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Sample records for phosphodiesterase-4 promotes brain

  1. Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

    PubMed Central

    Titus, David J.; Wilson, Nicole M.; Freund, Julie E.; Carballosa, Melissa M.; Sikah, Kevin E.; Furones, Concepcion; Dietrich, W. Dalton; Gurney, Mark E.

    2016-01-01

    Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI. SIGNIFICANCE STATEMENT Currently, there are an estimated 3.2–5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of

  2. Etazolate, a phosphodiesterase 4 inhibitor reverses chronic unpredictable mild stress-induced depression-like behavior and brain oxidative damage.

    PubMed

    Jindal, Ankur; Mahesh, Radhakrishnan; Bhatt, Shvetank

    2013-04-01

    Etazolate, a pyrazolopyridine class compound is selective inhibitor of type 4 phosphodiesterase (PDE4). Previous study in our laboratory has demonstrated that etazolate produced antidepressant-like effect in rodent models of behavioral despair. The present study was designed to investigate whether etazolate could affect the chronic unpredictable mild stress (CUMS)-induced depression in mice. The effect of etazolate on CUMS-induced depression was examined by measuring behavioral parameters and oxidant/antioxidant status of brain tissue. Mice were subjected to different stress paradigms daily for a period of 28days to induce depressive-like behavior. The results showed that CUMS caused depression-like behavior in mice, as indicated by significant (p<0.05) decrease in sucrose consumption and increase in duration of immobility. Moreover, CUMS also significantly (p<0.05) increased the oxidative stress markers and decreased the antioxidant enzymes activity. Chronic administration of etazolate (0.5 and 1mg/kg., p.o.) and fluoxetine (20mg/kg., p.o.) significantly (p<0.05) inhibited the CUMS-induced behavioral (decreased sucrose consumption and increased duration of immobility) and biochemical (increased lipid peroxidation and nitrite level; decreased glutathione, superoxide dismutase and catalase activity) changes. No alteration was observed in locomotor activity. Additionally, in the present study, the efficacy of etazolate (1mg/kg., p.o.) on the behavioral and biochemical paradigms was found comparable to that of fluoxetine, used as standard antidepressant. In conclusion, the results of the present study suggested that etazolate alleviated the CUMS-induced depression in mice, which is at least in part mediated by modulating oxidative-nitrosative stress status in mice brain.

  3. The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis.

    PubMed

    Kraft, Peter; Schwarz, Tobias; Göb, Eva; Heydenreich, Nadine; Brede, Marc; Meuth, Sven G; Kleinschnitz, Christoph

    2013-09-01

    Blood-brain-barrier (BBB) disruption, inflammation and thrombosis are important steps in the pathophysiology of acute ischemic stroke but are still inaccessible to therapeutic interventions. Rolipram specifically inhibits the enzyme phosphodiesterase (PDE) 4 thereby preventing the inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Rolipram has been shown to relief inflammation and BBB damage in a variety of neurological disorders. We investigated the therapeutic potential of rolipram in a model of brain ischemia/reperfusion injury in mice. Treatment with 10mg/kg rolipram, but not 2 mg/kg rolipram, 2 h after 60 min of transient middle cerebral artery occlusion (tMCAO) reduced infarct volumes by 50% and significantly improved clinical scores on day 1 compared with vehicle-treated controls. Rolipram maintained BBB function upon stroke as indicated by preserved expression of the tight junction proteins occludin and claudin-5. Accordingly, the formation of vascular brain edema was strongly attenuated in mice receiving rolipram. Moreover, rolipram reduced the invasion of neutrophils as well as the expression of the proinflammatory cytokines IL-1β and TNFα but increased the levels of TGFβ-1. Finally, rolipram exerted antithrombotic effects upon stroke and fewer neurons in the rolipram group underwent apoptosis. Rolipram is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.

  4. Selective Phosphodiesterase 4B Inhibitors: A Review

    PubMed Central

    Azam, Mohammed Afzal; Tripuraneni, Naga Srinivas

    2014-01-01

    Abstract Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B. PMID:25853062

  5. Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

    PubMed

    Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

    2015-09-15

    Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors.

  6. Practical enantioselective process for a chiral phosphodiesterase-4 inhibitor.

    PubMed

    Chen, Cheng-Yi

    2005-11-01

    L-869298 is a potent and selective phosphodiesterase-4 (PDE4) inhibitor, which is potentially useful in the treatment of asthma and chronic obstructive pulmonary disorder. A catalytic asymmetric synthesis that is suitable for the preparation of kilogram quantities of L-869298, and which does not require the use of chromatography, has been developed to support the on-going drug development program of L-869298 at Merck Research Laboratories. The catalytic asymmetric hydrogenation of an aromatic heteroaromatic ketone afforded the corresponding alcohol in almost perfect enantioselectivity. Activation of the alcohol via formation of the 4-toluenesulfonate, followed by an unprecedented displacement of the tosylate via the lithium enolate of ethyl-3-pyridyl acetate N-oxide, generated the chiral tetra-substituted ethane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Deprotection of the displacement adduct followed by decarboxylation, afforded L-869298 in excellent overall yield. The methodology developed could be readily extended to the synthesis of several other chiral PDE4 inhibitors.

  7. Phosphodiesterase 4D gene polymorphisms in sudden sensorineural hearing loss.

    PubMed

    Chien, Chen-Yu; Tai, Shu-Yu; Wang, Ling-Feng; Hsi, Edward; Chang, Ning-Chia; Wang, Hsun-Mo; Wu, Ming-Tsang; Ho, Kuen-Yao

    2016-09-01

    The phosphodiesterase 4D (PDE4D) gene has been reported as a risk gene for ischemic stroke. The vascular factors are between the hypothesized etiologies of sudden sensorineural hearing loss (SSNHL), and this genetic effect might be attributed for its role in SSNHL. We hypothesized that genetic variants of the PDE4D gene are associated with susceptibility to SSNHL. We conducted a case-control study with 362 SSNHL cases and 209 controls. Three single nucleotide polymorphisms (SNPs) were selected. The genotypes were determined using TaqMan technology. Hardy-Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated according to three inheritance modes. We carried out sex-specific analysis to analyze the overall data. All three SNPs were in HWE. When subjects were stratified by sex, the genetic effect was only evident in females but not in males. The TT genotype of rs702553 exhibited an adjusted odds ratio (OR) of 3.83 (95 % confidence interval = 1.46-11.18) (p = 0.006) in female SSNHL. The TT genotype of SNP rs702553 was associated with female SSNHL under the recessive model (p = 0.004, OR 3.70). In multivariate logistic regression analysis, TT genotype of rs702553 was significantly associated with female SSNHL (p = 0.0043, OR 3.70). These results suggest that PDE4D gene polymorphisms influence the susceptibility for the development of SSNHL in the southern Taiwanese female population.

  8. Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease.

    PubMed

    Tanaka, Motomasa; Ishizuka, Koko; Nekooki-Machida, Yoko; Endo, Ryo; Takashima, Noriko; Sasaki, Hideyuki; Komi, Yusuke; Gathercole, Amy; Huston, Elaine; Ishii, Kazuhiro; Hui, Kelvin Kai-Wan; Kurosawa, Masaru; Kim, Sun-Hong; Nukina, Nobuyuki; Takimoto, Eiki; Houslay, Miles D; Sawa, Akira

    2017-04-03

    Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general.

  9. Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

    PubMed Central

    Zhang, Han-Ting; Huang, Ying; Masood, Anbrin; Stolinski, Lisa R; Li, Yunfeng; Zhang, Lei; Dlaboga, Daniel; Jin, S-L Catherine; Conti, Marco; O’Donnell, James M

    2009-01-01

    Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B−/−). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B−/− mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B−/− mice. Compared to PDE4B + / + littermates, PDE4B−/− mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light–dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4B−/− mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B−/− mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B−/− mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior PMID:17700644

  10. Selaginpulvilins A-D, new phosphodiesterase-4 inhibitors with an unprecedented skeleton from Selaginella pulvinata.

    PubMed

    Liu, Xin; Luo, Hai-Bin; Huang, Yi-You; Bao, Jing-Mei; Tang, Gui-Hua; Chen, Yun-Yun; Wang, Jun; Yin, Sheng

    2014-01-03

    Selaginpulvilins A-D (1-4), four new phenols with an unprecedented 9,9-diphenyl-1-(phenylethynyl)-9H-fluorene skeleton, together with four known selaginellins (5-8) were isolated from Selaginella pulvinata. Their structures were elucidated by spectroscopic analysis and chemical correlation. The structure of 1 was confirmed by single-crystal X-ray diffraction. Compounds 1-8 exhibited remarkable inhibitory activities (IC50 values in the range of 0.11-5.13 μM) against phosphodiesterase-4 (PDE4), a drug target for the treatment of asthma and chronic obstructive pulmonary disease.

  11. Inhibition of Phosphodiesterase-4 during Pneumococcal Pneumonia Reduces Inflammation and Lung Injury in Mice.

    PubMed

    Tavares, Luciana P; Garcia, Cristiana C; Vago, Juliana P; Queiroz-Junior, Celso M; Galvão, Izabela; David, Bruna A; Rachid, Milene A; Silva, Patrícia M R; Russo, Remo C; Teixeira, Mauro M; Sousa, Lirlândia P

    2016-07-01

    Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, treated with ROL in a prophylactic or therapeutic schedule in combination, or not, with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed, and ex vivo phagocytosis assays were performed. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases.

  12. The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling

    PubMed Central

    Wang, Gang; Chen, Ling; Pan, Xiaoyu; Chen, Jiechun; Wang, Liqun; Wang, Weijie; Cheng, Ruochuan; Wu, Fan; Feng, Xiaoqing; Yu, Yingcong; Zhang, Han-Ting; O'Donnell, James M.; Xu, Ying

    2016-01-01

    Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling. PMID:26980711

  13. Structural Basis for the Design of Selective Phosphodiesterase 4B Inhibitors

    PubMed Central

    Fox, David; Burgin, Alex B.; Gurney, Mark E.

    2014-01-01

    Phosphodiesterase-4B (PDE4B) regulates the pro-inflammatory Toll Receptor –Tumor Necrosis Factor α (TNFα) pathway in monocytes, macrophages and microglial cells. As such, it is an important, although under-exploited molecular target for anti-inflammatory drugs. This is due in part to the difficulty of developing selective PDE4B inhibitors as the amino acid sequence of the PDE4 active site is identical in all PDE4 subtypes (PDE4A-D). We show that highly selective PDE4B inhibitors can be designed by exploiting sequence differences outside the active site. Specifically, PDE4B selectivity can be achieved by capture of a C-terminal regulatory helix, now termed CR3 (Control Region 3), across the active site in a conformation that closes access by cAMP. PDE4B selectivity is driven by a single amino acid polymorphism in CR3 (Leu674 in PDE4B1 versus Gln594 in PDE4D). The reciprocal mutations in PDE4B and PDE4D cause a 70-80 fold shift in selectivity. Our structural studies show that CR3 is flexible and can adopt multiple orientations and multiple registries in the closed conformation. The new co-crystal structure with bound ligand provides a guide map for the design of PDE4B selective anti-inflammatory drugs. PMID:24361374

  14. Pharmacologic Inhibition of Host Phosphodiesterase-4 Improves Isoniazid-Mediated Clearance of Mycobacterium tuberculosis.

    PubMed

    Subbian, Selvakumar; Koo, Mi-Sun; Tsenova, Liana; Khetani, Vikram; Zeldis, Jerome B; Fallows, Dorothy; Kaplan, Gilla

    2016-01-01

    The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment.

  15. Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.

    PubMed

    Wang, Huanchen; Peng, Ming-Sheng; Chen, Yi; Geng, Jie; Robinson, Howard; Houslay, Miles D; Cai, Jiwen; Ke, Hengming

    2007-12-01

    PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as potential therapeutics for the treatment of both depression and major inflammatory diseases, but their practical application has been compromised by side effects. A possible cause for the side effects is that current PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4 subfamilies. The development of PDE4 subfamily-selective inhibitors has been hampered by a lack of structural information. In the present study, we rectify this by providing the crystal structures of the catalytic domains of PDE4A, PDE4B and PDE4D in complex with the PDE4 inhibitor NVP {4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid} as well as the unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. However, detailed structural comparison reveals significant conformational differences. Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows significant displacements of the residues next to the invariant glutamine residue that is critical for substrate and inhibitor binding. PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors.

  16. Pharmacologic Inhibition of Host Phosphodiesterase-4 Improves Isoniazid-Mediated Clearance of Mycobacterium tuberculosis

    PubMed Central

    Subbian, Selvakumar; Koo, Mi-Sun; Tsenova, Liana; Khetani, Vikram; Zeldis, Jerome B.; Fallows, Dorothy; Kaplan, Gilla

    2016-01-01

    The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment. PMID:27379099

  17. Structures of the Four Subfamilies of Phosphodiesterase-4 Provide Insight into the Selectivity of Their Inhibitors

    SciTech Connect

    Wang, H.; Peng, M; Chen , Y; Geng, J; Robinson, H; Houslay , M; Cai, J; Ke, H

    2007-01-01

    PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as potential therapeutics for the treatment of both depression and major inflammatory diseases, but their practical application has been compromised by side effects. A possible cause for the side effects is that current PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4 subfamilies. The development of PDE4 subfamily-selective inhibitors has been hampered by a lack of structural information. In the present study, we rectify this by providing the crystal structures of the catalytic domains of PDE4A, PDE4B and PDE4D in complex with the PDE4 inhibitor NVP 4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid as well as the unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. However, detailed structural comparison reveals significant conformational differences. Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows significant displacements of the residues next to the invariant glutamine residue that is critical for substrate and inhibitor binding. PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors.

  18. Phosphodiesterase 4D and 5-Lipoxygenase Activating Protein in Ischemic Stroke

    PubMed Central

    Meschia, James F.; Brott, Thomas G.; Brown, Robert D.; Crook, Richard; Worrall, Bradford B.; Kissela, Brett; Brown, W. Mark; Rich, Stephen S.; Case, L. Douglas; Evans, E. Whitney; Hague, Stephen; Singleton, Andrew; Hardy, John

    2006-01-01

    Risk for ischemic stroke is mediated by both environmental and genetic factors. Although several environmental exposures have been implicated, relatively little is known about the genetic basis of predisposition to this disease. Recent studies in Iceland identified risk polymorphisms in two putative candidate genes for ischemic stroke: phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP). A collection of North American sibling pairs concordant for ischemic stroke and two cohorts of prospectively ascertained North American ischemic stroke cases and control subjects were used for evaluation of PDE4D and ALOX5AP. Although no evidence supported linkage of ischemic stroke with either of the two candidate genes, single-nucleotide polymorphisms and haplotypic associations were observed between PDE4D and ischemic stroke. There was no evidence of association between variants of ALOX5AP and ischemic stroke. These data suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations. PMID:16130105

  19. Phosphodiesterase 4D polymorphisms associate with the short-term outcome in ischemic stroke

    PubMed Central

    Song, Yan-li; Wang, Chun-juan; Wu, Yi-ping; Lin, Jie; Wang, Peng-lian; Du, Wan-liang; Liu, Li; Lin, Jin-xi; Wang, Yi-long; Wang, Yong-jun; Liu, Gai-fen

    2017-01-01

    It has been demonstrated that phosphodiesterase 4D (PDE4D) genetic polymorphism is associated with ischemic stroke. However, the association between PDE4D gene and prognosis after ischemic stroke remains unknown. We consecutively enrolled ischemic stroke patients admitted to Beijing Tiantan Hospital from October 2009 to December 2013. Clinical, laboratory and imaging data upon admission were collected. All patients were followed up 3 months after stroke onset. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the associations of genetic polymorphisms with 3-month outcome after ischemic stroke and different subtypes, under various genetic models. A total of 1447 patients were enrolled, and 3-month follow-up data were obtained from 1388 (95.92%). Multivariate regression analysis showed that SNP87 of PDE4D gene was associated with increased risk of unfavorable outcome after total ischemic stroke (OR = 1.47, 95%CI 1.12–1.93), as well as stroke due to large-artery atherosclerosis (OR = 1.49, 95%CI 1.04–2.11) and small-artery occlusion (OR = 1.76, 95%CI 1.05–2.96) under a recessive model. No association between SNP83 genotype and poor outcome was found. Overall, this study demonstrated that the TT genotype of SNP87 in PDE4D was associated with increased risk of poor outcome after total ischemic stroke, large-artery atherosclerosis and small-artery occlusion, in a Chinese population. PMID:28225001

  20. Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

    PubMed Central

    Subbian, Selvakumar; Tsenova, Liana; Holloway, Jennifer; Peixoto, Blas; O'Brien, Paul; Dartois, Véronique; Khetani, Vikram; Zeldis, Jerome B.; Kaplan, Gilla

    2016-01-01

    Objectives Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. Methods A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. Results Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. Conclusions Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment. PMID:26981575

  1. ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion.

    PubMed

    Song, Roy S; Massenburg, Ben; Wenderski, Wendy; Jayaraman, Vino; Thompson, Lauren; Neves, Susana R

    2013-09-17

    AMPA-type glutamate receptor (AMPAR) trafficking is essential for modulating synaptic transmission strength. Prior studies that have characterized signaling pathways underlying AMPAR trafficking have identified the cAMP/PKA-mediated phosphorylation of GluA1, an AMPAR subunit, as a key step in the membrane insertion of AMPAR. Inhibition of ERK impairs AMPAR membrane insertion, but the mechanism by which ERK exerts its effect is unknown. Dopamine, an activator of both PKA and ERK, induces AMPAR insertion, but the relationship between the two protein kinases in the process is not understood. We used a combination of computational modeling and live cell imaging to determine the relationship between ERK and PKA in AMPAR insertion. We developed a dynamical model to study the effects of phosphodiesterase 4 (PDE4), a cAMP phosphodiesterase that is phosphorylated and inhibited by ERK, on the membrane insertion of AMPAR. The model predicted that PKA could be a downstream effector of ERK in regulating AMPAR insertion. We experimentally tested the model predictions and found that dopamine-induced ERK phosphorylates and inhibits PDE4. This regulation results in increased cAMP levels and PKA-mediated phosphorylation of DARPP-32 and GluA1, leading to increased GluA1 trafficking to the membrane. These findings provide unique insight into an unanticipated network topology in which ERK uses PDE4 to regulate PKA output during dopamine signaling. The combination of dynamical models and experiments has helped us unravel the complex interactions between two protein kinase pathways in regulating a fundamental molecular process underlying synaptic plasticity.

  2. Overexpression of phosphodiesterase-4 subtypes involved in surgery-induced neuroinflammation and cognitive dysfunction in mice.

    PubMed

    Wang, Wei; Zhang, Xiao-Ying; Feng, Ze-Guo; Wang, Dong-Xin; Zhang, Hao; Sui, Bo; Zhang, Yong-Yi; Zhao, Wei-Xing; Fu, Qiang; Xu, Zhi-Peng; Mi, Wei-Dong

    2017-02-21

    Postoperative cognitive dysfunction (POCD) is characterized by cognitive impairments in patients after surgery. Hippocampal neuroinflammation induced by surgery is highly associated with POCD. Phosphodiesterase-4 (PDE4) is an enzyme that specifically hydrolyses cyclic adenosine monophosphate (cAMP), which plays an important role during neuroinflammation and the process of learning and memory. However, the role of PDE4 in the development of POCD remains unclear. Male 14-month-old C57BL/6 mice received carotid artery exposure to mimic POCD. First, we evaluated cognitive performance by a Morris water maze (MWM) and fear conditioning system (FCS) test after surgery. The expression of PDE4 subtypes, pro-inflammatory cytokines, p-CREB and PSD95 as well as cAMP levels were investigated. Then, we used rolipram, a PDE4 inhibitor, to block the effects of PDE4. The cognitive performance of the mice and the expression of PDE4 subtypes, pro-inflammatory cytokines, p-CREB and PSD95 as well as cAMP levels were examined again. Mice displayed learning and memory impairment, overexpression of PDE4B and PDE4D, elevation of pro-inflammatory cytokines, and reduction in the expression of p-CREB, PSD95 and cAMP levels after surgery. The expression of PDE4B and PDE4D in the hippocampus decreased following blocking of PDE4 by rolipram. Meanwhile, rolipram attenuated the cognitive impairment and the elevation of pro-inflammatory cytokines induced by surgery. Moreover, rolipram reversed the reduction of p-CREB and PSD95. These results indicate that PDE4 subtype overexpression may be involved in the development of surgery-induced cognitive dysfunction in mice.

  3. Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor

    SciTech Connect

    Dagues, Nicolas . E-mail: nicolas.dagues@pfizer.com; Pawlowski, Valerie; Guigon, Ghislaine; Ledieu, David; Sobry, Cecile; Hanton, Gilles; Freslon, Jean-Louis; Chevalier, Stephan

    2007-01-01

    Vascular injury is a relatively common finding during the pre-clinical toxicity testing of drugs. The mechanisms of the injury are poorly understood and in turn, sensitive and specific biomarkers for pre-clinical and clinical monitoring do not exist. The present study was undertaken to investigate the molecular mechanisms of drug-induced vascular injury in mesenteric tissue of rats treated with the selective phosphodiesterase 4 (PDE4) inhibitor CI-1044. In a time-course study, male Sprague Dawley rats were given daily doses of 40 or 80 mg/kg for 1, 2 or 3 successive days and were euthanized the following day. Gene expression profiles in mesenteric tissue were determined using Affymetrix RG{sub U}34A microarrays and fibrinogen and cytokine measurements were performed in blood samples. Hierarchical clustering analysis produced a clear pattern separation of the animals with inflammation, animal with inflammation and necrosis and animals without any lesion. Genes associated with inflammation, procoagulation, extracellular matrix remodeling were up-regulated. An altered expression of genes involved in vascular tone regulation, lipid and glucose metabolism was also observed. Selected genes expression changes were confirmed by TaqMan real-time RT-PCR. The inflammatory process was also detected in the bloodstream at the protein level since fibrinogen, IL6 and IL1{beta} concentrations were increased in treated animals. Overall, the present study reveals several molecular changes supporting the hypothesis by which PDE4 inhibitor-induced vascular lesions in rats are triggered by an inflammatory mechanism and/or a vascular tone dysregulation.

  4. Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade.

    PubMed

    Fernández-Martínez, Eduardo; Ponce-Monter, Héctor; Soria-Jasso, Luis E; Ortiz, Mario I; Arias-Montaño, José-Antonio; Barragán-Ramírez, Guillermo; Mayén-García, Cynthia

    2016-10-07

    Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K⁺-induced tonic, and Ca(2+)-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca(2+)-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.

  5. Inactivation of oncogenic cAMP-specific phosphodiesterase 4D by miR-139-5p in response to p53 activation

    PubMed Central

    Cao, Bo; Wang, Kebing; Liao, Jun-Ming; Zhou, Xiang; Liao, Peng; Zeng, Shelya X; He, Meifang; Chen, Lianzhou; He, Yulong; Li, Wen; Lu, Hua

    2016-01-01

    Increasing evidence highlights the important roles of microRNAs in mediating p53’s tumor suppression functions. Here, we report miR-139-5p as another new p53 microRNA target. p53 induced the transcription of miR-139-5p, which in turn suppressed the protein levels of phosphodiesterase 4D (PDE4D), an oncogenic protein involved in multiple tumor promoting processes. Knockdown of p53 reversed these effects. Also, overexpression of miR-139-5p decreased PDE4D levels and increased cellular cAMP levels, leading to BIM-mediated cell growth arrest. Furthermore, our analysis of human colorectal tumor specimens revealed significant inverse correlation between the expression of miR-139-5p and that of PDE4D. Finally, overexpression of miR-139-5p suppressed the growth of xenograft tumors, accompanied by decrease in PDE4D and increase in BIM. These results demonstrate that p53 inactivates oncogenic PDE4D by inducing the expression of miR-139-5p. DOI: http://dx.doi.org/10.7554/eLife.15978.001 PMID:27383270

  6. Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice

    PubMed Central

    Wang, Zhen-Zhen; Yang, Wei-Xing; Zhang, Yi; Zhao, Nan; Zhang, You-Zhi; Liu, Yan-Qin; Xu, Ying; Wilson, Steven P.; O'Donnell, James M.; Zhang, Han-Ting; Li, Yun-Feng

    2015-01-01

    Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices. PMID:26161529

  7. PET measurements of cAMP-mediated phosphodiesterase-4 with (R)-[11C]rolipram.

    PubMed

    Kenk, Miran; Thomas, Adam; Lortie, Mireille; Dekemp, Rob; Beanlands, Rob S; Dasilva, Jean N

    2011-01-01

    Cyclic adenosine monophosphate (cAMP) is the common second messenger in signal-transduction cascades originating at a number of monoamine receptors involved in neurotransmission, cardiac function and smooth muscle contraction. Altered regulation of cAMP synthesis (at receptors, G-protein subunits or adenylyl cyclase) and breakdown by phosphodiesterase (PDE) enzymes have been implicated in a number of pathologies. The PDE4 inhibitor (R)-rolipram, and the less active (S)- enantiomer, have been labeled with carbon-11 and characterized by in vivo and in vitro experiments for use in the evaluation of altered PDE4 levels in the brain and cardiac tissues. (R)-[11C]Rolipram has been shown to bind selectively to PDE4 over other PDE isozymes, with specific binding reflecting approximately 80 and 40% of the total detected radioactivity in the rat brain and the heart, respectively. Tracer retention in PDE4-rich tissues is increased by cAMP-elevating treatments, as detected by in vivo PET studies and ex vivo biodistribution experiments. In vivo PET imaging studies display strong region-specific signal in the brain and heart, as evaluated in rats, pigs, monkeys and humans. Impaired cAMP-mediated signaling was observed in animal models of aging, obesity, anthracycline-induced cardiotoxicity and myocardial infarction using (R)-[11C]rolipram. Given the critical role of cAMP in multiple hormonal pathways, the good safety profile and well-characterized pharmacokinetics, (R)-[11C]rolipram PET imaging provides a novel tool for serial monitoring of cAMP-mediated signaling at the PDE4 level, yielding insight into pathological progression with potential for directing therapy.

  8. AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B

    PubMed Central

    Johanns, M.; Lai, Y.-C.; Hsu, M.-F.; Jacobs, R.; Vertommen, D.; Van Sande, J.; Dumont, J. E.; Woods, A.; Carling, D.; Hue, L.; Viollet, B.; Foretz, M; Rider, M H

    2016-01-01

    Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the Vmax of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation. PMID:26952277

  9. Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes.

    PubMed

    Jimenez, José L; Iñiguez, Miguel A; Muñoz-Fernández, M Angeles; Fresno, Manuel

    2004-12-01

    Transcriptional induction of cyclooxygenase-2 (COX-2) occurs early after T cell receptor triggering and has functional implications in inflammation. Here, we show that phosphodiesterase (PDE)-4 inhibitors block COX-2 induction and prostaglandin synthesis in activated T cells. COX-2 inhibition by PDE4 inhibitors occurs mainly at the transcriptional level. Two response elements for the nuclear factor of activated T cells (NFAT) in the COX-2 promoter were required for inhibition by these drugs. PDE4 inhibitors did not affect NFAT nuclear translocation upon T cell activation; rather they prevented NFAT binding to DNA and induction of the transactivation function of GAL4-NFAT. These effects seem to be cAMP/PKA independent as they were not mimicked by the permeable analog dBcAMP or by forskolin, neither can be reverted by the PKA inhibitors H89 or KT-5720. These results may explain some of the anti-inflammatory properties of PDE4 inhibitors through the blockade of NFAT-mediated transactivation of pro-inflammatory genes such as COX-2.

  10. Phosphodiesterase 4B negatively regulates endotoxin-activated interleukin-1 receptor antagonist responses in macrophages

    PubMed Central

    Yang, Jing-Xing; Hsieh, Kou-Chou; Chen, Yi-Ling; Lee, Chien-Kuo; Conti, Marco; Chuang, Tsung-Hsien; Wu, Chin-Pyng; Jin, S.-L. Catherine

    2017-01-01

    Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability. Studies with PDE4-deficient macrophages revealed that the IL-1Ra upregulation elicited by LPS alone is PKA-independent, whereas the rolipram-enhanced response was mediated by inhibition of only PDE4B, one of the three PDE4 isoforms expressed in macrophages, and it requires PKA but not Epac activity. However, both pathways activate CREB to induce IL-1Ra expression. PDE4B ablation also promoted STAT3 phosphorylation (Tyr705) to LPS stimulation, but this STAT3 activation is not entirely responsible for the IL-1Ra upregulation in PDE4B-deficient macrophages. In a model of LPS-induced sepsis, only PDE4B-deficient mice displayed an increased circulating IL-1Ra, suggesting a protective role of PDE4B inactivation in vivo. These findings demonstrate that PDE4B negatively modulates anti-inflammatory cytokine expression in innate immune cells, and selectively targeting PDE4B should retain the therapeutic benefits of nonselective PDE4 inhibitors. PMID:28383060

  11. Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin-2 release from murine splenocytes by interacting with a ‘low-affinity' phosphodiesterase 4 conformer

    PubMed Central

    Souness, John E; Houghton, Clare; Sardar, Nughat; Withnall, Michael T

    1997-01-01

    We have investigated the suppressive effects of rolipram, RP 73401 (piclamilast) and other structurally diverse inhibitors of cyclic AMP-specific phosphodiesterase 4 (PDE4) on interleukin (IL)-2 generation from Balb/c mouse splenocytes exposed to the superantigen, Staphylococcocal enterotoxin-A (Staph. A). The purpose was to determine whether their potencies are more closely correlated with inhibition of PDE4 from CTLL cells, against which rolipram displays weak potency (low-affinity PDE4), or displacement of [3H]-(±)-rolipram from its high-affinity binding site (HARBS) in mouse brain cytosol. RP 73401 (IC50 0.46±0.07 nM, n=4) was a very potent inhibitor of Staph. A-induced IL-2 release from Balb/c mouse splenocytes, being >1100 fold more potent than (±)-rolipram (IC50 540±67 nM, n=3). A close correlation (r=0.95) was observed between suppression of IL-2 release by PDE inhibitors and inhibition of PDE4. In contrast, little correlation (r=0.39) was observed between suppression of IL-2 release and their affinities for the high-affinity rolipram binding site (HARBS). RP 73401 only inhibited partially (30–40%) Staph. A-induced incorporation of [3H]-thymidine into splenocyte DNA. The PDE3 inhibitor, siguazodan (10 μM), had little or no effect on IL-2 release or DNA synthesis. This concentration of siguazodan did not enhance the inhibitory action of RP 73401 on IL-2 release but potentiated its effect on DNA synthesis, increasing potency and efficacy. Staph. A-induced DNA synthesis was only partially inhibited by anti-IL-2 neutralizing antibody, whereas dexamethazone (100 nM) and cyclosporine A (100 nM) completely blocked the response. RP 73401 (IC50 6.3±1.9 nM, n=4) was 140 fold more potent than rolipram (IC50 900±300 nM, n=3) in inhibiting Staph. A-induced [3H]-thymidine incorporation into splenocyte DNA. The results implicate a low-affinity form of PDE4 in the suppression of Staph. A-induced IL-2 release from murine splenocytes by PDE inhibitors

  12. Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

    PubMed Central

    Subbian, Selvakumar; Tsenova, Liana; O'Brien, Paul; Yang, Guibin; Koo, Mi-Sun; Peixoto, Blas; Fallows, Dorothy; Dartois, Veronique; Muller, George; Kaplan, Gilla

    2011-01-01

    Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment. PMID:21949656

  13. The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats.

    PubMed

    Lai, Miaojun; Zhu, Huaqiang; Sun, Anna; Zhuang, Dingding; Fu, Dan; Chen, Weisheng; Zhang, Han-Ting; Zhou, Wenhua

    2014-09-01

    Inhibition of phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes cyclic adenosine monophosphate (cAMP) increases intracellular cAMP/cAMP-response element binding protein (CREB) signaling. Activation of this signaling is considered as an important compensatory response that decreases motivational properties of drugs of abuse. However, it is not known whether PDE4 is involved in heroin seeking. Self-administration of heroin (50 μg/kg/infusion) was performed under the fixed ratio 1 (FR1) schedule for 14 d and then drug seeking was extinguished for 10 d. The progressive ratio schedule was used to evaluate the relative motivational value of heroin reinforcement. After training, the conditioned cue or heroin priming (250 μg/kg) was introduced for the reinstatement of heroin-seeking behavior. Pretreatment (i.p.) with rolipram (0.03-0.3 mg/kg), a prototypical, selective PDE4 inhibitor, failed to inhibit heroin self-administration under the FR1 schedule, but decreased the reward values under the progressive ratio schedule in a dose-dependent manner. In addition, rolipram decreased the reinstatement of heroin seeking induced by cues or heroin priming even at the lowest dose (0.03 mg/kg); in contrast, the highest dose (0.3 mg/kg) of rolipram was required to decrease sucrose reinforcement. Finally, the effects of rolipram on heroin-seeking behavior were correlated with the increases in expression of phosphorylated CREB in the nucleus accumbens. The study demonstrated that rolipram inhibited heroin reward and heroin-seeking behavior. The results suggest that PDE4 plays an essential role in mediating heroin seeking and that PDE4 inhibitors may be used as a potential pharmacotherapeutic approach for heroin addiction.

  14. Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol.

    PubMed

    Ohnuki, Yoshiki; Umeki, Daisuke; Mototani, Yasumasa; Shiozawa, Kouichi; Nariyama, Megumi; Ito, Aiko; Kawamura, Naoya; Yagisawa, Yuka; Jin, Huiling; Cai, Wenqian; Suita, Kenji; Saeki, Yasutake; Fujita, Takayuki; Ishikawa, Yoshihiro; Okumura, Satoshi

    2016-05-01

    Clenbuterol (CB), a selective β2-adrenergic receptor (AR) agonist, induces muscle hypertrophy and counteracts muscle atrophy. However, it is paradoxically less effective in slow-twitch muscle than in fast-twitch muscle, though slow-twitch muscle has a greater density of β-AR We recently demonstrated that Epac1 (exchange protein activated by cyclic AMP [cAMP]1) plays a pivotal role in β2-AR-mediated masseter muscle hypertrophy through activation of the Akt and calmodulin kinase II (CaMKII)/histone deacetylase 4 (HDAC4) signaling pathways. Here, we investigated the role of Epac1 in the differential hypertrophic effect of CB using tibialis anterior muscle (TA; typical fast-twitch muscle) and soleus muscle (SOL; typical slow-twitch muscle) of wild-type (WT) and Epac1-null mice (Epac1KO). The TA mass to tibial length (TL) ratio was similar in WT and Epac1KO at baseline and was significantly increased after CB infusion in WT, but not in Epac1KO The SOL mass to TL ratio was also similar in WT and Epac1KO at baseline, but CB-induced hypertrophy was suppressed in both mice. In order to understand the mechanism involved, we measured the protein expression levels of β-AR signaling-related molecules, and found that phosphodiesterase 4 (PDE4) expression was 12-fold greater in SOL than in TA These results are consistent with the idea that increased PDE4-mediated cAMP hydrolysis occurs in SOL compared to TA, resulting in a reduced cAMP concentration that is insufficient to activate Epac1 and its downstream Akt and CaMKII/HDAC4 hypertrophic signaling pathways in SOL of WT This scenario can account for the differential effects of CB on fast- and slow-twitch muscles.

  15. Promoting brain remodeling to aid in stroke recovery

    PubMed Central

    Zhang, Zheng Gang; Chopp, Michael

    2015-01-01

    Endogenous brain repair after stroke involves a set of highly interactive processes, such as angiogenesis, neurogenesis, oligodendrogenesis, synaptogenesis and axonal outgrowth, which together orchestrate neurological recovery. During the past several years, there have been advances in our understanding of miRNAs and histone deacetylases (HDACs) in brain repair processes after stroke. Emerging data indicate the important role of exosomes for intercellular communication in promoting coupled brain remodeling processes. These advances will likely have a major impact on development of restorative therapies for ischemic brain repair, consequently leading to improvement of neurological function. In this review, we provide an update on our current understanding of cellular and molecular mechanisms of miRNAs, exosomes, and HDACs in brain restorative processes after stroke. PMID:26278490

  16. Emotions promote social interaction by synchronizing brain activity across individuals

    PubMed Central

    Nummenmaa, Lauri; Glerean, Enrico; Viinikainen, Mikko; Jääskeläinen, Iiro P.; Hari, Riitta; Sams, Mikko

    2012-01-01

    Sharing others’ emotional states may facilitate understanding their intentions and actions. Here we show that networks of brain areas “tick together” in participants who are viewing similar emotional events in a movie. Participants’ brain activity was measured with functional MRI while they watched movies depicting unpleasant, neutral, and pleasant emotions. After scanning, participants watched the movies again and continuously rated their experience of pleasantness–unpleasantness (i.e., valence) and of arousal–calmness. Pearson’s correlation coefficient was used to derive multisubject voxelwise similarity measures [intersubject correlations (ISCs)] of functional MRI data. Valence and arousal time series were used to predict the moment-to-moment ISCs computed using a 17-s moving average. During movie viewing, participants' brain activity was synchronized in lower- and higher-order sensory areas and in corticolimbic emotion circuits. Negative valence was associated with increased ISC in the emotion-processing network (thalamus, ventral striatum, insula) and in the default-mode network (precuneus, temporoparietal junction, medial prefrontal cortex, posterior superior temporal sulcus). High arousal was associated with increased ISC in the somatosensory cortices and visual and dorsal attention networks comprising the visual cortex, bilateral intraparietal sulci, and frontal eye fields. Seed-voxel–based correlation analysis confirmed that these sets of regions constitute dissociable, functional networks. We propose that negative valence synchronizes individuals’ brain areas supporting emotional sensations and understanding of another’s actions, whereas high arousal directs individuals’ attention to similar features of the environment. By enhancing the synchrony of brain activity across individuals, emotions may promote social interaction and facilitate interpersonal understanding. PMID:22623534

  17. Sleep after spatial learning promotes covert reorganization of brain activity.

    PubMed

    Orban, Pierre; Rauchs, Géraldine; Balteau, Evelyne; Degueldre, Christian; Luxen, André; Maquet, Pierre; Peigneux, Philippe

    2006-05-02

    Sleep promotes the integration of recently acquired spatial memories into cerebral networks for the long term. In this study, we examined how sleep deprivation hinders this consolidation process. Using functional MRI, we mapped regional cerebral activity during place-finding navigation in a virtual town, immediately after learning and 3 days later, in subjects either allowed regular sleep (RS) or totally sleep-deprived (TSD) on the first posttraining night. At immediate and delayed retrieval, place-finding navigation elicited increased brain activity in an extended hippocampo-neocortical network in both RS and TSD subjects. Behavioral performance was equivalent between groups. However, striatal navigation-related activity increased more at delayed retrieval in RS than in TSD subjects. Furthermore, correlations between striatal response and behavioral performance, as well as functional connectivity between the striatum and the hippocampus, were modulated by posttraining sleep. These data suggest that brain activity is restructured during sleep in such a way that navigation in the virtual environment, initially related to a hippocampus-dependent spatial strategy, becomes progressively contingent in part on a response-based strategy mediated by the striatum. Both neural strategies eventually relate to equivalent performance levels, indicating that covert reorganization of brain patterns underlying navigation after sleep is not necessarily accompanied by overt changes in behavior.

  18. Deep brain stimulation in the globus pallidus externa promotes sleep.

    PubMed

    Qiu, M H; Chen, M C; Wu, J; Nelson, D; Lu, J

    2016-05-13

    The basal ganglia, a network of subcortical structures, play a critical role in movements, sleep and mental behavior. Basal ganglia disorders such as Parkinson's disease and Huntington's disease affect sleep. Deep brain stimulation (DBS) to treat motor symptoms in Parkinson's disease can ameliorate sleep disturbances. Our series of previous studies lead the hypothesis that dopamine, acting on D2 receptors on the striatopallidal terminals, enhances activity in the globus pallidus externa (GPe) and promotes sleep. Here, we tested if DBS in the GPe promotes sleep in rats. We found that unilateral DBS (180 Hz at 100 μA) in the GPe in rats significantly increased both non-rapid eye movement and rapid eye movement sleep compared to sham DBS stimulation. The EEG power spectrum of sleep induced by DBS was similar to that of the baseline sleep, and sleep latency was not affected by DBS. The GPe is potentially a better site for DBS to treat both insomnia and motor disorders caused by basal ganglia dysfunction.

  19. Effects of rolipram and roflumilast, phosphodiesterase-4 inhibitors, on hypertension-induced defects in memory function in rats.

    PubMed

    Jabaris, Sobhana George Sugin Lal; Sumathy, Haridass; Kumar, Ramadass Satiesh; Narayanan, Shridhar; Thanikachalam, Sadagopan; Babu, Chidambaram Saravana

    2015-01-05

    Hypertension (HT) is a prevailing risk factor for cognitive impairment, the most common cause of vascular dementia; yet, no possible mechanism underlying the cognitive impairment induced by hypertension has been identified so far. Inhibition of PDE-4 has been shown to increase phosphorylation of cAMP-response element binding protein in the hippocampus and enhance the memory performance. Here, we examined the effects of PDE-4 inhibitors, rolipram and roflumilast, on the impairment of learning and memory observed in hypertensive rats. We used 2k-1c hypertensive model to induce learning and memory defects. In addition, mRNA expression of PDE-4 sub-types A-D was also assessed in the hippocampus tissue. Systolic blood pressure (SBP) was measured by tail-cuff method was significantly increased in 2k-1c rats when compared to sham operated rats; this effect was reversed by clonidine, whereas, PDE-4 inhibitors did not. PDE-4 inhibitors significantly reversed time induced memory deficit in novel object recognition task (NORT). Further, the retention latency on the second day in the elevated plus maze model was significantly shortened after repeated administration of rolipram and roflumilast. Plasma and brain concentrations of rolipram, roflumilast and roflumilast N-oxide were also measured after the NORT and showed linear increase in plasma and brain concentrations. The PDE4B and PDE4D gene expression was significantly enhanced in hypertensive rats compared with sham operated however PDE4A and PDE4C remained unaltered. Repeated treatment with PDE-4 inhibitors caused down regulation of PDE4B and PDE4D in hypertensive rats. These results suggest that inhibition of PDE-4 ameliorates HT-induced impairment of learning and memory functions.

