS) abnormalities in the offspring resulting in a broad spectrum of cognitive and behavioral impairments that constitute the most severe and long-lasting effects observed in fetal alcohol spectrum disorders (FASD). Alcohol-induced abnormalities in glial cells have been suspected of contributing to the adverse effects of alcohol on the developing brain for several years, although much research still needs to be done to causally link the effects of alcohol on specific brain structures and behavior to alterations in glial cell development and function. Damage to radial glia due to prenatal alcohol exposure may underlie observations of abnormal neuronal and glial migration in humans with Fetal Alcohol Syndrome (FAS), as well as primate and rodent models of FAS. A reduction in cell number and altered development has been reported for several glial cell types in animal models of FAS. In utero alcohol exposure can cause microencephaly when alcohol exposure occurs during the brain growth spurt a period characterized by rapid astrocyte proliferation and maturation; since astrocytes are the most abundant cells in the brain, microenchephaly may be caused by reduced astrocyte proliferation or survival, as observed in in vitro and in vivo studies. Delayed oligodendrocyte development and increased oligodendrocyte precursor apoptosis has also been reported in experimental models of FASD, which may be linked to altered myelination/white matter integrity found in FASD children. Children with FAS exhibit hypoplasia of the corpus callosum and anterior commissure, two areas requiring guidance from glial cells and proper maturation of oligodendrocytes. Finally, developmental alcohol exposure disrupts microglial function and induces microglial apoptosis; given the role of microglia in synaptic pruning during brain development, the effects of alcohol on microglia may be involved in the abnormal brain plasticity reported in FASD. The consequences of prenatal alcohol exposure on glial cells, including radial glia and other transient glial structures present in the developing brain, astrocytes, oligodendrocytes and their precursors, and microglia contributes to abnormal neuronal development, reduced neuron survival and disrupted brain architecture and connectivity. This review highlights the CNS structural abnormalities caused by in utero alcohol exposure and outlines which abnormalities are likely mediated by alcohol effects on glial cell development and function.

The transcription factor Nfix is essential for normal brain development.

PubMed

Campbell, Christine E; Piper, Michael; Plachez, Céline; Yeh, Yu-Ting; Baizer, Joan S; Osinski, Jason M; Litwack, E David; Richards, Linda J; Gronostajski, Richard M

2008-05-13

The Nuclear Factor I (NFI) multi-gene family encodes site-specific transcription factors essential for the development of a number of organ systems. We showed previously that Nfia-deficient mice exhibit agenesis of the corpus callosum and other forebrain defects; Nfib-deficient mice have defects in lung maturation and show callosal agenesis and forebrain defects resembling those seen in Nfia-deficient animals, while Nfic-deficient mice have defects in tooth root formation. Recently the Nfix gene has been disrupted and these studies indicated that there were largely uncharacterized defects in brain and skeletal development in Nfix-deficient mice. Here we show that disruption of Nfix by Cre-recombinase mediated excision of the 2nd exon results in defects in brain development that differ from those seen in Nfia and Nfib KO mice. In particular, complete callosal agenesis is not seen in Nfix-/- mice but rather there appears to be an overabundance of aberrant Pax6- and doublecortin-positive cells in the lateral ventricles of Nfix-/- mice, increased brain weight, expansion of the cingulate cortex and entire brain along the dorsal ventral axis, and aberrant formation of the hippocampus. On standard lab chow Nfix-/- animals show a decreased growth rate from ~P8 to P14, lose weight from ~P14 to P22 and die at ~P22. If their food is supplemented with a soft dough chow from P10, Nfix-/- animals show a lag in weight gain from P8 to P20 but then increase their growth rate. A fraction of the animals survive to adulthood and are fertile. The weight loss correlates with delayed eye and ear canal opening and suggests a delay in the development of several epithelial structures in Nfix-/- animals. These data show that Nfix is essential for normal brain development and may be required for neural stem cell homeostasis. The delays seen in eye and ear opening and the brain morphology defects appear independent of the nutritional deprivation, as rescue of perinatal lethality with soft dough does not eliminate these defects.

Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption.

PubMed

Kobus, Thiele; Zervantonakis, Ioannis K; Zhang, Yongzhi; McDannold, Nathan J

2016-09-28

HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the response by temporary disruption of the BBB using focused ultrasound in combination with microbubbles. To study this, we inoculated 30 nude rats with HER2-positive cells derived from a brain metastasis of a breast cancer patient (MDA-MB-361). The animals were divided into three groups: a control-group that received no treatment; an antibody-only group that received six weekly treatments of trastuzumab and pertuzumab; and an ultrasound+antibody group that received trastuzumab and pertuzumab in combination with six weekly sessions of BBB disruption using focused ultrasound. In two animals, the leakiness of the tumors before disruption was evaluated using contrast-enhanced T1-weighted magnetic resonance imaging and found that the tumors were not leaky. The same technique was used to evaluate the effectiveness of BBB disruption, which was successful in all sessions. The tumor in the control animals grew exponentially with a growth constant of 0.042±0.011mm(3)/day. None of the antibody-only animals responded to the treatment and the growth constant was 0.033±0.009mm(3)/day during the treatment period. Four of the ten animals in the ultrasound+antibody-group showed a response to the treatment with an average growth constant of 0.010±0.007mm(3)/day, compared to a growth constant 0.043±0.013mm(3)/day for the six non-responders. After the treatment period, the tumors in all groups grew at similar rates. As the tumors were not leaky before BBB disruption and there were no responders in the antibody-only group, these results show that at least in some cases disruption of the BBB is necessary for a response to the antibodies in these brain metastases. Interestingly, only some of the rats responded to the treatment. We did not observe a difference in tumor volume at the start of the treatment, nor in HER2 expression or in contrast-enhancement on MRI between the responders and non-responders to explain this. Better understanding of why certain animals respond is needed and will help in translating this technique to the clinic. In conclusion, we demonstrate that BBB disruption using focused ultrasound in combination with antibody therapy can inhibit growth of breast cancer brain metastasis. Copyright © 2016 Elsevier B.V. All rights reserved.

Adult Hippocampal Neurogenesis is Impaired by Transient and Moderate Developmental Thyroid Hormone Disruption

EPA Science Inventory

Severe thyroid hormone (TH) deprivation during development impairs neurogenesis throughout the brain. The hippocampus also maintains a capacity for neurogenesis throughout life which is reduced in adult-onset hypothyroidism. This study examined hippocampal volume in the neonate a...

Schizophrenia, vitamin D, and brain development.

PubMed

Mackay-Sim, Alan; Féron, François; Eyles, Darryl; Burne, Thomas; McGrath, John

2004-01-01

Schizophrenia research is invigorated at present by the recent discovery of several plausible candidate susceptibility genes identified from genetic linkage and gene expression studies of brains from persons with schizophrenia. It is a current challenge to reconcile this gathering evidence for specific candidate susceptibility genes with the "neurodevelopmental hypothesis," which posits that schizophrenia arises from gene-environment interactions that disrupt brain development. We make the case here that schizophrenia may result not from numerous genes of small effect, but a few genes of transcriptional regulation acting during brain development. In particular we propose that low vitamin D during brain development interacts with susceptibility genes to alter the trajectory of brain development, probably by epigenetic regulation that alters gene expression throughout adult life. Vitamin D is an attractive "environmental" candidate because it appears to explain several key epidemiological features of schizophrenia. Vitamin D is an attractive "genetic" candidate because its nuclear hormone receptor regulates gene expression and nervous system development. The polygenic quality of schizophrenia, with linkage to many genes of small effect, maybe brought together via this "vitamin D hypothesis." We also discuss the possibility of a broader set of environmental and genetic factors interacting via the nuclear hormone receptors to affect the development of the brain leading to schizophrenia.

Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain.

PubMed Central

Muldoon, L. L.; Nilaver, G.; Kroll, R. A.; Pagel, M. A.; Breakefield, X. O.; Chiocca, E. A.; Davidson, B. L.; Weissleder, R.; Neuwelt, E. A.

1995-01-01

Delivery of adenovirus, herpes simplex virus (HSV), and paramagnetic monocrystalline iron oxide nanoparticles (MION) to rat brain (n = 64) was assessed after intracerebral inoculation or osmotic disruption of the blood-brain barrier (BBB). After intracerebral inoculation, the area of distribution was 7.93 +/- 0.43 mm2 (n = 9) for MION and 9.17 +/- 1.27 mm2 (n = 9) for replication-defective adenovirus. The replication-compromised HSV RH105 spread to 14.00 +/- 0.87 mm2 (n = 8), but also had a large necrotic center (3.54 +/- 0.47 mm2). No infection was detected when virus was administered intra-arterially without hyperosmotic mannitol. After osmotic BBB disruption, delivery of the viruses and MIONs was detected throughout the disrupted cerebral cortex. Positive staining was found in 4 to 845 cells/100 microns thick coronal brain section (n = 7) after adenovirus administration, and in 13 to 197 cells/section (n = 8) after HSV administration. Cells of glial morphology were more frequently stained after administration of adenovirus, whereas neuronal cells were preferentially stained after delivery of both HSV vectors and MION. In a preliminary test of vector delivery in the feline, MION was detected throughout the white matter tracts after inoculation into normal cat brain. Thus MION may be a tool for use in vivo, to monitor the delivery of virus to the central nervous system. Additionally, BBB disruption may be an effective method to globally deliver recombinant viruses to the CNS. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:7495307

Blood-brain barrier disruption and vascular damage induced by ultrasound bursts combined with microbubbles can be influenced by choice of anesthesia protocol.

PubMed

McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia

2011-08-01

Numerous animal studies have demonstrated that ultrasound bursts combined with a microbubble-based ultrasound contrast agent can temporarily disrupt the blood-brain barrier (BBB) with little or no other apparent effects to the brain. As the BBB is a primary limitation to the use of most drugs in the brain, this method could enable a noninvasive means for targeted drug delivery in the brain. This work investigated whether BBB disruption and vessel damage when overexposure occurs can be influenced by choice of anesthesia protocol, which have different vasoactive effects. Four locations were sonicated transcranially in each brain of 16 rats using an unfocused 532 kHz piston transducer. Burst sonications (10 ms bursts applied at 1 Hz for 60 s) were combined with intravenous Definity (10 μl/kg) injections. BBB disruption was evaluated using contrast-enhanced MRI. Half of the animals were anesthetized with i.p. ketamine and xylazine, and the other half with inhaled isoflurane and oxygen. Over the range of exposure levels tested, MRI contrast enhancement was significantly higher (p < 0.05) for animals anesthetized with ketamine/xylazine. Furthermore, the threshold for extensive erythrocyte extravasation was lower with ketamine/xylazine. These results suggest that BBB disruption and/or vascular damage can be affected by vascular or other factors that are influenced by different anesthesia protocol. These experiments may also have been influenced by the recently reported findings that the circulation time for perfluorocarbon microbubbles is substantially reduced when oxygen is used as the carrier gas. Copyright © 2011 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Targeted, noninvasive blockade of cortical neuronal activity

NASA Astrophysics Data System (ADS)

McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

2015-11-01

Here we describe a novel method to noninvasively modulate targeted brain areas through the temporary disruption of the blood-brain barrier (BBB) via focused ultrasound, enabling focal delivery of a neuroactive substance. Ultrasound was used to locally disrupt the BBB in rat somatosensory cortex, and intravenous administration of GABA then produced a dose-dependent suppression of somatosensory-evoked potentials in response to electrical stimulation of the sciatic nerve. No suppression was observed 1-5 days afterwards or in control animals where the BBB was not disrupted. This method has several advantages over existing techniques: it is noninvasive; it is repeatable via additional GABA injections; multiple brain regions can be affected simultaneously; suppression magnitude can be titrated by GABA dose; and the method can be used with freely behaving subjects. We anticipate that the application of neuroactive substances in this way will be a useful tool for noninvasively mapping brain function, and potentially for surgical planning or novel therapies.

An optical assessment of the effects of glioma growth on resting state networks in mice (Conference Presentation)

NASA Astrophysics Data System (ADS)

Orukari, Inema E.; Bauer, Adam Q.; Baxter, Grant A.; Rubin, Joshua B.; Culver, Joseph P.

2017-02-01

Gliomas are known to cause significant changes in normal brain function that lead to cognitive deficits. Disruptions in resting state networks (RSNs) are thought to underlie these changes. However, investigating the effects of glioma growth on RSNs in humans is complicated by the heterogeneity in lesion size, type, and location across subjects. In this study, we evaluated the effects of tumor growth on RSNs over time in a controlled mouse model of glioma growth. Methods: Glioma cells (5x104-105 U87s) were stereotactically injected into the forepaw somatosensory cortex of adult nude mice (n=5). Disruptions in RSNs were evaluated weekly with functional connectivity optical intrinsic signal imaging (fcOIS). Tumor growth was monitored with MRI and weekly bioluminescence imaging (BLI). In order to characterize how tumor growth affected different RSNs over time, we calculated a number of functional connectivity (fc) metrics, including homotopic (bilateral) connectivity, spatial similarity, and node degree. Results: Deficits in fc initiate near the lesion, and over a period of several weeks, extend more globally. The reductions in spatial similarity were found to strongly correlate with the BLI signal indicating that increased tumor size is associated with increased RSN disruption. Conclusions: We have shown that fcOIS is capable of detecting alterations in mouse RSNs due to brain tumor growth. A better understanding of how RSN disruption contributes to the development of cognitive deficits in brain tumor patients may lead to better patient risk stratification and consequently improved cognitive outcomes.

Review: Neuroinflammation in intrauterine growth restriction.

PubMed

Wixey, Julie A; Chand, Kirat K; Colditz, Paul B; Bjorkman, S Tracey

2017-06-01

Disruption to the maternal environment during pregnancy from events such as hypoxia, stress, toxins, inflammation, and reduced placental blood flow can affect fetal development. Intrauterine growth restriction (IUGR) is commonly caused by chronic placental insufficiency, interrupting supply of oxygen and nutrients to the fetus resulting in abnormal fetal growth. IUGR is a major cause of perinatal morbidity and mortality, occurring in approximately 5-10% of pregnancies. The fetal brain is particularly vulnerable in IUGR and there is an increased risk of long-term neurological disorders including cerebral palsy, epilepsy, learning difficulties, behavioural difficulties and psychiatric diagnoses. Few studies have focused on how growth restriction interferes with normal brain development in the IUGR neonate but recent studies in growth restricted animal models demonstrate increased neuroinflammation. This review describes the role of neuroinflammation in the progression of brain injury in growth restricted neonates. Identifying the mediators responsible for alterations in brain development in the IUGR infant is key to prevention and treatment of brain injury in these infants. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Cerebellum, Sensitive Periods, and Autism

PubMed Central

Wang, Samuel S.-H.; Kloth, Alexander D.; Badura, Aleksandra

2014-01-01

Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism's key features. PMID:25102558

Proteomic analysis of zebrafish brain tissue following exposure to the pesticide prochloraz

EPA Science Inventory

The hypothalamus-pituitary-gonadal (HPG) axis plays a central role in the maintenance of homeostasis. Disruptions of this axis can have important implications for development and other critical biological processes. A number of compounds found in aquatic environments are known t...

Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals

EPA Science Inventory

The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endo...

Electrical Interactions between Mammalian Cortical Neutons

DTIC Science & Technology

1990-05-24

direct responses to acetyl- the entire mammalian central nervous sys- choline and nicotine. Deadvyler and col- teni (19, 32).’The development of...BERT J. (1985) Neurotoxic lesion ; of the athmic neurons recorded near the par-anterior hypothalamus disrupt the JoSentricular in vitro. Brain Res. Bull

Learning Disability: An Educational Adventure. The 1967 Kappa Delta Pi Lecture.

ERIC Educational Resources Information Center

Kephart, Newell C.

Educational implications and symptoms are described for learning disorders, the disruption in the processing of information within the central nervous system caused by brain damage, emotional disturbance, or inadequate presentation of learning experiences. Developmental sequences, developmental progression, and restoration of development are…

Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease

PubMed Central

Cabezas, Ricardo; Ávila, Marcos; Gonzalez, Janneth; El-Bachá, Ramon Santos; Báez, Eliana; García-Segura, Luis Miguel; Jurado Coronel, Juan Camilo; Capani, Francisco; Cardona-Gomez, Gloria Patricia; Barreto, George E.

2014-01-01

The blood–brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson’s Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson’s disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions. PMID:25136294

Magnetic Resonance Imaging and Volumetric Analysis: Novel Tools to Study Thyroid Hormone Disruption and Its Effect on White Matter Development

EPA Science Inventory

Humans and wildlife are exposed to environmental pollutants that have been shown to interfere with the thyroid hormone system and thus may affect brain development. Our goal was to expose pregnant rats to propylthiouracil (PTU) to measure the effects of a goitrogen on white matte...

Roles of elevated 20‑HETE in the breakdown of blood brain barrier and the severity of brain edema in experimental traumatic brain injury.

PubMed

Lu, Liyan; Wang, Mingliang; Yuan, Fang; Wei, Xiaoer; Li, Wenbin

2018-05-01

Breakdown of the blood brain barrier (BBB) is a secondary injury following traumatic brain injury (TBI) and can lead to the development of brain edema. However, the factors that contribute to the disruption of the BBB and increase the severity of brain edema in TBI remain to be elucidated. 20‑hydroxyeicosatetraenoic acid (20‑HETE) is a metabolite of arachidonic acid. The inhibition of 20‑HETEsynthesis by HET0016 has been suggested as a strategy to decrease brain edema. The present study aimed to investigate whether the elevated production of 20‑HETE in cerebral tissue may contribute to BBB breakdown and increase the severity of brain edema in rats with TBI. BBB permeability was quantified using dynamic contrast‑enhanced magnetic resonance imaging and brain edema was measured according to brain water content. Superoxide production in injured tissue was also assessed. Liquid chromatography‑mass spectrometry was used to evaluate 20‑HETE production in injured tissue. Western blot analysis was used to assess the expression of occludin, zonula occludens (ZO)‑1, matrix metalloproteinase (MMP)‑9, and proteins of the c‑Jun N‑terminal kinase (JNK) pathway. A total of 3, 24 and 72 h following the induction of TBI, 20‑HETE levels, BBB permeability and brain edema were identified to be increased, accompanied by an increase in superoxide production. Conversely, superoxide dismutase levels, in addition to the total antioxidative capability were decreased. In addition, the expression of MMP‑9 and proteins of the JNK pathway was upregulated, whereas the expression of occludin and ZO‑1 was observed to be suppressed. These results suggested that 20‑HETE may aggravate BBB disruption following TBI, via enhancing the expression of MMP‑9 and tight junction proteins. Furthermore, oxidative stress and the JNK signaling pathway may be involved in BBB dysregulation. In conclusion, the results of the present demonstrated that the production of 20‑HETE was increased in cerebral tissue following traumatic injury, thus suggesting that it may contribute to the compromise of BBB integrity and the development of brain edema.

Evaluation of laser speckle contrast imaging as an intrinsic method to monitor blood brain barrier integrity

PubMed Central

Dufour, Suzie; Atchia, Yaaseen; Gad, Raanan; Ringuette, Dene; Sigal, Iliya; Levi, Ofer

2013-01-01

The integrity of the blood brain barrier (BBB) can contribute to the development of many brain disorders. We evaluate laser speckle contrast imaging (LSCI) as an intrinsic modality for monitoring BBB disruptions through simultaneous fluorescence and LSCI with vertical cavity surface emitting lasers (VCSELs). We demonstrated that drug-induced BBB opening was associated with a relative change of the arterial and venous blood velocities. Cross-sectional flow velocity ratio (veins/arteries) decreased significantly in rats treated with BBB-opening drugs, ≤0.81 of initial values. PMID:24156049

Disrupted rich club network in behavioral variant frontotemporal dementia and early-onset Alzheimer's disease

PubMed Central

Daianu, Madelaine; Mezher, Adam; Mendez, Mario F.; Jahanshad, Neda; Jimenez, Elvira E.; Thompson, Paul M.

2016-01-01

In network analysis, the so-called ‘rich club’ describes the core areas of the brain that are more densely interconnected among themselves than expected by chance, and has been identified as a fundamental aspect of the human brain connectome. This is the first in-depth diffusion imaging study to investigate the rich club along with other organizational changes in the brain's anatomical network in behavioral frontotemporal dementia (bvFTD), and a matched cohort with early-onset Alzheimer's disease (EOAD). Our study sheds light on how bvFTD and EOAD affect connectivity of white matter fiber pathways in the brain, revealing differences and commonalities in the connectome among the dementias. To analyze the breakdown in connectivity, we studied 3 groups: 20 bvFTD, 23 EOAD and 37 healthy elderly controls. All participants were scanned with diffusion-weighted MRI, and based on whole-brain probabilistic tractography and cortical parcellations, we analyzed the rich club of the brain's connectivity network. This revealed distinct patterns of disruption in both forms of dementia. In the connectome, we detected less disruption overall in EOAD than in bvFTD (False Discovery Rate (FDR) critical Pperm=5.7×10−3, 10,000 permutations), with more involvement of richly interconnected areas of the brain (chi-squared PΧ2=1.4×10−4) – predominantly posterior cognitive alterations. In bvFTD, we found a greater spread of disruption including the rich club (FDR critical Pperm=6×10−4), but especially more peripheral alterations (PΧ2=6.5×10−3), particularly in medial frontal areas of the brain, in line with the known behavioral socioemotional deficits seen in these patients. PMID:26678225

Assessment of sex specific endocrine disrupting effects in the prenatal and pre-pubertal rodent brain.

PubMed

Rebuli, Meghan E; Patisaul, Heather B

2016-06-01

Brain sex differences are found in nearly every region of the brain and fundamental to sexually dimorphic behaviors as well as disorders of the brain and behavior. These differences are organized during gestation and early adolescence and detectable prior to puberty. Endocrine disrupting compounds (EDCs) interfere with hormone action and are thus prenatal exposure is hypothesized to disrupt the formation of sex differences, and contribute to the increased prevalence of pediatric neuropsychiatric disorders that present with a sex bias. Available evidence for the ability of EDCs to impact the emergence of brain sex differences in the rodent brain was reviewed here, with a focus on effects detected at or before puberty. The peer-reviewed literature was searched using PubMed, and all relevant papers published by January 31, 2015 were incorporated. Endpoints of interest included molecular cellular and neuroanatomical effects. Studies on behavioral endpoints were not included because numerous reviews of that literature are available. The hypothalamus was found to be particularly affected by estrogenic EDCs in a sex, time, and exposure dependent manner. The hippocampus also appears vulnerable to endocrine disruption by BPA and PCBs although there is little evidence from the pre-pubertal literature to make any conclusions about sex-specific effects. Gestational EDC exposure can alter fetal neurogenesis and gene expression throughout the brain including the cortex and cerebellum. The available literature primarily focuses on a few, well characterized EDCs, but little data is available for emerging contaminants. The developmental EDC exposure literature demonstrates evidence of altered neurodevelopment as early as fetal life, with sex specific effects observed throughout the brain even before puberty. Copyright © 2015 Elsevier Ltd. All rights reserved.

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

PubMed Central

Jiang, Xiaoyan; Zhang, Lili; Pu, Hongjian; Hu, Xiaoming; Zhang, Wenting; Cai, Wei; Gao, Yanqin; Leak, Rehana K.; Keep, Richard F.; Bennett, Michael V. L.; Chen, Jun

2017-01-01

The damage borne by the endothelial cells (ECs) forming the blood–brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs—namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30–60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs—but not within neurons—ameliorated BBB impairment 1–24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown. PMID:28137866

Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice.

PubMed

Manaenko, Anatol; Lekic, Tim; Ma, Qingyi; Zhang, John H; Tang, Jiping

2013-05-01

Hydrogen inhalation was neuroprotective in several brain injury models. Its mechanisms are believed to be related to antioxidative stress. We investigated the potential neurovascular protective effect of hydrogen inhalation especially effect on mast cell activation in a mouse model of intracerebral hemorrhage. Controlled in vivo laboratory study. Animal research laboratory. One hundred seventy-one 8-week-old male CD-1 mice were used. Collagenase-induced intracerebral hemorrhage model in 8-week-old male CD-1 mice was used. Hydrogen was administrated via spontaneous inhalation. The blood-brain barrier permeability and neurologic deficits were investigated at 24 and 72 hours after intracerebral hemorrhage. Mast cell activation was evaluated by Western blot and immuno-staining. The effects of hydrogen inhalation on mast cell activation were confirmed in an autologous blood injection model intracerebral hemorrhage. At 24 and 72 hours post intracerebral hemorrhage, animals showed blood-brain barrier disruption, brain edema, and neurologic deficits, accompanied with phosphorylation of Lyn kinase and release of tryptase, indicating mast cell activation. Hydrogen treatment diminished phosphorylation of Lyn kinase and release of tryptase, decreased accumulation and degranulation of mast cells, attenuated blood-brain barrier disruption, and improved neurobehavioral function. Activation of mast cells following intracerebral hemorrhage contributed to increase of blood-brain barrier permeability and brain edema. Hydrogen inhalation preserved blood-brain barrier disruption by prevention of mast cell activation after intracerebral hemorrhage.

Impairment of blood-brain barrier is an early event in R6/2 mouse model of Huntington Disease.

PubMed

Di Pardo, Alba; Amico, Enrico; Scalabrì, Francesco; Pepe, Giuseppe; Castaldo, Salvatore; Elifani, Francesca; Capocci, Luca; De Sanctis, Claudia; Comerci, Laura; Pompeo, Francesco; D'Esposito, Maurizio; Filosa, Stefania; Crispi, Stefania; Maglione, Vittorio

2017-01-24

Blood-brain barrier (BBB) breakdown, due to the concomitant disruption of the tight junctions (TJs), normally required for the maintenance of BBB function, and to the altered transport of molecules between blood and brain and vice-versa, has been suggested to significantly contribute to the development and progression of different brain disorders including Huntington's disease (HD). Although the detrimental consequence the BBB breakdown may have in the clinical settings, the timing of its alteration remains elusive for many neurodegenerative diseases. In this study we demonstrate for the first time that BBB disruption in HD is not confined to established symptoms, but occurs early in the disease progression. Despite the obvious signs of impaired BBB permeability were only detectable in concomitance with the onset of the disease, signs of deranged TJs integrity occur precociously in the disease and precede the onset of overt symptoms. To our perspective this finding may add a new dimension to the horizons of pathological mechanisms underlying this devastating disease, however much remains to be elucidated for understanding how specific BBB drug targets can be approached in the future.

[Complex application 2-ethyl-6-methyl-3-hydroxypyridine-succinate and vinpocetine in cerebrovascular disorder.

PubMed

Solovyeva, E Yu; Karneev, A N; Chekanov, A V; Baranova, O A; Choi, I V

Developing brain ischemia due to cerebral vascularization leads to disruption of brain metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of some types of dementia. Early use of antioxidants such as ethyl ether apovincamine acid (vinpocetine) and 2-ethyl-6-methyl-3-hydroxypyridine-succinate in the treatment of this pathology is seen as a real pathogenetically based method of correction of cerebral metabolism with cerebral vascular disorders, demonstrating the increase in cerebral blood flow and also neuroprotective effects. Clinical studies and studies on biological models show that the main mechanisms of action of vinpocetine and 2-ethyl-6-methyl-3-hydroxypyridine-succinate, although have a similar focus, but implementing neuroprotective and nootropic effects via various links in the pathogenesis of ischemic brain damage.

Anterior thalamic nuclei deep brain stimulation reduces disruption of the blood-brain barrier, albumin extravasation, inflammation and apoptosis in kainic acid-induced epileptic rats.

PubMed

Chen, Ying-Chuan; Zhu, Guan-Yu; Wang, Xiu; Shi, Lin; Du, Ting-Ting; Liu, De-Feng; Liu, Yu-Ye; Jiang, Yin; Zhang, Xin; Zhang, Jian-Guo

2017-12-01

Objective The therapeutic efficacy of anterior thalamic nuclei deep brain stimulation (ATN-DBS) against seizures has been largely accepted; however, the effects of ATN-DBS on disruption of the blood-brain barrier (BBB), albumin extravasation, inflammation and apoptosis still remain unclear. Methods Rats were distributed into four treatment groups: physiological saline (PS, N = 12), kainic acid (KA, N = 12), KA-sham-DBS (N = 12) and KA-DBS (N = 12). Seizures were monitored using video-electroencephalogram (EEG). One day after surgery, all rats were sacrificed. Then, samples were prepared for quantitative real-time PCR (qPCR), western blot, immunofluorescence (IF) staining, and transmission electron microscopy to evaluate the disruption of the BBB, albumin extravasation, inflammation, and apoptosis. Result Because of the KA injection, the disruption of the BBB, albumin extravasation, inflammation and apoptosis were more severe in the KA and the KA-sham-DBS groups compared to the PS group (all Ps < 0.05 or < 0.01). The ideal outcomes were observed in the KA-DBS group. ATN-DBS produced a 46.3% reduction in seizure frequency and alleviated the disruption of the BBB, albumin extravasation, inflammatory reaction and apoptosis in comparison to the KA-sham-DBS group (all Ps < 0.05 or < 0.01). Conclusion (1) Seizures can be reduced using ATN-DBS in the epileptogenic stage. (2) ATN-DBS can reduce the disruption of the BBB and albumin extravasation. (3) ATN-DBS has an anti-inflammatory effect in epileptic models.

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

PubMed Central

Preciados, Mark; Yoo, Changwon; Roy, Deodutta

2016-01-01

During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD—APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF—underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes—APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE—are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders. PMID:27983596

Autism: Oxytocin, serotonin, and social reward.

PubMed

Dölen, Gül

2015-01-01

Over 70 years since the first description of the disease, disrupted social behavior remains a core clinical feature of autistic spectrum disorder. The complex etiology of the disorder portends the need for a better understanding of the brain mechanisms that enable social behaviors, particularly those that are relevant to autism which is characterized by a failure to develop peer relationships, difficulty with emotional reciprocity and imitative play, and disrupted language and communication skills. Toward this end, the current review will examine recent progress that has been made toward understanding the neural mechanisms underlying consociate social attachments.

When Trauma Hinders Learning

ERIC Educational Resources Information Center

Barr, Donald A.

2018-01-01

Many kindergarten teachers have encountered children who enter school lacking the ability to control their behavior, but they may not understand the social and biological processes behind these children's disruptive behavior. The author reviews research into early childhood brain development to explain how trauma and chronic stress can make it…

Quantitative Adverse Outcome Pathway for Neurodevelopmental Effects of Thyroid Peroxidase-Induced Thyroid Hormone Synthesis Inhibition

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development and deficiencies lead to adverse neurological outcomes in humans and in animal models. Environmental chemicals have been shown to disrupt TH levels, yet the relationship between developmental exposur...

Developmental origins of brain disorders: roles for dopamine

PubMed Central

Money, Kelli M.; Stanwood, Gregg D.

2013-01-01

Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders. PMID:24391541

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?: Brain tumors and microcephaly arise from opposing derangements regulating progenitor growth. Drivers of microcephaly could be attractive brain tumor targets.

PubMed

Lang, Patrick Y; Gershon, Timothy R

2018-05-01

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity. © 2018 WILEY Periodicals, Inc.

Adenosine receptor agonist NECA increases cerebral extravasation of fluorescein and low molecular weight dextran independent of blood-brain barrier modulation

PubMed Central

Cheng, Chih-Chung; Yang, Ya Lan; Liao, Kate Hsiurong; Lai, Ted Weita

2016-01-01

Conventional methods for therapeutic blood-brain barrier (BBB) disruption facilitate drug delivery but are cumbersome to perform. A previous study demonstrated that adenosine receptor (AR) stimulation by 5′-N-ethylcarboxamide adenosine (NECA) increased the extravasation of intravascular tracers into the brain and proposed that AR agonism may be an effective method for therapeutic BBB disruption. We attempted to confirm the extravasation of tracers into the brain and also investigated tracer extravasation into peripheral organs and tracer retention in the blood. We found that NECA not only increased the extravasation of intravascular fluorescein and low molecular weight dextran into the brain of mice but also increased the concentrations of these tracers in the blood. In fact, the brain:blood ratio-normalized BBB permeability for either tracer is actually decreased by NECA administration. Elevated blood urea nitrogen levels in mice following NECA treatment suggested that renal function impairment was a probable cause of tracer retention. Therefore, NECA has almost no effect on the extravasation of intravascular Evans blue dye (EBD), an albumin-binding tracer with little renal clearance. Rather than inducing BBB disruption, our study demonstrated that NECA increased tracer extravasation into the brain by increasing the concentration gradient of the tracer across the BBB. PMID:27025761

Adenosine receptor agonist NECA increases cerebral extravasation of fluorescein and low molecular weight dextran independent of blood-brain barrier modulation.

PubMed

Cheng, Chih-Chung; Yang, Ya Lan; Liao, Kate Hsiurong; Lai, Ted Weita

2016-03-30

Conventional methods for therapeutic blood-brain barrier (BBB) disruption facilitate drug delivery but are cumbersome to perform. A previous study demonstrated that adenosine receptor (AR) stimulation by 5'-N-ethylcarboxamide adenosine (NECA) increased the extravasation of intravascular tracers into the brain and proposed that AR agonism may be an effective method for therapeutic BBB disruption. We attempted to confirm the extravasation of tracers into the brain and also investigated tracer extravasation into peripheral organs and tracer retention in the blood. We found that NECA not only increased the extravasation of intravascular fluorescein and low molecular weight dextran into the brain of mice but also increased the concentrations of these tracers in the blood. In fact, the brain:blood ratio-normalized BBB permeability for either tracer is actually decreased by NECA administration. Elevated blood urea nitrogen levels in mice following NECA treatment suggested that renal function impairment was a probable cause of tracer retention. Therefore, NECA has almost no effect on the extravasation of intravascular Evans blue dye (EBD), an albumin-binding tracer with little renal clearance. Rather than inducing BBB disruption, our study demonstrated that NECA increased tracer extravasation into the brain by increasing the concentration gradient of the tracer across the BBB.

Curcumin attenuates blood-brain barrier disruption after subarachnoid hemorrhage in mice.

PubMed

Yuan, Jichao; Liu, Wei; Zhu, Haitao; Zhang, Xuan; Feng, Yang; Chen, Yaxing; Feng, Hua; Lin, Jiangkai

2017-01-01

Early brain injury, one of the most important mechanisms underlying subarachnoid hemorrhage (SAH), comprises edema formation and blood-brain barrier (BBB) disruption. Curcumin, an active extract from the rhizomes of Curcuma longa, alleviates neuroinflammation by as yet unknown neuroprotective mechanisms. In this study, we examined whether curcumin treatment ameliorates SAH-induced brain edema and BBB permeability changes, as well as the mechanisms underlying this phenomenon. We induced SAH in mice via endovascular perforation, administered curcumin 15 min after surgery and evaluated neurologic scores, brain water content, Evans blue extravasation, Western blot assay results, and immunohistochemical analysis results 24 h after surgery. Curcumin significantly improved neurologic scores and reduced brain water content in treated mice compared with SAH mice. Furthermore, curcumin decreased Evans blue extravasation, matrix metallopeptidase-9 expression, and the number of Iba-1-positive microglia in treated mice compared with SAH mice. At last, curcumin treatment increased the expression of the tight junction proteins zonula occludens-1 and occludin in treated mice compared with vehicle-treated and sample SAH mice. We demonstrated that curcumin inhibits microglial activation and matrix metallopeptidase-9 expression, thereby reducing brain edema and attenuating post-SAH BBB disruption in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Mdivi-1 ameliorates early brain injury after subarachnoid hemorrhage via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.

PubMed

Fan, Lin-Feng; He, Ping-You; Peng, Yu-Cong; Du, Qing-Hua; Ma, Yi-Jun; Jin, Jian-Xiang; Xu, Hang-Zhe; Li, Jian-Ru; Wang, Zhi-Jiang; Cao, Sheng-Long; Li, Tao; Yan, Feng; Gu, Chi; Wang, Lin; Chen, Gao

2017-11-01

Aberrant modulation of mitochondrial dynamic network, which shifts the balance of fusion and fission towards fission, is involved in brain damage of various neurodegenerative diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. A recent research has shown that the inhibition of mitochondrial fission alleviates early brain injury after experimental subarachnoid hemorrhage, however, the underlying molecular mechanisms have remained to be elucidated. This study was undertaken to characterize the effects of the inhibition of dynamin-related protein-1 (Drp1, a dominator of mitochondrial fission) on blood-brain barrier (BBB) disruption and neuronal apoptosis following SAH and the potential mechanisms. The endovascular perforation model of SAH was performed in adult male Sprague Dawley rats. The results indicated Mdivi-1(a selective Drp1 inhibitor) reversed the morphologic changes of mitochondria and Drp1 translocation, reduced ROS levels, ameliorated the BBB disruption and brain edema remarkably, decreased the expression of MMP-9 and prevented degradation of tight junction proteins-occludin, claudin-5 and ZO-1. Mdivi-1 administration also inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB), leading to decreased expressions of TNF-ɑ, IL-6 and IL-1ß. Moreover, Mdivi-1 treatment attenuated neuronal cell death and improved neurological outcome. To investigate the underlying mechanisms further, we determined that Mdivi-1 reduced p-PERK, p-eIF2α, CHOP, cleaved caspase-3 and Bax expression as well as increased Bcl-2 expression. Rotenone (a selective inhibitor of mitochondrial complexes I) abolished both the anti-BBB disruption and anti-apoptosis effects of Mdivi-1. In conclusion, these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH, and the inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder.

PubMed

Konrad, Kerstin; Eickhoff, Simon B

2010-06-01

In recent years, a change in perspective in etiological models of attention deficit hyperactivity disorder (ADHD) has occurred in concordance with emerging concepts in other neuropsychiatric disorders such as schizophrenia and autism. These models shift the focus of the assumed pathology from regional brain abnormalities to dysfunction in distributed network organization. In the current contribution, we report findings from functional connectivity studies during resting and task states, as well as from studies on structural connectivity using diffusion tensor imaging, in subjects with ADHD. Although major methodological limitations in analyzing connectivity measures derived from noninvasive in vivo neuroimaging still exist, there is convergent evidence for white matter pathology and disrupted anatomical connectivity in ADHD. In addition, dysfunctional connectivity during rest and during cognitive tasks has been demonstrated. However, the causality between disturbed white matter architecture and cortical dysfunction remains to be evaluated. Both genetic and environmental factors might contribute to disruptions in interactions between different brain regions. Stimulant medication not only modulates regionally specific activation strength but also normalizes dysfunctional connectivity, pointing to a predominant network dysfunction in ADHD. By combining a longitudinal approach with a systems perspective in ADHD in the future, it might be possible to identify at which stage during development disruptions in neural networks emerge and to delineate possible new endophenotypes of ADHD. (c) 2010 Wiley-Liss, Inc.

Growth-related neural reorganization and the autism phenotype: a test of the hypothesis that altered brain growth leads to altered connectivity

PubMed Central

Lewis, John D.; Elman, Jeffrey L.

2009-01-01

Theoretical considerations, and findings from computational modeling, comparative neuroanatomy and developmental neuroscience, motivate the hypothesis that a deviant brain growth trajectory will lead to deviant patterns of change in cortico-cortical connectivity. Differences in brain size during development will alter the relative cost and effectiveness of short- and long-distance connections, and should thus impact the growth and retention of connections. Reduced brain size should favor long-distance connectivity; brain overgrowth should favor short-distance connectivity; and inconsistent deviations from the normal growth trajectory – as occurs in autism – should result in potentially disruptive changes to established patterns of functional and physical connectivity during development. To explore this hypothesis, neural networks which modeled inter-hemispheric interaction were grown at the rate of either typically developing children or children with autism. The influence of the length of the inter-hemispheric connections was analyzed at multiple developmental time-points. The networks that modeled autistic growth were less affected by removal of the inter-hemispheric connections than those that modeled normal growth – indicating a reduced reliance on long-distance connections – for short response times, and this difference increased substantially at approximately 24 simulated months of age. The performance of the networks showed a corresponding decline during development. And direct analysis of the connection weights showed a parallel reduction in connectivity. These modeling results support the hypothesis that the deviant growth trajectory in autism spectrum disorders may lead to a disruption of established patterns of functional connectivity during development, with potentially negative behavioral consequences, and a subsequent reduction in physical connectivity. The results are discussed in relation to the growing body of evidence of reduced functional and structural connectivity in autism, and in relation to the behavioral phenotype, particularly the developmental aspects. PMID:18171375

Experimental modelling of the consequences of brief late gestation asphyxia on newborn lamb behaviour and brain structure.

PubMed

Castillo-Melendez, Margie; Baburamani, Ana A; Cabalag, Carlos; Yawno, Tamara; Witjaksono, Anissa; Miller, Suzie L; Walker, David W

2013-01-01

Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term), the cuff was inflated to induce umbilical cord occlusion (UCO), or sham (control). Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i) use all four legs, (ii) attain a standing position, (iii) find the udder, and (iv) successfully suckle--compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies.

Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium.

PubMed

Doolittle, N D; Anderson, C P; Bleyer, W A; Cairncross, J G; Cloughesy, T; Eck, S L; Guastadisegni, P; Hall, W A; Muldoon, L L; Patel, S J; Peereboom, D; Siegal, T; Neuwelt, E A

2001-01-01

Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened in April 2000, at Government Camp, Mount Hood, Oregon. This meeting, which was supported by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders, brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. Optimizing chemotherapy delivery to the CNS is crucial, particularly in view of recent progress identifying certain brain tumors as chemosensitive. The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. This report summarizes the discussions, future directions, and key questions regarding dose-intensive treatment of primary CNS lymphoma, CNS relapse of systemic non-Hodgkin's lymphoma, anaplastic oligodendroglioma, high-grade glioma, and metastatic cancer of the brain. The promising role of cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies for malignant gliomas are discussed.

Developmental and perinatal brain diseases.

PubMed

Adle-Biassette, Homa; Golden, Jeffery A; Harding, Brian

2017-01-01

This chapter briefly describes the normal development of the nervous system, the neuropathology and pathophysiology of acquired and secondary disorders affecting the embryo, fetus, and child. They include CNS manifestations of chromosomal change; forebrain patterning defects; disorders of the brain size; cell migration and specification disorders; cerebellum, hindbrain and spinal patterning defects; hydrocephalus; secondary malformations and destructive pathologies; vascular malformations; arachnoid cysts and infectious diseases. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Copyright © 2017 Elsevier B.V. All rights reserved.

Changes in Brain Monoamines Underlie Behavioural Disruptions after Zebrafish Diet Exposure to Polycyclic Aromatic Hydrocarbons Environmental Mixtures

PubMed Central

Vignet, Caroline; Trenkel, Verena M.; Vouillarmet, Annick; Bricca, Giampiero; Bégout, Marie-Laure; Cousin, Xavier

2017-01-01

Zebrafish were exposed through diet to two environmentally relevant polycyclic aromatic hydrocarbons (PAHs) mixtures of contrasted compositions, one of pyrolytic (PY) origin and one from light crude oil (LO). Monoamine concentrations were quantified in the brains of the fish after six month of exposure. A significant decrease in noradrenaline (NA) was observed in fish exposed to both mixtures, while a decrease in serotonin (5HT) and dopamine (DA) was observed only in LO-exposed fish. A decrease in metabolites of 5HT and DA was observed in fish exposed to both mixtures. Several behavioural disruptions were observed that depended on mixtures, and parallels were made with changes in monoamine concentrations. Indeed, we observed an increase in anxiety in fish exposed to both mixtures, which could be related to the decrease in 5HT and/or NA, while disruptions of daily activity rhythms were observed in LO fish, which could be related to the decrease in DA. Taken together, these results showed that (i) chronic exposures to PAHs mixtures disrupted brain monoamine contents, which could underlie behavioural disruptions, and that (ii) the biological responses depended on mixture compositions. PMID:28273853

Evidence for differential changes of junctional complex proteins in murine neurocysticercosis dependent upon CNS vasculature.

PubMed

Alvarez, Jorge I; Teale, Judy M

2007-09-12

The delicate balance required to maintain homeostasis of the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). Upon injury, the BBB is disrupted compromising the CNS. BBB disruption has been represented as a uniform event. However, our group has shown in a murine model of neurocysticercosis (NCC) that BBB disruption varies depending upon the anatomical site/vascular bed analyzed. In this study further understanding of the mechanisms of BBB disruption was explored in blood vessels located in leptomeninges (pial vessels) and brain parenchyma (parenchymal vessels) by examining the expression of junctional complex proteins in murine brain infected with Mesocestoides corti. Both pial and parenchymal vessels from mock infected animals showed significant colocalization of junctional proteins and displayed an organized architecture. Upon infection, the patterned organization was disrupted and in some cases, particular tight junction and adherens junction proteins were undetectable or appeared to be undergoing proteolysis. The extent and timing of these changes differed between both types of vessels (pial vessel disruption within days versus weeks for parenchymal vessels). To approach potential mechanisms, the expression and activity of matrix metalloproteinase-9 (MMP-9) were evaluated by in situ zymography. The results indicated an increase in MMP-9 activity at sites of BBB disruption exhibiting leukocyte infiltration. Moreover, the timing of MMP activity in pial and parenchymal vessels correlated with the timing of permeability disruption. Thus, breakdown of the BBB is a mutable process despite the similar structure of the junctional complex between pial and parenchymal vessels and involvement of MMP activity.

Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eum, Sung Yong, E-mail: seum@miami.edu; Jaraki, Dima; András, Ibolya E.

Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2)more » after 24 h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs. - Highlights: • PCB153 disturbed human brain endothelial barrier through disruption of occludin. • Lipid raft-associated PP2A/MMP-2 induced PCB153-induced dysfunction of occludin. • Disrupted lipid rafts modulated PCB153-induced increase of permeability. • Lipid rafts act as a signaling platform for PCB153-induced dysfunction of occludin.« less

A common brain network links development, aging, and vulnerability to disease.

PubMed

Douaud, Gwenaëlle; Groves, Adrian R; Tamnes, Christian K; Westlye, Lars Tjelta; Duff, Eugene P; Engvig, Andreas; Walhovd, Kristine B; James, Anthony; Gass, Achim; Monsch, Andreas U; Matthews, Paul M; Fjell, Anders M; Smith, Stephen M; Johansen-Berg, Heidi

2014-12-09

Several theories link processes of development and aging in humans. In neuroscience, one model posits for instance that healthy age-related brain degeneration mirrors development, with the areas of the brain thought to develop later also degenerating earlier. However, intrinsic evidence for such a link between healthy aging and development in brain structure remains elusive. Here, we show that a data-driven analysis of brain structural variation across 484 healthy participants (8-85 y) reveals a largely--but not only--transmodal network whose lifespan pattern of age-related change intrinsically supports this model of mirroring development and aging. We further demonstrate that this network of brain regions, which develops relatively late during adolescence and shows accelerated degeneration in old age compared with the rest of the brain, characterizes areas of heightened vulnerability to unhealthy developmental and aging processes, as exemplified by schizophrenia and Alzheimer's disease, respectively. Specifically, this network, while derived solely from healthy subjects, spatially recapitulates the pattern of brain abnormalities observed in both schizophrenia and Alzheimer's disease. This network is further associated in our large-scale healthy population with intellectual ability and episodic memory, whose impairment contributes to key symptoms of schizophrenia and Alzheimer's disease. Taken together, our results suggest that the common spatial pattern of abnormalities observed in these two disorders, which emerge at opposite ends of the life spectrum, might be influenced by the timing of their separate and distinct pathological processes in disrupting healthy cerebral development and aging, respectively.

An Epigenetic Gateway to Brain Tumor Cell Identity

PubMed Central

Mack, Stephen C.; Hubert, Christopher G.; Miller, Tyler E.; Taylor, Michael D.; Rich, Jeremy N.

2017-01-01

Precise targeting of genetic lesions alone has been insufficient to extend brain tumor patient survival. Brain cancer cells are diverse in their genetic, metabolic, and microenvironmental compositions, accounting for their phenotypic heterogeneity and disparate responses to therapy. These factors converge at the level of the epigenome, representing a unified node that can be disrupted by pharmacologic inhibition. Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks, and disruption of chromatin structure. In this review, we describe the convergence of genetic, metabolic, and micro-environmental factors upon mechanisms of epigenetic deregulation in brain cancer. We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state, and neoplastic transformation, in addition to the potential to exploit these alterations as novel therapeutic strategies for the treatment of brain cancer. PMID:26713744

Gene Expression in Developing Brain is Altered by Modest Reductions in Circulating Levels of Thyroid Hormone.