  20. Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort.

    PubMed

    Kuhlenbäumer, G; Berger, K; Huge, A; Lange, E; Kessler, C; John, U; Funke, H; Nabavi, D G; Stögbauer, F; Ringelstein, E B; Stoll, M

    2006-04-01

    Genetic fine mapping of the first locus identified for genetically complex forms of stroke, STRK1 (which has been mapped to chromosome 5q12 in Icelandic families), has identified the phosphodiesterase 4D gene (PDE4D) gene as a good candidate gene. Association analysis of single nucleotide polymorphisms (SNPs) in the PDE4D gene in an Icelandic stroke cohort demonstrated genetic association between six SNPs in the 5' region of PDE4D and ischaemic stroke. The present study aimed to test whether the same six SNPs in PDE4D were also associated with stroke in a large stroke cohort from northern Germany (stroke patients with acute completed ischaemic stroke: n = 1181; population based controls: n = 1569). None of the six SNPs showed significant association with ischaemic stroke in the whole stroke sample before and after adjustment for conventional stroke risk factors (age, sex, hypertension, diabetes, and hypercholesterolaemia). Haplotype analysis did also not reveal any significant association. Marginally positive statistical measures of association in the subgroup with cardioembolic stroke did not remain significant after correction for multiple testing. In conclusion, this study was unable to demonstrate an association between the six SNPs which had showed significant single marker association with stroke in the Icelandic stroke cohort and ischaemic stroke in a large German cohort.

  1. Design, Synthesis, and Structure-Activity Relationship, Molecular Modeling, and NMR Studies of a Series of a Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors

    SciTech Connect

    Zheng, S.; Kaur, G; Wang, H; Li, M; MacNaughtan, M; Yang, X; Reid, S; Prestegard, J; Wang, B; et. al.

    2008-01-01

    Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC{sub 50} values. The most potent compounds have IC50 values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.

  2. Identification of a multifunctional docking site on the catalytic unit of phosphodiesterase-4 (PDE4) that is utilised by multiple interaction partners

    PubMed Central

    Houslay, Kirsty F.; Christian, Frank; MacLeod, Ruth; Adams, David R.; Houslay, Miles D.

    2017-01-01

    Cyclic AMP (cAMP)-specific phosphodiesterase-4 (PDE4) enzymes underpin compartmentalised cAMP signalling by localising to distinct signalling complexes. PDE4 long isoforms can be phosphorylated by mitogen-activated protein kinase-activated protein kinase 2 (MK2), which attenuates activation of such enzymes through their phosphorylation by protein kinase A. Here we show that MK2 interacts directly with PDE4 long isoforms and define the sites of interaction. One is a unique site that locates within the regulatory upstream conserved region 1 (UCR1) domain and contains a core Phe141, Leu142 and Tyr143 (FLY) cluster (PDE4A5 numbering). Located with the second site is a critical core Phe693, Glu694, Phe695 (FQF) motif that is also employed in the sequestering of PDE4 long forms by an array of other signalling proteins, including the signalling scaffold β-arrestin, the tyrosyl kinase Lyn, the SUMOylation E2 ligase UBC9, the dynein regulator Lis1 (PAFAH1B1) and the protein kinase Erk. We propose that the FQF motif lies at the heart of a multifunctional docking (MFD) site located within the PDE4 catalytic unit. It is clear from our data that, as well as aiding fidelity of interaction, the MFD site confers exclusivity of binding between PDE4 and a single specific partner protein from the cohort of signalling proteins whose interaction with PDE4 involves the FQF motif. PMID:27993970

  3. Hydroxycarbamide decreases sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial lutheran/basal cell adhesion molecule (Lu/BCAM) through phosphodiesterase 4A activation.

    PubMed

    Chaar, Vicky; Laurance, Sandrine; Lapoumeroulie, Claudine; Cochet, Sylvie; De Grandis, Maria; Colin, Yves; Elion, Jacques; Le Van Kim, Caroline; El Nemer, Wassim

    2014-04-18

    Vaso-occlusive crises are the main acute complication in sickle cell disease. They are initiated by abnormal adhesion of circulating blood cells to vascular endothelium of the microcirculation. Several interactions involving an intricate network of adhesion molecules have been described between sickle red blood cells and the endothelial vascular wall. We have shown previously that young sickle reticulocytes adhere to resting endothelial cells through the interaction of α4β1 integrin with endothelial Lutheran/basal cell adhesion molecule (Lu/BCAM). In the present work, we investigated the functional impact of endothelial exposure to hydroxycarbamide (HC) on this interaction using transformed human bone marrow endothelial cells and primary human pulmonary microvascular endothelial cells. Adhesion of sickle reticulocytes to HC-treated endothelial cells was decreased despite the HC-derived increase of Lu/BCAM expression. This was associated with decreased phosphorylation of Lu/BCAM and up-regulation of the cAMP-specific phosphodiesterase 4A expression. Our study reveals a novel mechanism for HC in endothelial cells where it could modulate the function of membrane proteins through the regulation of phosphodiesterase expression and cAMP-dependent signaling pathways.

  4. Design, Synthesis, and Structure–Activity Relationship, Molecular Modeling, and NMR Studies of a Series of Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors

    PubMed Central

    Zheng, Shilong; Kaur, Gurpreet; Wang, Huanchen; Li, Minyong; Macnaughtan, Megan; Yang, Xiaochuan; Reid, Suazette; Prestegard, James; Wang, Binghe; Ke, Hengming

    2010-01-01

    Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC50 values. The most potent compounds have IC50 values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159. PMID:19049349

  5. cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats

    PubMed Central

    Liu, Xu; Guo, Haibiao; Sayed, Mohammad Daud SOM; Lu, Yang; Yang, Ting; Zhou, Dongsheng; Chen, Zhongming; Wang, Haitao; Wang, Chuang; Xu, Jiangping

    2016-01-01

    Objectives GEBR-7b, a potential phosphodiesterase 4D inhibitor, has been shown to have memory-enhancing effects in rodents. However, it is still unknown whether GEBR-7b also has the antidepressant-like effects in rats. Herein, we examined the potential of GEBR-7b to attenuate depression-like behaviors in the rat model of depression induced by chronic unpredictable stress (CUS). Next, we also investigated the alterations of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) catalytic subunit (PKAca), cAMP response element-binding (CREB), and glutamate transporter 1 (GLT1) levels produced by GEBR-7b in the rats model of depression. Methods Effects of GEBR-7b on CUS (35 days)-induced depression-like behaviors were examined by measuring immobility time in the forced swimming test (FST). Hippocampal cAMP levels were examined by enzyme-linked immunosorbent assay, whereas PKAca, phosphorylation of CREB (pCREB), CREB, and GLT1 in the hippocampus of rats were subjected to Western blot analysis. Results CUS exposure caused a depression-like behavior evidenced by the increased immobility time in FST. Depression-like behavior induced by CUS was accompanied by a significant increased GLT, decreased cAMP, PKAca, pCREB activities in hippocampus. However, repeated GEBR-7b administration significantly reversed CUS-induced depression-like behavior and changes of cAMP/PKA/CREB/GLT1 signaling. No alteration was observed in locomotor activity in open field test. Conclusion These findings indicate that GEBR-7b reversed the depression-like behaviors induced by CUS in rats, which is at least in part mediated by modulating cAMP, PKAca, pCREB, and GLT1 levels in the hippocampus of rats, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by CUS. PMID:26855578

  6. Effects of repeated treatment with phosphodiesterase-4 inhibitors on cAMP signaling, hippocampal cell proliferation, and behavior in the forced-swim test.

    PubMed

    Xiao, Lan; O'Callaghan, James P; O'Donnell, James M

    2011-08-01

    The effects of repeated treatment with the phosphodiesterase-4 (PDE4) inhibitors rolipram, piclamilast, and 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)pyridine (CDP840), which differ in their interactions with high- and low-affinity binding conformers of the enzyme, were contrasted to those of acute treatment on cAMP signaling, hippocampal cell proliferation, and immobility in the forced-swim test in rats. Repeated treatment with rolipram (1 and 3 mg/kg), piclamilast (0.3 and 1 mg/kg), or CDP840 (10 and 30 mg/kg) for 16 days increased cAMP and phosphorylation of cAMP response element binding protein (pCREB) in hippocampus and prefrontal cortex. In addition, repeated treatment with the PDE4 inhibitors increased proliferation and survival of newborn cells in the hippocampus and produced antidepressant-like effects on behavior, as evidenced by decreased immobility in the forced-swim test. Acute treatment with rolipram (3 mg/kg), piclamilast (1 mg/kg), or CDP840 (30 mg/kg) induced transient increases in cAMP and pCREB in hippocampus and prefrontal cortex, but the dose and time dependence of these effects did not parallel the behavioral effects. Compared with rolipram and piclamilast, repeated treatment with CDP840 exerted lesser effects on neural and behavioral measures, probably because of its weak interaction with the high-affinity binding conformer of PDE4. This suggests the relative importance of the high-affinity binding conformer in the mediation of the long-term effects of PDE4 inhibition on cAMP/pCREB signaling, hippocampal cell proliferation, and antidepressant-like effects on behavior.

  7. GS-5759, a Bifunctional β2-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells.

    PubMed

    Joshi, Taruna; Yan, Dong; Hamed, Omar; Tannheimer, Stacey L; Phillips, Gary B; Wright, Clifford D; Kim, Musong; Salmon, Michael; Newton, Robert; Giembycz, Mark A

    2017-02-01

    (R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl] carbamoyl}phenyl)sulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide trifluoroacetic acid (GS-5759) is a bifunctional ligand composed of a quinolinone-containing pharmacophore [β2-adrenoceptor agonist orthostere (β2A)] found in several β2-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) by a pent-1-yn-1-ylbenzene spacer. GS-5759 had a similar affinity for PDE4B1 and the native β2-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared with the monofunctional parent compound, β2A, the KA of GS-5759 for the β2-adrenoceptor was 35-fold lower. Schild analysis determined that the affinities of the β-adrenoceptor antagonists, (2R,3R)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol (ICI 118551) and propranolol, were agonist-dependent, being significantly lower for GS-5759 than β2A. Collectively, these data can be explained by "forced proximity," bivalent binding where the pharmacophore in GS-5759 responsible for PDE4 inhibition also interacts with a nonallosteric domain within the β2-adrenoceptor that enhances the affinity of β2A for the orthosteric site. Microarray analyses revealed that, after 2-hour exposure, GS-5759 increased the expression of >3500 genes in BEAS-2B cells that were highly rank-order correlated with gene expression changes produced by indacaterol and GSK 256066 in combination (Ind/GSK). Moreover, the line of regression began close to the origin with a slope of 0.88, indicating that the magnitude of most gene expression changes produced by Ind/GSK was quantitatively replicated by GS-5759. Thus, GS-5759 is a novel compound exhibiting dual β2-adrenoceptor agonism and PDE4 inhibition

  8. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

    PubMed

    Qian, Qi; Liu, Qiuji; Zhou, Dongming; Pan, Hongyu; Liu, Zhiwei; He, Fangping; Ji, Suying; Wang, Dongpi; Bao, Wangxiao; Liu, Xinyi; Liu, Zhaoling; Zhang, Heng; Zhang, Xiaoqin; Zhang, Ling; Wang, Mingkai; Xu, Ying; Huang, Fude; Luo, Benyan; Sun, Binggui

    2017-02-13

    Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3a(f/f) mice and then crossed them with Nestin-Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho-MAPK and phospho-Akt. Furthermore, the number of TUNEL(+) cells was decreased in the subgranular zone of dentate gyrus in Efr3a-deficient mice compared with that of control mice. Our data suggest that brain-specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain.-Qian, Q., Liu, Q., Zhou, D., Pan, H., Liu, Z., He, F., Ji, S., Wang, D., Bao, W., Liu, X., Liu, Z., Zhang, H., Zhang, X., Zhang, L., Wang, M., Xu, Y., Huang, F., Luo, B., Sun B. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

  9. A regulatory toolbox of MiniPromoters to drive selective expression in the brain

    PubMed Central

    Portales-Casamar, Elodie; Swanson, Douglas J.; Liu, Li; de Leeuw, Charles N.; Banks, Kathleen G.; Ho Sui, Shannan J.; Fulton, Debra L.; Ali, Johar; Amirabbasi, Mahsa; Arenillas, David J.; Babyak, Nazar; Black, Sonia F.; Bonaguro, Russell J.; Brauer, Erich; Candido, Tara R.; Castellarin, Mauro; Chen, Jing; Chen, Ying; Cheng, Jason C. Y.; Chopra, Vik; Docking, T. Roderick; Dreolini, Lisa; D'Souza, Cletus A.; Flynn, Erin K.; Glenn, Randy; Hatakka, Kristi; Hearty, Taryn G.; Imanian, Behzad; Jiang, Steven; Khorasan-zadeh, Shadi; Komljenovic, Ivana; Laprise, Stéphanie; Liao, Nancy Y.; Lim, Jonathan S.; Lithwick, Stuart; Liu, Flora; Liu, Jun; Lu, Meifen; McConechy, Melissa; McLeod, Andrea J.; Milisavljevic, Marko; Mis, Jacek; O'Connor, Katie; Palma, Betty; Palmquist, Diana L.; Schmouth, Jean-François; Swanson, Magdalena I.; Tam, Bonny; Ticoll, Amy; Turner, Jenna L.; Varhol, Richard; Vermeulen, Jenny; Watkins, Russell F.; Wilson, Gary; Wong, Bibiana K. Y.; Wong, Siaw H.; Wong, Tony Y. T.; Yang, George S.; Ypsilanti, Athena R.; Jones, Steven J. M.; Holt, Robert A.; Goldowitz, Daniel; Wasserman, Wyeth W.; Simpson, Elizabeth M.

    2010-01-01

    The Pleiades Promoter Project integrates genomewide bioinformatics with large-scale knockin mouse production and histological examination of expression patterns to develop MiniPromoters and related tools designed to study and treat the brain by directed gene expression. Genes with brain expression patterns of interest are subjected to bioinformatic analysis to delineate candidate regulatory regions, which are then incorporated into a panel of compact human MiniPromoters to drive expression to brain regions and cell types of interest. Using single-copy, homologous-recombination “knockins” in embryonic stem cells, each MiniPromoter reporter is integrated immediately 5′ of the Hprt locus in the mouse genome. MiniPromoter expression profiles are characterized in differentiation assays of the transgenic cells or in mouse brains following transgenic mouse production. Histological examination of adult brains, eyes, and spinal cords for reporter gene activity is coupled to costaining with cell-type–specific markers to define expression. The publicly available Pleiades MiniPromoter Project is a key resource to facilitate research on brain development and therapies. PMID:20807748

  10. Viral Vector-Based Dissection of Marmoset GFAP Promoter in Mouse and Marmoset Brains

    PubMed Central

    Takahashi, Nobutaka; Matsuzaki, Yasunori; Kishi, Shoji; Hirai, Hirokazu

    2016-01-01

    Adeno-associated virus (AAV) vectors are small in diameter, diffuse easily in the brain, and represent a highly efficient means by which to transfer a transgene to the brain of a large animal. A major demerit of AAV vectors is their limited accommodation capacity for transgenes. Thus, a compact promoter is useful when delivering large transgenes via AAV vectors. In the present study, we aimed to identify the shortest astrocyte-specific GFAP promoter region that could be used for AAV-vector-mediated transgene expression in the marmoset brain. The 2.0-kb promoter region upstream of the GFAP gene was cloned from the marmoset genome, and short promoters (1.6 kb, 1.4 kb, 0.6 kb, 0.3 kb and 0.2 kb) were obtained by progressively deleting the original 2.0-kb promoter from the 5’ end. The short promoters were screened in the mouse cerebellum in terms of their strength and astrocyte specificity. We found that the 0.3-kb promoter maintained 40% of the strength of the original 2.0-kb promoter, and approximately 90% of its astrocyte specificity. These properties were superior to those of the 1.4-kb, 0.6-kb (20% promoter strength) and 0.2-kb (70% astrocyte specificity) promoters. Then, we verified whether the 0.3-kb GFAP promoter retained astrocyte specificity in the marmoset cerebral cortex. Injection of viral vectors carrying the 0.3-kb marmoset GFAP promoter specifically transduced astrocytes in both the cerebral cortex and cerebellar cortex of the marmoset. These results suggest that the compact 0.3-kb promoter region serves as an astrocyte-specific promoter in the marmoset brain, which permits us to express a large gene by AAV vectors that have a limited accommodation capacity. PMID:27571575

  11. Intrathecal injection of phosphodiesterase 4B-specific siRNA attenuates neuropathic pain in rats with L5 spinal nerve ligation.

    PubMed

    Ji, Qing; Di, Yan; He, Xiaoyun; Liu, Qingzhen; Liu, Jian; Li, Weiyan; Zhang, Lidong

    2016-02-01

    Phosphodiesterase 4 (PDE4) is an adenosine cyclic 3,5-monophosphate-specific degradative enzyme, which is closely associated with the inflammatory response. Among its four subtypes (A-D), it remains unclear which one exerts suppressive effects on inflammation and reduces neuropathic pain. The present study aimed to examine the modulation of neuroinflammation by PDE4 subtypes in the spinal cord of a rat model of L5 spinal nerve ligation (SNL)-induced neuropathic pain. The expression levels of PDE4A-D were measured in the lumbar spinal cords of naïve rats. The rats were then divided into seven groups: The sham group (sham surgery + saline), the saline group (SNL + saline), the vehicle group (SNL + Lipofectamine® RNAiMAX), the mismatch small interfering (si)RNA group (SNL + mismatch siRNA), the PDE4A-siRNA group (SNL + PDE4A-siRNA), the PDE4B-siRNA group (SNL + PDE4B-siRNA) and the PDE4D-siRNA group (SNL + PDE4D-siRNA). In order to determine behavioral changes, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded. The mRNA and protein expression levels of PDE4s were also detected. Furthermore, the association between behavioral changes and individual subtypes of PDE4 were studied following intrathecal administration of PDE4A, B and D-specific siRNA. The expression levels of protein kinases, including phosphorylated-extracellular signal-regulated kinases (p-ERK), and inflammatory cytokines were measured, in order to explore the underlying mechanisms. Subtypes A, B and D, but not C, were detected in the naïve rats. After SNL, both MWT and TWL were reduced. The mRNA and protein expression levels of PDE4A, B and D were significantly upregulated after 2, 4, 6 and 8 days of SNL. Subtype-specific siRNA significantly suppressed the elevated expression levels; however, only rats treated with PDE4B siRNA exhibited improved MWT and TWL. Further analysis of the PDE4B siRNA-treated rats demonstrated that 8 days after SNL, the intensity of p

  12. RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects

    PubMed Central

    Wang, Zhen-Zhen; Zhang, Yi; Liu, Yan-Qin; Zhao, Nan; Zhang, You-Zhi; Yuan, Li; An, Lei; Li, Jing; Wang, Xiao-Yun; Qin, Juan-Juan; Wilson, Steven P; O'Donnell, James M; Zhang, Han-Ting; Li, Yun-Feng

    2013-01-01

    Background and Purpose Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform-specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long-form PDE4D variants mediate antidepressant-like and cognition-enhancing effects, but are irrespective with emesis. Experimental Approach In mice microinfused with lentiviral vectors that contained shRNA-mir hairpin structure targeting long-form PDE4Ds into bilateral prefrontal cortices, the tail-suspension and forced-swim tests were used to measure antidepressant-like effects; novel object recognition and Morris water-maze tasks were used to determine cognition-enhancing effects. The emetic potential was assessed by alpha2 adrenergic receptor-mediated anaesthesia, a surrogate measure of emesis. Intracellular cAMP signalling was analysed by time-resolved FRET immunoassay and Western-blot. Dendritic complexity was assessed by Golgi staining. Key Results Microinfusions of lentiviral PDE4D-shRNA down-regulated PDE4D4 and PDE4D5, and imitated the antidepressant-like and cognition-enhancing effects of the prototypical PDE4 inhibitor rolipram. The behavioural effects were related to dendritic complexity and mediated by the increased cAMP signalling. In addition, these effects were not enhanced in the presence of rolipram. Finally, while rolipram shortened the duration of combined anaesthesia, RNA interference-mediated PDE4D knock-down in the prefrontal cortex did not. Conclusion and Implications These data suggest that long-form PDE4Ds, at least PDE4D4 and PDE4D5, may be the promising targets for the development of PDE4 variant-selective inhibitors as the new pharmacotherapies for depressive disorders and neurodegenerative

  13. Mitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site phosphorylation, influences cell cycle progression.

    PubMed

    Sheppard, Catherine L; Lee, Louisa C Y; Hill, Elaine V; Henderson, David J P; Anthony, Diana F; Houslay, Daniel M; Yalla, Krishna C; Cairns, Lynne S; Dunlop, Allan J; Baillie, George S; Huston, Elaine; Houslay, Miles D

    2014-09-01

    In Rat-1 cells, the dramatic decrease in the levels of both intracellular cyclic 3'5' adenosine monophosphate (cyclic AMP; cAMP) and in the activity of cAMP-activated protein kinase A (PKA) observed in mitosis was paralleled by a profound increase in cAMP hydrolyzing phosphodiesterase-4 (PDE4) activity. The decrease in PKA activity, which occurs during mitosis, was attributable to PDE4 activation as the PDE4 selective inhibitor, rolipram, but not the phosphodiesterase-3 (PDE3) inhibitor, cilostamide, specifically ablated this cell cycle-dependent effect. PDE4 inhibition caused Rat-1 cells to move from S phase into G2/M more rapidly, to transit through G2/M more quickly and to remain in G1 for a longer period. Inhibition of PDE3 elicited no observable effects on cell cycle dynamics. Selective immunopurification of each of the four PDE4 sub-families identified PDE4D as being selectively activated in mitosis. Subsequent analysis uncovered PDE4D9, an isoform whose expression can be regulated by Disrupted-In-Schizophrenia 1 (DISC1)/activating transcription factor 4 (ATF4) complex, as the sole PDE4 species activated during mitosis in Rat-1 cells. PDE4D9 becomes activated in mitosis through dual phosphorylation at Ser585 and Ser245, involving the combined action of ERK and an unidentified 'switch' kinase that has previously been shown to be activated by H2O2. Additionally, in mitosis, PDE4D9 also becomes phosphorylated at Ser67 and Ser81, through the action of MK2 (MAPKAPK2) and AMP kinase (AMPK), respectively. The multisite phosphorylation of PDE4D9 by all four of these protein kinases leads to decreased mobility (band-shift) of PDE4D9 on SDS-PAGE. PDE4D9 is predominantly concentrated in the perinuclear region of Rat-1 cells but with a fraction distributed asymmetrically at the cell margins. Our investigations demonstrate that the diminished levels of cAMP and PKA activity that characterise mitosis are due to enhanced cAMP degradation by PDE4D9. PDE4D9, was found to

  14. Short-term or long-term treatments with a phosphodiesterase-4 (PDE4) inhibitor result in opposing agonist-induced Ca2+ responses in endothelial cells

    PubMed Central

    Campos-Toimil, M; Keravis, T; Orallo, F; Takeda, K; Lugnier, C

    2008-01-01

    Background and purpose: We previously reported that agonist-induced rises in cytoplasmic Ca2+ concentration ([Ca2+]i) in human umbilical vein endothelial cells (HUVEC) were inhibited after a short-term (2 min) pre-treatment with cAMP-elevating agents. The aim of this work was to study the effects of longer term (8 h) pre-treatment with dibutyryl-cAMP (db-cAMP) or rolipram, a specific inhibitor of phosphodiesterase-4 (PDE4), on [Ca2+]i, cAMP levels and PDE activity and expression in HUVEC. Experimental approach: [Ca2+]i changes were measured in isolated HUVEC by Fura-2 imaging. Intracellular cAMP levels and PDE4 activity were assessed by enzyme-immunoassay and radio-enzymatic assay, respectively. PDE expression was measured by northern and western blot analysis. Key results: Long-term pre-treatment of HUVEC with rolipram or db-cAMP significantly increased ATP-, histamine- and thrombin-induced [Ca2+]i rises. Short-term pre-treatment with rolipram was associated with an increase in cAMP, whereas long-term pre-treatment was associated with a decrease in cAMP. Long-term pre-treatment with rolipram or db-cAMP induced a significant increase in PDE4 activity and the expression of 74 kDa-PDE4A and 73 kDa-PDE4B was specifically enhanced. All these effects were suppressed by cycloheximide. Conclusions and implications: Our data suggest that sustained inhibition of PDE4 by rolipram induced an increase in PDE4 activity, possibly as a compensatory mechanism to accelerate cAMP degradation and that PDE4A and PDE4B were implicated in the regulation of [Ca2+]i. Thus, isozyme-specific PDE4 inhibitors might be useful as therapeutic agents in diseases where [Ca2+]i handling is altered, such as atherosclerosis, hypertension and tolerance to β-adrenoceptor agonists. PMID:18311187

  15. Understanding How Exercise Promotes Cognitive Integrity in the Aging Brain.

    PubMed

    Laitman, Benjamin M; John, Gareth R

    2015-01-01

    Alterations in the structure and organization of the aging central nervous system (CNS), and associated functional deficits, result in cognitive decline and increase susceptibility to neurodegeneration. Age-related changes to the neurovascular unit (NVU), and their consequences for cerebrovascular function, are implicated as driving cognitive impairment during aging as well as in neurodegenerative disease. The molecular events underlying these effects are incompletely characterized. Similarly, the mechanisms underlying effects of factors that reduce the impact of aging on the brain, such as physical exercise, are also opaque. A study in this issue of PLOS Biology links the NVU to cognitive decline in the aging brain and suggests a potential underlying molecular mechanism. Notably, the study further links the protective effects of chronic exercise on cognition to neurovascular integrity during aging.

  16. 125 Brain Games for Babies: Simple Games To Promote Early Brain Development.

    ERIC Educational Resources Information Center

    Silberg, Jackie

    Scientists believe that the stimulation that infants and young children receive determines which synapses form in the brain. This book presents 125 games for infants from birth to 12 months and is designed to nurture brain development. The book is organized chronologically in 3-month increments. Each game description includes information from…

  17. Motor Skill Acquisition Promotes Human Brain Myelin Plasticity

    PubMed Central

    Lakhani, Bimal; Borich, Michael R.; Jackson, Jacob N.; Wadden, Katie P.; Peters, Sue; Villamayor, Anica; MacKay, Alex L.; Vavasour, Irene M.; Rauscher, Alexander; Boyd, Lara A.

    2016-01-01

    Experience-dependent structural changes are widely evident in gray matter. Using diffusion weighted imaging (DWI), the neuroplastic effect of motor training on white matter in the brain has been demonstrated. However, in humans it is not known whether specific features of white matter relate to motor skill acquisition or if these structural changes are associated to functional network connectivity. Myelin can be objectively quantified in vivo and used to index specific experience-dependent change. In the current study, seventeen healthy young adults completed ten sessions of visuomotor skill training (10,000 total movements) using the right arm. Multicomponent relaxation imaging was performed before and after training. Significant increases in myelin water fraction, a quantitative measure of myelin, were observed in task dependent brain regions (left intraparietal sulcus [IPS] and left parieto-occipital sulcus). In addition, the rate of motor skill acquisition and overall change in myelin water fraction in the left IPS were negatively related, suggesting that a slower rate of learning resulted in greater neuroplastic change. This study provides the first evidence for experience-dependent changes in myelin that are associated with changes in skilled movements in healthy young adults. PMID:27293906

  18. Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis.

    PubMed

    Theofilopoulos, Spyridon; Wang, Yuqin; Kitambi, Satish Srinivas; Sacchetti, Paola; Sousa, Kyle M; Bodin, Karl; Kirk, Jayne; Saltó, Carmen; Gustafsson, Magnus; Toledo, Enrique M; Karu, Kersti; Gustafsson, Jan-Åke; Steffensen, Knut R; Ernfors, Patrik; Sjövall, Jan; Griffiths, William J; Arenas, Ernest

    2013-02-01

    Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type-specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.

  19. Evolution of Brain Active Gene Promoters in Human Lineage Towards the Increased Plasticity of Gene Regulation.

    PubMed

    Gunbin, Konstantin V; Ponomarenko, Mikhail P; Suslov, Valentin V; Gusev, Fedor; Fedonin, Gennady G; Rogaev, Evgeny I

    2017-02-24

    Adaptability to a variety of environmental conditions is a prominent feature of Homo sapiens. We hypothesize that this feature can be explained by evolutionary changes in gene promoters active in the brain prefrontal cortex leading to a more flexible gene regulation network. The genotype-dependent range of gene expression can be broader in humans than in other higher primates. Thus, we searched for specific signatures of evolutionary changes in promoter architectures of multiple hominid genes, including the genes active in human cortical neurons that may indicate an increase of variability of gene expression rather than just changes in the level of expression, such as downregulation or upregulation of the genes. We performed a whole-genome search for genetic-based alterations that may impact gene regulation "flexibility" in a process of hominids evolution, such as (i) CpG dinucleotide content, (ii) predicted nucleosome-DNA dissociation constant, and (iii) predicted affinities for TATA-binding protein (TBP) in gene promoters. We tested all putative promoter regions across the human genome and especially gene promoters in active chromatin state in neurons of prefrontal cortex, the brain region critical for abstract thinking and social and behavioral adaptation. Our data imply that the origin of modern man has been associated with an increase of flexibility of promoter-driven gene regulation in brain. In contrast, after splitting from the ancestral lineages of H. sapiens, the evolution of ape species is characterized by reduced flexibility of gene promoter functioning, underlying reduced variability of the gene expression.

  20. Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury

    PubMed Central

    Chen, Michael J.; Plog, Benjamin A.; Zeppenfeld, Douglas M.; Soltero, Melissa; Yang, Lijun; Singh, Itender; Deane, Rashid; Nedergaard, Maiken

    2014-01-01

    Traumatic brain injury (TBI) is an established risk factor for the early development of dementia, including Alzheimer's disease, and the post-traumatic brain frequently exhibits neurofibrillary tangles comprised of aggregates of the protein tau. We have recently defined a brain-wide network of paravascular channels, termed the “glymphatic” pathway, along which CSF moves into and through the brain parenchyma, facilitating the clearance of interstitial solutes, including amyloid-β, from the brain. Here we demonstrate in mice that extracellular tau is cleared from the brain along these paravascular pathways. After TBI, glymphatic pathway function was reduced by ∼60%, with this impairment persisting for at least 1 month post injury. Genetic knock-out of the gene encoding the astroglial water channel aquaporin-4, which is importantly involved in paravascular interstitial solute clearance, exacerbated glymphatic pathway dysfunction after TBI and promoted the development of neurofibrillary pathology and neurodegeneration in the post-traumatic brain. These findings suggest that chronic impairment of glymphatic pathway function after TBI may be a key factor that renders the post-traumatic brain vulnerable to tau aggregation and the onset of neurodegeneration. PMID:25471560

  1. Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth.

    PubMed

    Orr, Brent A; Bai, Haibo; Odia, Yazmin; Jain, Deepali; Anders, Robert A; Eberhart, Charles G

    2011-07-01

    The hippo pathway and its downstream mediator yes-associated protein 1 (YAP1) regulate mammalian organ size in part through modulating progenitor cell numbers. YAP1 has also been implicated as an oncogene in multiple human cancers. Currently, little is known about the expression of YAP1 either in normal human brain tissue or in central nervous system neoplasms. We used immunohistochemistry to evaluate nuclear YAP1 expression in the fetal and normal adult human brains and in 264 brain tumors. YAP1 was expressed in fetal and adult brain regions known to harbor neural progenitor cells, but there was little YAP1 immunoreactivity in the adult cerebral cortex. YAP1 protein was also readily detected in the nuclei of human brain tumors. In medulloblastoma, the expression varied between histologic subtypes and was most prominent in nodular/desmoplastic tumors. In gliomas, it was frequently expressed in infiltrating astrocytomas and oligodendrogliomas but rarely in pilocytic astrocytomas. Using a loss-of-function approach, we show that YAP1 promoted growth of glioblastoma cell lines in vitro. High levels of YAP1 messenger RNA expression were associated with aggressive molecular subsets of glioblastoma and with a nonsignificant trend toward reduced mean survival in human astrocytoma patients. These findings suggest that YAP1 may play an important role in normal human brain development and that it could represent a new target in human brain tumors.

  2. Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer’s Disease

    DTIC Science & Technology

    2013-10-01

    Response to Traumatic Brain Injury Promotes Risk for Alzheimer’s Disease PRINCIPAL INVESTIGATOR: Giulio Maria Pasinetti MD., PhD...TITLE AND SUBTITLE Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury 5a. CONTRACT NUMBER Promotes Risk for Alzheimer’s...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Traumatic Brain Injury (TBI) is a risk factor for subsequent development of Alzheimer’s

  3. Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury.

    PubMed

    Anbari, Fatemeh; Khalili, Mohammad Ali; Bahrami, Ahmad Reza; Khoradmehr, Arezoo; Sadeghian, Fatemeh; Fesahat, Farzaneh; Nabi, Ali

    2014-05-01

    To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 10(6) rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells.

  4. Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury

    PubMed Central

    Anbari, Fatemeh; Khalili, Mohammad Ali; Bahrami, Ahmad Reza; Khoradmehr, Arezoo; Sadeghian, Fatemeh; Fesahat, Farzaneh; Nabi, Ali

    2014-01-01

    To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 106 rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells. PMID:25206912

  5. Brain inositol is a novel stimulator for promoting Cryptococcus penetration of the blood-brain barrier.

    PubMed

    Liu, Tong-Bao; Kim, Jong-Chul; Wang, Yina; Toffaletti, Dena L; Eugenin, Eliseo; Perfect, John R; Kim, Kee Jun; Xue, Chaoyang

    2013-01-01

    Cryptococcus neoformans is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of Cryptococcus infection in the central nervous system (CNS) is poorly understood. The facts that human and animal brains contain abundant inositol and that Cryptococcus has a sophisticated system for the acquisition of inositol from the environment suggests that host inositol utilization may contribute to the development of cryptococcal meningitis. In this study, we found that inositol plays an important role in Cryptococcus traversal across the blood-brain barrier (BBB) both in an in vitro human BBB model and in in vivo animal models. The capacity of inositol to stimulate BBB crossing was dependent upon fungal inositol transporters, indicated by a 70% reduction in transmigration efficiency in mutant strains lacking two major inositol transporters, Itr1a and Itr3c. Upregulation of genes involved in the inositol catabolic pathway was evident in a microarray analysis following inositol treatment. In addition, inositol increased the production of hyaluronic acid in Cryptococcus cells, which is a ligand known to binding host CD44 receptor for their invasion. These studies suggest an inositol-dependent Cryptococcus traversal of the BBB, and support our hypothesis that utilization of host-derived inositol by Cryptococcus contributes to CNS infection.

  6. Dopamine from the brain promotes spinal motor neuron generation during development and adult regeneration.

    PubMed

    Reimer, Michell M; Norris, Anneliese; Ohnmacht, Jochen; Patani, Rickie; Zhong, Zhen; Dias, Tatyana B; Kuscha, Veronika; Scott, Angela L; Chen, Yu-Chia; Rozov, Stanislav; Frazer, Sarah L; Wyatt, Cameron; Higashijima, Shin-ichi; Patton, E Elizabeth; Panula, Pertti; Chandran, Siddharthan; Becker, Thomas; Becker, Catherina G

    2013-06-10

    Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.

  7. A functional requirement for astroglia in promoting blood vessel development in the early postnatal brain.

    PubMed

    Ma, Shang; Kwon, Hyo Jun; Huang, Zhen

    2012-01-01

    Astroglia are a major cell type in the brain and play a key role in many aspects of brain development and function. In the adult brain, astrocytes are known to intimately ensheath blood vessels and actively coordinate local neural activity and blood flow. During development of the neural retina, blood vessel growth follows a meshwork of astrocytic processes. Several genes have also been implicated in retinal astrocytes for regulating vessel development. This suggests a role of astrocytes in promoting angiogenesis throughout the central nervous system. To determine the roles that astrocytes may play during brain angiogenesis, we employ genetic approaches to inhibit astrogliogenesis during perinatal corticogenesis and examine its effects on brain vessel development. We find that conditional deletion from glial progenitors of orc3, a gene required for DNA replication, dramatically reduces glial progenitor cell number in the subventricular zone and astrocytes in the early postnatal cerebral cortex. This, in turn, results in severe reductions in both the density and branching frequency of cortical blood vessels. Consistent with a delayed growth but not regression of vessels, we find neither significant net decreases in vessel density between different stages after normalizing for cortical expansion nor obvious apoptosis of endothelial cells in these mutants. Furthermore, concomitant with loss of astroglial interactions, we find increased endothelial cell proliferation, enlarged vessel luminal size as well as enhanced cytoskeletal gene expression in pericytes, which suggests compensatory changes in vascular cells. Lastly, we find that blood vessel morphology in mutant cortices recovers substantially at later stages, following astrogliosis. These results thus implicate a functional requirement for astroglia in promoting blood vessel growth during brain development.

  8. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report.

    PubMed

    Abdolmaleky, Hamid Mostafavi; Cheng, Kuang-hung; Russo, Andrea; Smith, Cassandra L; Faraone, Stephen V; Wilcox, Marsha; Shafa, Rahim; Glatt, Stephen J; Nguyen, Giang; Ponte, Joe F; Thiagalingam, Sam; Tsuang, Ming T

    2005-04-05

    DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol-chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the

  9. Damage to Arousal-Promoting Brainstem Neurons with Traumatic Brain Injury

    PubMed Central

    Valko, Philipp O.; Gavrilov, Yuri V.; Yamamoto, Mihoko; Noaín, Daniela; Reddy, Hasini; Haybaeck, Johannes; Weis, Serge; Baumann, Christian R.; Scammell, Thomas E.

    2016-01-01

    Study Objectives: Coma and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI. Methods: Postmortem examination of 8 TBI patients and 10 controls. Results: Compared to controls, TBI patients had 17% fewer serotonergic neurons in the dorsal raphe nucleus (effect size: 1.25), but the number of serotonergic neurons did not differ in the median raphe nucleus. TBI patients also had 29% fewer noradrenergic neurons in the locus coeruleus (effect size: 0.96). The number of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) was similar in TBI patients and controls. Conclusions: TBI injures arousal-promoting neurons of the mesopontine tegmentum, but this injury is less severe than previously observed in hypothalamic arousal-promoting neurons. Most likely, posttraumatic arousal disturbances are not primarily caused by damage to these brainstem neurons, but arise from an aggregate of injuries, including damage to hypothalamic arousal nuclei and disruption of other arousal-related circuitries. Citation: Valko PO, Gavrilov YV, Yamamoto M, Noain D, Reddy H, Haybaeck J, Weis S, Baumann CR, Scammell TE. Damage to arousal-promoting brainstem neurons with traumatic brain injury. SLEEP 2016;39(6):1249–1252. PMID:27091531

  10. Targeting Transporters: Promoting Blood-Brain Barrier Repair in Response to Oxidative Stress Injury

    PubMed Central

    Ronaldson, Patrick T.; Davis, Thomas P.

    2015-01-01

    The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., endogenous transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress. PMID:25796436

  11. Placental, Matrilineal, and Epigenetic Mechanisms Promoting Environmentally Adaptive Development of the Mammalian Brain

    PubMed Central

    Broad, Kevin D.; Rocha-Ferreira, Eridan; Hristova, Mariya

    2016-01-01

    The evolution of intrauterine development, vivipary, and placentation in eutherian mammals has introduced new possibilities and constraints in the regulation of neural plasticity and development which promote neural function that is adaptive to the environment that a developing brain is likely to encounter in the future. A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time (maternal, foetal, and postmeiotic oocytes). The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain. In conjunction with genomic imprinting, it also provides a template to integrate epigenetic information from both maternal and paternal lineages. Placentation also hands ultimate control of genomic imprinting and intergenerational epigenetic information transfer to the matriline as epigenetic markers undergo erasure and reprogramming in the developing oocyte. These developments, in conjunction with an expanded neocortex, provide a unique evolutionary template by which matrilineal transfer of maternal care, resources, and culture can be used to promote brain development and infant survival. PMID:27069693

  12. Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer’s Disease

    DTIC Science & Technology

    2014-10-01

    Award Number: W81XWH-12-1-0582 TITLE: Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer’s...Annual 3. DATES COVERED 25 Sep 2013 - 24 Sep 2014 4. TITLE AND SUBTITLE Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury...SUPPLEMENTARY NOTES 14. ABSTRACT Traumatic Brain Injury (TBI) is a risk factor for subsequent development of Alzheimer’s disease (AD). Abnormal tau

  13. Histamine from brain resident MAST cells promotes wakefulness and modulates behavioral states.

    PubMed

    Chikahisa, Sachiko; Kodama, Tohru; Soya, Atsushi; Sagawa, Yohei; Ishimaru, Yuji; Séi, Hiroyoshi; Nishino, Seiji

    2013-01-01

    Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/W(v)) mice. No significant difference was found in the basal amount of sleep/wake between W/W(v) mice and their wild-type littermates (WT), although W/W(v) mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/W(v) mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/W(v) mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/W(v) mice. W/W(v) mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior.