EPA Science Inventory

Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequatel...

Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development, deficiencies may lead to adverse neurological outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures an...

A PHYSIOLOGICALLY BASED COMPUTATIONAL MODEL OF THE BPG AXIS IN FATHEAD MINNOWS: PREDICTING EFFECTS OF ENDOCRINE DISRUPTING CHEMICAL EXPOSURE ON REPRODUCTIVE ENDPOINTS

EPA Science Inventory

This presentation describes development and application of a physiologically-based computational model that simulates the brain-pituitary-gonadal (BPG) axis and other endpoints important in reproduction such as concentrations of sex steroid hormones, 17-estradiol, testosterone, a...

Gene Expression as a Biomarker of Effect of Thyroid Hormone Action in Developing Brain: Relation to Serum Hormones.

EPA Science Inventory

Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have proved more diffic...

Aflatoxin B1-contaminated diet disrupts the blood-brain barrier and affects fish behavior: Involvement of neurotransmitters in brain synaptosomes.

PubMed

Baldissera, Matheus D; Souza, Carine F; Zeppenfeld, Carla Cristina; Descovi, Sharine N; Moreira, Karen Luise S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; da Silva, Aleksandro S; Baldisserotto, Bernardo

2018-06-01

It is known that the cytotoxic effects of aflatoxin B 1 (AFB 1 ) in endothelial cells of the blood-brain barrier (BBB) are associated with behavioral dysfunction. However, the effects of a diet contaminated with AFB 1 on the behavior of silver catfish remain unknown. Thus, the aim of this study was to evaluate whether an AFB 1 -contaminated diet (1177 ppb kg feed -1 ) impaired silver catfish behavior, as well as whether disruption of the BBB and alteration of neurotransmitters in brain synaptosomes are involved. Fish fed a diet contaminated with AFB 1 presented a behavioral impairment linked with hyperlocomotion on days 14 and 21 compared with the control group (basal diet). Neurotransmitter levels were also affected on days 14 and 21. The permeability of the BBB to Evans blue dye increased in the intoxicated animals compared with the control group, which suggests that the BBB was disrupted. Moreover, acetylcholinesterase (AChE) activity in brain synaptosomes was increased in fish fed a diet contaminated with AFB 1 , while activity of the sodium-potassium pump (Na + , K + -ATPase) was decreased. Based on this evidence, the present study shows that silver catfish fed a diet containing AFB 1 exhibit behavioral impairments related to hyperlocomotion. This diet caused a disruption of the BBB and brain lesions, which may contribute to the behavioral changes. Also, the alterations in the activities of AChE and Na + , K + -ATPase in brain synaptosomes may directly contribute to this behavior, since they may promote synapse dysfunction. In addition, the hyperlocomotion may be considered an important macroscopic marker indicating possible AFB 1 intoxication. Copyright © 2018 Elsevier B.V. All rights reserved.

Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia

PubMed Central

Kim, Jae Hwan; Lee, Yong Woo; Park, Kyung Ah; Lee, Won Taek; Lee, Jong Eun

2010-01-01

Brain edema is frequently shown after cerebral ischemia. It is an expansion of brain volume because of increasing water content in brain. It causes to increase mortality after stroke. Agmatine, formed by the decarboxylation of -arginine by arginine decarboxylase, has been shown to be neuroprotective in trauma and ischemia models. The purpose of this study was to investigate the effect of agmatine for brain edema in ischemic brain damage and to evaluate the expression of aquaporins (AQPs). Results showed that agmatine significantly reduced brain swelling volume 22 h after 2 h middle cerebral artery occlusion in mice. Water content in brain tissue was clearly decreased 24 h after ischemic injury by agmatine treatment. Blood–brain barrier (BBB) disruption was diminished with agmatine than without. The expressions of AQPs-1 and -9 were well correlated with brain edema as water channels, were significantly decreased by agmatine treatment. It can thus be suggested that agmatine could attenuate brain edema by limitting BBB disruption and blocking the accumulation of brain water content through lessening the expression of AQP-1 after cerebral ischemia. PMID:20029450

Sex differences and the development of the rabbit brain: effects of vinclozolin.

PubMed

Bisenius, Erin S; Veeramachaneni, D N Rao; Sammonds, Ginger E; Tobet, Stuart

2006-09-01

The preoptic/anterior hypothalamic area (POA/AH) is one of the most sexually dimorphic areas of the vertebrate brain and plays a pivotal role in regulating male sexual behavior. Vinclozolin is a fungicide thought to be an environmental antiandrogen, which disrupts masculine sexual behavior when administered to rabbits during development. In this study, we examined several characteristics of the rabbit POA/AH for sexual dimorphism and endocrine disruption by vinclozolin. Pregnant rabbits were dosed orally with vinclozolin (10 mg/kg body weight) or carrot paste vehicle once daily for 6 wk beginning at midgestation and continuing through nursing until Postpartum Week 4. At 6 wk, offspring were perfused with 4% paraformaldehyde and brains processed for immunocytochemical localization of tyrosine hydroxylase, calbindin, gonadotropin-releasing hormone (GnRH), or Nissl stain. There were significant sex differences in the distribution of calbindin in the POA/AH and the size of cells in the dorsal POA/AH (values greater in females than in males), but not in the number or distribution of tyrosine hydroxylase or GnRH neurons. In both sexes, exposure to vinclozolin significantly increased calbindin expression in the ventral POA/AH and significantly decreased number of GnRH neurons selectively in the region of the organum vasculosum of the lamina terminalis (OVLT) but not more caudally in the POA/AH. This is the first documentation of a sexually dimorphic region in the rabbit brain, and further supports the use of this species as a model for studying the influence of vinclozolin on reproductive development with potential application to human systems.

Methods to assess the effects of environmental chemicals on the brain-pituitary-gonad axis of the reproductive system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Magliulo-Cepriano, L.; Schreibman, M.P.

1999-07-01

In all vertebrates, the neuroendocrine system serves as the primary and essential link between the external and internal environments and a multitude of physiological systems, including the reproductive system. In response to changes in the environment and fluctuations in levels of circulating humoral agents, the neuroendocrine system is able to reverse, maintain or advance physiological events. Endocrine disrupting compounds are believed to wreak havoc on reproduction and development by interfering in the normal flow of information along the brain-pituitary-gonad axis. While the final effects of these compounds may be easily determined in a number of species, utilization of non-traditional researchmore » animals, such as some fishes in which the pattern of information flow along the brain-pituitary-gonad axis has been meticulously detailed and documented, will provide excellent and novel means of elucidating not only the final effects but the cytological, histological and systemic mechanisms of action of these endocrine disruptors. This report presents methods of assessing the effects of endocrine disrupting compounds on a variety of physiological and morphological parameters in fishes.« less

Model development, testing and experimentation in a CyberWorkstation for Brain-Machine Interface research.

PubMed

Rattanatamrong, Prapaporn; Matsunaga, Andrea; Raiturkar, Pooja; Mesa, Diego; Zhao, Ming; Mahmoudi, Babak; Digiovanna, Jack; Principe, Jose; Figueiredo, Renato; Sanchez, Justin; Fortes, Jose

2010-01-01

The CyberWorkstation (CW) is an advanced cyber-infrastructure for Brain-Machine Interface (BMI) research. It allows the development, configuration and execution of BMI computational models using high-performance computing resources. The CW's concept is implemented using a software structure in which an "experiment engine" is used to coordinate all software modules needed to capture, communicate and process brain signals and motor-control commands. A generic BMI-model template, which specifies a common interface to the CW's experiment engine, and a common communication protocol enable easy addition, removal or replacement of models without disrupting system operation. This paper reviews the essential components of the CW and shows how templates can facilitate the processes of BMI model development, testing and incorporation into the CW. It also discusses the ongoing work towards making this process infrastructure independent.

Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling.

PubMed

Nikolakopoulou, Angeliki Maria; Zhao, Zhen; Montagne, Axel; Zlokovic, Berislav V

2017-01-01

Pericytes regulate key neurovascular functions of the brain. Studies in pericyte-deficient transgenic mice with aberrant signaling between endothelial-derived platelet-derived growth factor BB (PDGF-BB) and platelet-derived growth factor receptor β (PDGFRβ) in pericytes have contributed to better understanding of the role of pericytes in the brain. Here, we studied PdgfrβF7/F7 mice, which carry seven point mutations that disrupt PDGFRβ signaling causing loss of pericytes and vascular smooth muscle cells (VSMCs) in the developing brain. We asked whether these mice have a stable or progressive vascular phenotype after birth, and whether both pericyte and VSMCs populations are affected in the adult brain. We found an early and progressive region-dependent loss of brain pericytes, microvascular reductions and blood-brain barrier (BBB) breakdown, which were more pronounced in the cortex, hippocampus and striatum than in the thalamus, whereas VSMCs population remained unaffected at the time when pericyte loss was already established. For example, compared to age-matched controls, PdgfrβF7/F7 mice between 4-6 and 36-48 weeks of age developed a region-dependent loss in pericyte coverage (22-46, 24-44 and 4-31%) and cell numbers (36-49, 34-64 and 11-36%), reduction in capillary length (20-39, 13-46 and 1-30%), and an increase in extravascular fibrinogen-derived deposits (3.4-5.2, 2.8-4.1 and 0-3.6-fold) demonstrating BBB breakdown in the cortex, hippocampus and thalamus, respectively. Capillary reductions and BBB breakdown correlated with loss of pericyte coverage. Our data suggest that PdgfrβF7/F7 mice develop an aggressive and rapid vascular phenotype without appreciable early involvement of VSMCs, therefore providing a valuable model to study regional effects of pericyte loss on brain vascular and neuronal functions. This model could be a useful tool for future studies directed at understanding the role of pericytes in the pathogenesis of neurological disorders associated with pericyte loss such as vascular dementia, Alzheimer's disease, amyotrophic lateral sclerosis, stroke and human immunodeficiency virus-associated neurocognitive disorder.

Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats

PubMed Central

2010-01-01

Background The Blood Brain Barrier (BBB) maintains the homeostasis of central nervous system by preventing the free passage of macromolecules from the systemic circulation into the brain. This normal physiological function of the BBB presents a challenge for delivery of therapeutic compounds into the brain. Recent studies have shown that the application of focused ultrasound together with ultrasound contrast agent (microbubbles) temporarily increases the permeability of the BBB. This effect is associated with breakdown of tight junctions, the structures that regulate the paracellular permeability of the endothelial cell layer. The influence of this ultrasound effect on the activation of intracellular signaling proteins is currently not well understood. Therefore, the aim of this study was to investigate the activation of cell survival signaling molecules in response to ultrasound-mediated BBB opening; Methods The BBB was disrupted in two four-spot lines (1-1.5 mm spacing) along the right hemisphere of rat brain with ultrasound beams (0.3 MPa, 120 s, 10 ms bursts, repetition frequency = 1 Hz) in the presence Definity microbubbles. Contrast-enhanced MRI images were acquired to assess the extent of BBB opening upon which the animals were sacrificed and the brains removed and processed for biochemical and immunohistochemical analyses; Results Immunoblotting of sonicated brain lysates resolved by SDS-PAGE demonstrated an increase in phosphorylation of Akt and its downstream signaling molecule, GSK3β, while the phosphorylation of MAPK remained unchanged. The elevated levels of pAkt and pGSK3β are still evident after 24 hours post-sonication, a time point where the integrity of the BBB is known to be re-established. Furthermore, immunofluoresence staining localized this increase in pAkt and pGSK3β levels to neuronal cells flanking the region of the disrupted BBB; Conclusions Our data demonstrates that ultrasound-mediated BBB disruption causes an activation of the Akt signaling pathway in neuronal cells surrounding the disrupted BBB. PMID:21078165

Neonatal RU-486 (mifepristone) exposure increases androgen receptor immunoreactivity and sexual behavior in male rats.

PubMed

Forbes-Lorman, Robin; Auger, Anthony P; Auger, Catherine J

2014-01-16

Progesterone and progestin receptors (PRs) are known to play a role in the development of brain physiology and behavior in many different species. The distribution and regulation of PRs within the developing brain suggest that they likely contribute to the organization of the brain and behavior in a sex-specific manner. We examined the role of PR signaling during development on the organization of adult sexual behavior and androgen receptor (AR) expression in the brain. We administered the PR antagonist, RU-486, subcutaneously to male and female rats on postnatal days 1-7 (0=day of birth) and examined adult sexual behavior and AR-immunoreactivity (AR-ir) in the adult brain. A typical sex difference in lordosis quotient (LQ) was observed and neonatal RU-486 treatment did not alter this behavior. In contrast, neonatal RU-486 treatment increased adult male sexual behavior and AR-ir in several brain areas in males. These data indicate that a transient disruption in PR signaling during development can have lasting consequences on the male brain and may increase male sexual behavior in part by increasing AR expression, and therefore androgen sensitivity, in adulthood. © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Deep-brain stimulation for aggressive and disruptive behavior.

PubMed

Franzini, Angelo; Broggi, Giovanni; Cordella, Roberto; Dones, Ivano; Messina, Giuseppe

2013-01-01

To describe our institutional experience with deep-brain stimulation (DBS) used in the treatment of aggressive and disruptive behavior refractory to conservative treatment. With stereotactic methodology and under general anesthesia, seven patients (from 2002 to 2010) were given DBS in the posterior hypothalamic region, bilaterally, and with the aid of intraoperative microrecording. Six of seven patients presented a clear reduction in the aggression and disruptive bouts, with subsequent simplification of familiar management. DBS of the posterior hypothalamic region could be an effective treatment for patients affected by mental retardation in whom disruptive and drug-refractory aggressive behavior coexists. Although several experimental data are available on this target, further studies are necessary to confirm the long-term efficacy and safety of this procedure. Copyright © 2013. Published by Elsevier Inc.

mTOR regulates brain morphogenesis by mediating GSK3 signaling

PubMed Central

Ka, Minhan; Condorelli, Gianluigi; Woodgett, James R.; Kim, Woo-Yang

2014-01-01

Balanced control of neural progenitor maintenance and neuron production is crucial in establishing functional neural circuits during brain development, and abnormalities in this process are implicated in many neurological diseases. However, the regulatory mechanisms of neural progenitor homeostasis remain poorly understood. Here, we show that mammalian target of rapamycin (mTOR) is required for maintaining neural progenitor pools and plays a key role in mediating glycogen synthase kinase 3 (GSK3) signaling during brain development. First, we generated and characterized conditional mutant mice exhibiting deletion of mTOR in neural progenitors and neurons in the developing brain using Nestin-cre and Nex-cre lines, respectively. The elimination of mTOR resulted in abnormal cell cycle progression of neural progenitors in the developing brain and thereby disruption of progenitor self-renewal. Accordingly, production of intermediate progenitors and postmitotic neurons were markedly suppressed. Next, we discovered that GSK3, a master regulator of neural progenitors, interacts with mTOR and controls its activity in cortical progenitors. Finally, we found that inactivation of mTOR activity suppresses the abnormal proliferation of neural progenitors induced by GSK3 deletion. Our findings reveal that the interaction between mTOR and GSK3 signaling plays an essential role in dynamic homeostasis of neural progenitors during brain development. PMID:25273085

Developmental neurotoxicity of monocrotophos and lead is linked to thyroid disruption

PubMed Central

Kumar, B. Kala; Reddy, A. Gopala; Krishna, A. Vamsi; Quadri, S. S. Y. H.; Kumar, P. Shiva

2016-01-01

Aim: A role of thyroid disruption in developmental neurotoxicity of monocrotophos (MCP) and lead is studied. Materials and Methods: A total of 24 female rats after conception were randomized into four groups of six each and treated as follows: Group I - Sham was administered distilled water orally. Group II - A positive control was administered methyl methimazole at 0.02% orally in drinking water. Group III - MCP orally at 0.3 mg/kg and Group IV - Lead acetate at 0.2% orally in drinking water. The drug was administered from gestation day 3 through post-natal day 21 in all the groups. Acetylcholinesterase (AChE) inhibition, thyroid profile (thyroid stimulating hormone, T3 and T4), neurodevelopment (brain wet weights, DNA, RNA and protein), and neurobehavioral (elevated plus maze, photoactometry, and Morris water maze) parameters were assessed in pups. A histopathology of thyroid of dams and brain of progeny was conducted. Results: Inhibition of AChE was <20%. Thyroid profile decreased in the treatment groups. Neurodevelopmental and neurobehavioral parameters did not reveal any significant changes. Thyroid architecture was affected significantly with MCP and lead. Cortical layers too were affected. The three layers of cerebellum either had abnormal arrangement or decreased cellularity in all treated groups relating to thyroid disruption. Conclusion: MCP and lead might have affected the development of cerebrum and cerebellum via thyroid disruption leading to developmental neurotoxicity. PMID:27051198

Correlations between Blood–Brain Barrier Disruption and Neuroinflammation in an Experimental Model of Penetrating Ballistic-Like Brain Injury

PubMed Central

Cartagena, Casandra M.; Lu, Xi-Chun M.; Konopko, Melissa; Dave, Jitendra R.; Tortella, Frank C.; Shear, Deborah A.

2014-01-01

Abstract Blood–brain barrier (BBB) disruption is a pathological hallmark of severe traumatic brain injury (TBI) and is associated with neuroinflammatory events contributing to brain edema and cell death. The goal of this study was to elucidate the profile of BBB disruption after penetrating ballistic-like brain injury (PBBI) in conjunction with changes in neuroinflammatory markers. Brain uptake of biotin-dextran amine (BDA; 3 kDa) and horseradish peroxidase (HRP; 44 kDa) was evaluated in rats at 4 h, 24 h, 48 h, 72 h, and 7 days post-PBBI and compared with the histopathologic and molecular profiles for inflammatory markers. BDA and HRP both displayed a uniphasic profile of extravasation, greatest at 24 h post-injury and which remained evident out to 48 h for HRP and 7 days for BDA. This profile was most closely associated with markers for adhesion (mRNA for intercellular adhesion molecule-1) and infiltration of peripheral granulocytes (mRNA for matrix metalloproteinase-9 [MMP-9] and myeloperoxidase staining). Improvement of BBB dysfunction coincided with increased expression of markers implicated in tissue remodeling and repair. The results of this study reveal a uniphasic and gradient opening of the BBB after PBBI and suggest MMP-9 and resident inflammatory cell activation as candidates for future neurotherapeutic intervention after PBBI. PMID:24138024

Social dysfunction after pediatric traumatic brain injury: a translational perspective

PubMed Central

Ryan, Nicholas P.; Catroppa, Cathy; Godfrey, Celia; Noble-Haeusslein, Linda J.; Shultz, Sandy R.; O'Brien, Terence J.; Anderson, Vicki; Semple, Bridgette D.

2016-01-01

Social dysfunction is common after traumatic brain injury (TBI), contributing to reduced quality of life for survivors. Factors which influence the emergence, development or persistence of social deficits after injury remain poorly understood, particularly in the context of ongoing brain maturation during childhood. Aberrant social interactions have recently been modeled in adult and juvenile rodents after experimental TBI, providing an opportunity to gain new insights into the underlying neurobiology of these behaviors. Here, we review our current understanding of social dysfunction in both humans and rodent models of TBI, with a focus on brain injuries acquired during early development. Modulators of social outcomes are discussed, including injury-related and environmental risk and resilience factors. Disruption of social brain network connectivity and aberrant neuroendocrine function are identified as potential mechanisms of social impairments after pediatric TBI. Throughout, we highlight the overlap and disparities between outcome measures and findings from clinical and experimental approaches, and explore the translational potential of future research to prevent or ameliorate social dysfunction after childhood TBI. PMID:26949224

Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms

PubMed Central

Bolton, Jessica L.; Bilbo, Staci D.

2014-01-01

Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment. PMID:25364282

Involvement of Atm and Trp53 in neural cell loss due to Terf2 inactivation during mouse brain development.

PubMed

Kim, Jusik; Choi, Inseo; Lee, Youngsoo

2017-11-01

Maintenance of genomic integrity is one of the critical features for proper neurodevelopment and inhibition of neurological diseases. The signals from both ATM and ATR to TP53 are well-known mechanisms to remove neural cells with DNA damage during neurogenesis. Here we examined the involvement of Atm and Atr in genomic instability due to Terf2 inactivation during mouse brain development. Selective inactivation of Terf2 in neural progenitors induced apoptosis, resulting in a complete loss of the brain structure. This neural loss was rescued partially in both Atm and Trp53 deficiency, but not in an Atr-deficient background in the mouse. Atm inactivation resulted in incomplete brain structures, whereas p53 deficiency led to the formation of multinucleated giant neural cells and the disruption of the brain structure. These giant neural cells disappeared in Lig4 deficiency. These data demonstrate ATM and TP53 are important for the maintenance of telomere homeostasis and the surveillance of telomere dysfunction during neurogenesis.

Cross-hemispheric functional connectivity in the human fetal brain.

PubMed

Thomason, Moriah E; Dassanayake, Maya T; Shen, Stephen; Katkuri, Yashwanth; Alexis, Mitchell; Anderson, Amy L; Yeo, Lami; Mody, Swati; Hernandez-Andrade, Edgar; Hassan, Sonia S; Studholme, Colin; Jeong, Jeong-Won; Romero, Roberto

2013-02-20

Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.

The plausibility of maternal toxicant exposure and nutritional status as contributing factors to the risk of autism spectrum disorders.

PubMed

Nuttall, Johnathan R

2017-05-01

Recent research suggests the maternal environment may be especially important for the risk of developing autism spectrum disorders (ASD). In particular maternal infections, micronutrient deficiencies, obesity, and toxicant exposures are likely to interact with genetic risk factors to disrupt fetal brain development. The goal of this paper is to investigate the plausibility of maternal toxicant exposure and nutritional status as causal factors in the development of ASD. This paper reviews current research investigating the hypothesis that maternal toxicant exposure and prenatal micronutrient intake are important modifiable risk factors for ASD. Zinc, copper, iron, and vitamin B9 are identified as specific micronutrients with relevance to the etiology of ASD. Specific toxicants induce a maternal inflammatory response leading to fetal micronutrient deficiencies that disrupt early brain development. Importantly, maternal micronutrient supplementation is associated with reduced risk of ASD. Furthermore, animal studies show that micronutrient supplementation can prevent the teratogenicity and developmental neurotoxicity of specific toxicants. These findings lead to the hypothesis that maternal infection, obesity, and toxicant exposures (e.g. valproic acid, endocrine disrupting plasticizers, ethanol, and heavy metals) are all environmental risk factors for ASD that lead to fetal micronutrient deficiencies resulting from a maternal inflammatory response. It could be possible to use markers of inflammation and micronutrient status to identify women that would benefit from micronutrient supplementation or dietary interventions to reduce the risk of ASD. However, more research is needed to demonstrate a causal role of fetal micronutrient deficiencies and clarify the underlying mechanisms that contribute to ASD.

Rich club analysis in the Alzheimer's disease connectome reveals a relatively undisturbed structural core network

PubMed Central

Daianu, Madelaine; Jahanshad, Neda; Nir, Talia M.; Jack, Clifford R.; Weiner, Michael W.; Bernstein, Matthew; Thompson, Paul M.

2015-01-01

Diffusion imaging can assess the white matter connections within the brain, revealing how neural pathways break down in Alzheimer's disease (AD). We analyzed 3-Tesla whole-brain diffusion-weighted images from 202 participants scanned by the Alzheimer's Disease Neuroimaging Initiative – 50 healthy controls, 110 with mild cognitive impairment (MCI) and 42 AD patients. From whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We tested whether AD disrupts the ‘rich-club’ – a network property where high-degree network nodes are more interconnected than expected by chance. We calculated the rich-club properties at a range of degree thresholds, as well as other network topology measures including global degree, clustering coefficient, path length and efficiency. Network disruptions predominated in the low-degree regions of the connectome in patients, relative to controls. The other metrics also showed alterations, suggesting a distinctive pattern of disruption in AD, less pronounced in MCI, targeting global brain connectivity, and focusing on more remotely connected nodes rather than the central core of the network. AD involves severely reduced structural connectivity; our step-wise rich club coefficients analyze points to disruptions predominantly in the peripheral network components; other modalities of data are needed to know if this indicates impaired communication among non rich-club regions. The highly connected core was relatively preserved, offering new evidence on the neural basis of progressive risk for cognitive decline. PMID:26037224

Loss of Cation-Chloride Cotransporter Expression in Preterm Infants With White Matter Lesions: Implications for the Pathogenesis of Epilepsy

PubMed Central

Robinson, Shenandoah; Mikolaenko, Irina; Thompson, Ian; Cohen, Mark L.; Goyal, Monisha

2011-01-01

Epilepsy associated with preterm birth is often refractory to anticonvulsants. Children who are born preterm are also prone to cognitive delay and behavioral problems. Brains from these children often show diffuse abnormalities in cerebral circuitry that is likely caused by disrupted development during critical stages of cortical formation. To test the hypothesis that prenatal injury impairs the developmental switch of γ-amino butyric acid (GABA)ergic synapses from excitatory to inhibitory, thereby disrupting cortical circuit formation and predisposing to epilepsy, we used immunohistochemistry to compare the expression of cation-chloride transporters that developmentally regulate postsynaptic GABAergic discharges in postmortem cerebral samples from infants born preterm with known white matter injury (n = 11) with that of controls with minimal white matter gliosis (n = 7). Controls showed the expected developmental expression of cation-chloride transporters NKCC1 and KCC2 and of calretinin, a marker of a GABAergic neuronal subpopulation. Samples from infants with white matter damage showed a significant loss of expression of both NKCC1 and KCC2 in subplate and white matter. By contrast, there were no significant differences in total cell number or glutamate transporter VGLUT1 expression. Together, these novel findings suggest a molecular mechanism involved in the disruption of a critical stage of cerebral circuit development after brain injury from preterm birth that may predispose to epilepsy. PMID:20467335

Organotins in Neuronal Damage, Brain Function, and Behavior: A Short Review

PubMed Central

Ferraz da Silva, Igor; Freitas-Lima, Leandro Ceotto; Graceli, Jones Bernardes; Rodrigues, Lívia Carla de Melo

2018-01-01

The consequences of exposure to environmental contaminants have shown significant effects on brain function and behavior in different experimental models. The endocrine-disrupting chemicals (EDC) present various classes of pollutants with potential neurotoxic actions, such as organotins (OTs). OTs have received special attention due to their toxic effects on the central nervous system, leading to abnormal mammalian neuroendocrine axis function. OTs are organometallic pollutants with a tin atom bound to one or more carbon atoms. OT exposure may occur through the food chain and/or contaminated water, since they have multiple applications in industry and agriculture. In addition, OTs have been used with few legal restrictions in the last decades, despite being highly toxic. In addition to their action as EDC, OTs can also cross the blood–brain barrier and show relevant neurotoxic effects, as observed in several animal model studies specifically involving the development of neurodegenerative processes, neuroinflammation, and oxidative stress. Thus, the aim of this short review is to summarize the toxic effects of the most common OT compounds, such as trimethyltin, tributyltin, triethyltin, and triphenyltin, on the brain with a focus on neuronal damage as a result of oxidative stress and neuroinflammation. We also aim to present evidence for the disruption of behavioral functions, neurotransmitters, and neuroendocrine pathways caused by OTs. PMID:29358929

Disruption of the blood–brain barrier in pigs naturally infected with Taenia solium, untreated and after anthelmintic treatment

PubMed Central

Guerra-Giraldez, Cristina; Marzal, Miguel; Cangalaya, Carla; Balboa, Diana; Orrego, Miguel Ángel; Paredes, Adriana; Gonzales-Gustavson, Eloy; Arroyo, Gianfranco; García, Hector H.; González, Armando E.; Mahanty, Siddhartha; Nash, Theodore E.

2014-01-01

Neurocysticercosis is a widely prevalent disease in the tropics that causes seizures and a variety of neurological symptoms in most of the world. Experimental models are limited and do not allow assessment of the degree of inflammation around brain cysts. The vital dye Evans Blue (EB) was injected into 11 pigs naturally infected with Taenia solium cysts to visually identify the extent of disruption of the blood brain barrier. A total of 369 cysts were recovered from the 11 brains and classified according to the staining of their capsules as blue or unstained. The proportion of cysts with blue capsules was significantly higher in brains from pigs that had received anthelmintic treatment 48 and 120 h before the EB infusion, indicating a greater compromise of the blood brain barrier due to treatment. The model could be useful for understanding the pathology of treatment-induced inflammation in neurocysticercosis. PMID:23684909

DOSE-DEPENDENT REDUCTIONS IN SPATIAL LEARING AND SYNAPTIC FUNCTION IN THE DENTATE GYRUS OF ADULT RATS FOLLOWING DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY.

EPA Science Inventory

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

Youth Court: An Alternative Response to School Bullying

ERIC Educational Resources Information Center

Copich, Cindy

2012-01-01

Bullying and school violence are critical issues facing 21st century educational leaders. U.S. public schools have been scrambling to develop and implement anti-bullying programs with varying degrees of success. Bullying leads to disruption of learning, and its lasting effects of anxiety, depression, anger, and actual brain damage follow victims…

Canavan Disease: A White Matter Disorder

ERIC Educational Resources Information Center

Kumar, Shalini; Mattan, Natalia S.; de Vellis, Jean

2006-01-01

Breakdown of oligodendrocyte-neuron interactions in white matter (WM), such as the loss of myelin, results in axonal dysfunction and hence a disruption of information processing between brain regions. The major feature of leukodystrophies is the lack of proper myelin formation during early development or the onset of myelin loss late in life.…

IMPAIRMENT IN SHORT-TERM BUT ENHANCED LONG-TERM SYNAPTIC POTENTIATION AND ERK ACTIVATION IN ADULT HIPPOCAMPAL AREA CA1 FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM.

EPA Science Inventory

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

Severe blood-brain barrier disruption and surrounding tissue injury.

PubMed

Chen, Bo; Friedman, Beth; Cheng, Qun; Tsai, Phil; Schim, Erica; Kleinfeld, David; Lyden, Patrick D

2009-12-01

Blood-brain barrier opening during ischemia follows a biphasic time course, may be partially reversible, and allows plasma constituents to enter brain and possibly damage cells. In contrast, severe vascular disruption after ischemia is unlikely to be reversible and allows even further extravasation of potentially harmful plasma constituents. We sought to use simple fluorescent tracers to allow wide-scale visualization of severely damaged vessels and determine whether such vascular disruption colocalized with regions of severe parenchymal injury. Severe vascular disruption and ischemic injury was produced in adult Sprague Dawley rats by transient occlusion of the middle cerebral artery for 1, 2, 4, or 8 hours, followed by 30 minutes of reperfusion. Fluorescein isothiocyanate-dextran (2 MDa) was injected intravenously before occlusion. After perfusion-fixation, brain sections were processed for ultrastructure or fluorescence imaging. We identified early evidence of tissue damage with Fluoro-Jade staining of dying cells. With increasing ischemia duration, greater quantities of high molecular weight dextran-fluorescein isothiocyanate invaded and marked ischemic regions in a characteristic pattern, appearing first in the medial striatum, spreading to the lateral striatum, and finally involving cortex; maximal injury was seen in the mid-parietal areas, consistent with the known ischemic zone in this model. The regional distribution of the severe vascular disruption correlated with the distribution of 24-hour 2,3,5-triphenyltetrazolium chloride pallor (r=0.75; P<0.05) and the cell death marker Fluoro-Jade (r=0.86; P<0.05). Ultrastructural examination showed significantly increased areas of swollen astrocytic foot process and swollen mitochondria in regions of high compared to low leakage, and compared to contralateral homologous regions (ANOVA P<0.01). Dextran extravasation into the basement membrane and surrounding tissue increased significantly from 2 to 8 hours of occlusion duration (Independent samples t test, P<0.05). Severe vascular disruption, as labeled with high-molecular-weight dextran-fluorescein isothiocyanate leakage, is associated with severe tissue injury. This marker of severe vascular disruption may be useful in further studies of the pathoanatomic mechanisms of vascular disruption-mediated tissue injury.

Impact of Low Dose Oral Exposure to Bisphenol A (BPA) on the Neonatal Rat Hypothalamic and Hippocampal Transcriptome: A CLARITY-BPA Consortium Study

PubMed Central

Arambula, Sheryl E.; Belcher, Scott M.; Planchart, Antonio; Turner, Stephen D.

2016-01-01

Bisphenol A (BPA) is an endocrine disrupting, high volume production chemical found in a variety of products. Evidence of prenatal exposure has raised concerns that developmental BPA may disrupt sex-specific brain organization and, consequently, induce lasting changes on neurophysiology and behavior. We and others have shown that exposure to BPA at doses below the no-observed-adverse-effect level can disrupt the sex-specific expression of estrogen-responsive genes in the neonatal rat brain including estrogen receptors (ERs). The present studies, conducted as part of the Consortium Linking Academic and Regulatory Insights of BPA Toxicity program, expanded this work by examining the hippocampal and hypothalamic transcriptome on postnatal day 1 with the hypothesis that genes sensitive to estrogen and/or sexually dimorphic in expression would be altered by prenatal BPA exposure. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (0-, 2.5-, 25-, 250-, 2500-, or 25 000-μg/kg body weight [bw]/d). Ethinyl estradiol was used as a reference estrogen (0.05- or 0.5-μg/kg bw/d). Postnatal day 1 brains were microdissected and gene expression was assessed with RNA-sequencing (0-, 2.5-, and 2500-μg/kg bw BPA groups only) and/or quantitative real-time PCR (all exposure groups). BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ERα and ERβ (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain. PMID:27571134

Impact of Low Dose Oral Exposure to Bisphenol A (BPA) on the Neonatal Rat Hypothalamic and Hippocampal Transcriptome: A CLARITY-BPA Consortium Study.

PubMed

Arambula, Sheryl E; Belcher, Scott M; Planchart, Antonio; Turner, Stephen D; Patisaul, Heather B

2016-10-01

Bisphenol A (BPA) is an endocrine disrupting, high volume production chemical found in a variety of products. Evidence of prenatal exposure has raised concerns that developmental BPA may disrupt sex-specific brain organization and, consequently, induce lasting changes on neurophysiology and behavior. We and others have shown that exposure to BPA at doses below the no-observed-adverse-effect level can disrupt the sex-specific expression of estrogen-responsive genes in the neonatal rat brain including estrogen receptors (ERs). The present studies, conducted as part of the Consortium Linking Academic and Regulatory Insights of BPA Toxicity program, expanded this work by examining the hippocampal and hypothalamic transcriptome on postnatal day 1 with the hypothesis that genes sensitive to estrogen and/or sexually dimorphic in expression would be altered by prenatal BPA exposure. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (0-, 2.5-, 25-, 250-, 2500-, or 25 000-μg/kg body weight [bw]/d). Ethinyl estradiol was used as a reference estrogen (0.05- or 0.5-μg/kg bw/d). Postnatal day 1 brains were microdissected and gene expression was assessed with RNA-sequencing (0-, 2.5-, and 2500-μg/kg bw BPA groups only) and/or quantitative real-time PCR (all exposure groups). BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ERα and ERβ (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain.

O-GlcNAc modification of radial glial vimentin filaments in the developing chick brain.

PubMed

Farach, Andrew M; Galileo, Deni S

2008-12-01

We examined the post-translational modification of intracellular proteins by beta-O-linked N-acetylglucosamine (O-GlcNAc) with regard to neurofilament phosphorylation in the developing chick optic tectum. A regulated developmental pattern of O-GlcNAcylation was discovered in the developing brain. Most notably, discernible staining occurs along radial glial filaments but not along neuronal filaments in vivo. Immunohistochemical analyses in sections of progressive stages of development suggest upregulation of O-GlcNAc in the ependyma, tectofugal neuron bodies, and radial glial processes, but not in axons. In contrast, double-label immunostaining of monolayer cultures made from dissociated embryonic day (E) 7 optic tecta revealed O-GlcNAcylation of most axons. Labeling of brain sections together with Western blot analyses showed O-GlcNAc modification of a few discrete proteins throughout development, and suggested vimentin as the protein in radial glia. Immunoprecipitation of vimentin from E9 whole brain lysates confirmed O-GlcNAcylation of vimentin in development. These results indicate a regulated pattern of O-GlcNAc modification of vimentin filaments, which in turn suggests a role for O-GlcNAc-modified intermediate filaments in radial glia, but not in neurons during brain development. The control mechanisms that regulate this pattern in vivo, however, are disrupted when cells are placed in vitro.

Axon-glial disruption: the link between vascular disease and Alzheimer's disease?

PubMed

Horsburgh, Karen; Reimer, Michell M; Holland, Philip; Chen, Guiquan; Scullion, Gillian; Fowler, Jill H

2011-08-01

Vascular risk factors play a critical role in the development of cognitive decline and AD (Alzheimer's disease), during aging, and often result in chronic cerebral hypoperfusion. The neurobiological link between hypoperfusion and cognitive decline is not yet defined, but is proposed to involve damage to the brain's white matter. In a newly developed mouse model, hypoperfusion, in isolation, produces a slowly developing and diffuse damage to myelinated axons, which is widespread in the brain, and is associated with a selective impairment in working memory. Cerebral hypoperfusion, an early event in AD, has also been shown to be associated with white matter damage and notably an accumulation of amyloid. The present review highlights some of the published data linking white matter disruption to aging and AD as a result of vascular dysfunction. A model is proposed by which chronic cerebral hypoperfusion, as a result of vascular factors, results in both the generation and accumulation of amyloid and injury to white matter integrity, resulting in cognitive impairment. The generation of amyloid and accumulation in the vasculature may act to perpetuate further vascular dysfunction and accelerate white matter pathology, and as a consequence grey matter pathology and cognitive decline.

Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study

PubMed Central

Palmela, Inês; Correia, Leonor; Silva, Rui F. M.; Sasaki, Hiroyuki; Kim, Kwang S.; Brites, Dora; Brito, Maria A.

2015-01-01

Ursodeoxycholic acid and its main conjugate glycoursodeoxycholic acid are bile acids with neuroprotective properties. Our previous studies demonstrated their anti-apoptotic, anti-inflammatory, and antioxidant properties in neural cells exposed to elevated levels of unconjugated bilirubin (UCB) as in severe jaundice. In a simplified model of the blood-brain barrier, formed by confluent monolayers of a cell line of human brain microvascular endothelial cells, UCB has shown to induce caspase-3 activation and cell death, as well as interleukin-6 release and a loss of blood-brain barrier integrity. Here, we tested the preventive and restorative effects of these bile acids regarding the disruption of blood-brain barrier properties by UCB in in vitro conditions mimicking severe neonatal hyperbilirubinemia and using the same experimental blood-brain barrier model. Both bile acids reduced the apoptotic cell death induced by UCB, but only glycoursodeoxycholic acid significantly counteracted caspase-3 activation. Bile acids also prevented the upregulation of interleukin-6 mRNA, whereas only ursodeoxycholic acid abrogated cytokine release. Regarding barrier integrity, only ursodeoxycholic acid abrogated UCB-induced barrier permeability. Better protective effects were obtained by bile acid pre-treatment, but a strong efficacy was still observed by their addition after UCB treatment. Finally, both bile acids showed ability to cross confluent monolayers of human brain microvascular endothelial cells in a time-dependent manner. Collectively, data disclose a therapeutic time-window for preventive and restorative effects of ursodeoxycholic acid and glycoursodeoxycholic acid against UCB-induced blood-brain barrier disruption and damage to human brain microvascular endothelial cells. PMID:25821432

Early Blood-Brain Barrier Disruption after Mechanical Thrombectomy in Acute Ischemic Stroke.

PubMed

Shi, Zhong-Song; Duckwiler, Gary R; Jahan, Reza; Tateshima, Satoshi; Szeder, Viktor; Saver, Jeffrey L; Kim, Doojin; Sharma, Latisha K; Vespa, Paul M; Salamon, Noriko; Villablanca, J Pablo; Viñuela, Fernando; Feng, Lei; Loh, Yince; Liebeskind, David S

2018-05-01

The impact of blood-brain barrier (BBB) disruption can be detected by intraparenchymal hyperdense lesion on the computed tomography (CT) scan after endovascular stroke therapy. The purpose of this study was to determine whether early BBB disruption predicts intracranial hemorrhage and poor outcome in patients with acute ischemic stroke treated with mechanical thrombectomy. We analyzed patients with anterior circulation stroke treated with mechanical thrombectomy and identified BBB disruption on the noncontrast CT images immediately after endovascular treatment. Follow-up CT or magnetic resonance imaging scan was performed at 24 hours to assess intracranial hemorrhage. We dichotomized patients into those with moderate BBB disruption versus those with minor BBB disruption and no BBB disruption. We evaluated the association of moderate BBB disruption after mechanical thrombectomy with intracranial hemorrhage and clinical outcomes. Moderate BBB disruption after mechanical thrombectomy was found in 56 of 210 patients (26.7%). Moderate BBB disruption was independently associated with higher rates of hemorrhagic transformation (OR 25.33; 95% CI 9.93-64.65; P < .001), parenchymal hematoma (OR 20.57; 95% CI 5.64-74.99; P < .001), and poor outcome at discharge (OR 2.35; 95% CI 1.09-5.07; P = .03). The association of BBB disruption with intracranial hemorrhage remained in patients with successful reperfusion after mechanical thrombectomy. The location of BBB disruption was not associated with intracranial hemorrhage and poor outcome. Moderate BBB disruption is common after mechanical thrombectomy in a quarter of patients with acute ischemic stroke and increases the risk of intracranial hemorrhage and poor outcome. Copyright © 2018 by the American Society of Neuroimaging.

Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection.

PubMed

Li, Fang; Wang, Yueyun; Yu, Lan; Cao, Shengbo; Wang, Ke; Yuan, Jiaolong; Wang, Chong; Wang, Kunlun; Cui, Min; Fu, Zhen F

2015-05-01

Japanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage. In vitro studies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB. Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate that JEV gains entry into the CNS prior to BBB disruption. Furthermore, it is not JEV infection per se, but the inflammatory cytokines/chemokines induced by JEV infection that inhibit the expression of TJ proteins and ultimately result in the enhancement of BBB permeability. Neutralization of gamma interferon (IFN-γ) ameliorated the enhancement of BBB permeability in JEV-infected mice, suggesting that IFN-γ could be a potential therapeutic target. This study would lead to identification of potential therapeutic avenues for the treatment of JEV infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Epigenetic mechanisms in sexual differentiation of the brain and behaviour.

PubMed

Forger, Nancy G

2016-02-19

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour. © 2016 The Author(s).

Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease

PubMed Central

Simon, Matthew J.; Iliff, Jeffrey J.

2015-01-01

Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer’s disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the ‘glymphatic’ system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. PMID:26499397

Insight from animal models of environmentally-driven epigenetic changes in the developing and adult brain

PubMed Central

Doherty, Tiffany S.; Roth, Tania L.

2017-01-01

The efforts of many neuroscientists are directed toward understanding the appreciable plasticity of the brain and behavior. In recent years, epigenetics has become a core of this focus as a prime mechanistic candidate for behavioral modifications. Animal models have been instrumental in advancing our understanding of environmentally-driven changes to the epigenome in the developing and adult brain. This review focuses mainly on such discoveries driven by adverse environments along with their associated behavioral outcomes. While much of the evidence discussed focuses on epigenetics within the central nervous system, several peripheral studies in humans who have experienced significant adversity are also highlighted. As we continue to unravel the link between epigenetics and phenotype, discerning the complexity and specificity of epigenetic changes induced by environments is an important step toward understanding optimal development and how to prevent or ameliorate behavioral deficits bred by disruptive environments. PMID:27687803

Heart-rate sensitive optical coherence angiography for measuring vascular changes due to posttraumatic brain injury in mice

NASA Astrophysics Data System (ADS)

Tremoleda, Jordi L.; Alvarez, Karl; Aden, Abdirahman; Donnan, Robert; Michael-Titus, Adina T.; Tomlins, Peter H.

2017-12-01

Traumatic brain injury (TBI) results in direct vascular disruption, triggering edema, and reduction in cerebral blood flow. Therefore, understanding the pathophysiology of brain microcirculation following TBI is important for the development of effective therapies. Optical coherence angiography (OCA) is a promising tool for evaluating TBI in rodent models. We develop an approach to OCA that uses the heart-rate frequency to discriminate between static tissue and vasculature. This method operates on intensity data and is therefore not phase sensitive. Furthermore, it does not require spatial overlap of voxels and thus can be applied to pre-existing datasets for which oversampling may not have been explicitly considered. Heart-rate sensitive OCA was developed for dynamic assessment of mouse microvasculature post-TBI. Results show changes occurring at 5-min intervals within the first 50 min of injury.

Disrupted resting-state brain network properties in obesity: decreased global and putaminal cortico-striatal network efficiency.

PubMed

Baek, K; Morris, L S; Kundu, P; Voon, V

2017-03-01

The efficient organization and communication of brain networks underlie cognitive processing and their disruption can lead to pathological behaviours. Few studies have focused on whole-brain networks in obesity and binge eating disorder (BED). Here we used multi-echo resting-state functional magnetic resonance imaging (rsfMRI) along with a data-driven graph theory approach to assess brain network characteristics in obesity and BED. Multi-echo rsfMRI scans were collected from 40 obese subjects (including 20 BED patients) and 40 healthy controls and denoised using multi-echo independent component analysis (ME-ICA). We constructed a whole-brain functional connectivity matrix with normalized correlation coefficients between regional mean blood oxygenation level-dependent (BOLD) signals from 90 brain regions in the Automated Anatomical Labeling atlas. We computed global and regional network properties in the binarized connectivity matrices with an edge density of 5%-25%. We also verified our findings using a separate parcellation, the Harvard-Oxford atlas parcellated into 470 regions. Obese subjects exhibited significantly reduced global and local network efficiency as well as decreased modularity compared with healthy controls, showing disruption in small-world and modular network structures. In regional metrics, the putamen, pallidum and thalamus exhibited significantly decreased nodal degree and efficiency in obese subjects. Obese subjects also showed decreased connectivity of cortico-striatal/cortico-thalamic networks associated with putaminal and cortical motor regions. These findings were significant with ME-ICA with limited group differences observed with conventional denoising or single-echo analysis. Using this data-driven analysis of multi-echo rsfMRI data, we found disruption in global network properties and motor cortico-striatal networks in obesity consistent with habit formation theories. Our findings highlight the role of network properties in pathological food misuse as possible biomarkers and therapeutic targets.

Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

PubMed

Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi

2018-05-16

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases. SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our results suggest that proper control of TGF-β/Smads/CRMP2 signaling pathways is critical for the precise execution of neuronal morphogenesis, whose impairment eventually results in neurodevelopmental disorders. Copyright © 2018 the authors 0270-6474/18/384791-20$15.00/0.

Family members' experiences of driving disruption after acquired brain injury.

PubMed

Liang, Phyllis; Fleming, Jennifer; Gustafsson, Louise; Griffin, Janelle; Liddle, Jacki

2017-01-01

1) To explore family members' lived experiences of driving disruption at early and later stages of the recovery continuum following acquired brain injury (ABI). 2) To describe health-related quality of life of family members of individuals with ABI who are experiencing driving disruption. Mixed methods phenomenological research approach. Semi-structured interviews and health-related quality of life questionnaires were conducted with 15 family members of individuals with ABI (early group: 1-12 months post-injury, n = 6; later group: >1 year post-injury, n = 9). Two main themes were identified: Different for everyone: how driving disruption affects families, and Making it harder: context of driving disruption. The challenges of driving disruption were reported more frequently and with a more intense focus by family members who were caring for their relative for more than 1 year post-injury. This group also reported higher caregiver strain and poorer health-related quality of life. Reduced satisfaction with life, poor mental health and affected family functioning were reported by both groups. Driving disruption impacts on family members and has long-lasting consequences. It is important for clinicians to work with family members to manage these challenges even years after ABI and consider individual contextual factors.

Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood-brain barrier disruption in a murine model of osmotic demyelination syndrome.