  14. GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease

    PubMed Central

    Pierson, Emily R.; Goverman, Joan M.

    2017-01-01

    Experimental autoimmune encephalomyelitis (EAE) has been used as an animal model of multiple sclerosis to identify pathogenic cytokines that could be therapeutic targets. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is the only cytokine reported to be essential for EAE. We investigated the role of GM-CSF in EAE in C3HeB/FeJ mice that uniquely exhibit extensive brain and spinal cord inflammation. Unexpectedly, GM-CSF–deficient C3HeB/FeJ mice were fully susceptible to EAE because IL-17 activity compensated for the loss of GM-CSF during induction of spinal cord–targeted disease. In contrast, both GM-CSF and IL-17 were needed to fully overcome the inhibitory influence of IFN-γ on the induction of inflammation in the brain. Both GM-CSF and IL-17 independently promoted neutrophil accumulation in the brain, which was essential for brain-targeted disease. These results identify a GM-CSF/IL-17/IFN-γ axis that regulates inflammation in the central nervous system and suggest that a combination of cytokine-neutralizing therapies may be needed to dampen central nervous system autoimmunity.

  15. Effects of APOE promoter polymorphism on the topological organization of brain structural connectome in nondemented elderly

    PubMed Central

    Shu, Ni; Li, Xin; Ma, Chao; Zhang, Junying; Chen, Kewei; Liang, Ying; Chen, Yaojing; Zhang, Zhanjun

    2015-01-01

    The polymorphism of the Apolipoprotein E (APOE) promoter rs405509 can regulate the transcriptional activity of the APOE gene and is related to Alzheimer’s disease (AD). However, its effects on cognitive performance and the underlying brain mechanisms remain unknown. Here, we performed a battery of neuropsychological tests in a large sample (837 subjects) of nondemented elderly Chinese people, and explored the related brain mechanisms via the construction of diffusion MRI-based structural connectome and graph analysis from a subset (84 subjects) of the sample. Cognitively, the rs405509 risk allele (TT) carriers showed decreased attention and execution functions compared with non-carriers (GG/GT). Regarding the topological alterations of the brain connectome, the risk allele group exhibited reduced global and local efficiency of white matter structural networks, mainly in the left anterior and posterior cingulate cortices (PCC). Importantly, the efficiency of the left PCC is correlated with the impaired attention function and mediates the impacts of the rs405509 genotype on attention. These results demonstrated that the rs405509 polymorphism affects attention function in nondemented elderly people, possibly by modulating brain structural connectivity of the PCC. This polymorphism may help us to understand the neural mechanisms of cognitive aging and to serve as a potential marker assessing the risk of AD. PMID:26314833

  16. ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway.

    PubMed

    Lin, Chen-Yuan; Chen, Hung-Jen; Huang, Cheng-Chung; Lai, Liang-Chuan; Lu, Tzu-Pin; Tseng, Guan-Chin; Kuo, Ting-Ting; Kuok, Qian-Yu; Hsu, Jennifer L; Sung, Shian-Ying; Hung, Mien-Chie; Sher, Yuh-Pyng

    2014-09-15

    The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease.

  17. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor.

    PubMed

    Parkhurst, Christopher N; Yang, Guang; Ninan, Ipe; Savas, Jeffrey N; Yates, John R; Lafaille, Juan J; Hempstead, Barbara L; Littman, Dan R; Gan, Wen-Biao

    2013-12-19

    Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.

  18. Brain-derived neurotrophic factor promoter methylation and cortical thickness in recurrent major depressive disorder.

    PubMed

    Na, Kyoung-Sae; Won, Eunsoo; Kang, June; Chang, Hun Soo; Yoon, Ho-Kyoung; Tae, Woo Suk; Kim, Yong-Ku; Lee, Min-Soo; Joe, Sook-Haeng; Kim, Hyun; Ham, Byung-Joo

    2016-02-15

    Recent studies have reported that methylation of the brain-derived neurotrophic factor (BDNF) gene promoter is associated with major depressive disorder (MDD). This study aimed to investigate the association between cortical thickness and methylation of BDNF promoters as well as serum BDNF levels in MDD. The participants consisted of 65 patients with recurrent MDD and 65 age- and gender-matched healthy controls. Methylation of BDNF promoters and cortical thickness were compared between the groups. The right medial orbitofrontal, right lingual, right lateral occipital, left lateral orbitofrontal, left pars triangularis, and left lingual cortices were thinner in patients with MDD than in healthy controls. Among the MDD group, right pericalcarine, right medical orbitofrontal, right rostral middle frontal, right postcentral, right inferior temporal, right cuneus, right precuneus, left frontal pole, left superior frontal, left superior temporal, left rostral middle frontal and left lingual cortices had inverse correlations with methylation of BDNF promoters. Higher levels of BDNF promoter methylation may be closely associated with the reduced cortical thickness among patients with MDD. Serum BDNF levels were significantly lower in MDD, and showed an inverse relationship with BDNF methylation only in healthy controls. Particularly the prefrontal and occipital cortices seem to indicate key regions in which BDNF methylation has a significant effect on structure.

  19. Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration.

    PubMed

    Yip, Ping Kei; Carrillo-Jimenez, Alejandro; King, Paul; Vilalta, Anna; Nomura, Koji; Chau, Chi Cheng; Egerton, Alexander Michael Scott; Liu, Zhuo-Hao; Shetty, Ashray Jayaram; Tremoleda, Jordi L; Davies, Meirion; Deierborg, Tomas; Priestley, John V; Brown, Guy Charles; Michael-Titus, Adina Teodora; Venero, Jose Luis; Burguillos, Miguel Angel

    2017-01-27

    Traumatic brain injury (TBI) is currently a major cause of morbidity and poor quality of life in Western society, with an estimate of 2.5 million people affected per year in Europe, indicating the need for advances in TBI treatment. Within the first 24 h after TBI, several inflammatory response factors become upregulated, including the lectin galectin-3. In this study, using a controlled cortical impact (CCI) model of head injury, we show a large increase in the expression of galectin-3 in microglia and also an increase in the released form of galectin-3 in the cerebrospinal fluid (CSF) 24 h after head injury. We report that galectin-3 can bind to TLR-4, and that administration of a neutralizing antibody against galectin-3 decreases the expression of IL-1β, IL-6, TNFα and NOS2 and promotes neuroprotection in the cortical and hippocampal cell populations after head injury. Long-term analysis demonstrated a significant neuroprotection in the cortical region in the galectin-3 knockout animals in response to TBI. These results suggest that following head trauma, released galectin-3 may act as an alarmin, binding, among other proteins, to TLR-4 and promoting inflammation and neuronal loss. Taking all together, galectin-3 emerges as a clinically relevant target for TBI therapy.

  20. Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration

    PubMed Central

    Yip, Ping Kei; Carrillo-Jimenez, Alejandro; King, Paul; Vilalta, Anna; Nomura, Koji; Chau, Chi Cheng; Egerton, Alexander Michael Scott; Liu, Zhuo-Hao; Shetty, Ashray Jayaram; Tremoleda, Jordi L.; Davies, Meirion; Deierborg, Tomas; Priestley, John V.; Brown, Guy Charles; Michael-Titus, Adina Teodora; Venero, Jose Luis; Burguillos, Miguel Angel

    2017-01-01

    Traumatic brain injury (TBI) is currently a major cause of morbidity and poor quality of life in Western society, with an estimate of 2.5 million people affected per year in Europe, indicating the need for advances in TBI treatment. Within the first 24 h after TBI, several inflammatory response factors become upregulated, including the lectin galectin-3. In this study, using a controlled cortical impact (CCI) model of head injury, we show a large increase in the expression of galectin-3 in microglia and also an increase in the released form of galectin-3 in the cerebrospinal fluid (CSF) 24 h after head injury. We report that galectin-3 can bind to TLR-4, and that administration of a neutralizing antibody against galectin-3 decreases the expression of IL-1β, IL-6, TNFα and NOS2 and promotes neuroprotection in the cortical and hippocampal cell populations after head injury. Long-term analysis demonstrated a significant neuroprotection in the cortical region in the galectin-3 knockout animals in response to TBI. These results suggest that following head trauma, released galectin-3 may act as an alarmin, binding, among other proteins, to TLR-4 and promoting inflammation and neuronal loss. Taking all together, galectin-3 emerges as a clinically relevant target for TBI therapy. PMID:28128358

  1. Cerebral mast cells contribute to postoperative cognitive dysfunction by promoting blood brain barrier disruption.

    PubMed

    Zhang, Susu; Dong, Hongquan; Zhang, Xiang; Li, Nana; Sun, Jie; Qian, Yanning

    2016-02-01

    Trauma induced neuroinflammation plays a key role in the development of postoperative cognitive dysfunction (POCD). The blood-brain barrier (BBB), a highly specialized endothelial layer, is exquisitely sensitive to inflammatory insults, which can result in numerous neurocognitive syndromes. While brain mast cells are the "first responder" in the injury, the functional interactions between mast cells and the BBB remain poorly understood. Our results demonstrate that tibial fracture surgery can induce cognitive impairment relating to an inflammatory response and destabilization of the BBB. Disodium cromoglycate (cromolyn)--which acts as a mast cell stabilizer--inhibited this effect. Specifically, cromolyn resulted in ameliorated cognitive ability, decrease of inflammatory cytokines and increase of BBB stability. Taken together, these results suggest that activated mast cells contributed to central nervous system inflammation and cognitive dysfunction by promoting BBB disruption, and interactions between mast cells and the BBB could constitute a new and unique therapeutic target for POCD.

  2. Rapid eye movement sleep promotes cortical plasticity in the developing brain.

    PubMed

    Dumoulin Bridi, Michelle C; Aton, Sara J; Seibt, Julie; Renouard, Leslie; Coleman, Tammi; Frank, Marcos G

    2015-07-01

    Rapid eye movement sleep is maximal during early life, but its function in the developing brain is unknown. We investigated the role of rapid eye movement sleep in a canonical model of developmental plasticity in vivo (ocular dominance plasticity in the cat) induced by monocular deprivation. Preventing rapid eye movement sleep after monocular deprivation reduced ocular dominance plasticity and inhibited activation of a kinase critical for this plasticity (extracellular signal-regulated kinase). Chronic single-neuron recording in freely behaving cats further revealed that cortical activity during rapid eye movement sleep resembled activity present during monocular deprivation. This corresponded to times of maximal extracellular signal-regulated kinase activation. These findings indicate that rapid eye movement sleep promotes molecular and network adaptations that consolidate waking experience in the developing brain.

  3. Rapid eye movement sleep promotes cortical plasticity in the developing brain

    PubMed Central

    Dumoulin Bridi, Michelle C.; Aton, Sara J.; Seibt, Julie; Renouard, Leslie; Coleman, Tammi; Frank, Marcos G.

    2015-01-01

    Rapid eye movement sleep is maximal during early life, but its function in the developing brain is unknown. We investigated the role of rapid eye movement sleep in a canonical model of developmental plasticity in vivo (ocular dominance plasticity in the cat) induced by monocular deprivation. Preventing rapid eye movement sleep after monocular deprivation reduced ocular dominance plasticity and inhibited activation of a kinase critical for this plasticity (extracellular signal–regulated kinase). Chronic single-neuron recording in freely behaving cats further revealed that cortical activity during rapid eye movement sleep resembled activity present during monocular deprivation. This corresponded to times of maximal extracellular signal–regulated kinase activation. These findings indicate that rapid eye movement sleep promotes molecular and network adaptations that consolidate waking experience in the developing brain. PMID:26601213

  4. Constraint-induced movement therapy promotes brain functional reorganization in stroke patients with hemiplegia

    PubMed Central

    Wang, Wenqing; Wang, Aihui; Yu, Limin; Han, Xuesong; Jiang, Guiyun; Weng, Changshui; Zhang, Hongwei; Zhou, Zhiqiang

    2012-01-01

    Stroke patients with hemiplegia exhibit flexor spasms in the upper limb and extensor spasms in the lower limb, and their movement patterns vary greatly. Constraint-induced movement therapy is an upper limb rehabilitation technique used in stroke patients with hemiplegia; however, studies of lower extremity rehabilitation are scarce. In this study, stroke patients with lower limb hemiplegia underwent conventional Bobath therapy for 4 weeks as baseline treatment, followed by constraint-induced movement therapy for an additional 4 weeks. The 10-m maximum walking speed and Berg balance scale scores significantly improved following treatment, and lower extremity motor function also improved. The results of functional MRI showed that constraint-induced movement therapy alleviates the reduction in cerebral functional activation in patients, which indicates activation of functional brain regions and a significant increase in cerebral blood perfusion. These results demonstrate that constraint-induced movement therapy promotes brain functional reorganization in stroke patients with lower limb hemiplegia. PMID:25337108

  5. Brain-derived neurotrophic factor promotes neurite growth and survival of antennal lobe neurons in brain from the silk moth, Bombyx mori in vitro.

    PubMed

    Kim, Jin Hee; Sung, Dong Kyung; Park, Chan Woo; Park, Hun Hee; Park, Cheolin; Jeon, Soung-Hoo; Kang, Pil Don; Kwon, O-Yu; Lee, Bong Hee

    2005-03-01

    This study was conducted to investigate effects of brain-derived neurotrophic factor on the neurite growth and the survival rate of antennal lobe neurons in vitro, and secretion of brain-derived neurotrophic factor-like neuropeptide from brain into hemolymph in the silk moth, Bombyx mori. In primary culture of antennal lobe neurons with brain-derived neurotrophic factor, it promoted both a neurite extension of putative antennal lobe projection neurons and an outgrowth of branches from principal neurites of putative antennal interneurons with significance (p<0.05). Brain-derived neurotrophic factor also increased significantly a survival rate of antennal lobe neurons (p<0.05). Results from immunolabeling of brain and retrocerebral complex, and ELISA assay of hemolymph showed that brain-derived neurotrophic factor-like neuropeptide was synthesized by both median and lateral neurosecretory cells of brain, then transported to corpora allata for storage, and finally secreted into hemolymph for action. These results will provide valuable information for differentiation of invertebrate brain neurons with brain-derived neurotrophic factor.

  6. Promoting social plasticity in developmental disorders with non-invasive brain stimulation techniques

    PubMed Central

    Boggio, Paulo S.; Asthana, Manish K.; Costa, Thiago L.; Valasek, Cláudia A.; Osório, Ana A. C.

    2015-01-01

    Being socially connected directly impacts our basic needs and survival. People with deficits in social cognition might exhibit abnormal behaviors and face many challenges in our highly social-dependent world. These challenges and limitations are associated with a substantial economical and subjective impact. As many conditions where social cognition is affected are highly prevalent, more treatments have to be developed. Based on recent research, we review studies where non-invasive neuromodulatory techniques have been used to promote Social Plasticity in developmental disorders. We focused on three populations where non-invasive brain stimulation seems to be a promising approach in inducing social plasticity: Schizophrenia, Autism Spectrum Disorder (ASD) and Williams Syndrome (WS). There are still very few studies directly evaluating the effects of transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) in the social cognition of these populations. However, when considering the promising preliminary evidences presented in this review and the limited amount of clinical interventions available for treating social cognition deficits in these populations today, it is clear that the social neuroscientist arsenal may profit from non-invasive brain stimulation techniques for rehabilitation and promotion of social plasticity. PMID:26388712

  7. Why and How Physical Activity Promotes Experience-Induced Brain Plasticity

    PubMed Central

    Kempermann, Gerd; Fabel, Klaus; Ehninger, Dan; Babu, Harish; Leal-Galicia, Perla; Garthe, Alexander; Wolf, Susanne A.

    2010-01-01

    Adult hippocampal neurogenesis is an unusual case of brain plasticity, since new neurons (and not just neurites and synapses) are added to the network in an activity-dependent way. At the behavioral level the plasticity-inducing stimuli include both physical and cognitive activity. In reductionistic animal studies these types of activity can be studied separately in paradigms like voluntary wheel running and environmental enrichment. In both of these, adult neurogenesis is increased but the net effect is primarily due to different mechanisms at the cellular level. Locomotion appears to stimulate the precursor cells, from which adult neurogenesis originates, to increased proliferation and maintenance over time, whereas environmental enrichment, as well as learning, predominantly promotes survival of immature neurons, that is the progeny of the proliferating precursor cells. Surprisingly, these effects are additive: boosting the potential for adult neurogenesis by physical activity increases the recruitment of cells following cognitive stimulation in an enriched environment. Why is that? We argue that locomotion actually serves as an intrinsic feedback mechanism, signaling to the brain, including its neural precursor cells, increasing the likelihood of cognitive challenges. In the wild (other than in front of a TV), no separation of physical and cognitive activity occurs. Physical activity might thus be much more than a generally healthy garnish to leading “an active life” but an evolutionarily fundamental aspect of “activity,” which is needed to provide the brain and its systems of plastic adaptation with the appropriate regulatory input and feedback. PMID:21151782

  8. cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling.

    PubMed

    Houslay, Miles D; Baillie, George S; Maurice, Donald H

    2007-04-13

    Cyclic AMP regulates a vast number of distinct events in all cells. Early studies established that its hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) controlled both the magnitude and the duration of its influence. Recent evidence shows that PDEs also act as coincident detectors linking cyclic-nucleotide- and non-cyclic-nucleotide-based cellular signaling processes and are tethered with great selectively to defined intracellular structures, thereby integrating and spatially restricting their cellular effects in time and space. Although 11 distinct families of PDEs have been defined, and cells invariably express numerous individual PDE enzymes, a large measure of our increased appreciation of the roles of these enzymes in regulating cyclic nucleotide signaling has come from studies on the PDE4 family. Four PDE4 genes encode more than 20 isoforms. Alternative mRNA splicing and the use of different promoters allows cells the possibility of expressing numerous PDE4 enzymes, each with unique amino-terminal-targeting and/or regulatory sequences. Dominant negative and small interfering RNA-mediated knockdown strategies have proven that particular isoforms can uniquely control specific cellular functions. Thus the protein kinase A phosphorylation status of the beta(2) adrenoceptor and, thereby, its ability to switch its signaling to extracellular signal-regulated kinase activation, is uniquely regulated by PDE4D5 in cardiomyocytes. We describe how cardiomyocytes and vascular smooth muscle cells selectively vary both the expression and the catalytic activities of PDE4 isoforms to regulate their various functions and how altered regulation of these processes can influence the development, or resolution, of cardiovascular pathologies, such as heart failure, as well as various vasculopathies.

  9. Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a 'low-affinity' phosphodiesterase 4 conformer.

    PubMed Central

    Souness, J. E.; Griffin, M.; Maslen, C.; Ebsworth, K.; Scott, L. C.; Pollock, K.; Palfreyman, M. N.; Karlsson, J. A.

    1996-01-01

    1. We have investigated the inhibitory effects of RP 73401 (piclamilast) and rolipram against human monocyte cyclic AMP-specific phosphodiesterase (PDE4) in relation to their effects on prostaglandin (PG)E2-induced cyclic AMP accumulation and lipopolysaccharide (LPS)-induced TNF alpha production and TNF alpha mRNA expression. 2. PDE4 was found to be the predominant PDE isoenzyme in the cytosolic fraction of human monocytes. Cyclic GMP-inhibited PDE (PDE3) was also detected in the cytosolic and particulate fractions. Reverse transcription polymerase chain reaction (RT-PCR) of human monocyte poly (A+) mRNA revealed amplified products corresponding to PDE4 subtypes A and B of which the former was most highly expressed. A faint band corresponding in size to PDE4D was also observed. 3. RP 73401 was a potent inhibitor of cytosolic PDE4 (IC50: 1.5 +/- 0.6 nM, n = 3). (+/-)-Rolipram (IC50: 313 +/- 6.7 nM, n = 3) was at least 200 fold less potent than RP 73401. R-(-)-rolipram was approximately 3 fold more potent than S-(+)-rolipram against cytosolic PDE4. 4. RP 73401 (IC50: 9.2 +/- 2.1 nM, n = 6) was over 50 fold more potent than (+/-)-rolipram (IC50: 503 +/- 134 nM, n = 6) ) in potentiating PGE2-induced cyclic AMP accumulation. R-(-)-rolipram (IC50: 289 +/- 121 nM, n = 5) was 4.7 fold more potent than its S-(+)-enantiomer (IC50: 1356 +/- 314 nM, n = 5). A strong and highly-significant, linear correlation (r = 0.95, P < 0.01, n = 13) was observed between the inhibitory potencies of a range of structurally distinct PDE4 inhibitors against monocyte PDE4 and their ED50 values in enhancing monocyte cyclic AMP accumulation. A poorer, though still significant, linear correlation (r = 0.67, P < 0.01, n = 13) was observed between the potencies of the same compounds in potentiating PGE2-induced monocyte cyclic AMP accumulation and their abilities to displace [3H]-rolipram binding to brain membranes. 5. RP 73401 (IC50: 6.9 +/- 3.3 nM, n = 5) was 71 fold more potent than

  10. Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury

    PubMed Central

    Ning, Ruizhuo; Xiong, Ye; Mahmood, Asim; Zhang, Yanlu; Meng, Yuling; Qu, Changsheng; Chopp, Michael

    2011-01-01

    Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 mo) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: 1) Saline group (n = 7); 2) EPO-6h group (n = 8); and 3) EPO-24h group (n = 8). EPO (5,000 U/kg in saline) was administered intraperitoneally at 6 h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) post injury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 mos after injury and brain sections stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO. PMID:21295557

  11. Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury.

    PubMed

    Ning, Ruizhuo; Xiong, Ye; Mahmood, Asim; Zhang, Yanlu; Meng, Yuling; Qu, Changsheng; Chopp, Michael

    2011-04-12

    Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 months) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: (1) saline group (n=7); (2) EPO-6h group (n=8); and (3) EPO-24h group (n=8). EPO (5000 U/kg in saline) was administered intraperitoneally at 6h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) postinjury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 months after injury and brain sections were stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO.

  12. An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice

    PubMed Central

    Ruseva, Marieta M.; Ramaglia, Valeria; Morgan, B. Paul; Harris, Claire L.

    2015-01-01

    Activation of complement is a key determinant of neuropathology and disability after traumatic brain injury (TBI), and inhibition is neuroprotective. However, systemic complement is essential to fight infections, a critical complication of TBI. We describe a targeted complement inhibitor, comprising complement receptor of the Ig superfamily (CRIg) fused with complement regulator CD59a, designed to inhibit membrane attack complex (MAC) assembly at sites of C3b/iC3b deposition. CRIg and CD59a were linked via the IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited MAC formation and prevented complement-mediated lysis in vitro. CD59-2a-CRIg dimer bound C3b-coated surfaces with submicromolar affinity (KD). In experimental TBI, CD59-2a-CRIg administered posttrauma homed to sites of injury and significantly reduced MAC deposition, microglial accumulation, mitochondrial stress, and axonal damage and enhanced neurologic recovery compared with placebo controls. CD59-2a-CRIg inhibited MAC-induced inflammasome activation and IL-1β production in microglia. Given the important anti-infection roles of complement opsonization, site-targeted inhibition of MAC should be considered to promote recovery postneurotrauma. PMID:26578778

  13. Brain-derived Neurotrophic Factor Promotes the Migration of Olfactory Ensheathing Cells Through TRPC Channels.

    PubMed

    Wang, Ying; Teng, Hong-Lin; Gao, Yuan; Zhang, Fan; Ding, Yu-Qiang; Huang, Zhi-Hui

    2016-12-01

    Olfactory ensheathing cells (OECs) are a unique type of glial cells with axonal growth-promoting properties in the olfactory system. Organized migration of OECs is essential for neural regeneration and olfactory development. However, the molecular mechanism of OEC migration remains unclear. In the present study, we examined the effects of brain-derived neurotrophic factor (BDNF) on OEC migration. Initially, the "scratch" migration assay, the inverted coverslip and Boyden chamber migration assays showed that BDNF could promote the migration of primary cultured OECs. Furthermore, BDNF gradient attracted the migration of OECs in single-cell migration assays. Mechanistically, TrkB receptor expressed in OECs mediated BDNF-induced OEC migration, and BDNF triggered calcium signals in OECs. Finally, transient receptor potential cation channels (TRPCs) highly expressed in OECs were responsible for BDNF-induced calcium signals, and required for BDNF-induced OEC migration. Taken together, these results demonstrate that BDNF promotes the migration of cultured OECs and an unexpected finding is that TRPCs are required for BDNF-induced OEC migration. GLIA 2016;64:2154-2165.

  14. β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post-stroke brain.

    PubMed

    Fujioka, Teppei; Kaneko, Naoko; Ajioka, Itsuki; Nakaguchi, Kanako; Omata, Taichi; Ohba, Honoka; Fässler, Reinhard; García-Verdugo, José Manuel; Sekiguchi, Kiyotoshi; Matsukawa, Noriyuki; Sawamoto, Kazunobu

    2017-02-01

    Cerebral ischemic stroke is a main cause of chronic disability. However, there is currently no effective treatment to promote recovery from stroke-induced neurological symptoms. Recent studies suggest that after stroke, immature neurons, referred to as neuroblasts, generated in a neurogenic niche, the ventricular-subventricular zone, migrate toward the injured area, where they differentiate into mature neurons. Interventions that increase the number of neuroblasts distributed at and around the lesion facilitate neuronal repair in rodent models for ischemic stroke, suggesting that promoting neuroblast migration in the post-stroke brain could improve efficient neuronal regeneration. To move toward the lesion, neuroblasts form chain-like aggregates and migrate along blood vessels, which are thought to increase their migration efficiency. However, the molecular mechanisms regulating these migration processes are largely unknown. Here we studied the role of β1-class integrins, transmembrane receptors for extracellular matrix proteins, in these migrating neuroblasts. We found that the neuroblast chain formation and blood vessel-guided migration critically depend on β1 integrin signaling. β1 integrin facilitated the adhesion of neuroblasts to laminin and the efficient translocation of their soma during migration. Moreover, artificial laminin-containing scaffolds promoted neuroblast chain formation and migration toward the injured area. These data suggest that laminin signaling via β1 integrin supports vasculature-guided neuronal migration to efficiently supply neuroblasts to injured areas. This study also highlights the importance of vascular scaffolds for cell migration in development and regeneration.

  15. Early-life exercise may promote lasting brain and metabolic health through gut bacterial metabolites.

    PubMed

    Mika, Agnieszka; Fleshner, Monika

    2016-02-01

    The 100 trillion microorganisms residing within our intestines contribute roughly 5 million additional genes to our genetic gestalt, thus posing the potential to influence many aspects of our physiology. Microbial colonization of the gut shortly after birth is vital for the proper development of immune, neural and metabolic systems, while sustaining a balanced, diverse gut flora populated with beneficial bacteria is necessary for maintaining optimal function of these systems. Although symbiotic host-microbial interactions are important throughout the lifespan, these interactions can have greater and longer lasting impacts during certain critical developmental periods. A better understanding of these sensitive periods is necessary to improve the impact and effectiveness of health-promoting interventions that target the microbial ecosystem. We have recently reported that exercise initiated in early life increases gut bacterial species involved in promoting psychological and metabolic health. In this review, we emphasize the ability of exercise during this developmentally receptive time to promote optimal brain and metabolic function across the lifespan through microbial signals.

  16. LRG1 promotes angiogenesis through upregulating the TGF-β1 pathway in ischemic rat brain

    PubMed Central

    Meng, Hongmei; Song, Yuejia; Zhu, Jiyuan; Liu, Qi; Lu, Pengtian; Ye, Na; Zhang, Zhen; Pang, Yuxin; Qi, Jiping; Wu, He

    2016-01-01

    Stroke is a life-threatening disease that results in significant disability in the human population. Despite the advances in current stroke therapies, a host of patients do not benefit from the conventional treatments. Thus, more effective therapies are required. It has been previously reported that leucine-rich-α2-glycoprotein 1 (LRG1) is crucial during the formation of new blood vessels in retinal diseases. However, the function of LRG1 in the brain during the neovessel growth process following ischemic stroke has not been fully elucidated and the mechanism underlying its effect on angiogenesis remains unclear. The purpose of the current study was to demonstrate whether LRG1 may promote angiogenesis through the transforming growth factor (TGF)-β1 signaling pathway in ischemic rat brain following middle cerebral artery occlusion (MCAO). In the present study, the spatial and temporal expression of LRG1, TGF-β1, vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were detected in ischemic rat brain following MCAO using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunohistochemistry. CD34 immunohistochemistry staining was used as an indicator of microvessel density (MVD). The RT-qPCR and western blotting results revealed that the levels of LRG1 and TGF-β1 mRNA and protein expression were significantly increased as early as 6 and 12 h after MCAO (P<0.05), respectively, peaked at 3 days and persisted at significantly higher level until 14 days, in comparison with the control group. Additionally, VEGF and Ang-2 were also increased following MCAO. Furthermore, the immunohistochemistry results suggested that the MVD was increased following MCAO. In addition, the results also revealed that the percentage of LRG1-positive cells was positively correlated with the percentage of TGF-β1-positive cells, and the percentage of LRG1-positive and TGF-β1-positive cells had a positively correlation with the

  17. Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer.

    PubMed

    Shen, Liqin; Chen, Lei; Wang, Yongsheng; Jiang, Xiaochun; Xia, Hongping; Zhuang, Zhixiang

    2015-01-01

    Brain metastasis often has a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Therefore, it is urgent to identify factors associated with lung cancer brain metastasis. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) also known as noncoding nuclear-enriched abundant transcript 2 is a long noncoding RNA, which is highly conserved amongst mammals. It has been shown to be increased in a variety of tumors including NSCLC and regulate the expression of metastasis-associated genes. However, the role of MALAT1 in lung cancer brain metastasis has not been investigated. In this study, we examined the level of MALAT1 in 78 cases of NSCLC samples with 19 brain metastasis and 59 non-brain metastasis by qRT-PCR. We observed that the level of MALAT1 was significantly higher in brain metastasis than that of non brain metastasis samples (P < 0.001). The level of MALAT1 was associated with patients' survival. To investigate the role of MALAT1 in brain metastasis, we established a highly invasive and metastatic cell subline using the brain metastasis lung cancer cell H1915. We found that MALAT1 is increased in highly invasive subline of brain metastasis lung cancer cells. Further functional studies indicate that silencing MALAT1 inhibits highly invasive subline of brain metastasis lung cancer cell migration and metastasis by inducing epithelial-mesenchymal transition (EMT). Therefore, increased level of long noncoding RNA MALAT1 promotes lung cancer brain metastasis by inducing EMT, which may be a promising prognosis factor and therapeutic target to treat lung cancer brain metastasis in future.

  18. Dietary cholesterol promotes repair of demyelinated lesions in the adult brain

    PubMed Central

    Berghoff, Stefan A.; Gerndt, Nina; Winchenbach, Jan; Stumpf, Sina K.; Hosang, Leon; Odoardi, Francesca; Ruhwedel, Torben; Böhler, Carolin; Barrette, Benoit; Stassart, Ruth; Liebetanz, David; Dibaj, Payam; Möbius, Wiebke; Edgar, Julia M.; Saher, Gesine

    2017-01-01

    Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes. PMID:28117328

  19. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits.

    PubMed

    De Vadder, Filipe; Kovatcheva-Datchary, Petia; Goncalves, Daisy; Vinera, Jennifer; Zitoun, Carine; Duchampt, Adeline; Bäckhed, Fredrik; Mithieux, Gilles

    2014-01-16

    Soluble dietary fibers promote metabolic benefits on body weight and glucose control, but underlying mechanisms are poorly understood. Recent evidence indicates that intestinal gluconeogenesis (IGN) has beneficial effects on glucose and energy homeostasis. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate, which are generated by fermentation of soluble fiber by the gut microbiota, activate IGN via complementary mechanisms. Butyrate activates IGN gene expression through a cAMP-dependent mechanism, while propionate, itself a substrate of IGN, activates IGN gene expression via a gut-brain neural circuit involving the fatty acid receptor FFAR3. The metabolic benefits on body weight and glucose control induced by SCFAs or dietary fiber in normal mice are absent in mice deficient for IGN, despite similar modifications in gut microbiota composition. Thus, the regulation of IGN is necessary for the metabolic benefits associated with SCFAs and soluble fiber.

  20. Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: a novel mechanism for the clinical efficacy of roflumilast in severe chronic obstructive pulmonary disease.

    PubMed

    Moodley, Thunicia; Wilson, Sylvia M; Joshi, Taruna; Rider, Christopher F; Sharma, Pawan; Yan, Dong; Newton, Robert; Giembycz, Mark A

    2013-04-01

    Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit. In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized. Given that roflumilast is recommended as an "add-on" medication to patients with severe disease who will inevitably be taking a long-acting β2-adrenoceptor agonist (LABA)/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity. Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells [both bronchial epithelium + adenovirus 12 - SV40 hybrid (BEAS-2B) cells and primary cultures], roflumilast enhanced fluticasone propionate-induced GRE-dependent transcription. Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the LABA formoterol. In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential. We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy. Roflumilast may, therefore, be especially effective in patients with severe COPD.

  1. Methamphetamine-induced nitric oxide promotes vesicular transport in blood-brain barrier endothelial cells.

    PubMed

    Martins, Tânia; Burgoyne, Thomas; Kenny, Bridget-Ann; Hudson, Natalie; Futter, Clare E; Ambrósio, António F; Silva, Ana P; Greenwood, John; Turowski, Patric

    2013-02-01

    Methamphetamine's (METH) neurotoxicity is thought to be in part due to its ability to induce blood-brain barrier (BBB) dysfunction. Here, we investigated the effect of METH on barrier properties of cultured rat primary brain microvascular endothelial cells (BMVECs). Transendothelial flux doubled in response to METH, irrespective of the size of tracer used. At the same time, transendothelial electrical resistance was unchanged as was the ultrastructural appearance of inter-endothelial junctions and the distribution of key junction proteins, suggesting that METH promoted vesicular but not junctional transport. Indeed, METH significantly increased uptake of horseradish peroxidase into vesicular structures. METH also enhanced transendothelial migration of lymphocytes indicating that the endothelial barrier against both molecules and cells was compromised. Barrier breakdown was only observed in response to METH at low micromolar concentrations, with enhanced vesicular uptake peaking at 1 μM METH. The BMVEC response to METH also involved rapid activation of endothelial nitric oxide synthase and its inhibition abrogated METH-induced permeability and lymphocyte migration, indicating that nitric oxide was a key mediator of BBB disruption in response to METH. This study underlines the key role of nitric oxide in BBB function and describes a novel mechanism of drug-induced fluid-phase transcytosis at the BBB.

  2. Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia.

    PubMed

    Mori, Marco Aurélio; Meyer, Erika; Soares, Ligia Mendes; Milani, Humberto; Guimarães, Francisco Silveira; de Oliveira, Rúbia Maria Weffort

    2017-04-03

    This study investigated the effects of cannabidiol (CBD), a non-psychotomimetic phytochemical present in Cannabis sativa, on the cognitive and emotional impairments induced by bilateral common carotid artery occlusion (BCCAO) in mice. Using a multi-tiered behavioral testing battery during 21days, we found that BCCAO mice exhibited long-lasting functional deficits reflected by increase in anxiety-like behavior (day 9), memory impairments (days 12-18) and despair-like behavior (day 21). Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO. In addition, ischemic mice treated with CBD exhibited an increase in the hippocampal brain derived neurotrophic factor (BDNF) protein levels. CBD also stimulated neurogenesis and promoted dendritic restructuring in the hippocampus of BCCAO animals. Collectively, the present results demonstrate that short-term CBD treatment results in global functional recovery in ischemic mice and impacts multiple and distinct targets involved in the pathophysiology of brain ischemic injury.

  3. Strategies to promote differentiation of newborn neurons into mature functional cells in Alzheimer brain.

    PubMed

    Schaeffer, Evelin L; Novaes, Barbara A; da Silva, Emanuelle R; Skaf, Heni D; Mendes-Neto, Alvaro G

    2009-10-01

    Adult neurogenesis occurs in the subgranular zone (SGZ) and subventricular zone (SVZ). New SGZ neurons migrate into the granule cell layer of the dentate gyrus (DG). New SVZ neurons seem to enter the association neocortex and entorhinal cortex besides the olfactory bulb. Alzheimer disease (AD) is characterized by neuron loss in the hippocampus (DG and CA1 field), entorhinal cortex, and association neocortex, which underlies the learning and memory deficits. We hypothesized that, if the AD brain can support neurogenesis, strategies to stimulate the neurogenesis process could have therapeutic value in AD. We reviewed the literature on: (a) the functional significance of adult-born neurons; (b) the occurrence of endogenous neurogenesis in AD; and (c) strategies to stimulate the adult neurogenesis process. We found that: (a) new neurons in the adult DG contribute to memory function; (b) new neurons are generated in the SGZ and SVZ of AD brains, but they fail to differentiate into mature neurons in the target regions; and (c) numerous strategies (Lithium, Glatiramer Acetate, nerve growth factor, environmental enrichment) can enhance adult neurogenesis and promote maturation of newly generated neurons. Such strategies might help to compensate for the loss of neurons and improve the memory function in AD.

  4. Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke.

    PubMed

    Cook, Douglas J; Nguyen, Cynthia; Chun, Hyun N; L Llorente, Irene; Chiu, Abraham S; Machnicki, Michal; Zarembinski, Thomas I; Carmichael, S Thomas

    2017-03-01

    Stroke is the leading cause of adult disability. Systemic delivery of candidate neural repair therapies is limited by the blood-brain barrier and off-target effects. We tested a bioengineering approach for local depot release of BDNF from the infarct cavity for neural repair in chronic periods after stroke. The brain release levels of a hyaluronic acid hydrogel + BDNF were tested in several stroke models in mouse (strains C57Bl/6, DBA) and non-human primate ( Macaca fascicularis) and tracked with MRI. The behavioral recovery effects of hydrogel + BDNF and the effects on tissue repair outcomes were determined. Hydrogel-delivered BDNF diffuses from the stroke cavity into peri-infarct tissue over 3 weeks in two mouse stroke models, compared with 1 week for direct BDNF injection. Hydrogel delivery of BDNF promotes recovery of motor function. Mapping of motor system connections indicates that hydrogel-BDNF induces axonal sprouting within existing cortical and cortico-striatal systems. Pharmacogenetic studies show that hydrogel-BDNF induces the initial migration of immature neurons into the peri-infarct cortex and their long-term survival. In chronic stroke in the non-human primate, hydrogel-released BDNF can be detected up to 2 cm from the infarct, a distance relevant to human functional recovery in stroke. The hydrogel can be tracked by MRI in mouse and primate.

  5. Ovarian brain-derived neurotrophic factor (BDNF) promotes the development of oocytes into preimplantation embryos

    PubMed Central

    Kawamura, Kazuhiro; Kawamura, Nanami; Mulders, Sabine M.; Gelpke, Maarten D. Sollewijn; Hsueh, Aaron J. W.

    2005-01-01

    Optimal development of fertilized eggs into preimplantation embryos is essential for reproduction. Although mammalian oocytes ovulated after luteinizing hormone (LH) stimulation can be fertilized and promoted into early embryos in vitro, little is known about ovarian factors important for the conditioning of eggs for early embryo development. Because LH interacts only with ovarian somatic cells, its potential regulation of oocyte functions is presumably mediated by local paracrine factors. We performed DNA microarray analyses of ovarian transcripts and identified brain-derived neurotrophic factor (BDNF) secreted by granulosa and cumulus cells as an ovarian factor stimulated by the preovulatory LH surge. Ovarian BDNF acts on TrkB receptors expressed exclusively in oocytes to enhance first polar body extrusion of oocytes and to promote the in vitro development of zygotes into preimplantation embryos. Furthermore, in vivo treatment with a Trk receptor inhibitor suppressed first polar body extrusion and the progression of zygotes into blastocysts. Thus, ovarian BDNF is important to nuclear and cytoplasmic maturation of the oocyte, which is essential for successful oocyte development into preimplantation embryos. Treatment with BDNF could condition the cultured oocytes for optimal progression into the totipotent blastocysts. PMID:15967989

  6. Promoting Adaptive Behavior in Persons with Acquired Brain Injury, Extensive Motor and Communication Disabilities, and Consciousness Disorders

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Belardinelli, Marta Olivetti; Buonocunto, Francesca; Sacco, Valentina; Navarro, Jorge; Lanzilotti, Crocifissa; De Tommaso, Marina; Megna, Marisa; Badagliacca, Francesco

    2012-01-01

    These two studies extended the evidence on the use of technology-based intervention packages to promote adaptive behavior in persons with acquired brain injury and multiple disabilities. Study I involved five participants in a minimally conscious state who were provided with intervention packages based on specific arrangements of optic, tilt, or…

  7. Transcriptional activity of novel ALDH1L1 promoters in the rat brain following AAV vector-mediated gene transfer

    PubMed Central

    Mudannayake, Janitha M; Mouravlev, Alexandre; Fong, Dahna M; Young, Deborah

    2016-01-01

    Aldehyde dehydrogenase family 1, member L1 (ALDH1L1) is a recently characterized pan-astrocytic marker that is more homogenously expressed throughout the brain than the classic astrocytic marker, glial fibrillary acidic protein. We generated putative promoter sequence variants of the rat ALDH1L1 gene for use in adeno-associated viral vector-mediated gene transfer, with an aim to achieve selective regulation of transgene expression in astrocytes in the rat brain. Unexpectedly, ALDH1L1 promoter variants mediated transcriptional activity exclusively in neurons in the substantia nigra pars compacta as assessed by luciferase reporter expression at 3 weeks postvector infusion. This selectivity for neurons in the substantia nigra pars compacta also persisted in the context of adeno-associated viral serotype 5, 8 or 9 vector-mediated gene delivery. An in vivo promoter comparison showed the highest performing ALDH1L1 promoter variant mediated higher transgene expression than the neuronal-specific synapsin 1 and tyrosine hydroxylase promoters. The ALDH1L1 promoter was also transcriptionally active in dentate granule neurons following intrahippocampal adeno-associated viral vector infusion, whereas transgene expression was detected in both striatal neurons and astrocytes following vector infusion into the striatum. Our results demonstrate the potential suitability of the ALDH1L1 promoter as a new tool in the development of gene therapy and disease modelling applications. PMID:27990448

  8. Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1.