PubMed

Bouchat, Joanna; Couturier, Bruno; Marneffe, Catherine; Gankam-Kengne, Fabrice; Balau, Benoît; De Swert, Kathleen; Brion, Jean-Pierre; Poncelet, Luc; Gilloteaux, Jacques; Nicaise, Charles

2018-03-01

The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post-correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post-correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood-brain barrier (BBB) leakages. Expression levels of IL-1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post-correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS. © 2017 Wiley Periodicals, Inc.

Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain

NASA Astrophysics Data System (ADS)

Arvanitis, Costas D.; Livingstone, Margaret S.; McDannold, Nathan

2013-07-01

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation—the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies.

Selective Toll-Like Receptor 4 Antagonists Prevent Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice.

PubMed

Okada, Takeshi; Kawakita, Fumihiro; Nishikawa, Hirofumi; Nakano, Fumi; Liu, Lei; Suzuki, Hidenori

2018-05-31

There are no direct evidences showing the linkage between Toll-like receptor 4 (TLR4) and blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). The purpose of this study was to examine if selective blockage of TLR4 prevents BBB disruption after SAH in mice and if the TLR4 signaling involves mitogen-activated protein kinases (MAPKs). One hundred and fifty-one C57BL/6 male mice underwent sham or endovascular perforation SAH operation, randomly followed by an intracerebroventricular infusion of vehicle or two dosages (117 or 585 ng) of a selective TLR4 antagonist IAXO-102 at 30 min post-operation. The effects were evaluated by survival rates, neurological scores, and brain water content at 24-72 h and immunoglobulin G immunostaining and Western blotting at 24 h post-SAH. IAXO-102 significantly prevented post-SAH neurological impairments, brain edema, and BBB disruption, resulting in improved survival rates. IAXO-102 also significantly suppressed post-SAH activation of a major isoform of MAPK p46 c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-9 as well as periostin induction and preserved tight junction protein zona occludens-1. Another selective TLR4 antagonist TAK-242, which has a different binding site from IAXO-102, also showed similar effects to IAXO-102. This study first provided the evidence that TLR4 signaling is involved in post-SAH acute BBB disruption and that the signaling is mediated at least partly by JNK activation. TLR4-targeted therapy may be promising to reduce post-SAH morbidities and mortalities.

Development of large-scale functional brain networks in children.

PubMed

Supekar, Kaustubh; Musen, Mark; Menon, Vinod

2009-07-01

The ontogeny of large-scale functional organization of the human brain is not well understood. Here we use network analysis of intrinsic functional connectivity to characterize the organization of brain networks in 23 children (ages 7-9 y) and 22 young-adults (ages 19-22 y). Comparison of network properties, including path-length, clustering-coefficient, hierarchy, and regional connectivity, revealed that although children and young-adults' brains have similar "small-world" organization at the global level, they differ significantly in hierarchical organization and interregional connectivity. We found that subcortical areas were more strongly connected with primary sensory, association, and paralimbic areas in children, whereas young-adults showed stronger cortico-cortical connectivity between paralimbic, limbic, and association areas. Further, combined analysis of functional connectivity with wiring distance measures derived from white-matter fiber tracking revealed that the development of large-scale brain networks is characterized by weakening of short-range functional connectivity and strengthening of long-range functional connectivity. Importantly, our findings show that the dynamic process of over-connectivity followed by pruning, which rewires connectivity at the neuronal level, also operates at the systems level, helping to reconfigure and rebalance subcortical and paralimbic connectivity in the developing brain. Our study demonstrates the usefulness of network analysis of brain connectivity to elucidate key principles underlying functional brain maturation, paving the way for novel studies of disrupted brain connectivity in neurodevelopmental disorders such as autism.

Development of Large-Scale Functional Brain Networks in Children

PubMed Central

Supekar, Kaustubh; Musen, Mark; Menon, Vinod

2009-01-01

The ontogeny of large-scale functional organization of the human brain is not well understood. Here we use network analysis of intrinsic functional connectivity to characterize the organization of brain networks in 23 children (ages 7–9 y) and 22 young-adults (ages 19–22 y). Comparison of network properties, including path-length, clustering-coefficient, hierarchy, and regional connectivity, revealed that although children and young-adults' brains have similar “small-world” organization at the global level, they differ significantly in hierarchical organization and interregional connectivity. We found that subcortical areas were more strongly connected with primary sensory, association, and paralimbic areas in children, whereas young-adults showed stronger cortico-cortical connectivity between paralimbic, limbic, and association areas. Further, combined analysis of functional connectivity with wiring distance measures derived from white-matter fiber tracking revealed that the development of large-scale brain networks is characterized by weakening of short-range functional connectivity and strengthening of long-range functional connectivity. Importantly, our findings show that the dynamic process of over-connectivity followed by pruning, which rewires connectivity at the neuronal level, also operates at the systems level, helping to reconfigure and rebalance subcortical and paralimbic connectivity in the developing brain. Our study demonstrates the usefulness of network analysis of brain connectivity to elucidate key principles underlying functional brain maturation, paving the way for novel studies of disrupted brain connectivity in neurodevelopmental disorders such as autism. PMID:19621066

Trace elements during primordial plexiform network formation in human cerebral organoids

PubMed Central

Sartore, Rafaela C.; Cardoso, Simone C.; Lages, Yury V.M.; Paraguassu, Julia M.; Stelling, Mariana P.; Madeiro da Costa, Rodrigo F.; Guimaraes, Marilia Z.; Pérez, Carlos A.

2017-01-01

Systematic studies of micronutrients during brain formation are hindered by restrictions to animal models and adult post-mortem tissues. Recently, advances in stem cell biology have enabled recapitulation of the early stages of human telencephalon development in vitro. In the present work, we analyzed cerebral organoids derived from human pluripotent stem cells by synchrotron radiation X-ray fluorescence in order to measure biologically valuable micronutrients incorporated and distributed into the exogenously developing brain. Our findings indicate that elemental inclusion in organoids is consistent with human brain tissue and involves P, S, K, Ca, Fe and Zn. Occurrence of different concentration gradients also suggests active regulation of elemental transmembrane transport. Finally, the analysis of pairs of elements shows interesting elemental interaction patterns that change from 30 to 45 days of development, suggesting short- or long-term associations, such as storage in similar compartments or relevance for time-dependent biological processes. These findings shed light on which trace elements are important during human brain development and will support studies aimed to unravel the consequences of disrupted metal homeostasis for neurodevelopmental diseases, including those manifested in adulthood. PMID:28194309

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

NASA Astrophysics Data System (ADS)

Fini, Jean-Baptiste; Mughal, Bilal B.; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A.

2017-03-01

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

The Role of Neurogenic Inflammation in Blood-Brain Barrier Disruption and Development of Cerebral Oedema Following Acute Central Nervous System (CNS) Injury

PubMed Central

Sorby-Adams, Annabel J.; Marcoionni, Amanda M.; Dempsey, Eden R.; Woenig, Joshua A.; Turner, Renée J.

2017-01-01

Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke. In particular, release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) appear to be critically involved. In particular, increased SP expression is observed in perivascular tissue following acute CNS injury, with the magnitude of SP release being related to both the frequency and degree of the insult. SP release is associated with profound blood-brain barrier disruption and the subsequent development of vasogenic oedema, as well as neuronal injury and poor functional outcomes. Inhibition of SP through use of a neurokinin 1 (NK1) antagonist is highly beneficial following both TBI and ischaemic stroke in pre-clinical models. The role of CGRP is more unclear, especially with respect to TBI, with both elevations and reductions in CGRP levels reported following trauma. However, a beneficial role has been delineated in stroke, given its potent vasodilatory effects. Thus, modulating neuropeptides represents a novel therapeutic target in the treatment of cerebral oedema following acute CNS injury. PMID:28817088

Disrupting nicotine reinforcement: from cigarette to brain.

PubMed

Rose, Jed E

2008-10-01

Cigarette smoking is a tenacious addiction that is maintained to a significant extent by the reinforcing effects of nicotine. An emerging theme in smoking cessation treatment is the development of methods for interfering with these reinforcing effects. By attenuating nicotine reinforcement, treatments may enhance a smoker's chances of successfully remaining abstinent. Several treatment approaches will be described, including the use of denicotinized cigarettes, nicotine vaccines, nicotinic receptor agonists and antagonists, and modulators of brain reinforcement processes. These techniques highlight the numerous sites along the path between the cigarette and the brain that can be targeted for intervention. In addition to unimodal therapies, treatment combinations will be discussed that might more effectively block cigarette reward and thereby further enhance smoking abstinence.

Hyperconnectivity is a fundamental response to neurological disruption.

PubMed

Hillary, Frank G; Roman, Cristina A; Venkatesan, Umesh; Rajtmajer, Sarah M; Bajo, Ricardo; Castellanos, Nazareth D

2015-01-01

In the cognitive and clinical neurosciences, the past decade has been marked by dramatic growth in a literature examining brain "connectivity" using noninvasive methods. We offer a critical review of the blood oxygen level dependent functional MRI (BOLD fMRI) literature examining neural connectivity changes in neurological disorders with focus on brain injury and dementia. The goal is to demonstrate that there are identifiable shifts in local and large-scale network connectivity that can be predicted by the degree of pathology. We anticipate that the most common network response to neurological insult is hyperconnectivity but that this response depends upon demand and resource availability. To examine this hypothesis, we initially reviewed the results from 1,426 studies examining functional brain connectivity in individuals diagnosed with multiple sclerosis, traumatic brain injury, mild cognitive impairment, and Alzheimer's disease. Based upon inclusionary criteria, 126 studies were included for detailed analysis. RESULTS from 126 studies examining local and whole brain connectivity demonstrated increased connectivity in traumatic brain injury and multiple sclerosis. This finding is juxtaposed with findings in mild cognitive impairment and Alzheimer's disease where there is a shift to diminished connectivity as degeneration progresses. This summary of the functional imaging literature using fMRI methods reveals that hyperconnectivity is a common response to neurological disruption and that it may be differentially observable across brain regions. We discuss the factors contributing to both hyper- and hypoconnectivity results after neurological disruption and the implications these findings have for network plasticity. PsycINFO Database Record (c) 2015 APA, all rights reserved.

Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study.

PubMed

Dennis, Emily L; Babikian, Talin; Alger, Jeffry; Rashid, Faisal; Villalon-Reina, Julio E; Jin, Yan; Olsen, Alexander; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C; Thompson, Paul M; Asarnow, Robert F

2018-05-10

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging. © 2018 Wiley Periodicals, Inc.

Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration.

PubMed

Morley, Wendy A; Seneff, Stephanie

2014-01-01

The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical 'work around' processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup(®), may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.

Disruption of White Matter Integrity in Adult Survivors of Childhood Brain Tumors: Correlates with Long-Term Intellectual Outcomes.

PubMed

King, Tricia Z; Wang, Liya; Mao, Hui

2015-01-01

Although chemotherapy and radiation treatment have contributed to increased survivorship, treatment-induced brain injury has been a concern when examining long-term intellectual outcomes of survivors. Specifically, disruption of brain white matter integrity and its relationship to intellectual outcomes in adult survivors of childhood brain tumors needs to be better understood. Fifty-four participants underwent diffusion tensor imaging in addition to structural MRI and an intelligence test (IQ). Voxel-wise group comparisons of fractional anisotropy calculated from DTI data were performed using Tract Based Spatial Statistics (TBSS) on 27 survivors (14 treated with radiation with and without chemotherapy and 13 treated without radiation treatment on average over 13 years since diagnosis) and 27 healthy comparison participants. Whole brain white matter fractional anisotropy (FA) differences were explored between each group. The relationships between IQ and FA in the regions where statistically lower FA values were found in survivors were examined, as well as the role of cumulative neurological factors. The group of survivors treated with radiation with and without chemotherapy had lower IQ relative to the group of survivors without radiation treatment and the healthy comparison group. TBSS identified white matter regions with significantly different mean fractional anisotropy between the three different groups. A lower level of white matter integrity was found in the radiation with or without chemotherapy treated group compared to the group without radiation treatment and also the healthy control group. The group without radiation treatment had a lower mean FA relative to healthy controls. The white matter disruption of the radiation with or without chemotherapy treated survivors was positively correlated with IQ and cumulative neurological factors. Lower long-term intellectual outcomes of childhood brain tumor survivors are associated with lower white matter integrity. Radiation and adjunct chemotherapy treatment may play a role in greater white matter disruption. The relationships between white matter integrity and IQ, as well as cumulative neurological risk factors exist in young adult survivors of childhood brain tumors.

Disruption of Epithalamic Left-Right Asymmetry Increases Anxiety in Zebrafish.

PubMed

Facchin, Lucilla; Duboué, Erik R; Halpern, Marnie E

2015-12-02

Differences between the left and right sides of the brain are found throughout the animal kingdom, but the consequences of altered neural asymmetry are not well understood. In the zebrafish epithalamus, the parapineal is located on the left side of the brain where it influences development of the adjacent dorsal habenular (dHb) nucleus, causing the left and right dHb to differ in their organization, gene expression, and connectivity. Left-right (L-R) reversal of parapineal position and dHb asymmetry occurs spontaneously in a small percentage of the population, whereas the dHb develop symmetrically following experimental ablation of the parapineal. The habenular region was previously implicated in modulating fear in both mice and zebrafish, but the relevance of its L-R asymmetry is unclear. We now demonstrate that disrupting directionality of the zebrafish epithalamus causes reduced exploratory behavior and increased cortisol levels, indicative of enhanced anxiety. Accordingly, exposure to buspirone, an anxiolytic agent, significantly suppresses atypical behavior. Axonal projections from the parapineal to the dHb are more variable when it is located on the right side of the brain, revealing that L-R reversals do not necessarily represent a neuroanatomical mirror image. The results highlight the importance of directional asymmetry of the epithalamus in the regulation of stress responses in zebrafish. Copyright © 2015 the authors 0270-6474/15/3515847-13$15.00/0.

How functional connectivity between emotion regulation structures can be disrupted: preliminary evidence from adolescents with moderate to severe traumatic brain injury.

PubMed

Newsome, Mary R; Scheibel, Randall S; Mayer, Andrew R; Chu, Zili D; Wilde, Elisabeth A; Hanten, Gerri; Steinberg, Joel L; Lin, Xiaodi; Li, Xiaoqi; Merkley, Tricia L; Hunter, Jill V; Vasquez, Ana C; Cook, Lori; Lu, Hanzhang; Vinton, Kami; Levin, Harvey S

2013-09-01

Outcome of moderate to severe traumatic brain injury (TBI) includes impaired emotion regulation. Emotion regulation has been associated with amygdala and rostral anterior cingulate (rACC). However, functional connectivity between the two structures after injury has not been reported. A preliminary examination of functional connectivity of rACC and right amygdala was conducted in adolescents 2 to 3 years after moderate to severe TBI and in typically developing (TD)control adolescents, with the hypothesis that the TBI adolescents would demonstrate altered functional connectivity in the two regions. Functional connectivity was determined by correlating fluctuations in the blood oxygen level dependent(BOLD) signal of the rACC and right amygdala with that of other brain regions. In the TBI adolescents, the rACC was found to be significantly less functionally connected to medial prefrontal cortices and to right temporal regions near the amygdala (height threshold T = 2.5, cluster level p < .05, FDR corrected), while the right amygdala showed a trend in reduced functional connectivity with the rACC (height threshold T = 2.5, cluster level p = .06, FDR corrected). Data suggest disrupted functional connectivity in emotion regulation regions. Limitations include small sample sizes. Studies with larger sample sizes are necessary to characterize the persistent neural damage resulting from moderate to severe TBI during development.

Some Problems for Representations of Brain Organization Based on Activation in Functional Imaging

ERIC Educational Resources Information Center

Sidtis, John J.

2007-01-01

Functional brain imaging has overshadowed traditional lesion studies in becoming the dominant approach to the study of brain-behavior relationships. The proponents of functional imaging studies frequently argue that this approach provides an advantage over lesion studies by observing normal brain activity in vivo without the disruptive effects of…

Memory Disrupting Effects of Nonmuscle Myosin II Inhibition Depend on the Class of Abused Drug and Brain Region

ERIC Educational Resources Information Center

Briggs, Sherri B.; Blouin, Ashley M.; Young, Erica J.; Rumbaugh, Gavin; Miller, Courtney A.

2017-01-01

Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared…

Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain.

PubMed

Carbajosa, Guillermo; Malki, Karim; Lawless, Nathan; Wang, Hong; Ryder, John W; Wozniak, Eva; Wood, Kristie; Mein, Charles A; Dobson, Richard J B; Collier, David A; O'Neill, Michael J; Hodges, Angela K; Newhouse, Stephen J

2018-05-17

Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell-type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial gene-enriched subnetwork at 4 months, including a shift toward a more central role for the amyloid precursor protein gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signaling hub, suggesting an underlying link between immune response and vascular disease in dementia. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

PubMed

Simpkins, Alexis N; Dias, Christian; Leigh, Richard

2016-09-01

Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption. Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression. Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013). This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator. © 2016 American Heart Association, Inc.

Brain Opioids and Autism: An Updated Analysis of Possible Linkages.

ERIC Educational Resources Information Center

Sahley, Tony L.; Panksepp, Jaak

1987-01-01

The paper summarizes experimental evidence supporting a neurological theory which posits that autism, at least partially, represents a disruptive overactivation of hypersensitization of neurohormone systems in the brain, such as brain opioids. These substances modulate social-emotional processes. (Author/DB)

Excessive Stress Disrupts the Architecture of the Developing Brain. Working Paper #3

ERIC Educational Resources Information Center

National Scientific Council on the Developing Child, 2005

2005-01-01

New research suggests that exceptionally stressful experiences early in life may have long-term consequences for a child's learning, behavior, and both physical and mental health. Some types of "positive stress" in a child's life--overcoming the challenges and frustrations of learning a new, difficult task, for instance--can be beneficial. Severe,…

LACK OF ALTERATIONS IN THYROID HORMONES FOLLOWING EXPOSURE TO POLYBROMINATED DIPHENYL ETHER 47 DURING A PERIOD OF RAPID BRAIN DEVELOPMENT IN MICE

EPA Science Inventory

Polybrominated diphenyl ether 47 (PBDE-47) is one of a class of commonly used flame retardants that are accumulating in the environment, including human tissues. There are reports of thyroid alterations following exposure to PBDE mixtures, and it is possible that disruptions in t...

Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum.

PubMed

Lunardi, N; Oklopcic, A; Prillaman, M; Erisir, A; Jevtovic-Todorovic, V

2015-10-01

Exposure to general anesthesia (GA) during critical stages of brain development induces widespread neuronal apoptosis and causes long-lasting behavioral deficits in numerous animal species. Although several studies have focused on the morphological fate of neurons dying acutely by GA-induced developmental neuroapoptosis, the effects of an early exposure to GA on the surviving synapses remain unclear. The aim of this study is to study whether exposure to GA disrupts the fine regulation of the dynamic spatial organization and trafficking of synaptic vesicles in presynaptic terminals. We exposed postnatal day 7 (PND7) rat pups to a clinically relevant anesthetic combination of midazolam, nitrous oxide, and isoflurane and performed a detailed ultrastructural analysis of the synaptic vesicle architecture at presynaptic terminals in the subiculum of rats at PND 12. In addition to a significant decrease in the density of presynaptic vesicles, we observed a reduction of docked vesicles, as well as a reduction of vesicles located within 100 nm from the active zone, in animals 5 days after an initial exposure to GA. We also found that the synaptic vesicles of animals exposed to GA are located more distally with respect to the plasma membrane than those of sham control animals and that the distance between presynaptic vesicles is increased in GA-exposed animals compared to sham controls. We report that exposure of immature rats to GA during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum.

Social Origins of Developmental Risk for Mental and Physical Illness.

PubMed

Cameron, Judy L; Eagleson, Kathie L; Fox, Nathan A; Hensch, Takao K; Levitt, Pat

2017-11-08

Adversity in early childhood exerts an enduring impact on mental and physical health, academic achievement, lifetime productivity, and the probability of interfacing with the criminal justice system. More science is needed to understand how the brain is affected by early life stress (ELS), which produces excessive activation of stress response systems broadly throughout the child's body (toxic stress). Our research examines the importance of sex, timing and type of stress exposure, and critical periods for intervention in various brain systems across species. Neglect (the absence of sensitive and responsive caregiving) or disrupted interaction with offspring induces robust, lasting consequences in mice, monkeys, and humans. Complementary assessment of internalizing disorders and brain imaging in children suggests that early adversity can interfere with white matter development in key brain regions, which may increase risk for emotional difficulties in the long term. Neural circuits that are most plastic during ELS exposure in monkeys sustain the greatest change in gene expression, offering a mechanism whereby stress timing might lead to markedly different long-term behaviors. Rodent models reveal that disrupted maternal-infant interactions yield metabolic and behavioral outcomes often differing by sex. Moreover, ELS may further accelerate or delay critical periods of development, which reflect GABA circuit maturation, BDNF, and circadian Clock genes. Such factors are associated with several mental disorders and may contribute to a premature closure of plastic windows for intervention following ELS. Together, complementary cross-species studies are elucidating principles of adaptation to adversity in early childhood with molecular, cellular, and whole organism resolution. Copyright © 2017 the authors 0270-6474/17/3710783-09$15.00/0.

Nanoparticles for imaging and treating brain cancer

PubMed Central

Meyers, Joseph D; Doane, Tennyson; Burda, Clemens; Basilion, James P

2013-01-01

Brain cancer tumors cause disruption of the selective properties of vascular endothelia, even causing disruptions in the very selective blood–brain barrier, which are collectively referred to as the blood–brain–tumor barrier. Nanoparticles (NPs) have previously shown great promise in taking advantage of this increased vascular permeability in other cancers, which results in increased accumulation in these cancers over time due to the accompanying loss of an effective lymph system. NPs have therefore attracted increased attention for treating brain cancer. While this research is just beginning, there have been many successes demonstrated thus far in both the laboratory and clinical setting. This review serves to present the reader with an overview of NPs for treating brain cancer and to provide an outlook on what may come in the future. For NPs, just like the blood–brain–tumor barrier, the future is wide open. PMID:23256496

Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder.

PubMed

Kamat, Pradip K; Kyles, Philip; Kalani, Anuradha; Tyagi, Neetu

2016-05-01

Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca(2+) indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy-induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H2S for cerebrovascular diseases such as Alzheimer's disease. Graphical Abstract ᅟ.

Disrupted cortical connectivity theory as an explanatory model for autism spectrum disorders.

PubMed

Kana, Rajesh K; Libero, Lauren E; Moore, Marie S

2011-12-01

Recent findings of neurological functioning in autism spectrum disorder (ASD) point to altered brain connectivity as a key feature of its pathophysiology. The cortical underconnectivity theory of ASD (Just et al., 2004) provides an integrated framework for addressing these new findings. This theory suggests that weaker functional connections among brain areas in those with ASD hamper their ability to accomplish complex cognitive and social tasks successfully. We will discuss this theory, but will modify the term underconnectivity to 'disrupted cortical connectivity' to capture patterns of both under- and over-connectivity in the brain. In this paper, we will review the existing literature on ASD to marshal supporting evidence for hypotheses formulated on the disrupted cortical connectivity theory. These hypotheses are: 1) underconnectivity in ASD is manifested mainly in long-distance cortical as well as subcortical connections rather than in short-distance cortical connections; 2) underconnectivity in ASD is manifested only in complex cognitive and social functions and not in low-level sensory and perceptual tasks; 3) functional underconnectivity in ASD may be the result of underlying anatomical abnormalities, such as problems in the integrity of white matter; 4) the ASD brain adapts to underconnectivity through compensatory strategies such as overconnectivity mainly in frontal and in posterior brain areas. This may be manifested as deficits in tasks that require frontal-parietal integration. While overconnectivity can be tested by examining the cortical minicolumn organization, long-distance underconnectivity can be tested by cognitively demanding tasks; and 5) functional underconnectivity in brain areas in ASD will be seen not only during complex tasks but also during task-free resting states. We will also discuss some empirical predictions that can be tested in future studies, such as: 1) how disrupted connectivity relates to cognitive impairments in skills such as Theory-of-Mind, cognitive flexibility, and information processing; and 2) how connection abnormalities relate to, and may determine, behavioral symptoms hallmarked by the triad of Impairments in ASD. Furthermore, we will relate the disrupted cortical connectivity model to existing cognitive and neural models of ASD. Published by Elsevier B.V.

Disrupted cortical connectivity theory as an explanatory model for autism spectrum disorders

NASA Astrophysics Data System (ADS)

Kana, Rajesh K.; Libero, Lauren E.; Moore, Marie S.

2011-12-01

Recent findings of neurological functioning in autism spectrum disorder (ASD) point to altered brain connectivity as a key feature of its pathophysiology. The cortical underconnectivity theory of ASD (Just et al., 2004) provides an integrated framework for addressing these new findings. This theory suggests that weaker functional connections among brain areas in those with ASD hamper their ability to accomplish complex cognitive and social tasks successfully. We will discuss this theory, but will modify the term underconnectivity to ‘disrupted cortical connectivity’ to capture patterns of both under- and over-connectivity in the brain. In this paper, we will review the existing literature on ASD to marshal supporting evidence for hypotheses formulated on the disrupted cortical connectivity theory. These hypotheses are: 1) underconnectivity in ASD is manifested mainly in long-distance cortical as well as subcortical connections rather than in short-distance cortical connections; 2) underconnectivity in ASD is manifested only in complex cognitive and social functions and not in low-level sensory and perceptual tasks; 3) functional underconnectivity in ASD may be the result of underlying anatomical abnormalities, such as problems in the integrity of white matter; 4) the ASD brain adapts to underconnectivity through compensatory strategies such as overconnectivity mainly in frontal and in posterior brain areas. This may be manifested as deficits in tasks that require frontal-parietal integration. While overconnectivity can be tested by examining the cortical minicolumn organization, long-distance underconnectivity can be tested by cognitively demanding tasks; and 5) functional underconnectivity in brain areas in ASD will be seen not only during complex tasks but also during task-free resting states. We will also discuss some empirical predictions that can be tested in future studies, such as: 1) how disrupted connectivity relates to cognitive impairments in skills such as Theory-of-Mind, cognitive flexibility, and information processing; and 2) how connection abnormalities relate to, and may determine, behavioral symptoms hallmarked by the triad of Impairments in ASD. Furthermore, we will relate the disrupted cortical connectivity model to existing cognitive and neural models of ASD.

Out of time: a possible link between mirror neurons, autism and electromagnetic radiation.

PubMed

Thornton, Ian M

2006-01-01

Recent evidence suggests a link between autism and the human mirror neuron system. In this paper, I argue that temporal disruption from the environment may play an important role in the observed mirror neuron dysfunction, leading in turn to the pattern of deficits associated with autism. I suggest that the developing nervous system of an infant may be particularly prone to temporal noise that can interfere with the initial calibration of brain networks such as the mirror neuron system. The most likely source of temporal noise in the environment is artificially generated electromagnetic radiation. To date, there has been little evidence that electromagnetic radiation poses a direct biological hazard. It is clear, however, that time-varying electromagnetic waves have the potential to temporally modulate the nervous system, particularly when populations of neurons are required to act together. This modulation may be completely harmless for the fully developed nervous system of an adult. For an infant, this same temporal disruption might act to severely delay or disrupt vital calibration processes.

New perspectives on central and peripheral immune responses to acute traumatic brain injury

PubMed Central

2012-01-01

Traumatic injury to the brain (TBI) results in a complex set of responses involving various symptoms and long-term consequences. TBI of any form can cause cognitive, behavioral and immunologic changes in later life, which underscores the problem of underdiagnosis of mild TBI that can cause long-term neurological deficits. TBI disrupts the blood–brain barrier (BBB) leading to infiltration of immune cells into the brain and subsequent inflammation and neurodegeneration. TBI-induced peripheral immune responses can also result in multiorgan damage. Despite worldwide research efforts, the methods of diagnosis, monitoring and treatment for TBI are still relatively ineffective. In this review, we delve into the mechanism of how TBI-induced central and peripheral immune responses affect the disease outcome and discuss recent developments in the continuing effort to combat the consequences of TBI and new ways to enhance repair of the damaged brain. PMID:23061919

Relationship between diet, the gut microbiota, and brain function.

PubMed

Tengeler, Anouk C; Kozicz, Tamas; Kiliaan, Amanda J

2018-04-28

The human intestinal microbiota, comprising trillions of microorganisms, exerts a substantial effect on the host. The microbiota plays essential roles in the function and development of several physiological processes, including those in the brain. A disruption in the microbial composition of the gut has been associated with many metabolic, inflammatory, neurodevelopmental, and neurodegenerative disorders. Nutrition is one of several key factors that shape the microbial composition during infancy and throughout life, thereby affecting brain structure and function. This review examines the effect of the gut microbiota on brain function. The ability of external factors, such as diet, to influence the microbial composition implies a certain vulnerability of the gut microbiota. However, it also offers a potential therapeutic strategy for ameliorating symptoms of mental and physical disorders. Therefore, this review examines the potential effect of nutritional components on gut microbial composition and brain function.

Gray matter network disruptions and amyloid beta in cognitively normal adults.

PubMed

Tijms, Betty M; Kate, Mara Ten; Wink, Alle Meije; Visser, Pieter Jelle; Ecay, Mirian; Clerigue, Montserrat; Estanga, Ainara; Garcia Sebastian, Maite; Izagirre, Andrea; Villanua, Jorge; Martinez Lage, Pablo; van der Flier, Wiesje M; Scheltens, Philip; Sanz Arigita, Ernesto; Barkhof, Frederik

2016-01-01

Gray matter networks are disrupted in Alzheimer's disease (AD). It is unclear when these disruptions start during the development of AD. Amyloid beta 1-42 (Aβ42) is among the earliest changes in AD. We studied, in cognitively healthy adults, the relationship between Aβ42 levels in cerebrospinal fluid (CSF) and single-subject cortical gray matter network measures. Single-subject gray matter networks were extracted from structural magnetic resonance imaging scans in a sample of cognitively healthy adults (N = 185; age range 39-79, mini-mental state examination >25, N = 12 showed abnormal Aβ42 < 550 pg/mL). Degree, clustering coefficient, and path length were computed at whole brain level and for 90 anatomical areas. Associations between continuous Aβ42 CSF levels and single-subject cortical gray matter network measures were tested. Smoothing splines were used to determine whether a linear or nonlinear relationship gave a better fit to the data. Lower Aβ42 CSF levels were linearly associated at whole brain level with lower connectivity density, and nonlinearly with lower clustering values and higher path length values, which is indicative of a less-efficient network organization. These relationships were specific to medial temporal areas, precuneus, and the middle frontal gyrus (all p < 0.05). These results suggest that mostly within the normal spectrum of amyloid, lower Aβ42 levels can be related to gray matter networks disruptions. Copyright © 2016 Elsevier Inc. All rights reserved.

Experimental Modelling of the Consequences of Brief Late Gestation Asphyxia on Newborn Lamb Behaviour and Brain Structure

PubMed Central

Yawno, Tamara; Witjaksono, Anissa; Miller, Suzie L.; Walker, David W.

2013-01-01

Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term), the cuff was inflated to induce umbilical cord occlusion (UCO), or sham (control). Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i) use all four legs, (ii) attain a standing position, (iii) find the udder, and (iv) successfully suckle - compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies. PMID:24223120

Cocaine Analog Coupled to Disrupted Adenovirus: A Vaccine Strategy to Evoke High-titer Immunity Against Addictive Drugs

PubMed Central

Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B; Davidson, Jesse T; Moreno, Amira Y; Janda, Kim D; Wee, Sunmee; Koob, George F; Hackett, Neil R; Kaminsky, Stephen M; Worgall, Stefan; Toth, Miklos; Mezey, Jason G; Crystal, Ronald G

2011-01-01

Based on the concept that anticocaine antibodies could prevent inhaled cocaine from reaching its target receptors in the brain, an effective anticocaine vaccine could help reverse cocaine addiction. Leveraging the knowledge that E1−E3− adenovirus (Ad) gene transfer vectors are potent immunogens, we have developed a novel vaccine platform for addictive drugs by covalently linking a cocaine analog to the capsid proteins of noninfectious, disrupted Ad vector. The Ad-based anticocaine vaccine evokes high-titer anticocaine antibodies in mice sufficient to completely reverse, on a persistent basis, the hyperlocomotor activity induced by intravenous administration of cocaine. PMID:21206484

Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration.

PubMed

Starkman, Monica N

2013-09-01

This article reviews the neuropsychiatric presentations elicited by spontaneous hypercortisolism and exogenous supraphysiologic glucocorticoids. Patients with Cushing disease and syndrome develop a depressive syndrome: irritable and depressed mood, decreased libido, disrupted sleep and cognitive decrements. Exogenous short-term glucocorticoid administration may elicit a hypomanic syndrome with mood, sleep and cognitive disruptions. Treatment options are discussed. Brain imaging and neuropsychological studies indicate elevated cortisol and other glucocorticoids are especially deleterious to hippocampus and frontal lobe. The research findings also shed light on neuropsychiatric abnormalities in conditions that have substantial subgroups exhibiting elevated and dysregulated cortisol: aging, major depressive disorder and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

Disrupted Small-World Networks in Schizophrenia

ERIC Educational Resources Information Center

Liu, Yong; Liang, Meng; Zhou, Yuan; He, Yong; Hao, Yihui; Song, Ming; Yu, Chunshui; Liu, Haihong; Liu, Zhening; Jiang, Tianzi

2008-01-01

The human brain has been described as a large, sparse, complex network characterized by efficient small-world properties, which assure that the brain generates and integrates information with high efficiency. Many previous neuroimaging studies have provided consistent evidence of "dysfunctional connectivity" among the brain regions in…

The autistic brain in the context of normal neurodevelopment.

PubMed

Ziats, Mark N; Edmonson, Catherine; Rennert, Owen M

2015-01-01

The etiology of autism spectrum disorders (ASDs) is complex and largely unclear. Among various lines of inquiry, many have suggested convergence onto disruptions in both neural circuitry and immune regulation/glial cell function pathways. However, the interpretation of the relationship between these two putative mechanisms has largely focused on the role of exogenous factors and insults, such as maternal infection, in activating immune pathways that in turn result in neural network abnormalities. Yet, given recent insights into our understanding of human neurodevelopment, and in particular the critical role of glia and the immune system in normal brain development, it is important to consider these putative pathological processes in their appropriate normal neurodevelopmental context. In this review, we explore the hypothesis that the autistic brain cellular phenotype likely represents intrinsic abnormalities of glial/immune processes constitutively operant in normal brain development that result in the observed neural network dysfunction. We review recent studies demonstrating the intercalated role of neural circuit development, the immune system, and glial cells in the normal developing brain, and integrate them with studies demonstrating pathological alterations in these processes in autism. By discussing known abnormalities in the autistic brain in the context of normal brain development, we explore the hypothesis that the glial/immune component of ASD may instead be related to intrinsic exaggerated/abnormal constitutive neurodevelopmental processes such as network pruning. Moreover, this hypothesis may be relevant to other neurodevelopmental disorders that share genetic, pathologic, and clinical features with autism.

Propofol disrupts functional interactions between sensory and high-order processing of auditory verbal memory.

PubMed

Liu, Xiaolin; Lauer, Kathryn K; Ward, Barney D; Rao, Stephen M; Li, Shi-Jiang; Hudetz, Anthony G

2012-10-01

Current theories suggest that disrupting cortical information integration may account for the mechanism of general anesthesia in suppressing consciousness. Human cognitive operations take place in hierarchically structured neural organizations in the brain. The process of low-order neural representation of sensory stimuli becoming integrated in high-order cortices is also known as cognitive binding. Combining neuroimaging, cognitive neuroscience, and anesthetic manipulation, we examined how cognitive networks involved in auditory verbal memory are maintained in wakefulness, disrupted in propofol-induced deep sedation, and re-established in recovery. Inspired by the notion of cognitive binding, an functional magnetic resonance imaging-guided connectivity analysis was utilized to assess the integrity of functional interactions within and between different levels of the task-defined brain regions. Task-related responses persisted in the primary auditory cortex (PAC), but vanished in the inferior frontal gyrus (IFG) and premotor areas in deep sedation. For connectivity analysis, seed regions representing sensory and high-order processing of the memory task were identified in the PAC and IFG. Propofol disrupted connections from the PAC seed to the frontal regions and thalamus, but not the connections from the IFG seed to a set of widely distributed brain regions in the temporal, frontal, and parietal lobes (with exception of the PAC). These later regions have been implicated in mediating verbal comprehension and memory. These results suggest that propofol disrupts cognition by blocking the projection of sensory information to high-order processing networks and thus preventing information integration. Such findings contribute to our understanding of anesthetic mechanisms as related to information and integration in the brain. Copyright © 2011 Wiley Periodicals, Inc.

MRI-guided targeted blood-brain barrier disruption with focused ultrasound: histological findings in rabbits.

PubMed

McDannold, Nathan; Vykhodtseva, Natalia; Raymond, Scott; Jolesz, Ferenc A; Hynynen, Kullervo

2005-11-01

Focused ultrasound offers a method to disrupt the blood-brain barrier (BBB) noninvasively and reversibly at targeted locations. The purpose of this study was to test the safety of this method by searching for ischemia and apoptosis in areas with BBB disruption induced by pulsed ultrasound in the presence of preformed gas bubbles and by looking for delayed effects up to one month after sonication. Pulsed ultrasound exposures (sonications) were performed in the brains of 24 rabbits under monitoring by magnetic resonance imaging (MRI) (ultrasound: frequency = 1.63 MHz, burst length = 100 ms, PRF = 1 Hz, duration = 20 s, pressure amplitude 0.7 to 1.0 MPa). Before sonication, an ultrasound contrast agent (Optison, GE Healthcare, Milwaukee, WI, USA) was injected IV. BBB disruption was confirmed with contrast-enhanced MR images. Whole brain histologic examination was performed using haematoxylin and eosin staining for general histology, vanadium acid fuchsin-toluidine blue staining for ischemic neurons and TUNEL staining for apoptosis. The main effects observed were tiny regions of extravasated red blood cells scattered around the sonicated locations, indicating affected capillaries. Despite these vasculature effects, only a few cells in some of the sonicated areas showed evidence for apoptosis or ischemia. No ischemic or apoptotic regions were detected that would indicate a compromised blood supply was induced by the sonications. No delayed effects were observed either by MRI or histology up to 4 wk after sonication. Ultrasound-induced BBB disruption is possible without inducing substantial vascular damage that would result in ischemic or apoptotic death to neurons. These findings indicate that this method is safe for targeted drug delivery, at least when compared with the currently available invasive methods.

What are the disruptive symptoms of behavioral disorders after traumatic brain injury? A systematic review leading to recommendations for good practices.

PubMed

Stéfan, Angélique; Mathé, Jean-François

2016-02-01

Behavioral disorders are major sequelae of severe traumatic brain injury. Before considering care management of these disorders, and in the absence of a precise definition for TBI-related behavioral disorder, it is essential to refine, according to the data from the literature, incidence, prevalence, predictive factors of commonly admitted disruptive symptoms. Systematic review of the literature targeting epidemiological data related to behavioral disorders after traumatic brain injury in order to elaborate good practice recommendations according to the methodology established by the French High Authority for Health. Two hundred and ninety-nine articles were identified. The responsibility of traumatic brain injury (TBI) in the onset of behavioral disorders is unequivocal. Globally, behavioral disorders are twice more frequent after TBI than orthopedic trauma without TBI (Masson et al., 1996). These disorders are classified into disruptive primary behaviors by excess (agitation 11-70%, aggression 25-39%, irritability 29-71%, alcohol abuse 7-26% drug abuse 2-20%), disruptive primary behaviors by default (apathy 20-71%), affective disorders - anxiety - psychosis (depression 12-76%, anxiety 0.8-24,5%, posttraumatic stress 11-18%, obsessive-compulsive disorders 1.2-30%, psychosis 0.7%), suicide attempts and suicide 1%. The improvement of care management for behavioral disorders goes through a first step of defining a common terminology. Four categories of posttraumatic behavioral clinical symptoms are defined: disruptive primary behaviors by excess, by default, affective disorders-psychosis-anxiety, suicide attempts and suicide. All these symptoms yield a higher prevalence than in the general population. They impact all of life's domains and are sustainable over time. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits

PubMed Central

Niwa, Minae; Kamiya, Atsushi; Murai, Rina; Kubo, Ken-ichiro; Gruber, Aaron J; Tomita, Kenji; Lu, Lingling; Tomisato, Shuta; Jaaro-Peled, Hanna; Seshadri, Saurav; Hiyama, Hideki; Huang, Beverly; Kohda, Kazuhisa; Noda, Yukihiro; O’Donnell, Patricio; Nakajima, Kazunori; Sawa, Akira; Nabeshima, Toshitaka

2011-01-01

SUMMARY Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming “pathways” or “signalosomes.” Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses, such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and peri-natal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty. PMID:20188653

Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: an fMRI study.

PubMed

Duarte, João V; Pereira, João M S; Quendera, Bruno; Raimundo, Miguel; Moreno, Carolina; Gomes, Leonor; Carrilho, Francisco; Castelo-Branco, Miguel

2015-10-01

Type 2 diabetes (T2DM) patients develop vascular complications and have increased risk for neurophysiological impairment. Vascular pathophysiology may alter the blood flow regulation in cerebral microvasculature, affecting neurovascular coupling. Reduced fMRI signal can result from decreased neuronal activation or disrupted neurovascular coupling. The uncertainty about pathophysiological mechanisms (neurodegenerative, vascular, or both) underlying brain function impairments remains. In this cross-sectional study, we investigated if the hemodynamic response function (HRF) in lesion-free brains of patients is altered by measuring BOLD (Blood Oxygenation Level-Dependent) response to visual motion stimuli. We used a standard block design to examine the BOLD response and an event-related deconvolution approach. Importantly, the latter allowed for the first time to directly extract the true shape of HRF without any assumption and probe neurovascular coupling, using performance-matched stimuli. We discovered a change in HRF in early stages of diabetes. T2DM patients show significantly different fMRI response profiles. Our visual paradigm therefore demonstrated impaired neurovascular coupling in intact brain tissue. This implies that functional studies in T2DM require the definition of HRF, only achievable with deconvolution in event-related experiments. Further investigation of the mechanisms underlying impaired neurovascular coupling is needed to understand and potentially prevent the progression of brain function decrements in diabetes.

Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential

PubMed Central

Wang, Lulu; Habib, Amyn A.; Mintz, Akiva; Li, King C.; Zhao, Dawen

2017-01-01

Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood–brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors. PMID:28654387

Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential.

PubMed

Wang, Lulu; Habib, Amyn A; Mintz, Akiva; Li, King C; Zhao, Dawen

2017-01-01

Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood-brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors.

Plateau Waves of Intracranial Pressure and Multimodal Brain Monitoring.

PubMed

Dias, Celeste; Maia, Isabel; Cerejo, Antonio; Smielewski, Peter; Paiva, José-Artur; Czosnyka, Marek

2016-01-01

The aim of this study was to describe multimodal brain monitoring characteristics during plateau waves of intracranial pressure (ICP) in patients with head injury, using ICM+ software for continuous recording. Plateau waves consist of an abrupt elevation of ICP above 40 mmHg for 5-20 min. This is a prospective observational study of patients with head injury who were admitted to a neurocritical care unit and who developed plateau waves. We analyzed 59 plateau waves that occurred in 8 of 18 patients (44 %). At the top of plateau waves arterial blood pressure remained almost constant, but cerebral perfusion pressure, cerebral blood flow, brain tissue oxygenation, and cerebral oximetry decreased. After plateau waves, patients with a previously better autoregulation status developed hyperemia, demonstrated by an increase in cerebral blood flow and brain oxygenation. Pressure and oxygen cerebrovascular reactivity indexes (pressure reactivity index and ORxshort) increased significantly during the plateau wave as a sign of disruption of autoregulation. Bedside multimodal brain monitoring is important to characterize increases in ICP and give differential diagnoses of plateau waves, as management of this phenomenon differs from that of regular ICP.

Cannabis and adolescent brain development.

PubMed

Lubman, Dan I; Cheetham, Ali; Yücel, Murat

2015-04-01

Heavy cannabis use has been frequently associated with increased rates of mental illness and cognitive impairment, particularly amongst adolescent users. However, the neurobiological processes that underlie these associations are still not well understood. In this review, we discuss the findings of studies examining the acute and chronic effects of cannabis use on the brain, with a particular focus on the impact of commencing use during adolescence. Accumulating evidence from both animal and human studies suggests that regular heavy use during this period is associated with more severe and persistent negative outcomes than use during adulthood, suggesting that the adolescent brain may be particularly vulnerable to the effects of cannabis exposure. As the endocannabinoid system plays an important role in brain development, it is plausible that prolonged use during adolescence results in a disruption in the normative neuromaturational processes that occur during this period. We identify synaptic pruning and white matter development as two processes that may be adversely impacted by cannabis exposure during adolescence. Potentially, alterations in these processes may underlie the cognitive and emotional deficits that have been associated with regular use commencing during adolescence. Copyright © 2014 Elsevier Inc. All rights reserved.

Germline Chd8 haploinsufficiency alters brain development in mouse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gompers, Andrea L.; Su-Feher, Linda; Ellegood, Jacob

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. In this paper, we examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8 +/ del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8 +/ del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8 +/ del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes andmore » neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8 +/ del5 mice. Finally, this integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.« less

Germline Chd8 haploinsufficiency alters brain development in mouse

DOE PAGES

Gompers, Andrea L.; Su-Feher, Linda; Ellegood, Jacob; ...

2017-06-26

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. In this paper, we examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8 +/ del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8 +/ del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8 +/ del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes andmore » neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8 +/ del5 mice. Finally, this integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.« less

Concussion Awareness: Getting School Psychologists into the Game

ERIC Educational Resources Information Center

Davies, Susan C.

2011-01-01

A concussion is a serious injury--a mild traumatic brain injury (TBI)--that induces physiological disruption of brain function. A concussion is caused by a bump, blow, or jolt to the head or body. The sudden movement causes stretching and tearing of brain cells; cells become damaged and chemical changes occur within the brain. Concussions can lead…

Disruption to control network function correlates with altered dynamic connectivity in the wider autism spectrum.

PubMed

de Lacy, N; Doherty, D; King, B H; Rachakonda, S; Calhoun, V D

2017-01-01

Autism is a common developmental condition with a wide, variable range of co-occurring neuropsychiatric symptoms. Contrasting with most extant studies, we explored whole-brain functional organization at multiple levels simultaneously in a large subject group reflecting autism's clinical diversity, and present the first network-based analysis of transient brain states, or dynamic connectivity , in autism. Disruption to inter-network and inter-system connectivity, rather than within individual networks, predominated. We identified coupling disruption in the anterior-posterior default mode axis, and among specific control networks specialized for task start cues and the maintenance of domain-independent task positive status, specifically between the right fronto-parietal and cingulo-opercular networks and default mode network subsystems. These appear to propagate downstream in autism, with significantly dampened subject oscillations between brain states, and dynamic connectivity configuration differences. Our account proposes specific motifs that may provide candidates for neuroimaging biomarkers within heterogeneous clinical populations in this diverse condition.

Disruption of DNA methylation-dependent long gene repression in Rett syndrome

PubMed Central

Gabel, Harrison W.; Kinde, Benyam Z.; Stroud, Hume; Gilbert, Caitlin S.; Harmin, David A.; Kastan, Nathaniel R.; Hemberg, Martin; Ebert, Daniel H.; Greenberg, Michael E.

2015-01-01

Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism1. MECP2 encodes a methyl-DNA-binding protein2 that has been proposed to function as a transcriptional repressor, but despite numerous studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 regulates transcription3–9. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain. PMID:25762136

Stem cells for brain repair in neonatal hypoxia-ischemia.

PubMed

Chicha, L; Smith, T; Guzman, R

2014-01-01

Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain.