    PubMed

    McCarty, Mark F; DiNicolantonio, James J; O'Keefe, James H

    2015-11-01

    Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1's obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet - an effect plausibly attributable to Sirt1 activation. Increased activities of HIF-1 and Sirt1, and a decrease in mTORC1 activity, could be expected to collaborate in the induction of neuronal macroautophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration, presumably contribute to this protection. Hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis - notably carnitine and hydroxycitrate - in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance.

  9. Astrocytes Promote Oligodendrogenesis after White Matter Damage via Brain-Derived Neurotrophic Factor

    PubMed Central

    Miyamoto, Nobukazu; Maki, Takakuni; Shindo, Akihiro; Liang, Anna C.; Maeda, Mitsuyo; Egawa, Naohiro; Itoh, Kanako; Lo, Evan K.; Lok, Josephine; Ihara, Masafumi

    2015-01-01

    Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAPcre/BDNFwt/fl) in which BDNF expression is downregulated specifically in GFAP+ astrocytes. Both wild-type (GFAPwt/BDNFwt/fl mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF. SIGNIFICANCE STATEMENT The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white

  10. GAL4-NF-kappaB fusion protein augments transgene expression from neuronal promoters in the rat brain.

    PubMed

    Liu, B H; Yang, Y; Paton, J F R; Li, F; Boulaire, J; Kasparov, S; Wang, S

    2006-12-01

    Targeted gene expression mediated by a mammalian cellular promoter is desirable for gene therapy in the brain, where there are a variety of different neuronal phenotypes, several types of supportive cells, and blood vessels. However, this approach can be hampered by weak activity of some cellular promoters. In view of the potency of the transcription factor NF-kappaB in regulating neuronal gene expression, we have assessed whether it can be used to enhance the strength of neuron-specific promoters. Our approach was to use a neuronal promoter to drive expression of a chimeric transactivator, which consisted of a part of the transcriptional activation domain of the NF-kappaB p65 protein fused to the DNA-binding domain of GAL4 protein from yeast. The second copy of the neuronal promoter was modified by introducing the unique GAL4 binding sequences at its 5' end and used to drive the expression of a transgene. Binding of the chimeric transcriptional activator upstream of the second promoter was expected to potentiate its transcriptional activity. In this study, the approach was applied to the platelet-derived growth factor beta chain and synapsin-1 neuron-specific promoters and tested in vitro and in vivo using plasmid, lentiviral, and baculoviral vectors. We observed up to a 100-fold improvement in reporter gene expression in cultured neurons and 20-fold improvement in the rat brain in vivo. Moreover, the cell-type specificity of the two tested promoters was well preserved and restricted to neurons. Finally, the expression driven by the new lentiviral vectors with the p65-potentiated synapsin-1 promoter showed no signs of decline or cell damage 4 weeks after injection. This approach should be suitable for constructing powerful and stable gene expression systems based on weak cell-specific promoters in neuronal phenotypes.

  11. Lack of DNA binding in the rat nasal mucosa and other tissues of the nasal toxicants roflumilast, a phosphodiesterase 4 inhibitor, and a metabolite, 4-amino-3,5-dichloropyridine, in contrast to the nasal carcinogen 2,6-dimethylaniline.

    PubMed

    Jeffrey, Alan M; Luo, Feng-Qi; Amin, Shantilal; Krzeminski, Jacek; Zech, Karl; Williams, Gary M

    2002-02-01

    The phosphodiesterase 4 inhibitor Roflumilast (B9302-107) (RF) and its metabolite 4-amino-3,5-dichloropyridine (ADCP) produced nasal toxicity in preclinical safety studies with rats. The purpose of this study was to assess the possible formation of DNA adducts, by RF and ADCP, in the nasal mucosa, liver and testes of male rats using the 32P-postlabeling assay. For comparison, rats were exposed to the DNA-reactive carcinogens 2,6-dimethylaniline (DMA), also known as 2,6-xylidine, a nasal carcinogen, and the aromatic amine carcinogens 4,4'-methylene-bis(2-chloroaniline) (MOCA), which yields monocyclic DNA adducts, and 2-acetylaminofluorene (2-AAF). In the case of RF, possible sources of DNA adducts include the parent molecule and its ADCP moiety by enzymatic N-hydroxylation and sulfation, reactions typical of carcinogenic aromatic amines. 4-Acetoxylamino-3,5-dichloropyridine (N-acetoxy-ADCP), a chemically activated derivative of ADCP, was prepared and used to modify DNA which was then used to establish the chromatographic conditions with which to reliably detect whether or not such adducts were formed metabolically from RF and ADCP. Similarly, a standard N-hydroxy-DMA was prepared, but the corresponding N-acetoxy derivative was unstable and decomposed during synthesis. Both N-hydroxy-DMA and N-acetoxy-ADCP were mutagenic in the Salmonella typhimurium Ames assay using strain TA100 without an exogenous bioactivation system, with the former being more potent. N-hydroxy-ADCP was essentially inactive in this assay. For the 32P-postlabeling assay, male Wistar rats were exposed to the test substances and carrier control compounds by intragastric instillation at the selected dose levels for 7 days. Subsequently, the nasal mucosa, liver, and testes of the rats exposed to the test or control compounds were extirpated, the DNA extracted and the samples postlabeled. The patterns of adducts formed with the test compounds were compared to those formed in N-acetoxy-ADCP- and N

  12. Linking ATM Promoter Methylation to Cell Cycle Protein Expression in Brain Tumor Patients: Cellular Molecular Triangle Correlation in ATM Territory.

    PubMed

    Mehdipour, P; Karami, F; Javan, Firouzeh; Mehrazin, M

    2015-08-01

    Ataxia telangiectasia mutated (ATM) is a key gene in DNA double-strand break (DSB), and therefore, most of its disabling genetic alterations play an important initiative role in many types of cancer. However, the exact role of ATM gene and its epigenetic alterations, especially promoter methylation in different grades of brain tumors, remains elusive. The current study was conducted to query possible correlations among methylation statue of ATM gene, ATM/ retinoblastoma (RB) protein expression, D1853N ATM polymorphism, telomere length (TL), and clinicopathological characteristics of various types of brain tumors. Isolated DNA from 30 fresh tissues was extracted from different types of brain tumors and two brain tissues from deceased normal healthy individuals. DNAs were treated with bisulfate sodium using DNA modification kit (Qiagen). Methylation-specific polymerase chain reaction (MSP-PCR) was implicated to determine the methylation status of treated DNA templates confirmed by promoter sequencing. Besides, the ATM and RB protein levels were determined by immunofluorescence (IF) assay using monoclonal mouse antihuman against ATM, P53, and RB proteins. To achieve an interactive correlation, the methylation data were statistically analyzed by considering TL and D1853N ATM polymorphism. More than 73% of the brain tumors were methylated in ATM gene promoter. There was strong correlation between ATM promoter methylation and its protein expression (p < 0.001). As a triangle, meaningful correlation was also found between methylated ATM promoter and ATM protein expression with D1853N ATM polymorphism (p = 0.01). ATM protein expression was not in line with RB protein expression while it was found to be significantly correlated with ATM promoter methylation (p = 0.01). There was significant correlation between TL neither with ATM promoter methylation nor with ATM protein expression nor with D1853N polymorphism. However, TL has shown strong correlation with patient's age and

  13. Promotion

    PubMed Central

    Alam, Hasan B.

    2013-01-01

    This article gives an overview of the promotion process in an academic medical center. A description of different promotional tracks, tenure and endowed chairs, and the process of submitting an application is provided. Finally, some practical advice about developing skills and attributes that can help with academic growth and promotion is dispensed. PMID:24436683

  14. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

    PubMed

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-21

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.

  15. Defining the critical hypoxic threshold that promotes vascular remodeling in the brain.

    PubMed

    Boroujerdi, Amin; Milner, Richard

    2015-01-01

    In animal models, hypoxic pre-conditioning confers protection against subsequent neurological insults, mediated in part through an extensive vascular remodeling response. In light of the therapeutic potential of this effect, the goal of this study was to establish the dose-response relationship between level of hypoxia and the extent of cerebrovascular modeling, and to define the mildest level of hypoxia that promotes remodeling. Mice were exposed to different levels of continuous hypoxia (8-21% O2) for seven days before several aspects of vascular remodeling were evaluated, including endothelial proliferation, total vascular area, arteriogenesis, and fibronectin/α5β1 integrin expression. For most events, the threshold level of hypoxia that stimulated remodeling was 12-13% O2. Interestingly, many parameters displayed a biphasic dose-response curve, with peak levels attained at 10% O2, but declined thereafter. Further analysis in the 12-13% O2 range revealed that vascular remodeling occurs by two separate mechanisms: (i) endothelial hyperplasia, triggered by a hypoxic threshold of 13% O2, which leads to increased capillary growth, and (ii) endothelial hypertrophy, triggered by a more severe hypoxic threshold of 12% O2, which leads to expansion of large vessels and arteriogenesis. Taken together, these results define the hypoxic thresholds for vascular remodeling in the brain, and point to two separate mechanisms mediating this process.

  16. Viral-mediated delivery of an RXFP3 agonist into brain promotes arousal in mice.

    PubMed

    Smith, Craig M; Blasiak, Anna; Ganella, Despina E; Chua, Berenice E; Layfield, Sharon L; Bathgate, Ross A D; Gundlach, Andrew L

    2013-01-01

    Anatomical and functional studies of central relaxin-3/RXFP3 systems suggest they constitute an ascending arousal network. For example, relaxin-3 knockout mice display circadian hypoactivity compared to wild type littermate controls. In studies to explore the effect of chronic RXFP3 activation on behaviour, we engineered a lentiviral construct to constitutively secrete the RXFP3 agonist, R3/I5, and express a green fluorescent protein (GFP) marker in transduced cells. Intracerebroventricular injection of the lenti-R3/I5-GFP virus (-10(power)8 genomic copies in 2 microl) in adult C57BL/6J mice resulted in GFP expression within cells of the ventricle walls and choroid plexus over a period of 1-4 weeks, suggesting likely chronic R3/I5 secretion and RXFP3 activation in brain regions proximal to the ventricular system. Subsequent testing in automated locomotor cells on day 8 and 9 post-injection revealed that lenti-R3/I5-GFP treated mice displayed prolonged, elevated locomotor activity (-18% higher over the last 15 min on day 8, and over the entire 30 min test on day 9) compared to mice injected with a control lenti-GFP virus, which habituated normally to the novel environment (n = 18/12 respectively, p < 0.05). These findings are consistent with an earlier report of increased activity scores in rats acutely injected centrally with R3/I5, and further suggest a role for relaxin-3/RXFP3 signalling in promoting behavioural arousal.

  17. Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain.

    PubMed

    Xing, Fei; Kobayashi, Aya; Okuda, Hiroshi; Watabe, Misako; Pai, Sudha K; Pandey, Puspa R; Hirota, Shigeru; Wilber, Andrew; Mo, Yin-Yuan; Moore, Brian E; Liu, Wen; Fukuda, Koji; Iiizumi, Megumi; Sharma, Sambad; Liu, Yin; Wu, Kerui; Peralta, Elizabeth; Watabe, Kounosuke

    2013-03-01

    Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then 'activated' surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.

  18. Serpins promote cancer cell survival and vascular co-option in brain metastasis.

    PubMed

    Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

    2014-02-27

    Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

  19. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

    PubMed

    Zhang, Kuan; Zhou, Yanzhao; Zhao, Tong; Wu, Liying; Huang, Xin; Wu, Kuiwu; Xu, Lun; Li, Dahu; Liu, Shuhong; Zhao, Yongqi; Fan, Ming; Zhu, Lingling

    2015-01-01

    Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

  20. Molecular pathways: tumor cells Co-opt the brain-specific metabolism gene CPT1C to promote survival.

    PubMed

    Reilly, Patrick T; Mak, Tak W

    2012-11-01

    The metabolic adaptations of cancer cells are receiving renewed attention as potential targets for therapeutic exploitation. Recent work has highlighted the importance of fatty acid catabolism through β-oxidation to cellular energy homeostasis. In this article, we describe recent preclinical studies suggesting that a gene usually expressed only in the brain, carnitine palmitoyltransferase (CPT)1C, promotes cancer cell survival and tumor growth. CTP1C confers rapamycin resistance on breast cancer cells, indicating that this gene may act in a pathway parallel to mTOR-enhanced glycolysis. Because of CPT1C's normally brain-restricted expression and the inability of most drugs to pass the blood-brain barrier, CPT1C may be an ideal candidate for specific small-molecule inhibition. We further speculate that concurrent targeting of CPT1C activity and glycolysis in tumor cells could be a highly effective anticancer approach.

  1. Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion

    SciTech Connect

    Chatterjee, Somik; Yin, Hongshan; Nam, Deokhwa; Li, Yong; Ma, Ke

    2015-02-01

    Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1{sup −/−} mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases. - Highlights: • Bmal1 is highly inducible by muscle injury and myogenic stimuli. • Genetic ablation of Bmal1 significantly impairs muscle regeneration. • Bmal1 promotes satellite cell expansion during muscle regeneration. • Bmal1-deficient primary myoblasts display attenuated growth and proliferation.

  2. Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters.

    PubMed

    Kokaia, Z; Metsis, M; Kokaia, M; Bengzon, J; Elmér, E; Smith, M L; Timmusk, T; Siesjö, B K; Persson, H; Lindvall, O

    1994-04-01

    The rat brain-derived neurotrophic factor (BDNF) gene consists of four short 5'-exons linked to separate promoters and one 3'-exon encoding the mature BDNF protein. Using in situ hybridization we demonstrate here that kindling-induced seizures, cerebral ischaemia and insulin-induced hypoglycaemic coma increase BDNF mRNA levels through insult- and region-specific usage of three promoters within the BDNF gene. Both brief (2 min) and longer (10 min) periods of forebrain ischaemia induced significant and major increases only of exon III mRNA in the dentate gyrus. Following hypoglycaemic coma (1 and 30 min), exon III mRNA was markedly elevated in the dentate gyrus and, in addition, exon I mRNA showed a moderate increase. Single and recurrent (n = 40) hippocampal seizures significantly increased expression of exon I, II and III mRNAs in the dentate gyrus granule cells. After recurrent seizures, including generalized convulsions, there were also major increases of both exon I and III mRNAs in the CA3 region, amygdala, piriform cortex and neocortex, whereas in the hippocampal CA1 sector marked elevations were detected only for exon III mRNA. The insults had no effect on the level of exon IV mRNA in the brain. The region- and insult-specific pattern of promoter activation might be of importance for the effectiveness of protective responses as well as for the regulation of plastic changes following brain insults.

  3. Neuroprotective effect of buyang huanwu decoction on rat ischemic/reperfusion brain damage by promoting migration of neural precursor cells.

    PubMed

    Kong, Xiangying; Su, Xiaohui; Zhu, Jia; Wang, Jianzhu; Wan, Hongye; Zhong, Micun; Li, Li; Lin, Na

    2014-06-01

    Buyang Huanwu Decoction (BYHWD) is a classic formula widely used for treating stroke-induced disability, the highest morbidity of neurological disorders in China. However, the mechanism of its neuroprotection has not been fully clarified. Previous reports indicated that BYHWD may promote growth and differentiation of neural precursor cells (NPCs). The present study focused on the effects of BYHWD on migration of NPCs in rats with middle cerebral artery occlusion (MCAO). Rats were treated with different doses of BYHWD (12 and 24 grams/kg) from day 1 to day 21 after model building. BYHWD could increase the survival rate and decrease neurological scores and infarct volume as compared with the vehicle-treated MCAO rats. Moreover, BYHWD treatment significantly increased 5-bromo-2-deoxyuridine (BrdU)-positive cells in the subventricular zone (SVZ), subgranular zone (SGZ), and corpus striatum (CS) of the infarct brain. Interestingly, BYHWD could markedly enhance BrdU(+)/doublecortin(+) cells not only in the SVZ and SGZ but also in CS, by up-regulating the protein expression of migration activators, including stromal cell derived factor-1, CXC chemokine receptor 4, vascular endothelial growth factor, Reelin, and brain-derived neurotrophic factor in the ipsilateral infarct area after MCAO. In addition, BYHWD treatment was able to promote the neuronal differentiation, which was closely related to the migratory process of NPCs in MCAO rats. These findings offer evidence for the first time that BYHWD may exert its neuroprotective effects partially by promotion of NPCs migration to ischemic brain areas.

  4. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate

    PubMed Central

    Sleiman, Sama F; Henry, Jeffrey; Al-Haddad, Rami; El Hayek, Lauretta; Abou Haidar, Edwina; Stringer, Thomas; Ulja, Devyani; Karuppagounder, Saravanan S; Holson, Edward B; Ratan, Rajiv R; Ninan, Ipe; Chao, Moses V

    2016-01-01

    Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF. DOI: http://dx.doi.org/10.7554/eLife.15092.001 PMID:27253067

  5. Injection parameters and virus dependent choice of promoters to improve neuron targeting in the nonhuman primate brain.

    PubMed

    Lerchner, W; Corgiat, B; Der Minassian, V; Saunders, R C; Richmond, B J

    2014-03-01

    We, like many others, wish to use modern molecular methods to alter neuronal functionality in primates. For us, this requires expression in a large proportion of the targeted cell population. Long generation times make germline modification of limited use. The size and intricate primate brain anatomy poses additional challenges. We surved methods using lentiviruses and serotypes of adeno-associated viruses (AAVs) to introduce active molecular material into cortical and subcortical regions of old-world monkey brains. Slow injections of AAV2 give well-defined expression of neurons in the cortex surrounding the injection site. Somewhat surprisingly we find that in the monkey the use of cytomegalovirus promoter in lentivirus primarily targets glial cells but few neurons. In contrast, with a synapsin promoter fragment the lentivirus expression is neuron specific at high transduction levels in all cortical layers. We also achieve specific targeting of tyrosine hydroxlase (TH)- rich neurons in the locus coeruleus and substantia nigra with a lentvirus carrying a fragment of the TH promoter. Lentiviruses carrying neuron specific promoters are suitable for both cortical and subcortical injections even when injected quickly.

  6. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.

    PubMed

    Sleiman, Sama F; Henry, Jeffrey; Al-Haddad, Rami; El Hayek, Lauretta; Abou Haidar, Edwina; Stringer, Thomas; Ulja, Devyani; Karuppagounder, Saravanan S; Holson, Edward B; Ratan, Rajiv R; Ninan, Ipe; Chao, Moses V

    2016-06-02

    Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

  7. Cancer-associated fibroblast promote transmigration through endothelial brain cells in three-dimensional in vitro models.

    PubMed

    Choi, Yoon Pyo; Lee, Joo Hyun; Gao, Ming-Qing; Kim, Baek Gil; Kang, Suki; Kim, Se Hoon; Cho, Nam Hoon

    2014-11-01

    Brain metastases are associated with high morbidity as well as with poor prognosis and survival in breast cancer patients. Despite its clinical importance, metastasis of breast cancer cells through the blood-brain barrier (BBB) is poorly understood. The objective of our study was to investigate whether cancer-associated fibroblasts (CAFs) play crucial roles in breast cancer brain metastasis. Using a cell adhesion assays, in vitro BBB permeability and transmigration assays and soft agar colony formation assays, we investigated the physical roles of CAFs in breast cancer brain metastasis. We also performed immunofluorescence, flow cytometric analysis, Droplet Digital PCR and Simon™ Simple Western System to confirm changes in expression levels. We established two novel three-dimensional (3D) culture systems using a perpendicular slide chamber and applying 3D embedded culture method to reflect brain metastasis conditions. With a newly developed device, CAFs was proven to promote cell adhesion to human brain microvascular endothelial cells, in vitro BBB permeability and transmigration and colony formation of breast cancer cells. Furthermore, CAFs enhanced the invasive migration of breast cancer cells in two kinds of 3D cultures. These 3D models also reliably recapitulate the initial steps of BBB transmigration, micro-metastasis and colonization. Expression of integrin α5β1 and αvβ3, c-MET and α2,6-siayltransferase was increased in breast cancer cells that migrated through the BBB. In conclusion, based on our in vitro BBB and co-culture models, our data suggest that CAFs may play a role in breast cancer brain metastasis.

  8. Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

    PubMed Central

    Dawson, Neil; McDonald, Martin; Higham, Desmond J; Morris, Brian J; Pratt, Judith A

    2014-01-01

    Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia. PMID:24492765

  9. Increases in levels of brain-derived neurotrophic factor mRNA and its promoters after transient forebrain ischemia in the rat brain.

    PubMed

    Tsukahara, T; Iihara, K; Hashimoto, N; Nishijima, T; Taniguchi, T

    1998-08-01

    Expression of brain-derived neurotrophic factor (BDNF) may play a role in the mechanism of neuronal cell death after cerebral ischemia. We investigated the changes in levels of mRNAs encoding BDNF and its promoters in the rat brain after transient forebrain ischemia. Transient forebrain ischemia was induced by occlusion of bilateral common carotid arteries and systemic hypotension for 8 min. The alterations in BDNF gene expression in the hippocampus and in the cerebral cortex were examined by in situ hybridization using a mouse BDNF cDNA probe and cDNA probes including exon-specific promoters. BDNF transcripts were rapidly enhanced after the ischemic insult, both in the hippocampus and the cerebral cortex. NBQX suppressed the enhanced gene expression of BDNF markedly in the dentate gyrus (DG). In contrast, MK-801 had little effect on BDNF expression. In the piriform cortex, MK-801 or NBQX reduced the expression only moderately. After the ischemic insult, promoter specific BDNF 5'-exon I and exon III were increased remarkably in the DG. The increase in exon I in DG was suppressed partially by MK-801 and NBQX, while the increase in exon III in CA3 was suppressed by MK-801 but that in DG was not suppressed by either antagonist. In the piriform cortex, exon III was increased remarkably and this increase was not influenced by either agonist. These results suggest that the gene expression of BDNF was enhanced by transient ischemia both in the hippocampus and the cerebral cortex and that the cerebral ischemia stimulated at least two different promoter- and neuron type-specific pathways regulating expression of the BDNF gene mediated by glutamate receptors of non-NMDA type and NMDA type.

  10. NK cells promote neutrophil recruitment in the brain during sepsis-induced neuroinflammation

    PubMed Central

    He, Hao; Geng, Tingting; Chen, Piyun; Wang, Meixiang; Hu, Jingxia; Kang, Li; Song, Wengang; Tang, Hua

    2016-01-01

    Sepsis could affect the central nervous system and thus induces neuroinflammation, which subsequently leads to brain damage or dysfunction. However, the mechanisms of generation of neuroinflammation during sepsis remain poorly understood. By administration of lipopolysaccharides (LPS) in mice to mimic sepsis, we found that shortly after opening the blood–brain barrier, conventional CD11b+CD27+ NK subset migrated into the brain followed by subsequent neutrophil infiltration. Interestingly, depletion of NK cells prior to LPS treatment severely impaired neutrophil recruitment in the inflamed brain. By in vivo recruitment assay, we found that brain-infiltrated NK cells displayed chemotactic activity to neutrophils, which depended on the higher expression of chemokines such as CXCL2. Moreover, microglia were also responsible for neutrophil recruitment, and their chemotactic activity was significantly impaired by ablation of NK cells. Furthermore, depletion of NK cells could significantly ameliorate depression-like behavior in LPS-treated mice. These data indicated a NK cell-regulated neutrophil recruitment in the blamed brain, which also could be seen on another sepsis model, cecal ligation and puncture. So, our findings revealed an important scenario in the generation of sepsis-induced neuroinflammation. PMID:27270556

  11. Snx14 Regulates Neuronal Excitability, Promotes Synaptic Transmission, and Is Imprinted in the Brain of Mice

    PubMed Central

    Huang, Hsien-Sung; Yoon, Bong-June; Brooks, Sherian; Bakal, Robert; Berrios, Janet; Larsen, Rylan S.; Wallace, Michael L.; Han, Ji Eun; Chung, Eui Hwan; Zylka, Mark J.; Philpot, Benjamin D.

    2014-01-01

    Genomic imprinting describes an epigenetic process through which genes can be expressed in a parent-of-origin-specific manner. The monoallelic expression of imprinted genes renders them particularly susceptible to disease causing mutations. A large proportion of imprinted genes are expressed in the brain, but little is known about their functions. Indeed, it has proven difficult to identify cell type-specific imprinted genes due to the heterogeneity of cell types within the brain. Here we used laser capture microdissection of visual cortical neurons and found evidence that sorting nexin 14 (Snx14) is a neuronally imprinted gene in mice. SNX14 protein levels are high in the brain and progressively increase during neuronal development and maturation. Snx14 knockdown reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission. These data reveal a role for monoallelic Snx14 expression in maintaining normal neuronal excitability and synaptic transmission. PMID:24859318

  12. Identification of cis-acting regulatory elements in the promoter region of the rat brain creatine kinase gene.

    PubMed Central

    Hobson, G M; Molloy, G R; Benfield, P A

    1990-01-01

    The functional organization of the rat brain creatine kinase (ckb) promoter was analyzed by deletion, linker scanning, and substitution mutagenesis. Mutations were introduced into the ckb promoter of hybrid ckb/neo (neomycin resistance gene) genes, and the mutant genes were expressed transiently in HeLa cells. Expression was assayed by primer extension analysis of neo RNA, which allowed the transcription start sites and the amount of transcription to be determined. Transfections and primer extension reactions were internally controlled by simultaneous analysis of transcription from the adenovirus VA gene located on the same plasmid as the hybrid ckb/neo gene. We demonstrate that 195 bp of the ckb promoter is sufficient for efficient in vivo expression in HeLa cells. A nonconsensus TTAA element at -28 bp appears to provide the TATA box function for the ckb promoter in vivo. Two CCAAT elements, one at -84 bp and the other at -54 bp, and a TATAAA TA element (a consensus TATA box sequence) at -66 bp are required for efficient transcription from the TTAA element. In addition, we present evidence that the consensus beta-globin TATA box responds to the TATAAATA element in the same way as the ckb nonconsensus TTAA element. Images PMID:2247071

  13. TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination.

    PubMed

    Wong, Agnes W; Giuffrida, Lauren; Wood, Rhiannon; Peckham, Haley; Gonsalvez, David; Murray, Simon S; Hughes, Richard A; Xiao, Junhua

    2014-11-01

    Brain-derived neurotrophic factor (BDNF) plays critical roles in the development and maintenance of the central (CNS) and peripheral nervous systems (PNS). BDNF exerts its biological effects via tropomyosin-related kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR). We have recently identified that BDNF promotes CNS myelination via oligodendroglial TrkB receptors. In order to selectively target TrkB to promote CNS myelination, we have used a putative TrkB agonist, a small multicyclic peptide (tricyclic dimeric peptide 6, TDP6) previously described by us that structurally mimics a region of BDNF that binds TrkB. We confirmed that TDP6 acts as a TrkB agonist as it provoked autophosphorylation of TrkB and its downstream signalling effector extracellular related-kinase 1 and 2 (Erk1/2) in primary oligodendrocytes. Using an in vitro myelination assay, we show that TDP6 significantly promotes myelination by oligodendrocytes in vitro, as evidenced by enhanced myelin protein expression and an increased number of myelinated axonal segments. In contrast, a second, structurally distinct BDNF mimetic (cyclo-dPAKKR) that targets p75NTR had no effect upon oligodendrocyte myelination in vitro, despite the fact that cyclo-dPAKKR is a very effective promoter of peripheral (Schwann cell) myelination. The selectivity of TDP6 was further verified by using TrkB-deficient oligodendrocytes, in which TDP6 failed to promote myelination, indicating that the pro-myelinating effect of TDP6 is oligodendroglial TrkB-dependent. Together, our results demonstrate that TDP6 is a novel BDNF mimetic that promotes oligodendrocyte myelination in vitro via targeting TrkB.

  14. Circulating tumor cell is a common property of brain glioma and promotes the monitoring system

    PubMed Central

    Gao, Faliang; Cui, Yong; Jiang, Haihui; Sui, Dali; Wang, Yonggang; Jiang, Zhongli; Zhao, Jizong; Lin, Song

    2016-01-01

    Brain glioma is the most common primary intracranial tumor characterized by dismal prognosis and frequent recurrence, yet a real-time and reliable biological approach to monitor tumor response and progression is still lacking. Recently, few studies have reported that circulating tumor cells (CTCs) could be detected in glioblastoma multiform (GBM), providing the possibility of its application in brain glioma monitoring system. But its application limits still exist, because the detection rate of CTCs is still low and was exclusively limited to high- grade gliomas. Here, we adopted an advanced integrated cellular and molecular approach of SE-iFISH to detect CTCs in the peripheral blood (PB) of patients with 7 different subtypes of brain glioma, uncovering the direct evidences of glioma migration. We identified CTCs in the PB from 24 of 31 (77%) patients with glioma in all 7 subtypes. No statistical difference of CTC incidence and count was observed in different pathological subtypes or WHO grades of glioma. Clinical data revealed that CTCs, to some extent, was superior to MRI in monitoring the treatment response and differentiating radionecrosis from recurrence of glioma. Conclusively, CTCs is a common property of brain gliomas of various pathological subtypes, which has provided an ultimate paradox for the hypothesis “soil and seed”. It can be used to monitor the microenvironment of gliomas dynamically, which will be a meaningful complement to radiographic imaging. PMID:27517490

  15. Metabolite of tryptophan promoting changes in EEG signal and the oxidative status of the brain.

    PubMed

    Ferrari, Rosana; Pugini, Silvana Maria Picolli; Arce, Aldo Ivan Cespedes; Costa, Ernane Jose Xavier; de Melo, Mariza Pires

    2014-08-01

    Tryptophan is an essential amino acid precursor of neurotransmitter serotonin and triptamine. During its metabolism, indole-3-acetic acid (IAA) is generated; this substance presents both antioxidant and prooxidant effects in different biological systems in addition to hipoglicemic effects. To date, electroencephalography (EEG) has been used to evaluate the temporal effect of several substances in neurotransmission. The goal of this study was to characterize the effect of IAA in the brain by analysing the EEG signal and evaluate the oxidative status by means of biochemical parameters. The EEG was acquired by using a noninvasive method, and the brain electric signal was analysed by advanced digital signal processing techniques to determinate the energy signal filtered in different band frequencies. Furthermore, the oxidative status of the brain was investigated by measuring the activity of antioxidant enzymes and lipid peroxidation as well as blood glucose rates of the animals treated with different doses of IAA. Our results showed the relationship of IAA administration with changes in EEG signals. The oxidative status of the brain was modified by IAA after 14 days of treatment.

  16. Clueless regulates aPKC activity and promotes self-renewal cell fate in Drosophila lgl mutant larval brains.

    PubMed

    Goh, Li Hui; Zhou, Xiu; Lee, Mei Chin; Lin, Shuping; Wang, Huashan; Luo, Yan; Yang, Xiaohang

    2013-09-15

    Asymmetric cell division of Drosophila neural stem cells or neuroblasts is an important process which gives rise to two different daughter cells, one of which is the stem cell itself and the other, a committed or differentiated daughter cell. During neuroblast asymmetric division, atypical Protein Kinase C (aPKC) activity is tightly regulated; aberrant levels of activity could result in tumorigenesis in third instar larval brain. We identified clueless (clu), a genetic interactor of parkin (park), as a novel regulator of aPKC activity. It preferentially binds to the aPKC/Bazooka/Partition Defective 6 complex and stabilizes aPKC levels. In clu mutants, Miranda (Mira) and Numb are mislocalized in small percentages of dividing neuroblasts. Adult mutants are short-lived with severe locomotion defects. Clu promotes tumorigenesis caused by loss of function of lethal(2) giant larvae (lgl) in the larval brain. Removal of clu in lgl mutants rescues Mira and Numb mislocalization and restores the enlarged brain size. Western blot analyses indicate that the rescue is due to the down-regulation of aPKC levels in the lgl clu double mutant. Interestingly, the phenotype of the park mutant, which causes Parkinson's Disease-like symptoms in adult flies, is reminiscent of that of clu in neuroblast asymmetric division. Our study provides the first clue for the potential missing pathological link between temporally separated neurogenesis and neurodegeneration events; the minor defects during early neurogenesis could be a susceptible factor contributing to neurodegenerative diseases at later stages of life.

  17. 2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke.

    PubMed

    Chern, Chang-Ming; Wang, Yea-Hwey; Liou, Kuo-Tong; Hou, Yu-Chang; Chen, Chien-Chih; Shen, Yuh-Chiang

    2014-02-01

    2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10-100 μg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3β which in turn upregulating β-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3β to enhance β-catenin signaling for upexpression of neuroprotective genes and proteins.

  18. A Proposal for Undergraduate Students’ Inclusion in Brain Awareness Week: Promoting Interest in Curricular Neuroscience Components

    PubMed Central

    Martins, Alexandre; Mello-Carpes, Pâmela Billig

    2014-01-01

    Brain Awareness Week (BAW) is a global campaign aimed at raising awareness of neuroscience and the progress and benefits of brain research. Our proposal was to include undergraduate physiology students in the organization and presentation of BAW activities. In this sense, we proposed the BAW as a neurophysiology teaching strategy. BAW 2013 occurred between March 11–17, and physiology students in the Nursing, Pharmacy and Physiotherapy programs of our university were involved in the organization of and participation in the activities. To evaluate student perceptions of their participation, a questionnaire was used to establish whether their involvement increased their interest in physiology/neuroscience. Our results indicated that this strategy was successful and increased the students’ interest in neuroscience and physiology. In addition a survey of undergraduate and graduate students participating in BAW established their interest in the various activities available. The attention and reaction time workshop and the neuroanatomy workshop were the most popular of the eight activities available. PMID:25565918

  19. The promoter of brain-specific angiogenesis inhibitor 1-associated protein 4 drives developmentally targeted transgene expression mainly in adult cerebral cortex and hippocampus.

    PubMed

    Kim, Mi-Young; Ahn, Kyu Youn; Lee, Seon Min; Koh, Jeong Tae; Chun, Byeong Jo; Bae, Choon Sang; Lee, Kee Sook; Kim, Kyung Keun

    2004-05-21

    Restricting transgene expression to specific cell types and maintaining long-term expression are major goals for gene therapy. Previously, we cloned brain-specific angiogenesis inhibitor 1-associated protein 4 (BAI1-AP4), a novel brain-specific protein that interacts with BAI1, and found that it was developmentally upregulated in the adult brain. In this report, we isolated 5 kb of the 5' upstream sequence of the mouse BAI1-AP4 gene and analyzed its promoter activity. Functional analyses demonstrated that an Sp1 site was the enhancer, and the region containing the transcription initiation site and an AP2-binding site was the basal promoter. We examined the ability of the BAI1-AP4 promoter to drive adult brain-specific expression by using it to drive lacZ expression in transgenic (TG) mice. Northern blot analyses showed a unique pattern of beta-galactosidase expression in TG brain, peaking at 1 month after birth, like endogenous BAI1-AP4. Histological analyses demonstrated the same localization and developmental expression of beta-galactosidase and BAI1-AP4 in most neurons of the cerebral cortex and hippocampus. Our data indicate that TG mice carrying the BAI1-AP4 promoter could be a valuable model system for region-specific brain diseases.

  20. The effects of 860 MHz radiofrequency radiation on the induction or promotion of brain tumors and other neoplasms in rats.

    PubMed

    Zook, B C; Simmens, S J

    2001-04-01

    Sprague-Dawley rats were irradiated with a continuous- wave (CW) or a pulsed-wave (P) radiofrequency (RF) for 6 h/day, 5 days/week from 2 up to 24 months of age. The RFs emanated from dipole antennas (1 W average output) 2.0 +/- 0.5 cm from the tip of each rat's nose. The RFs had an 860 MHz frequency, and the specific absorption rate was 1.0 W/ kg averaged over the brain. Fifteen groups of 60 rats (900 total) were formed from offspring of females injected i.v. with 0 (groups 1, 2, 9, 10, 13), 2.5 (groups 5, 6, 7, 8, 11, 12, 14) or 10 mg/kg (groups 3, 4, 15) ethylnitrosourea (ENU) to induce brain tumors. Groups 1, 3, 5 and 7 received the PRF, and groups 9 and 11 the CWRF; groups 2, 4, 6, 8, 10 and 12 were sham-irradiated, and groups 13-15 were cage controls. All rats but 2, totaling 898, were necropsied, and major tissues were studied histopathologically. There was no statistically significant evidence that the PRF or CWRF induced neoplasia in any tissues. Additionally, there was no significant evidence of promotion of cranial or spinal nerve or spinal cord tumors. The PRF or CWRF had no statistically significant effect on the number, volume, location, multiplicity, histological type, malignancy or fatality of brain tumors. There was a trend for the group that received a high dose of ENU and was exposed to the PRF to develop fatal brain tumors at a higher rate than its sham group; however, the result was not significant using the log-rank test (P = 0.14, 2-tailed). No statistically significant differences were related to the PRF or CWRF compared to controls in the low- or zero-dose groups regarding tumors of any kind.

  1. Cyclin A2 promotes DNA repair in the brain during both development and aging

    PubMed Central

    Gygli, Patrick E.; Chang, Joshua C.; Gokozan, Hamza N.; Catacutan, Fay P.; Schmidt, Theresa A.; Kaya, Behiye; Goksel, Mustafa; Baig, Faisal S.; Chen, Shannon; Griveau, Amelie; Michowski, Wojciech; Wong, Michael; Palanichamy, Kamalakannan; Sicinski, Piotr; Nelson, Randy J.; Czeisler, Catherine; Otero, José J.

    2016-01-01

    Various stem cell niches of the brain have differential requirements for Cyclin A2. Cyclin A2 loss results in marked cerebellar dysmorphia, whereas forebrain growth is retarded during early embryonic development yet achieves normal size at birth. To understand the differential requirements of distinct brain regions for Cyclin A2, we utilized neuroanatomical, transgenic mouse, and mathematical modeling techniques to generate testable hypotheses that provide insight into how Cyclin A2 loss results in compensatory forebrain growth during late embryonic development. Using unbiased measurements of the forebrain stem cell niche, we parameterized a mathematical model whereby logistic growth instructs progenitor cells as to the cell-types of their progeny. Our data was consistent with prior findings that progenitors proliferate along an auto-inhibitory growth curve. The growth retardation in CCNA2-null brains corresponded to cell cycle lengthening, imposing a developmental delay. We hypothesized that Cyclin A2 regulates DNA repair and that CCNA2-null progenitors thus experienced lengthened cell cycle. We demonstrate that CCNA2-null progenitors suffer abnormal DNA repair, and implicate Cyclin A2 in double-strand break repair. Cyclin A2's DNA repair functions are conserved among cell lines, neural progenitors, and hippocampal neurons. We further demonstrate that neuronal CCNA2 ablation results in learning and memory deficits in aged mice. PMID:27425845

  2. Slow oscillation electrical brain stimulation during waking promotes EEG theta activity and memory encoding.

    PubMed

    Kirov, Roumen; Weiss, Carsten; Siebner, Hartwig R; Born, Jan; Marshall, Lisa

    2009-09-08

    The application of transcranial slow oscillation stimulation (tSOS; 0.75 Hz) was previously shown to enhance widespread endogenous EEG slow oscillatory activity when applied during a sleep period characterized by emerging endogenous slow oscillatory activity. Processes of memory consolidation typically occurring during this state of sleep were also enhanced. Here, we show that the same tSOS applied in the waking brain also induced an increase in endogenous EEG slow oscillations (0.4-1.2 Hz), although in a topographically restricted fashion. Applied during wakefulness tSOS, additionally, resulted in a marked and widespread increase in EEG theta (4-8 Hz) activity. During wake, tSOS did not enhance consolidation of memories when applied after learning, but improved encoding of hippocampus-dependent memories when applied during learning. We conclude that the EEG frequency and related memory processes induced by tSOS critically depend on brain state. In response to tSOS during wakefulness the brain transposes stimulation by responding preferentially with theta oscillations and facilitated encoding.

  3. Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia

    PubMed Central

    de la Torre, Jack C.

    2012-01-01

    Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer's disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE4, atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia. PMID:23243502

  4. Glycine transporters type 1 inhibitor promotes brain preconditioning against NMDA-induced excitotoxicity.

    PubMed

    Pinto, Mauro Cunha Xavier; Lima, Isabel Vieira de Assis; da Costa, Flávia Lage Pessoa; Rosa, Daniela Valadão; Mendes-Goulart, Vânia Aparecida; Resende, Rodrigo Ribeiro; Romano-Silva, Marco Aurélio; de Oliveira, Antônio Carlos Pinheiro; Gomez, Marcus Vinícius; Gomez, Renato Santiago

    2015-02-01

    Brain preconditioning is a protective mechanism, which can be activated by sub-lethal stimulation of the NMDA receptors (NMDAR) and be used to achieve neuroprotection against stroke and neurodegenerative diseases models. Inhibitors of glycine transporters type 1 modulate glutamatergic neurotransmission through NMDAR, suggesting an alternative therapeutic strategy of brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by NFPS, a GlyT1 inhibitor, against NMDA-induced excitotoxicity in mice hippocampus, as well as to study its neurochemical mechanisms. C57BL/6 mice (male, 10-weeks-old) were preconditioned by intraperitoneal injection of NFPS at doses of 1.25, 2.5 or 5.0 mg/kg, 24 h before intrahippocampal injection of NMDA. Neuronal death was evaluated by fluoro jade C staining and neurochemical parameters were evaluated by gas chromatography-mass spectrometry, scintillation spectrometry and western blot. We observed that NFPS preconditioning reduced neuronal death in CA1 region of hippocampus submitted to NMDA-induced excitotoxicity. The amino acids (glycine and glutamate) uptake and content were increased in hippocampus of animals treated with NFPS 5.0 mg/kg, which were associated to an increased expression of type-2 glycine transporter (GlyT2) and glutamate transporters (EAAT1, EAAT2 and EAAT3). The expression of GlyT1 was reduced in animals treated with NFPS. Interestingly, the preconditioning reduced expression of GluN2B subunits of NMDAR, whereas did not change the expression of GluN1 or GluN2A in all tested doses. Our study suggests that NFPS preconditioning induces resistance against excitotoxicity, which is associated with neurochemical changes and reduction of GluN2B-containing NMDAR expression.

  5. Cbln family proteins promote synapse formation by regulating distinct neurexin signaling pathways in various brain regions.

    PubMed

    Matsuda, Keiko; Yuzaki, Michisuke

    2011-04-01

    Cbln1 (a.k.a. precerebellin) is a unique bidirectional synaptic organizer that plays an essential role in the formation and maintenance of excitatory synapses between granule cells and Purkinje cells in the mouse cerebellum. Cbln1 secreted from cerebellar granule cells directly induces presynaptic differentiation and indirectly serves as a postsynaptic organizer by binding to its receptor, the δ2 glutamate receptor. However, it remains unclear how Cbln1 binds to the presynaptic sites and interacts with other synaptic organizers. Furthermore, although Cbln1 and its family members Cbln2 and Cbln4 are expressed in brain regions other than the cerebellum, it is unknown whether they regulate synapse formation in these brain regions. In this study, we showed that Cbln1 and Cbln2, but not Cbln4, specifically bound to its presynaptic receptor -α and β isoforms of neurexin carrying the splice site 4 insert [NRXs(S4+)] - and induced synaptogenesis in cerebellar, hippocampal and cortical neurons in vitro. Cbln1 competed with synaptogenesis mediated by neuroligin 1, which lacks the splice sites A and B, but not leucine-rich repeat transmembrane protein 2, possibly by sharing the presynaptic receptor NRXs(S4+). However, unlike neurexins/neuroligins or neurexins/leucine-rich repeat transmembrane proteins, the interaction between NRX1β(S4+) and Cbln1 was insensitive to extracellular Ca(2+) concentrations. These findings revealed the unique and general roles of Cbln family proteins in mediating the formation and maintenance of synapses not only in the cerebellum but also in various other brain regions.

  6. Fibrin deposited in the Alzheimer’s disease brain promotes neuronal degeneration

    PubMed Central

    Cortes-Canteli, Marta; Mattei, Larissa; Richards, Allison T.; Norris, Erin H.; Strickland, Sidney

    2014-01-01

    Alzheimer’s disease (AD) is the most common form of dementia and has no effective treatment. Besides the well-known pathological characteristics, this disease also has a vascular component, and substantial evidence shows increased thrombosis as well as a critical role for fibrin(ogen) in AD. This molecule has been implicated in neuroinflammation, neurovascular damage, blood brain barrier permeability, vascular amyloid deposition, and memory deficits that are observed in AD. Here we present evidence demonstrating that fibrin deposition increases in the AD brain and correlates with the degree of pathology. Moreover, we show that fibrin(ogen) is present in areas of dystrophic neurites and that a modest decrease in fibrinogen levels improves neuronal health and ameliorates amyloid pathology in the subiculum of AD mice. Our results further characterize the important role of fibrin(ogen) in this disease and support the design of therapeutic strategies aimed at blocking the interaction between fibrinogen and Aβ and/or normalizing the increased thrombosis present in AD. PMID:25475538

  7. Anesthetics rapidly promote synaptogenesis during a critical period of brain development.

    PubMed

    De Roo, Mathias; Klauser, Paul; Briner, Adrian; Nikonenko, Irina; Mendez, Pablo; Dayer, Alexandre; Kiss, Jozsef Z; Muller, Dominique; Vutskits, Laszlo

    2009-09-16

    Experience-driven activity plays an essential role in the development of brain circuitry during critical periods of early postnatal life, a process that depends upon a dynamic balance between excitatory and inhibitory signals. Since general anesthetics are powerful pharmacological modulators of neuronal activity, an important question is whether and how these drugs can affect the development of synaptic networks. To address this issue, we examined here the impact of anesthetics on synapse growth and dynamics. We show that exposure of young rodents to anesthetics that either enhance GABAergic inhibition or block NMDA receptors rapidly induce a significant increase in dendritic spine density in the somatosensory cortex and hippocampus. This effect is developmentally regulated; it is transient but lasts for several days and is also reproduced by selective antagonists of excitatory receptors. Analyses of spine dynamics in hippocampal slice cultures reveals that this effect is mediated through an increased rate of protrusions formation, a better stabilization of newly formed spines, and leads to the formation of functional synapses. Altogether, these findings point to anesthesia as an important modulator of spine dynamics in the developing brain and suggest the existence of a homeostatic process regulating spine formation as a function of neural activity. Importantly, they also raise concern about the potential impact of these drugs on human practice, when applied during critical periods of development in infants.

  8. Orexin/Hypocretin and Organizing Principles for a Diversity of Wake-Promoting Neurons in the Brain.

    PubMed

    Schöne, Cornelia; Burdakov, Denis

    2016-11-10

    An enigmatic feature of behavioural state control is the rich diversity of wake-promoting neural systems. This diversity has been rationalized as 'robustness via redundancy', wherein wakefulness control is not critically dependent on one type of neuron or molecule. Studies of the brain orexin/hypocretin system challenge this view by demonstrating that wakefulness control fails upon loss of this neurotransmitter system. Since orexin neurons signal arousal need, and excite other wake-promoting neurons, their actions illuminate nonredundant principles of arousal control. Here, we suggest such principles by reviewing the orexin system from a collective viewpoint of biology, physics and engineering. Orexin peptides excite other arousal-promoting neurons (noradrenaline, histamine, serotonin, acetylcholine neurons), either by activating mixed-cation conductances or by inhibiting potassium conductances. Ohm's law predicts that these opposite conductance changes will produce opposite effects on sensitivity of neuronal excitability to current inputs, thus enabling orexin to differentially control input-output gain of its target networks. Orexin neurons also produce other transmitters, including glutamate. When orexin cells fire, glutamate-mediated downstream excitation displays temporal decay, but orexin-mediated excitation escalates, as if orexin transmission enabled arousal controllers to compute a time integral of arousal need. Since the anatomical and functional architecture of the orexin system contains negative feedback loops (e.g. orexin ➔ histamine ➔ noradrenaline/serotonin-orexin), such computations may stabilize wakefulness via integral feedback, a basic engineering strategy for set point control in uncertain environments. Such dynamic behavioural control requires several distinct wake-promoting modules, which perform nonredundant transformations of arousal signals and are connected in feedback loops.

  9. Consumption of tyrosine in royal jelly increases brain levels of dopamine and tyramine and promotes transition from normal to reproductive workers in queenless honey bee colonies.

    PubMed

    Matsuyama, Syuhei; Nagao, Takashi; Sasaki, Ken

    2015-01-15

    Dopamine (DA) and tyramine (TA) have neurohormonal roles in the production of reproductive workers in queenless colonies of honey bees, but the regulation of these biogenic amines in the brain are still largely unclear. Nutrition is an important factor in promoting reproduction and might be involved in the regulation of these biogenic amines in the brain. To test this hypothesis, we examined the effect of oral treatments of tyrosine (Tyr; a common precursor of DA, TA and octopamine, and a component of royal jelly) in queenless workers and quantified the resulting production of biogenic amines. Tyrosine treatments enhanced the levels of DA, TA and their metabolites in the brain. Workers fed royal jelly had significantly larger brain levels of Tyr, DA, TA and the metabolites in the brains compared with those bees fed honey or sucrose (control). Treatment with Tyr also inhibited the behavior of workers outside of the hive and promoted ovarian development. These results suggest that there is a link between nutrition and the regulation of DA and TA in the brain to promote the production of reproductive workers in queenless honey bee colonies.

  10. Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum.

    PubMed

    Grade, Sofia; Weng, Yuan C; Snapyan, Marina; Kriz, Jasna; Malva, João O; Saghatelyan, Armen

    2013-01-01

    Stroke induces the recruitment of neuronal precursors from the subventricular zone (SVZ) into the ischemic striatum. In injured areas, de-routed neuroblasts use blood vessels as a physical scaffold to their migration, in a process that resembles the constitutive migration seen in the rostral migratory stream (RMS). The molecular mechanism underlying injury-induced vasculature-mediated migration of neuroblasts in the post-stroke striatum remains, however, elusive. Using adult mice we now demonstrate that endothelial cells in the ischemic striatum produce brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the vasculature-mediated migration of neuronal precursors in the RMS, and that recruited neuroblasts maintain expression of p75NTR, a low-affinity receptor for BDNF. Reactive astrocytes, which are widespread throughout the damaged area, ensheath blood vessels and express TrkB, a high-affinity receptor for BDNF. Despite the absence of BDNF mRNA, we observed strong BDNF immunolabeling in astrocytes, suggesting that these glial cells trap extracellular BDNF. Importantly, this pattern of expression is reminiscent of the adult RMS, where TrkB-expressing astrocytes bind and sequester vasculature-derived BDNF, leading to the entry of migrating cells into the stationary phase. Real-time imaging of cell migration in acute brain slices revealed a direct role for BDNF in promoting the migration of neuroblasts to ischemic areas. We also demonstrated that cells migrating in the ischemic striatum display higher exploratory behavior and longer stationary periods than cells migrating in the RMS. Our findings suggest that the mechanisms involved in the injury-induced vasculature-mediated migration of neuroblasts recapitulate, at least partially, those observed during constitutive migration in the RMS.

  11. Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate.

    PubMed

    Janik, Rafal; Thomason, Lynsie A M; Stanisz, Andrew M; Forsythe, Paul; Bienenstock, John; Stanisz, Greg J

    2016-01-15

    The gut microbiome has been shown to regulate the development and functions of the enteric and central nervous systems. Its involvement in the regulation of behavior has attracted particular attention because of its potential translational importance in clinical disorders, however little is known about the pathways involved. We previously have demonstrated that administration of Lactobacillus rhamnosus (JB-1) to healthy male BALB/c mice, promotes consistent changes in GABA-A and -B receptor sub-types in specific brain regions, accompanied by reductions in anxiety and depression-related behaviors. In the present study, using magnetic resonance spectroscopy (MRS), we quantitatively assessed two clinically validated biomarkers of brain activity and function, glutamate+glutamine (Glx) and total N-acetyl aspartate+N-acetyl aspartyl glutamic acid (tNAA), as well as GABA, the chief brain inhibitory neurotransmitter. Mice received 1×10(9) cfu of JB-1 per day for 4weeks and were subjected to MRS weekly and again 4weeks after cessation of treatment to ascertain temporal changes in these neurometabolites. Baseline concentrations for Glx, tNAA and GABA were equal to 10.4±0.3mM, 8.7±0.1mM, and 1.2±0.1mM, respectively. Delayed increases were first seen for Glx (~10%) and NAA (~37%) at 2weeks which persisted only to the end of treatment. However, Glx was still elevated 4weeks after treatment had ceased. Significantly elevated GABA (~25%) was only seen at 4weeks. These results suggest specific metabolic pathways in our pursuit of mechanisms of action of psychoactive bacteria. They also offer through application of standard clinical neurodiagnostic techniques, translational opportunities to assess biomarkers accompanying behavioral changes induced by alterations in the gut microbiome.

  12. Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain.

    PubMed

    Ryu, Sun; Lee, Seung-Hoon; Kim, Seung U; Yoon, Byung-Woo

    2016-02-01

    Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2'-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen NeuN, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2'-deoxyuridine-positive ⁄ anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke.

  13. Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization.

    PubMed

    Yang, Jr-M; Schiapparelli, P; Nguyen, H-N; Igarashi, A; Zhang, Q; Abbadi, S; Amzel, L M; Sesaki, H; Quiñones-Hinojosa, A; Iijima, M

    2017-03-06

    PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity. Cellular and biochemical analyses as well as structural modelling revealed that two mutations disrupt intramolecular interaction of PTEN and open its conformation, enhancing polyubiquitination of PTEN and decreasing protein stability. Moreover, promoting mono-ubiquitination increases protein stability and nuclear localization of mutant PTEN. Thus, our findings provide a molecular mechanism for cancer-associated PTEN defects and may lead to a brain cancer treatment that targets PTEN mono-ubiquitination.Oncogene advance online publication, 6 March 2017; doi:10.1038/onc.2016.493.

  14. Activation of P2X7 promotes cerebral edema and neurological injury after traumatic brain injury in mice.

    PubMed

    Kimbler, Donald E; Shields, Jessica; Yanasak, Nathan; Vender, John R; Dhandapani, Krishnan M

    2012-01-01

    Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP) and is a common life-threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part to the absence of viable drug targets. In the present study, genetic inhibition (P2X7-/- mice) of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-1β (IL-1β) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, brilliant blue G (BBG), a clinically non-toxic P2X7 inhibitor, inhibited IL-1β expression, limited edemic development, and improved neurobehavioral outcomes after TBI. The beneficial effects of BBG followed either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and attenuated the expression of aquaporin-4 (AQP4), an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation.

  15. Healthy aging persons and their brains: promoting resilience through creative engagement.

    PubMed

    McFadden, Susan H; Basting, Anne D

    2010-02-01

    Creative engagement, as an expression of and a support for resilience, may have a neuroprotective effect among older adults, contributing to retention of cognitive capacity. Recent research on creative activities shows that they strengthen social networks and give persons a sense of control; both outcomes have been associated with brain health. The authors cite evidence suggesting that positive social interactions can nurture resilience and creative engagement among older persons, including those living with dementia. The motivational, attentional, affective, and social components of creative activities combine to offer older persons meaningful opportunities to express and strengthen their resilience, regardless of their cognitive status, despite the biopsychosocial challenges of aging. The article addresses implications for future research, clinical practice, and public policy, and suggests how gaps in current research on resilience and creativity might be addressed.

  16. Cortical Thickness Maturation and Duration of Music Training: Health-Promoting Activities Shape Brain Development

    PubMed Central

    Hudziak, James J.; Albaugh, Matthew D.; Ducharme, Simon; Karama, Sherif; Spottswood, Margaret; Crehan, Eileen; Evans, Alan C.; Botteron, Kelly N.

    2014-01-01

    Objective To assess the extent to which playing a musical instrument is associated with cortical thickness development among healthy youths. Method Participants were part of the National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development. This study followed a longitudinal design such that participants underwent MRI scanning and behavioral testing on up to three separate visits, occurring at 2-year intervals. MRI, IQ, and music training data were available for 232 youths (334 scans), ranging from 6–18 years of age. Cortical thickness was regressed against the number of years each youth had played a musical instrument. Next, thickness was regressed against an “Age × Years of Playing” interaction term. Age, gender, total brain volume, and scanner were controlled for in analyses. Participant ID was entered as a random effect to account for within-person dependence. False discovery rate correction was applied (p ≤ 0.05). Results There was no association between thickness and years playing a musical instrument. The “Age × Years of Playing” interaction was associated with thickness in motor, premotor, and supplementary motor cortices, as well as prefrontal and parietal cortices. Follow-up analysis revealed that musical training was associated with an increased rate of thickness maturation. Results were largely unchanged when IQ and handedness were included as covariates. Conclusion Playing a musical instrument was associated with more rapid cortical thickness maturation within areas implicated in motor planning and coordination, visuospatial ability, and emotion and impulse regulation. However, given the quasi-experimental nature of this study, we cannot rule out the influence of confounding variables. PMID:25440305

  17. Neuronal Ca2+-Activated K+ Channels Limit Brain Infarction and Promote Survival

    PubMed Central

    Liao, Yiliu; Gu, Ning; Rundén-Pran, Elise; Ruth, Peter; Sausbier, Matthias; Storm, Johan F.

    2010-01-01

    Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca2+ ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by selective BK-channel manipulations in vivo. To elucidate the in vivo contribution of neuronal BK channels in acute focal cerebral ischemia, we performed middle cerebral artery occlusion (MCAO) in mice lacking BK channels (homozygous mice lacking the BK channel alpha subunit, BK−/−). MCAO was performed in BK−/− and WT mice for 90 minutes followed by a 7-hour-reperfusion period. Coronal 1 mm thick sections were stained with 2,3,5-triphenyltetrazolium chloride to reveal the infarction area. We found that transient focal cerebral ischemia by MCAO produced larger infarct volume, more severe neurological deficits, and higher post-ischemic mortality in BK−/− mice compared to WT littermates. However, the regional cerebral blood flow was not significantly different between genotypes as measured by Laser Doppler (LD) flowmetry pre-ischemically, intra-ischemically, and post-ischemically, suggesting that the different impact of MCAO in BK−/− vs. WT was not due to vascular BK channels. Furthermore, when NMDA was injected intracerebrally in non-ischemic mice, NMDA-induced neurotoxicity was found to be larger in BK−/− mice compared to WT. Whole-cell patch clamp recordings from CA1 pyramidal cells in organotypic hippocampal slice cultures revealed that BK channels contribute to rapid action potential repolarization, as previously found in acute slices. When these cultures were exposed to ischemia-like conditions this induced significantly more neuronal death in BK−/− than in WT cultures. These results indicate that neuronal BK channels are important for protection against ischemic brain damage. PMID:21209897

  18. TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain.

    PubMed

    Huang, Wen-Xian; Yu, Fang; Sanchez, Russell M; Liu, Yu-Qiang; Min, Jia-Wei; Hu, Jiang-Jian; Bsoul, Najeeb Bassam; Han, Song; Yin, Jun; Liu, Wan-Hong; He, Xiao-Hua; Peng, Bi-Wen

    2015-08-01

    Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures.

  19. Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines.

    PubMed

    Momeny, Majid; Saunus, Jodi M; Marturana, Flavia; McCart Reed, Amy E; Black, Debra; Sala, Gianluca; Iacobelli, Stefano; Holland, Jane D; Yu, Dihua; Da Silva, Leonard; Simpson, Peter T; Khanna, Kum Kum; Chenevix-Trench, Georgia; Lakhani, Sunil R

    2015-02-28

    HER2-positive breast tumors are associated with a high risk of brain relapse. HER3 is thought to be an indispensible signaling substrate for HER2 (encoded by ERBB2) and is induced in breast cancer-brain metastases, though the molecular mechanisms by which this oncogenic dimer promotes the development of brain metastases are still elusive. We studied the effects of the HER3-HER2 ligand, heregulin (neuregulin-1, broadly expressed in the brain), on luminal breast cancer cell lines in vitro. Treatment of SKBr3 (ERBB2-amplified), MDA-MB-361 (ERBB2-amplified, metastatic brain tumor-derived) and MCF7 (HER2-positive, not ERBB2-amplified) cells with exogenous heregulin increased proliferation and adhesive potential, concomitant with induction of cyclin D1 and ICAM-1, and suppression of p27. All three cell lines invaded through matrigel toward a heregulin chemotactic signal in transwell experiments, associated with activation of extracellular cathepsin B and matrix metalloproteinase-9 (MMP-9). Moreover, heregulin induced breast cancer cell transmigration across a tight barrier of primary human brain microvascular endothelia. This was dependent on the activity of HER2, HER3 and MMPs, and was completely abrogated by combination HER2-HER3 blockade using Herceptin® and the humanized HER3 monoclonal antibody, EV20. Collectively these data suggest mechanisms by which the HER3-HER2 dimer promotes development of metastatic tumors in the heregulin-rich brain microenvironment.

  20. Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery.

    PubMed

    Yang, Yi; Thompson, Jeffrey F; Taheri, Saeid; Salayandia, Victor M; McAvoy, Thera A; Hill, Jeff W; Yang, Yirong; Estrada, Eduardo Y; Rosenberg, Gary A

    2013-07-01

    In cerebral ischemia, matrix metalloproteinases (MMPs) have a dual role by acutely disrupting tight junction proteins (TJPs) in the blood-brain barrier (BBB) and chronically promoting angiogenesis. Since TJP remodeling of the neurovascular unit (NVU) is important in recovery and early inhibition of MMPs is neuroprotective, we hypothesized that short-term MMP inhibition would reduce infarct size and promote angiogenesis after ischemia. Adult spontaneously hypertensive rats had a transient middle cerebral artery occlusion with reperfusion. At the onset of ischemia, they received a single dose of the MMP inhibitor, GM6001. They were studied at multiple times up to 4 weeks with immunohistochemistry, biochemistry, and magnetic resonance imaging (MRI). We observed newly formed vessels in peri-infarct regions at 3 weeks after reperfusion. Dynamic contrast-enhanced MRI showed BBB opening in new vessels. Along with the new vessels, pericytes expressed zonula occludens-1 (ZO-1) and MMP-3, astrocytes expressed ZO-1, occludin, and MMP-2, while endothelial cells expressed claudin-5. The GM6001, which reduced tissue loss at 3 to 4 weeks, significantly increased new vessel formation with expression of TJPs and MMPs. Our results show that pericytes and astrocytes act spatiotemporally, contributing to extraendothelial TJP formation, and that MMPs are involved in BBB restoration during recovery. Early MMP inhibition benefits neurovascular remodeling after stroke.

  1. Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery

    PubMed Central

    Yang, Yi; Thompson, Jeffrey F; Taheri, Saeid; Salayandia, Victor M; McAvoy, Thera A; Hill, Jeff W; Yang, Yirong; Estrada, Eduardo Y; Rosenberg, Gary A

    2013-01-01

    In cerebral ischemia, matrix metalloproteinases (MMPs) have a dual role by acutely disrupting tight junction proteins (TJPs) in the blood–brain barrier (BBB) and chronically promoting angiogenesis. Since TJP remodeling of the neurovascular unit (NVU) is important in recovery and early inhibition of MMPs is neuroprotective, we hypothesized that short-term MMP inhibition would reduce infarct size and promote angiogenesis after ischemia. Adult spontaneously hypertensive rats had a transient middle cerebral artery occlusion with reperfusion. At the onset of ischemia, they received a single dose of the MMP inhibitor, GM6001. They were studied at multiple times up to 4 weeks with immunohistochemistry, biochemistry, and magnetic resonance imaging (MRI). We observed newly formed vessels in peri-infarct regions at 3 weeks after reperfusion. Dynamic contrast-enhanced MRI showed BBB opening in new vessels. Along with the new vessels, pericytes expressed zonula occludens-1 (ZO-1) and MMP-3, astrocytes expressed ZO-1, occludin, and MMP-2, while endothelial cells expressed claudin-5. The GM6001, which reduced tissue loss at 3 to 4 weeks, significantly increased new vessel formation with expression of TJPs and MMPs. Our results show that pericytes and astrocytes act spatiotemporally, contributing to extraendothelial TJP formation, and that MMPs are involved in BBB restoration during recovery. Early MMP inhibition benefits neurovascular remodeling after stroke. PMID:23571276

  2. Possible promotion of neuronal differentiation in fetal rat brain neural progenitor cells after sustained exposure to static magnetism.

    PubMed

    Nakamichi, Noritaka; Ishioka, Yukichi; Hirai, Takao; Ozawa, Shusuke; Tachibana, Masaki; Nakamura, Nobuhiro; Takarada, Takeshi; Yoneda, Yukio

    2009-08-15

    We have previously shown significant potentiation of Ca(2+) influx mediated by N-methyl-D-aspartate receptors, along with decreased microtubules-associated protein-2 (MAP2) expression, in hippocampal neurons cultured under static magnetism without cell death. In this study, we investigated the effects of static magnetism on the functionality of neural progenitor cells endowed to proliferate for self-replication and differentiate into neuronal, astroglial, and oligodendroglial lineages. Neural progenitor cells were isolated from embryonic rat neocortex and hippocampus, followed by culture under static magnetism at 100 mT and subsequent determination of the number of cells immunoreactive for a marker protein of particular progeny lineages. Static magnetism not only significantly decreased proliferation of neural progenitor cells without affecting cell viability, but also promoted differentiation into cells immunoreactive for MAP2 with a concomitant decrease in that for an astroglial marker, irrespective of the presence of differentiation inducers. In neural progenitors cultured under static magnetism, a significant increase was seen in mRNA expression of several activator-type proneural genes, such as Mash1, Math1, and Math3, together with decreased mRNA expression of the repressor type Hes5. These results suggest that sustained static magnetism could suppress proliferation for self-renewal and facilitate differentiation into neurons through promoted expression of activator-type proneural genes by progenitor cells in fetal rat brain.

  3. Differential Promoter Methylation and Histone Modification Contribute to the Brain Specific Expression of the Mouse Mbu-1 Gene

    PubMed Central

    Kim, Byungtak; Kang, Seongeun; Kim, Sun Jung

    2012-01-01

    Mbu-1 (Csrnp-3) is a mouse gene that was identified in our previous study as showing highly restricted expression to the central nervous system. In this study, to elucidate the regulatory mechanism for tissue specificity of the gene, epigenetic approaches that identify the profiles of CpG methylation, as well as histone modifications at the promoter region were conducted. Methylation-specific PCR revealed that the CpG sites in brain tissues from embryo to adult stages showed virtually no methylation (0.052–0.67%). Lung (9.0%) and pancreas (3.0%) also showed lower levels. Other tissues such as liver, kidney, and heart showed much higher methylation levels ranging from approximately 39–93%. Treatment of 5-aza-2′-deoxycytidine (5-Aza-dC) significantly decreased promoter methylation, reactivating Mbu-1 expression in NG108-15 and Neuro-2a neuronal cells. Chromatin immunoprecipitation assay revealed that 5-Aza-dC decreased levels of acetylated H3K9 and methylated H3K4, and increased methylated H3K9. This result indicates that CpG methylation converses with histone modifications in an opposing sense of regulating Mbu-1 expression. PMID:23076708

  4. IDH1/2 Mutation and MGMT Promoter Methylation - the Relevant Survival Predictors in Czech Patients with Brain Gliomas.

    PubMed

    Kramář, F; Minárik, M; Benešová, L; Halková, T; Netuka, D; Bradáč, O; Beneš, V

    2016-01-01

    Gliomas are a heterogeneous group of tumours varying in prognosis, treatment approach, and overall survival. Recently, novel markers have been identified which are linked to patient prognosis and therapeutic response. Especially the mutation of the enzyme isocitrate dehydrogenase 1 or 2 (IDH1/2) gene and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status seem to be the most important predictors of survival. From 2012 to 2015, 94 Czech patients with primary brain tumours were enrolled into the study. The IDH1/2 mutation was detected by denaturing capillary electrophores.The methylation status of the MGMT gene and other 46 genes was revealed by MS-MLPA. In all 94 patients, the clinical data were correlated with molecular markers by Kaplan-Meier analyses and Cox regression model. The MGMT promoter methylation status was established and compared to clinical data. In our study eight different probes were used to elucidate the MGMT methylation status; hypermethylation was proclaimed if four and more probes were positive. This 3 : 5 ratio was tested and confirmed by Kaplan-Meier and Cox analyses. The study confirmed the importance of the IDH1/2 mutation and hypermethylation of the MGMT gene promoter being present in tumour tissue. Both markers are independent positive survival predictors; in the Cox model the IDH hazard ratio was 0.10 and in the case of MGMT methylation it reached 0.32. The methylation analysis of the panel of additional 46 genes did not reveal any other significant epigenetic markers; none of the candidate genes have been confirmed in the Cox regression analyses as an independent prognostic factor.

  5. Brain-derived neurotrophic factor promotes central nervous system myelination via a direct effect upon oligodendrocytes.

    PubMed

    Xiao, Junhua; Wong, Agnes W; Willingham, Melanie M; van den Buuse, Maarten; Kilpatrick, Trevor J; Murray, Simon S

    2010-01-01

    The extracellular factors that are responsible for inducing myelination in the central nervous system (CNS) remain elusive. We investigated whether brain-derived neurotrophic factor (BDNF) is implicated, by first confirming that BDNF heterozygous mice exhibit delayed CNS myelination during early postnatal development. We next established that the influence of BDNF upon myelination was direct, by acting on oligodendrocytes, using co-cultures of dorsal root ganglia neurons and oligodendrocyte precursor cells. Importantly, we found that BDNF retains its capacity to enhance myelination of neurons or by oligodendrocytes derived from p75NTR knockout mice, indicating the expression of p75NTR is not necessary for BDNF-induced myelination. Conversely, we observed that phosphorylation of TrkB correlated with myelination, and that inhibiting TrkB signalling also inhibited the promyelinating effect of BDNF, suggesting that BDNF enhances CNS myelination via activating oligodendroglial TrkB-FL receptors. Together, our data reveal a previously unknown role for BDNF in potentiating the normal development of CNS myelination, via signalling within oligodendrocytes.

  6. Multistimulation group therapy in Alzheimer's disease promotes changes in brain functioning.

    PubMed

    Baglio, Francesca; Griffanti, Ludovica; Saibene, Francesca Lea; Ricci, Cristian; Alberoni, Margherita; Critelli, Raffaella; Villanelli, Fabiana; Fioravanti, Raffaella; Mantovani, Federica; D'amico, Alessandra; Cabinio, Monia; Preti, Maria Giulia; Nemni, Raffaello; Farina, Elisabetta

    2015-01-01

    Background. The growing social emergency represented by Alzheimer's disease (AD) and the lack of medical treatments able to modify the disease course have kindled the interest in nonpharmacological therapies. Objective. We introduced a novel nonpharmacological approach for people with AD (PWA) named Multidimensional Stimulation group Therapy (MST) to improve PWA condition in different disease domains: cognition, behavior, and motor functioning. Methods. Enrolling 60 PWA in a mild to moderate stage of the disease, we evaluated the efficacy of MST with a randomized-controlled study. Neuropsychological and neurobehavioral measures and functional magnetic resonance imaging (fMRI) data were considered as outcome measures. Results. The following significant intervention-related changes were observed: reduction in Neuropsychiatric Inventory scale score, improvement in language and memory subscales of Alzheimer's Disease Assessment Scale-Cognitive subscale, and increased fMRI activations in temporal brain areas, right insular cortex, and thalamus. Conclusions. Cognitive-behavioral and fMRI results support the notion that MST has significant effects in improving PWA cognitive-behavioral status by restoring neural functioning.

  7. Music Making as a Tool for Promoting Brain Plasticity across the Life Span

    PubMed Central

    Wan, Catherine Y.; Schlaug, Gottfried

    2010-01-01

    Playing a musical instrument is an intense, multisensory, and motor experience that usually commences at an early age and requires the acquisition and maintenance of a range of skills over the course of a musician's lifetime. Thus, musicians offer an excellent human model for studying the brain effects of acquiring specialized sensorimotor skills. For example, musicians learn and repeatedly practice the association of motor actions with specific sound and visual patterns (musical notation) while receiving continuous multisensory feedback. This association learning can strengthen connections between auditory and motor regions (e.g., arcuate fasciculus) while activating multimodal integration regions (e.g., around the intraparietal sulcus). We argue that training of this neural network may produce cross-modal effects on other behavioral or cognitive operations that draw on this network. Plasticity in this network may explain some of the sensorimotor and cognitive enhancements that have been associated with music training. These enhancements suggest the potential for music making as an interactive treatment or intervention for neurological and developmental disorders, as well as those associated with normal aging. PMID:20889966

  8. Music making as a tool for promoting brain plasticity across the life span.

    PubMed

    Wan, Catherine Y; Schlaug, Gottfried

    2010-10-01

    Playing a musical instrument is an intense, multisensory, and motor experience that usually commences at an early age and requires the acquisition and maintenance of a range of skills over the course of a musician's lifetime. Thus, musicians offer an excellent human model for studying the brain effects of acquiring specialized sensorimotor skills. For example, musicians learn and repeatedly practice the association of motor actions with specific sound and visual patterns (musical notation) while receiving continuous multisensory feedback. This association learning can strengthen connections between auditory and motor regions (e.g., arcuate fasciculus) while activating multimodal integration regions (e.g., around the intraparietal sulcus). We argue that training of this neural network may produce cross-modal effects on other behavioral or cognitive operations that draw on this network. Plasticity in this network may explain some of the sensorimotor and cognitive enhancements that have been associated with music training. These enhancements suggest the potential for music making as an interactive treatment or intervention for neurological and developmental disorders, as well as those associated with normal aging.

  9. Cobalt supplementation promotes hypoxic tolerance and facilitates acclimatization to hypobaric hypoxia in rat brain.

    PubMed

    Shrivastava, Kalpana; Ram, M Sai; Bansal, Anju; Singh, S S; Ilavazhagan, G

    2008-01-01

    In the present study, we report the molecular mechanisms of action by cobalt in facilitating acclimatization to hypobaric hypoxia using male Sprague-Dawley rats as the model system. We determined hypoxic gasping time and survival time as a measure to assess the degree of tolerance of animals to hypobaric hypoxia by exposing the animals to an altitude of 10,668 m. Oral administration of cobalt chloride (12.5 mg Co/kg body weight, BW, for 7 days) increased gasping time and hypoxic survival time by 3 to 4 times compared to the control animals. This could be attributed to an increased expression and the DNA binding activity of hypoxia inducible transcriptional factor (HIF-1alpha) and its regulated genes, that is, erythropoietin (EPO), vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1), and nitric oxide synthase (NOS) levels. This in turn leads to better oxygenation, oxygen delivery, glucose transport, and maintenance of vascular tone, respectively, under oxygen-limited conditions. This was further confirmed by lower levels of lactate dehydrogenase (LDH) activity and lactate in the brain of cobalt + hypoxia group compared with animals exposed to hypoxia. Glucose levels also increased after cobalt supplementation. The findings of the study provide a basis for the possible use of cobalt for facilitating acclimatization to hypoxia and other conditions involving oxygen deprivation.

  10. Low-level laser therapy promotes dendrite growth via upregulating brain-derived neurotrophic factor expression

    NASA Astrophysics Data System (ADS)

    Meng, Chengbo; He, Zhiyong; Xing, Da

    2014-09-01

    Downregulation of brain-derived neurotrophic factor (BDNF) in the hippocampus occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival and dendrite growth, BDNF upregulation may contribute to rescue dendrite atrophy and cell loss in AD. Low-level laser therapy (LLLT) has been demonstrated to regulate neuronal function both in vitro and in vivo. In the present study, we found that LLLT rescued neurons loss and dendritic atrophy via the increase of both BDNF mRNA and protein expression. In addition, dendrite growth was improved after LLLT, characterized by upregulation of PSD95 expression, and the increase in length, branching, and spine density of dendrites in hippocampal neurons. Together, these studies suggest that upregulation of BDNF with LLLT can ameliorate Aβ-induced neurons loss and dendritic atrophy, thus identifying a novel pathway by which LLLT protects against Aβ-induced neurotoxicity. Our research may provide a feasible therapeutic approach to control the progression of Alzheimer's disease.

  11. Enhancement of Contralesional Motor Control Promotes Locomotor Recovery after Unilateral Brain Lesion

    PubMed Central

    Hua, Xu-Yun; Qiu, Yan-Qun; Wang, Meng; Zheng, Mou-Xiong; Li, Tie; Shen, Yun-Dong; Jiang, Su; Xu, Jian-Guang; Gu, Yu-Dong; Tsien, JoeZ.; Xu, Wen-Dong

    2016-01-01

    There have been controversies on the contribution of contralesional hemispheric compensation to functional recovery of the upper extremity after a unilateral brain lesion. Some studies have demonstrated that contralesional hemispheric compensation may be an important recovery mechanism. However, in many cases where the hemispheric lesion is large, this form of compensation is relatively limited, potentially due to insufficient connections from the contralesional hemisphere to the paralyzed side. Here, we used a new procedure to increase the effect of contralesional hemispheric compensation by surgically crossing a peripheral nerve at the neck in rats, which may provide a substantial increase in connections between the contralesional hemisphere and the paralyzed limb. This surgical procedure, named cross-neck C7-C7 nerve transfer, involves cutting the C7 nerve on the healthy side and transferring it to the C7 nerve on the paretic side. Intracortical microstimulation, Micro-PET and histological analysis were employed to explore the cortical changes in contralesional hemisphere and to reveal its correlation with behavioral recovery. These results showed that the contralesional hemispheric compensation was markedly strengthened and significantly related to behavioral improvements. The findings also revealed a feasible and effective way to maximize the potential of one hemisphere in controlling both limbs. PMID:26732072

  12. De novo expression of parvalbumin in ependymal cells in response to brain injury promotes ependymal remodeling and wound repair.

    PubMed

    Szabolcsi, Viktória; Celio, Marco R

    2015-04-01

    The calcium-binding protein parvalbumin (PV) hallmarks subpopulations of interneurons in the murine brain. We serendipitously observed the de novo expression of PV in ependymal cells of the lateral ventricle wall following in vivo lesioning and brain slicing for the preparation of organotypic hippocampal slice cultures (OHSCs). In OHSCs, de novo PV-expression begins shortly after the onset of culturing, and the number of ependymal cells implicated in this process increases with time. PV-immunopositive ependymal cells aggregate and form compact cell clusters, which are characterized by lumen-formation and beating cilia. Scratches inflicted on such clusters with a sharp knife are rapidly closed. Exposure of OHSCs to NF-КB-inhibitors and to antioxidants reduces PV-expression in ependymal cells, thereby implicating injury-induced inflammation in this process. Indeed, in vivo stab injury enhances PV-expression in ependymal cells adjacent to the lesion, whereas neuraminidase denudation is without effect. PV-knock-out mice manifest an impaired wound-healing response to in vivo injury, and a reduced scratch-wound reparation capacity in OHSCs. Whole-transcriptome analysis of ependymal-cell clusters in OHSCs revealed down-regulation of genes involved in cytoskeletal rearrangement, cell motility and cell adhesion in PV-knock out mice as compared with wild-type mice. Our data indicate that the injury-triggered up-regulation of PV-expression is mediated by inflammatory cytokines, and promotes the motility and adhesion of ependymal cells, thereby contributing to leakage closure by the re-establishment of a continuous ependymal layer.

  13. Sex-dichotomous effects of NOS1AP promoter DNA methylation on intracranial aneurysm and brain arteriovenous malformation.

    PubMed

    Wang, Zhepei; Zhao, Jikuang; Sun, Jie; Nie, Sheng; Li, Keqing; Gao, Feng; Zhang, Tiefeng; Duan, Shiwei; Di, Yazhen; Huang, Yi; Gao, Xiang

    2016-05-16

    The goal of this study was to investigate the contribution of NOS1AP-promoter DNA methylation to the risk of intracranial aneurysm (IA) and brain arteriovenous malformation (BAVM) in a Han Chinese population. A total of 48 patients with IAs, 22 patients with BAVMs, and 26 control individuals were enrolled in the study. DNA methylation was tested using bisulfite pyrosequencing technology. We detected significantly higher DNA methylation levels in BAVM patients than in IA patients based on the multiple testing correction (CpG4-5 methylation: 5.86±1.04% vs. 4.37±2.64%, P=0.006). In women, CpG4-5 methylation levels were much lower in IA patients (3.64±1.97%) than in BAVM patients (6.11±1.20%, P<0.0001). However, in men, CpG1-3 methylation levels were much higher in the controls (6.92±0.78%) than in BAVM patients (5.99±0.70%, P=0.008). Additionally, there was a gender-based difference in CpG1 methylation within the controls (men vs. women: 5.75±0.50% vs. 4.99±0.53%, P=0.003) and BAVM patients (men vs. women: 4.70±0.74% vs. 5.50±0.87%, P=0.026). A subgroup analysis revealed significantly higher CpG3 methylation in patients who smoked than in those who did not (P=0.041). Our results suggested that gender modulated the interaction between NOS1AP promoter DNA methylation in IA and BAVM patients. Our results also confirmed that regular tobacco smoking was associated with increased NOS1AP methylation in humans. Additional studies with larger sample sizes are required to replicate and extend these findings.

  14. Glycoprotein nonmetastatic melanoma protein B (GPNMB) promotes the progression of brain glioblastoma via Na(+)/K(+)-ATPase.

    PubMed

    Ono, Yoko; Chiba, Shinsuke; Yano, Hirohito; Nakayama, Noriyuki; Saio, Masanao; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Iwama, Toru; Hara, Hideaki

    2016-12-02

    Glycoprotein nonmetastatic melanoma protein B (GPNMB), which is involved in invasion and metastasis, was found to be overexpressed in various cancers. High levels of GPNMB and Na(+)/K(+)-ATPase α subunits are associated with a poor prognosis in glioblastoma patients. We showed that GPNMB interacts with Na(+)/K(+)-ATPase α subunits to activate PI3K/Akt and MEK/ERK pathways. However, it remains unclear whether the interaction of GPNMB and Na(+)/K(+)-ATPase α subunits is involves in progression of glioma. The tumor size induced by the injection of glioma GL261 cells was larger in transgenic mice overexpressing GPNMB when compared with wild-type mice. Additionally, the interaction of GPNMB and Na(+)/K(+)-ATPase α subunits was identified in the murine glioma model and in the tumors of glioblastoma patients. Ouabain, a Na(+)/K(+)-ATPase inhibitor, suppressed the glioma growth induced by the injection of glioma cells in the transgenic mice overexpressing GPNMB and blocked the GPNMB-induced migration of glioma cells. These findings indicate that GPNMB promotes glioma growth via Na(+)/K(+)-ATPase α subunits. Thus, the interaction between GPNMB and Na(+), K(+)-ATPase α subunits represents a novel therapeutic target for the treatment of brain glioblastomas.