Congenital Amusia Persists in the Developing Brain after Daily Music Listening

PubMed Central

Mignault Goulet, Geneviève; Moreau, Patricia; Robitaille, Nicolas; Peretz, Isabelle

2012-01-01

Congenital amusia is a neurodevelopmental disorder that affects about 3% of the adult population. Adults experiencing this musical disorder in the absence of macroscopically visible brain injury are described as cases of congenital amusia under the assumption that the musical deficits have been present from birth. Here, we show that this disorder can be expressed in the developing brain. We found that (10–13 year-old) children exhibit a marked deficit in the detection of fine-grained pitch differences in both musical and acoustical context in comparison to their normally developing peers comparable in age and general intelligence. This behavioral deficit could be traced down to their abnormal P300 brain responses to the detection of subtle pitch changes. The altered pattern of electrical activity does not seem to arise from an anomalous functioning of the auditory cortex, because all early components of the brain potentials, the N100, the MMN, and the P200 appear normal. Rather, the brain and behavioral measures point to disrupted information propagation from the auditory cortex to other cortical regions. Furthermore, the behavioral and neural manifestations of the disorder remained unchanged after 4 weeks of daily musical listening. These results show that congenital amusia can be detected in childhood despite regular musical exposure and normal intellectual functioning. PMID:22606299

Role of nitric oxide synthases in early blood-brain barrier disruption following transient focal cerebral ischemia.

PubMed

Jiang, Zheng; Li, Chun; Arrick, Denise M; Yang, Shu; Baluna, Alexandra E; Sun, Hong

2014-01-01

The role of nitric oxide synthases (NOSs) in early blood-brain barrier (BBB) disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA) at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor) abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS) inhibitor) significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS) inhibitors) significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG) (an inducible NOS (iNOS) inhibitor) had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV) not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.

Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound

PubMed Central

Miller, G. Wilson; Song, Ji; Louttit, Cameron; Klibanov, Alexander L; Shih, Ting-Yu; Swaminathan, Ganesh; Tamargo, Rafael J.; Woodworth, Graeme F.; Hanes, Justin; Price, Richard J.

2014-01-01

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer’s, Parkinson’s and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a noninvasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPN in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60 nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain. PMID:24979210

The gut in trauma.

PubMed

Patel, Jayshil J; Rosenthal, Martin D; Miller, Keith R; Martindale, Robert G

2016-08-01

The purpose of this review is to describe established and emerging mechanisms of gut injury and dysfunction in trauma, describe emerging strategies to improve gut dysfunction, detail the effect of trauma on the gut microbiome, and describe the gut-brain connection in traumatic brain injury. Newer data suggest intraluminal contents, pancreatic enzymes, and hepatobiliary factors disrupt the intestinal mucosal layer. These mechanisms serve to perpetuate the inflammatory response leading to multiple organ dysfunction syndrome (MODS). To date, therapies to mitigate acute gut dysfunction have included enteral nutrition and immunonutrition; emerging therapies aimed to intestinal mucosal layer disruption, however, include protease inhibitors such as tranexamic acid, parenteral nutrition-supplemented bombesin, and hypothermia. Clinical trials to demonstrate benefit in humans are needed before widespread applications can be recommended. Despite resuscitation, gut dysfunction promotes distant organ injury. In addition, postresuscitation nosocomial and iatrogenic 'hits' exaggerate the immune response, contributing to MODS. This was a provocative concept, suggesting infectious and noninfectious causes of inflammation may trigger, heighten, and perpetuate an inflammatory response culminating in MODS and death. Emerging evidence suggests posttraumatic injury mechanisms, such as intestinal mucosal disruption and shifting of the gut microbiome to a pathobiome. In addition, traumatic brain injury activates the gut-brain axis and increases intestinal permeability.

Disrupted Topological Patterns of Large-Scale Network in Conduct Disorder

PubMed Central

Jiang, Yali; Liu, Weixiang; Ming, Qingsen; Gao, Yidian; Ma, Ren; Zhang, Xiaocui; Situ, Weijun; Wang, Xiang; Yao, Shuqiao; Huang, Bingsheng

2016-01-01

Regional abnormalities in brain structure and function, as well as disrupted connectivity, have been found repeatedly in adolescents with conduct disorder (CD). Yet, the large-scale brain topology associated with CD is not well characterized, and little is known about the systematic neural mechanisms of CD. We employed graphic theory to investigate systematically the structural connectivity derived from cortical thickness correlation in a group of patients with CD (N = 43) and healthy controls (HCs, N = 73). Nonparametric permutation tests were applied for between-group comparisons of graphical metrics. Compared with HCs, network measures including global/local efficiency and modularity all pointed to hypo-functioning in CD, despite of preserved small-world organization in both groups. The hubs distribution is only partially overlapped with each other. These results indicate that CD is accompanied by both impaired integration and segregation patterns of brain networks, and the distribution of highly connected neural network ‘hubs’ is also distinct between groups. Such misconfiguration extends our understanding regarding how structural neural network disruptions may underlie behavioral disturbances in adolescents with CD, and potentially, implicates an aberrant cytoarchitectonic profiles in the brain of CD patients. PMID:27841320

Lycium barbarum Extracts Protect the Brain from Blood-Brain Barrier Disruption and Cerebral Edema in Experimental Stroke

PubMed Central

Yang, Di; Li, Suk-Yee; Yeung, Chung-Man; Chang, Raymond Chuen-Chung; So, Kwok-Fai; Wong, David; Lo, Amy C. Y.

2012-01-01

Background and Purpose Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP), a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model. Methods C57BL/6N male mice were first fed with either vehicle (PBS) or LBP (1 or 10 mg/kg) daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO) by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB) extravasation was determined to assess blood-brain barrier (BBB) disruption after MCAO. Results LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains. Conclusions Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke. PMID:22438957

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

PubMed Central

Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam; Castro, Kamilah; Zhang, Jingya; Asp, Linnea; Loo, Hannah; Laitman, Benjamin M.; Mariani, John N.; Straus Farber, Rebecca; Zaslavsky, Elena; Nudelman, German; Raine, Cedric S.

2015-01-01

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood–brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood–brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood–brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood–brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood–brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood–brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood–brain barrier breakdown. PMID:25805644

Anomalous single-subject based morphological cortical networks in drug-naive, first-episode major depressive disorder.

PubMed

Chen, Taolin; Kendrick, Keith M; Wang, Jinhui; Wu, Min; Li, Kaiming; Huang, Xiaoqi; Luo, Yuejia; Lui, Su; Sweeney, John A; Gong, Qiyong

2017-05-01

Major depressive disorder (MDD) has been associated with disruptions in the topological organization of brain morphological networks in group-level data. Such disruptions have not yet been identified in single-patients, which is needed to show relations with symptom severity and to evaluate their potential as biomarkers for illness. To address this issue, we conducted a cross-sectional structural brain network study of 33 treatment-naive, first-episode MDD patients and 33 age-, gender-, and education-matched healthy controls (HCs). Weighted graph-theory based network models were used to characterize the topological organization of brain networks between the two groups. Compared with HCs, MDD patients exhibited lower normalized global efficiency and higher modularity in their whole-brain morphological networks, suggesting impaired integration and increased segregation of morphological brain networks in the patients. Locally, MDD patients exhibited lower efficiency in anatomic organization for transferring information predominantly in default-mode regions including the hippocampus, parahippocampal gyrus, precuneus and superior parietal lobule, and higher efficiency in the insula, calcarine and posterior cingulate cortex, and in the cerebellum. Morphological connectivity comparisons revealed two subnetworks that exhibited higher connectivity strength in MDD mainly involving neocortex-striatum-thalamus-cerebellum and thalamo-hippocampal circuitry. MDD-related alterations correlated with symptom severity and differentiated individuals with MDD from HCs with a sensitivity of 87.9% and specificity of 81.8%. Our findings indicate that single subject grey matter morphological networks are often disrupted in clinically relevant ways in treatment-naive, first episode MDD patients. Circuit-specific changes in brain anatomic network organization suggest alterations in the efficiency of information transfer within particular brain networks in MDD. Hum Brain Mapp 38:2482-2494, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Altered functional connectivity of the language network in ASD: Role of classical language areas and cerebellum☆

PubMed Central

Verly, Marjolein; Verhoeven, Judith; Zink, Inge; Mantini, Dante; Peeters, Ronald; Deprez, Sabine; Emsell, Louise; Boets, Bart; Noens, Ilse; Steyaert, Jean; Lagae, Lieven; De Cock, Paul; Rommel, Nathalie; Sunaert, Stefan

2014-01-01

The development of language, social interaction and communicative skills is remarkably different in the child with autism spectrum disorder (ASD). Atypical brain connectivity has frequently been reported in this patient population. However, the neural correlates underlying their disrupted language development and functioning are still poorly understood. Using resting state fMRI, we investigated the functional connectivity properties of the language network in a group of ASD patients with clear comorbid language impairment (ASD-LI; N = 19) and compared them to the language related connectivity properties of 23 age-matched typically developing children. A verb generation task was used to determine language components commonly active in both groups. Eight joint language components were identified and subsequently used as seeds in a resting state analysis. Interestingly, both the interregional and the seed-based whole brain connectivity analysis showed preserved connectivity between the classical intrahemispheric language centers, Wernicke's and Broca's areas. In contrast however, a marked loss of functional connectivity was found between the right cerebellar region and the supratentorial regulatory language areas. Also, the connectivity between the interhemispheric Broca regions and modulatory control dorsolateral prefrontal region was found to be decreased. This disruption of normal modulatory control and automation function by the cerebellum may underlie the abnormal language function in children with ASD-LI. PMID:24567909

Is Dyslexia a Brain Disorder?

PubMed Central

Parrila, Rauno

2018-01-01

Specific word reading difficulty, commonly termed ‘developmental dyslexia’, refers to the low end of the word reading skill distribution but is frequently considered to be a neurodevelopmental disorder. This term implies that brain development is thought to be disrupted, resulting in an abnormal and dysfunctional brain. We take issue with this view, pointing out that there is no evidence of any obvious neurological abnormality in the vast majority of cases of word reading difficulty cases. The available relevant evidence from neuroimaging studies consists almost entirely of correlational and group-differences studies. However, differences in brains are certain to exist whenever differences in behavior exist, including differences in ability and performance. Therefore, findings of brain differences do not constitute evidence for abnormality; rather, they simply document the neural substrate of the behavioral differences. We suggest that dyslexia is best viewed as one of many expressions of ordinary ubiquitous individual differences in normal developmental outcomes. Thus, terms such as “dysfunctional” or “abnormal” are not justified when referring to the brains of persons with dyslexia. PMID:29621138

Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

PubMed

Simon, Matthew J; Iliff, Jeffrey J

2016-03-01

Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. Copyright © 2015 Elsevier B.V. All rights reserved.

Improving the Nation's Health. Step One: Reduce Toxic Stress in Early Childhood. Perspectives

ERIC Educational Resources Information Center

Louv, Richard

2006-01-01

To reduce risk factors for adult disease in our society, we must tackle the problem of toxic stress in early childhood. This condition is associated with the excessive release of a stream of hormones whose persistent elevation can disrupt the wiring of the developing brain and the functioning of the immune system. Children who experience toxic…

Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats.

PubMed

Zhang, Tingting; Su, Jingyuan; Guo, Bingyu; Wang, Kaiwen; Li, Xiaoming; Liang, Guobiao

2015-09-01

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro-inflammatory cytokines and chemokines. Disruption of blood-brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-κB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-κB and their downstream pro-inflammatory cytokines in the cortex and by up-regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption. Copyright © 2015 Elsevier B.V. All rights reserved.

Mild hypothermia alleviates brain oedema and blood-brain barrier disruption by attenuating tight junction and adherens junction breakdown in a swine model of cardiopulmonary resuscitation

PubMed Central

Li, Jiebin; Li, Chunsheng; Yuan, Wei; Wu, Junyuan; Li, Jie; Li, Zhenhua; Zhao, Yongzhen

2017-01-01

Mild hypothermia improves survival and neurological recovery after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). However, the mechanism underlying this phenomenon is not fully elucidated. The aim of this study was to determine whether mild hypothermia alleviates early blood–brain barrier (BBB) disruption. We investigated the effects of mild hypothermia on neurologic outcome, survival rate, brain water content, BBB permeability and changes in tight junctions (TJs) and adherens junctions (AJs) after CA and CPR. Pigs were subjected to 8 min of untreated ventricular fibrillation followed by CPR. Mild hypothermia (33°C) was intravascularly induced and maintained at this temperature for 12 h, followed by active rewarming. Mild hypothermia significantly reduced cortical water content, decreased BBB permeability and attenuated TJ ultrastructural and basement membrane breakdown in brain cortical microvessels. Mild hypothermia also attenuated the CPR-induced decreases in TJ (occludin, claudin-5, ZO-1) and AJ (VE-cadherin) protein and mRNA expression. Furthermore, mild hypothermia decreased the CA- and CPR-induced increases in matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression and increased angiogenin-1 (Ang-1) expression. Our findings suggest that mild hypothermia attenuates the CA- and resuscitation-induced early brain oedema and BBB disruption, and this improvement might be at least partially associated with attenuation of the breakdown of TJ and AJ, suppression of MMP-9 and VEGF expression, and upregulation of Ang-1 expression. PMID:28355299

Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology

PubMed Central

Kyzar, Evan J.; Floreani, Christina; Teppen, Tara L.; Pandey, Subhash C.

2016-01-01

Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can disrupt these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD) and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood. PMID:27303256

78 FR 734 - Medical Imaging Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-04

..., LLC. The proposed indication (use) for this product is for magnetic resonance imaging in brain...) to detect and visualize areas with disruption of the blood brain barrier (specialized tissues that help protect the brain) and/or abnormal vascularity (abnormal blood circulation). FDA intends to make...

White Matter Damage and Cognitive Impairment after Traumatic Brain Injury

ERIC Educational Resources Information Center

Kinnunen, Kirsi Maria; Greenwood, Richard; Powell, Jane Hilary; Leech, Robert; Hawkins, Peter Charlie; Bonnelle, Valerie; Patel, Maneesh Chandrakant; Counsell, Serena Jane; Sharp, David James

2011-01-01

White matter disruption is an important determinant of cognitive impairment after brain injury, but conventional neuroimaging underestimates its extent. In contrast, diffusion tensor imaging provides a validated and sensitive way of identifying the impact of axonal injury. The relationship between cognitive impairment after traumatic brain injury…

Assessing the effects of common variation in the FOXP2 gene on human brain structure.

PubMed

Hoogman, Martine; Guadalupe, Tulio; Zwiers, Marcel P; Klarenbeek, Patricia; Francks, Clyde; Fisher, Simon E

2014-01-01

The FOXP2 transcription factor is one of the most well-known genes to have been implicated in developmental speech and language disorders. Rare mutations disrupting the function of this gene have been described in different families and cases. In a large three-generation family carrying a missense mutation, neuroimaging studies revealed significant effects on brain structure and function, most notably in the inferior frontal gyrus, caudate nucleus, and cerebellum. After the identification of rare disruptive FOXP2 variants impacting on brain structure, several reports proposed that common variants at this locus may also have detectable effects on the brain, extending beyond disorder into normal phenotypic variation. These neuroimaging genetics studies used groups of between 14 and 96 participants. The current study assessed effects of common FOXP2 variants on neuroanatomy using voxel-based morphometry (VBM) and volumetric techniques in a sample of >1300 people from the general population. In a first targeted stage we analyzed single nucleotide polymorphisms (SNPs) claimed to have effects in prior smaller studies (rs2253478, rs12533005, rs2396753, rs6980093, rs7784315, rs17137124, rs10230558, rs7782412, rs1456031), beginning with regions proposed in the relevant papers, then assessing impact across the entire brain. In the second gene-wide stage, we tested all common FOXP2 variation, focusing on volumetry of those regions most strongly implicated from analyses of rare disruptive mutations. Despite using a sample that is more than 10 times that used for prior studies of common FOXP2 variation, we found no evidence for effects of SNPs on variability in neuroanatomy in the general population. Thus, the impact of this gene on brain structure may be largely limited to extreme cases of rare disruptive alleles. Alternatively, effects of common variants at this gene exist but are too subtle to be detected with standard volumetric techniques.

Baicalin Attenuates Subarachnoid Hemorrhagic Brain Injury by Modulating Blood-Brain Barrier Disruption, Inflammation, and Oxidative Damage in Mice

PubMed Central

Fu, Yongjian; Zhang, SongSong; Ding, Hao; Chen, Jin

2017-01-01

In subarachnoid hemorrhagic brain injury, the early crucial events are edema formation due to inflammatory responses and blood-brain barrier disruption. Baicalin, a flavone glycoside, has antineuroinflammatory and antioxidant properties. We examined the effect of baicalin in subarachnoid hemorrhagic brain injury. Subarachnoid hemorrhage was induced through filament perforation and either baicalin or vehicle was administered 30 min prior to surgery. Brain tissues were collected 24 hours after surgery after evaluation of neurological scores. Brain tissues were processed for water content, real-time PCR, and immunoblot analyses. Baicalin improved neurological score and brain water content. Decreased levels of tight junction proteins (occludin, claudin-5, ZO-1, and collagen IV) required for blood-brain barrier function were restored to normal level by baicalin. Real-time PCR data demonstrated that baicalin attenuated increased proinflammatory cytokine (IL-1β, IL-6, and CXCL-3) production in subarachnoid hemorrhage mice. In addition to that, baicalin attenuated microglial cell secretion of IL-1β and IL-6 induced by lipopolysaccharide (100 ng/ml) dose dependently. Finally, baicalin attenuated induction of NOS-2 and NOX-2 in SAH mice at the mRNA and protein level. Thus, we demonstrated that baicalin inhibited microglial cell activation and reduced inflammation, oxidative damage, and brain edema. PMID:28912935

A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD

DTIC Science & Technology

2013-08-01

sleep disturbance, and other hyperarousal symptoms typical of PTSD (11). Specific stimulation of CNS alpha-1 adreno- receptors disrupts REM sleep (36...result from excessive brain responsiveness to released norepinephrine disrupting rapid eye movement ( REM ) and other sleep stages (Mellman, Kumar, Kulick...in 2006, sought help for distressing combat trauma night- mares, sleep disruption, and daytime intrusive ruminations about previous combat events. He

Prediction of brain maturity in infants using machine-learning algorithms.

PubMed

Smyser, Christopher D; Dosenbach, Nico U F; Smyser, Tara A; Snyder, Abraham Z; Rogers, Cynthia E; Inder, Terrie E; Schlaggar, Bradley L; Neil, Jeffrey J

2016-08-01

Recent resting-state functional MRI investigations have demonstrated that much of the large-scale functional network architecture supporting motor, sensory and cognitive functions in older pediatric and adult populations is present in term- and prematurely-born infants. Application of new analytical approaches can help translate the improved understanding of early functional connectivity provided through these studies into predictive models of neurodevelopmental outcome. One approach to achieving this goal is multivariate pattern analysis, a machine-learning, pattern classification approach well-suited for high-dimensional neuroimaging data. It has previously been adapted to predict brain maturity in children and adolescents using structural and resting state-functional MRI data. In this study, we evaluated resting state-functional MRI data from 50 preterm-born infants (born at 23-29weeks of gestation and without moderate-severe brain injury) scanned at term equivalent postmenstrual age compared with data from 50 term-born control infants studied within the first week of life. Using 214 regions of interest, binary support vector machines distinguished term from preterm infants with 84% accuracy (p<0.0001). Inter- and intra-hemispheric connections throughout the brain were important for group categorization, indicating that widespread changes in the brain's functional network architecture associated with preterm birth are detectable by term equivalent age. Support vector regression enabled quantitative estimation of birth gestational age in single subjects using only term equivalent resting state-functional MRI data, indicating that the present approach is sensitive to the degree of disruption of brain development associated with preterm birth (using gestational age as a surrogate for the extent of disruption). This suggests that support vector regression may provide a means for predicting neurodevelopmental outcome in individual infants. Copyright © 2016 Elsevier Inc. All rights reserved.

Prediction of brain maturity in infants using machine-learning algorithms

PubMed Central

Smyser, Christopher D.; Dosenbach, Nico U.F.; Smyser, Tara A.; Snyder, Abraham Z.; Rogers, Cynthia E.; Inder, Terrie E.; Schlaggar, Bradley L.; Neil, Jeffrey J.

2016-01-01

Recent resting-state functional MRI investigations have demonstrated that much of the large-scale functional network architecture supporting motor, sensory and cognitive functions in older pediatric and adult populations is present in term- and prematurely-born infants. Application of new analytical approaches can help translate the improved understanding of early functional connectivity provided through these studies into predictive models of neurodevelopmental outcome. One approach to achieving this goal is multivariate pattern analysis, a machine-learning, pattern classification approach well-suited for high-dimensional neuroimaging data. It has previously been adapted to predict brain maturity in children and adolescents using structural and resting state-functional MRI data. In this study, we evaluated resting state-functional MRI data from 50 preterm-born infants (born at 23–29 weeks of gestation and without moderate–severe brain injury) scanned at term equivalent postmenstrual age compared with data from 50 term-born control infants studied within the first week of life. Using 214 regions of interest, binary support vector machines distinguished term from preterm infants with 84% accuracy (p < 0.0001). Inter- and intra-hemispheric connections throughout the brain were important for group categorization, indicating that widespread changes in the brain's functional network architecture associated with preterm birth are detectable by term equivalent age. Support vector regression enabled quantitative estimation of birth gestational age in single subjects using only term equivalent resting state-functional MRI data, indicating that the present approach is sensitive to the degree of disruption of brain development associated with preterm birth (using gestational age as a surrogate for the extent of disruption). This suggests that support vector regression may provide a means for predicting neurodevelopmental outcome in individual infants. PMID:27179605

Micro-SPECT/CT-based pharmacokinetic analysis of 99mTc-diethylenetriaminepentaacetic acid in rats with blood-brain barrier disruption induced by focused ultrasound.

PubMed

Yang, Feng-Yi; Wang, Hsin-Ell; Lin, Guan-Liang; Teng, Ming-Che; Lin, Hui-Hsien; Wong, Tai-Tong; Liu, Ren-Shyan

2011-03-01

This study evaluated the pharmacokinetics of (99m)Tc-diethylenetriamine pentaacetate acid ((99m)Tc-DTPA) after intravenous administration in healthy and F98 glioma-bearing F344 rats in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). The pharmacokinetics of the healthy and tumor-containing brains after BBB-D were compared to identify the optimal time period for combined treatment. Healthy and F98 glioma-bearing rats were injected intravenously with Evans blue (EB) and (99m)Tc-DTPA; these treatments took place with or without BBB-D induced by transcranial FUS of 1 hemisphere of the brain. The permeability of the BBB was quantified by EB extravasation. Twelve rats were scanned for 2 h to estimate uptake of (99m)Tc radioactivity with respect to time for the pharmacokinetic analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed to examine tissue damage. The accumulations of EB and (99m)Tc-DTPA in normal brains or brains with a tumor were significantly elevated after the intravenous injection when BBB-D was induced. The disruption-to-nondisruption ratio of the brains and the tumor-to-ipsilateral brain ratio of the tumors in terms of radioactivity reached a peak at 45 and 60 min, respectively. EB injection followed by sonication showed that there was an increase of about 2-fold in the tumor-to-ipsilateral brain EB ratio of the target tumors (7.36), compared with the control tumors (3.73). TUNEL staining showed no significant differences between the sonicated tumors and control tumors. This study demonstrates that (99m)Tc-DTPA micro-SPECT/CT can be used for the pharmacokinetic analysis of BBB-D induced by FUS. This method should be able to provide important information that will help with establishing an optimal treatment protocol for drug administration after FUS-induced BBB-D in clinical brain disease therapy.

Hydrogen inhalation ameliorated mast cell mediated brain injury after ICH in mice

PubMed Central

Manaenko, Anatol; Lekic, Tim; Ma, Qingyi; Zhang, John H.; Tang, Jiping

2012-01-01

OBJECTIVE Hydrogen inhalation was neuroprotective in several brain injury models. Its mechanisms are believed to be related to anti-oxidative stress. We investigated the potential neurovascular protective effect of hydrogen inhalation especially effect on mast cell activation in a mouse model of intracerebral hemorrhage (ICH). DESIGN Controlled in vivo laboratory study. SETTING Animal research laboratory SUBJECTS 171, 8 weeks old male CD-1 mice were used. INTERVENTIONS Collagenase-induced ICH model in 8 weeks old, male, CD-1 mice was used. Hydrogen was administrated via spontaneous inhalation. The blood-brain barrier (BBB) permeability and neurological deficits were investigated at 24 and 72 hours after ICH. Mast cell activation was evaluated by Western blot and immuno-staining. The effects of hydrogen inhalation on mast cell activation were confirmed in an autologous blood injection model ICH. MEASURMENT AND MAIN RESULTS At 24 and 72 hours post-ICH, animals showed BBB disruption, brain edema, neurological deficits, accompanied with phosphorylation of Lyn kinase and release of tryptase, indicating mast cell activation. Hydrogen treatment diminished phosphorylation of Lyn kinase and release of tryptase, decreased accumulation and degranulation of mast cells, attenuated BBB disruption and improved neurobehavioral function. CONCLUSION Activation of mast cells following ICH contributed to increase of BBB permeability and brain edema. Hydrogen inhalation preserved BBB disruption by prevention of mast cell activation after ICH. PMID:23388512

Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure

PubMed Central

Chen, Florence; Ohashi, Norifumi; Li, Wensheng; Eckman, Christopher; Nguyen, Justin H.

2010-01-01

Brain edema in acute liver failure (ALF) remains lethal. The role of vasogenic mechanisms of brain edema has not been explored. We previously demonstrated that matrix metalloproteinase-9 (MMP-9) contributes to the pathogenesis of brain edema. Here, we show that MMP-9 mediates disruptions in tight junction proteins in vitro and in brains of mice with ALF. We transfected murine brain endothelial cells with MMP-9 cDNA using pc DNA3.1 (+)/Myc-His A expression vector. Tissue inhibitor of matrix metalloproteinases (TIMP-1) cDNA transfection or GM6001 was used to inhibit MMP-9. ALF was induced in mice with azoxymethane. Endogenous overexpression of MMP-9 in brain endothelial cells resulted in significant degradation of tight junction proteins occludin and claudin-5. The alterations in tight junction proteins correlated with increased permeability to FITC-dextran molecules. The degradation of tight junction proteins and the increased permeability were reversed by TIMP-1 and GM6001. Similar results were found when MMP-9 was exogenously added to brain EC. We also found that tight junction proteins degradation was reversed with GM6001 in brains of mice with ALF. Conclusions Tight junction proteins are significantly perturbed in brains of mice with ALF. These data corroborate the important role of MMP-9 in the vasogenic mechanism of brain edema in ALF. PMID:19821483

Multicolor Fluorescence Imaging of Traumatic Brain Injury in a Cryolesion Mouse Model

PubMed Central

2012-01-01

Traumatic brain injury is characterized by initial tissue damage, which then can lead to secondary processes such as cell death and blood-brain-barrier disruption. Clinical and preclinical studies of traumatic brain injury typically employ anatomical imaging techniques and there is a need for new molecular imaging methods that provide complementary biochemical information. Here, we assess the ability of a targeted, near-infrared fluorescent probe, named PSS-794, to detect cell death in a brain cryolesion mouse model that replicates certain features of traumatic brain injury. In short, the model involves brief contact of a cold rod to the head of a living, anesthetized mouse. Using noninvasive whole-body fluorescence imaging, PSS-794 permitted visualization of the cryolesion in the living animal. Ex vivo imaging and histological analysis confirmed PSS-794 localization to site of brain cell death. The nontargeted, deep-red Tracer-653 was validated as a tracer dye for monitoring blood-brain-barrier disruption, and a binary mixture of PSS-794 and Tracer-653 was employed for multicolor imaging of cell death and blood-brain-barrier permeability in a single animal. The imaging data indicates that at 3 days after brain cryoinjury the amount of cell death had decreased significantly, but the integrity of the blood-brain-barrier was still impaired; at 7 days, the blood-brain-barrier was still three times more permeable than before cryoinjury. PMID:22860222

Disconnection of the Ascending Arousal System in Traumatic Coma

PubMed Central

Edlow, Brian L.; Haynes, Robin L.; Takahashi, Emi; Klein, Joshua P.; Cummings, Peter; Benner, Thomas; Greer, David M.; Greenberg, Steven M.; Wu, Ona; Kinney, Hannah C.; Folkerth, Rebecca D.

2013-01-01

Traumatic coma is associated with disruption of axonal pathways throughout the brain but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging (HARDI) to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness – arousal and awareness – in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. HARDI tractography guided tissue sampling in the neuropathological analysis. HARDI tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical “awareness pathways.” Neuropathologic examination, which utilized β-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of HARDI tract disruption. Axonal injury was also present within the grey matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain. PMID:23656993

The blood-brain barrier: an engineering perspective

PubMed Central

Wong, Andrew D.; Ye, Mao; Levy, Amanda F.; Rothstein, Jeffrey D.; Bergles, Dwight E.; Searson, Peter C.

2013-01-01

It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore, advances in our understanding of the structure and function of the blood-brain barrier are key to developing effective treatments for a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases. PMID:24009582

Identification of autism spectrum disorder using deep learning and the ABIDE dataset.

PubMed

Heinsfeld, Anibal Sólon; Franco, Alexandre Rosa; Craddock, R Cameron; Buchweitz, Augusto; Meneguzzi, Felipe

2018-01-01

The goal of the present study was to apply deep learning algorithms to identify autism spectrum disorder (ASD) patients from large brain imaging dataset, based solely on the patients brain activation patterns. We investigated ASD patients brain imaging data from a world-wide multi-site database known as ABIDE (Autism Brain Imaging Data Exchange). ASD is a brain-based disorder characterized by social deficits and repetitive behaviors. According to recent Centers for Disease Control data, ASD affects one in 68 children in the United States. We investigated patterns of functional connectivity that objectively identify ASD participants from functional brain imaging data, and attempted to unveil the neural patterns that emerged from the classification. The results improved the state-of-the-art by achieving 70% accuracy in identification of ASD versus control patients in the dataset. The patterns that emerged from the classification show an anticorrelation of brain function between anterior and posterior areas of the brain; the anticorrelation corroborates current empirical evidence of anterior-posterior disruption in brain connectivity in ASD. We present the results and identify the areas of the brain that contributed most to differentiating ASD from typically developing controls as per our deep learning model.

Use of Ultrasound Pulses Combined with Definity for Targeted Blood-Brain Barrier Disruption

NASA Astrophysics Data System (ADS)

McDannold, Nathan; Vykhodtseva, Natalia; Hynynen, Kullervo

2007-05-01

We have developed a method to combine an ultrasound contrast agent (USCA) with low-intensity focused ultrasound pulses combined to produce temporary blood-brain barrier disruption (BBBD), a potential non-invasive means for targeted drug delivery in the brain. All of our previous work used the USCA Optison. The purpose of this work was to test the feasibility of using the USCA Definity for BBBD. Thirty-six non-overlapping locations were sonicated through a craniotomy in experiments in the brains of nine rabbits (4 locations per rabbit; US frequency: 0.69MHz, burst: 10ms, PRF: 1Hz, duration: 20s; pressure amplitude: 0.2-1.5 MPa). Eleven locations were sonicated using Optison at 0.5 MPa. For both agents, the probability for BBBD was estimated to be 50% at 0.4 MPa using probit regression. In histology, small isolated areas of extravasated erythrocytes were observed in some locations. At 0.8 MPa and above, this extravasation was sometimes accompanied by tiny (dimensions of 100 μm or less) regions of damaged brain parenchyma. The magnitude of the BBBD was larger with Optison than with Definity at 0.5 MPa (P=0.04), and more areas with extravasated erythrocytes were observed (P=0.03). We conclude that BBBD is possible using Definity for the dosage of USCA and the acoustic parameters tested in this study. While the probability for BBBD as a function of pressure amplitude and the type of acute tissue effects was similar to findings with Optison, under these experimental conditions, Optison produced a larger effect.

Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis.

PubMed

Lopez, Adam M; Chuang, Jen-Chieh; Posey, Kenneth S; Turley, Stephen D

2017-01-01

Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) are the principal cause of Rett syndrome, a progressive neurodevelopmental disorder afflicting 1 in 10,000 to 15,000 females. Studies using hemizygous Mecp2 mouse models have revealed disruptions to some aspects of their lipid metabolism including a partial suppression of cholesterol synthesis in the brains of mature Mecp2 mutants. The present studies investigated whether this suppression is evident from early neonatal life, or becomes manifest at a later stage of development. We measured the rate of cholesterol synthesis, in vivo, in the brains of male Mecp2 - /y and their Mecp2 +/y littermates at 7, 14, 21, 28, 42 and 56 days of age. Brain weight was consistently lower in the Mecp2 -/y mice than in their Mecp2 +/y controls except at 7 days of age. In the 7- and 14-day-old mice there was no genotypic difference in the rate of brain cholesterol synthesis but, from 21 days and later, it was always marginally lower in the Mecp2 -/y mice than in age-matched Mecp2 +/y littermates. At no age was a genotypic difference detected in either the rate of fatty acid synthesis or cholesterol concentration in the brain. Cholesterol synthesis rates in the liver and lungs of 56-day-old Mecp2 -/y mice were normal. The onset of lower rates of brain cholesterol synthesis at about the time closure of the blood brain barrier purportedly occurs might signify a disruption to mechanism(s) that dictate intracellular levels of cholesterol metabolites including oxysterols known to exert a regulatory influence on the cholesterol biosynthetic pathway. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

The State of the NIH BRAIN Initiative.

PubMed

Koroshetz, Walter; Gordon, Joshua; Adams, Amy; Beckel-Mitchener, Andrea; Churchill, James; Farber, Gregory; Freund, Michelle; Gnadt, Jim; Hsu, Nina; Langhals, Nicholas; Lisanby, Sarah; Liu, Guoying; Peng, Grace; Ramos, Khara; Steinmetz, Michael; Talley, Edmund; White, Samantha

2018-06-19

The BRAIN Initiative® arose from a grand challenge to "accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought." The BRAIN Initiative is a public-private effort focused on the development and use of powerful tools for acquiring fundamental insights about how information processing occurs in the central nervous system. As the Initiative enters its fifth year, NIH has supported over 500 principal investigators, who have answered the Initiative's challenge via hundreds of publications describing novel tools, methods, and discoveries that address the Initiative's seven scientific priorities. We describe scientific advances produced by individual labs, multi-investigator teams, and entire consortia that, over the coming decades, will produce more comprehensive and dynamic maps of the brain, deepen our understanding of how circuit activity can produce a rich tapestry of behaviors, and lay the foundation for understanding how its circuitry is disrupted in brain disorders. Much more work remains to bring this vision to fruition, and NIH continues to look to the diverse scientific community, from mathematics, to physics, chemistry, engineering, neuroethics, and neuroscience, to ensure that the greatest scientific benefit arises from this unique research Initiative. Copyright © 2018 the authors.

Chitosan nanoparticles and their Tween 80 modified counterparts disrupt the developmental profile of zebrafish embryos.

PubMed

Yuan, Zhongyue; Li, Ying; Hu, Yulan; You, Jian; Higashisaka, Kazuma; Nagano, Kazuya; Tsutsumi, Yasuo; Gao, Jianqing

2016-12-30

Chitosan nanoparticles (CS-NPs) and their Tween 80 modified counterparts (TmCS-NPs) are among the most commonly used brain-targeted vehicles. However, their potential developmental toxicity is poorly understood. In this study, zebrafish embryos are introduced as an in vivo platform. Both NPs showed a dose-dependent increase in developmental toxicity (decreased hatching rate, increased mortality and incidences of malformation). Neurobehavioral changes included decreased spontaneous movement in TmCS-NP treated embryos and hyperactive effect in CS-NP treated larvae. Both NPs remarkably inhibited axonal development of primary and secondary motor neurons, and affected the muscle structure. Overall, this study demonstrated that CS-NPs and TmCS-NPs could affect embryonic development, disrupt neurobehavior of zebrafish larvae and affect muscle and neuron development, suggesting more attention on biodegradable chitosan nanoparticles. Copyright © 2016 Elsevier B.V. All rights reserved.

Prenatal Nicotine Exposure Disrupts Infant Neural Markers of Orienting.

PubMed

King, Erin; Campbell, Alana; Belger, Aysenil; Grewen, Karen

2018-06-07

Prenatal nicotine exposure (PNE) from maternal cigarette smoking is linked to developmental deficits, including impaired auditory processing, language, generalized intelligence, attention, and sleep. Fetal brain undergoes massive growth, organization, and connectivity during gestation, making it particularly vulnerable to neurotoxic insult. Nicotine binds to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity, and function of developing neural circuitry and neurotransmitter systems. Thus, PNE may have long-term impact on neurobehavioral development. The purpose of this study was to compare the auditory K-complex, an event-related potential reflective of auditory gating, sleep preservation and memory consolidation during sleep, in infants with and without PNE and to relate these neural correlates to neurobehavioral development. We compared brain responses to an auditory paired-click paradigm in 3- to 5-month-old infants during Stage 2 sleep, when the K-complex is best observed. We measured component amplitude and delta activity during the K-complex. Infants with PNE demonstrated significantly smaller amplitude of the N550 component and reduced delta-band power within elicited K-complexes compared to nonexposed infants and also were less likely to orient with a head turn to a novel auditory stimulus (bell ring) when awake. PNE may impair auditory sensory gating, which may contribute to disrupted sleep and to reduced auditory discrimination and learning, attention re-orienting, and/or arousal during wakefulness reported in other studies. Links between PNE and reduced K-complex amplitude and delta power may represent altered cholinergic and GABAergic synaptic programming and possibly reflect early neural bases for PNE-linked disruptions in sleep quality and auditory processing. These may pose significant disadvantage for language acquisition, attention, and social interaction necessary for academic and social success.

Biallelic missense variants in ZBTB11 can cause intellectual disability in human.

PubMed

Fattahi, Zohreh; Sheikh, Taimoor I; Musante, Luciana; Rasheed, Memoona; Taskiran, Ibrahim Ihsan; Harripaul, Ricardo; Hu, Hao; Kazeminasab, Somayeh; Alam, Muhammad Rizwan; Hosseini, Masoumeh; Larti, Farzaneh; Ghaderi, Zhila; Celik, Arzu; Ayub, Muhammad; Ansar, Muhammad; Haddadi, Mohammad; Wienker, Thomas F; Ropers, Hans Hilger; Kahrizi, Kimia; Vincent, John B; Najmabadi, H

2018-06-08

Exploring genes and pathways underlying Intellectual Disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next generation sequencing revealed ZBTB11, as a novel candidate ID gene. ZBTB11 encodes a less-studied transcription regulator and the two identified missense variants in this study may disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding. Using HEK293T cells transfected with wild type and mutant GFP-ZBTB11 constructs, we found the ZBTB11 mutants being excluded from the nucleolus, where the wild-type recombinant protein is predominantly localized. Pathway analysis applied to ChIP-seq data deposited in the ENCODE database supports the localization of ZBTB11 in nucleoli, highlighting associated pathways such as rRNA synthesis, ribosomal assembly, RNA modification, stress sensing and provides a direct link between subcellular ZBTB11 location and its function. Furthermore, considering the report of prominent brain and spinal cord degeneration in a zebrafish Zbtb11 mutant, we investigated ZBTB11-ortholog knockdown in Drosophila melanogaster brain by targeting RNAi using the UAS/Gal4 system. The observed approximate reduction to a third of the mushroom body size - possibly through neuronal reduction or degeneration - may affect neuronal circuits in the brain that are required for adaptive behavior, specifying the role of this gene in nervous system. In conclusion, we report two ID families segregating ZBTB11 biallelic mutations disrupting Zn2+-binding motifs, and provide functional evidence linking ZBTB11 dysfunction to this phenotype.

Prediction of specific damage or infarction from the measurement of tissue impedance following repetitive brain ischaemia in the rat.

PubMed

Klein, H C; Krop-Van Gastel, W; Go, K G; Korf, J

1993-02-01

The development of irreversible brain damage during repetitive periods of hypoxia and normoxia was studied in anaesthetized rats with unilateral occlusion of the carotid artery (modified Levine model). Rats were exposed to 10 min hypoxia and normoxia until severe damage developed. As indices of damage, whole striatal tissue impedance (reflecting cellular water uptake), sodium/potassium contents (due to exchange with blood). Evans Blue staining (blood-brain barrier [BBB] integrity) and silver staining (increased in irreversibly damaged neurons) were used. A substantial decrease in blood pressure was observed during the hypoxic periods possibly producing severe ischaemia. Irreversibly increased impedance, massive changes in silver staining, accumulation of whole tissue Na and loss of K occurred only after a minimum of two periods of hypoxia, but there was no disruption of the BBB. Microscopic examination of tissue sections revealed that cell death was selective with reversible impedance changes, but became massive and non-specific after irreversible increase of the impedance. The development of brain infarcts could, however, not be predicted from measurements of physiological parameters in the blood. We suggest that the development of cerebral infarction during repetitive periods of hypoxia may serve as a model for the development of brain damage in a variety of clinical conditions. Furthermore, the present model allows the screening of potential therapeutic measuring of the prevention and treatment of both infarction and selective cell death.

Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: Potential for targeting experimental brain tumors

PubMed Central

Diaz, Roberto Jose; McVeigh, Patrick Z.; O’Reilly, Meaghan A.; Burrell, Kelly; Bebenek, Matthew; Smith, Christian; Etame, Arnold; Zadeh, Gelareh; Hynynen, Kullervo; Wilson, Brian C.; Rutka, James T.

2014-01-01

Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50 nm or 120 nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120 nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors. PMID:24374363

The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats.

PubMed

Lee, Jae-Min; Park, Jong-Min; Song, Min Kyung; Oh, Yoo Joung; Kim, Chang-Ju; Kim, Youn-Jung

2017-01-18

Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.

PubMed

O'Tuathaigh, Colm M P; Fumagalli, Fabio; Desbonnet, Lieve; Perez-Branguli, Francesc; Moloney, Gerard; Loftus, Samim; O'Leary, Claire; Petit, Emilie; Cox, Rachel; Tighe, Orna; Clarke, Gerard; Lai, Donna; Harvey, Richard P; Cryan, John F; Mitchell, Kevin J; Dinan, Timothy G; Riva, Marco A; Waddington, John L

2017-01-01

Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders

PubMed Central

Karasawa, Takatoshi; Lombroso, Paul J.

2014-01-01

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific tyrosine phosphatase that plays a major role in the development of synaptic plasticity. Recent findings have implicated STEP in several psychiatric and neurological disorders, including Alzheimer’s disease, schizophrenia, fragile X syndrome, Huntington’s disease, stroke/ischemia, and stress-related psychiatric disorders. In these disorders, STEP protein expression levels and activity are dysregulated, contributing to the cognitive deficits that are present. In this review, we focus on the most recent findings on STEP, discuss how STEP expression and activity are maintained during normal cognitive function, and how disruptions in STEP activity contribute to a number of illnesses. PMID:25218562

Elucidating the Links Between Endocrine Disruptors and Neurodevelopment

PubMed Central

Blawas, Ashley M.; Gray, Kimberly; Heindel, Jerrold J.; Lawler, Cindy P.

2015-01-01

Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes. PMID:25714811

Toward Developmental Connectomics of the Human Brain

PubMed Central

Cao, Miao; Huang, Hao; Peng, Yun; Dong, Qi; He, Yong

2016-01-01

Imaging connectomics based on graph theory has become an effective and unique methodological framework for studying structural and functional connectivity patterns of the developing brain. Normal brain development is characterized by continuous and significant network evolution throughout infancy, childhood, and adolescence, following specific maturational patterns. Disruption of these normal changes is associated with neuropsychiatric developmental disorders, such as autism spectrum disorders or attention-deficit hyperactivity disorder. In this review, we focused on the recent progresses regarding typical and atypical development of human brain networks from birth to early adulthood, using a connectomic approach. Specifically, by the time of birth, structural networks already exhibit adult-like organization, with global efficient small-world and modular structures, as well as hub regions and rich-clubs acting as communication backbones. During development, the structure networks are fine-tuned, with increased global integration and robustness and decreased local segregation, as well as the strengthening of the hubs. In parallel, functional networks undergo more dramatic changes during maturation, with both increased integration and segregation during development, as brain hubs shift from primary regions to high order functioning regions, and the organization of modules transitions from a local anatomical emphasis to a more distributed architecture. These findings suggest that structural networks develop earlier than functional networks; meanwhile functional networks demonstrate more dramatic maturational changes with the evolution of structural networks serving as the anatomical backbone. In this review, we also highlighted topologically disorganized characteristics in structural and functional brain networks in several major developmental neuropsychiatric disorders (e.g., autism spectrum disorders, attention-deficit hyperactivity disorder and developmental dyslexia). Collectively, we showed that delineation of the brain network from a connectomics perspective offers a unique and refreshing view of both normal development and neuropsychiatric disorders. PMID:27064378

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.

PubMed

Teng, S; Thomson, P A; McCarthy, S; Kramer, M; Muller, S; Lihm, J; Morris, S; Soares, D C; Hennah, W; Harris, S; Camargo, L M; Malkov, V; McIntosh, A M; Millar, J K; Blackwood, D H; Evans, K L; Deary, I J; Porteous, D J; McCombie, W R

2018-05-01

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWER across ), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWER across P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWER across P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.

78 FR 53764 - Proposed Data Collections Submitted for Public Comment and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-30

... days of this notice. Proposed Project Examining Traumatic Brain Injury in Youth--NEW--National Center...). Background and Brief Description Traumatic brain injury (TBI) is one of the highest priorities in public... penetrating head injury that disrupts the normal function of the brain. The severity of a TBI may range from...

Scared or scarred: Could 'dissociogenic' lesions predispose to nonepileptic seizures after head trauma?

PubMed

Popkirov, Stoyan; Carson, Alan J; Stone, Jon

2018-04-14

A history of head injury is common in patients with psychogenic nonepileptic seizures (PNES). This association has so far been interpreted as either spurious or psychologically mediated. Biased recall and misattribution could foster illness beliefs about brain damage that promote symptom production. Furthermore, the emotional impact of head injury could induce long-term changes in stress responsivity. Lastly, maladaptive cognitive-behavioural processes involving symptom modelling and aversive conditioning, known to play a role in functional neurological disorders, could contribute to the development of PNES after head trauma. Lesional effects of head injury, on the other hand, remain unexplored in the context of PNES. However, even mild traumatic brain injury without structural MRI abnormalities on routine imaging can lead to disruptions of network connectivity that correlate with short-term cognitive impairments and psychiatric symptoms. Since alterations in global functional connectivity have been demonstrated in PNES patients using imaging and electroencephalography, we hypothesize that, in some patients, TBI and the associated disruption of long-range association fibres could contribute to the individual propensity for dissociative experiences in general and PNES in particular. This possibility is explored in the context of new cognitive-behavioural models of PNES pathogenesis, and the concept of a "dissociogenic" brain lesion is introduced. Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Does gender matter? Differences in social-emotional behavior among infants and toddlers before and after mild traumatic brain injury: a preliminary study.

PubMed

Kaldoja, Mari-Liis; Kolk, Anneli

2015-06-01

Traumatic brain injury is a common cause of acquired disability in childhood. While much is known about cognitive sequelae of brain trauma, gender-specific social-emotional problems in children with mild traumatic brain injury is far less understood. The aims of the study were to investigate gender differences in social-emotional behavior before and after mild traumatic brain injury. Thirty-five 3- to 65-month-old children with mild traumatic brain injury and 70 controls were assessed with Ages and Stages Questionnaires: Social-Emotional. Nine months later, 27 of 35 patients and 54 of 70 controls were reassessed. We found that before injury, boys had more self-regulation and autonomy difficulties and girls had problems with adaptive functioning. Nine months after injury, boys continued to struggle with self-regulation and autonomy and new difficulties with interaction had emerged, whereas in girls, problems in interaction had evolved. Even mild traumatic brain injury in early childhood disrupts normal social-emotional development having especially devastating influence on interaction skills. © The Author(s) 2014.

C-type natriuretic peptide-modified lipid vesicles: fabrication and use for the treatment of brain glioma.