  15. Modulating Astrocyte Transition after Stroke to Promote Brain Rescue and Functional Recovery: Emerging Targets Include Rho Kinase.

    PubMed

    Abeysinghe, Hima Charika S; Phillips, Ellie L; Chin-Cheng, Heung; Beart, Philip M; Roulston, Carli L

    2016-02-26

    Stroke is a common and serious condition, with few therapies. Whilst previous focus has been directed towards biochemical events within neurons, none have successfully prevented the progression of injury that occurs in the acute phase. New targeted treatments that promote recovery after stroke might be a better strategy and are desperately needed for the majority of stroke survivors. Cells comprising the neurovascular unit, including blood vessels and astrocytes, present an alternative target for supporting brain rescue and recovery in the late phase of stroke, since alteration in the unit also occurs in regions outside of the lesion. One of the major changes in the unit involves extensive morphological transition of astrocytes resulting in altered energy metabolism, decreased glutamate reuptake and recycling, and retraction of astrocyte end feed from both blood vessels and neurons. Whilst globally inhibiting transitional change in astrocytes after stroke is reported to result in further damage and functional loss, we discuss the available evidence to suggest that the transitional activation of astrocytes after stroke can be modulated for improved outcomes. In particular, we review the role of Rho-kinase (ROCK) in reactive gliosis and show that inhibiting ROCK after stroke results in reduced scar formation and improved functional recovery.

  16. Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced expression in transgenic mice

    PubMed Central

    1995-01-01

    The structure of rat brain-derived neurotrophic factor (BDNF) gene is complex; four 5' exons are linked to separate promoters and one 3' exon is encoding the BDNF protein. To analyze the relative importance of the regulatory regions in vivo, we have generated transgenic mice with six different promoter constructs of the BDNF gene fused to the chloramphenicol acetyl transferase reporter gene. High level and neuronal expression of the reporter gene, that in many respects recapitulated BDNF gene expression, was achieved by using 9 kb of genomic sequences covering the promoter regions that lie adjacent to each other in the genome (promoters I and II and promoters III and IV, respectively) and by including sequences of BDNF intron-exon splice junctions and 3' untranslated region in the constructs. The genomic regions responsible for the in vivo upregulation of BDNF expression in the axotomized sciatic nerve and in the brain after kainic acid-induced seizures and KCl-induced spreading depression were mapped. These data show that regulation of the different aspects of BDNF expression is controlled by different regions in vivo, and they suggest that these promoter constructs may be useful for targeted expression of heterologous genes to specific regions of the central and peripheral nervous systems in an inducible manner. PMID:7822414

  17. DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients.

    PubMed

    Dong, E; Ruzicka, W B; Grayson, D R; Guidotti, A

    2015-09-01

    The down regulation of glutamic acid decarboxylase67 (GAD1), reelin (RELN), and BDNF expression in brain of schizophrenia (SZ) and bipolar (BP) disorder patients is associated with overexpression of DNA methyltransferase1 (DNMT1) and ten-eleven translocase methylcytosine dioxygenase1 (TET1). DNMT1 and TET1 belong to families of enzymes that methylate and hydroxymethylate cytosines located proximal to and within cytosine phosphodiester guanine (CpG) islands of many gene promoters, respectively. Altered promoter methylation may be one mechanism underlying the down-regulation of GABAergic and glutamatergic gene expression. However, recent reports suggest that both DNMT1 and TET1 directly bind to unmethylated CpG rich promoters through their respective Zinc Finger (ZF-CXXC) domains. We report here, that the binding of DNMT1 to GABAergic (GAD1, RELN) and glutamatergic (BDNF-IX) promoters is increased in SZ and BP disorder patients and this increase does not necessarily correlate with enrichment in promoter methylation. The increased DNMT1 binding to these promoter regions is detected in the cortex but not in the cerebellum of SZ and BP disorder patients, suggesting a brain region and neuron specific dependent mechanism. Increased binding of DNMT1 positively correlates with increased expression of DNMT1 and with increased binding of MBD2. In contrast, the binding of TET1 to RELN, GAD1 and BDNF-IX promoters failed to change. These data are consistent with the hypothesis that the down-regulation of specific GABAergic and glutamatergic genes in SZ and BP disorder patients may be mediated, at least in part, by a brain region specific and neuronal-activity dependent DNMT1 action that is likely independent of its DNA methylation activity.

  18. Human FGF1 promoter is active in ependymal cells and dopaminergic neurons in the brains of F1B-GFP transgenic mice.

    PubMed

    Chen, Mei-Shu; Lin, Hua-Kuo; Chiu, Hsun; Lee, Don-Ching; Chung, Yu-Fen; Chiu, Ing-Ming

    2015-03-01

    FGF1 is involved in multiple biological functions and exhibits the importance in neuroprotective effects. Our previous studies indicated that, in human brain and retina, the FGF1B promoter controlled the expression of FGF1. However, the exact function and regulation of FGF1 in brain is still unclear. Here, we generated F1B-GFP transgenic mice that expressed the GFP reporter gene under the control of human FGF1B promoter (-540 to +31). Using the fresh brain sections of F1B-GFP transgenic mice, we found that the F1B-GFP cells expressed strong fluorescent signals in the ventricular system throughout the brain. The results of immunohistochemistry further showed that two distinct populations of F1B-GFP(+) cells existed in the brains of F1B-GFP transgenic mice. We demonstrated that one population of F1B-GFP(+) cells was ependymal cells, which distributed along the entire ventricles, and the second population of F1B-GFP(+) cells was neuronal cells that projected their long processes into multiple directions in specific areas of the brain. The double labeling of F1B-GFP(+) cells and tyrosine hydroxylase indicated that a subpopulation of F1B-GFP(+) -neuronal cells was dopaminergic neurons. Importantly, these F1B-GFP(+) /TH(+) cells were distributed in the main dopaminergic neuronal groups including hypothalamus, ventral tegmental area, and raphe nuclei. These results suggested that human FGF1B promoter was active in ependymal cells, neurons, and a portion of dopaminergic neurons. Thus, the F1B-GFP transgenic mice provide an animal model not only for studying FGF1 gene expression in vivo but also for understanding the role of FGF1 contribution in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.

  19. Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

    PubMed Central

    2014-01-01

    Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

  20. Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage.

    PubMed

    Feng, Zhichun; Liu, Jing; Ju, Rong

    2013-05-05

    Hyperbaric oxygen therapy for the treatment of neonatal hypoxic-ischemic brain damage has been used clinically for many years, but its effectiveness remains controversial. In addition, the mechanism of this potential neuroprotective effect remains unclear. This study aimed to investigate the influence of hyperbaric oxygen on the proliferation of neural stem cells in the subventricular zone of neonatal Sprague-Dawley rats (7 days old) subjected to hypoxic-ischemic brain damage. Six hours after modeling, rats were treated with hyperbaric oxygen once daily for 7 days. Immunohistochemistry revealed that the number of 5-bromo-2'-deoxyuridine positive and nestin positive cells in the subventricular zone of neonatal rats increased at day 3 after hypoxic-ischemic brain damage and peaked at day 5. After hyperbaric oxygen treatment, the number of 5-bromo-2'-deoxyuridine positive and nestin positive cells began to increase at day 1, and was significantly higher than that in normal rats and model rats until day 21. Hematoxylin-eosin staining showed that hyperbaric oxygen treatment could attenuate pathological changes to brain tissue in neonatal rats, and reduce the number of degenerating and necrotic nerve cells. Our experimental findings indicate that hyperbaric oxygen treatment enhances the proliferation of neural stem cells in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage, and has therapeutic potential for promoting neurological recovery following brain injury.

  1. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    USGS Publications Warehouse

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in v

  2. Red-Backed Vole Brain Promotes Highly Efficient In Vitro Amplification of Abnormal Prion Protein from Macaque and Human Brains Infected with Variant Creutzfeldt-Jakob Disease Agent

    PubMed Central

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human

  3. Differential Associations of Early- and Late-Night Sleep with Functional Brain States Promoting Insight to Abstract Task Regularity

    PubMed Central

    Wagner, Ullrich; Verleger, Rolf

    2010-01-01

    Background Solving a task with insight has been associated with occipital and right-hemisphere activations. The present study tested the hypothesis if sleep-related alterations in functional activation states modulate the probability of insight into a hidden abstract regularity of a task. Methodology State-dependent functional activation was measured by beta and alpha electroencephalographic (EEG) activity and spatial synchronization. Task-dependent functional activation was assessed by slow cortical potentials (SPs). EEG parameters during the performance of the Number Reduction Task (NRT) were compared between before sleep and after sleep sessions. In two different groups, the relevant sleep occurred either in the first or in the second half of the night, dominated by slow wave sleep (SWS) or by rapid eye movement (REM) sleep. Principal Findings Changes in EEG parameters only occurred in the early-night group, not in the late-night group and indicated occipital and right-hemisphere functional alterations. These changes were associated with off-line consolidation of implicit task representations and with the amount of SWS but they did not predict subsequent insight. The gain of insight was, however, independently associated with changes of spectral beta and alpha measures only in those subjects from the two sleep groups who would subsequently comprehend the hidden regularity of the task. Insight-related enhancement of right frontal asymmetry after sleep did not depend on sleep stages. Significance It is concluded that off-line restructuring of implicit information during sleep is accompanied by alterations of functional activation states after sleep. This mechanism is promoted by SWS but not by REM sleep and may contribute to attaining insight after sleep. Original neurophysiologic evidence is provided for alterations of the functional activation brain states after sleep. These alterations are associated with a decrease in controlled processing within the visual

  4. High Ca2+ load promotes hydrogen peroxide generation via activation of α-glycerophosphate dehydrogenase in brain mitochondria.

    PubMed

    Tretter, Laszlo; Adam-Vizi, Vera

    2012-12-01

    H(2)O(2) generation associated with α-glycerophosphate (α-GP) oxidation was addressed in guinea pig brain mitochondria challenged with high Ca(2+) load (10 μM). Exposure to 10 μM Ca(2+) induced an abrupt 2.5-fold increase in H(2)O(2) release compared to that measured in the presence of a physiological cytosolic Ca(2+) concentration (100 nM) from mitochondria respiring on 5 mM α-GP in the presence of ADP (2 mM). The Ca(2+)-induced stimulation of H(2)O(2) generation was reversible and unaltered by the uniporter blocker Ru 360, indicating that it did not require Ca(2+) uptake into mitochondria. Enhanced H(2)O(2) generation by Ca(2+) was also observed in the absence of ADP when mitochondria exhibited permeability transition pore opening with a decrease in the NAD(P)H level, dissipation of membrane potential, and mitochondrial swelling. Furthermore, mitochondria treated with the pore-forming peptide alamethicin also responded with an elevated H(2)O(2) generation to a challenge with 10 μM Ca(2+). Ca(2+)-induced promotion of H(2)O(2) formation was further enhanced by the complex III inhibitor myxothiazol. With 20 mM α-GP concentration, stimulation of H(2)O(2) formation by Ca(2+) was detected only in the presence, not in the absence, of ADP. It is concluded that α-glycerophosphate dehydrogenase, which is accessible to and could be activated by a rise in the level of cytosolic Ca(2+), makes a major contribution to Ca(2+)-stimulated H(2)O(2) generation. This work highlights a unique high-Ca(2+)-stimulated reactive oxygen species-forming mechanism in association with oxidation of α-GP, which is largely independent of the bioenergetic state and can proceed even in damaged, functionally incompetent mitochondria.

  5. Chromatin immunoprecipitation scanning identifies glucocorticoid receptor binding regions in the proximal promoter of a ubiquitously expressed glucocorticoid target gene in brain.

    PubMed

    van der Laan, Siem; Sarabdjitsingh, R Angela; Van Batenburg, Marcel F; Lachize, Servane B; Li, Hualing; Dijkmans, Thomas F; Vreugdenhil, Erno; de Kloet, E Ron; Meijer, Onno C

    2008-09-01

    While the actions of glucocorticoids on brain functions have been comprehensively studied, the underlying genomic mechanisms are poorly understood. In this study, we show that glucocorticoid-induced leucine zipper (GILZ) mRNA is strongly and ubiquitously induced in rat brain. To decipher the molecular mechanisms underlying these genomic effects, it is of interest to identify the regulatory sites in the promoter region. Alignment of the rat GILZ promoter with the well-characterized human promoter resulted in poor sequence homology. Consequently, we analyzed the rat 5' flanking sequence by Matrix REDUCE and identified two high-affinity glucocorticoid response elements (GRE) located 2 kb upstream of the transcription start site. These findings were corroborated using the glucocorticoid receptor (GR) expressing Ns-1 PC12 rat cell-line. In these cells, dexamethasone treatment leads to a progressive increase of GILZ mRNA expression levels via a GR-dependent mechanism. Subsequently, using chromatin immunoprecipitation assays we show that the two high-affinity GREs are located within the GR-binding regions. Lastly, we demonstrate using multiple tissue in situ hybridization a marked increase in mRNA expression levels in spleen, thymus, heart, lung, liver, muscle, testis, kidney, colon, ileum, as well as in brain and conclude that the GILZ gene can be used to study glucocorticoid effects in many additional rodent tissues.

  6. Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and Psychotic bipolar disorder.

    PubMed

    Abdolmaleky, Hamid M; Pajouhanfar, Sara; Faghankhani, Masoomeh; Joghataei, Mohammad Taghi; Mostafavi, Ashraf; Thiagalingam, Sam

    2015-12-01

    Due to the lack of genetic association between individual genes and schizophrenia (SCZ) pathogenesis, the current consensus is to consider both genetic and epigenetic alterations. Here, we report the examination of DNA methylation status of DTNBP1 promoter region, one of the most credible candidate genes affected in SCZ, assayed in saliva and post-mortem brain samples. The Illumina DNA methylation profiling and bisulfite sequencing of representative samples were used to identify methylation status of the DTNBP1 promoter region. Quantitative methylation specific PCR (qMSP) was employed to assess methylation of DTNBP1 promoter CpGs flanking a SP1 binding site in the saliva of SCZ patients, their first-degree relatives and control subjects (30, 15, and 30/group, respectively) as well as in post-mortem brains of patients with SCZ and bipolar disorder (BD) versus controls (35/group). qRT-PCR was used to assess DTNBP1 expression. We found DNA hypermethylation of DTNBP1 promoter in the saliva of SCZ patients (∼12.5%, P = 0.036), particularly in drug-naïve patients (∼20%, P = 0.011), and a trend toward hypermethylation in their first-degree relatives (P = 0.085) versus controls. Analysis of post-mortem brain samples revealed an inverse correlation between DTNBP1 methylation and expression, and normalization of this epigenetic change by classic antipsychotic drugs. Additionally, BD patients with psychotic depression exhibited higher degree of methylation versus other BD patients (∼80%, P = 0.025). DTNBP1 promoter DNA methylation may become a key element in a panel of biomarkers for diagnosis, prevention, or therapy in SCZ and at risk individuals pending confirmatory studies with larger sample sizes to attain a higher degree of significance.

  7. Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter

    PubMed Central

    1992-01-01

    We have previously shown that postnatal expression of the viral oncoprotein SV40 T antigen in rod photoreceptors (transgene MOT1), at a time when retinal cells have withdrawn from the mitotic cycle, leads to photoreceptor cell death (Al-Ubaidi et al., 1992. Proc. Natl. Acad. Sci. USA. 89:1194-1198). To study the effect of the specificity of the promoter, we replaced the mouse opsin promoter in MOT1 by a 1.3-kb promoter fragment of the human IRBP gene which is expressed in both rod and cone photoreceptors during embryonic development. The resulting construct, termed HIT1, was injected into mouse embryos and five transgenic mice lines were established. Mice heterozygous for HIT1 exhibited early bilateral retinal and brain tumors with varying degrees of incidence. Histopathological examination of the brain and eyes of three of the families showed typical primitive neuroectodermal tumors. In some of the bilateral retinal tumors, peculiar rosettes were observed, which were different from the Flexner-Wintersteiner rosettes typically associated with human retinoblastomas. The ocular and cerebral tumors, however, contained Homer-Wright rosettes, and showed varying degrees of immunoreactivity to antibodies against the neuronal specific antigens, synaptophysin and Leu7, but not to antibodies against photoreceptor specific proteins. Taken together, the results indicate that the specificity of the promoter used for T antigen and/or the time of onset of transgene expression determines the fate of photoreceptor cells expressing T antigen. PMID:1334963

  8. Enhanced brain-derived neurotrophic factor delivery by ultrasound and microbubbles promotes white matter repair after stroke.

    PubMed

    Rodríguez-Frutos, Berta; Otero-Ortega, Laura; Ramos-Cejudo, Jaime; Martínez-Sánchez, Patricia; Barahona-Sanz, Inés; Navarro-Hernanz, Teresa; Gómez-de Frutos, María Del Carmen; Díez-Tejedor, Exuperio; Gutiérrez-Fernández, María

    2016-09-01

    Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury.

  9. Role of phosphodiesterase-4 on ethanol elicited locomotion and narcosis.

    PubMed

    Baliño, Pablo; Ledesma, Juan Carlos; Aragon, Carlos M G

    2016-02-01

    The cAMP signaling pathway has emerged as an important modulator of the pharmacological effects of ethanol. In this respect, the cAMP-dependent protein kinase has been shown to play an important role in the modulation of several ethanol-induced behavioral actions. Cellular levels of cAMP are maintained by the activity of adenylyl cyclases and phosphodiesterases. In the present work we have focused on ascertaining the role of PDE4 in mediating the neurobehavioral effects of ethanol. For this purpose, we have used the selective PDE4 inhibitor Ro 20-1724. This compound has been proven to enhance cellular cAMP response by PDE4 blockade and can be administered systemically. Swiss mice were injected intraperitoneally (i.p.) with Ro 20-1724 (0-5 mg/kg; i.p.) at different time intervals before ethanol (0-4 g/kg; i.p.) administration. Immediately after the ethanol injection, locomotor activity, loss of righting reflex, PKA footprint and enzymatic activity were assessed. Pretreatment with Ro 20-1724 increased ethanol-induced locomotor stimulation in a dose-dependent manner. Doses that increased locomotor stimulation did not modify basal locomotion or the suppression of motor activity produced by high doses of this alcohol. Ro 20-1724 did not alter the locomotor activation produced by amphetamine or cocaine. The time of loss of righting reflex evoked by ethanol was increased after pretreatment with Ro 20-1724. This effect was selective for the narcotic effects of ethanol since Ro 20-1724 did not affect pentobarbital-induced narcotic effects. Moreover, Ro 20-1724 administration increased the PKA footprint and enzymatic activity response elicited by ethanol. These data provide further evidence of the key role of the cAMP signaling pathway in the central effects of ethanol.

  10. Cytomegalovirus Infection of the Rat Developing Brain In Utero Prominently Targets Immune Cells and Promotes Early Microglial Activation

    PubMed Central

    Cloarec, Robin; Bauer, Sylvian; Luche, Hervé; Buhler, Emmanuelle; Pallesi-Pocachard, Emilie; Salmi, Manal; Courtens, Sandra; Massacrier, Annick; Grenot, Pierre; Teissier, Natacha; Watrin, Françoise; Schaller, Fabienne; Adle-Biassette, Homa; Gressens, Pierre; Malissen, Marie; Stamminger, Thomas; Streblow, Daniel N.; Bruneau, Nadine; Szepetowski, Pierre

    2016-01-01

    Background Congenital cytomegalovirus infections are a leading cause of neurodevelopmental disorders in human and represent a major health care and socio-economical burden. In contrast with this medical importance, the pathophysiological events remain poorly known. Murine models of brain cytomegalovirus infection, mostly neonatal, have brought recent insights into the possible pathogenesis, with convergent evidence for the alteration and possible involvement of brain immune cells. Objectives and Methods In order to confirm and expand those findings, particularly concerning the early developmental stages following infection of the fetal brain, we have created a model of in utero cytomegalovirus infection in the developing rat brain. Rat cytomegalovirus was injected intraventricularly at embryonic day 15 (E15) and the brains analyzed at various stages until the first postnatal day, using a combination of gene expression analysis, immunohistochemistry and multicolor flow cytometry experiments. Results Rat cytomegalovirus infection was increasingly seen in various brain areas including the choroid plexi and the ventricular and subventricular areas and was prominently detected in CD45low/int, CD11b+ microglial cells, in CD45high, CD11b+ cells of the myeloid lineage including macrophages, and in CD45+, CD11b– lymphocytes and non-B non-T cells. In parallel, rat cytomegalovirus infection of the developing rat brain rapidly triggered a cascade of pathophysiological events comprising: chemokines upregulation, including CCL2-4, 7 and 12; infiltration by peripheral cells including B-cells and monocytes at E17 and P1, and T-cells at P1; and microglia activation at E17 and P1. Conclusion In line with previous findings in neonatal murine models and in human specimen, our study further suggests that neuroimmune alterations might play critical roles in the early stages following cytomegalovirus infection of the brain in utero. Further studies are now needed to determine which

  11. Human neural stem cells genetically modified to overexpress brain-derived neurotrophic factor promote functional recovery and neuroprotection in a mouse stroke model.

    PubMed

    Lee, Hong J; Lim, In J; Lee, Min C; Kim, Seung U

    2010-11-15

    Intracerebral hemorrhage (ICH) is a lethal stroke type; mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, so an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and promote functional recovery in rat ICH model, and others have shown that intracerebral infusion of brain-derived neurotrophic factor (BDNF) results in improved structural and functional outcome from cerebral ischemia. We postulated that human NSCs overexpressing BDNF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs and increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by injection of bacterial collagenase into striatum. The HB1.F3.BDNF (F3.BDNF) human NSC line produces sixfold higher amounts of BDNFF over the parental F3 cell line in vitro, induces behavioral improvement, and produces a threefold increase in cell survival at 2 weeks and 8 weeks posttransplantation. Brain transplantation of human NSCs overexpressing BDNF provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results indicate that the F3.BDNF human NSCs should be of great value as a cellular source for experimental studies involving cellular therapy for human neurological disorders, including ICH.

  12. Cryptococcus neoformans activates RhoGTPase proteins followed by protein kinase C, focal adhesion kinase, and ezrin to promote traversal across the blood-brain barrier.

    PubMed

    Kim, Jong-Chul; Crary, Benjamin; Chang, Yun C; Kwon-Chung, Kyung J; Kim, Kee J

    2012-10-19

    Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis. Previous studies have demonstrated that Cryptococcus binding and invasion of human brain microvascular endothelial cells (HBMEC) is a prerequisite for transmigration across the blood-brain barrier. However, the molecular mechanism involved in the cryptococcal blood-brain barrier traversal is poorly understood. In this study we examined the signaling events in HBMEC during interaction with C. neoformans. Analysis with inhibitors revealed that cryptococcal association, invasion, and transmigration require host actin cytoskeleton rearrangement. Rho pulldown assays revealed that Cryptococcus induces activation of three members of RhoGTPases, e.g. RhoA, Rac1, and Cdc42, and their activations are required for cryptococcal transmigration across the HBMEC monolayer. Western blot analysis showed that Cryptococcus also induces phosphorylation of focal adhesion kinase (FAK), ezrin, and protein kinase C α (PKCα), all of which are involved in the rearrangement of host actin cytoskeleton. Down-regulation of FAK, ezrin, or PKCα by shRNA knockdown, dominant-negative transfection, or inhibitors significantly reduces cryptococcal ability to traverse the HBMEC monolayer, indicating their positive role in cryptococcal transmigration. In addition, activation of RhoGTPases is the upstream event for phosphorylation of FAK, ezrin, and PKCα during C. neoformans-HBMEC interaction. Taken together, our findings demonstrate that C. neoformans activates RhoGTPases and subsequently FAK, ezrin, and PKCα to promote their traversal across the HBMEC monolayer, which is the critical step for cryptococcal brain infection and development of meningitis.

  13. Processing demands upon cognitive, linguistic, and articulatory functions promote grey matter plasticity in the adult multilingual brain: Insights from simultaneous interpreters.

    PubMed

    Elmer, Stefan; Hänggi, Jürgen; Jäncke, Lutz

    2014-05-01

    Until now, considerable effort has been made to determine structural brain characteristics related to exceptional multilingual skills. However, at least one important question has not yet been satisfactorily addressed in the previous literature, namely whether and to which extent the processing demands upon cognitive, linguistic, and articulatory functions may promote grey matter plasticity in the adult multilingual brain. Based on the premise that simultaneous interpretation is a highly demanding linguistic task that places strong demands on executive and articulatory functions, here we compared grey matter volumes between professional simultaneous interpreters (SI) and multilingual control subjects. Thereby, we focused on a specific set of a-priori defined bilateral brain regions that have previously been shown to support neurocognitional aspects of language control and linguistic functions in the multilingual brain. These regions are the cingulate gyrus, caudate nucleus, frontal operculum (pars triangularis and opercularis), inferior parietal lobe (IPL) (supramarginal and angular gyrus), and the insula. As a main result, we found reduced grey matter volumes in professional SI, compared to multilingual controls, in the left middle-anterior cingulate gyrus, bilateral pars triangularis, left pars opercularis, bilateral middle part of the insula, and in the left supramarginal gyrus (SMG). Interestingly, grey matter volume in left pars triangularis, right pars opercularis, middle-anterior cingulate gyrus, and in the bilateral caudate nucleus was negatively correlated with the cumulative number of interpreting hours. Hence, we provide first evidence for an expertise-related grey matter architecture that may reflect a composite of brain characteristics that were still present before interpreting training and training-related changes.

  14. Arguments against promoting organ transplants from brain-dead donors, and views of contemporary Japanese on life and death.

    PubMed

    Asai, Atsushi; Kadooka, Yasuhiro; Aizawa, Kuniko

    2012-05-01

    As of 2009, the number of donors in Japan is the lowest among developed countries. On July 13, 2009, Japan's Organ Transplant Law was revised for the first time in 12 years. The revised and old laws differ greatly on four primary points: the definition of death, age requirements for donors, requirements for brain-death determination and organ extraction, and the appropriateness of priority transplants for relatives. In the four months of deliberations in the National Diet before the new law was established, various arguments regarding brain death and organ transplantation were offered. An amazing variety of opinions continue to be offered, even after more than 40 years have elapsed since the first heart organ transplant in Japan. Some are of the opinion that with the passage of the revised law, Japan will finally become capable of performing transplants according to global standards. Contrarily, there are assertions that organ transplants from brain-dead donors are unacceptable because they result in organs being taken from living human beings. Considering the current conditions, we will organize and introduce the arguments for and against organ transplants from brain-dead donors in contemporary Japan. Subsequently, we will discuss the primary arguments against organ transplants from brain-dead donors from the perspective of contemporary Japanese views on life and death. After introducing the recent view that brain death should not be regarded as equivalent to the death of a human being, we would like to probe the deeply-rooted views on life and death upon which it is based.

  15. Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

    PubMed

    Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J; Bergeson, Susan E; Henderson, George I; Kruman, Inna I

    2012-12-21

    The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

  16. Alcohol-induced One-carbon Metabolism Impairment Promotes Dysfunction of DNA Base Excision Repair in Adult Brain*

    PubMed Central

    Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G.; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J.; Bergeson, Susan E.; Henderson, George I.; Kruman, Inna I.

    2012-01-01

    The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr+/− mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain. PMID:23118224

  17. Tissue plasminogen activator followed by antioxidant-loaded nanoparticle delivery promotes activation/mobilization of progenitor cells in infarcted rat brain

    PubMed Central

    Petro, Marianne; Jaffer, Hayder; Yang, Jun; Kabu, Shushi; Morris, Viola B.; Labhasetwar, Vinod

    2015-01-01

    Inherent neuronal and circulating progenitor cells play important roles in facilitating neuronal and functional recovery post stroke. However, this endogenous repair process is rather limited, primarily due to unfavorable conditions in the infarcted brain involving reactive oxygen species (ROS)-mediated oxidative stress and inflammation following ischemia/reperfusion injury. We hypothesized that during reperfusion, effective delivery of antioxidants to ischemic brain would create an environment without such oxidative stress and inflammation, thus promoting activation and mobilization of progenitor cells in the infarcted brain. We administered recombinant human tissue-type plasminogen activator (tPA) via carotid artery at 3 h post stroke in a thromboembolic rat model, followed by sequential administration of the antioxidants catalase (CAT) and superoxide dismutase (SOD), encapsulated in biodegradable nanoparticles (nano-CAT/SOD). Brains were harvested at 48 h post stroke for immunohistochemical analysis. Ipsilateral brain slices from animals that had received tPA + nano-CAT/SOD showed a widespread distribution of glial fibrillary acidic protein-positive cells (with morphology resembling radial glia-like neural precursor cells) and nestin-positive cells (indicating the presence of immature neurons); such cells were considerably fewer in untreated animals or those treated with tPA alone. Brain sections from animals receiving tPA + nano-CAT/SOD also showed much greater numbers of SOX2- and nestin-positive progenitor cells migrating from subventricular zone of the lateral ventricle and entering the rostral migratory stream than in t-PA alone treated group or untreated control. Further, animals treated with tPA + nano-CAT/SOD showed far fewer caspase-positive cells and fewer neutrophils than did other groups, as well as an inhibition of hippocampal swelling. These results suggest that the antioxidants mitigated the inflammatory response, protected neuronal cells from

  18. Researching the Practice, Practicing the Research, and Promoting Responsible Policy: Usable Knowledge in Mind, Brain, and Education

    ERIC Educational Resources Information Center

    Christodoulou, Joanna A.; Daley, Samantha G.; Katzir, Tami

    2009-01-01

    The theme of Usable Knowledge in Mind, Brain, and Education will be a special section that will appear regularly in the journal. The section will focus on the synergistic connections between biology, cognitive science, and human development on the one hand and educational thought, policy, and practice on the other. Efforts to create usable…

  19. Beyond Neural Cubism: Promoting a Multidimensional View of Brain Disorders by Enhancing the Integration of Neurology and Psychiatry in Education

    PubMed Central

    Taylor, Joseph J.; Williams, Nolan R.; George, Mark S.

    2014-01-01

    Cubism was an influential early 20th century art movement characterized by angular, disjointed imagery. The two-dimensional appearance of Cubist figures and objects is created through juxtaposition of angles. The authors posit that the constrained perspectives found in Cubism may also be found in the clinical classification of brain disorders. Neurological disorders are often separated from psychiatric disorders as if they stem from different organ systems. Maintaining two isolated clinical disciplines fractionalizes the brain in the same way that Pablo Picasso fractionalized figures and objects in his Cubist art. This Neural Cubism perpetuates a clinical divide that does not reflect the scope and depth of neuroscience. All brain disorders are complex and multidimensional, with aberrant circuitry and resultant psychopharmacology manifesting as altered behavior, affect, mood or cognition. Trainees should receive a multidimensional education based on modern neuroscience, not a partial education based on clinical precedent. The authors briefly outline the rationale for increasing the integration of neurology and psychiatry and discuss a nested model with which clinical neuroscientists (neurologists and psychiatrists) can approach and treat brain disorders. PMID:25340364

  20. Beyond neural cubism: promoting a multidimensional view of brain disorders by enhancing the integration of neurology and psychiatry in education.

    PubMed

    Taylor, Joseph J; Williams, Nolan R; George, Mark S

    2015-05-01

    Cubism was an influential early-20th-century art movement characterized by angular, disjointed imagery. The two-dimensional appearance of Cubist figures and objects is created through juxtaposition of angles. The authors posit that the constrained perspectives found in Cubism may also be found in the clinical classification of brain disorders. Neurological disorders are often separated from psychiatric disorders as if they stemmed from different organ systems. Maintaining two isolated clinical disciplines fractionalizes the brain in the same way that Pablo Picasso fractionalized figures and objects in his Cubist art. This Neural Cubism perpetuates a clinical divide that does not reflect the scope and depth of neuroscience. All brain disorders are complex and multidimensional, with aberrant circuitry and resultant psychopharmacology manifesting as altered behavior, affect, mood, or cognition. Trainees should receive a multidimensional education based on modern neuroscience, not a partial education based on clinical precedent. The authors briefly outline the rationale for increasing the integration of neurology and psychiatry and discuss a nested model with which clinical neuroscientists (neurologists and psychiatrists) can approach and treat brain disorders.

  1. High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4.

    PubMed

    Laird, Melissa D; Shields, Jessica S; Sukumari-Ramesh, Sangeetha; Kimbler, Donald E; Fessler, R David; Shakir, Basheer; Youssef, Patrick; Yanasak, Nathan; Vender, John R; Dhandapani, Krishnan M

    2014-01-01

    Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.

  2. Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals

    PubMed Central

    Bomba, M; Ciavardelli, D; Silvestri, E; Canzoniero, L MT; Lattanzio, R; Chiappini, P; Piantelli, M; Di Ilio, C; Consoli, A; Sensi, S L

    2013-01-01

    Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate. PMID:23640454

  3. The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans.

    PubMed

    Sashindranath, Maithili; Sales, Eunice; Daglas, Maria; Freeman, Roxann; Samson, Andre L; Cops, Elisa J; Beckham, Simone; Galle, Adam; McLean, Catriona; Morganti-Kossmann, Cristina; Rosenfeld, Jeffrey V; Madani, Rime; Vassalli, Jean-Dominique; Su, Enming J; Lawrence, Daniel A; Medcalf, Robert L

    2012-11-01

    The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix

  4. Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice.

    PubMed

    Chien, Mei-Yin; Chuang, Cheng-Hung; Chern, Chang-Ming; Liou, Kou-Tong; Liu, Der-Zen; Hou, Yu-Chang; Shen, Yuh-Chiang

    2016-10-01

    Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalA's protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100μg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5. SalA also intensively limited cortical infarction and promoted the expression of neurogenesis protein near the peri-infarct cortex and subgranular zone of the hippocampal dentate gyrus by compromising the activation of GSK3β and p25/Cdk5, which in turn upregulated β-catenin, doublecortin (DCX), and Bcl-2, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor. We conclude that SalA blocks inflammatory responses by impairing NF-κB signaling, thereby limiting inflammation/nitrosative stress and preserving the integrity of the BBB; SalA also concomitantly promotes neurogenesis-related protein expression by compromising GSK3β/Cdk5 activity to enhance the expression levels of β-catenin/DCX and Bcl-2 for neuroprotection.

  5. c-myc and N-myc promote active stem cell metabolism and cycling as architects of the developing brain.

    PubMed

    Wey, Alice; Knoepfler, Paul S

    2010-06-01

    myc genes are associated with a wide variety of human cancers including most types of nervous system tumors. While the mechanisms by which myc overexpression causes tumorigenesis are multifaceted and have yet to be clearly elucidated, they are at least in part related to endogenous myc function in normal cells. Knockout (KO) of either c-myc or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre impairs mouse brain growth and mutation of N-myc also causes microcephaly in humans in Feingold Syndrome. To further define myc function in NSC and nervous system development, we created a double KO (DKO) for c- and N-myc using nestin-cre. The DKO mice display profoundly impaired overall brain growth associated with decreased cell cycling and migration of NSC, which are strikingly decreased in number. The DKO brain also exhibits specific changes in gene expression including downregulation of genes involved in protein and nucleotide metabolism, mitosis, and chromatin structure as well as upregulation of genes associated with differentiation. Together these data support a model of nervous system tumorigenesis in which excess myc aberrantly locks in a developmentally active chromatin state characterized by overactive cell cycling, and metabolism as well as blocked differentiation.

  6. Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury.

    PubMed

    Helmy, Adel; Guilfoyle, Mathew R; Carpenter, Keri Lh; Pickard, John D; Menon, David K; Hutchinson, Peter J

    2016-08-01

    Interleukin-1 receptor antagonist (IL1ra) has demonstrated efficacy in a wide range of animal models of neuronal injury. We have previously published a randomised controlled study of IL1ra in human severe TBI, with concomitant microdialysis and plasma sampling of 42 cytokines and chemokines. In this study, we have used partial least squares discriminant analysis to model the effects of drug administration and time following injury on the cytokine milieu within the injured brain. We demonstrate that treatment with rhIL1ra causes a brain-specific modification of the cytokine and chemokine response to injury, particularly in samples from the first 48 h following injury. The magnitude of this response is dependent on the concentration of IL1ra achieved in the brain extracellular space. Chemokines related to recruitment of macrophages from the plasma compartment (MCP-1) and biasing towards a M1 microglial phenotype (GM-CSF, IL1) are increased in patient samples in the rhIL1ra-treated patients. In control patients, cytokines and chemokines biased to a M2 microglia phenotype (IL4, IL10, MDC) are relatively increased. This pattern of response suggests that a simple classification of IL1ra as an 'anti-inflammatory' cytokine may not be appropriate and highlights the importance of the microglial response to injury.

  7. Transcriptional activation of the human brain-derived neurotrophic factor gene promoter III by dopamine signaling in NT2/N neurons.

    PubMed

    Fang, Hung; Chartier, Joanne; Sodja, Caroline; Desbois, Angele; Ribecco-Lutkiewicz, Maria; Walker, P Roy; Sikorska, Marianna

    2003-07-18

    We have identified a functional cAMP-response element (CRE) in the human brain-derived neurotrophic factor (BDNF) gene promoter III and established that it participated in the modulation of BDNF expression in NT2/N neurons via downstream signaling from the D1 class of dopamine (DA) receptors. The up-regulation of BDNF expression, in turn, produced neuroprotective signals through receptor tyrosine kinase B (TrkB) and promoted cell survival under the conditions of oxygen and glucose deprivation. To our knowledge this is the first evidence showing the presence of a functional CRE in the human BDNF gene and the role of DA signaling in establishing transcriptional competence of CRE in post-mitotic NT2/N neurons. This ability of DA to regulate the expression of the BDNF survival factor has a profound significance for the nigrostriatal pathway, because it indicates the existence of a feedback loop between the neutrophin, which promotes both the maturation and survival of dopaminergic neurons, and the neurotransmitter, which the mature neurons ultimately produce and release.

  8. Expression of the woodchuck N-myc2 retroposon in brain and in liver tumors is driven by a cryptic N-myc promoter.

    PubMed Central

    Fourel, G; Transy, C; Tennant, B C; Buendia, M A

    1992-01-01

    The woodchuck intronless proto-oncogene N-myc2 was initially discovered as a frequent target site for hepadnavirus integration in hepatocellular carcinoma. N-myc2 possesses characteristics of a functional retroposon derived from the woodchuck N-myc gene. We have investigated the regulatory signals governing N-myc2 expression and found that a short promoter, including a variant TATA box and potential binding sites for several transcription factors, is localized in the N-myc2 sequences homologous to the 5' untranslated region of the second N-myc exon. The corresponding region in the intron-containing woodchuck N-myc gene also exhibited promoter activity in transient transfection assays. The high evolutionary conservation of these sequences in mammalian N-myc genes suggests that they contain a cryptic N-myc promoter which may be unmasked in the particular context provided by the N-myc2 retroposon. Although N-myc2, like the woodchuck N-myc gene, contributes to an extended CpG island and was found constitutively hypomethylated, it presents a highly restricted expression pattern in adult animals. Whereas the intron-containing N-myc gene is expressed at low levels in different tissues, N-myc2 mRNA was detected only in brain tissue, raising questions about the functional significance of the maintenance of a second N-myc gene in the woodchuck genome. Images PMID:1333041

  9. Putting the Mind in the Brain: Promoting an Appreciation of the Biological Basis to Understanding Human Behavior

    ERIC Educational Resources Information Center

    Neumann, David L.

    2010-01-01

    A surprising number of students in psychology, behavioral science, and related social science classes fail to appreciate the importance of biological mechanisms to understanding behavior. To help teachers promote this understanding, this paper outlines six sources of evidence. These are (a) phylogenetic, (b) genetic/developmental, (c) clinical,…

  10. Preinduction of HSP70 promotes hypoxic tolerance and facilitates acclimatization to acute hypobaric hypoxia in mouse brain

    PubMed Central

    Zhang, Kuan; Zhao, Tong; Huang, Xin; Liu, Zhao-hui; Xiong, Lei; Li, Ming-ming; Wu, Li-ying; Zhao, Yong-qi

    2008-01-01

    It has been shown that induction of HSP70 by administration of geranylgeranylacetone (GGA) leads to protection against ischemia/reperfusion injury. The present study was performed to determine the effect of GGA on the survival of mice and on brain damage under acute hypobaric hypoxia. The data showed that the mice injected with GGA survived significantly longer than control animals (survival time of 9.55 ± 3.12 min, n = 16 vs. controls at 4.28 ± 4.29 min, n = 15, P < 0.005). Accordingly, the cellular necrosis or degeneration of the hippocampus and the cortex induced by sublethal hypoxia for 6 h could be attenuated by preinjection with GGA, especially in the CA2 and CA3 regions of the hippocampus. In addition, the activity of nitric oxide synthase (NOS) of the hippocampus and the cortex was increased after exposure to sublethal hypoxia for 6 h but could be inhibited by the preinjection of GGA. Furthermore, the expression of HSP70 was significantly increased at 1 h after GGA injection. These results suggest that administration of GGA improved survival rate and prevented acute hypoxic damage to the brain and that the underlying mechanism involved induction of HSP70 and inhibition of NOS activity. PMID:19105051

  11. Surface functionalizing of a lipid nanosystem to promote brain targeting: step-by-step design and physico-chemical characterization.