PubMed

Wu, Jia-Shuan; Mu, Li-Min; Bu, Ying-Zi; Liu, Lei; Yan, Yan; Hu, Ying-Jie; Bai, Jing; Zhang, Jing-Ying; Lu, Weiyue; Lu, Wan-Liang

2017-06-20

Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo. The results showed that the CNP-modified vinorelbine lipid vesicles could transport vinorelbine across the BBB, kill the brain glioma, and destroy neovasculatures effectively. The above mechanisms could be associated with the following aspects, namely, long circulation in the blood; drug transport across the BBB via natriuretic peptide receptor B (NPRB)-mediated transcytosis; elimination of brain glioma cells and disruption of neovasculatures by targeting uptake and cytotoxic injury. Besides, CNP-modified vinorelbine lipid vesicles could induce apoptosis of the glioma cells. The mechanisms could be related to the activations of caspase 8, caspase 3, p53, and reactive oxygen species (ROS), and inhibition of survivin. Hence, CNP-modified lipid vesicles could be used as a carrier material for treating brain glioma and disabling glioma neovasculatures.

Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

PubMed Central

Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

2014-01-01

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB. PMID:24462453

Electrical stimulation of a small brain area reversibly disrupts consciousness.

PubMed

Koubeissi, Mohamad Z; Bartolomei, Fabrice; Beltagy, Abdelrahman; Picard, Fabienne

2014-08-01

The neural mechanisms that underlie consciousness are not fully understood. We describe a region in the human brain where electrical stimulation reproducibly disrupted consciousness. A 54-year-old woman with intractable epilepsy underwent depth electrode implantation and electrical stimulation mapping. The electrode whose stimulation disrupted consciousness was between the left claustrum and anterior-dorsal insula. Stimulation of electrodes within 5mm did not affect consciousness. We studied the interdependencies among depth recording signals as a function of time by nonlinear regression analysis (h(2) coefficient) during stimulations that altered consciousness and stimulations of the same electrode at lower current intensities that were asymptomatic. Stimulation of the claustral electrode reproducibly resulted in a complete arrest of volitional behavior, unresponsiveness, and amnesia without negative motor symptoms or mere aphasia. The disruption of consciousness did not outlast the stimulation and occurred without any epileptiform discharges. We found a significant increase in correlation for interactions affecting medial parietal and posterior frontal channels during stimulations that disrupted consciousness compared with those that did not. Our findings suggest that the left claustrum/anterior insula is an important part of a network that subserves consciousness and that disruption of consciousness is related to increased EEG signal synchrony within frontal-parietal networks. Copyright © 2014 Elsevier Inc. All rights reserved.

Modulatory effects of perforin gene dosage on pathogen-associated blood-brain barrier (BBB) disruption.

PubMed

Willenbring, Robin C; Jin, Fang; Hinton, David J; Hansen, Mike; Choi, Doo-Sup; Pavelko, Kevin D; Johnson, Aaron J

2016-08-31

CD8 T cell-mediated blood-brain barrier (BBB) disruption is dependent on the effector molecule perforin. Human perforin has extensive single nucleotide variants (SNVs), the significance of which is not fully understood. These SNVs can result in reduced, but not ablated, perforin activity or expression. However, complete loss of perforin expression or activity results in the lethal disease familial hemophagocytic lymphohistiocytosis type 2 (FHL 2). In this study, we address the hypothesis that a single perforin allele can alter the severity of BBB disruption in vivo using a well-established model of CNS vascular permeability in C57Bl/6 mice. The results of this study provide insight into the significance of perforin SNVs in the human population. We isolated the effect a single perforin allele has on CNS vascular permeability through the use of perforin-heterozygous (perforin+/-) C57BL/6 mice in the peptide-induced fatal syndrome (PIFS) model of immune-mediated BBB disruption. Seven days following Theiler's murine encephalomyelitis virus (TMEV) CNS infection, neuroinflammation and TMEV viral control were assessed through flow cytometric analysis and quantitative real-time PCR of the viral genome, respectively. Following immune-mediated BBB disruption, gadolinium-enhanced T1-weighted MRI, with 3D volumetric analysis, and confocal microscopy were used to define CNS vascular permeability. Finally, the open field behavior test was used to assess locomotor activity of mice following immune-mediated BBB disruption. Perforin-null mice had negligible CNS vascular permeability. Perforin-WT mice have extensive CNS vascular permeability. Interestingly, perforin-heterozygous mice had an intermediate level of CNS vascular permeability as measured by both gadolinium-enhanced T1-weighted MRI and fibrinogen leakage in the brain parenchyma. Differences in BBB disruption were not a result of increased CNS immune infiltrate. Additionally, TMEV was controlled in a perforin dose-dependent manner. Furthermore, a single perforin allele is sufficient to induce locomotor deficit during immune-mediated BBB disruption. Perforin modulates BBB disruption in a dose-dependent manner. This study demonstrates a potentially advantageous role for decreased perforin expression in reducing BBB disruption. This study also provides insight into the effect SNVs in a single perforin allele could have on functional deficit in neurological disease.

Endocannabinoid dysregulation in cognitive and stress-related brain regions in the Nrg1 mouse model of schizophrenia.

PubMed

Clarke, David J; Stuart, Jordyn; McGregor, Iain S; Arnold, Jonathon C

2017-01-04

The endocannabinoid system is dysregulated in schizophrenia. Mice with heterozygous deletion of neuregulin 1 (Nrg1 HET mice) provide a well-characterised animal model of schizophrenia, and display enhanced sensitivity to stress and cannabinoids during adolescence. However, no study has yet determined whether these mice have altered brain endocannabinoid concentrations. Nrg1 application to hippocampal slices decreased 2-arachidonoylglycerol (2-AG) signalling and disrupted long-term depression, a form of synaptic plasticity critical to spatial learning. Therefore we specifically aimed to examine whether Nrg1 HET mice exhibit increased 2-AG concentrations and disruption of spatial learning. As chronic stress influences brain endocannabinoids, we also sought to examine whether Nrg1 deficiency moderates adolescent stress-induced alterations in brain endocannabinoids. Adolescent Nrg1 HET and wild-type (WT) mice were submitted to chronic restraint stress and brain endocannabinoid concentrations were analysed. A separate cohort of WT and Nrg1 HET mice was also assessed for spatial learning performance in the Morris Water Maze. Partial genetic deletion of Nrg1 increased anandamide concentrations in the amygdala and decreased 2-AG concentrations in the hypothalamus. Further, Nrg1 HET mice exhibited increased 2-AG concentrations in the hippocampus and impaired spatial learning performance. Chronic adolescent stress increased anandamide concentrations in the amygdala, however, Nrg1 disruption did not influence this stress-induced change. These results demonstrate for the first time in vivo interplay between Nrg1 and endocannabinoids in the brain. Our results demonstrate that aberrant Nrg1 and endocannabinoid signalling may cooperate in the hippocampus to impair cognition, and that Nrg1 deficiency alters endocannabinoid signalling in brain stress circuitry. Copyright © 2016 Elsevier Inc. All rights reserved.

Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease.

PubMed

Sharoar, M G; Shi, Q; Ge, Y; He, W; Hu, X; Perry, G; Zhu, X; Yan, R

2016-09-01

Pathological features in Alzheimer's brains include mitochondrial dysfunction and dystrophic neurites (DNs) in areas surrounding amyloid plaques. Using a mouse model that overexpresses reticulon 3 (RTN3) and spontaneously develops age-dependent hippocampal DNs, here we report that DNs contain both RTN3 and REEPs, topologically similar proteins that can shape tubular endoplasmic reticulum (ER). Importantly, ultrastructural examinations of such DNs revealed gradual accumulation of tubular ER in axonal termini, and such abnormal tubular ER inclusion is found in areas surrounding amyloid plaques in biopsy samples from Alzheimer's disease (AD) brains. Functionally, abnormally clustered tubular ER induces enhanced mitochondrial fission in the early stages of DN formation and eventual mitochondrial degeneration at later stages. Furthermore, such DNs are abrogated when RTN3 is ablated in aging and AD mouse models. Hence, abnormally clustered tubular ER can be pathogenic in brain regions: disrupting mitochondrial integrity, inducing DNs formation and impairing cognitive function in AD and aging brains.

Lesion of the Olfactory Epithelium Accelerates Prion Neuroinvasion and Disease Onset when Prion Replication Is Restricted to Neurons

PubMed Central

Crowell, Jenna; Wiley, James A.; Bessen, Richard A.

2015-01-01

Natural prion diseases of ruminants are moderately contagious and while the gastrointestinal tract is the primary site of prion agent entry, other mucosae may be entry sites in a subset of infections. In the current study we examined prion neuroinvasion and disease induction following disruption of the olfactory epithelium in the nasal mucosa since this site contains environmentally exposed olfactory sensory neurons that project directly into the central nervous system. Here we provide evidence for accelerated prion neuroinvasion and clinical onset from the olfactory mucosa after disruption and regeneration of the olfactory epithelium and when prion replication is restricted to neurons. In transgenic mice with neuron restricted replication of prions, there was a reduction in survival when the olfactory epithelium was disrupted prior to intranasal inoculation and there was >25% decrease in the prion incubation period. In a second model, the neurotropic DY strain of transmissible mink encephalopathy was not pathogenic in hamsters by the nasal route, but 50% of animals exhibited brain infection and/or disease when the olfactory epithelium was disrupted prior to intranasal inoculation. A time course analysis of prion deposition in the brain following loss of the olfactory epithelium in models of neuron-restricted prion replication suggests that neuroinvasion from the olfactory mucosa is via the olfactory nerve or brain stem associated cranial nerves. We propose that induction of neurogenesis after damage to the olfactory epithelium can lead to prion infection of immature olfactory sensory neurons and accelerate prion spread to the brain. PMID:25822718

Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.

PubMed

Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam; Castro, Kamilah; Zhang, Jingya; Asp, Linnea; Loo, Hannah; Laitman, Benjamin M; Mariani, John N; Straus Farber, Rebecca; Zaslavsky, Elena; Nudelman, German; Raine, Cedric S; John, Gareth R

2015-06-01

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Combined Ultrasound and MR Imaging to Guide Focused Ultrasound Therapies in the Brain

PubMed Central

Arvanitis, Costas D.; Livingstone, Margaret S.; McDannold, Nathan

2013-01-01

Purpose Several emerging therapies with potential for use in the brain harness effects produced by acoustic cavitation – the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength, and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. Materials and Methods We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. Results The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. Conclusion While preliminary, these data clearly demonstrate, for the first time, that is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies. PMID:23788054

Spinal Cord Injury Disrupts Resting-State Networks in the Human Brain.

PubMed

Hawasli, Ammar H; Rutlin, Jerrel; Roland, Jarod L; Murphy, Rory K J; Song, Sheng-Kwei; Leuthardt, Eric C; Shimony, Joshua S; Ray, Wilson Z

2018-03-15

Despite 253,000 spinal cord injury (SCI) patients in the United States, little is known about how SCI affects brain networks. Spinal MRI provides only structural information with no insight into functional connectivity. Resting-state functional MRI (RS-fMRI) quantifies network connectivity through the identification of resting-state networks (RSNs) and allows detection of functionally relevant changes during disease. Given the robust network of spinal cord afferents to the brain, we hypothesized that SCI produces meaningful changes in brain RSNs. RS-fMRIs and functional assessments were performed on 10 SCI subjects. Blood oxygen-dependent RS-fMRI sequences were acquired. Seed-based correlation mapping was performed using five RSNs: default-mode (DMN), dorsal-attention (DAN), salience (SAL), control (CON), and somatomotor (SMN). RSNs were compared with normal control subjects using false-discovery rate-corrected two way t tests. SCI reduced brain network connectivity within the SAL, SMN, and DMN and disrupted anti-correlated connectivity between CON and SMN. When divided into separate cohorts, complete but not incomplete SCI disrupted connectivity within SAL, DAN, SMN and DMN and between CON and SMN. Finally, connectivity changed over time after SCI: the primary motor cortex decreased connectivity with the primary somatosensory cortex, the visual cortex decreased connectivity with the primary motor cortex, and the visual cortex decreased connectivity with the sensory parietal cortex. These unique findings demonstrate the functional network plasticity that occurs in the brain as a result of injury to the spinal cord. Connectivity changes after SCI may serve as biomarkers to predict functional recovery following an SCI and guide future therapy.

Postnatal Vitamin D Intake Modulates Hippocampal Learning and Memory in Adult Mice

PubMed Central

Liang, Qiujuan; Cai, Chunhui; Duan, Dongxia; Hu, Xinyu; Hua, Wanhao; Jiang, Peicheng; Zhang, Liu; Xu, Jun; Gao, Zhengliang

2018-01-01

Vitamin D (VD) is a neuroactive steroid crucial for brain development, function and homeostasis. Its deficiency is associated with numerous brain conditions. As such, VD and its variants are routinely taken by a broad of groups with/without known VD deficiency. In contrast, the harmful effects of VD overdose have been poorly studied. Similarly, the developmental stage-specific VD deficiency and overdose have been rarely explored. In the present work, we showed that postnatal VD supplementation enhanced the motor function transiently in the young adult, but not in the older one. Postnatal VD intake abnormality did not impact the anxiety and depressive behavior but was detrimental to spatial learning and hippocampus-dependent memory. At the molecular level we failed to observe an obvious and constant change with the neural development and activity-related genes examined. However, disrupted developmental expression dynamics were observed for most of the genes, suggesting that the altered neural development dynamics and therefore aberrant adult plasticity might underlie the functional deficits. Our work highlights the essence of VD homeostasis in neural development and adult brain function. Further studies are needed to determine the short- and long-term effects VD intake status may have on brain development, homeostasis, and diseases. PMID:29666565

Disrupted Structural and Functional Networks and Their Correlation with Alertness in Right Temporal Lobe Epilepsy: A Graph Theory Study.

PubMed

Jiang, Wenyu; Li, Jianping; Chen, Xuemei; Ye, Wei; Zheng, Jinou

2017-01-01

Previous studies have shown that temporal lobe epilepsy (TLE) involves abnormal structural or functional connectivity in specific brain areas. However, limited comprehensive studies have been conducted on TLE associated changes in the topological organization of structural and functional networks. Additionally, epilepsy is associated with impairment in alertness, a fundamental component of attention. In this study, structural networks were constructed using diffusion tensor imaging tractography, and functional networks were obtained from resting-state functional MRI temporal series correlations in 20 right temporal lobe epilepsy (rTLE) patients and 19 healthy controls. Global network properties were computed by graph theoretical analysis, and correlations were assessed between global network properties and alertness. The results from these analyses showed that rTLE patients exhibit abnormal small-world attributes in structural and functional networks. Structural networks shifted toward more regular attributes, but functional networks trended toward more random attributes. After controlling for the influence of the disease duration, negative correlations were found between alertness, small-worldness, and the cluster coefficient. However, alertness did not correlate with either the characteristic path length or global efficiency in rTLE patients. Our findings show that disruptions of the topological construction of brain structural and functional networks as well as small-world property bias are associated with deficits in alertness in rTLE patients. These data suggest that reorganization of brain networks develops as a mechanism to compensate for altered structural and functional brain function during disease progression.

Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy.

PubMed

Sullan, Molly J; Asken, Breton M; Jaffee, Michael S; DeKosky, Steven T; Bauer, Russell M

2018-01-01

Traumatic brain injury (TBI) is an increasingly important issue among veterans, athletes and the general public. Difficulties with sleep onset and maintenance are among the most commonly reported symptoms following injury, and sleep debt is associated with increased accumulation of beta amyloid (Aβ) and phosphorylated tau (p-tau) in the interstitial space. Recent research into the glymphatic system, a lymphatic-like metabolic clearance mechanism in the central nervous system (CNS) which relies on cerebrospinal fluid (CSF), interstitial fluid (ISF), and astrocytic processes, shows that clearance is potentiated during sleep. This system is damaged in the acute phase following mTBI, in part due to re-localization of aquaporin-4 channels away from astrocytic end feet, resulting in reduced potential for waste removal. Long-term consequences of chronic dysfunction within this system in the context of repetitive brain trauma and insomnia have not been established, but potentially provide one link in the explanatory chain connecting repetitive TBI with later neurodegeneration. Current research has shown p-tau deposition in perivascular spaces and along interstitial pathways in chronic traumatic encephalopathy (CTE), pathways related to glymphatic flow; these are the main channels by which metabolic waste is cleared. This review addresses possible links between mTBI-related damage to glymphatic functioning and physiological changes found in CTE, and proposes a model for the mediating role of sleep disruption in increasing the risk for developing CTE-related pathology and subsequent clinical symptoms following repetitive brain trauma. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced Therapeutic Potential of Nano-Curcumin Against Subarachnoid Hemorrhage-Induced Blood-Brain Barrier Disruption Through Inhibition of Inflammatory Response and Oxidative Stress.

PubMed

Zhang, Zong-Yong; Jiang, Ming; Fang, Jie; Yang, Ming-Feng; Zhang, Shuai; Yin, Yan-Xin; Li, Da-Wei; Mao, Lei-Lei; Fu, Xiao-Yan; Hou, Ya-Jun; Fu, Xiao-Ting; Fan, Cun-Dong; Sun, Bao-Liang

2017-01-01

Curcumin and nano-curcumin both exhibit neuroprotective effects in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). However, the mechanism that whether curcumin and its nanoparticles affect the blood-brain barrier (BBB) following SAH remains unclear. This study investigated the effect of curcumin and the poly(lactide-co-glycolide) (PLGA)-encapsulated curcumin nanoparticles (Cur-NPs) on BBB disruption and evaluated the possible mechanism underlying BBB dysfunction in EBI using the endovascular perforation rat SAH model. The results indicated that Cur-NPs showed enhanced therapeutic effects than that of curcumin in improving neurological function, reducing brain water content, and Evans blue dye extravasation after SAH. Mechanically, Cur-NPs attenuated BBB dysfunction after SAH by preventing the disruption of tight junction protein (ZO-1, occludin, and claudin-5). Cur-NPs also up-regulated glutamate transporter-1 and attenuated glutamate concentration of cerebrospinal fluid following SAH. Moreover, inhibition of inflammatory response and microglia activation both contributed to Cur-NPs' protective effects. Additionally, Cur-NPs markedly suppressed SAH-mediated oxidative stress and eventually reversed SAH-induced cell apoptosis in rats. Our findings revealed that the strategy of using Cur-NPs could be a promising way in improving neurological function in EBI after experimental rat SAH.

Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics

PubMed Central

Cruz, Gonzalo; Foster, Warren; Paredes, Alfonso; Yi, Kun Don; Uzumcu, Mehmet

2014-01-01

Estrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is thought that developmental exposure to environmental estrogens can disrupt neural and reproductive tract development potentially resulting in long-term alterations in neurobehavior and reproductive function. Many chemicals have been shown to have estrogenic activity whereas others affect estrogen production and turnover resulting in disruption of estrogen signaling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on estrogen sensitive target tissues. Hence, alternative mechanisms are thought to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including estrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying disruption of ovarian follicular development. In addition, we discuss how exposure to environmental estrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. PMID:25040227

Long-term effects of early-life exposure to environmental oestrogens on ovarian function: role of epigenetics.

PubMed

Cruz, G; Foster, W; Paredes, A; Yi, K D; Uzumcu, M

2014-09-01

Oestrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is considered that developmental exposure to environmental oestrogens can disrupt neural and reproductive tract development, potentially resulting in long-term alterations in neurobehaviour and reproductive function. Many chemicals have been shown to have oestrogenic activity, whereas others affect oestrogen production and turnover, resulting in the disruption of oestrogen signalling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on oestrogen-sensitive target tissues. Hence, alternative mechanisms are assumed to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including oestrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying the disruption of ovarian follicular development. In addition, we discuss how exposure to environmental oestrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. © 2014 British Society for Neuroendocrinology.

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

PubMed Central

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei

2017-01-01

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. PMID:28188218

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.

PubMed

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei; Iliff, Jeffrey J; Nedergaard, Maiken

2017-03-15

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. Copyright © 2017 the authors 0270-6474/17/372870-08$15.00/0.

Hypoxia-ischemia brain damage disrupts brain cholesterol homeostasis in neonatal rats.

PubMed

Yu, Z; Li, S; Lv, S H; Piao, H; Zhang, Y H; Zhang, Y M; Ma, H; Zhang, J; Sun, C K; Li, A P

2009-08-01

The first 3 weeks of life is the peak time of oligodendrocytes development and also the critical period of cholesterol increasing dramatically in central nervous system in rats. Neonatal hypoxia-ischemia (HI) brain damage happening in this period may disturb the brain cholesterol balance as well as white matter development. To test this hypothesis, postnatal day 7 (P7) Sprague-Dawley rats were subjected to HI insult. Cholesterol concentrations from brain and plasma were measured. White matter integrity was evaluated by densitometric analysis of myelin basic protein (MBP) immunostaining and electron microscopy. Brain TNF-alpha and IL-6 levels were also measured. HI-induced brain cholesterol, but not the plasma cholesterol, levels decreased significantly during the first three days after HI compared with naïve and sham operated rats (p<0.05). Obvious hypomyelination was indicated by marked reductions in MBP immunostaining on both P10 and P14 (p<0.01) and less and thinner myelinated axons were detected on P21 by electron microscopy observation. High expressions of brain TNF-alpha and IL-6 12 h after HI (p<0.05) were also observed. The present work provides evidence that HI insult destroyed brain cholesterol homeostasis, which might be important in the molecular pathology of hypoxic-ischemic white matter injury. Proinflammatory cytokines insulting oligodendrocytes, may cause cholesterol unbalance. Furthermore, specific therapeutic interventions to maintain brain cholesterol balance may be effective for the recovery of white matter function. Georg Thieme Verlag KG Stuttgart New York.

Transducer design and characterization for dorsal-based ultrasound exposure and two-photon imaging of in vivo blood-brain barrier disruption in a rat model.

PubMed

Nhan, Tam; Burgess, Alison; Hynynen, Kullervo

2013-07-01

Focused ultrasound (FUS) and microbubbles have been used effectively for transient, noninvasive blood¿ brain barrier disruption (BBBD). The use of two-photon microscopy (2PM) imaging of BBBD can provide valuable insights into the associated cellular mechanisms and fundamental biological effects. Coupling a thin ring-shaped transducer to a coverslip offers a robust solution for simultaneous dorsal application of FUS for BBBD and in vivo 2PM imaging of the cerebral microvasculature under treatment conditions. Two modes of vibration (thickness and height) from the transducer configuration were investigated for BBBD in an animal model. With the transducer operating in the thickness mode at 1.2 MHz frequency, shallow and localized BBBD near the cortical surface of animal brain was detected via 2PM and confirmed by Evans blue (EB) extravasation. Acoustic pressures ranging from 0.2 to 0.8 MPa were tested and the probability for successful BBBD was identified. Two distinct types of disruption characterized by different leakage kinetics were observed and appeared to be dependent on acoustic pressure.

Effects of perinatal bisphenol A exposure on the volume of sexually-dimorphic nuclei of juvenile rats: A CLARITY-BPA consortium study.

PubMed

Arambula, Sheryl E; Fuchs, Joelle; Cao, Jinyan; Patisaul, Heather B

2017-12-01

Bisphenol A (BPA) is a high volume endocrine disrupting chemical found in a wide variety of products including plastics and epoxy resins. Human exposure is nearly ubiquitous, and higher in children than adults. Because BPA has been reported to interfere with sex steroid hormone signaling, there is concern that developmental exposure, even at levels below the current FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, can disrupt brain sexual differentiation. The current studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and tested the hypothesis that perinatal BPA exposure would induce morphological changes in hormone sensitive, sexually dimorphic brain regions. Sprague-Dawley rats were randomly assigned to 5 groups: BPA (2.5, 25, or 2500μg/kgbw/day), a reference estrogen (0.5μg ethinylestradiol (EE 2 )/kgbw/day), or vehicle. Exposure occurred by gavage to the dam from gestational day 6 until parturition, and then to the offspring from birth through weaning. Unbiased stereology was used to quantify the volume of the sexually dimorphic nucleus (SDN), the anteroventral periventricular nucleus (AVPV), the posterodorsal portion of the medial amygdala (MePD), and the locus coeruleus (LC) at postnatal day 28. No appreciable effects of BPA were observed on the volume of the SDN or LC. However, AVPV volume was enlarged in both sexes, even at levels below the FDA NOAEL. Collectively, these data suggest the developing brain is vulnerable to endocrine disruption by BPA at exposure levels below previous estimates by regulatory agencies. Copyright © 2017 Elsevier B.V. All rights reserved.

Early neural disruption and auditory processing outcomes in rodent models: implications for developmental language disability

PubMed Central

Fitch, R. Holly; Alexander, Michelle L.; Threlkeld, Steven W.

2013-01-01

Most researchers in the field of neural plasticity are familiar with the “Kennard Principle,” which purports a positive relationship between age at brain injury and severity of subsequent deficits (plateauing in adulthood). As an example, a child with left hemispherectomy can recover seemingly normal language, while an adult with focal injury to sub-regions of left temporal and/or frontal cortex can suffer dramatic and permanent language loss. Here we present data regarding the impact of early brain injury in rat models as a function of type and timing, measuring long-term behavioral outcomes via auditory discrimination tasks varying in temporal demand. These tasks were created to model (in rodents) aspects of human sensory processing that may correlate—both developmentally and functionally—with typical and atypical language. We found that bilateral focal lesions to the cortical plate in rats during active neuronal migration led to worse auditory outcomes than comparable lesions induced after cortical migration was complete. Conversely, unilateral hypoxic-ischemic (HI) injuries (similar to those seen in premature infants and term infants with birth complications) led to permanent auditory processing deficits when induced at a neurodevelopmental point comparable to human “term,” but only transient deficits (undetectable in adulthood) when induced in a “preterm” window. Convergent evidence suggests that regardless of when or how disruption of early neural development occurs, the consequences may be particularly deleterious to rapid auditory processing (RAP) outcomes when they trigger developmental alterations that extend into subcortical structures (i.e., lower sensory processing stations). Collective findings hold implications for the study of behavioral outcomes following early brain injury as well as genetic/environmental disruption, and are relevant to our understanding of the neurologic risk factors underlying developmental language disability in human populations. PMID:24155699

Neonatal experiences with ethanol intoxication modify respiratory and thermoregulatory plasticity and affect subsequent ethanol intake in rats.

PubMed

Acevedo, María Belén; Macchione, Ana Fabiola; Anunziata, Florencia; Haymal, Olga Beatriz; Molina, Juan Carlos

2017-01-01

Different studies have focused on the deleterious consequences of binge-like or chronic exposure to ethanol during the brain growth spurt period (third human gestational trimester) that in the rat corresponds to postnatal days (PDs) 3-10. The present study analyzed behavioral and physiological disruptions caused by relatively brief binge-like exposures (PDs 3, 5, and 7) with an ethanol dose lower (3.0 g/kg) than those frequently employed to examine teratological effects during this stage in development. At PD 9, pups were exposed to ethanol doses ranging between .0-3.0 g/kg and tested in terms of breathing patterns and thermoregulation. At PDs 11 and 12, ethanol intake was examined. The main findings were as follows: i) pre-exposure to the drug resulted in brief depressions in breathing frequencies and an exacerbated predisposition toward apneic episodes; ii) these effects were not dependent upon thermoregulatory alterations; iii) early ethanol treatment increased initial consumption of the drug which also caused a marked hypothermia that appeared to regulate a subsequent decrement in ethanol consumption; and iv) ethanol exposure retarded overall body growth and even one exposure to the drug (PD 9) was sufficient to reduce brain weights although there were no indications of microcephaly. In conjunction with studies performed during the late gestational period in the rat, the results indicate that relatively brief binge-like episodes during a critical window of brain vulnerability disrupts the respiratory network and exacerbates initial acceptance of the drug. In addition, ethanol treatments were not found to induce tolerance relative to respiratory and thermal disruptions. © 2016 Wiley Periodicals, Inc.

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

PubMed

Lionel, Anath C; Tammimies, Kristiina; Vaags, Andrea K; Rosenfeld, Jill A; Ahn, Joo Wook; Merico, Daniele; Noor, Abdul; Runke, Cassandra K; Pillalamarri, Vamsee K; Carter, Melissa T; Gazzellone, Matthew J; Thiruvahindrapuram, Bhooma; Fagerberg, Christina; Laulund, Lone W; Pellecchia, Giovanna; Lamoureux, Sylvia; Deshpande, Charu; Clayton-Smith, Jill; White, Ann C; Leather, Susan; Trounce, John; Melanie Bedford, H; Hatchwell, Eli; Eis, Peggy S; Yuen, Ryan K C; Walker, Susan; Uddin, Mohammed; Geraghty, Michael T; Nikkel, Sarah M; Tomiak, Eva M; Fernandez, Bridget A; Soreni, Noam; Crosbie, Jennifer; Arnold, Paul D; Schachar, Russell J; Roberts, Wendy; Paterson, Andrew D; So, Joyce; Szatmari, Peter; Chrysler, Christina; Woodbury-Smith, Marc; Brian Lowry, R; Zwaigenbaum, Lonnie; Mandyam, Divya; Wei, John; Macdonald, Jeffrey R; Howe, Jennifer L; Nalpathamkalam, Thomas; Wang, Zhuozhi; Tolson, Daniel; Cobb, David S; Wilks, Timothy M; Sorensen, Mark J; Bader, Patricia I; An, Yu; Wu, Bai-Lin; Musumeci, Sebastiano Antonino; Romano, Corrado; Postorivo, Diana; Nardone, Anna M; Monica, Matteo Della; Scarano, Gioacchino; Zoccante, Leonardo; Novara, Francesca; Zuffardi, Orsetta; Ciccone, Roberto; Antona, Vincenzo; Carella, Massimo; Zelante, Leopoldo; Cavalli, Pietro; Poggiani, Carlo; Cavallari, Ugo; Argiropoulos, Bob; Chernos, Judy; Brasch-Andersen, Charlotte; Speevak, Marsha; Fichera, Marco; Ogilvie, Caroline Mackie; Shen, Yiping; Hodge, Jennelle C; Talkowski, Michael E; Stavropoulos, Dimitri J; Marshall, Christian R; Scherer, Stephen W

2014-05-15

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

PubMed Central

Booij, Linda; Tremblay, Richard E.; Szyf, Moshe; Benkelfat, Chawki

2015-01-01

Background Despite more than 60 years of research in the role of serotonin (5-HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development. Methods Studies were identified using common databases (e.g., PubMed, Google Scholar) and reference lists. Results Despite the widely supported view that the 5-HT system matures in early life, different 5-HT receptors, proteins and enzymes have different developmental patterns, and development is brain region–specific. A disruption in 5-HT homeostasis during development may lead to structural and functional changes in brain circuits that modulate emotional stress responses, including subcortical limbic and (pre)frontal areas. This may result in a predisposition to psychopathology. DNA methylation might be one of the underlying physiologic mechanisms. Limitations There is a need for prospective studies. The impact of stressors during adolescence on the 5-HT system is understudied. Questions regarding efficacy of drugs acting on 5-HT still remain. Conclusion A multidisciplinary and longitudinal approach in designing studies on the role of 5-HT in psychopathology might help to bring us closer to the understanding of the role of 5-HT in psychopathology. PMID:25285876

Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours

PubMed Central

Patisaul, Heather B.

2017-01-01

A wide range of health benefits have been ascribed to soya intake including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms. Because it is a hormonally active diet, however, soya can also be endocrine disrupting, suggesting that intake has the potential to cause adverse health effects in certain circumstances, particularly when exposure occurs during development. Consequently, the question of whether or not soya phyto-oestrogens are beneficial or harmful to human health is neither straightforward nor universally applicable to all groups. Possible benefits and risks depend on age, health status, and even the presence or absence of specific gut microflora. As global consumption increases, greater awareness and consideration of the endocrine-disrupting properties of soya by nutrition specialists and other health practitioners is needed. Consumption by infants and small children is of particular concern because their hormone-sensitive organs, including the brain and reproductive system, are still undergoing sexual differentiation and maturation. Thus, their susceptibility to the endocrine-disrupting activities of soya phyto-oestrogens may be especially high. As oestrogen receptor partial agonists with molecular and cellular properties similar to anthropogenic endocrine disruptors such as bisphenol A, the soya phyto-oestrogens provide an interesting model for how attitudes about what is ‘synthetic’ v. what is ‘natural,’ shapes understanding and perception of what it means for a compound to be endocrine disrupting and/or potentially harmful. This review describes the endocrine-disrupting properties of soya phyto-oestrogens with a focus on neuroendocrine development and behaviour. PMID:27389644

Using the Optical Fractionator to Estimate Total Cell Numbers in the Normal and Abnormal Developing Human Forebrain.

PubMed

Larsen, Karen B

2017-01-01

Human fetal brain development is a complex process which is vulnerable to disruption at many stages. Although histogenesis is well-documented, only a few studies have quantified cell numbers across normal human fetal brain growth. Due to the present lack of normative data it is difficult to gauge abnormal development. Furthermore, many studies of brain cell numbers have employed biased counting methods, whereas innovations in stereology during the past 20-30 years enable reliable and efficient estimates of cell numbers. However, estimates of cell volumes and densities in fetal brain samples are unreliable due to unpredictable shrinking artifacts, and the fragility of the fetal brain requires particular care in handling and processing. The optical fractionator design offers a direct and robust estimate of total cell numbers in the fetal brain with a minimum of handling of the tissue. Bearing this in mind, we have used the optical fractionator to quantify the growth of total cell numbers as a function of fetal age. We discovered a two-phased development in total cell numbers in the human fetal forebrain consisting of an initial steep rise in total cell numbers between 13 and 20 weeks of gestation, followed by a slower linear phase extending from mid-gestation to 40 weeks of gestation. Furthermore, we have demonstrated a reduced total cell number in the forebrain in fetuses with Down syndome at midgestation and in intrauterine growth-restricted fetuses during the third trimester.

Investigating the Microstructural Correlation of White Matter in Autism Spectrum Disorder.

PubMed

Dean, Douglas C; Travers, Brittany G; Adluru, Nagesh; Tromp, Do P M; Destiche, Daniel J; Samsin, Danica; Prigge, Molly B; Zielinski, Brandon A; Fletcher, P Thomas; Anderson, Jeffrey S; Froehlich, Alyson L; Bigler, Erin D; Lange, Nicholas; Lainhart, Janet E; Alexander, Andrew L

2016-06-01

White matter microstructure forms a complex and dynamical system that is critical for efficient and synchronized brain function. Neuroimaging findings in children with autism spectrum disorder (ASD) suggest this condition is associated with altered white matter microstructure, which may lead to atypical macroscale brain connectivity. In this study, we used diffusion tensor imaging measures to examine the extent that white matter tracts are interrelated within ASD and typical development. We assessed the strength of inter-regional white matter correlations between typically developing and ASD diagnosed individuals. Using hierarchical clustering analysis, clustering patterns of the pairwise white matter correlations were constructed and revealed to be different between the two groups. Additionally, we explored the use of graph theory analysis to examine the characteristics of the patterns formed by inter-regional white matter correlations and compared these properties between ASD and typical development. We demonstrate that the ASD sample has significantly less coherence in white matter microstructure across the brain compared to that in the typical development sample. The ASD group also presented altered topological characteristics, which may implicate less efficient brain networking in ASD. These findings highlight the potential of graph theory based network characteristics to describe the underlying networks as measured by diffusion magnetic resonance imaging and furthermore indicates that ASD may be associated with altered brain network characteristics. Our findings are consistent with those of a growing number of studies and hypotheses that have suggested disrupted brain connectivity in ASD.

Investigating the Microstructural Correlation of White Matter in Autism Spectrum Disorder

PubMed Central

Travers, Brittany G.; Adluru, Nagesh; Tromp, Do P.M.; Destiche, Daniel J.; Samsin, Danica; Prigge, Molly B.; Zielinski, Brandon A.; Fletcher, P. Thomas; Anderson, Jeffrey S.; Froehlich, Alyson L.; Bigler, Erin D.; Lange, Nicholas; Lainhart, Janet E.; Alexander, Andrew L.

2016-01-01

Abstract White matter microstructure forms a complex and dynamical system that is critical for efficient and synchronized brain function. Neuroimaging findings in children with autism spectrum disorder (ASD) suggest this condition is associated with altered white matter microstructure, which may lead to atypical macroscale brain connectivity. In this study, we used diffusion tensor imaging measures to examine the extent that white matter tracts are interrelated within ASD and typical development. We assessed the strength of inter-regional white matter correlations between typically developing and ASD diagnosed individuals. Using hierarchical clustering analysis, clustering patterns of the pairwise white matter correlations were constructed and revealed to be different between the two groups. Additionally, we explored the use of graph theory analysis to examine the characteristics of the patterns formed by inter-regional white matter correlations and compared these properties between ASD and typical development. We demonstrate that the ASD sample has significantly less coherence in white matter microstructure across the brain compared to that in the typical development sample. The ASD group also presented altered topological characteristics, which may implicate less efficient brain networking in ASD. These findings highlight the potential of graph theory based network characteristics to describe the underlying networks as measured by diffusion magnetic resonance imaging and furthermore indicates that ASD may be associated with altered brain network characteristics. Our findings are consistent with those of a growing number of studies and hypotheses that have suggested disrupted brain connectivity in ASD. PMID:27021440

Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura.

PubMed

Hougaard, Anders; Amin, Faisal M; Christensen, Casper E; Younis, Samaira; Wolfram, Frauke; Cramer, Stig P; Larsson, Henrik B W; Ashina, Messoud

2017-06-01

See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability in any of the investigated regions. There was no correlation between blood-brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood-brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood-brain barrier disruption as a possible mechanism linking aura and headache.awx089media15422686892001. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Unraveling the complexities of invasive multimodality neuromonitoring.

PubMed

Sinha, Saurabh; Hudgins, Eric; Schuster, James; Balu, Ramani

2017-11-01

Acute brain injuries are a major cause of death and disability worldwide. Survivors of life-threatening brain injury often face a lifetime of dependent care, and novel approaches that improve outcome are sorely needed. A delayed cascade of brain damage, termed secondary injury, occurs hours to days and even weeks after the initial insult. This delayed phase of injury provides a crucial window for therapeutic interventions that could limit brain damage and improve outcome. A major barrier in the ability to prevent and treat secondary injury is that physicians are often unable to target therapies to patients' unique cerebral physiological disruptions. Invasive neuromonitoring with multiple complementary physiological monitors can provide useful information to enable this tailored, precision approach to care. However, integrating the multiple streams of time-varying data is challenging and often not possible during routine bedside assessment. The authors review and discuss the principles and evidence underlying several widely used invasive neuromonitors. They also provide a framework for integrating data for clinical decision making and discuss future developments in informatics that may allow new treatment paradigms to be developed.

Unbalanced neuronal circuits in addiction.

PubMed

Volkow, Nora D; Wang, Gen-Jack; Tomasi, Dardo; Baler, Ruben D

2013-08-01

Through sequential waves of drug-induced neurochemical stimulation, addiction co-opts the brain's neuronal circuits that mediate reward, motivation to behavioral inflexibility and a severe disruption of self-control and compulsive drug intake. Brain imaging technologies have allowed neuroscientists to map out the neural landscape of addiction in the human brain and to understand how drugs modify it. Published by Elsevier Ltd.

75 FR 75681 - Peripheral and Central Nervous System Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-06

... of [beta]-amyloid (beta-amyloid) aggregates in the brain to help rule out Alzheimer's disease. On... children (2 years of age and older) to detect and visualize areas with disrupted blood brain barrier (BBB... bloodstream into the brain. FDA intends to make background material available to the public no later than 2...

Prenatal exposure to common environmental factors affects brain lipids and increases risk of developing autism spectrum disorders.

PubMed

Wong, Christine T; Wais, Joshua; Crawford, Dorota A

2015-11-01

The prevalence of autism spectrum disorders (ASDs) has been on the rise over recent years. The presence of diverse subsets of candidate genes in each individual with an ASD and the vast variability of phenotypical differences suggest that the interference of an exogenous environmental component may greatly contribute to the development of ASDs. The lipid mediator prostaglandin E2 (PGE2 ) is released from phospholipids of cell membranes, and is important in brain development and function; PGE2 is involved in differentiation, synaptic plasticity and calcium regulation. The previous review already described extrinsic factors, including deficient dietary supplementation, and exposure to oxidative stress, infections and inflammation that can disrupt signaling of the PGE2 pathway and contribute to ASDs. In this review, the structure and establishment of two key protective barriers for the brain during early development are described: the blood-brain barrier; and the placental barrier. Then, the first comprehensive summary of other environmental factors, such as exposure to chemicals in air pollution, pesticides and consumer products, which can also disturb PGE2 signaling and increase the risk for developing ASDs is provided. Also, how these exogenous agents are capable of crossing the protective barriers of the brain during critical developmental periods when barrier components are still being formed is described. This review underlines the importance of avoiding or limiting exposure to these factors during vulnerable periods in development. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

ECMO support for right main bronchial disruption in multiple trauma patient with brain injury--a case report and literature review.

PubMed

Zhou, R; Liu, B; Lin, K; Wang, R; Qin, Z; Liao, R; Qiu, Y

2015-07-01

Extracorporeal membrane oxygenation (ECMO) may offer life-saving treatment in severe pulmonary contusion or acute respiratory distress syndrome when conventional treatments have failed. However, because of the bleeding risk of systemic anticoagulation, ECMO should be performed only as a last resort in multiple trauma victims. Here, we report ECMO as a bridge for right main bronchus reconstruction and recovery of traumatic wet lung in a 31-year-old male multi-trauma patient with right main bronchial disruption, bilateral pulmonary contusion, cerebral contusion and long bone fracture. The patient was discharged without any obvious complication. ECMO support in a traumatic brain injured patient with severe hypoxemia caused by lung contusion and/or tracheal bronchus disruption is not an absolute contraindication. © The Author(s) 2014.

Structural network efficiency is associated with cognitive impairment in small-vessel disease.

PubMed

Lawrence, Andrew J; Chung, Ai Wern; Morris, Robin G; Markus, Hugh S; Barrick, Thomas R

2014-07-22

To characterize brain network connectivity impairment in cerebral small-vessel disease (SVD) and its relationship with MRI disease markers and cognitive impairment. A cross-sectional design applied graph-based efficiency analysis to deterministic diffusion tensor tractography data from 115 patients with lacunar infarction and leukoaraiosis and 50 healthy individuals. Structural connectivity was estimated between 90 cortical and subcortical brain regions and efficiency measures of resulting graphs were analyzed. Networks were compared between SVD and control groups, and associations between efficiency measures, conventional MRI disease markers, and cognitive function were tested. Brain diffusion tensor tractography network connectivity was significantly reduced in SVD: networks were less dense, connection weights were lower, and measures of network efficiency were significantly disrupted. The degree of brain network disruption was associated with MRI measures of disease severity and cognitive function. In multiple regression models controlling for confounding variables, associations with cognition were stronger for network measures than other MRI measures including conventional diffusion tensor imaging measures. A total mediation effect was observed for the association between fractional anisotropy and mean diffusivity measures and executive function and processing speed. Brain network connectivity in SVD is disturbed, this disturbance is related to disease severity, and within a mediation framework fully or partly explains previously observed associations between MRI measures and SVD-related cognitive dysfunction. These cross-sectional results highlight the importance of network disruption in SVD and provide support for network measures as a disease marker in treatment studies. © 2014 American Academy of Neurology.

Structural network efficiency is associated with cognitive impairment in small-vessel disease

PubMed Central

Chung, Ai Wern; Morris, Robin G.; Markus, Hugh S.; Barrick, Thomas R.

2014-01-01

Objective: To characterize brain network connectivity impairment in cerebral small-vessel disease (SVD) and its relationship with MRI disease markers and cognitive impairment. Methods: A cross-sectional design applied graph-based efficiency analysis to deterministic diffusion tensor tractography data from 115 patients with lacunar infarction and leukoaraiosis and 50 healthy individuals. Structural connectivity was estimated between 90 cortical and subcortical brain regions and efficiency measures of resulting graphs were analyzed. Networks were compared between SVD and control groups, and associations between efficiency measures, conventional MRI disease markers, and cognitive function were tested. Results: Brain diffusion tensor tractography network connectivity was significantly reduced in SVD: networks were less dense, connection weights were lower, and measures of network efficiency were significantly disrupted. The degree of brain network disruption was associated with MRI measures of disease severity and cognitive function. In multiple regression models controlling for confounding variables, associations with cognition were stronger for network measures than other MRI measures including conventional diffusion tensor imaging measures. A total mediation effect was observed for the association between fractional anisotropy and mean diffusivity measures and executive function and processing speed. Conclusions: Brain network connectivity in SVD is disturbed, this disturbance is related to disease severity, and within a mediation framework fully or partly explains previously observed associations between MRI measures and SVD-related cognitive dysfunction. These cross-sectional results highlight the importance of network disruption in SVD and provide support for network measures as a disease marker in treatment studies. PMID:24951477

Overexpression of caveolin-1 attenuates brain edema by inhibiting tight junction degradation.

PubMed

Choi, Kang-Ho; Kim, Hyung-Seok; Park, Man-Seok; Lee, Eun-Bin; Lee, Jung-Kil; Kim, Joon-Tae; Kim, Ja-Hae; Lee, Min-Cheol; Lee, Hong-Joon; Cho, Ki-Hyun

2016-10-18

Cerebral edema from the disruption of the blood-brain barrier (BBB) after cerebral ischemia is a major cause of morbidity and mortality as well as a common event in patients with stroke. Caveolins (Cavs) are thought to regulate BBB functions. Here, we report for the first time that Cav-1 overexpression (OE) decreased brain edema from BBB disruption following ischemic insult. Edema volumes and Cav-1 expression levels were measured following photothrombosis and middle cerebral artery occlusion (MCAO). Endothelial cells that were transduced with a Cav-1 lentiviral expression vector were transplanted into rats. BBB permeability was quantified with Evans blue extravasation. Edema volume was determined from measures of the extravasation area, brain water content, and average fluorescence intensity after Cy5.5 injections. Tight junction (TJ) protein expression was measured with immunoblotting. Cav-1 expression levels and vasogenic brain edema correlated strongly after ischemic insult. Cav-1 expression and BBB disruption peaked 3 d after the MCAO. In addition, intravenous administration of endothelial cells expressing Cav-1 effectively increased the Cav-1 levels 3 d after the MCAO ischemic insult. Importantly, Cav-1 OE ameliorated the vasogenic edema by inhibiting the degradation of TJ protein expression in the acute phase of ischemic stroke. These results suggested that Cav-1 OE protected the integrity of the BBB mainly by preventing the degradation of TJ proteins in rats. These findings need to be confirmed in a clinical setting in human subjects.

Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase.

PubMed

Chitambar, Christopher R; Al-Gizawiy, Mona M; Alhajala, Hisham S; Pechman, Kimberly R; Wereley, Janine P; Wujek, Robert; Clark, Paul A; Kuo, John S; Antholine, William E; Schmainda, Kathleen M

2018-06-01

Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMEC) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSC) lines express TfRs, and that their growth is inhibited by gallium maltolate (GaM) in vitro After 24 hours of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). IHC staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2, and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control ( P = 0.0159) and reduced tumor mitotic figures ( P = 0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals, thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells in vitro We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma in vivo, thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted. Mol Cancer Ther; 17(6); 1240-50. ©2018 AACR . ©2018 American Association for Cancer Research.

Animal models of speech and vocal communication deficits associated with psychiatric disorders

PubMed Central

Konopka, Genevieve; Roberts, Todd F.

2015-01-01

Disruptions in speech, language and vocal communication are hallmarks of several neuropsychiatric disorders, most notably autism spectrum disorders. Historically, the use of animal models to dissect molecular pathways and connect them to behavioral endophenotypes in cognitive disorders has proven to be an effective approach for developing and testing disease-relevant therapeutics. The unique aspects of human language when compared to vocal behaviors in other animals make such an approach potentially more challenging. However, the study of vocal learning in species with analogous brain circuits to humans may provide entry points for understanding this human-specific phenotype and diseases. Here, we review animal models of vocal learning and vocal communication, and specifically link phenotypes of psychiatric disorders to relevant model systems. Evolutionary constraints in the organization of neural circuits and synaptic plasticity result in similarities in the brain mechanisms for vocal learning and vocal communication. Comparative approaches and careful consideration of the behavioral limitations among different animal models can provide critical avenues for dissecting the molecular pathways underlying cognitive disorders that disrupt speech, language and vocal communication. PMID:26232298

Disrupted Cerebro-cerebellar Intrinsic Functional Connectivity in Young Adults with High-functioning Autism Spectrum Disorder: A Data-driven, Whole-brain, High Temporal Resolution fMRI Study.