    PubMed

    Cózar-Bernal, M J; García-Esteban, E; Sánchez-Soto, P J; Rabasco, A M; González-Rodríguez, M L

    2016-11-01

    The use of lipid nanosystems as drug delivery to the central nervous system may be advantageous over the current strategies. The aim of this study was to develop and characterize functionalized liposomes for treatment of brain diseases. The covalent method of coupling IgG to liposomes via the derivatized lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidophenyl)butyramide](MPB-PE) was investigated. Optimized coupling conditions are shown to result in the efficient conjugation of IgG to liposomes containing low concentrations of MPB-PE (3/1 SH:IgG). The qualitative analysis has shown that after the extrusion process, more homogeneous populations of vesicles have been obtained with a nanometric size suitable to be effective to further anchor the protein. Negative values of zeta potential demonstrate that they are stable systems. Lyophilization was used to maintain the stability of the formulation. These very interesting results encourage further investigations to formulate peptide- and protein-loaded immunoliposomes, making targeting of liposomes as an attractive approach for brain drug delivery.

  12. Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome

    PubMed Central

    2014-01-01

    Background Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS. Methods Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles. Results MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10. Conclusions The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS. PMID:24669826

  13. Methylene blue exerts a neuroprotective effect against traumatic brain injury by promoting autophagy and inhibiting microglial activation

    PubMed Central

    ZHAO, MINGFEI; LIANG, FENG; XU, HANGDI; YAN, WEI; ZHANG, JIANMIN

    2016-01-01

    Traumatic brain injury (TBI) leads to permanent neurological impairment, and methylene blue (MB) exerts central nervous system neuroprotective effects. However, only one previous study has investigated the effectiveness of MB in a controlled cortical impact injury model of TBI. In addition, the specific mechanisms underlying the effect of MB against TBI remain to be elucidated. Therefore, the present study investigated the neuroprotective effect of MB on TBI and the possible mechanisms involved. In a mouse model of TBI, the animals were randomly divided into sham, vehicle (normal saline) or MB groups. The treatment time-points were 24 and 72 h (acute phase of TBI), and 14 days (chronic phase of TBI) post-TBI. The brain water content (BWC), and levels of neuronal death, and autophagy were determined during the acute phase, and neurological deficit, injury volume and microglial activation were assessed at all time-points. The injured hemisphere BWC was significantly increased 24 h post-TBI, and this was attenuated following treatment with MB. There was a significantly higher number of surviving neurons in the MB group, compared with the Vehicle group at 24 and 72 h post-TBI. In the acute phase, the MB-treated animals exhibited significantly upregulated expression of Beclin 1 and increased LC3-II to LC3-I ratios, compared with the vehicle group, indicating an increased rate of autophagy. Neurological functional deficits, measured using the modified neurological severity score, were significantly lower in the acute phase in the MB-treated animals and cerebral lesion volumes in the MB-treated animals were significantly lower, compared with the other groups at all time-points. Microglia were activated 24 h after TBI, peaked at 72 h and persisted until 14 days after TBI. Although the number of Iba-1-positive cells in the vehicle and MB groups 24 h post-TBI were not significantly different, marked microglial inhibition was observed in the MB group 72 h and 14 days after

  14. Ischemic post-conditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats.

    PubMed

    Xie, Rong; Wang, Peng; Ji, Xunming; Zhao, Heng

    2013-12-01

    While pre-conditioning is induced before stroke onset, ischemic post-conditioning (IPostC) is performed after reperfusion, which typically refers to a series of mechanical interruption of blood reperfusion after stroke. IPostC is known to reduce infarction in wild-type animals. We investigated if IPostC protects against brain injury induced by focal ischemia in Tcell-deficient nude rats and to examine its effects on Akt and the mammalian target of rapamycin (mTOR) pathway. Although IPostC reduced infarct size at 2 days post-stroke in wild-type rats, it did not attenuate infarction in nude rats. Despite the unaltered infarct size in nude rats, IPostC increased levels of phosphorylated Akt (p-Akt) and Akt isoforms (Akt1, Akt2, Akt3), and p-mTOR, p-S6K and p-4EBP1 in the mTOR pathway, as well as growth associated Protein 43 (GAP43), both in the peri-infarct area and core, 24 h after stroke. IPostC improved neurological function in nude rats 1-30 days after stroke and reduced the extent of brain damage 30 days after stroke. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC. We determined that IPostC did not inhibit acute infarction in nude rats but did provide long-term protection by enhancing Akt and mTOR activity during the acute post-stroke phase. Post-conditioning did not attenuate infarction in nude rats measured 2 days post-stroke, but improved neurological function in nude rats and reduced brain damage 30 days after stroke. It resulted in increased-activities of Akt and mTOR, S6K and p-4EBP1. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC.

  15. Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection.

    PubMed

    McLean, Jesse R; Smith, Gaynor A; Rocha, Emily M; Hayes, Melissa A; Beagan, Jonathan A; Hallett, Penelope J; Isacson, Ole

    2014-07-25

    Adeno-associated viral (AAV) gene transfer holds great promise for treating a wide-range of neurodegenerative disorders. The AAV9 serotype crosses the blood-brain barrier and shows enhanced transduction efficiency compared to other serotypes, thus offering advantageous targeting when global transgene expression is required. Neonatal intravenous or intracerebroventricular (i.c.v.) delivery of recombinant AAV9 (rAAV9) have recently proven effective for modeling and treating several rodent models of neurodegenerative disease, however, the technique is associated with variable cellular tropism, making tailored gene transfer a challenge. In the current study, we employ the human synapsin 1 (hSYN1) gene promoter to drive neuron-specific expression of green fluorescent protein (GFP) after neonatal i.c.v. injection of rAAV9 in mice. We observed widespread GFP expression in neurons throughout the brain, spinal cord, and peripheral nerves and ganglia at 6 weeks-of-age. Region-specific quantification of GFP expression showed high neuronal transduction rates in substantia nigra pars reticulata (43.9±5.4%), motor cortex (43.5±3.3%), hippocampus (43.1±2.7%), cerebellum (29.6±2.3%), cervical spinal cord (24.9±3.9%), and ventromedial striatum (16.9±4.3%), among others. We found that 14.6±2.2% of neuromuscular junctions innervating the gastrocnemius muscle displayed GFP immunoreactivity. GFP expression was identified in several neuronal sub-types, including nigral tyrosine hydroxylase (TH)-positive dopaminergic cells, striatal dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32)-positive neurons, and choline acetyltransferase (ChAT)-positive motor neurons. These results build on contemporary gene transfer techniques, demonstrating that the hSYN1 promoter can be used with rAAV9 to drive robust neuron-specific transgene expression throughout the nervous system.

  16. Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity.

    PubMed

    Triplett, Judy C; Tramutola, Antonella; Swomley, Aaron; Kirk, Jessime; Grimes, Kelly; Lewis, Kaitilyn; Orr, Miranda; Rodriguez, Karl; Cai, Jian; Klein, Jon B; Perluigi, Marzia; Buffenstein, Rochelle; Butterfield, D Allan

    2015-10-01

    The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained health span. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extend human health span and lifespan. The ubiquitin-proteasome and autophagy-lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared with shorter-lived rodents. Using a 2-D PAGE proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan and may contribute to the extraordinary health span of these rodents. The potential of augmenting human health span via activating the proteostasis network will require further studies.

  17. Age-related Changes in the Proteostasis Network in the Brain of the Naked Mole-Rat: Implications Promoting Healthy Longevity

    PubMed Central

    Triplett, Judy C.; Tramutola, Antonella; Swomley, Aaron; Kirk, Jessime; Grimes, Kelly; Lewis, Kaitilyn; Orr, Miranda; Rodriguez, Karl; Cai, Jian; Klein, Jon B.; Perluigi, Marzia; Buffenstein, Rochelle; Butterfield, D. Allan

    2016-01-01

    The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained healthspan. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extended human healthspan and lifespan. The ubiquitin-proteasome and autophagy-lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared to shorter-lived rodents. Using a 2-D PAGE proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan. PMID:26248058

  18. Using architecture and technology to promote improved quality of life for military service members with traumatic brain injury.

    PubMed

    Pasquina, Paul F; Pasquina, Lavinia Fici; Anderson-Barnes, Victoria C; Giuggio, Jeffrey S; Cooper, Rory A

    2010-02-01

    Today, injured service members are surviving wounds that would have been fatal in previous wars. A recent RAND report estimates that approximately 320,000 service members may have experienced a traumatic brain injury (TBI) during deployment, and it is not uncommon for a soldier to sustain multiple associated injuries such as limb loss, paralysis, sensory loss, and psychological damage. As a result, many military service members and their families face significant challenges returning to a high quality of independent life. The architectural concepts of universal design (UD) and evidence-based design (EBD) are gaining interest as an integral part of the rehabilitation process of veterans with TBI. This article examines the possibilities presented by UD and EBD in accordance with the Americans with Disabilities Act of 1990, in terms of high-end building and interior design quality, and possible technological options for individuals with disabilities.

  19. Combining brain stimulation and video game to promote long-term transfer of learning and cognitive enhancement

    PubMed Central

    Looi, Chung Yen; Duta, Mihaela; Brem, Anna-Katharine; Huber, Stefan; Nuerk, Hans-Christoph; Cohen Kadosh, Roi

    2016-01-01

    Cognitive training offers the potential for individualised learning, prevention of cognitive decline, and rehabilitation. However, key research challenges include ecological validity (training design), transfer of learning and long-term effects. Given that cognitive training and neuromodulation affect neuroplasticity, their combination could promote greater, synergistic effects. We investigated whether combining transcranial direct current stimulation (tDCS) with cognitive training could further enhance cognitive performance compared to training alone, and promote transfer within a short period of time. Healthy adults received real or sham tDCS over their dorsolateral prefrontal cortices during two 30-minute mathematics training sessions involving body movements. To examine the role of training, an active control group received tDCS during a non-mathematical task. Those who received real tDCS performed significantly better in the game than the sham group, and showed transfer effects to working memory, a related but non-numerical cognitive domain. This transfer effect was absent in active and sham control groups. Furthermore, training gains were more pronounced amongst those with lower baseline cognitive abilities, suggesting the potential for reducing cognitive inequalities. All effects associated with real tDCS remained 2 months post-training. Our study demonstrates the potential benefit of this approach for long-term enhancement of human learning and cognition. PMID:26902664

  20. Combining brain stimulation and video game to promote long-term transfer of learning and cognitive enhancement.

    PubMed

    Looi, Chung Yen; Duta, Mihaela; Brem, Anna-Katharine; Huber, Stefan; Nuerk, Hans-Christoph; Cohen Kadosh, Roi

    2016-02-23

    Cognitive training offers the potential for individualised learning, prevention of cognitive decline, and rehabilitation. However, key research challenges include ecological validity (training design), transfer of learning and long-term effects. Given that cognitive training and neuromodulation affect neuroplasticity, their combination could promote greater, synergistic effects. We investigated whether combining transcranial direct current stimulation (tDCS) with cognitive training could further enhance cognitive performance compared to training alone, and promote transfer within a short period of time. Healthy adults received real or sham tDCS over their dorsolateral prefrontal cortices during two 30-minute mathematics training sessions involving body movements. To examine the role of training, an active control group received tDCS during a non-mathematical task. Those who received real tDCS performed significantly better in the game than the sham group, and showed transfer effects to working memory, a related but non-numerical cognitive domain. This transfer effect was absent in active and sham control groups. Furthermore, training gains were more pronounced amongst those with lower baseline cognitive abilities, suggesting the potential for reducing cognitive inequalities. All effects associated with real tDCS remained 2 months post-training. Our study demonstrates the potential benefit of this approach for long-term enhancement of human learning and cognition.

  1. Testing promotes long-term learning via stabilizing activation patterns in a large network of brain areas.

    PubMed

    Keresztes, Attila; Kaiser, Daniel; Kovács, Gyula; Racsmány, Mihály

    2014-11-01

    The testing effect refers to the phenomenon that repeated retrieval of memories promotes better long-term retention than repeated study. To investigate the neural correlates of the testing effect, we used event-related functional magnetic resonance imaging methods while participants performed a cued recall task. Prior to the neuroimaging experiment, participants learned Swahili-German word pairs, then half of the word pairs were repeatedly studied, whereas the other half were repeatedly tested. For half of the participants, the neuroimaging experiment was performed immediately after the learning phase; a 1-week retention interval was inserted for the other half of the participants. We found that a large network of areas identified in a separate 2-back functional localizer scan were active during the final recall of the word pair associations. Importantly, the learning strategy (retest or restudy) of the word pairs determined the manner in which the retention interval affected the activations within this network. Recall of previously restudied memories was accompanied by reduced activation within this network at long retention intervals, but no reduction was observed for previously retested memories. We suggest that retrieval promotes learning via stabilizing cue-related activation patterns in a network of areas usually associated with cognitive and attentional control functions.

  2. Long-term consumption of sugar-sweetened beverage during the growth period promotes social aggression in adult mice with proinflammatory responses in the brain.

    PubMed

    Choi, Jung-Yun; Park, Mi-Na; Kim, Chong-Su; Lee, Young-Kwan; Choi, Eun Young; Chun, Woo Young; Shin, Dong-Mi

    2017-04-10

    Overconsumption of sugar-sweetened beverages (SSBs) is known to be a key contributor to the obesity epidemic; however, its effects on behavioral changes are yet to be fully studied. In the present study, we examined the long-term effects of SSB on social aggression in mice. Three-week-old weaned mice started to drink either a 30 w/v% sucrose solution (S30), plain water (CT), or an aspartame solution with sweetness equivalent to the sucrose solution (A30) and continued to drink until they were 11-week-old adults. Aggressive behaviors were assessed by the resident-intruder test. We found that SSB significantly promoted social aggression, accompanied by heightened serum corticosterone and reduced body weight. To understand the underlying mechanism, we performed transcriptome analyses of brain. The profiles of mice on S30 were dramatically different from those on CT or A30. Transcriptional networks related to immunological function were significantly dysregulated by SSB. FACS analysis of mice on S30 revealed increased numbers of inflammatory cells in peripheral blood. Interestingly, the artificial sweetener failed to mimic the effects of sugar on social aggression and inflammatory responses. These results demonstrate that SSB promotes aggressive behaviors and provide evidence that sugar reduction strategies may be useful in efforts to prevent social aggression.

  3. Long-term consumption of sugar-sweetened beverage during the growth period promotes social aggression in adult mice with proinflammatory responses in the brain

    PubMed Central

    Choi, Jung-Yun; Park, Mi-Na; Kim, Chong-Su; Lee, Young-Kwan; Choi, Eun Young; Chun, Woo Young; Shin, Dong-Mi

    2017-01-01

    Overconsumption of sugar-sweetened beverages (SSBs) is known to be a key contributor to the obesity epidemic; however, its effects on behavioral changes are yet to be fully studied. In the present study, we examined the long-term effects of SSB on social aggression in mice. Three-week-old weaned mice started to drink either a 30 w/v% sucrose solution (S30), plain water (CT), or an aspartame solution with sweetness equivalent to the sucrose solution (A30) and continued to drink until they were 11-week-old adults. Aggressive behaviors were assessed by the resident-intruder test. We found that SSB significantly promoted social aggression, accompanied by heightened serum corticosterone and reduced body weight. To understand the underlying mechanism, we performed transcriptome analyses of brain. The profiles of mice on S30 were dramatically different from those on CT or A30. Transcriptional networks related to immunological function were significantly dysregulated by SSB. FACS analysis of mice on S30 revealed increased numbers of inflammatory cells in peripheral blood. Interestingly, the artificial sweetener failed to mimic the effects of sugar on social aggression and inflammatory responses. These results demonstrate that SSB promotes aggressive behaviors and provide evidence that sugar reduction strategies may be useful in efforts to prevent social aggression. PMID:28393871

  4. Long-term viral brain-derived neurotrophic factor delivery promotes spasticity in rats with a cervical spinal cord hemisection.

    PubMed

    Fouad, Karim; Bennett, David J; Vavrek, Romana; Blesch, Armin

    2013-01-01

    We have recently reported that rats with complete thoracic spinal cord injury (SCI) that received a combinatorial treatment, including viral brain-derived neurotrophic factor (BDNF) delivery in the spinal cord, not only showed enhanced axonal regeneration, but also deterioration of hind-limb motor function. By demonstrating that BDNF over-expression can trigger spasticity-like symptoms in a rat model of sacral SCI, we proposed a causal relationship between the observed spasticity-like symptoms (i.e., resistance to passive range of motion) and the over-expression of BDNF. The current study was originally designed to evaluate a comparable combined treatment for cervical SCI in the rat to improve motor recovery. Once again we found similar signs of spasticity involving clenching of the paws and wrist flexion. This finding changed the focus of the study and, we then explored whether this spasticity-like symptom is directly related to the over-expression of BDNF by administering a BDNF antagonist. Using electromyographic measurements we showed that this treatment gradually diminished the resistance to overcome forelimb flexion in an acute experiment. Thus, we conclude that neuro-excitatory effects of chronic BDNF delivery together with diminished descending control after SCI can result in adverse effects.

  5. Low Message Sensation Health Promotion Videos Are Better Remembered and Activate Areas of the Brain Associated with Memory Encoding

    PubMed Central

    Jaganathan, Kanchana; Loughead, James W.; Blady, Shira J.; Childress, Anna Rose; Romer, Daniel; Langleben, Daniel D.

    2014-01-01

    Greater sensory stimulation in advertising has been postulated to facilitate attention and persuasion. For this reason, video ads promoting health behaviors are often designed to be high in “message sensation value” (MSV), a standardized measure of sensory intensity of the audiovisual and content features of an ad. However, our previous functional Magnetic Resonance Imaging (fMRI) study showed that low MSV ads were better remembered and produced more prefrontal and temporal and less occipital cortex activation, suggesting that high MSV may divert cognitive resources from processing ad content. The present study aimed to determine whether these findings from anti-smoking ads generalize to other public health topics, such as safe sex. Thirty-nine healthy adults viewed high- and low MSV ads promoting safer sex through condom use, during an fMRI session. Recognition memory of the ads was tested immediately and 3 weeks after the session. We found that low MSV condom ads were better remembered than the high MSV ads at both time points and replicated the fMRI patterns previously reported for the anti-smoking ads. Occipital and superior temporal activation was negatively related to the attitudes favoring condom use (see Condom Attitudes Scale, Methods and Materials section). Psychophysiological interaction (PPI) analysis of the relation between occipital and fronto-temporal (middle temporal and inferior frontal gyri) cortices revealed weaker negative interactions between occipital and fronto-temporal cortices during viewing of the low MSV that high MSV ads. These findings confirm that the low MSV video health messages are better remembered than the high MSV messages and that this effect generalizes across public health domains. The greater engagement of the prefrontal and fronto-temporal cortices by low MSV ads and the greater occipital activation by high MSV ads suggest that that the “attention-grabbing” high MSV format could impede the learning and retention of

  6. Brain-Derived Neurotrophic Factor (BDNF) Promotes Cochlear Spiral Ganglion Cell Survival and Function in Deafened, Developing Cats

    PubMed Central

    Leake, Patricia A.; Hradek, Gary T.; Hetherington, Alexander M.; Stakhovskaya, Olga

    2011-01-01

    Postnatal development and survival of spiral ganglion (SG) neurons depend upon both neural activity and neurotrophic support. Our previous studies showed that electrical stimulation from a cochlear implant only partly prevents SG degeneration after early deafness. Thus, neurotrophic agents that might be combined with an implant to improve neural survival are of interest. Recent studies reporting that BDNF promotes SG survival after deafness, have been conducted in rodents and limited to relatively short durations. Our study examined longer duration BDNF treatment in deafened cats that may better model the slow progression of SG degeneration in human cochleae and provides the first study of BDNF in the developing auditory system. Kittens were deafened neonatally, implanted at 4-5 weeks with intracochlear electrodes containing a drug-delivery cannula, and BDNF or artificial perilymph was infused for 10 weeks from a mini-osmotic pump. In BDNF-treated cochleae SG cells grew to normal size and were significantly larger than cells on the contralateral side. However, their morphology was not completely normal and many neurons lacked or had thinned perikaryl myelin. Unbiased stereology was employed to estimate SG cell density, independent of cell size. BDNF was effective in promoting significantly improved survival of SG neurons in these developing animals. BDNF treatment also resulted in higher density and larger size of myelinated radial nerve fibers, sprouting of fibers into the scala tympani, and improvement in electrically-evoked auditory brainstem response thresholds. Although BDNF may have potential therapeutic value in the developing auditory system, many serious obstacles currently preclude clinical application. PMID:21452221

  7. Immune modulation mediated by cryptococcal laccase promotes pulmonary growth and brain dissemination of virulent Cryptococcus neoformans in mice.

    PubMed

    Qiu, Yafeng; Davis, Michael J; Dayrit, Jeremy K; Hadd, Zachary; Meister, Daniel L; Osterholzer, John J; Williamson, Peter R; Olszewski, Michal A

    2012-01-01

    C. neoformans is a leading cause of fatal mycosis linked to CNS dissemination. Laccase, encoded by the LAC1 gene, is an important virulence factor implicated in brain dissemination yet little is known about the mechanism(s) accounting for this observation. Here, we investigated whether the presence or absence of laccase altered the local immune response in the lungs by comparing infections with the highly virulent strain, H99 (which expresses laccase) and mutant strain of H99 deficient in laccase (lac1Δ) in a mouse model of pulmonary infection. We found that LAC1 gene deletion decreased the pulmonary fungal burden and abolished CNS dissemination at weeks 2 and 3. Furthermore, LAC1 deletion lead to: 1) diminished pulmonary eosinophilia; 2) increased accumulation of CD4+ and CD8+ T cells; 3) increased Th1 and Th17 cytokines yet decreased Th2 cytokines; and 4) lung macrophage shifting of the lung macrophage phenotype from M2- towards M1-type activation. Next, we used adoptively transferred CD4+ T cells isolated from pulmonary lymph nodes of mice infected with either lac1Δ or H99 to evaluate the role of laccase-induced immunomodulation on CNS dissemination. We found that in comparison to PBS treated mice, adoptively transferred CD4+ T cells isolated from lac1Δ-infected mice decreased CNS dissemination, while those isolated from H99-infected mice increased CNS dissemination. Collectively, our findings reveal that immune modulation away from Th1/Th17 responses and towards Th2 responses represents a novel mechanism through which laccase can contribute to cryptococcal virulence. Furthermore, our data support the hypothesis that laccase-induced changes in polarization of CD4+ T cells contribute to CNS dissemination.

  8. Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid hemorrhage.

    PubMed

    Mutoh, Tomoko; Mutoh, Tatsushi; Nakamura, Kazuhiro; Yamamoto, Yukiko; Tsuru, Yoshiharu; Tsubone, Hirokazu; Ishikawa, Tatsuya; Taki, Yasuyuki

    2016-12-23

    Early brain injury/ischemia (EBI) is a serious complication early after subarachnoid hemorrhage (SAH) that contributes to development of delayed cerebral ischemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 μg/kg/min) between 1.5 and 2.5h after SAH induction was monitored with Doppler-echocardiography. MRI-continuous arterial spin labeling was used for quantitative CBF measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P <0.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P <0.05). The neuroprotective effects afforded by MIL or Control were attenuated by HIF inhibition (P <0.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator. This article is protected by copyright. All rights reserved.

  9. Neural Progenitor Cell Transplantation Promotes Neuroprotection, Enhances Hippocampal Neurogenesis, and Improves Cognitive Outcomes after Traumatic Brain Injury

    PubMed Central

    Blaya, Meghan O.; Tsoulfas, Pantelis; Bramlett, Helen M.; Dietrich, W. Dalton

    2014-01-01

    Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1 week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism towards contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant

  10. Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury.

    PubMed

    Blaya, Meghan O; Tsoulfas, Pantelis; Bramlett, Helen M; Dietrich, W Dalton

    2015-02-01

    Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post-surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism toward contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant

  11. An elevated level of circulating galanin promotes developmental expression of myelin basic protein in the mouse brain.

    PubMed

    Lyubetska, H; Zhang, L; Kong, J; Vrontakis, M

    2015-01-22

    Myelinogenesis is a scheduled process that is regulated by the intrinsic properties of the cell and extracellular signals. Galanin (GAL) is a bioactive neuropeptide that is widely distributed throughout the nervous system. Chronic increase in circulating GAL levels protects the demyelination processes. Furthermore, GAL is synthesized in myelin-producing glial cells, such as oligodendrocytes and its expression level is at its highest between postnatal days 10 and 40. In the present study, we use our GAL transgenic mouse model to examine the effects of GAL on postnatal myelinogenesis in the CNS. Although we observed no difference in the proliferation of oligodendrocyte precursor cells, we found that GAL has a strong pro-myelinating effect. The transgenic mice at postnatal day 10 appeared to undergo myelinogenesis at an accelerated rate, as demonstrated by the increase in myelin basic protein (MBP) synthesis. The immunohistochemical results are consistent with our preliminary findings that suggest that GAL is a regulator of myelination and may be one of the myelination promoters. This finding is especially important for studies focusing on endogenous molecules for treating myelin-related diseases, such as multiple sclerosis and other leukodystrophies.

  12. Promoting neuroplasticity for motor rehabilitation after stroke: considering the effects of aerobic exercise and genetic variation on brain-derived neurotrophic factor.

    PubMed

    Mang, Cameron S; Campbell, Kristin L; Ross, Colin J D; Boyd, Lara A

    2013-12-01

    Recovery of motor function after stroke involves relearning motor skills and is mediated by neuroplasticity. Recent research has focused on developing rehabilitation strategies that facilitate such neuroplasticity to maximize functional outcome poststroke. Although many molecular signaling pathways are involved, brain-derived neurotrophic factor (BDNF) has emerged as a key facilitator of neuroplasticity involved in motor learning and rehabilitation after stroke. Thus, rehabilitation strategies that optimize BDNF effects on neuroplasticity may be especially effective for improving motor function poststroke. Two potential poststroke rehabilitation strategies that consider the importance of BDNF are the use of aerobic exercise to enhance brain function and the incorporation of genetic information to individualize therapy. Converging evidence demonstrates that aerobic exercise increases BDNF production and consequently enhances learning and memory processes. Nevertheless, a common genetic variant reduces activity-dependent secretion of the BDNF protein. Thus, BDNF gene variation may affect response to motor rehabilitation training and potentially modulate the effects of aerobic exercise on neuroplasticity. This perspective article discusses evidence that aerobic exercise promotes neuroplasticity by increasing BDNF production and considers how aerobic exercise may facilitate the acquisition and retention of motor skills for poststroke rehabilitation. Next, the impact of the BDNF gene val66met polymorphism on motor learning and response to rehabilitation is explored. It is concluded that the effects of aerobic exercise on BDNF and motor learning may be better exploited if aerobic exercise is paired more closely in time with motor training. Additionally, information about BDNF genotype could provide insight into the type and magnitude of effects that aerobic exercise may have across individuals and potentially help guide an individualized prescription of aerobic exercise

  13. Promoting Neuroplasticity for Motor Rehabilitation After Stroke: Considering the Effects of Aerobic Exercise and Genetic Variation on Brain-Derived Neurotrophic Factor

    PubMed Central

    Mang, Cameron S.; Campbell, Kristin L.; Ross, Colin J.D.

    2013-01-01

    Recovery of motor function after stroke involves relearning motor skills and is mediated by neuroplasticity. Recent research has focused on developing rehabilitation strategies that facilitate such neuroplasticity to maximize functional outcome poststroke. Although many molecular signaling pathways are involved, brain-derived neurotrophic factor (BDNF) has emerged as a key facilitator of neuroplasticity involved in motor learning and rehabilitation after stroke. Thus, rehabilitation strategies that optimize BDNF effects on neuroplasticity may be especially effective for improving motor function poststroke. Two potential poststroke rehabilitation strategies that consider the importance of BDNF are the use of aerobic exercise to enhance brain function and the incorporation of genetic information to individualize therapy. Converging evidence demonstrates that aerobic exercise increases BDNF production and consequently enhances learning and memory processes. Nevertheless, a common genetic variant reduces activity-dependent secretion of the BDNF protein. Thus, BDNF gene variation may affect response to motor rehabilitation training and potentially modulate the effects of aerobic exercise on neuroplasticity. This perspective article discusses evidence that aerobic exercise promotes neuroplasticity by increasing BDNF production and considers how aerobic exercise may facilitate the acquisition and retention of motor skills for poststroke rehabilitation. Next, the impact of the BDNF gene val66met polymorphism on motor learning and response to rehabilitation is explored. It is concluded that the effects of aerobic exercise on BDNF and motor learning may be better exploited if aerobic exercise is paired more closely in time with motor training. Additionally, information about BDNF genotype could provide insight into the type and magnitude of effects that aerobic exercise may have across individuals and potentially help guide an individualized prescription of aerobic exercise

  14. The nuclear splicing factor RNA binding motif 5 promotes caspase activation in human neuronal cells, and increases after traumatic brain injury in mice

    PubMed Central

    Jackson, Travis C; Du, Lina; Janesko-Feldman, Keri; Vagni, Vincent A; Dezfulian, Cameron; Poloyac, Samuel M; Jackson, Edwin K; Clark, Robert SB; Kochanek, Patrick M

    2015-01-01

    Splicing factors (SFs) coordinate nuclear intron/exon splicing of RNA. Splicing factor disturbances can cause cell death. RNA binding motif 5 (RBM5) and 10 (RBM10) promote apoptosis in cancer cells by activating detrimental alternative splicing of key death/survival genes. The role(s) of RBM5/10 in neurons has not been established. Here, we report that RBM5 knockdown in human neuronal cells decreases caspase activation by staurosporine. In contrast, RBM10 knockdown augments caspase activation. To determine whether brain injury alters RBM signaling, we measured RBM5/10 protein in mouse cortical/hippocampus homogenates after controlled cortical impact (CCI) traumatic brain injury (TBI) plus hemorrhagic shock (CCI+HS). The RBM5/10 staining was higher 48  to 72 hours after injury and appeared to be increased in neuronal nuclei of the hippocampus. We also measured levels of other nuclear SFs known to be essential for cellular viability and report that splicing factor 1 (SF1) but not splicing factor 3A (SF3A) decreased 4  to 72 hours after injury. Finally, we confirm that RBM5/10 regulate protein expression of several target genes including caspase-2, cellular FLICE-like inhibitory protein (c-FLIP), LETM1 Domain-Containing Protein 1 (LETMD1), and amyloid precursor-like protein 2 (APLP2) in neuronal cells. Knockdown of RBM5 appeared to increase expression of c-FLIP(s), LETMD1, and APLP2 but decrease caspase-2. PMID:25586139

  15. rAAV-mediated delivery of brain-derived neurotrophic factor promotes neurite outgrowth and protects neurodegeneration in focal ischemic model.

    PubMed

    Zhang, Jingyu; Yu, Zhigang; Yu, Zhiqiang; Yang, Zichao; Zhao, Hong; Liu, Luran; Zhao, Jiexu

    2011-06-20

    Stroke is one of the neurological diseases which lead to permanently neuronal damage after temporary or long-term occlusion of vessels or after heart attack. However, there are few efficient strategies to prevent or treat this kind of insult in clinical because the consequence is irreversible and could be long-lasting after the onset of stroke. Gene therapy especially using viral system has long been addressed to be of great potential to reduce the damage. Here, we generated recombinant adeno-associated virus (rAAV) carrying brain-derived neurotrophic factor (BDNF) gene. Cells infected with rAAV-BDNF could be able to produce functional BDNF which promoted neurite outgrowth and protected neurons from apoptosis induced by serum deprivation. Further more, single injection of rAAV showed neuroprotection against cell death in focal ischemic model. These results showed that rAAV-mediated gene delivery is functional, which shed light to the future application of viral system-based gene therapy in clinical.

  16. TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains.

    PubMed

    Zucchelli, Silvia; Codrich, Marta; Marcuzzi, Federica; Pinto, Milena; Vilotti, Sandra; Biagioli, Marta; Ferrer, Isidro; Gustincich, Stefano

    2010-10-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.

  17. Post-Injury Treatment with Rolipram Increases Hemorrhage After Traumatic Brain Injury

    PubMed Central

    Atkins, C.M.; Kang, Y.; Furones, C.; Truettner, J.S.; Alonso, O.F.; Dietrich, W.D.

    2012-01-01

    The pathology caused by traumatic brain injury (TBI) is exacerbated by the inflammatory response of the injured brain. Two pro-inflammatory cytokines that contribute to inflammation after TBI are tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). In previous studies using the parasagittal fluid-percussion brain injury model, we reported that the anti-inflammatory drug rolipram, a phosphodiesterase 4 inhibitor, reduced TNF-α and IL-1β levels and improved histopathological outcome when administered 30 min prior to injury. We now report that treatment with (±)-rolipram given 30 min after injury significantly reduced TNF-α levels in the cortex and hippocampus. However, post-injury administration of (±)-rolipram significantly increased cortical contusion volume and increased atrophy of the cortex as compared to vehicle-treated animals at 10 days post-injury. Thus, despite the reduction in pro-inflammatory cytokine levels, histopathological outcome was worsened with post-TBI (±)-rolipram treatment. Further histological analysis of (±)-rolipram-treated TBI animals revealed significant hemorrhage in the contused brain. Given the well known role of (±)-rolipram to increase vasodilation, it is likely that (±)-rolipram worsened outcome after fluid-percussion brain injury by causing increased bleeding. PMID:22535545

  18. Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke.

    PubMed

    Gustafsson, Elin; Andsberg, Gunnar; Darsalia, Vladimer; Mohapel, Paul; Mandel, Ronald J; Kirik, Deniz; Lindvall, Olle; Kokaia, Zaal

    2003-06-01

    To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.

  19. Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-α-induced apoptosis

    PubMed Central

    Basuroy, Shyamali; Tcheranova, Dilyara; Bhattacharya, Sujoy; Leffler, Charles W.

    2011-01-01

    We investigated the role of reactive oxygen species (ROS) in promoting cell survival during oxidative stress induced by the inflammatory mediator tumor necrosis factor-α (TNF-α) in cerebral microvascular endothelial cells (CMVEC) from newborn piglets. Nox4 is the major isoform of NADPH oxidase responsible for TNF-α-induced oxidative stress and apoptosis in CMVEC. We present novel data that Nox4 NADPH oxidase-derived ROS also initiate a cell survival mechanism by increasing production of a gaseous antioxidant mediator carbon monoxide (CO) by constitutive heme oxygenase-2 (HO-2). TNF-α rapidly enhanced endogenous CO production in a superoxide- and NADPH oxidase-dependent manner in CMVEC with innate, but not with small interfering RNA (siRNA)-downregulated Nox4 activity. CORM-A1, a CO-releasing compound, inhibited Nox4-mediated ROS production and enhanced cell survival in TNF-α-challenged CMVEC. The ROS-induced CO-mediated survival mechanism requires functional interactions between the protein kinase B/Akt and extracellular signal-related kinase (ERK)/p38 MAPK signaling pathways activated by TNF-α. In Akt siRNA-transfected CMVEC and in cells with pharmacologically inhibited Akt, Erk1/2, and p38 mitogen-activated protein kinase (MAPK) activities, CORM-A1 was no longer capable of blocking Nox4 activation and apoptosis caused by TNF-α. Overall, Nox4 NADPH oxidase-derived ROS initiate both death and survival pathways in TNF-α-challenged CMVEC. The ROS-dependent cell survival pathway is mediated by an endogenous antioxidant CO, which inhibits Nox4 activation via a mechanism that includes Akt, ERK1/2, and p38 MAPK signaling pathways. The ability of CO to inhibit TNF-α-induced ERK1/2 and p38 MAPK activities in an Akt-dependent manner appears to be the key element in ROS-dependent survival of endothelial cells during TNF-α-mediated brain inflammatory disease. PMID:21123734

  20. Microglial TNF-α-dependent elevation of MHC class I expression on brain endothelium induced by amyloid-beta promotes T cell transendothelial migration.

    PubMed

    Yang, Yi-Ming; Shang, De-Shu; Zhao, Wei-Dong; Fang, Wen-Gang; Chen, Yu-Hua

    2013-11-01

    The blood-brain barrier (BBB) normally bars peripheral T lymphocytes from entering the cerebrum. Interestingly, activated T cells exist as infiltrates in the brains of Alzheimer's disease (AD) patients, but little is known about the mechanisms involved. In this study, we observed significantly higher MHC class I expression in rat brain endothelial cells compared with controls following the induction of experimental AD models. An in vitro BBB model, which was constructed with human brain microvascular endothelial cells, was established to study the mechanisms underlying the transendothelial migration of T cells. Using in vitro studies, we demonstrated that secretion of TNF-α from Aβ1-42-treated BV2 microglia contributes to the elevated expression of MHC class I on the brain microvessel endothelium. Transmigration assays and adhesion assays confirmed that the upregulation of MHC class I molecules was associated with T cell transendothelial migration. MHC class I knock-down in HBMECs significantly attenuated the migratory and adhesive capability of the T cells. Interestingly, a TNF-α neutralizing antibody effectively blocked the transendothelial migration of T cells triggered by treatment with the supernatant from Aβ1-42-treated BV2 microglia. We propose that microglia-derived TNF-α upregulates MHC class I molecule expression on brain endothelial cells, which represents a mechanism of T cell migration into the brain. This study may provide a new insight into the potential pathomechanism of Alzheimer's disease.

  1. Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease--phagocyte influx to the brain is promoted by bilberry-enriched diet.

    PubMed

    Virel, Ana; Rehnmark, Anna; Orädd, Greger; Olmedo-Díaz, Sonia; Faergemann, Erik; Strömberg, Ingrid

    2015-11-01

    Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant-treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6-OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry-enriched or control diet. T2*-weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*-weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood-derived immune cells. Gadolinium-enhanced MRI demonstrated no difference in leakage of the blood-brain barrier independent of diets. To conclude, bilberry-enriched diet promotes an influx of periphery-derived immune cells to the brain early after injury.

  2. Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain.

    PubMed

    Sawicki, C M; McKim, D B; Wohleb, E S; Jarrett, B L; Reader, B F; Norden, D M; Godbout, J P; Sheridan, J F

    2015-08-27

    Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. Here we show that social defeat caused an exposure- and brain region-dependent increase in several key adhesion molecules and chemokines involved in the recruitment of myeloid cells. For example, RSD induced distinct patterns of adhesion molecule expression that may explain brain region-dependent myeloid cell trafficking. VCAM-1 and ICAM-1 mRNA expression were increased in an exposure-dependent manner. Furthermore, RSD-induced VCAM-1 and ICAM-1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Next, mRNA expression of additional adhesion molecules (E- and P-selectin, PECAM-1) and chemokines (CXCL1, CXCL2, CXCL12, CCL2) were determined in the brain. Social defeat induced an exposure-dependent increase in mRNA levels of E-selectin, CXCL1, and CXCL2 that increased with additional days of social defeat. While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1β, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner.

  3. Recommendations for Development of New Standardized Forms of Cocoa Breeds and Cocoa Extract Processing for the Prevention of Alzheimer's Disease: Role of Cocoa in Promotion of Cognitive Resilience and Healthy Brain Aging.

    PubMed

    Dubner, Lauren; Wang, Jun; Ho, Lap; Ward, Libby; Pasinetti, Giulio M

    2015-01-01

    It is currently thought that the lackluster performance of translational paradigms in the prevention of age-related cognitive deteriorative disorders, such as Alzheimer's disease (AD), may be due to the inadequacy of the prevailing approach of targeting only a single mechanism. Age-related cognitive deterioration and certain neurodegenerative disorders, including AD, are characterized by complex relationships between interrelated biological phenotypes. Thus, alternative strategies that simultaneously target multiple underlying mechanisms may represent a more effective approach to prevention, which is a strategic priority of the National Alzheimer's Project Act and the National Institute on Aging. In this review article, we discuss recent strategies designed to clarify the mechanisms by which certain brain-bioavailable, bioactive polyphenols, in particular, flavan-3-ols also known as flavanols, which are highly represented in cocoa extracts, may beneficially influence cognitive deterioration, such as in AD, while promoting healthy brain aging. However, we note that key issues to improve consistency and reproducibility in the development of cocoa extracts as a potential future therapeutic agent requires a better understanding of the cocoa extract sources, their processing, and more standardized testing including brain bioavailability of bioactive metabolites and brain target engagement studies. The ultimate goal of this review is to provide recommendations for future developments of cocoa extracts as a therapeutic agent in AD.

  4. Rho kinase inhibition following traumatic brain injury in mice promotes functional improvement and acute neuron survival but has little effect on neurogenesis, glial responses or neuroinflammation.