PubMed

Arnold Anteraper, Sheeba; Guell, Xavier; D'Mello, Anila; Joshi, Neha; Whitfield-Gabrieli, Susan; Joshi, Gagan

2018-06-13

To examine the resting-state functional-connectivity (RsFc) in young adults with high-functioning autism spectrum disorder (HF-ASD) using state-of-the-art fMRI data acquisition and analysis techniques. Simultaneous multi-slice, high temporal resolution fMRI acquisition; unbiased whole-brain connectome-wide multivariate pattern analysis (MVPA) techniques for assessing RsFc; and post-hoc whole-brain seed-to-voxel analyses using MVPA results as seeds. MVPA revealed two clusters of abnormal connectivity in the cerebellum. Whole-brain seed-based functional connectivity analyses informed by MVPA-derived clusters showed significant under connectivity between the cerebellum and social, emotional, and language brain regions in the HF-ASD group compared to healthy controls. The results we report are coherent with existing structural, functional, and RsFc literature in autism, extend previous literature reporting cerebellar abnormalities in the neuropathology of autism, and highlight the cerebellum as a potential target for therapeutic, diagnostic, predictive, and prognostic developments in ASD. The description of functional connectivity abnormalities using whole-brain, data-driven analyses as reported in the present study may crucially advance the development of ASD biomarkers, targets for therapeutic interventions, and neural predictors for measuring treatment response.

Nitric oxide as an initiator of brain lesions during the development of Alzheimer disease.

PubMed

Aliev, Gjumrakch; Palacios, Hector H; Lipsitt, Amanda E; Fischbach, Kathryn; Lamb, Bruce T; Obrenovich, Mark E; Morales, Ludis; Gasimov, Eldar; Bragin, Valentin

2009-10-01

Nitric oxide (NO) is an important regulatory molecule for the host defense that plays a fundamental role in the cardiovascular, immune, and nervous systems. NO is synthesized through the conversion of L-arginine to L-citrulline by the enzyme NO synthase (NOS), which is found in three isoforms classified as neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). Recent evidence supports the theory that this bioactive molecule has an influential role in the disruption of normal brain and vascular homeostasis, a condition known to elucidate chronic hypoperfusion which ultimately causes the development of brain lesions and the pathology that typify Alzheimer disease (AD). In addition, vascular NO activity appears to be a major contributor to this pathology before any overexpression of NOS isoforms is observed in the neuron, glia, and microglia of the brain tree, where the overexpression the NOS isoforms causes the formation of a large amount of NO. We hypothesize that since an imbalance between the NOS isoforms and endothelin-1 (ET-1), a human gene that encodes for blood vessel constriction, can cause antioxidant system insufficiency; by using pharmacological intervention with NO donors and/or NO suppressors, the brain lesions and the downstream progression of brain pathology and dementia in AD should be delayed or minimized.

Developmental Hypothyroidism Alters Brain-Derived Neurotrophic Factor (BDNF) Expression in Adulthood.

EPA Science Inventory

Severe developmental thyroid hormone (TH) insufficiency results in alterations in brain structure/function and lasting behavioral impairments. Environmental toxicants reduce circulating levels of TH, but the disruption is modest and the doseresponse relationships of TH and neuro...

Identification of a Novel Indoline Derivative for in Vivo Fluorescent Imaging of Blood-Brain Barrier Disruption in Animal Models

PubMed Central

2013-01-01

Disruption of the blood-brain barrier (BBB) can occur in various pathophysiological conditions. Administration of extraneous tracers that can pass the disrupted, but not the intact, BBB and detection of the extravasation have been widely used to assess BBB disruption in animal models. Although several fluorescent tracers have been successfully used, the administration of these tracers basically requires intravascular injection, which can be laborious when using small animals such as zebrafish. To identify fluorescent tracers that could be easily administered into various animal models and visualize the BBB disruption in vivo, we prepared nine structurally related indoline derivatives (IDs) as a minimum set of diverse fluorescent compounds. We found that one ID, ZMB741, had the highest affinity for serum albumin and emitted the strongest fluorescence in the presence of serum albumin of the nine IDs tested. The affinity to serum albumin and the fluorescence intensity was superior to those of Evans blue and indocyanine green that have been conventionally used to assess the BBB disruption. We showed that ZMB741 could be administered into zebrafish by static immersion or mice by intraperitoneal injection and visualizes the active disruption of their BBB. These results suggest that ZMB741 can be a convenient and versatile tool for in vivo fluorescent imaging of BBB disruption in various animal models. The strategy used in this study can also be applied to diversity-oriented libraries to identify novel fluorescent tracers that may be superior to ZMB741. PMID:23668665

Fear extinction, persistent disruptive behavior and psychopathic traits: fMRI in late adolescence.

PubMed

Cohn, Moran D; van Lith, Koen; Kindt, Merel; Pape, Louise E; Doreleijers, Theo A H; van den Brink, Wim; Veltman, Dick J; Popma, Arne

2016-07-01

Children diagnosed with a Disruptive Behavior Disorder (DBD, i.e. Oppositional Defiant Disorder or Conduct Disorder), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Reduced fear conditioning has been proposed to underlie persistent antisocial development. However, we have recently shown that both DBD persisters and desisters are characterized by increased fear conditioning compared with healthy controls (HCs). In this study, we investigated whether brain function during fear extinction is associated with DBD subgroup-membership and psychopathic traits. Adolescents from a childhood arrestee cohort (mean age 17.6 years, s.d. 1.4) who met criteria for a DBD diagnosis during previous assessments were re-assessed and categorized as persistent DBD (n = 25) or desistent DBD (n = 25). Functional MRI during the extinction phase of a classical fear-conditioning task was used to compare regional brain function between these subgroups and 25 matched controls. Both DBD persisters and desisters showed hyperreactivity during fear extinction, when compared with HCs. Impulsive-irresponsible psychopathic traits were positively associated with responses in the fear neurocircuitry and mediated the association between neural activation and group membership. These results suggest that fear acquisition and fear extinction deficits may provide an endophenotype for an emotionally hyperreactive subtype of antisocial development. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

MR-Guided Unfocused Ultrasound Disruption of the Rat Blood-Brain Barrier

NASA Astrophysics Data System (ADS)

Townsend, Kelly A.; King, Randy L.; Zaharchuk, Greg; Pauly, Kim Butts

2011-09-01

Therapeutic ultrasound with microbubbles can temporarily disrupt the blood-brain barrier (BBB) for drug delivery. Contrast-enhanced MRI (CE-MRI) can visualize gadolinium passage into the brain, indicating BBB opening. Previous studies used focused ultrasound, which is appropriate for the targeted delivery of drugs. The purpose of this study was to investigate unfocused ultrasound for BBB opening across the whole brain. In 10 rats, gadolinium-based MR contrast agent (Gd; 0.25 ml) was administered concurrent with ultrasound microbubbles (Optison, 0.25 ml) and circulated for 20 sec before sonication. A 753 kHz planar PZT transducer, diameter 1.8 cm, sonicated each rat brain with supplied voltage of 300, 400, or 500 mVpp for 10 sec in continuous wave mode, or at 500 mVpp at 20% duty cycle at 10 Hz for 30-300 sec. After sonication, coronal T1-weighted FSE CE-MRI images were acquired with a 3in surface coil. The imaging protocol was repeated 3-5 times after treatment. One control animal was given Gd and microbubbles, but not sonicated, and the other was given Gd and sonicated without microbubbles. Signal change in ROIs over the muscle, mesencephalon/ventricles, and the cortex/striatum were measured at 3-5 time points up to 36 min after sonication. Signal intensity was converted to % signal change compared to the initial image. In the controls, CE-MRI showed brightening of surrounding structures, but not the brain. In the continuous wave subjects, cortex/striatum signal did not increase, but ventricle/mesenchephalon signal did. Those that received pulsed sonications showed signal increases in both the cortex/striatum and ventricles/mesenchephalon. In conclusion, after pulsed unfocused ultrasound sonication, the BBB is disrupted across the whole brain, including cortex and deep grey matter, while continuous wave sonication affects only the ventricles and possibly deeper structures, without opening the cortex BBB. As time passes, the timeline of Gd passage into the brain can be visualized.

Microglial disruption in young mice with early chronic lead exposure☆

PubMed Central

Sobin, Christina; Montoya, Mayra Gisel Flores; Parisi, Natali; Schaub, Tanner; Cervantes, Miguel; Armijos, Rodrigo X.

2013-01-01

The mechanisms by which early chronic lead (Pb) exposure alter brain development have not been identified. We examined neuroimmune system effects in C57BL/6J mice with Pb exposure, including levels that may be common among children in lower socioeconomic income environments. Pups were exposed via dams’ drinking water from birth to post-natal day 28 to low, high or no Pb conditions. We compared gene expression of neuroinflammatory markers (study 1); and microglial mean cell body volume and mean cell body number in dentate gyrus, and dentate gyrus volume (study 2). Blood Pb levels in exposed animals at sacrifice (post-natal day 28) ranged from 2.66 to 20.31 μg/dL. Only interleukin-6 (IL6) differed between groups and reductions were dose-dependent. Microglia cell body number also differed between groups and reductions were dose-dependent. As compared with controls, microglia cell body volume was greater but highly variable in only low-dose animals; dentate gyri volumes in low- and high-dose animals were reduced. The results did not support a model of increased neuroinflammation. Instead, early chronic exposure to Pb disrupted microglia via damage to, loss of, or lack of proliferation of microglia in the developing brains of Pb-exposed animals. PMID:23598043

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity.

PubMed

Qosa, Hisham; Mohamed, Loqman A; Al Rihani, Sweilem B; Batarseh, Yazan S; Duong, Quoc-Viet; Keller, Jeffrey N; Kaddoumi, Amal

2016-07-06

The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer's disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76-4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

High-throughput screening for identification of blood-brain barrier integrity enhancers: a drug repurposing opportunity to rectify vascular amyloid toxicity

PubMed Central

Qosa, Hisham; Mohamed, Loqman A.; Al Rihani, Sweilem B.; Batarseh, Yazan S.; Duong, Quoc-Viet; Keller, Jeffrey N.; Kaddoumi, Amal

2016-01-01

The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer’s disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76–4.56 μM. Of these 7 drugs, five were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD. PMID:27392852

Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes.

PubMed

Agrawal, Rahul; Zhuang, Yumei; Cummings, Bethany P; Stanhope, Kimber L; Graham, James L; Havel, Peter J; Gomez-Pinilla, Fernando

2014-09-01

The rising prevalence of type-2 diabetes is becoming a pressing issue based on emerging reports that T2DM can also adversely impact mental health. We have utilized the UCD-T2DM rat model in which the onset of T2DM develops spontaneously across time and can serve to understand the pathophysiology of diabetes in humans. An increased insulin resistance index and plasma glucose levels manifested the onset of T2DM. There was a decrease in hippocampal insulin receptor signaling in the hippocampus, which correlated with peripheral insulin resistance index along the course of diabetes onset (r=-0.56, p<0.01). T2DM increased the hippocampal levels of 4-hydroxynonenal (4-HNE; a marker of lipid peroxidation) in inverse proportion to the changes in the mitochondrial regulator PGC-1α. Disrupted energy homeostasis was further manifested by a concurrent reduction in energy metabolic markers, including TFAM, SIRT1, and AMPK phosphorylation. In addition, T2DM influenced brain plasticity as evidenced by a significant reduction of BDNF-TrkB signaling. These results suggest that the pathology of T2DM in the brain involves a progressive and coordinated disruption of insulin signaling, and energy homeostasis, with profound consequences for brain function and plasticity. All the described consequences of T2DM were attenuated by treatment with the glucagon-like peptide-1 receptor agonist, liraglutide. Similar results to those of liraglutide were obtained by exposing T2DM rats to a food energy restricted diet, which suggest that normalization of brain energy metabolism is a crucial factor to counteract central insulin sensitivity and synaptic plasticity associated with T2DM. Copyright © 2014 Elsevier B.V. All rights reserved.

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

PubMed Central

Colon-Perez, Luis M; Tran, Kelvin; Thompson, Khalil; Pace, Michael C; Blum, Kenneth; Goldberger, Bruce A; Gold, Mark S; Bruijnzeel, Adriaan W; Setlow, Barry; Febo, Marcelo

2016-01-01

The abuse of ‘bath salts' has raised concerns because of their adverse effects, which include delirium, violent behavior, and suicide ideation in severe cases. The bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) has been closely linked to these and other adverse effects. The abnormal behavioral pattern produced by acute high-dose MDPV intake suggests possible disruptions of neural communication between brain regions. Therefore, we determined if MDPV exerts disruptive effects on brain functional connectivity, particularly in areas of the prefrontal cortex. Male rats were imaged following administration of a single dose of MDPV (0.3, 1.0, or 3.0 mg/kg) or saline. Resting state brain blood oxygenation level-dependent (BOLD) images were acquired at 4.7 T. To determine the role of dopamine transmission in MDPV-induced changes in functional connectivity, a group of rats received the dopamine D1/D2 receptor antagonist cis-flupenthixol (0.5 mg/kg) 30 min before MDPV. MDPV dose-dependently reduced functional connectivity. Detailed analysis of its effects revealed that connectivity between frontal cortical and striatal areas was reduced. This included connectivity between the prelimbic prefrontal cortex and other areas of the frontal cortex and the insular cortex with hypothalamic, ventral, and dorsal striatal areas. Although the reduced connectivity appeared widespread, connectivity between these regions and somatosensory cortex was not as severely affected. Dopamine receptor blockade did not prevent the MDPV-induced decrease in functional connectivity. The results provide a novel signature of MDPV's in vivo mechanism of action. Reduced brain functional connectivity has been reported in patients suffering from psychosis and has been linked to cognitive dysfunction, audiovisual hallucinations, and negative affective states akin to those reported for MDPV-induced intoxication. The present results suggest that disruption of functional connectivity networks involving frontal cortical and striatal regions could contribute to the adverse effects of MDPV. PMID:26997298

Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP.

PubMed

Wang, Zemin; Jackson, Rosemary J; Hong, Wei; Taylor, Walter M; Corbett, Grant T; Moreno, Arturo; Liu, Wen; Li, Shaomin; Frosch, Matthew P; Slutsky, Inna; Young-Pearse, Tracy L; Spires-Jones, Tara L; Walsh, Dominic M

2017-12-06

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aβ, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aβ depend on expression of APP and that the Aβ-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aβ localizing to synapses and binding of soluble Aβ aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD. SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid β-protein (Aβ) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aβ-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aβ localizing to synapses and genetic ablation of APP prevents both Aβ binding and Aβ-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation. Copyright © 2017 the authors 0270-6474/17/3711947-20$15.00/0.

Apolipoprotein E Mimetic Peptide Increases Cerebral Glucose Uptake by Reducing Blood-Brain Barrier Disruption after Controlled Cortical Impact in Mice: An 18F-Fluorodeoxyglucose PET/CT Study.

PubMed

Qin, Xinghu; You, Hong; Cao, Fang; Wu, Yue; Peng, Jianhua; Pang, Jinwei; Xu, Hong; Chen, Yue; Chen, Ligang; Vitek, Michael P; Li, Fengqiao; Sun, Xiaochuan; Jiang, Yong

2017-02-15

Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB) and reduces cerebral glucose uptake. Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI, and COG1410 has demonstrated neuroprotective activity in several models of TBI. However, the effects of COG1410 on VEGF and glucose metabolism following TBI are unknown. The current study aimed to investigate the expression of VEGF and glucose metabolism effects in C57BL/6J male mice subjected to experimental TBI. The results showed that controlled cortical impact (CCI)-induced vestibulomotor deficits were accompanied by increases in brain edema and the expression of VEGF, with a decrease in cerebral glucose uptake. COG1410 treatment significantly improved vestibulomotor deficits and glucose uptake and produced decreases in VEGF in the pericontusion and ipsilateral hemisphere of injury, as well as in brain edema and neuronal degeneration compared with the control group. These data support that COG1410 may have potential as an effective drug therapy for TBI.

FISH OIL IMPROVES MOTOR FUNCTION, LIMITS BLOOD-BRAIN BARRIER DISRUPTION, AND REDUCES MMP9 GENE EXPRESSION IN A RAT MODEL OF JUVENILE TRAUMATIC BRAIN INJURY

PubMed Central

Russell, K. L.; Berman, N. E. J.; Gregg, P. R. A.; Levant, B.

2014-01-01

SUMMARY The effects of an oral fish oil treatment regimen on sensorimotor, blood-brain barrier, and biochemical outcomes of traumatic brain injury (TBI) were investigated in a juvenile rat model. Seventeen-day old Long-Evans rats were given a 15 mL/kg fish oil (2.01 g/kg EPA, 1.34 g/kg DHA) or soybean oil dose via oral gavage 30 minutes prior to being subjected to a controlled cortical impact injury or sham surgery, followed by daily doses for seven days. Fish oil treatment resulted in less severe hindlimb deficits after TBI as assessed with the beam walk test, decreased cerebral IgG infiltration, and decreased TBI-induced expression of the Mmp9h gene one day after injury. These results indicate that fish oil improved functional outcome after TBI resulting, at least in part from decreased disruption of the blood-brain barrier through a mechanism that includes attenuation of TBI-induced expression of Mmp9. PMID:24342130

Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury.

PubMed

Russell, K L; Berman, N E J; Gregg, P R A; Levant, B

2014-01-01

The effects of an oral fish oil treatment regimen on sensorimotor, blood-brain barrier, and biochemical outcomes of traumatic brain injury (TBI) were investigated in a juvenile rat model. Seventeen-day old Long-Evans rats were given a 15mL/kg fish oil (2.01g/kg EPA, 1.34g/kg DHA) or soybean oil dose via oral gavage 30min prior to being subjected to a controlled cortical impact injury or sham surgery, followed by daily doses for seven days. Fish oil treatment resulted in less severe hindlimb deficits after TBI as assessed with the beam walk test, decreased cerebral IgG infiltration, and decreased TBI-induced expression of the Mmp9 gene one day after injury. These results indicate that fish oil improved functional outcome after TBI resulting, at least in part from decreased disruption of the blood-brain barrier through a mechanism that includes attenuation of TBI-induced expression of Mmp9. © 2013 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gompers, Andrea L.; Su-Feher, Linda; Ellegood, Jacob

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. In this paper, we examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8 +/ del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8 +/ del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8 +/ del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes andmore » neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8 +/ del5 mice. Finally, this integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.« less

Two-photon microscopy for real-time monitoring of focused ultrasound-mediated drug delivery to the brain in a mouse model of Alzheimer's disease

NASA Astrophysics Data System (ADS)

Burgess, Alison; Eterman, Naomi; Aubert, Isabelle; Hynynen, Kullervo

2013-02-01

There is substantial evidence that focused ultrasound (FUS) in combination with microbubble contrast agent can cause disruption of the blood-brain barrier (BBB) to aid in drug delivery to the brain. We have previously demonstrated that FUS efficiently delivers antibodies against amyloid-β peptides (Aβ) through the BBB, leading to a reduction in amyloid pathology at 4 days in a mouse model of Alzheimer's disease. In the current study, we used two-photon microscopy to characterize the effect of FUS in real time on amyloid pathology in the mouse brain. Mice were anesthetized and a cranial window was made in the skull. A custom-built ultrasound transducer was fixed to a coverslip and attached to the skull, covering the cranial window. Methoxy-X04 [2-5mg/kg] delivered intravenously 1 hr prior to the experiment clearly labelled the Aβ surrounding the vessels and the amyloid plaques in the cortex. Dextran conjugated Texas Red (70kDa) administered intravenously, confirmed BBB disruption. BBB disruption occurred in transgenic and non-transgenic animals at similar ultrasound pressures tested. However, the time required for BBB closure following FUS was longer in the Tg mice. We have conjugated Aβ antibodies to the fluorescent molecule FITC for real time monitoring of the antibody distribution in the brain. Our current experiments are aimed at optimizing the parameters to achieve maximal fluorescent intensity of the BAM10 antibody at the plaque surface. Two-photon microscopy has proven to be a valuable tool for evaluating the efficacy of FUS mediated drug delivery, including antibodies, to the Alzheimer brain.

Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis

PubMed Central

Kozol, Robert A.; Cukier, Holly N.; Zou, Bing; Mayo, Vera; De Rubeis, Silvia; Cai, Guiqing; Griswold, Anthony J.; Whitehead, Patrice L.; Haines, Jonathan L.; Gilbert, John R.; Cuccaro, Michael L.; Martin, Eden R.; Baker, James D.; Buxbaum, Joseph D.; Pericak-Vance, Margaret A.; Dallman, Julia E.

2015-01-01

Despite significant progress in the genetics of autism spectrum disorder (ASD), how genetic mutations translate to the behavioral changes characteristic of ASD remains largely unknown. ASD affects 1–2% of children and adults, and is characterized by deficits in verbal and non-verbal communication, and social interactions, as well as the presence of repetitive behaviors and/or stereotyped interests. ASD is clinically and etiologically heterogeneous, with a strong genetic component. Here, we present functional data from syngap1 and shank3 zebrafish loss-of-function models of ASD. SYNGAP1, a synaptic Ras GTPase activating protein, and SHANK3, a synaptic scaffolding protein, were chosen because of mounting evidence that haploinsufficiency in these genes is highly penetrant for ASD and intellectual disability (ID). Orthologs of both SYNGAP1 and SHANK3 are duplicated in the zebrafish genome and we find that all four transcripts (syngap1a, syngap1b, shank3a and shank3b) are expressed at the earliest stages of nervous system development with pronounced expression in the larval brain. Consistent with early expression of these genes, knockdown of syngap1b or shank3a cause common embryonic phenotypes including delayed mid- and hindbrain development, disruptions in motor behaviors that manifest as unproductive swim attempts, and spontaneous, seizure-like behaviors. Our findings indicate that both syngap1b and shank3a play novel roles in morphogenesis resulting in common brain and behavioral phenotypes. PMID:25882707

Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.

PubMed

Bilbo, Staci D; Block, Carina L; Bolton, Jessica L; Hanamsagar, Richa; Tran, Phuong K

2018-01-01

Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs - in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD. Copyright © 2017 Elsevier Inc. All rights reserved.

Strabismus and the Oculomotor System: Insights from Macaque Models

PubMed Central

Das, Vallabh E.

2017-01-01

Disrupting binocular vision in infancy leads to strabismus and oftentimes to a variety of associated visual sensory deficits and oculomotor abnormalities. Investigation of this disorder has been aided by the development of various animal models, each of which has advantages and disadvantages. In comparison to studies of binocular visual responses in cortical structures, investigations of neural oculomotor structures that mediate the misalignment and abnormalities of eye movements have been more recent, and these studies have shown that different brain areas are intimately involved in driving several aspects of the strabismic condition, including horizontal misalignment, dissociated deviations, A and V patterns of strabismus, disconjugate eye movements, nystagmus, and fixation switch. The responses of cells in visual and oculomotor areas that potentially drive the sensory deficits and also eye alignment and eye movement abnormalities follow a general theme of disrupted calibration, lower sensitivity, and poorer specificity compared with the normally developed visual oculomotor system. PMID:28532347

Brain Connectivity Alterations Are Associated with the Development of Dementia in Parkinson's Disease.

PubMed

Bertrand, Josie-Anne; McIntosh, Anthony R; Postuma, Ronald B; Kovacevic, Natasha; Latreille, Véronique; Panisset, Michel; Chouinard, Sylvain; Gagnon, Jean-François

2016-04-01

Dementia affects a high proportion of Parkinson's disease (PD) patients and poses a burden on caregivers and healthcare services. Electroencephalography (EEG) is a common nonevasive and nonexpensive technique that can easily be used in clinical settings to identify brain functional abnormalities. Only few studies had identified EEG abnormalities that can predict PD patients at higher risk for dementia. Brain connectivity EEG measures, such as multiscale entropy (MSE) and phase-locking value (PLV) analyses, may be more informative and sensitive to brain alterations leading to dementia than previously used methods. This study followed 62 dementia-free PD patients for a mean of 3.4 years to identify cerebral alterations that are associated with dementia. Baseline resting state EEG of patients who developed dementia (N = 18) was compared to those of patients who remained dementia-free (N = 44) and of 37 healthy subjects. MSE and PLV analyses were performed. Partial least squares statistical analysis revealed group differences associated with the development of dementia. Patients who developed dementia showed higher signal complexity and lower PLVs in low frequencies (mainly in delta frequency) than patients who remained dementia-free and controls. Conversely, both patient groups showed lower signal variability and higher PLVs in high frequencies (mainly in gamma frequency) compared to controls, with the strongest effect in patients who developed dementia. These findings suggest that specific disruptions of brain communication can be measured before PD patients develop dementia, providing a new potential marker to identify patients at highest risk of developing dementia and who are the best candidates for neuroprotective trials.

FGF signaling is required for brain left-right asymmetry and brain midline formation.

PubMed

Neugebauer, Judith M; Yost, H Joseph

2014-02-01

Early disruption of FGF signaling alters left-right (LR) asymmetry throughout the embryo. Here we uncover a role for FGF signaling that specifically disrupts brain asymmetry, independent of normal lateral plate mesoderm (LPM) asymmetry. When FGF signaling is inhibited during mid-somitogenesis, asymmetrically expressed LPM markers southpaw and lefty2 are not affected. However, asymmetrically expressed brain markers lefty1 and cyclops become bilateral. We show that FGF signaling controls expression of six3b and six7, two transcription factors required for repression of asymmetric lefty1 in the brain. We found that Z0-1, atypical PKC (aPKC) and β-catenin protein distribution revealed a midline structure in the forebrain that is dependent on a balance of FGF signaling. Ectopic activation of FGF signaling leads to overexpression of six3b, loss of organized midline adherins junctions and bilateral loss of lefty1 expression. Reducing FGF signaling leads to a reduction in six3b and six7 expression, an increase in cell boundary formation in the brain midline, and bilateral expression of lefty1. Together, these results suggest a novel role for FGF signaling in the brain to control LR asymmetry, six transcription factor expressions, and a midline barrier structure. Copyright © 2013 Elsevier Inc. All rights reserved.

Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

PubMed Central

Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

2013-01-01

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

A biased competition account of attention and memory in Alzheimer's disease

PubMed Central

Finke, Kathrin; Myers, Nicholas; Bublak, Peter; Sorg, Christian

2013-01-01

The common view of Alzheimer's disease (AD) is that of an age-related memory disorder, i.e. declarative memory deficits are the first signs of the disease and associated with progressive brain changes in the medial temporal lobes and the default mode network. However, two findings challenge this view. First, new model-based tools of attention research have revealed that impaired selective attention accompanies memory deficits from early pre-dementia AD stages on. Second, very early distributed lesions of lateral parietal networks may cause these attention deficits by disrupting brain mechanisms underlying attentional biased competition. We suggest that memory and attention impairments might indicate disturbances of a common underlying neurocognitive mechanism. We propose a unifying account of impaired neural interactions within and across brain networks involved in attention and memory inspired by the biased competition principle. We specify this account at two levels of analysis: at the computational level, the selective competition of representations during both perception and memory is biased by AD-induced lesions; at the large-scale brain level, integration within and across intrinsic brain networks, which overlap in parietal and temporal lobes, is disrupted. This account integrates a large amount of previously unrelated findings of changed behaviour and brain networks and favours a brain mechanism-centred view on AD. PMID:24018724

A biased competition account of attention and memory in Alzheimer's disease.

PubMed

Finke, Kathrin; Myers, Nicholas; Bublak, Peter; Sorg, Christian

2013-10-19

The common view of Alzheimer's disease (AD) is that of an age-related memory disorder, i.e. declarative memory deficits are the first signs of the disease and associated with progressive brain changes in the medial temporal lobes and the default mode network. However, two findings challenge this view. First, new model-based tools of attention research have revealed that impaired selective attention accompanies memory deficits from early pre-dementia AD stages on. Second, very early distributed lesions of lateral parietal networks may cause these attention deficits by disrupting brain mechanisms underlying attentional biased competition. We suggest that memory and attention impairments might indicate disturbances of a common underlying neurocognitive mechanism. We propose a unifying account of impaired neural interactions within and across brain networks involved in attention and memory inspired by the biased competition principle. We specify this account at two levels of analysis: at the computational level, the selective competition of representations during both perception and memory is biased by AD-induced lesions; at the large-scale brain level, integration within and across intrinsic brain networks, which overlap in parietal and temporal lobes, is disrupted. This account integrates a large amount of previously unrelated findings of changed behaviour and brain networks and favours a brain mechanism-centred view on AD.

FGF Signaling is Required for Brain Left-Right Asymmetry and Brain Midline Formation

PubMed Central

Neugebauer, Judith M.; Yost, H. Joseph

2014-01-01

Early disruption of FGF signaling alters left-right (LR) asymmetry throughout the embryo. Here we uncover a role for FGF signaling that specifically disrupts brain asymmetry, independent of normal lateral plate mesoderm (LPM) asymmetry. When FGF signaling is inhibited during mid-somitogenesis, asymmetrically expressed LPM markers southpaw and lefty2 are not affected. However, asymmetrically expressed brain markers lefty1 and cyclops become bilateral. We show that FGF signaling controls expression of six3b and six7, two transcription factors required for repression of asymmetric lefty1 in the brain. We found that Z0-1, atypical PKC (aPKC) and β-catenin protein distribution revealed a midline structure in the forebrain that is dependent on a balance of FGF signaling. Ectopic activation of FGF signaling leads to overexpression of six3b, loss of organized midline adherins junctions and bilateral loss of lefty1 expression. Reducing FGF signaling leads to a reduction in six3b and six7 expression, an increase in cell boundary formation in the brain midline, and bilateral expression of lefty1. Together, these results suggest a novel role for FGF signaling in the brain to control LR asymmetry, six transcription factor expression, and a midline barrier structure. PMID:24333178

Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound.

PubMed

Stavarache, Mihaela A; Petersen, Nicholas; Jurgens, Eric M; Milstein, Elizabeth R; Rosenfeld, Zachary B; Ballon, Douglas J; Kaplitt, Michael G

2018-04-27

OBJECTIVE Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain. METHODS Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses. RESULTS Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%-75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons. CONCLUSIONS This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.

Transport of Poly(n-butylcyano-acrylate) nanoparticles across the blood-brain barrier in vitro and their influence on barrier integrity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rempe, Ralf; Cramer, Sandra; Huewel, Sabine

2011-03-04

Research highlights: {yields} Poly(n-butylcyano-acrylate) (PBCA) nanoparticles may be promising drug carriers. {yields} Influence of PBCA nanoparticles on the integrity of the blood-brain barrier in vitro. {yields} PBCA nanoparticles lead to a reversible disruption of the BBB in vitro after 4 h. {yields} Potential application as time-dependent and specific opener of the BBB. -- Abstract: In previous studies it was shown that polysorbate 80(PS80)-coated poly(n-butylcyano-acrylate) nanoparticles (PBCA-NP) are able to cross the blood-brain barrier (BBB) in vitro and in vivo. In order to explore and extend the potential applications of PBCA-NP as drug carriers, it is important to ascertain their effectmore » on the BBB. The objective of the present study was to determine the effect of PS80-coated PBCA-NP on the BBB integrity of a porcine in vitro model. This has been investigated by monitoring the development of the transendothelial electrical resistance (TEER) after the addition of PBCA-NP employing impedance spectroscopy. Additionally, the integrity of the BBB in vitro was verified by measuring the passage of the reference substances {sup 14}C-sucrose and FITC-BSA after addition of PBCA-NP. In this study we will show that the application of PS80-coated PBCA-NP leads to a reversible disruption of the barrier after 4 h. The observed disruption of the barrier could also be confirmed by {sup 14}C-sucrose and FITC-BSA permeability studies. Comparing the TEER and permeability studies the lowest resistances and maximal values for permeabilities were both observed after 4 h. These results indicate that PS80-coated PBCA-NP might be suitable for the use as drug carriers. The reversible disruption also offers the possibility to use these particles as specific opener of the BBB. Instead of incorporating the therapeutic agents into the NP, the drugs may cross the BBB after being applied simultaneously with the PBCA-NP.« less

Bisphenol A disrupts glucose transport and neurophysiological role of IR/IRS/AKT/GSK3β axis in the brain of male mice.

PubMed

Li, Jing; Wang, Yixin; Fang, Fangfang; Chen, Donglong; Gao, Yue; Liu, Jingli; Gao, Rong; Wang, Jun; Xiao, Hang

2016-04-01

Bisphenol A (BPA), one of the most prevalent chemicals for daily use, was recently reported to disturb the homeostasis of energy metabolism and insulin signaling pathways, which might contribute to the increasing prevalence rate of mild cognitive impairment (MCI). However, the underlying mechanisms are remained poorly understood. Here we studied the effects of low dose BPA on glucose transport and the IR/IRS/AKT/GSK3β axis in adult male mice to delineate the association between insulin signaling disruption and neurotoxicity mediated by BPA. Mice were treated with subcutaneous injection of 100μg/kg/d BPA or vehicle for 30 days, then the insulin signaling and glucose transporters in the hippocampus and prefrontal cortex were detected by western blot. Our results showed that mice treated with BPA displayed significant decrease of insulin sensitivity, and in glucose transporter 1, 3 (GLUT1, 3) protein levels in mouse brain. Meanwhile, hyperactivation of IR/IRS/AKT/GSK3β axis was detected in the brain of BPA treated mice. Noteworthily, significant increases of phosphorylated tau and β-APP were observed in BPA treated mice. These results strongly suggest that BPA exposure significantly disrupts brain insulin signaling and might be considered as a potential risk factor for neurodegenerative diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Peripheral Interventions Enhancing Brain Glutamate Homeostasis Relieve Amyloid β- and TNFα- Mediated Synaptic Plasticity Disruption in the Rat Hippocampus.

PubMed

Zhang, Dainan; Mably, Alexandra J; Walsh, Dominic M; Rowan, Michael J

2017-07-01

Dysregulation of glutamate homeostasis in the interstitial fluid of the brain is strongly implicated in causing synaptic dysfunction in many neurological and psychiatric illnesses. In the case of Alzheimer's disease (AD), amyloid β (Aβ)-mediated disruption of synaptic plasticity and memory can be alleviated by interventions that directly remove glutamate or block certain glutamate receptors. An alternative strategy is to facilitate the removal of excess glutamate from the nervous system by activating peripheral glutamate clearance systems. One such blood-based system, glutamate oxaloacetate transaminase (GOT), is activated by oxaloacetate, which acts as a co-substrate. We report here that synthetic and AD brain-derived Aβ-mediated inhibition of synaptic long-term potentiation in the hippocampus is alleviated by oxaloacetate. Moreover the effect of oxaloacetate was GOT-dependent. The disruptive effects of a general inhibitor of excitatory amino acid transport or TNFα, a pro-inflammatory mediator of Aβ action, were also reversed by oxaloacetate. Furthermore, another intervention that increases peripheral glutamate clearance, peritoneal dialysis, mimicked the beneficial effect of oxaloacetate. These findings lend support to the promotion of the peripheral clearance of glutamate as a means to alleviate synaptic dysfunction that is caused by impaired glutamate homeostasis in the brain. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Microbiota-gut-brain axis: Interaction of gut microbes and their metabolites with host epithelial barriers.

PubMed

Bhattarai, Y

2018-06-01

The gastrointestinal barrier and the blood brain barrier represent an important line of defense to protect the underlying structures against harmful external stimuli. These host barriers are composed of epithelial and endothelial cells interconnected by tight junction proteins along with several other supporting structures. Disruption in host barrier structures has therefore been implicated in various diseases of the gastrointestinal tract and the central nervous system. While there are several factors that influence host barrier, recently there is an increasing appreciation of the role of gut microbiota and their metabolites in regulating barrier integrity. In the current issue of Neurogastroenterology and Motility, Marungruang et al. describe the effect of gastrointestinal barrier maturation on gut microbiota and the blood brain barrier adding to the growing evidence of microbiota-barrier interactions. In this mini-review I will discuss the effect of gut microbiota on host epithelial barriers and its implications for diseases associated with disrupted gut-brain axis. © 2018 John Wiley & Sons Ltd.

Disrupted functional connectome in antisocial personality disorder.

PubMed

Jiang, Weixiong; Shi, Feng; Liao, Jian; Liu, Huasheng; Wang, Tao; Shen, Celina; Shen, Hui; Hu, Dewen; Wang, Wei; Shen, Dinggang

2017-08-01

Studies on antisocial personality disorder (ASPD) subjects focus on brain functional alterations in relation to antisocial behaviors. Neuroimaging research has identified a number of focal brain regions with abnormal structures or functions in ASPD. However, little is known about the connections among brain regions in terms of inter-regional whole-brain networks in ASPD patients, as well as possible alterations of brain functional topological organization. In this study, we employ resting-state functional magnetic resonance imaging (R-fMRI) to examine functional connectome of 32 ASPD patients and 35 normal controls by using a variety of network properties, including small-worldness, modularity, and connectivity. The small-world analysis reveals that ASPD patients have increased path length and decreased network efficiency, which implies a reduced ability of global integration of whole-brain functions. Modularity analysis suggests ASPD patients have decreased overall modularity, merged network modules, and reduced intra- and inter-module connectivities related to frontal regions. Also, network-based statistics show that an internal sub-network, composed of 16 nodes and 16 edges, is significantly affected in ASPD patients, where brain regions are mostly located in the fronto-parietal control network. These results suggest that ASPD is associated with both reduced brain integration and segregation in topological organization of functional brain networks, particularly in the fronto-parietal control network. These disruptions may contribute to disturbances in behavior and cognition in patients with ASPD. Our findings may provide insights into a deeper understanding of functional brain networks of ASPD.

Disrupted functional connectome in antisocial personality disorder

PubMed Central

Jiang, Weixiong; Shi, Feng; Liao, Jian; Liu, Huasheng; Wang, Tao; Shen, Celina; Shen, Hui; Hu, Dewen

2017-01-01

Studies on antisocial personality disorder (ASPD) subjects focus on brain functional alterations in relation to antisocial behaviors. Neuroimaging research has identified a number of focal brain regions with abnormal structures or functions in ASPD. However, little is known about the connections among brain regions in terms of inter-regional whole-brain networks in ASPD patients, as well as possible alterations of brain functional topological organization. In this study, we employ resting-state functional magnetic resonance imaging (R-fMRI) to examine functional connectome of 32 ASPD patients and 35 normal controls by using a variety of network properties, including small-worldness, modularity, and connectivity. The small-world analysis reveals that ASPD patients have increased path length and decreased network efficiency, which implies a reduced ability of global integration of whole-brain functions. Modularity analysis suggests ASPD patients have decreased overall modularity, merged network modules, and reduced intra- and inter-module connectivities related to frontal regions. Also, network-based statistics show that an internal sub-network, composed of 16 nodes and 16 edges, is significantly affected in ASPD patients, where brain regions are mostly located in the fronto-parietal control network. These results suggest that ASPD is associated with both reduced brain integration and segregation in topological organization of functional brain networks, particularly in the fronto-parietal control network. These disruptions may contribute to disturbances in behavior and cognition in patients with ASPD. Our findings may provide insights into a deeper understanding of functional brain networks of ASPD. PMID:27541949

Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area

PubMed Central

Gavrilov, Yury V.; Ellison, Brian A.; Yamamoto, Mihoko; Reddy, Hasini; Haybaeck, Johannes; Mignot, Emmanuel; Baumann, Christian R.; Scammell, Thomas E.; Valko, Philipp O.

2016-01-01

Study Objectives: To examine the integrity of sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients. Methods: Postmortem examination of five narcolepsy and eight control brains. Results: VLPO galanin neuron count did not differ between narcolepsy patients (11,151 ± 3,656) and controls (13,526 ± 9,544). Conclusions: A normal number of galanin-immunoreactive VLPO neurons in narcolepsy type 1 brains at autopsy suggests that VLPO cell loss is an unlikely explanation for the sleep fragmentation that often accompanies the disease. Citation: Gavrilov YV, Ellison BA, Yamamoto M, Reddy H, Haybaeck J, Mignot E, Baumann CR, Scammell TE, Valko PO. Disrupted sleep in narcolepsy: exploring the integrity of galanin neurons in the ventrolateral preoptic area. SLEEP 2016;39(5):1059–1062. PMID:26951397

Aberrant Network Activity in Schizophrenia.

PubMed

Hunt, Mark J; Kopell, Nancy J; Traub, Roger D; Whittington, Miles A

2017-06-01

Brain dynamic changes associated with schizophrenia are largely equivocal, with interpretation complicated by many factors, such as the presence of therapeutic agents and the complex nature of the syndrome itself. Evidence for a brain-wide change in individual network oscillations, shared by all patients, is largely equivocal, but stronger for lower (delta) than for higher (gamma) bands. However, region-specific changes in rhythms across multiple, interdependent, nested frequencies may correlate better with pathology. Changes in synaptic excitation and inhibition in schizophrenia disrupt delta rhythm-mediated cortico-cortical communication, while enhancing thalamocortical communication in this frequency band. The contrasting relationships between delta and higher frequencies in thalamus and cortex generate frequency mismatches in inter-regional connectivity, leading to a disruption in temporal communication between higher-order brain regions associated with mental time travel. Copyright © 2017 Elsevier Ltd. All rights reserved.

Morphofunctional aspects of the blood-brain barrier.

PubMed

Nico, Beatrice; Ribatti, Domenico

2012-01-01

The blood-brain barrier (BBB) selectively controls the homeostasis of the Central Nervous System (CNS) environment by the specific structural and biochemical features of the endothelial cells, pericytes and glial endfeet, which represent the cellular components of the mature BBB. Endothelial tight junctions (TJs) are the most important structural component of the BBB, and molecular alteration in the phosphorylation state of some TJs proteins, like ZO-1 or occludin, are crucial in determining alterations in the control of BBB vascular permeability. Astrocytes endfeet enveloping the vessels wall, are considered important in the induction and maintenance of the BBB, through secretion of soluble factors, which modulate the expression of enzymatic complexes and antigens by endothelial cells and TJs - associated proteins. Moreover, astrocytes control water flux at BBB site by expressing a specific water channel, namely aquaporin-4 (AQP4), involved in the molecular composition of the orthogonal particles arrays (OAPs) on the perivascular glial endfeet and tightly coupled with the maintenance of the BBB integrity. Disruption of the BBB is a consistent event occurring in the development of several CNS diseases, including demyelinating lesions in the course of relapsing multiple sclerosis, stroke, Duchenne muscular dystrophy (DMD), but also mechanical injures, neurological insults, septic encephalopathy, brain tumors, permanent ischemia or transient ischemia followed by reperfusion. In most cases, these pathological conditions are associated with an increase in microvascular permeability, vasogenic edema, swollen atrocyte endfeet, and BBB disruption.

IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice.

PubMed

Toth, Peter; Tucsek, Zsuzsanna; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

2014-12-01

Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.

Drugs of abuse that cause developing neurons to commit suicide.

PubMed

Farber, Nuri B; Olney, John W

2003-12-30

When neuronal activity is abnormally suppressed during the developmental period of synaptogenesis, the timing and sequence of synaptic connections is disrupted, and this causes nerve cells to receive an internal signal to commit suicide, a form of cell death known as "apoptosis". By altering glutamate and GABA transmission alcohol suppresses neuronal activity, causing millions of nerve cells to commit suicide in the developing brain. This proapoptotic effect of alcohol provides a likely explanation for the diminished brain size and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome. These findings have public health significance, not only in relation to fetal alcohol syndrome, but also in relation to several other drugs of abuse and various drugs used in obstetric and pediatric medicine, because these additional drugs (e.g. phencyclidine, ketamine, benzodiazepines, barbiturates) also suppress neuronal activity and drive developing neurons to commit suicide.

Mechanical disruption of the blood-brain barrier following experimental concussion.

PubMed

Johnson, Victoria E; Weber, Maura T; Xiao, Rui; Cullen, D Kacy; Meaney, David F; Stewart, William; Smith, Douglas H

2018-05-01

Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood-brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6-72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray-white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion.

The ketogenic diet: metabolic influences on brain excitability and epilepsy

PubMed Central

Lutas, Andrew; Yellen, Gary

2012-01-01

A dietary therapy for pediatric epilepsy known as the ketogenic diet has seen a revival in its clinical use in the past decade. Though the diet’s underlying mechanism remains unknown, modern scientific approaches like genetic disruption of glucose metabolism are allowing for more detailed questions to be addressed. Recent work indicates that several mechanisms may exist for the ketogenic diet including disruption of glutamatergic synaptic transmission, inhibition of glycolysis, and activation of ATP-sensitive potassium channels. Here we describe on-going work in these areas that is providing a better understanding of metabolic influences on brain excitability and epilepsy. PMID:23228828

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer’s Disease

PubMed Central

Dulla, Chris G.; Coulter, Douglas A.; Ziburkus, Jokubas

2015-01-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer’s disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. PMID:25948650

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer's Disease.

PubMed

Dulla, Chris G; Coulter, Douglas A; Ziburkus, Jokubas

2016-06-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer's disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. © The Author(s) 2015.

Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults.

PubMed

Calderón-Garcidueñas, Lilian; Solt, Anna C; Henríquez-Roldán, Carlos; Torres-Jardón, Ricardo; Nuse, Bryan; Herritt, Lou; Villarreal-Calderón, Rafael; Osnaya, Norma; Stone, Ida; García, Raquel; Brooks, Diane M; González-Maciel, Angelica; Reynoso-Robles, Rafael; Delgado-Chávez, Ricardo; Reed, William

2008-02-01

Air pollution is a serious environmental problem. We investigated whether residency in cities with high air pollution is associated with neuroinflammation/neurodegeneration in healthy children and young adults who died suddenly. We measured mRNA cyclooxygenase-2, interleukin-1beta, and CD14 in target brain regions from low (n = 12) or highly exposed residents (n = 35) aged 25.1 +/- 1.5 years. Upregulation of cyclooxygenase-2, interleukin-1beta, and CD14 in olfactory bulb, frontal cortex, substantia nigrae and vagus nerves; disruption of the blood-brain barrier; endothelial activation, oxidative stress, and inflammatory cell trafficking were seen in highly exposed subjects. Amyloid beta42 (Abeta42) immunoreactivity was observed in 58.8% of apolipoprotein E (APOE) 3/3 < 25 y, and 100% of the APOE 4 subjects, whereas alpha-synuclein was seen in 23.5% of < 25 y subjects. Particulate material (PM) was seen in olfactory bulb neurons, and PM < 100 nm were observed in intraluminal erythrocytes from lung, frontal, and trigeminal ganglia capillaries. Exposure to air pollution causes neuroinflammation, an altered brain innate immune response, and accumulation of Abeta42 and alpha-synuclein starting in childhood. Exposure to air pollution should be considered a risk factor for Alzheimer's and Parkinson's diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.

PubMed

Gust, Juliane; Hay, Kevin A; Hanafi, Laïla-Aïcha; Li, Daniel; Myerson, David; Gonzalez-Cuyar, Luis F; Yeung, Cecilia; Liles, W Conrad; Wurfel, Mark; Lopez, Jose A; Chen, Junmei; Chung, Dominic; Harju-Baker, Susanna; Özpolat, Tahsin; Fink, Kathleen R; Riddell, Stanley R; Maloney, David G; Turtle, Cameron J

2017-12-01

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19 + cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity. Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404-19. ©2017 AACR. See related commentary by Mackall and Miklos, p. 1371 This article is highlighted in the In This Issue feature, p. 1355 . ©2017 American Association for Cancer Research.

Small vessel disease is linked to disrupted structural network covariance in Alzheimer's disease.

PubMed

Nestor, Sean M; Mišić, Bratislav; Ramirez, Joel; Zhao, Jiali; Graham, Simon J; Verhoeff, Nicolaas P L G; Stuss, Donald T; Masellis, Mario; Black, Sandra E

2017-07-01

Cerebral small vessel disease (SVD) is thought to contribute to Alzheimer's disease (AD) through abnormalities in white matter networks. Gray matter (GM) hub covariance networks share only partial overlap with white matter connectivity, and their relationship with SVD has not been examined in AD. We developed a multivariate analytical pipeline to elucidate the cortical GM thickness systems that covary with major network hubs and assessed whether SVD and neurodegenerative pathologic markers were associated with attenuated covariance network integrity in mild AD and normal elderly control subjects. SVD burden was associated with reduced posterior cingulate corticocortical GM network integrity and subneocorticocortical hub network integrity in AD. These findings provide evidence that SVD is linked to the selective disruption of cortical hub GM networks in AD brains and point to the need to consider GM hub covariance networks when assessing network disruption in mixed disease. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Experimental 'jet lag' inhibits adult neurogenesis and produces long-term cognitive deficits in female hamsters.

PubMed

Gibson, Erin M; Wang, Connie; Tjho, Stephanie; Khattar, Neera; Kriegsfeld, Lance J

2010-12-01

Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. In the present study, we investigated whether experimental 'jet lag' (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory.

Rapid Morphological Brain Abnormalities during Acute Methamphetamine Intoxication in the Rat. An Experimental study using Light and Electron Microscopy

PubMed Central

Sharma, Hari S.; Kiyatkin, Eugene A.

2009-01-01

This study describes morphological abnormalities of brain cells during acute methamphetamine (METH) intoxication in the rat and demonstrates the role of hyperthermia, disruption of the blood-brain barrier (BBB) and edema in their development. Rats with chronically implanted brain, muscle and skin temperature probes and an intravenous (iv) catheter were exposed to METH (9 mg/kg) at standard (23°C) and warm (29°C) ambient temperatures, allowing for the observation of hyperthermia ranging from mild to pathological levels (38–42°C). When brain temperature peaked or reached a level suggestive of possible lethality (>41.5°C), rats were injected with Evans blue (EB), rapidly anesthetized, perfused, and their brains were taken for further analyses. Four brain areas (cortex, hippocampus, thalamus and hypothalamus) were analyzed for EB extravasation, water and electrolyte (Na+, K+, Cl−) contents, immunostained for albumin and glial fibrillary acidic protein, and examined for neuronal, glial and axonal alterations using standard light and electron microscopy. These examinations revealed profound abnormalities in neuronal, glial, and endothelial cells, which were stronger with METH administered at 29°C than 23°C and tightly correlated with brain and body hyperthermia. These changes had some structural specificity, but in each structure they tightly correlated with increases in EB levels, the numbers of albumin-positive cells, and water and ion contents, suggesting leakage of the BBB, acutely developing brain edema, and serious shifts in brain ion homeostasis as leading factors underlying brain abnormalities. While most of these acute structural and functional abnormalities appear to be reversible, they could trigger subsequent cellular alterations in the brain and accelerate neurodegeneration—the most dangerous complication of chronic amphetamine-like drug abuse. PMID:18773954

White matter tract network disruption explains reduced conscientiousness in multiple sclerosis.

PubMed

Fuchs, Tom A; Dwyer, Michael G; Kuceyeski, Amy; Choudhery, Sanjeevani; Carolus, Keith; Li, Xian; Mallory, Matthew; Weinstock-Guttman, Bianca; Jakimovski, Dejan; Ramasamy, Deepa; Zivadinov, Robert; Benedict, Ralph H B

2018-05-08

Quantifying white matter (WM) tract disruption in people with multiple sclerosis (PwMS) provides a novel means for investigating the relationship between defective network connectivity and clinical markers. PwMS exhibit perturbations in personality, where decreased Conscientiousness is particularly prominent. This trait deficit influences disease trajectory and functional outcomes such as work capacity. We aimed to identify patterns of WM tract disruption related to decreased Conscientiousness in PwMS. Personality assessment and brain MRI were obtained in 133 PwMS and 49 age- and sex-matched healthy controls (HC). Lesion maps were applied to determine the severity of WM tract disruption between pairs of gray matter regions. Next, the Network-Based-Statistics tool was applied to identify structural networks whose disruption negatively correlates with Conscientiousness. Finally, to determine whether these networks explain unique variance above conventional MRI measures and cognition, regression models were applied controlling for age, sex, brain volume, T2-lesion volume, and cognition. Relative to HCs, PwMS exhibited lower Conscientiousness and slowed cognitive processing speed (p = .025, p = .006). Lower Conscientiousness in PwMS was significantly associated with WM tract disruption between frontal, frontal-parietal, and frontal-cingulate pathways in the left (p = .02) and right (p = .01) hemisphere. The mean disruption of these pathways explained unique additive variance in Conscientiousness, after accounting for conventional MRI markers of pathology and cognition (ΔR 2  = .049, p = .029). Damage to WM tracts between frontal, frontal-parietal, and frontal-cingulate cortical regions is significantly correlated with reduced Conscientiousness in PwMS. Tract disruption within these networks explains decreased Conscientiousness observed in PwMS as compared with HCs. © 2018 Wiley Periodicals, Inc.

Peripheral ammonia and blood brain barrier structure and function after methamphetamine.

PubMed

Northrop, Nicole A; Halpin, Laura E; Yamamoto, Bryan K

2016-08-01

An effect of the widely abuse psychostimulant, methamphetamine (Meth), is blood-brain-barrier (BBB) disruption; however, the mechanism by which Meth causes BBB disruption remains unclear. Recently it has been shown that Meth produces liver damage and consequent increases in plasma ammonia. Ammonia can mediate oxidative stress and inflammation, both of which are known to cause BBB disruption. Therefore, the current studies examined the role of peripheral ammonia in Meth-induced disruption of BBB structure and function. A neurotoxic Meth regimen (10 mg/kg, ip, q 2 h, ×4) administered to rats increased plasma ammonia and active MMP-9 in the cortex 2 h after the last Meth injection, compared to saline treated rats. At 24 h after Meth treatment, decreased immunoreactivity of BBB structural proteins, occludin and claudin-5, and increased extravasation of 10,000 Da FITC-dextran were observed, as compared to saline controls. Pretreatment with lactulose (5.3 g/kg, po, q 12 h), a drug that remains in the lumen of the intestine and promotes ammonia excretion, prevented the Meth-induced increases in plasma ammonia. These results were paralleled by the prevention of decreases in BBB structural proteins, increases in extravasation of 10,000 Da FITC-dextran and increases in active MMP-9. The results indicate that Meth-induced increases in ammonia produce BBB disruption and suggest that MMP-9 activation mediates the BBB disruption. These findings identify a novel mechanism of Meth-induced BBB disruption that is mediated by plasma ammonia and are the first to identify a peripheral contribution to Meth-induced BBB disruption. Copyright © 2016 Elsevier Ltd. All rights reserved.

Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine.

PubMed

Pérez-Rodríguez, Maribel; García-Mendoza, Esperanza; Farfán-García, Eunice D; Das, Bhaskar C; Ciprés-Flores, Fabiola J; Trujillo-Ferrara, José G; Tamay-Cach, Feliciano; Soriano-Ursúa, Marvin A

2017-09-01

Several striatal toxins can be used to induce motor disruption. One example is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3-Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five-membered cycle), as well as boric acid and 3TB. These boron-containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2-Thienyl and 2-furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five-membered cycle as substituent. Possible explanations are given for the diverse chemico-morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure-toxicity relationship. Copyright © 2017 Elsevier B.V. All rights reserved.

Family members' needs and experiences of driving disruption over time following an acquired brain injury: an evolving issue.

PubMed

Liang, Phyllis; Gustafsson, Louise; Liddle, Jacki; Fleming, Jennifer

2017-07-01

Family members often assume the role of driver for individuals who are not driving post-acquired brain injury (ABI). Given that return to driving can be unpredictable and uncertain, the impact of driving disruption on family members may vary at different stages post-injury. This study aims to understand the needs and experiences of family members over time during driving disruption following an ABI. A qualitative prospective longitudinal research design was used with semi-structured interviews at recruitment to study, 3 and 6 months later. Fourteen family members completed 41 interviews. The longitudinal data revealed four phases of driving disruption: (1) Wait and see, (2) Holding onto a quick fix, (3) No way out, and (4) Resolution and adjustment. The phases described a process of building tension and a need for support and resolution over time. Holding onto a quick fix is a pivotal phase whereby supports, such as engagement in realistic goal setting, are essential to facilitate family members' resolution of driving disruption issues. Family members who see no way out might not actively seek help and these points to a need for long-term and regular follow-ups. Future research can explore ways to support family members at these key times. Implications for rehabilitation Health professionals need to facilitate the process of fostering hope in family members to set realistic expectations of return to driving and the duration of driving disruption. It is necessary to follow-up with family members even years after ABI as the issue of driving disruption could escalate to be a crisis and family members might not actively seek help. Health professionals can consider both practical support for facilitating transport and emotional support when addressing the issue of driving disruption with family members.

Deferoxamine inhibits microglial activation, attenuates blood-brain barrier disruption, rescues dendritic damage, and improves spatial memory in a mouse model of microhemorrhages.

PubMed

He, Xiao-Fei; Lan, Yue; Zhang, Qun; Liu, Dong-Xu; Wang, Qinmei; Liang, Feng-Ying; Zeng, Jin-Sheng; Xu, Guang-Qing; Pei, Zhong

2016-08-01

Cerebral microbleeds are strongly linked to cognitive dysfunction in the elderly. Iron accumulation plays an important role in the pathogenesis of intracranial hemorrhage. Deferoxamine (DFX), a metal chelator, removes iron overload and protects against brain damage in intracranial hemorrhage. In this study, the protective effects of DFX against microhemorrhage were examined in mice. C57BL6 and Thy-1 green fluorescent protein transgenic mice were subjected to perforating artery microhemorrhages on the right posterior parietal cortex using two-photon laser irradiation. DFX (100 mg/kg) was administered 6 h after microhemorrhage induction, followed by every 12 h for three consecutive days. The water maze task was conducted 7 days after induction of microhemorrhages, followed by measurement of blood-brain barrier permeability, iron deposition, microglial activation, and dendritic damage. Laser-induced multiple microbleeds in the right parietal cortex clearly led to spatial memory disruption, iron deposits, microglial activation, and dendritic damage, which were significantly attenuated by DFX, supporting the targeting of iron overload as a therapeutic option and the significant potential of DFX in microhemorrhage treatment. Irons accumulation after intracranial hemorrhage induced a serious secondary damage to the brain. We proposed that irons accumulation after parietal microhemorrhages impaired spatial cognition. After parietal multiple microhemorrhages, increased irons and ferritin contents induced blood-brain barrier disruption, microglial activation, and further induced dendrites loss, eventually impaired the water maze, deferoxamine treatment protected from these damages. © 2016 International Society for Neurochemistry.

Diffusion tractography and graph theory analysis reveal the disrupted rich-club organization of white matter structural networks in early Tourette Syndrome children

NASA Astrophysics Data System (ADS)

Wen, Hongwei; Liu, Yue; Wang, Shengpei; Zhang, Jishui; Peng, Yun; He, Huiguang

2017-03-01

Tourette syndrome (TS) is a childhood-onset neurobehavioral disorder. At present, the topological disruptions of the whole brain white matter (WM) structural networks remain poorly understood in TS children. Considering the unique position of the topologically central role of densely interconnected brain hubs, namely the rich club regions, therefore, we aimed to investigate whether the rich club regions and their related connections would be particularly vulnerable in early TS children. In our study, we used diffusion tractography and graph theoretical analyses to explore the rich club structures in 44 TS children and 48 healthy children. The structural networks of TS children exhibited significantly increased normalized rich club coefficient, suggesting that TS is characterized by increased structural integrity of this centrally embedded rich club backbone, potentially resulting in increased global communication capacity. In addition, TS children showed a reorganization of rich club regions, as well as significantly increased density and decreased number in feeder connections. Furthermore, the increased rich club coefficients and feeder connections density of TS children were significantly positively correlated to tic severity, indicating that TS may be characterized by a selective alteration of the structural connectivity of the rich club regions, tending to have higher bridging with non-rich club regions, which may increase the integration among tic-related brain circuits with more excitability but less inhibition for information exchanges between highly centered brain regions and peripheral areas. In all, our results suggest the disrupted rich club organization in early TS children and provide structural insights into the brain networks.

CAVEOLIN-1 REGULATES HIV-1 TAT-INDUCED ALTERATIONS OF TIGHT JUNCTION PROTEIN EXPRESSION VIA MODULATION OF THE RAS SIGNALING

PubMed Central

Zhong, Yu; Smart, Eric J.; Weksler, Babette; Couraud, Pierre-Olivier; Hennig, Bernhard; Toborek, Michal

2009-01-01

The blood-brain barrier (BBB) is the critical structure for preventing HIV trafficking into the brain. Specific HIV proteins, such as Tat protein, can contribute to the dysfunction of tight junctions at the BBB and HIV entry into the brain. Tat is released by HIV-1 infected cells and can interact with a variety of cell surface receptors activating several signal transduction pathways, including those localized in caveolae. The present study focused on the mechanisms of Tat-induced caveolae-associated Ras signaling at the level of the BBB. Treatment with Tat activated the Ras pathway in human brain microvascular endothelial cells (HBMEC). However, caveolin-1 silencing markedly attenuated these effects. Because the integrity of the brain endothelium is regulated by intercellular tight junctions, these structural elements of the BBB were also evaluated in the present study. Exposure to Tat diminished the expression of several tight junction proteins, namely, occludin, zonula occludens (ZO)-1, and ZO-2 in the caveolar fraction of HBMEC. These effects were effectively protected by pharmacological inhibition of the Ras signaling and by silencing of caveolin-1. The present data indicate the importance of caveolae-associated signaling in the disruption of tight junctions upon Tat exposure. They also demonstrate that caveolin-1 may constitute an early and critical modulator that controls signaling pathways leading to the disruption of tight junction proteins. Thus, caveolin-1 may provide an effective target to protect against Tat-induced HBMEC dysfunction and the disruption of the BBB in HIV-1-infected patients. PMID:18667611

Cortical gyrification is abnormal in children with prenatal alcohol exposure.

PubMed

Hendrickson, Timothy J; Mueller, Bryon A; Sowell, Elizabeth R; Mattson, Sarah N; Coles, Claire D; Kable, Julie A; Jones, Kenneth L; Boys, Christopher J; Lim, Kelvin O; Riley, Edward P; Wozniak, Jeffrey R

2017-01-01

Prenatal alcohol exposure (PAE) adversely affects early brain development. Previous studies have shown a wide range of structural and functional abnormalities in children and adolescents with PAE. The current study adds to the existing literature specifically on cortical development by examining cortical gyrification in a large sample of children with PAE compared to controls. Relationships between cortical development and intellectual functioning are also examined. Included were 92 children with PAE and 83 controls ages 9-16 from four sites in the Collaborative Initiative on FASD (CIFASD). All PAE participants had documented heavy PAE. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Cortical gyrification was examined using a semi-automated procedure. Whole brain group comparisons using Monte Carlo z-simulation for multiple comparisons showed significantly lower cortical gyrification across a large proportion of the cerebral cortex amongst PAE compared to controls. Whole brain comparisons and ROI based analyses showed strong positive correlations between cortical gyrification and IQ (i.e. less developed cortex was associated with lower IQ). Abnormalities in cortical development were seen across the brain in children with PAE compared to controls. Cortical gyrification and IQ were strongly correlated, suggesting that examining mechanisms by which alcohol disrupts cortical formation may yield clinically relevant insights and potential directions for early intervention.

Resting-State Functional Connectivity in the Human Connectome Project: Current Status and Relevance to Understanding Psychopathology.

PubMed

Barch, Deanna M

A key tenet of modern psychiatry is that psychiatric disorders arise from abnormalities in brain circuits that support human behavior. Our ability to examine hypotheses around circuit-level abnormalities in psychiatric disorders has been made possible by advances in human neuroimaging technologies. These advances have provided the basis for recent efforts to develop a more complex understanding of the function of brain circuits in health and of their relationship to behavior-providing, in turn, a foundation for our understanding of how disruptions in such circuits contribute to the development of psychiatric disorders. This review focuses on the use of resting-state functional connectivity MRI to assess brain circuits, on the advances generated by the Human Connectome Project, and on how these advances potentially contribute to understanding neural circuit dysfunction in psychopathology. The review gives particular attention to the methods developed by the Human Connectome Project that may be especially relevant to studies of psychopathology; it outlines some of the key findings about what constitutes a brain region; and it highlights new information about the nature and stability of brain circuits. Some of the Human Connectome Project's new findings particularly relevant to psychopathology-about neural circuits and their relationships to behavior-are also presented. The review ends by discussing the extension of Human Connectome Project methods across the lifespan and into manifest illness. Potential treatment implications are also considered.

Essential Role of Cyclin-G–associated Kinase (Auxilin-2) in Developing and Mature Mice

PubMed Central

Lee, Dong-won; Zhao, Xiaohong; Yim, Yang-In; Eisenberg, Evan

2008-01-01

Hsc70 with its cochaperone, either auxilin or GAK, not only uncoats clathrin-coated vesicles but also acts as a chaperone during clathrin-mediated endocytosis. However, because synaptojanin is also involved in uncoating, it is not clear whether GAK is an essential gene. To answer this question, GAK conditional knockout mice were generated and then mated to mice expressing Cre recombinase under the control of the nestin, albumin, or keratin-14 promoters, all of which turn on during embryonic development. Deletion of GAK from brain, liver, or skin dramatically altered the histology of these tissues, causing the mice to die shortly after birth. Furthermore, by expressing a tamoxifen-inducible promoter to express Cre recombinase we showed that deletion of GAK caused lethality in adult mice. Mouse embryonic fibroblasts in which the GAK was disrupted showed a lack of clathrin-coated pits and a complete block in clathrin-mediated endocytosis. We conclude that GAK deletion blocks development and causes lethality in adult animals by disrupting clathrin-mediated endocytosis. PMID:18434600

Cortical DNA methylation maintains remote memory.

PubMed

Miller, Courtney A; Gavin, Cristin F; White, Jason A; Parrish, R Ryley; Honasoge, Avinash; Yancey, Christopher R; Rivera, Ivonne M; Rubio, María D; Rumbaugh, Gavin; Sweatt, J David

2010-06-01

A behavioral memory's lifetime represents multiple molecular lifetimes, suggesting the necessity for a self-perpetuating signal. One candidate is DNA methylation, a transcriptional repression mechanism that maintains cellular memory throughout development. We found that persistent, gene-specific cortical hypermethylation was induced in rats by a single, hippocampus-dependent associative learning experience and pharmacologic inhibition of methylation 1 month after learning disrupted remote memory. We propose that the adult brain utilizes DNA methylation to preserve long-lasting memories.

Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model.

PubMed

Patabendige, Adjanie; Michael, Benedict D; Craig, Alister G; Solomon, Tom

2018-06-01

Japanese encephalitis virus (JEV) remains a leading cause of encephalitis, globally, which continues to grow in importance despite the availability of vaccines. Viral entry into the brain can occur via the blood-brain barrier (BBB), and inflammation at the BBB is a common final pathway in many brain infections. However, the role of the BBB during JEV infection and the contribution of the endothelial and astrocytic cell inflammation in facilitating virus entry into the brain are incompletely understood. We established a BBB model using human brain endothelial cells (HBECs) and human astrocytes. HBECs are polarised, and therefore the model was inoculated by JEV from the apical side to simulate the in vivo situation. The effects of JEV on the BBB permeability and release of inflammatory mediators from both apical and basolateral sides, representing the blood and the brain side respectively were investigated. JEV infected HBECs with limited active virus production, before crossing the BBB and infecting astrocytes. Control of JEV production by HBECs was associated with a significant increase in permeability, and with elevation of many host mediators, including cytokines, chemokines, cellular adhesion molecules, and matrix metalloproteases. When compared to the controls, significantly higher amounts of mediators were released from the apical side as opposed to the basolateral side. The increased release of mediators over time also correlated with increased BBB permeability. Treatment with dexamethasone led to a significant reduction in the release of interleukin 6 (IL6), C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) from the apical side with a reduction in BBB disruption and no change in JEV production. The results are consistent with the hypothesis that JEV infection of the BBB triggers the production of a range of host mediators from both endothelial cells and astrocytes, which control JEV production but disrupt BBB integrity thus allowing virus entry into the brain. Dexamethasone treatment controlled the host response and limited BBB disruption in the model without increasing JEV production, supporting a re-investigation of its use therapeutically. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Anesthetic Agents and Neuronal Autophagy. What We Know and What We Don't.

PubMed

Xu, Lili; Shen, Jianjun; McQuillan, Patrick M; Hu, Zhiyong

2018-01-01

Ethanol is known to have both γ-Aminobutyric acid agonist and Nmethyl- D-aspartate antagonist characteristics similar to commonly used volatile anesthetic agents. Recent evidence demonstrates that autophagy can reduce the development of ethanol induced neurotoxicity. Recent studies have found that general anesthesia can cause longterm impairment of both mitochondrial morphogenesis and synaptic transmission in the developing rat brain, both of which are accompanied by enhanced autophagy activity. Autophagy may play an important role in general anesthetic mediated neurotoxicity. This review outlines the role of autophagy in the development of anesthetic related neurotoxicity and includes an explanation of the role of autophagy in neuronal cell survival and death, the relationship between anesthetic agents and neuronal autophagy, possible molecular and cellular mechanisms underlying general anesthetic agent induced activation of neuronal autophagy in the developing brain, and potential therapeutic approaches aimed at modulating autophagic pathways. In a time- and concentration-dependent pattern, general anesthetic agents can disrupt intracellular calcium homeostasis which enhances both autophagy and apoptosis activation. The degree of neural cell injury may be ultimately determined by the interplay between autophagy and apoptosis. It appears likely that the increase in calcium flux associated with some anesthetic agents disrupts lysosomal function. This results in an over-activation of endosomal- lysosomal trafficking causing mitochondrial damage, reactive oxygen species upregulation, and lipid peroxidation. Autophagy may play a role in the development of anesthetic related neurotoxicity. Understanding this may lead to strategies or therapies aimed at preventing or ameliorating general anesthetic agent mediated neurotoxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology.

PubMed

Layé, Sophie; Nadjar, Agnès; Joffre, Corinne; Bazinet, Richard P

2018-01-01

Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Developmental Programming and Endocrine Disruptor Effects on Reproductive Neuroendocrine Systems

PubMed Central

Gore, Andrea C.

2009-01-01

The ability of a species to reproduce successfully requires the careful orchestration of developmental processes during critical time points, particularly the late embryonic and early postnatal periods. This article begins with a brief presentation of the evidence for how gonadal steroid hormones exert these imprinting effects upon the morphology of sexually differentiated hypothalamic brain regions, the mechanisms underlying these effects, and their implications in adulthood. Then, I review the evidence that aberrant exposure to hormonally-active substances such as exogenous endocrine-disrupting chemicals (EDCs), may result in improper hypothalamic programming, thereby decreasing reproductive success in adulthood. The field of endocrine disruption has shed new light on the discipline of basic reproductive neuroendocrinology through studies on how early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation. Importantly, these effects may be transmitted to future generations if the germline is affected via transgenerational, epigenetic actions. By understanding the mechanisms by which natural hormones and xenobiotics affect reproductive neuroendocrine systems, we will gain a better understanding of normal developmental processes, as well as to develop the potential ability to intervene when development is disrupted. PMID:18394690

Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone.

PubMed

Zhou, Ting; Zhao, Lei; Zhan, Rui; He, Qihua; Tong, Yawei; Tian, Xiaosheng; Wang, Hecheng; Zhang, Tao; Fu, Yaoyun; Sun, Yang; Xu, Feng; Guo, Xiangyang; Fan, Dongsheng; Han, Hongbin; Chui, Dehua

2014-10-24

Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

An unusual autopsy case of cytokine storm-derived influenza-associated encephalopathy without typical histopathological findings: autopsy case report.

PubMed

Nara, Akina; Nagai, Hisashi; Yamaguchi, Rutsuko; Yoshida, Ken-ichi; Iwase, Hirotaro; Mizuguchi, Masashi

2015-03-01

Cytokine storm-derived influenza-associated encephalopathy is a severe complication, affecting not only the brain but also multiple systemic organs including the heart and lungs. Hundreds of Japanese children are afflicted by influenza-associated encephalopathy every year. Influenza-associated encephalopathy can be diagnosed by pathological changes, such as advanced brain edema and disruption of astrocytic projections, which is known as clasmatodendrosis. In the present case, despite the absence of significant histopathological findings in the brain, the diagnosis of influenza-associated encephalopathy was made on the basis of autopsy findings such as brain swelling, pathological findings including diffuse alveolar damage, and increase in the concentrations of interleukin-6 in both the serum and cerebrospinal fluid. In this case, the interval from high fever to death was approximately 7 hours and may have been too short for histopathological features to develop. This is an unusual autopsy case of cytokine storm-derived influenza-associated encephalopathy without typical histopathological findings.

Endocrine-disrupting activity of chemicals in diesel exhaust and diesel exhaust particles.

PubMed

Takeda, Ken; Tsukue, Naomi; Yoshida, Seiichi

2004-01-01

Diesel exhaust (DE) is known as the main cause of air pollution. DE is a complex mixture of particulate and vapor-phase compounds. The soluble organic fraction of the particulate materials in DE contains thousands of compounds including a variety of polycyclic aromatic hydrocarbons and heavy metals. To clarify the endocrine-disrupting activities of DE, we have reviewed the reports about the effects of DE on the reproductive and brain-nervous systems, and the endocrine-disrupting action of diesel exhaust particles (DEP). In utero exposure to low levels (0.1 mg DEP/m3) of DE from day 2 postcoitum (p.c.) until day 13 p.c. reduced the expression level of Ad4BP/SF-1 mRNA and thereby might affect the development of gonads. Low levels of DE also reduced the expression of several genes known to play key roles in gonadal development, including an enzyme necessary for testosterone synthesis. Mature male rats exposed to DE during the fetal period showed an irreversible decrease in daily sperm production due to an insufficient number of Sertoli cells. DE exposure during the fetal period influenced the brain tissue in newborn mice. In the 3 mg DEP/m3 exposure group at 10 weeks of age, a significant reduction in performance was observed in the passive avoidance learning test in both male and female mice. In addition, the fetal exposure of mice to DE affected the emotional behaviors associated with the serotonergic and dopaminergic systems in the mouse brain. In toluidine blue-stained specimens from the DE-exposed group, edema around the vessels where fluorescent granular perithelial (FGP) cells exist and degenerated granules within the FGP cytoplasm were observed; similar findings were obtained by electron microscopic examination. DEP contain many substances that stimulate Ah receptors, such as the polycyclic aromatic hydrocarbon containing benzo[a]pyrene. DEP also contain substances with estrogenic, antiestrogenic and antiandrogenic activities. The neutral substance fraction of DEP has the causal substance that reduces estrogen receptor mRNA expression. Evaluating the influence of these chemicals present in the environment on human health is an important task.

Effects of exogenous agents on brain development: stress, abuse and therapeutic compounds.

PubMed

Archer, Trevor

2011-10-01

The range of exogenous agents likely to affect, generally detrimentally, the normal development of the brain and central nervous system defies estimation although the amount of accumulated evidence is enormous. The present review is limited to certain types of chemotherapeutic and "use-and-abuse" compounds and environmental agents, exemplified by anesthetic, antiepileptic, sleep-inducing and anxiolytic compounds, nicotine and alcohol, and stress as well as agents of infection; each of these agents have been investigated quite extensively and have been shown to contribute to the etiopathogenesis of serious neuropsychiatric disorders. To greater or lesser extent, all of the exogenous agents discussed in the present treatise have been investigated for their influence upon neurodevelopmental processes during the period of the brain growth spurt and during other phases uptill adulthood, thereby maintaining the notion of critical phases for the outcome of treatment whether prenatal, postnatal, or adolescent. Several of these agents have contributed to the developmental disruptions underlying structural and functional brain abnormalities that are observed in the symptom and biomarker profiles of the schizophrenia spectrum disorders and the fetal alcohol spectrum disorders. In each case, the effects of the exogenous agents upon the status of the affected brain, within defined parameters and conditions, is generally permanent and irreversible. © 2010 Blackwell Publishing Ltd.

Increased Sensitivity to Alcohol Induced Changes in ERK Map Kinase Phosphorylation and Memory Disruption in Adolescent as Compared to Adult C57BL/6J Mice

PubMed Central

Spanos, Marina; Besheer, Joyce; Hodge, Clyde W.

2012-01-01

Adolescence is a critical period of brain development that is accompanied by increased probability of risky behavior, such as alcohol use. Emerging research indicates that adolescents are differentially sensitive to the behavioral effects of acute ethanol as compared to adults but the neurobiological mechanisms of this effect remain to be fully elucidated. This study was designed to evaluate effects of acute ethanol on extracellular signal-regulated kinase phosphorylation (p-ERK1/2) in mesocorticolimbic brain regions. We also sought to determine if age-specific effects of ethanol on p-ERK1/2 are associated with ethanol-induced behavioral deficits on acquisition of the hippocampal-dependent novel object recognition (NOR) test. Adolescent and adult C57BL/6J mice were administered acute ethanol (0 0.5, 1, or 3 g/kg, i.p.). Brains were removed 30-min post injection and processed for analysis of p-ERK1/2 immunoreactivity (IR). Additional groups of mice were administered ethanol (0 or 1 g/kg) prior to the NOR test. Analysis of p-ERK1/2 IR showed that untreated adolescent mice had significantly higher levels of p-ERK1/2 IR in the nucleus accumbens shell, basolateral amygdala (BLA), central amygdala (CeA), and medial prefrontal cortex (mPFC) as compared to adults. Ethanol (1 g/kg) selectively reduced p-ERK1/2 IR in the dentate gyrus and increased p-ERK1/2 IR in the BLA only in adolescent mice. Ethanol (3 g/kg) produced the same effects on p-ERK1/2 IR in both age groups with increases in CeA and mPFC, but a decrease in the dentate gyrus, as compared to age-matched saline controls. Pretreatment with ethanol (1 g/kg) disrupted performance on the NOR test specifically in adolescents, which corresponds with the ethanol-induced inhibition of p-ERK1/2 IR in the hippocampus. These data show that adolescent mice have differential expression of basal p-ERK1/2 IR in mesocorticolimbic brain regions. Acute ethanol produces a unique set of changes in ERK1/2 phosphorylation in the adolescent brain that are associated with disruption of hippocampal-dependent memory acquisition. PMID:22348893

Clinical Application of High-intensity Focused Ultrasound in Cancer Therapy

PubMed Central

Hsiao, Yi-Hsuan; Kuo, Shou-Jen; Tsai, Horng-Der; Chou, Ming-Chih; Yeh, Guang-Perng

2016-01-01

The treatment of cancer is an important issue in both developing and developed countries. Clinical use of ultrasound in cancer is not only for the diagnosis but also for the treatment. Focused ultrasound surgery (FUS) is a noninvasive technique. By using the combination of high-intensity focused ultrasound (HIFU) and imaging method, FUS has the potential to ablate tumor lesions precisely. The main mechanisms of HIFU ablation involve mechanical and thermal effects. Recent advances in HIFU have increased its popularity. Some promising results were achieved in managing various malignancies, including pancreas, prostate, liver, kidney, breast and bone. Other applications include brain tumor ablation and disruption of the blood-brain barrier. We aim at briefly outlining the clinical utility of FUS as a noninvasive technique for a variety of types of cancer treatment. PMID:26918034

[Immune dysfunction and cognitive deficit in stress and physiological aging (Part I): Pathogenesis and risk factors].

PubMed

Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A

2014-01-01

The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.

Preterm birth disrupts cerebellar development by affecting granule cell proliferation program and Bergmann glia.

PubMed

Iskusnykh, Igor Y; Buddington, Randal K; Chizhikov, Victor V

2018-08-01

Preterm birth is a leading cause of long-term motor and cognitive deficits. Clinical studies suggest that some of these deficits result from disruption of cerebellar development, but the mechanisms that mediate cerebellar abnormalities in preterm infants are largely unknown. Furthermore, it remains unclear whether preterm birth and precocious exposure to the ex-utero environment directly disrupt cerebellar development or indirectly by increasing the probability of cerebellar injury, including that resulting from clinical interventions and protocols associated with the care of preterm infants. In this study, we analyzed the cerebellum of preterm pigs delivered via c-section at 91% term and raised for 10 days, until term-equivalent age. The pigs did not receive any treatments known or suspected to affect cerebellar development and had no evidence of brain damage. Term pigs sacrificed at birth were used as controls. Immunohistochemical analysis revealed that preterm birth did not affect either size or numbers of Purkinje cells or molecular layer interneurons at term-equivalent age. The number of granule cell precursors and Bergmann glial fibers, however, were reduced in preterm pigs. Preterm pigs had reduced proliferation but not differentiation of granule cells. qRT-PCR analysis of laser capture microdissected external granule cell layer showed that preterm pigs had a reduced expression of Ccnd1 (Cyclin D1), Ccnb1 (Cyclin B1), granule cell master regulatory transcription factor Atoh1, and signaling molecule Jag1. In vitro rescue experiments identified Jag1 as a central granule cell gene affected by preterm birth. Thus, preterm birth and precocious exposure to the ex-utero environment disrupt cerebellum by modulating expression of key cerebellar developmental genes, predominantly affecting development of granule precursors and Bergmann glia. Copyright © 2018 Elsevier Inc. All rights reserved.

Therapeutic approaches for HER2-positive brain metastases: Circumventing the blood–brain barrier

PubMed Central

Mehta, Ankit I.; Brufsky, Adam M.; Sampson, John H.

2015-01-01

We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood–brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2-positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting. PMID:22727691

Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions

PubMed Central

Corlett, P. R.; Murray, G. K.; Honey, G. D.; Aitken, M. R. F.; Shanks, D. R.; Robbins, T.W.; Bullmore, E.T.; Dickinson, A.; Fletcher, P. C.

2012-01-01

Delusions are maladaptive beliefs about the world. Based upon experimental evidence that prediction error—a mismatch between expectancy and outcome—drives belief formation, this study examined the possibility that delusions form because of disrupted prediction-error processing. We used fMRI to determine prediction-error-related brain responses in 12 healthy subjects and 12 individuals (7 males) with delusional beliefs. Frontal cortex responses in the patient group were suggestive of disrupted prediction-error processing. Furthermore, across subjects, the extent of disruption was significantly related to an individual’s propensity to delusion formation. Our results support a neurobiological theory of delusion formation that implicates aberrant prediction-error signalling, disrupted attentional allocation and associative learning in the formation of delusional beliefs. PMID:17690132

Repetitive Concussions in Adolescent Athletes – Translating Clinical and Experimental Research into Perspectives on Rehabilitation Strategies

PubMed Central

Semple, Bridgette D.; Lee, Sangmi; Sadjadi, Raha; Fritz, Nora; Carlson, Jaclyn; Griep, Carrie; Ho, Vanessa; Jang, Patrice; Lamb, Annick; Popolizio, Beth; Saini, Sonia; Bazarian, Jeffrey J.; Prins, Mayumi L.; Ferriero, Donna M.; Basso, D. Michele; Noble-Haeusslein, Linda J.

2015-01-01

Sports-related concussions are particularly common during adolescence, a time when even mild brain injuries may disrupt ongoing brain maturation and result in long-term complications. A recent focus on the consequences of repetitive concussions among professional athletes has prompted the development of several new experimental models in rodents, as well as the revision of guidelines for best management of sports concussions. Here, we consider the utility of rodent models to understand the functional consequences and pathobiology of concussions in the developing brain, identifying the unique behavioral and pathological signatures of concussive brain injuries. The impact of repetitive concussions on behavioral consequences and injury progression is also addressed. In particular, we focus on the epidemiological, clinical, and experimental evidence underlying current recommendations for physical and cognitive rest after concussion, and highlight key areas in which further research is needed. Lastly, we consider how best to promote recovery after injury, recognizing that optimally timed, activity-based rehabilitative strategies may hold promise for the adolescent athlete who has sustained single or repetitive concussions. The purpose of this review is to inform the clinical research community as it strives to develop and optimize evidence-based guidelines for the concussed adolescent, in terms of both acute and long-term management. PMID:25883586

Vitamins and neural and cognitive developmental outcomes in children.

PubMed

Benton, David

2012-02-01

The role of vitamin status in the development of the brain and the subsequent functioning of the brain was considered. There are data with a range of vitamins, from animal studies and human studies in developing countries, suggesting that a clinical deficiency during the critical period when the brain is developing causes permanent damage. To date there is, however, with the exception of cases of clinical deficiency such as those that might be associated with a vegan diet, little evidence that variations in the diet of those living in industrialised countries have a lasting developmental influence. Similarly, later in life clinical deficiencies of various vitamins disrupt cognition although there is to date limited evidence that variations in the intake of single vitamins in industrialised societies influence functioning. It may well be, however, unreasonable to expect that vitamins examined in isolation will be associated with differences in cognitive functioning. The output of the brain reflects millions of metabolic processes, each potentially susceptible to any of a range of vitamins. A diet poor in one respect is likely to be poor in other respects as well. As such, the preliminary reports in double-blind placebo-controlled trials that aspects of cognition and behaviour respond to supplementation with multi-micronutrients may indicate the way forward.

Default mode network as a potential biomarker of chemotherapy-related brain injury

PubMed Central

Kesler, Shelli R.

2014-01-01

Chronic medical conditions and/or their treatments may interact with aging to alter or even accelerate brain senescence. Adult onset cancer, for example, is a disease associated with advanced aging and emerging evidence suggests a profile of subtle but diffuse brain injury following cancer chemotherapy. Breast cancer is currently the primary model for studying these “chemobrain” effects. Given the widespread changes to brain structure and function as well as the common impairment of integrated cognitive skills observed following breast cancer chemotherapy, it is likely that large-scale brain networks are involved. Default mode network (DMN) is a strong candidate considering its preferential vulnerability to aging and sensitivity to toxicity and disease states. Additionally, chemotherapy is associated with several physiologic effects including increased inflammation and oxidative stress that are believed to elevate toxicity in the DMN. Biomarkers of DMN connectivity could aid in the development of treatments for chemotherapy-related cognitive decline. For example, certain nutritional interventions could potentially reduce the metabolic changes (e.g. amyloid beta toxicity) associated with DMN disruption. PMID:24913897

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on foetal guinea pig brain development.

PubMed

Kelleher, Meredith A; Palliser, Hannah K; Walker, David W; Hirst, Jonathan J

2011-03-01

Progesterone and its neuroactive metabolite, allopregnanolone, are present in high concentrations during pregnancy, but drop significantly following birth. Allopregnanolone influences foetal arousal and enhances cognitive and behavioural recovery following traumatic brain injury. Inhibition of allopregnanolone synthesis increases cell death in foetal animal brains with experimental hypoxia. We hypothesised that complications during pregnancy, such as early or preterm loss of placental steroids and intrauterine growth restriction (IUGR), would disrupt the foetal neurosteroid system, contributing to poor neurodevelopmental outcomes. This study aimed to investigate the effects of chronic inhibition of allopregnanolone synthesis before term and IUGR on developmental processes in the foetal brain. Guinea pig foetuses were experimentally growth restricted at mid-gestation and treated with finasteride, an inhibitor of allopregnanolone synthesis. Finasteride treatment reduced foetal brain allopregnanolone concentrations by up to 75% and was associated with a reduction in myelin basic protein (MBP) (P = 0.001) and an increase in glial fibrillary acidic protein expression in the subcortical white matter brain region (P < 0.001). IUGR resulted in decreased MBP expression (P < 0.01) and was associated with a reduction in the expression of steroidogenic enzyme 5α-reductase (5αR) type 2 in the foetal brain (P = 0.061). Brain levels of 5αR1 were higher in male foetuses (P = 0.008). Both IUGR and reduced foetal brain concentrations of allopregnanolone were associated with altered expression of myelination and glial cell markers within the developing foetal brain. The potential role of neurosteroids in protecting and regulating neurodevelopmental processes in the foetal brain may provide new directions for treatment of neurodevelopmental disorders in infants who are exposed to perinatal insults and pathologies.

Absence of Colony Stimulation Factor-1 Receptor Results in Loss of Microglia, Disrupted Brain Development and Olfactory Deficits

PubMed Central

Etgen, Anne M.; Dobrenis, Kostantin; Pollard, Jeffrey W.

2011-01-01

The brain contains numerous mononuclear phagocytes called microglia. These cells express the transmembrane tyrosine kinase receptor for the macrophage growth factor colony stimulating factor-1 (CSF-1R). Using a CSF-1R-GFP reporter mouse strain combined with lineage defining antibody staining we show in the postnatal mouse brain that CSF-1R is expressed only in microglia and not neurons, astrocytes or glial cells. To study CSF-1R function we used mice homozygous for a null mutation in the Csflr gene. In these mice microglia are >99% depleted at embryonic day 16 and day 1 post-partum brain. At three weeks of age this microglial depletion continues in most regions of the brain although some contain clusters of rounded microglia. Despite the loss of microglia, embryonic brain development appears normal but during the post-natal period the brain architecture becomes perturbed with enlarged ventricles and regionally compressed parenchyma, phenotypes most prominent in the olfactory bulb and cortex. In the cortex there is increased neuronal density, elevated numbers of astrocytes but reduced numbers of oligodendrocytes. Csf1r nulls rarely survive to adulthood and therefore to study the role of CSF-1R in olfaction we used the viable null mutants in the Csf1 (Csf1op) gene that encodes one of the two known CSF-1R ligands. Food-finding experiments indicate that olfactory capacity is significantly impaired in the absence of CSF-1. CSF-1R is therefore required for the development of microglia, for a fully functional olfactory system and the maintenance of normal brain structure. PMID:22046273

Sugar for the brain: the role of glucose in physiological and pathological brain function

PubMed Central

Mergenthaler, Philipp; Lindauer, Ute; Dienel, Gerald A.; Meisel, Andreas

2013-01-01

The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We aim at synthesizing these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation which lead to disease. PMID:23968694

Octylphenol and UV-B radiation alter larval development and hypothalamic gene expression in the leopard frog (Rana pipiens).

PubMed Central

Crump, Douglas; Lean, David; Trudeau, Vance L

2002-01-01

We assessed octylphenol (OP), an estrogenic endocrine-disrupting chemical, and UV-B radiation, a known stressor in amphibian development, for their effects on hypothalamic gene expression and premetamorphic development in the leopard frog Rana pipiens. Newly hatched tadpoles were exposed for 10 days to OP alone at two different dose levels; to subambient UV-B radiation alone; and to two combinations of OP and UV-B. Control animals were exposed to ethanol vehicle (0.01%) exposure, a subset of tadpoles from each treatment group was raised to metamorphosis to assess differences in body weight and time required for hindlimb emergence. Tadpoles from one of the OP/UV-B combination groups had greater body weight and earlier hindlimb emergence (p < 0.05), but neither OP nor UV-B alone produced significant changes in body weight or hindlimb emergence, indicating a potential mechanism of interaction between OP and UV-B. We hypothesized that the developing hypothalamus might be a potential environmental sensor for neurotoxicologic studies because of its role in the endocrine control of metamorphosis. We used a differential display strategy to identify candidate genes differentially expressed in the hypothalamic region of the exposed tadpoles. Homology cloning was performed to obtain R. pipiens glutamate decarboxylases--GAD65 and GAD67, enzymes involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). cDNA expression profiles revealed that OP and UV-B affected the levels of several candidate transcripts in tadpole (i.e., Nck, Ash, and phospholipase C gamma-binding protein 4 and brain angiogenesis inhibitor-3) and metamorph (i.e., GAD67, cytochrome C oxidase, and brain angiogenesis inhibitor-2 and -3) brains. This study represents a novel approach in toxicology that combines physiologic and molecular end points and indicates that levels of OP commonly found in the environment and subambient levels of UV-B alter the expression of important hypothalamic genes and disrupt tadpole growth patterns. PMID:11882479

Octylphenol and UV-B radiation alter larval development and hypothalamic gene expression in the leopard frog (Rana pipiens).

PubMed

Crump, Douglas; Lean, David; Trudeau, Vance L

2002-03-01

We assessed octylphenol (OP), an estrogenic endocrine-disrupting chemical, and UV-B radiation, a known stressor in amphibian development, for their effects on hypothalamic gene expression and premetamorphic development in the leopard frog Rana pipiens. Newly hatched tadpoles were exposed for 10 days to OP alone at two different dose levels; to subambient UV-B radiation alone; and to two combinations of OP and UV-B. Control animals were exposed to ethanol vehicle (0.01%) exposure, a subset of tadpoles from each treatment group was raised to metamorphosis to assess differences in body weight and time required for hindlimb emergence. Tadpoles from one of the OP/UV-B combination groups had greater body weight and earlier hindlimb emergence (p < 0.05), but neither OP nor UV-B alone produced significant changes in body weight or hindlimb emergence, indicating a potential mechanism of interaction between OP and UV-B. We hypothesized that the developing hypothalamus might be a potential environmental sensor for neurotoxicologic studies because of its role in the endocrine control of metamorphosis. We used a differential display strategy to identify candidate genes differentially expressed in the hypothalamic region of the exposed tadpoles. Homology cloning was performed to obtain R. pipiens glutamate decarboxylases--GAD65 and GAD67, enzymes involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). cDNA expression profiles revealed that OP and UV-B affected the levels of several candidate transcripts in tadpole (i.e., Nck, Ash, and phospholipase C gamma-binding protein 4 and brain angiogenesis inhibitor-3) and metamorph (i.e., GAD67, cytochrome C oxidase, and brain angiogenesis inhibitor-2 and -3) brains. This study represents a novel approach in toxicology that combines physiologic and molecular end points and indicates that levels of OP commonly found in the environment and subambient levels of UV-B alter the expression of important hypothalamic genes and disrupt tadpole growth patterns.

Anterior Temporal Lobe Connectivity Correlates with Functional Outcome after Aphasic Stroke

ERIC Educational Resources Information Center

Warren, Jane E.; Crinion, Jennifer T.; Ralph, Matthew A. Lambon; Wise, Richard J. S.

2009-01-01

Focal brain lesions are assumed to produce language deficits by two basic mechanisms: local cortical dysfunction at the lesion site, and remote cortical dysfunction due to disruption of the transfer and integration of information between connected brain regions. However, functional imaging studies investigating language outcome after aphasic…

Developmental Hypothyroidism Reduces the Expression of Activity-Dependent Plasticity Genes in Denate Gyrus of the Adult Following Long Term Potentiation

EPA Science Inventory

Disruption of thyroid hormone (TH) is a known effect of environmental contaminants. Neurotrophins including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been implicated in brain dysfunction resulting from severe developmental TH insufficiency. Neuro...

Training the Brain: Practical Applications of Neural Plasticity From the Intersection of Cognitive Neuroscience, Developmental Psychology, and Prevention Science

PubMed Central

Bryck, Richard L.; Fisher, Philip A.

2012-01-01

Prior researchers have shown that the brain has a remarkable ability for adapting to environmental changes. The positive effects of such neural plasticity include enhanced functioning in specific cognitive domains and shifts in cortical representation following naturally occurring cases of sensory deprivation; however, maladaptive changes in brain function and development owing to early developmental adversity and stress have also been well documented. Researchers examining enriched rearing environments in animals have revealed the potential for inducing positive brain plasticity effects and have helped to popularize methods for training the brain to reverse early brain deficits or to boost normal cognitive functioning. In this paper, two classes of empirically based methods of brain training in children are reviewed and critiqued: laboratory-based, mental process training paradigms and ecological interventions based upon neurocognitive conceptual models. Given the susceptibility of executive function disruption, special attention is paid to training programs that emphasize executive function enhancement. In addition, a third approach to brain training, aimed at tapping into compensatory processes, is postulated. Study results showing the effectiveness of this strategy in the field of neurorehabilitation and in terms of naturally occurring compensatory processing in human aging lend credence to the potential of this approach. PMID:21787037

Training the brain: practical applications of neural plasticity from the intersection of cognitive neuroscience, developmental psychology, and prevention science.

PubMed

Bryck, Richard L; Fisher, Philip A

2012-01-01

Prior researchers have shown that the brain has a remarkable ability for adapting to environmental changes. The positive effects of such neural plasticity include enhanced functioning in specific cognitive domains and shifts in cortical representation following naturally occurring cases of sensory deprivation; however, maladaptive changes in brain function and development owing to early developmental adversity and stress have also been well documented. Researchers examining enriched rearing environments in animals have revealed the potential for inducing positive brain plasticity effects and have helped to popularize methods for training the brain to reverse early brain deficits or to boost normal cognitive functioning. In this article, two classes of empirically based methods of brain training in children are reviewed and critiqued: laboratory-based, mental process training paradigms and ecological interventions based upon neurocognitive conceptual models. Given the susceptibility of executive function disruption, special attention is paid to training programs that emphasize executive function enhancement. In addition, a third approach to brain training, aimed at tapping into compensatory processes, is postulated. Study results showing the effectiveness of this strategy in the field of neurorehabilitation and in terms of naturally occurring compensatory processing in human aging lend credence to the potential of this approach. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Involvement of serotoninergic 5-HT1A/2A, alpha-adrenergic and dopaminergic D1 receptors in St. John's wort-induced prepulse inhibition deficit: a possible role of hyperforin.

PubMed

Tadros, Mariane G; Mohamed, Mohamed R; Youssef, Amal M; Sabry, Gilane M; Sabry, Nagwa A; Khalifa, Amani E

2009-05-16

Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

Assessment of Blood-brain Barrier Permeability by Intravenous Infusion of FITC-labeled Albumin in a Mouse Model of Neurodegenerative Disease.

PubMed

Di Pardo, Alba; Castaldo, Salvatore; Capocci, Luca; Amico, Enrico; Vittorio, Maglione

2017-11-08

Disruption of blood-brain barrier (BBB) integrity is a common feature for different neurological and neurodegenerative diseases. Although the interplay between perturbed BBB homeostasis and the pathogenesis of brain disorders needs further investigation, the development and validation of a reliable procedure to accurately detect BBB alterations may be crucial and represent a useful tool for potentially predicting disease progression and developing targeted therapeutic strategies. Here, we present an easy and efficient procedure for evaluating BBB leakage in a neurodegenerative condition like that occurring in a preclinical mouse model of Huntington disease, in which defects in the permeability of BBB are clearly detectable precociously in the disease. Specifically, the high molecular weight fluorescein isothiocyanate labelled (FITC)-albumin, which is able to cross the BBB only when the latter is impaired, is acutely infused into a mouse jugular vein and its distribution in the vascular or parenchymal districts is then determined by fluorescence microscopy. Accumulation of green fluorescent-albumin in the brain parenchyma functions as an index of aberrant BBB permeability and, when quantitated by using Image J processing software, is reported as Green Fluorescence Intensity.

The effects of Kiaa0319 knockdown on cortical and subcortical anatomy in male rats

PubMed Central

Szalkowski, Caitlin E.; Fiondella, Christopher F.; Truong, Dongnhu T.; Rosen, Glenn D.; LoTurco, Joseph J.; Fitch, Roslyn H.

2012-01-01

Developmental dyslexia is a disorder characterized by a specific deficit in reading despite adequate overall intelligence and educational resources. The neurological substrate underlying these significant behavioral impairments is not known. Studies of post mortem brain tissue from male and female dyslexic individuals revealed focal disruptions of neuronal migration concentrated in the left hemisphere, along with aberrant symmetry of the right and left the planum temporale, and changes in cell size distribution within the medial geniculate nucleus of the thalamus (Galaburda et al., 1985; Humphreys et al., 1990). More recent neuroimaging studies have identified several changes in the brains of dyslexic individuals, including regional changes in gray matter, changes in white matter, and changes in patterns of functional activation. In a further effort to elucidate the etiology of dyslexia, epidemiological and genetic studies have identified several candidate dyslexia susceptibility genes. Some recent work has investigated associations between some of these genetic variants and structural changes in the brain. Variants of one candidate dyslexia susceptibility gene, KIAA0319, have been linked to morphological changes in the cerebellum and functional activational changes in the superior temporal sulcus (Jamadar et al., 2011; Pinel et al., 2012). Animal models have been used to create a knockdown of Kiaa0319 (the rodent homolog of the human gene) via in utero RNA interference in order to study the gene’s effects on brain development and behavior. Studies using this animal model have demonstrated that knocking down the gene leads to focal disruptions of neuronal migration in the form of ectopias and heterotopias, similar to those observed in the brains of human dyslexics. However, further changes to the structure of the brain have not been studied following this genetic disruption. The current study sought to determine the effects of embryonic Kiaa0319 knockdown on volume of the cortex and hippocampus, as well as midsagittal area of the corpus callosum in male rats. Results demonstrate that Kiaa0319 knockdown did not change the volume of the cortex or hippocampus, but did result in a significant reduction in the midsagittal area of the corpus callosum. Taken in the context of previous reports of behavioral deficits following Kiaa0319 knockdown (Szalkowski et al., 2012), and reports that reductions of corpus callosum size are related to processing deficits in humans (Paul et al., 2011), these results suggest that Kiaa0319 has a specific involvement in neural systems important for temporal processing. PMID:23220223

Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers.

PubMed

Mitragotri, Samir

2013-01-01

Overcoming biological barriers including skin, mucosal membranes, blood brain barrier as well as cell and nuclear membrane constitutes a key hurdle in the field of drug delivery. While these barriers serve the natural protective function in the body, they limit delivery of drugs into the body. A variety of methods have been developed to overcome these barriers including formulations, targeting peptides and device-based technologies. This review focuses on the use of physical methods including acoustic devices, electric devices, high-pressure devices, microneedles and optical devices for disrupting various barriers in the body including skin and other membranes. A summary of the working principles of these devices and their ability to enhance drug delivery is presented. Copyright © 2012. Published by Elsevier B.V.

The brain's default network: origins and implications for the study of psychosis.

PubMed

Buckner, Randy L

2013-09-01

The brain's default network is a set of regions that is spontaneously active during passive moments. The network is also active during directed tasks that require participants to remember past events or imagine upcoming events. One hypothesis is that the network facilitates construction of mental models (simulations) that can be used adaptively in many contexts. Extensive research has considered whether disruption of the default network may contribute to disease. While an intriguing possibility, a specific challenge to this notion is the fact that it is difficult to accurately measure the default network in patients where confounds of head motion and compliance are prominent. Nonetheless, some intriguing recent findings suggest that dysfunctional interactions between front-oparietal control systems and the default network contribute to psychosis. Psychosis may be a network disturbance that manifests as disordered thought partly because it disrupts the fragile balance between the default network and competing brain systems.

The brain's default network: origins and implications for the study of psychosis

PubMed Central

Buckner, Randy L.

2013-01-01

The brain's default network is a set of regions that is spontaneously active during passive moments. The network is also active during directed tasks that require participants to remember past events or imagine upcoming events. One hypothesis is that the network facilitates construction of mental models (simulations) that can be used adaptively in many contexts. Extensive research has considered whether disruption of the default network may contribute to disease. While an intriguing possibility, a specific challenge to this notion is the fact that it is difficult to accurately measure the default network in patients where confounds of head motion and compliance are prominent. Nonetheless, some intriguing recent findings suggest that dysfunctional interactions between front-oparietal control systems and the default network contribute to psychosis. Psychosis may be a network disturbance that manifests as disordered thought partly because it disrupts the fragile balance between the default network and competing brain systems. PMID:24174906

Cortical Development Requires Mesodermal Expression of Tbx1, a Gene Haploinsufficient in 22q11.2 Deletion Syndrome.

PubMed

Flore, Gemma; Cioffi, Sara; Bilio, Marchesa; Illingworth, Elizabeth

2017-03-01

In mammals, proper temporal control of neurogenesis and neural migration during embryonic development ensures correct formation of the cerebral cortex. Changes in the distribution of cortical projection neurons and interneurons are associated with behavioral disorders and psychiatric diseases, including schizophrenia and autism, suggesting that disrupted cortical connectivity contributes to the brain pathology. TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS), a chromosomal deletion disorder characterized by a greatly increased risk for schizophrenia. We have previously shown that Tbx1 heterozygous mice have reduced prepulse inhibition, a behavioral abnormality that is associated with 22q11.2DS and nonsyndromic schizophrenia. Here, we show that loss of Tbx1 disrupts corticogenesis in mice by promoting premature neuronal differentiation in the medio-lateral embryonic cortex, which gives rise to the somatosensory cortex (S1). In addition, we found altered polarity in both radially migrating excitatory neurons and tangentially migrating inhibitory interneurons. Together, these abnormalities lead to altered lamination in the S1 at the terminal stages of corticogenesis in Tbx1 null mice and similar anomalies in Tbx1 heterozygous adult mice. Finally, we show that mesoderm-specific inactivation of Tbx1 is sufficient to recapitulate the brain phenotype indicating that Tbx1 exerts a cell nonautonomous role in cortical development from the mesoderm. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Disrupted topology of hippocampal connectivity is associated with short-term antidepressant response in major depressive disorder.

PubMed

Gong, Liang; Hou, Zhenghua; Wang, Zan; He, Cancan; Yin, Yingying; Yuan, Yonggui; Zhang, Haisan; Lv, Luxian; Zhang, Hongxing; Xie, Chunming; Zhang, Zhijun

2018-01-01

Graph theoretical analyses have identified disrupted functional topological organization across the brain in patients with major depressive disorder (MDD). However, the relationship between brain topology and short-term treatment responses in patients with MDD remains unknown. Sixty-eight patients with MDD and 63 cognitively normal (CN) subjects were recruited at baseline and underwent resting-state functional magnetic resonance imaging scans. Graph theory analysis was used to examine group differences in the whole-brain functional topological properties. The association between altered brain topology and the early antidepressant response was examined. Patients with MDD showed lower normalized clustering coefficients, lower small-worldness scalars and increased nodal efficiencies in the default mode network and decreased nodal efficiencies in basal ganglia and hippocampal networks. In addition, the decreased nodal efficiency in left hippocampus was negatively correlated with depressive severity at baseline and positively correlated with changes in the depressive scores after two weeks of antidepressant treatment. The patients in the present study received different medications. These findings indicated that the altered brain functional topological organization in patients with MDD is associated with the treatment response in the early phase of medication. Therefore, brain topology assessments might be considered a useful and convenient predictor of short-term antidepressant responses. Copyright © 2017 Elsevier B.V. All rights reserved.

Topological Organization of Metabolic Brain Networks in Pre-Chemotherapy Cancer with Depression: A Resting-State PET Study

PubMed Central

An, Jianping; Chen, Xuejiao; Xie, Yuanwei; Zhao, Hui; Mao, Junfeng; Liang, Wangsheng; Ma, Xiangxing

2016-01-01

This study aimed to investigate the metabolic brain network and its relationship with depression symptoms using 18F-fluorodeoxyglucose positron emission tomography data in 78 pre-chemotherapy cancer patients with depression and 80 matched healthy subjects. Functional and structural imbalance or disruption of brain networks frequently occur following chemotherapy in cancer patients. However, few studies have focused on the topological organization of the metabolic brain network in cancer with depression, especially those without chemotherapy. The nodal and global parameters of the metabolic brain network were computed for cancer patients and healthy subjects. Significant decreases in metabolism were found in the frontal and temporal gyri in cancer patients compared with healthy subjects. Negative correlations between depression and metabolism were found predominantly in the inferior frontal and cuneus regions, whereas positive correlations were observed in several regions, primarily including the insula, hippocampus, amygdala, and middle temporal gyri. Furthermore, a higher clustering efficiency, longer path length, and fewer hubs were found in cancer patients compared with healthy subjects. The topological organization of the whole-brain metabolic networks may be disrupted in cancer. Finally, the present findings may provide a new avenue for exploring the neurobiological mechanism, which plays a key role in lessening the depression effects in pre-chemotherapy cancer patients. PMID:27832148

Pediatric respiratory and systemic effects of chronic air pollution exposure: nose, lung, heart, and brain pathology.

PubMed

Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; Torres-Jardón, Ricardo; Henriquez-Roldán, Carlos; Barragán-Mejía, Gerardo; Valencia-Salazar, Gildardo; González-Maciel, Angelica; Reynoso-Robles, Rafael; Villarreal-Calderón, Rafael; Reed, William

2007-01-01

Exposures to particulate matter and gaseous air pollutants have been associated with respiratory tract inflammation, disruption of the nasal respiratory and olfactory barriers, systemic inflammation, production of mediators of inflammation capable of reaching the brain and systemic circulation of particulate matter. Mexico City (MC) residents are exposed to significant amounts of ozone, particulate matter and associated lipopolysaccharides. MC dogs exhibit brain inflammation and an acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by air pollutants. MC children, adolescents and adults have a significant upregulation of cyclooxygenase-2 (COX2) and interleukin-1beta (IL-1beta) in olfactory bulb and frontal cortex, as well as neuronal and astrocytic accumulation of the 42 amino acid form of beta -amyloid peptide (Abeta 42), including diffuse amyloid plaques in frontal cortex. The pathogenesis of Alzheimer's disease (AD) is characterized by brain inflammation and the accumulation of Abeta 42, which precede the appearance of neuritic plaques and neurofibrillary tangles, the pathological hallmarks of AD. Our findings of nasal barrier disruption, systemic inflammation, and the upregulation of COX2 and IL-1beta expression and Abeta 42 accumulation in brain suggests that sustained exposures to significant concentrations of air pollutants such as particulate matter could be a risk factor for AD and other neurodegenerative diseases.

Topological Organization of Metabolic Brain Networks in Pre-Chemotherapy Cancer with Depression: A Resting-State PET Study.

PubMed

Fang, Lei; Yao, Zhijun; An, Jianping; Chen, Xuejiao; Xie, Yuanwei; Zhao, Hui; Mao, Junfeng; Liang, Wangsheng; Ma, Xiangxing

2016-01-01

This study aimed to investigate the metabolic brain network and its relationship with depression symptoms using 18F-fluorodeoxyglucose positron emission tomography data in 78 pre-chemotherapy cancer patients with depression and 80 matched healthy subjects. Functional and structural imbalance or disruption of brain networks frequently occur following chemotherapy in cancer patients. However, few studies have focused on the topological organization of the metabolic brain network in cancer with depression, especially those without chemotherapy. The nodal and global parameters of the metabolic brain network were computed for cancer patients and healthy subjects. Significant decreases in metabolism were found in the frontal and temporal gyri in cancer patients compared with healthy subjects. Negative correlations between depression and metabolism were found predominantly in the inferior frontal and cuneus regions, whereas positive correlations were observed in several regions, primarily including the insula, hippocampus, amygdala, and middle temporal gyri. Furthermore, a higher clustering efficiency, longer path length, and fewer hubs were found in cancer patients compared with healthy subjects. The topological organization of the whole-brain metabolic networks may be disrupted in cancer. Finally, the present findings may provide a new avenue for exploring the neurobiological mechanism, which plays a key role in lessening the depression effects in pre-chemotherapy cancer patients.

Survival of adult neurons lacking cholesterol synthesis in vivo.

PubMed

Fünfschilling, Ursula; Saher, Gesine; Xiao, Le; Möbius, Wiebke; Nave, Klaus-Armin

2007-01-02

Cholesterol, an essential component of all mammalian plasma membranes, is highly enriched in the brain. Both during development and in the adult, brain cholesterol is derived from local cholesterol synthesis and not taken up from the circulation. However, the contribution of neurons and glial cells to total brain cholesterol metabolism is unknown. Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1), which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function. We conclude that at least some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surrounding. Glia are a likely source of cholesterol in the central nervous system.

Oxytocin: parallel processing in the social brain?

PubMed

Dölen, Gül

2015-06-01

Early studies attempting to disentangle the network complexity of the brain exploited the accessibility of sensory receptive fields to reveal circuits made up of synapses connected both in series and in parallel. More recently, extension of this organisational principle beyond the sensory systems has been made possible by the advent of modern molecular, viral and optogenetic approaches. Here, evidence supporting parallel processing of social behaviours mediated by oxytocin is reviewed. Understanding oxytocinergic signalling from this perspective has significant implications for the design of oxytocin-based therapeutic interventions aimed at disorders such as autism, where disrupted social function is a core clinical feature. Moreover, identification of opportunities for novel technology development will require a better appreciation of the complexity of the circuit-level organisation of the social brain. © 2015 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.

Attention-deficit hyperactivity disorder (ADHD) and tuberous sclerosis complex.

PubMed

D'Agati, Elisa; Moavero, Romina; Cerminara, Caterina; Curatolo, Paolo

2009-10-01

The neurobiological basis of attention-deficit hyperactivity disorder (ADHD) in tuberous sclerosis complex is still largely unknown. Cortical tubers may disrupt several brain networks that control different types of attention. Frontal lobe dysfunction due to seizures or epileptiform electroencephalographic discharges may perturb the development of brain systems that underpin attentional and hyperactive functions during a critical early stage of brain maturation. Comorbidity of attention-deficit hyperactivity disorder (ADHD) with mental retardation and autism spectrum disorders is frequent in children with tuberous sclerosis. Attention-deficit hyperactivity disorder (ADHD) may also reflect a direct effect of the abnormal genetic program. Treatment of children with tuberous sclerosis complex with combined symptoms of attention-deficit hyperactivity disorder (ADHD) and epilepsy may represent a challenge for clinicians, because antiepileptic therapy and drugs used to treat attention-deficit hyperactivity disorder (ADHD) may aggravate the clinical picture of each other.

BBB disruption with unfocused ultrasound alone-A paradigm shift

NASA Astrophysics Data System (ADS)

Kyle, Al

2012-10-01

One paradigm for ultrasound-enabled blood brain barrier disruption uses image guided focused ultrasound and preformed microbubble agents to enable drug delivery to the brain. We propose an alternative approach: unguided, unfocused ultrasound with no adjunctive agent. Compared with the focused approach, the proposed method affects a larger region of the brain, and is aimed at treatment of regional neurological disease including glioblastoma multiforme (GBM). Avoidance of image guidance and focusing reduces cost for equipment and staff training. Avoidance of adjunctive agents also lowers cost and is enabled by a longer exposure time. Since 2004, our group has worked with two animal models, three investigators in four laboratories to safely deliver five compounds, increasing the concentration of large molecule markers in brain tissue two fold or more. Safety and effectiveness data for four studies have been presented at the Ultrasound Industry Association meetings in 2007 and 2010. This paper describes new safety and effectiveness results for a fifth study. We present evidence of delivery of large molecules - including Avastin-to the brains of a large animal model correlated with acoustic pressure, and summarize the advantages and disadvantages of this novel approach.

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

PubMed Central

Kundakovic, Marija; Jaric, Ivana

2017-01-01

Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. PMID:28335457

Blood-Brain Barrier Disruption After Cardiopulmonary Bypass: Diagnosis and Correlation to Cognition.

PubMed

Abrahamov, Dan; Levran, Oren; Naparstek, Sharon; Refaeli, Yael; Kaptson, Shani; Abu Salah, Mahmud; Ishai, Yaron; Sahar, Gideon

2017-07-01

Cardiopulmonary bypass (CPB) elicits a systemic inflammatory response that may impair blood-brain barrier (BBB) integrity. BBB disruption can currently be detected by dynamic contrast enhancement magnetic resonance imaging (MRI), reflected by an increase in the permeability constant (K trans ). We aimed to determine (1) whether CPB induces BBB disruption, (2) duration until BBB disruption resolution, and (3) the obtainable correlation between BBB injury (location and intensity) and neurocognitive dysfunction. Seven patients undergoing CPB with coronary artery bypass grafting (CABG) were assigned to serial cerebral designated MRI evaluations, preoperatively and on postoperative day (POD) 1 and 5. Examinations were analyzed for BBB disruption and microemboli using dynamic contrast enhancement MRI and diffusion-weighted imaging methods, respectively. Neuropsychologic tests were performed 1 day preoperatively and on POD 5. A significant local K trans increase (0.03 min -1 vs 0.07 min -1 , p = 0.033) compatible with BBB disruption was evident in 5 patients (71%) on POD 1. Resolution was observed by POD 5 (mean, 0.012 min -1 ). The location of the disruption was most prominent in the frontal lobes (400% vs 150% K trans levels upsurge, p = 0.05). MRI evidence of microembolization was demonstrated in only 1 patient (14%). The postoperative global cognitive score was reduced in all patients (98.2 ± 12 vs 95.1 ± 11, p = 0.032), predominantly in executive and attention (frontal lobe-related) functions (91.8 ± 13 vs 86.9 ± 12, p = 0.042). The intensity of the dynamic contrast enhancement MRI BBB impairment correlated with the magnitude of cognition reduction (r = 0.69, p = 0.04). BBB disruption was evident in most patients, primarily in the frontal lobes. The location and intensity of the BBB disruption, rather than the microembolic load, correlated with postoperative neurocognitive dysfunction. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Hypothalamic inflammation and gliosis in obesity

PubMed Central

Dorfman, Mauricio D.; Thaler, Joshua P.

2015-01-01

Structured Abstract Purpose of review Hypothalamic inflammation and gliosis are recently discovered mechanisms that may contribute to obesity pathogenesis. Current research in this area suggests that investigation of these CNS responses may provide opportunities to develop new weight loss treatments. Recent findings In rodents, hypothalamic inflammation and gliosis occur rapidly with high-fat diet consumption prior to significant weight gain. In addition, sensitivity or resistance to diet-induced obesity in rodents generally correlates with the presence or absence of hypothalamic inflammation and reactive gliosis (brain response to injury). Moreover, functional interventions that increase or decrease inflammation in neurons and glia correspondingly alter diet-associated weight gain. However, some conflicting data have recently emerged that question the contribution of hypothalamic inflammation to obesity pathogenesis. However, several studies have detected gliosis and disrupted connectivity in obese humans, highlighting the potential translational importance of this mechanism. Summary There is growing evidence that obesity is associated with brain inflammation in humans, particularly in the hypothalamus where its presence may disrupt body weight control and glucose homeostasis. More work is needed to determine whether this response is common in human obesity and to what extent it can be manipulated for therapeutic benefit. PMID:26192704

Chronic peripheral inflammation, hippocampal neurogenesis, and behavior.

PubMed

Chesnokova, Vera; Pechnick, Robert N; Wawrowsky, Kolja

2016-11-01

Adult hippocampal neurogenesis is involved in memory and learning, and disrupted neurogenesis is implicated in cognitive impairment and mood disorders, including anxiety and depression. Some long-term peripheral illnesses and metabolic disorders, as well as normal aging, create a state of chronic peripheral inflammation. These conditions are associated with behavioral disturbances linked to disrupted adult hippocampal neurogenesis, such as cognitive impairment, deficits in learning and memory, and depression and anxiety. Pro-inflammatory cytokines released in the periphery are involved in peripheral immune system-to-brain communication by activating resident microglia in the brain. Activated microglia reduce neurogenesis by suppressing neuronal stem cell proliferation, increasing apoptosis of neuronal progenitor cells, and decreasing survival of newly developing neurons and their integration into existing neuronal circuits. In this review, we summarize evolving evidence that the state of chronic peripheral inflammation reduces adult hippocampal neurogenesis, which, in turn, produces the behavioral disturbances observed in chronic inflammatory disorders. As there are no data available on neurogenesis in humans with chronic peripheral inflammatory disease, we focus on animal models and, in parallel, consider the evidence of cognitive disturbance and mood disorders in human patients. Copyright © 2016 Elsevier Inc. All rights reserved.

PCB disruption of the hypothalamus-pituitary-interrenal axis involves brain glucocorticoid receptor downregulation in anadromous Arctic charr

USGS Publications Warehouse

Aluru, N.; Jorgensen, E.H.; Maule, A.G.; Vijayan, M.M.

2004-01-01

We examined whether brain glucocorticoid receptor (GR) modulation by polychlorinated biphenyls (PCBs) was involved in the abnormal cortisol response to stress seen in anadromous Arctic charr (Salvelinus alpinus). Fish treated with Aroclor 1254 (0, 1, 10, and 100 mg/kg body mass) were maintained for 5 mo without feeding in the winter to mimic their seasonal fasting cycle, whereas a fed group with 0 and 100 mg/kg Aroclor was maintained for comparison. Fasting elevated plasma cortisol levels and brain GR content but depressed heat shock protein 90 (hsp90) and interrenal cortisol production capacity. Exposure of fasted fish to Aroclor 1254 resulted in a dose-dependent increase in brain total PCB content. This accumulation in fish with high PCB dose was threefold higher in fasted fish compared with fed fish. PCBs depressed plasma cortisol levels but did not affect in vitro interrenal cortisol production capacity in fasted charr. At high PCB dose, the brain GR content was significantly lower in the fasted fish and this corresponded with a lower brain hsp70 and hsp90 content. The elevation of plasma cortisol levels and upregulation of brain GR content may be an important adaptation to extended fasting in anadromous Arctic charr, and this response was disrupted by PCBs. Taken together, the hypothalamus-pituitary- interrenal axis is a target for PCB impact during winter emaciation in anadromous Arctic charr.

Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder.

PubMed

Shaw, Philip; Lalonde, Francois; Lepage, Claude; Rabin, Cara; Eckstrand, Kristen; Sharp, Wendy; Greenstein, Deanna; Evans, Alan; Giedd, J N; Rapoport, Judith

2009-08-01

Just as typical development of anatomical asymmetries in the human brain has been linked with normal lateralization of motor and cognitive functions, disruption of asymmetry has been implicated in the pathogenesis of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). No study has examined the development of cortical asymmetry using longitudinal neuroanatomical data. To delineate the development of cortical asymmetry in children with and without ADHD. Longitudinal study. Government Clinical Research Institute. A total of 218 children with ADHD and 358 typically developing children, from whom 1133 neuroanatomical magnetic resonance images were acquired prospectively. Cortical thickness was estimated at 40 962 homologous points in the left and right hemispheres, and the trajectory of change in asymmetry was defined using mixed-model regression. In right-handed typically developing individuals, a mean (SE) increase in the relative thickness of the right orbitofrontal and inferior frontal cortex with age of 0.011 (0.0018) mm per year (t(337) = 6.2, P < .001) was balanced against a relative left-hemispheric increase in the occipital cortical regions of 0.013 (0.0015) mm per year (t(337) = 8.1, P < .001). Age-related change in asymmetry in non-right-handed typically developing individuals was less extensive and was localized to different cortical regions. In ADHD, the posterior component of this evolving asymmetry was intact, but the prefrontal component was lost. These findings explain the way that, in typical development, the increased dimensions of the right frontal and left occipital cortical regions emerge in adulthood from the reversed pattern of childhood cortical asymmetries. Loss of the prefrontal component of this evolving asymmetry in ADHD is compatible with disruption of prefrontal function in the disorder and demonstrates the way that disruption of typical processes of asymmetry can inform our understanding of neurodevelopmental disorders.

InVivo Imaging of Myelination for Drug Discovery and Development in Multiple Sclerosis

DTIC Science & Technology

2012-10-01

oligodendrocyte precursor cells, which are subsequently activated and distributed to the damaged axons. However, the remyelination process is often disrupted in...emitting carbon -11, and used for PET imaging of myelination (Wu et al., 2008; Wu et al., 2010). We demonstrated that [11C]MeDAS can readily penetrate...conducted. The animals were killed by a transcardial perfusion of saline followed by 4% polyformaldhyde ( PFA ) under anesthesia. The spinal cord and brain

[Components of plastic disrupt the function of the nervous system].

PubMed

Szychowski, Konrad Andrzej; Wójtowicz, Anna Katarzyna

2013-05-27

Development of the chemical industry leads to the development of new chemical compounds, which naturally do not exist in the environment. These chemicals are used to reduce flammability, increase plasticity, or improve solubility of other substances. Many of these compounds, which are components of plastic, the new generation of cosmetics, medical devices, food packaging and other everyday products, are easily released into the environment. Many studies have shown that a major lipophilicity characterizes substances such as phthalates, BPA, TBBPA and PCBs. This feature allows them to easily penetrate into living cells, accumulate in the tissues and the organs, and affect human and animal health. Due to the chemical structures, these compounds are able to mimic some endogenous hormones such as estradiol and to disrupt the hormone homeostasis. They can also easily pass the placental barrier and the blood-brain barrier. As numerous studies have shown, these chemicals disturb the proper functions of the nervous system from the earliest moments of life. It has been proven that these compounds affect neurogenesis as well as the synaptic transmission process. As a consequence, they interfere with the formation of the sex of the brain, as well as with the learning processes, memory and behavior. Additionally, the cytotoxic and pro-apoptotic effect may cause neurodegenerative diseases. This article presents the current state of knowledge about the effects of phthalates, BPA, TBBPA, and PCBs on the nervous system.

Selectively altering belief formation in the human brain

PubMed Central

Sharot, Tali; Kanai, Ryota; Marston, David; Korn, Christoph W.; Rees, Geraint; Dolan, Raymond J.

2012-01-01

Humans form beliefs asymmetrically; we tend to discount bad news but embrace good news. This reduced impact of unfavorable information on belief updating may have important societal implications, including the generation of financial market bubbles, ill preparedness in the face of natural disasters, and overly aggressive medical decisions. Here, we selectively improved people’s tendency to incorporate bad news into their beliefs by disrupting the function of the left (but not right) inferior frontal gyrus using transcranial magnetic stimulation, thereby eliminating the engrained “good news/bad news effect.” Our results provide an instance of how selective disruption of regional human brain function paradoxically enhances the ability to incorporate unfavorable information into beliefs of vulnerability. PMID:23011798

Delayed Maturation in Brain Electrical Activity Partially Explains the Association Between Early Environmental Deprivation and Symptoms of Attention-Deficit/Hyperactivity Disorder

PubMed Central

McLaughlin, Katie A.; Fox, Nathan A.; Zeanah, Charles H.; Sheridan, Margaret A.; Marshall, Peter; Nelson, Charles A.

2010-01-01

Background Children raised in institutional settings are exposed to social and environmental circumstances that may deprive them of expected environmental inputs during sensitive periods of brain development that are necessary to foster healthy development. This deprivation is thought to underlie the abnormalities in neurodevelopment that have been found in previously institutionalized children. It is unknown whether deviations in neurodevelopment explain the high rates of developmental problems evident in previously institutionalized children, including psychiatric disorders. Methods We present data from a sample of children raised in institutions in Bucharest, Romania (n = 117) and an age- and sex-matched sample of community control subjects (n = 49). Electroencephalogram data were acquired following entry into the study at age 6 to 30 months, and a structured diagnostic interview of psychiatric disorders was completed at age 54 months. Results Children reared in institutions evidenced greater symptoms of attention-deficit/hyperactivity disorder, anxiety, depression, and disruptive behavior disorders than community controls. Electroencephalogram revealed significant reductions in alpha relative power and increases in theta relative power among children reared in institutions in frontal, temporal, and occipital regions, suggesting a delay in cortical maturation. This pattern of brain activity predicted symptoms of hyperactivity and impulsivity at age 54 months, and significantly mediated the association between institutionalization and attention-deficit/hyperactivity disorder symptoms. Electroencephalogram power was unrelated to depression, anxiety, or disruptive behaviors. Conclusions These findings document a potential neurodevelopmental mechanism underlying the association between institutionalization and psychiatric morbidity. Deprivation in social and environmental conditions may perturb early patterns of neurodevelopment and manifest as psychiatric problems later in life. PMID:20497899

Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders.

PubMed

Sakurai, Takeshi; Ramoz, Nicolas; Barreto, Marta; Gazdoiu, Mihaela; Takahashi, Nagahide; Gertner, Michael; Dorr, Nathan; Gama Sosa, Miguel A; De Gasperi, Rita; Perez, Gissel; Schmeidler, James; Mitropoulou, Vivian; Le, H Carl; Lupu, Mihaela; Hof, Patrick R; Elder, Gregory A; Buxbaum, Joseph D

2010-05-01

SLC25A12, a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate production. We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies. Slc25a12-knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In postnatal day 13 to 14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cell-autonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/N-acetylaspartate and/or alterations in the dihydronicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide(+) ratio, resulting in myelin defects. Our data implicate AGC1 activity in myelination and in neuronal structure and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development, contributing to increased autism susceptibility. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Atypical sulcal anatomy in young children with autism spectrum disorder

PubMed Central

Auzias, G.; Viellard, M.; Takerkart, S.; Villeneuve, N.; Poinso, F.; Fonséca, D. Da; Girard, N.; Deruelle, C.

2014-01-01

Autism spectrum disorder is associated with an altered early brain development. However, the specific cortical structure abnormalities underlying this disorder remain largely unknown. Nonetheless, atypical cortical folding provides lingering evidence of early disruptions in neurodevelopmental processes and identifying changes in the geometry of cortical sulci is of primary interest for characterizing these structural abnormalities in autism and their evolution over the first stages of brain development. Here, we applied state-of-the-art sulcus-based morphometry methods to a large highly-selective cohort of 73 young male children of age spanning from 18 to 108 months. Moreover, such large cohort was selected through extensive behavioral assessments and stringent inclusion criteria for the group of 59 children with autism. After manual labeling of 59 different sulci in each hemisphere, we computed multiple shape descriptors for each single sulcus element, hereby separating the folding measurement into distinct factors such as the length and depth of the sulcus. We demonstrated that the central, intraparietal and frontal medial sulci showed a significant and consistent pattern of abnormalities across our different geometrical indices. We also found that autistic and control children exhibited strikingly different relationships between age and structural changes in brain morphology. Lastly, the different measures of sulcus shapes were correlated with the CARS and ADOS scores that are specific to the autistic pathology and indices of symptom severity. Inherently, these structural abnormalities are confined to regions that are functionally relevant with respect to cognitive disorders in ASD. In contrast to those previously reported in adults, it is very unlikely that these abnormalities originate from general compensatory mechanisms unrelated to the primary pathology. Rather, they most probably reflect an early disruption on developmental trajectory that could be part of the primary pathology. PMID:24936410

Investigating the Neural Correlates of Emotion–Cognition Interaction Using an Affective Stroop Task

PubMed Central

Raschle, Nora M.; Fehlbaum, Lynn V.; Menks, Willeke M.; Euler, Felix; Sterzer, Philipp; Stadler, Christina

2017-01-01

The human brain has the capacity to integrate various sources of information and continuously adapts our behavior according to situational needs in order to allow a healthy functioning. Emotion–cognition interactions are a key example for such integrative processing. However, the neuronal correlates investigating the effects of emotion on cognition remain to be explored and replication studies are needed. Previous neuroimaging studies have indicated an involvement of emotion and cognition related brain structures including parietal and prefrontal cortices and limbic brain regions. Here, we employed whole brain event-related functional magnetic resonance imaging (fMRI) during an affective number Stroop task and aimed at replicating previous findings using an adaptation of an existing task design in 30 healthy young adults. The Stroop task is an indicator of cognitive control and enables the quantification of interference in relation to variations in cognitive load. By the use of emotional primes (negative/neutral) prior to Stroop task performance, an emotional variation is added as well. Behavioral in-scanner data showed that negative primes delayed and disrupted cognitive processing. Trials with high cognitive demand furthermore negatively influenced cognitive control mechanisms. Neuronally, the emotional primes consistently activated emotion-related brain regions (e.g., amygdala, insula, and prefrontal brain regions) while Stroop task performance lead to activations in cognition networks of the brain (prefrontal cortices, superior temporal lobe, and insula). When assessing the effect of emotion on cognition, increased cognitive demand led to decreases in neural activation in response to emotional stimuli (negative > neutral) within prefrontal cortex, amygdala, and insular cortex. Overall, these results suggest that emotional primes significantly impact cognitive performance and increasing cognitive demand leads to reduced neuronal activation in emotion related brain regions, and therefore support previous findings investigating emotion–cognition interaction in healthy adults. Moreover, emotion and cognition seem to be tightly related to each other, as indicated by shared neural networks involved in both of these processes. Emotion processing, cognitive control, and their interaction are crucial for healthy functioning and a lack thereof is related to psychiatric disorders such as, disruptive behavior disorders. Future studies may investigate the neural characteristics of children and adolescents with disruptive behavior disorders. PMID:28919871

The Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis.

PubMed

Ball, Lonnele J; Palesh, Oxana; Kriegsfeld, Lance J

2016-10-01

Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health.

The Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis

PubMed Central

Ball, Lonnele J.; Palesh, Oxana

2016-01-01

Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health. PMID:27712099

Short-term exposure to dim light at night disrupts rhythmic behaviors and causes neurodegeneration in fly models of tauopathy and Alzheimer's disease.

PubMed

Kim, Mari; Subramanian, Manivannan; Cho, Yun-Ho; Kim, Gye-Hyeong; Lee, Eunil; Park, Joong-Jean

2018-01-08

The accumulation and aggregation of phosphorylated tau proteins in the brain are the hallmarks for the onset of Alzheimer's disease (AD). In addition, disruptions in circadian rhythms (CRs) with altered sleep-wake cycles, dysregulation of locomotion, and increased memory defects have been reported in patients with AD. Drosophila flies that have an overexpression of human tau protein in neurons exhibit most of the symptoms of human patients with AD, including locomotion defects and neurodegeneration. Using the fly model for tauopathy/AD, we investigated the effects of an exposure to dim light at night on AD symptoms. We used a light intensity of 10 lux, which is considered the lower limit of light pollution in many countries. After the tauopathy flies were exposed to the dim light at night for 3 days, the flies showed disrupted CRs, altered sleep-wake cycles due to increased pTau proteins and neurodegeneration, in the brains of the AD flies. The results indicate that the nighttime exposure of tauopathy/AD model Drosophila flies to dim light disrupted CR and sleep-wake behavior and promoted neurodegeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

Tetramethylpyrazine-2'-O-sodium ferulate attenuates blood-brain barrier disruption and brain oedema after cerebral ischemia/reperfusion.

PubMed

Xu, S-H; Yin, M-S; Liu, B; Chen, M-L; He, G-W; Zhou, P-P; Cui, Y-J; Yang, D; Wu, Y-L

2017-07-01

Disruption of blood-brain barrier (BBB) and subsequent oedema are major causes of the pathogenesis in ischaemic stroke with which the current clinical therapy remains unsatisfied. In this study, we examined the therapeutic effect of tetramethylpyrazine-2'-O-sodium ferulate (TSF)-a novel analogue of tetramethylpyrazine in alleviating BBB breakdown and brain oedema after cerebral ischaemia/reperfusion (I/R). Then, we explored the potential mechanism of the protection on BBB disruption in cerebral I/R rat models. Male Sprague-Dawley rats (250-300 g) were subjected to 120 min middle cerebral artery occlusion (MCAO), followed by 48 h reperfusion. TSF (10.8, 18 and 30 mg kg -1 ) and ozagrel (18 mg kg -1 ) were administrated by intravenous injection immediately for the first time and then received the same dose every 24 h for 2 days. We found that TSF treatment significantly attenuated the cerebral water content, infarction volume and improved neurological outcomes in MCAO rats compared to I/R models. Moreover, we investigated the effect of TSF on the BBB for that cerebral oedema is closely related to the permeability of the BBB. We found that the permeability of BBB was improved significantly in TSF groups compared to I/R model group by Evans blue leakage testing. Furthermore, the expressions of tight junction (TJ) proteins junction adhesion molecule-1 and occludin significantly decreased, but the protein expression of matrix metalloproteinase-9 (MMP-9) and aquaporin 4 (AQP4) increased after cerebral I/R, all of which were alleviated by TSF treatment. In conclusion, TSF significantly reduced BBB permeability and brain oedema, which were correlated with regulating the expression of TJ proteins, MMP-9 and AQP4. These findings provide a novel approach to the treatment of ischaemic stroke.

Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke.

PubMed

Alfieri, Alessio; Srivastava, Salil; Siow, Richard C M; Cash, Diana; Modo, Michel; Duchen, Michael R; Fraser, Paul A; Williams, Steven C R; Mann, Giovanni E

2013-12-01

Disruption of the blood-brain barrier (BBB) and cerebral edema are the major pathogenic mechanisms leading to neurological dysfunction and death after ischemic stroke. The brain protects itself against infarction via activation of endogenous antioxidant defense mechanisms, and we here report the first evidence that sulforaphane-mediated preactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) in the cerebral vasculature protects the brain against stroke. To induce ischemic stroke, Sprague-Dawley rats were subjected to 70 min middle cerebral artery occlusion (MCAo) followed by 4, 24, or 72 h reperfusion. Nrf2 and HO-1 protein expression was upregulated in cerebral microvessels of peri-infarct regions after 4-72 h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In naïve rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1h) was associated with increased HO-1 expression in perivascular astrocytes in peri-infarct regions and cerebral endothelium in the infarct core. BBB disruption, lesion progression, as analyzed by MRI, and neurological deficits were reduced by sulforaphane pretreatment. As sulforaphane pretreatment led to a moderate increase in peroxynitrite generation, we suggest that hormetic preconditioning underlies sulforaphane-mediated protection against stroke. In conclusion, we propose that pharmacological or dietary interventions aimed to precondition the brain via activation of the Nrf2 defense pathway in the cerebral microvasculature provide a novel therapeutic approach for preventing BBB breakdown and neurological dysfunction in stroke. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Disrupted Brain Functional Network Architecture in Chronic Tinnitus Patients

PubMed Central

Chen, Yu-Chen; Feng, Yuan; Xu, Jin-Jing; Mao, Cun-Nan; Xia, Wenqing; Ren, Jun; Yin, Xindao

2016-01-01

Purpose: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated the disruptions of multiple brain networks in tinnitus patients. Nonetheless, several studies found no differences in network processing between tinnitus patients and healthy controls (HCs). Its neural bases are poorly understood. To identify aberrant brain network architecture involved in chronic tinnitus, we compared the resting-state fMRI (rs-fMRI) patterns of tinnitus patients and HCs. Materials and Methods: Chronic tinnitus patients (n = 24) with normal hearing thresholds and age-, sex-, education- and hearing threshold-matched HCs (n = 22) participated in the current study and underwent the rs-fMRI scanning. We used degree centrality (DC) to investigate functional connectivity (FC) strength of the whole-brain network and Granger causality to analyze effective connectivity in order to explore directional aspects involved in tinnitus. Results: Compared to HCs, we found significantly increased network centrality in bilateral superior frontal gyrus (SFG). Unidirectionally, the left SFG revealed increased effective connectivity to the left middle orbitofrontal cortex (OFC), left posterior lobe of cerebellum (PLC), left postcentral gyrus, and right middle occipital gyrus (MOG) while the right SFG exhibited enhanced effective connectivity to the right supplementary motor area (SMA). In addition, the effective connectivity from the bilateral SFG to the OFC and SMA showed positive correlations with tinnitus distress. Conclusions: Rs-fMRI provides a new and novel method for identifying aberrant brain network architecture. Chronic tinnitus patients have disrupted FC strength and causal connectivity mostly in non-auditory regions, especially the prefrontal cortex (PFC). The current findings will provide a new perspective for understanding the neuropathophysiological mechanisms in chronic tinnitus. PMID:27458377

Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease.

PubMed

Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Szalai, Gabor; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

2014-10-01

There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood-brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein-dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood-brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

VEGI attenuates the inflammatory injury and disruption of blood-brain barrier partly by suppressing the TLR4/NF-κB signaling pathway in experimental traumatic brain injury.

PubMed

Gao, Weiwei; Zhao, Zilong; Yu, Gongjie; Zhou, Ziwei; Zhou, Yuan; Hu, Tingting; Jiang, Rongcai; Zhang, Jianning

2015-10-05

Acute traumatic brain injury (TBI) tends to cause the over-activation of inflammatory response and disruption of blood brain barrier (BBB), associating with long-term cognitive and behavioral dysfunction. Vascular endothelial growth inhibitor (VEGI), as a suppressor in the angiogenesis specifically by inducing apoptosis in proliferating endothelial cells, has been applied to different diseases, especially the tumors. But rare study had been done in the field of brain injury. So in this study, we investigated the effects and mechanisms associated with VEGI-induced neuroprotection following CNS injury in mice TBI models. We demonstrated that the VEGI treatment reduced the contusion brain tissue loss, the permeation of inflammatory cells (MPO(+)) and the activation of microglia (Iba-1(+)). The treatment up-regulated the tight junction proteins (CLN5, ZO-1 and OCLN), which are vital importance for the integrity of the blood brain barrier (BBB), the B-cell lymphoma 2 (Bcl-2) cell survival factors, while down-regulated the expression of TLR4, NF-κB and inflammatory cytokines (IL-1β, TNF-α, iNOS). The treatment also decreased the expression of reactive astrocytes (GFAP(+)), as well as the VEGF, and lowered the permeability of Evens Blue (EB). These findings suggested that the VEGI-treatment could alleviate the post-traumatic excessive inflammatory response, and maintain the stability of blood vessels, remitting the secondary brain damage. Copyright © 2015. Published by Elsevier B.V.

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

PubMed Central

Tagge, Chad A; Fisher, Andrew M; Minaeva, Olga V; Gaudreau-Balderrama, Amanda; Moncaster, Juliet A; Zhang, Xiao-Lei; Wojnarowicz, Mark W; Casey, Noel; Lu, Haiyan; Kokiko-Cochran, Olga N; Saman, Sudad; Ericsson, Maria; Onos, Kristen D; Veksler, Ronel; Senatorov, Vladimir V; Kondo, Asami; Zhou, Xiao Z; Miry, Omid; Vose, Linnea R; Gopaul, Katisha R; Upreti, Chirag; Nowinski, Christopher J; Cantu, Robert C; Alvarez, Victor E; Hildebrandt, Audrey M; Franz, Erich S; Konrad, Janusz; Hamilton, James A; Hua, Ning; Tripodis, Yorghos; Anderson, Andrew T; Howell, Gareth R; Kaufer, Daniela; Hall, Garth F; Lu, Kun P; Ransohoff, Richard M; Cleveland, Robin O; Kowall, Neil W; Stein, Thor D; Lamb, Bruce T; Huber, Bertrand R; Moss, William C; Friedman, Alon; Stanton, Patric K; McKee, Ann C; Goldstein, Lee E

2018-01-01

Abstract 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. PMID:29360998

Neural Reward Processing Mediates the Relationship between Insomnia Symptoms and Depression in Adolescence.

PubMed

Casement, Melynda D; Keenan, Kate E; Hipwell, Alison E; Guyer, Amanda E; Forbes, Erika E

2016-02-01

Emerging evidence suggests that insomnia may disrupt reward-related brain function-a potentially important factor in the development of depressive disorder. Adolescence may be a period during which such disruption is especially problematic given the rise in the incidence of insomnia and ongoing development of neural systems that support reward processing. The present study uses longitudinal data to test the hypothesis that disruption of neural reward processing is a mechanism by which insomnia symptoms-including nocturnal insomnia symptoms (NIS) and nonrestorative sleep (NRS)-contribute to depressive symptoms in adolescent girls. Participants were 123 adolescent girls and their caregivers from an ongoing longitudinal study of precursors to depression across adolescent development. NIS and NRS were assessed annually from ages 9 to 13 years. Girls completed a monetary reward task during a functional MRI scan at age 16 years. Depressive symptoms were assessed at ages 16 and 17 years. Multivariable regression tested the prospective associations between NIS and NRS, neural response during reward anticipation, and the mean number of depressive symptoms (omitting sleep problems). NRS, but not NIS, during early adolescence was positively associated with late adolescent dorsal medial prefrontal cortex (dmPFC) response to reward anticipation and depressive symptoms. DMPFC response mediated the relationship between early adolescent NRS and late adolescent depressive symptoms. These results suggest that NRS may contribute to depression by disrupting reward processing via altered activity in a region of prefrontal cortex involved in affective control. The results also support the mechanistic differentiation of NIS and NRS. © 2016 Associated Professional Sleep Societies, LLC.

Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease.

PubMed

Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi; Lohr, Kelly M; Hoffman, Carlie A; Bernstein, Alison I; Li, Yingjie; Wang, Minzheng; Sgobio, Carmelo; Sastry, Namratha; Cai, Huaibin; Caudle, W Michael; Miller, Gary W

2017-03-14

Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.

Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dickerson, Sarah M.; Cunningham, Stephanie L.; Gore, Andrea C., E-mail: andrea.gore@mail.utexas.edu

Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; ormore » estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor {alpha} (ER{alpha}) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ER{alpha}, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA{sub B} receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGF{alpha}. Collectively, these results suggest that the disrupted sexual differentiation of the POA by prenatal EDC exposures is already evident as early as the day after birth, effects that may change the trajectory of postnatal development and compromise adult reproductive function.« less