    PubMed

    Bye, Nicole; Christie, Kimberly J; Turbic, Alisa; Basrai, Harleen S; Turnley, Ann M

    2016-05-01

    Inhibition of the Rho/Rho kinase pathway has been shown to be beneficial in a variety of neural injuries and diseases. In this manuscript we investigate the role of Rho kinase inhibition in recovery from traumatic brain injury using a controlled cortical impact model in mice. Mice subjected to a moderately severe TBI were treated for 1 or 4 weeks with the Rho kinase inhibitor Y27632, and functional outcomes and neuronal and glial cell responses were analysed at 1, 7 and 35 days post-injury. We hypothesised that Y27632-treated mice would show functional improvement, with augmented recruitment of neuroblasts from the SVZ and enhanced survival of newborn neurons in the pericontusional cortex, with protection against neuronal degeneration, neuroinflammation and modulation of astrocyte reactivity and blood-brain-barrier permeability. While Rho kinase inhibition enhanced recovery of motor function after trauma, there were no substantial increases in the recruitment of DCX(+) neuroblasts or the number of BrdU(+) or EdU(+) labelled newborn neurons in the pericontusional cortex of Y27632-treated mice. Inhibition of Rho kinase significantly reduced the number of degenerating cortical neurons at 1day post-injury compared to saline controls but had no longer term effect on neuronal degeneration, with only modest effects on astrocytic reactivity and macrophage/microglial responses. Overall, this study showed that Rho kinase contributes to acute neurodegenerative processes in the injured cortex but does not play a significant role in SVZ neural precursor cell-derived adult neurogenesis, glial responses or blood-brain barrier permeability following a moderately severe brain injury.

  5. PKCε Promotes HuD-Mediated Neprilysin mRNA Stability and Enhances Neprilysin-Induced Aβ Degradation in Brain Neurons

    PubMed Central

    Lim, Chol Seung; Alkon, Daniel L.

    2014-01-01

    Amyloid-beta (Aβ) peptide accumulation in the brain is a pathological hallmark of all forms of Alzheimer’s disease. An imbalance between Aβ production and clearance from the brain may contribute to accumulation of neurotoxic Aβ and subsequent synaptic loss, which is the strongest correlate of the extent of memory loss in AD. The activity of neprilysin (NEP), a potent Aβ-degrading enzyme, is decreased in the AD brain. Expression of HuD, an mRNA-binding protein important for synaptogenesis and neuronal plasticity, is also decreased in the AD brain. HuD is regulated by protein kinase Cε (PKCε), and we previously demonstrated that PKCε activation decreases Aβ levels. We hypothesized that PKCε acts through HuD to stabilize NEP mRNA, modulate its localization, and support NEP activity. Conversely, loss of PKCε-activated HuD in AD leads to decreased NEP activity and accumulation of Aβ. Here we show that HuD is associated with NEP mRNA in cultures of human SK-N-SH cells. Treatment with bryostatin, a PKCε-selective activator, enhanced NEP association with HuD and increased NEP mRNA stability. Activation of PKCε also increased NEP protein levels, increased NEP phosphorylation, and induced cell surface expression. In addition, specific PKCε activation directly stimulated NEP activity, leading to degradation of a monomeric form of Aβ peptide and decreased Aβ neuronal toxicity, as measured by cell viability. Bryostatin treatment also rescued Aβ-mediated inhibition of HuD-NEP mRNA binding, NEP protein expression, and NEP cell membrane translocation. These results suggest that PKCε activation reduces Aβ by up-regulating, via the mRNA-binding protein HuD, Aβ-degrading enzymes such as NEP. Thus, PKCε activation may have therapeutic efficacy for AD by reducing neurotoxic Aβ accumulation as well as having direct anti-apoptotic and synaptogenic effects. PMID:24848988

  6. The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury.

    PubMed

    Tchantchou, Flaubert; Tucker, Laura B; Fu, Amanda H; Bluett, Rebecca J; McCabe, Joseph T; Patel, Sachin; Zhang, Yumin

    2014-10-01

    Traumatic brain injury (TBI) is the leading cause of death in young adults in the United States, but there is still no effective agent for treatment. N-arachidonoylethanolamine (anandamide, AEA) is a major endocannabinoid in the brain. Its increase after brain injury is believed to be protective. However, the compensatory role of AEA is transient due to its rapid hydrolysis by the fatty acid amide hydrolase (FAAH). Thus, inhibition of FAAH can boost the endogenous levels of AEA and prolong its protective effect. Using a TBI mouse model, we found that post-injury chronic treatment with PF3845, a selective and potent FAAH inhibitor, reversed TBI-induced impairments in fine motor movement, hippocampus dependent working memory and anxiety-like behavior. Treatment with PF3845 inactivated FAAH activity and enhanced the AEA levels in the brain. It reduced neurodegeneration in the dentate gyrus, and up-regulated the expression of Bcl-2 and Hsp70/72 in both cortex and hippocampus. PF3845 also suppressed the increased production of amyloid precursor protein, prevented dendritic loss and restored the levels of synaptophysin in the ipsilateral dentate gyrus. Furthermore, PF3845 suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 post-TBI, suggesting a shift of microglia/macrophages from M1 to M2 phenotype. The effects of PF3845 on TBI-induced behavioral deficits and neurodegeneration were mediated by activation of cannabinoid type 1 and 2 receptors and might be attributable to the phosphorylation of ERK1/2 and AKT. These results suggest that selective inhibition of FAAH is likely to be beneficial for TBI treatment.

  7. Activating Developmental Reserve Capacity Via Cognitive Training or Non-invasive Brain Stimulation: Potentials for Promoting Fronto-Parietal and Hippocampal-Striatal Network Functions in Old Age

    PubMed Central

    Passow, Susanne; Thurm, Franka; Li, Shu-Chen

    2017-01-01

    Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate

  8. Activation of melatonin receptor (MT1/2) promotes P-gp transporter in methamphetamine-induced toxicity on primary rat brain microvascular endothelial cells.

    PubMed

    Jumnongprakhon, Pichaya; Sivasinprasasn, Sivanan; Govitrapong, Piyarat; Tocharus, Chainarong; Tocharus, Jiraporn

    2017-02-20

    Melatonin has been known as a neuroprotective agent for the central nervous system (CNS) and the blood-brain barrier (BBB), which is the primary structure that comes into contact with several neurotoxins including methamphetamine (METH). Previous studies have reported that the activation of melatonin receptors (MT1/2) by melatonin could protect against METH-induced toxicity in brain endothelial cells via several mechanisms. However, its effects on the P-glycoprotein (P-gp) transporter, the active efflux pump involved in cell homeostasis, are still unclear. Thus, this study investigated the role of melatonin and its receptors on the METH-impaired P-gp transporter in primary rat brain microvascular endothelial cells (BMVECs). The results showed that METH impaired the function of the P-gp transporter, significantly decreasing the efflux of Rho123 and P-gp expression, which caused a significant increase in the intracellular accumulation of Rho123, and these responses were reversed by the interaction of melatonin with its receptors. Blockade of the P-gp transporter by verapamil caused oxidative stress, apoptosis, and cell integrity impairment after METH treatment, and these effects could be reversed by melatonin. Our results, together with previous findings, suggest that the interaction of melatonin with its receptors protects against the effects of the METH-impaired P-gp transporter and that the protective role in METH-induced toxicity was at least partially mediated by the regulation of the P-gp transporter. Thus, melatonin and its receptors (MT1/2) are essential for protecting against BBB impairment caused by METH.

  9. Activating Developmental Reserve Capacity Via Cognitive Training or Non-invasive Brain Stimulation: Potentials for Promoting Fronto-Parietal and Hippocampal-Striatal Network Functions in Old Age.

    PubMed

    Passow, Susanne; Thurm, Franka; Li, Shu-Chen

    2017-01-01

    Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate

  10. Pho4 Is Essential for Dissemination of Cryptococcus neoformans to the Host Brain by Promoting Phosphate Uptake and Growth at Alkaline pH

    PubMed Central

    Kaufman-Francis, Keren; Desmarini, Desmarini; Juillard, Pierre G.; Li, Cecilia; Stifter, Sebastian A.; Feng, Carl G.; Sorrell, Tania C.; Grau, Georges E. R.; Bahn, Yong-Sun

    2017-01-01

    ABSTRACT Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans disseminates from the lung to the brain and is the commonest cause of fungal meningitis worldwide. To investigate the contribution of PHO signaling to cryptococcal dissemination, we characterized a transcription factor knockout strain (hlh3Δ/pho4Δ) defective in phosphate acquisition. Despite little similarity with other fungal Pho4 proteins, Hlh3/Pho4 functioned like a typical phosphate-responsive transcription factor in phosphate-deprived cryptococci, accumulating in nuclei and triggering expression of genes involved in phosphate acquisition. The pho4Δ mutant strain was susceptible to a number of stresses, the effect of which, except for alkaline pH, was alleviated by phosphate supplementation. Even in the presence of phosphate, the PHO pathway was activated in wild-type cryptococci at or above physiological pH, and under these conditions, the pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ mutant was hypovirulent in a mouse inhalation model, where dissemination to the brain was reduced dramatically, and markedly hypovirulent in an intravenous dissemination model. The pho4Δ mutant was not detected in blood, nor did it proliferate significantly when cultured with peripheral blood monocytes. In conclusion, dissemination of infection and the pathogenesis of meningitis are dependent on cryptococcal phosphate uptake and stress tolerance at alkaline pH, both of which are Pho4 dependent. IMPORTANCE Cryptococcal meningitis is fatal without treatment and responsible for more than 500,000 deaths annually. To be a successful pathogen, C. neoformans must obtain an adequate supply of essential nutrients, including phosphate, from various host niches. Phosphate acquisition in fungi is regulated by the PHO signaling cascade, which is activated when intracellular phosphate decreases below a critical

  11. Brain herniation

    MedlinePlus

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  12. Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice.

    PubMed

    Canugovi, Chandrika; Yoon, Jeong Seon; Feldman, Neil H; Croteau, Deborah L; Mattson, Mark P; Bohr, Vilhelm A

    2012-09-11

    Recent findings suggest that neurons can efficiently repair oxidatively damaged DNA, and that both DNA damage and repair are enhanced by activation of excitatory glutamate receptors. However, in pathological conditions such as ischemic stroke, excessive DNA damage can trigger the death of neurons. Oxidative DNA damage is mainly repaired by base excision repair (BER), a process initiated by DNA glycosylases that recognize and remove damaged DNA bases. Endonuclease VIII-like 1 (NEIL1) is a DNA glycosylase that recognizes a broad range of oxidative lesions. Here, we show that mice lacking NEIL1 exhibit impaired memory retention in a water maze test, but no abnormalities in tests of motor performance, anxiety, or fear conditioning. NEIL1 deficiency results in increased brain damage and a defective functional outcome in a focal ischemia/reperfusion model of stroke. The incision capacity on a 5-hydroxyuracil-containing bubble substrate was lower in the ipsilateral side of ischemic brains and in the mitochondrial lysates of unstressed old NEIL1-deficient mice. These results indicate that NEIL1 plays an important role in learning and memory and in protection of neurons against ischemic injury.

  13. Hyperbaric oxygenation promotes neural stem cell proliferation and protects the learning and memory ability in neonatal hypoxic-ischemic brain damage.

    PubMed

    Wei, Lixia; Wang, Jinshen; Cao, Yuntao; Ren, Qing; Zhao, Lili; Li, Xingang; Wang, Jiwen

    2015-01-01

    The aim of our study was to evaluate whether hyperbaric oxygenation (HBO) was an effective therapy for neonatal hypoxic ischemic brain damage (HIBD). Seven-day-old rat pups were divided into 3 groups: sham, hypoxia-ischemia (HI) control and HI-HBO group. HBO was administered for HI rats daily. The pathologic changes in brain tissues were observed by hematoxylin-eosin (H-E) staining. The immunohistochemical staining was applied to detect the Nestin and 5-bromo-2-deoxyuridine (BrdU) positive cells in hippocampal dentate gyrus region. The learning and memory function of rats was examined by Morris water maze. The HI rats showed obvious pathologic changes accompanied by levels decreasing and disorder arrangement of pyramidal cells, glial cells proliferation in postoperative, and nerve nuclei broken, while pathologic changes of rats in sham group was approximate to that in the HI + HBO group that was opposite to the HI group. Compared with the sham group, the Nestin and BrdU positive cells in HBO + HI group at different time points increased significantly (P < 0.01). Learning and memory function of rats in HI group was poor compared with the sham/HI + HBO group (P < 0.01), while that in HI + HBO group was approximate to that in sham group (P > 0.05). HBO treatment improved the learning and memory ability of the HI rats. HBO therapy may be effective for neonatal HIBD treatment.

  14. Pro-Brain-Derived Neurotrophic Factor (proBDNF)-Mediated p75NTR Activation Promotes Depolarizing Actions of GABA and Increases Susceptibility to Epileptic Seizures.

    PubMed

    Riffault, Baptiste; Kourdougli, Nazim; Dumon, Camille; Ferrand, Nadine; Buhler, Emmanuelle; Schaller, Fabienne; Chambon, Caroline; Rivera, Claudio; Gaiarsa, Jean-Luc; Porcher, Christophe

    2016-12-01

    The brain-derived neurotrophic factor (BDNF) is synthesized as a precursor, namely proBDNF, which can be processed into mature BDNF (mBDNF). Evidences suggest that proBDNF signaling through p75(NTR) may account for the emergence of neurological disorders. These findings support the view that the relative availability of mBDNF and proBDNF forms is an important mechanism underlying brain circuit formation and cognitive functions. Here we describe novel insights into the proBDNF/p75(NTR) mechanisms and function in vivo in modulating neuronal circuit and synaptic plasticity during the first postnatal weeks in rats. Our results showed that increased proBDNF/p75(NTR) signaling during development maintains a depolarizing γ-aminobutyric acid (GABA) response in a KCC2-dependent manner in mature neuronal cells. This resulted in altered excitation/inhibition balance and enhanced neuronal network activity. The enhanced proBDNF/p75(NTR) signaling ultimately led to increased seizure susceptibility that was abolished by in vivo injection of function blocking p75(NTR) antibody. Altogether, our study shed new light on how proBDNF/p75(NTR) signaling can orchestrate the GABA excitatory/inhibitory developmental sequence leading to depolarizing and excitatory actions of GABA in adulthood and subsequent epileptic disorders.

  15. Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain.

    PubMed

    van der Doelen, Rick H A; Arnoldussen, Ilse A; Ghareh, Hussein; van Och, Liselot; Homberg, Judith R; Kozicz, Tamás

    2015-02-01

    The interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.

  16. Minibrain drives the Dacapo-dependent cell cycle exit of neurons in the Drosophila brain by promoting asense and prospero expression.

    PubMed

    Shaikh, Mirja N; Gutierrez-Aviño, Francisco; Colonques, Jordi; Ceron, Julian; Hämmerle, Barbara; Tejedor, Francisco J

    2016-09-01

    A key aim of neurodevelopmental research is to understand how precursor cells decide to stop dividing and commence their terminal differentiation at the correct time and place. Here, we show that minibrain (mnb), the Drosophila ortholog of the Down syndrome candidate gene DYRK1A, is transiently expressed in newborn neuronal precursors known as ganglion cells (GCs). Mnb promotes the cell cycle exit of GCs through a dual mechanism that regulates the expression of the cyclin-dependent kinase inhibitor Dacapo, the homolog of vertebrate p27(Kip1) (Cdkn1b). Mnb upregulates the expression of the proneural transcription factor (TF) Asense, which promotes Dacapo expression. Mnb also induces the expression of Prospero, a homeodomain TF that in turn inhibits the expression of Deadpan, a pan-neural TF that represses dacapo In addition to its effects on Asense and Prospero, Mnb also promotes the expression of the neuronal-specific RNA regulator Elav, strongly suggesting that Mnb facilitates neuronal differentiation. These actions of Mnb ensure the precise timing of neuronal birth, coupling the mechanisms that regulate neurogenesis, cell cycle control and terminal differentiation of neurons.

  17. Neuregulin 1 Type II-ErbB Signaling Promotes Cell Divisions Generating Neurons from Neural Progenitor Cells in the Developing Zebrafish Brain.

    PubMed

    Sato, Tomomi; Sato, Fuminori; Kamezaki, Aosa; Sakaguchi, Kazuya; Tanigome, Ryoma; Kawakami, Koichi; Sehara-Fujisawa, Atsuko

    2015-01-01

    Post-mitotic neurons are generated from neural progenitor cells (NPCs) at the expense of their proliferation. Molecular and cellular mechanisms that regulate neuron production temporally and spatially should impact on the size and shape of the brain. While transcription factors such as neurogenin1 (neurog1) and neurod govern progression of neurogenesis as cell-intrinsic mechanisms, recent studies show regulatory roles of several cell-extrinsic or intercellular signaling molecules including Notch, FGF and Wnt in production of neurons/neural progenitor cells from neural stem cells/radial glial cells (NSCs/RGCs) in the ventricular zone (VZ). However, it remains elusive how production of post-mitotic neurons from neural progenitor cells is regulated in the sub-ventricular zone (SVZ). Here we show that newborn neurons accumulate in the basal-to-apical direction in the optic tectum (OT) of zebrafish embryos. While neural progenitor cells are amplified by mitoses in the apical ventricular zone, neurons are exclusively produced through mitoses of neural progenitor cells in the sub-basal zone, later in the sub-ventricular zone, and accumulate apically onto older neurons. This neurogenesis depends on Neuregulin 1 type II (NRG1-II)-ErbB signaling. Treatment with an ErbB inhibitor, AG1478 impairs mitoses in the sub-ventricular zone of the optic tectum. Removal of AG1478 resumes sub-ventricular mitoses without precedent mitoses in the apical ventricular zone prior to basal-to-apical accumulation of neurons, suggesting critical roles of ErbB signaling in mitoses for post-mitotic neuron production. Knockdown of NRG1-II impairs both mitoses in the sub-basal/sub-ventricular zone and the ventricular zone. Injection of soluble human NRG1 into the developing brain ameliorates neurogenesis of NRG1-II-knockdown embryos, suggesting a conserved role of NRG1 as a cell-extrinsic signal. From these results, we propose that NRG1-ErbB signaling stimulates cell divisions generating neurons from

  18. Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: Relevance to neurological disorders.

    PubMed

    Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Tarnowski, Maciej; Pilutin, Anna; Gutowska, Izabela; Strużyńska, Lidia; Chlubek, Dariusz; Adamczyk, Agata

    2016-03-10

    Hyperphosphorylation of Tau is involved in the pathomechanism of neurological disorders such as Alzheimer's, Parkinson's diseases as well as Autism. Epidemiological data suggest the significance of early life exposure to lead (Pb) in etiology of disorders affecting brain function. However, the precise mechanisms by which Pb exerts neurotoxic effects are not fully elucidated. The purpose of this study was to evaluate the effect of perinatal exposure to low dose of Pb on the Tau pathology in the developing rat brain. Furthermore, the involvement of two major Tau-kinases: glycogen synthase kinase-3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) in Pb-induced Tau modification was evaluated. Pregnant female rats were divided into control and Pb-treated group. The control animals were maintained on drinking water while females from the Pb-treated group received 0.1% lead acetate (PbAc) in drinking water, starting from the first day of gestation until weaning of the offspring. During the feeding of pups, mothers from the Pb-treated group were still receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and Tau mRNA and protein level as well as Tau phosphorylation were analyzed in forebrain cortex (FC), cerebellum (C) and hippocampus (H). Concomitantly, we examined the effect of Pb exposure on GSK-3β and CDK5 activation. Our data revealed that pre- and neonatal exposure to Pb (concentration of Pb in whole blood below 10μg/dL, considered safe for humans) caused significant increase in the phosphorylation of Tau at Ser396 and Ser199/202 with parallel rise in the level of total Tau protein in FC and C. Tau hyperphosphorylation in Pb-treated animals was accompanied by elevated activity of GSK-3β and CDK5. Western blot analysis revealed activation of GSK-3β in FC and C as well as CDK5 in C, via increased phosphorylation of Tyr-216 and calpain-dependent p25

  19. β-asarone and levodopa co-administration increase striatal dopamine level in 6-hydroxydopamine induced rats by modulating P-glycoprotein and tight junction proteins at the blood-brain barrier and promoting levodopa into the brain.

    PubMed

    Huang, Liping; Deng, Minzhen; He, Yuping; Lu, Shiyao; Ma, Ruanxin; Fang, Yongqi

    2016-06-01

    Levodopa (L-dopa) is widely considered as one of the most effective drug constituents in the treatment of Parkinson's disease (PD), but the blood-brain barrier (BBB) permeability of L-dopa is <5%, which causes low efficacy. Neuroprotective effects of β-asarone on 6-hydroxydopamine (6-OHDA)-induced PD rats were demonstrated by our previous studies. Co-administration of β-asarone and L-dopa has not been explored until being investigated on PD rats in this study. PD rats were divided into four groups: untreated, L-dopa-treated, β-asarone-treated and co-administered-treated groups. All of the treatments were administered to the rats twice per day for 30 days. The L-dopa, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), S100β and neuron-specific enolase (NSE) levels were subsequently determined. The P-glycoprotein (P-gp), zonula occludens-1 (ZO-1), claudin-5, occludin and actin expression was also assessed in cortex. Changes in BBB ultrastructure were observed using transmission electron microscopy. Our results showed that the co-administered treatment increased levels of L-dopa, DA, DOPAC and HVA in striatum, and S100β in plasma, but down-regulated NSE, P-gp, ZO-1, occludin, actin and claudin-5 in cortex. Crevices were observed between capillary endothelial cells at intercellular tight junction of the striatum in co-administered-treated group, while the endothelial cells in untreated group were tightly jointing each other. In addition, the correlations of L-dopa or DA and P-gp or tight junction proteins respectively were significantly negative in co-administered- and β-asarone-treated groups. These findings suggest that co-administered treatment may enhance the L-dopa BBB permeability and attenuate brain injury, which may be beneficial to PD treatment.

  20. Voltage-dependent anion channels (VDACs) promote mitophagy to protect neuron from death in an early brain injury following a subarachnoid hemorrhage in rats.

    PubMed

    Li, Jian; Lu, Jianfei; Mi, Yongjie; Shi, Zhao; Chen, Chunhua; Riley, John; Zhou, Changman

    2014-07-21

    The term mitophagy is coined to describe the selective removal of mitochondria by autophagy but the process itself is still contentious, especially in the early period following subarachnoid hemorrhage (SAH). In the present study, we investigated the role of mitophagy following 48h after SAH injury in rats. Specifically evaluating whether mitophagy, through voltage dependant anion channels (VDACs) interacting with microtubule-associated protein 1 light chain 3, could orchestrate the induction of apoptotic and necrotic cell death in neurons, a VDAC1siRNA and an activitor Rapamycian (RAPA), were engaged. One hundred and twelve male Sprague-Dawley rats were randomly divided into 4 groups: Sham, SAH, SAH+VDAC1siRNA, and SAH+RAPA. Outcomes measured included mortality rate, brain edema, BBB disruption, and neurobehavioral testing. We also used western blotting techniques to analyze the expressions of key mitophagic/autophagic proteins and pro-apoptotic protein such as ROS, VDAC1, LC-3II and Caspase-3. Rapamycin treatment significantly improved the mortality rate, cerebral edema, and neurobehavioral deficits; apoptotic and necrotic cell death in neurons were reduced by Rapamycin following SAH injury. However, VDAC1siRNA worsened the brain injury following SAH. Immunohistochemical staining and western blot analysis demonstrated a decreased expression of VDAC1, LC3II, and an increase of ROS and Caspase-3 followed by VDAC1siRNA administration. In conclusion, mitophagy induced by VDAC1 following SAH injury may in fact play a significant role in neuroprotection, the mechanism which may be through the attenuation of the apoptosic and necrosic molecular pathways. This translates a preservation of functional integrity and an improvement in mortality.

  1. Hyperglycaemia promotes human brain microvascular endothelial cell apoptosis via induction of protein kinase C-ßI and prooxidant enzyme NADPH oxidase

    PubMed Central

    Shao, Beili; Bayraktutan, Ulvi

    2014-01-01

    Blood–brain barrier disruption represents a key feature in hyperglycaemia-aggravated cerebral damage after an ischaemic stroke. Although the underlying mechanisms remain largely unknown, activation of protein kinase C (PKC) is thought to play a critical role. This study examined whether apoptosis of human brain microvascular endothelial cells (HBMEC) might contribute to hyperglycaemia-evoked barrier damage and assessed the specific role of PKC in this phenomenon. Treatments with hyperglycaemia (25 mM) or phorbol myristate acetate (PMA, a protein kinase C activator, 100 nM) significantly increased NADPH oxidase activity, O2•- generation, proapoptotic protein Bax expression, TUNEL-positive staining and caspase-3/7 activities. Pharmacological inhibition of NADPH oxidase, PKC-a, PKC-ß or PKC-ßI via their specific inhibitors and neutralisation of O2•- by a cell-permeable superoxide dismutase mimetic, MnTBAP normalised all the aforementioned increases induced by hyperglycaemia. Suppression of these PKC isoforms also negated the stimulatory effects of hyperglycaemia on the protein expression of NADPH oxidase membrane-bound components, Nox2 and p22-phox which determine the overall enzymatic activity. Silencing of PKC-ßI gene through use of specific siRNAs abolished the effects of both hyperglycaemia and PMA on endothelial cell NADPH oxidase activity, O2•- production and apoptosis and consequently improved the integrity and function of an in vitro model of human cerebral barrier comprising HBMEC, astrocytes and pericytes. Hyperglycaemia-mediated apoptosis of HBMEC contributes to cerebral barrier dysfunction and is modulated by sequential activations of PKC-ßI and NADPH oxidase. PMID:24936444

  2. Chicoric Acid Ameliorates Lipopolysaccharide-Induced Oxidative Stress via Promoting the Keap1/Nrf2 Transcriptional Signaling Pathway in BV-2 Microglial Cells and Mouse Brain.

    PubMed

    Liu, Qian; Hu, Yaya; Cao, Youfang; Song, Ge; Liu, Zhigang; Liu, Xuebo

    2017-01-18

    As a major nutraceutical component of a typical Mediterranean vegetable chicory, chicoric acid (CA) has been well-documented due to its excellent antioxidant and antiobesity bioactivities. In the current study, the effects of CA on lipopolysaccharide (LPS)-stimulated oxidative stress in BV-2 microglia and C57BL/6J mice and the underlying molecular mechanisms were investigated. Results demonstrated that CA significantly reversed LPS-elicited cell viability decrease, mitochondrial dysfunction, activation of NFκB and MAPK stress pathways, and inflammation responses via balancing cellular redox status. Furthermore, molecular modeling study demonstrated that CA could insert into the pocket of Keap1 and up-regulated Nrf2 signaling and, thus, transcriptionally regulate downstream expressions of antioxidant enzymes including HO-1 and NQO-1 in both microglial cells and ip injection of LPS-treated mouse brain. These results suggested that CA attenuated LPS-induced oxidative stress via mediating Keap1/Nrf2 transcriptional pathways and downstream enzyme expressions, which indicated that CA has great potential as a nutritional preventive strategy in oxidative stress-related neuroinflammation.

  3. RNA interference-mediated knockdown of brain-derived neurotrophic factor (BDNF) promotes cell cycle arrest and apoptosis in B-cell lymphoma cells.

    PubMed

    Xia, D; Li, W; Zhang, L; Qian, H; Yao, S; Qi, X

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily that has been reported to be involved in a number of neurological and psychological situations. Recently, high expression level of BDNF is observed in diverse human malignancies, delineating a role of BDNF in tumorigenesis. Nevertheless, its effect on B-cell lymphoma remains unclear. In this study, RNA interference technology mediated by short hairpin RNA (shRNA) was performed to inhibit endogenous BDNF expression in B-cell lymphoma cells. Results showed that knockdown of BDNF reduced cell growth and proliferation of Raji and Ramos cells. Furthermore, down-regulation of BDNF induced a cell cycle arrest at G0/G1 phase in Raji cells, and consequently led to cell apoptosis in vitro. Meanwhile, down-regulation of Bcl-2 and up-regulation of Bax, activated caspase-3 and caspase-9 and cleaved poly (ADP-ribose) polymerase (PARP) were observed in Raji cells when endogenous BDNF was inhibited. Besides, we also found that suppression of BDNF in Raji cells increased their sensitivity to chemotherapeutic drug, 5-Fluorouracil (5-FU). Our research provides a promising therapeutic strategy for human B-cell lymphoma by targeting BDNF.

  4. Angelica injection promotes peripheral nerve structure and function recovery with increased expressions of nerve growth factor and brain derived neurotrophic factor in diabetic rats.

    PubMed

    Li, Ruilin; Zhang, Junjian; Zhang, Lei; Cui, Qin; Liu, Hui

    2010-08-01

    Several nervous system injury models, such as sciatic crush and chronic cerebral hypoperfusion have been well studied in terms of neuroprotective effect of angelica injection. However, definitive experimental studies are lacking on diabetic peripheral neuropathy (DPN). This study sought to investigate the effects of angelica injection on DPN in type 1 diabetic rats. Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ). To examine whether DPN model succeeded, tail-flick latency (TFL) and motor nerve conduction velocity (MNCV) were measured at 6 weeks after diabetes induction. Then, diabetic rats were treated with high- and low-dose angelica injection for 4 weeks. TFL, MNCV, morphology of sciatic nerve, myelinated nerve fiber density and the expressions of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in soleus and sciatic nerve were measured at 10 weeks after diabetes induction. The results showed the TFL was significantly shortened (p<0.001) and the MNCV was reduced (p<0.01) in diabetic rats compared with normal control rats at 6 weeks after diabetes induction. The TFL was obviously prolonged and the MNCV was further reduced in diabetic control group at 10 weeks after diabetes induction. TFL, MNCV and morphology of sciatic nerve were remarkably ameliorated and myelinated nerve fiber density and the expressions of NGF and BDNF in soleus and sciatic nerve were increased in the angelica treatment groups. This study suggests angelica injection has potential therapeutic effects on DPN, and the mechanism might be related to direct increase in NGF expression and direct or indirect increase in BDNF expression.

  5. Brain-derived neurotrophic factor but not vesicular zinc promotes TrkB activation within mossy fibers of mouse hippocampus in vivo.

    PubMed

    Helgager, Jeffrey; Huang, Yang Zhong; Mcnamara, James O

    2014-12-01

    The neurotrophin receptor, TrkB receptor tyrosine kinase, is critical to central nervous system (CNS) function in health and disease. Elucidating the ligands mediating TrkB activation in vivo will provide insights into its diverse roles in the CNS. The canonical ligand for TrkB is brain-derived neurotrophic factor (BDNF). A diversity of stimuli also can activate TrkB in the absence of BDNF, a mechanism termed transactivation. Zinc, a divalent cation packaged in synaptic vesicles along with glutamate in axons of mammalian cortical neurons, can transactivate TrkB in neurons and heterologous cells in vitro. Yet the contributions of BDNF and zinc to TrkB activation in vivo are unknown. To address these questions, we conducted immunohistochemical (IHC) studies of the hippocampal mossy fiber axons and boutons using an antibody selective for pY816 of TrkB, a surrogate measure of TrkB activation. We found that conditional deletion of BDNF resulted in a reduction of pY816 in axons and synaptic boutons of hippocampal mossy fibers, thereby implicating BDNF in activation of TrkB in vivo. Unexpectedly, pY816 immunoreactivity was increased in axons but not synaptic boutons of mossy fibers in ZnT3 knockout mice that lack vesicular zinc. Marked increases of BDNF content were evident within the hippocampus of ZnT3 knockout mice and genetic elimination of BDNF reduced pY816 immunoreactivity in these mice, implicating BDNF in enhanced TrkB activation mediated by vesicular zinc depletion. These findings support the conclusion that BDNF but not vesicular zinc activates TrkB in hippocampal mossy fiber axons under physiological conditions.

  6. FK506-loaded chitosan conduit promotes the regeneration of injured sciatic nerves in the rat through the upregulation of brain-derived neurotrophic factor and TrkB.

    PubMed

    Zhao, Jia; Zheng, Xifu; Fu, Chongyang; Qu, Wei; Wei, Guoqiang; Zhang, Weiguo

    2014-09-15

    FK506 has been shown to exert neurotrophic and neuroprotective effects, but its long-term application for nerve regeneration is limited. This study evaluated the potential application of a novel FK506-loaded chitosan conduit for peripheral nerve repair, and explored the underlying mechanism. A sciatic nerve injury model was created in male Wistar rats, which were then randomly divided into three treatment groups (n=40, each): chitosan-only, chitosan+FK506 injection, and FK506-loaded chitosan. We found significant recovery of normal morphology of sciatic nerves and higher density of myelinated nerve fibers in rats treated with FK506-loaded chitosan. Similarly, the total number of myelinated nerve fibers, myelin sheath thickness, and axon diameters were significantly higher in this group compared with the others, and the compound muscle action potentials and motor nerve conduction velocity values of sciatic nerves were significantly higher. BDNF and TrkB levels in motor neurons were highest in rats treated with FK506-loaded chitosan. In conclusion, FK506-loaded chitosan promoted peripheral nerve repair and regeneration in a rat model of sciatic nerve injury. These effects are correlated with increased BDNF and TrkB expression in motor neurons.

  7. Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors.

    PubMed

    Rafael, Adilia; Torres, Tiago

    2016-01-01

    Psoriasis is a common, chronic and disabling skin disorder affecting approximately 2% of the population, associated with significant negative impact on the patient's quality of life. Approximately 80% of those affected with psoriasis have mild-to-moderate forms and are usually treated with topical therapy, whereas phototherapy and systemic therapies are used for those with severe disease. In the past three decades, the major advances in psoriasis therapy have been in systemic agents for the treatment of moderate-to-severe psoriasis, particularly new immunomodulatory and biological molecules, while topical therapies have remained relatively unchanged over the past decades. Indeed, topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis. Thus, there is a need to develop new and more effective topical agents in the short and long term, with a better efficacy and safety profile than corticosteroids and vitamin D3 analogs. Over the past five years, investigation into topical therapy has expanded, with exciting new drugs being developed. Preliminary results of these emerging agents that selectively target disease-defining pathogenic pathways seem to be promising, although long-term and large-scale studies assessing safety and efficacy are still lacking. The aim of this article was to review the clinical and research data of some emerging topical agents, focusing on Janus kinase-signal transducer and activator of transcription and phosphodiesterase type 4 inhibitors, which are currently being investigated.

  8. Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors

    PubMed Central

    Cardozo, Suzana Vanessa S.; Carvalho, Vinicius de Frias; Romeiro, Nelilma Correia; Silva, Patrícia Machado Rodrigues e; Martins, Marco Aurélio; Barreiro, Eliezer J.; Lima, Lídia Moreira

    2016-01-01

    Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448) presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral), 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg) also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma. PMID:27695125

  9. Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4

    SciTech Connect

    Kucka, Marek; Pogrmic-Majkic, Kristina; Fa, Svetlana; Stojilkovic, Stanko S.; Kovacevic, Radmila

    2012-11-15

    Atrazine, one of the most commonly used herbicides worldwide, acts as an endocrine disruptor, but the mechanism of its action has not been characterized. In this study, we show that atrazine rapidly increases cAMP levels in cultured rat pituitary and testicular Leydig cells in a concentration-dependent manner, but less effectively than 3-isobutyl-1-methylxanthine, a competitive non-specific inhibitor of phosphodiesterases (PDEs). In forskolin (an activator of adenylyl cyclase)- and probenecid (an inhibitor of cyclic nucleotide transporters)-treated cells, but not in 3-isobutyl-1-methylxanthine-treated cells, atrazine further increased cAMP levels, indicating that inhibition of PDEs accounts for accumulation of cAMP. In contrast to cAMP, atrazine did not alter cGMP levels, further indicating that it inhibits cAMP-specific PDEs. Atrazine-induced changes in cAMP levels were sufficient to stimulate prolactin release in pituitary cells and androgen production in Leydig cells, indicating that it acts as an endocrine disrupter both in cells that secrete by exocytosis of prestored hormones and in cells that secrete by de novo hormone synthesis. Rolipram abolished the stimulatory effect of atrazine on cAMP release in both cell types, suggesting that it acts as an inhibitor of PDE4s, isoforms whose mRNA transcripts dominate in pituitary and Leydig cells together with mRNA for PDE8A. In contrast, immortalized lacto-somatotrophs showed low expression of these mRNA transcripts and several fold higher cAMP levels compared to normal pituitary cells, and atrazine was unable to further increase cAMP levels. These results indicate that atrazine acts as a general endocrine disrupter by inhibiting cAMP-specific PDE4s. -- Highlights: ► Atrazine stimulates cAMP accumulation in pituitary and Leydig cells. ► Atrazine also stimulates PRL and androgens secretion. ► Stimulatory effects of atrazine were abolished in cells with IBMX-inhibited PDEs. ► Atrazine specificity toward cAMP-specific PDEs was indicated by no changes in cGMP. ► Rolipram, a specific PDE4 inhibitor, also prevents stimulatory effects of atrazine. ► Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific PDE4.

  10. Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches.

    PubMed

    Li, Jing; Zhou, Nan; Liu, Wen; Li, Jianzong; Feng, Yu; Wang, Xiaoyun; Wu, Chuanfang; Bao, Jinku

    2016-05-01

    cAMP, intracellular cyclic adenosine monophosphate, is a ubiquitous second messenger that plays a key role in many physiological processes. PDE4B which can reduce the cAMP level by hydrolyzing cAMP to 5'-AMP has become a therapeutic target for the treatment of human diseases such as respiratory disorders, inflammation diseases, neurological and psychiatric disorders. However, the use of currently available PDE4B inhibitors is restricted due to serious side effects caused by targeting PDE4D. Hence, we are attempting to find out subfamily-selective PDE4B inhibitors from natural products, using computer-aided approaches such as virtual screening, docking, and molecular dynamics simulation. Finally, four potential PDE4B-selective inhibitors (ZINC67912770, ZINC67912780, ZINC72320169, and ZINC28882432) were found. Compared to the reference drug (roflumilast), they scored better during the virtual screening process. Binding free energy for them was -317.51, -239.44, -215.52, and -165.77 kJ/mol, better than -129.05 kJ/mol of roflumilast. The pharmacophore model of the four candidate inhibitors comprised six features, including one hydrogen bond donor, four hydrogen bond acceptors, and one aromatic ring feature. It is expected that our study will pave the way for the design of potent PDE4B-selective inhibitors of new drugs to treat a wide variety of diseases such as asthma, COPD, psoriasis, depression, etc.

  11. Brain Tumors

    MedlinePlus

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  12. Persistent inflammation-induced up-regulation of brain-derived neurotrophic factor (BDNF) promotes synaptic delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunits in descending pain modulatory circuits.

    PubMed

    Tao, Wenjuan; Chen, Quan; Zhou, Wenjie; Wang, Yunping; Wang, Lu; Zhang, Zhi

    2014-08-08

    The enhanced AMPA receptor phosphorylation at GluA1 serine 831 sites in the central pain-modulating system plays a pivotal role in descending pain facilitation after inflammation, but the underlying mechanisms remain unclear. We show here that, in the rat brain stem, in the nucleus raphe magnus, which is a critical relay in the descending pain-modulating system of the brain, persistent inflammatory pain induced by complete Freund adjuvant (CFA) can enhance AMPA receptor-mediated excitatory postsynaptic currents and the GluA2-lacking AMPA receptor-mediated rectification index. Western blot analysis showed an increase in GluA1 phosphorylation at Ser-831 but not at Ser-845. This was accompanied by an increase in distribution of the synaptic GluA1 subunit. In parallel, the level of histone H3 acetylation at bdnf gene promoter regions was reduced significantly 3 days after CFA injection, as indicated by ChIP assays. This was correlated with an increase in BDNF mRNA levels and BDNF protein levels. Sequestering endogenous extracellular BDNF with TrkB-IgG in the nucleus raphe magnus decreased AMPA receptor-mediated synaptic transmission and GluA1 phosphorylation at Ser-831 3 days after CFA injection. Under the same conditions, blockade of TrkB receptor functions, phospholipase C, or PKC impaired GluA1 phosphorylation at Ser-831 and decreased excitatory postsynaptic currents mediated by GluA2-lacking AMPA receptors. Taken together, these results suggest that epigenetic up-regulation of BDNF by peripheral inflammation induces GluR1 phosphorylation at Ser-831 sites through activation of the phospholipase C-PKC signaling cascade, leading to the trafficking of GluA1 to pain-modulating neuronal synapses.

  13. Brain surgery

    MedlinePlus

    Craniotomy; Surgery - brain; Neurosurgery; Craniectomy; Stereotactic craniotomy; Stereotactic brain biopsy; Endoscopic craniotomy ... cut depends on where the problem in the brain is located. The surgeon creates a hole in ...

  14. Brain Malformations

    MedlinePlus

    Most brain malformations begin long before a baby is born. Something damages the developing nervous system or causes it ... medicines, infections, or radiation during pregnancy interferes with brain development. Parts of the brain may be missing, ...

  15. Brain components

    MedlinePlus Videos and Cool Tools

    The brain is composed of more than a thousand billion neurons. Specific groups of them, working in concert, provide ... of information. The 3 major components of the brain are the cerebrum, cerebellum, and brain stem. The ...

  16. Brain-derived neurotrophic factor promotes vesicular glutamate transporter 3 expression and neurite outgrowth of dorsal root ganglion neurons through the activation of the transcription factors Etv4 and Etv5.

    PubMed

    Liu, Dong; Liu, Zhen; Liu, Huaxiang; Li, Hao; Pan, Xinliang; Li, Zhenzhong

    2016-03-01

    Brain-derived neurotrophic factor (BDNF) is critical for sensory neuron survival and is necessary for vesicular glutamate transporter 3 (VGLUT3) expression. Whether the transcription factors Etv4 and Etv5 are involved in these BDNF-induced effects remains unclear. In the present study, primary cultured dorsal root ganglion (DRG) neurons were used to test the link between BDNF and transcription factors Etv4 and Etv5 on VGLUT3 expression and neurite outgrowth. BDNF promoted the mRNA and protein expression of Etv4 and Etv5 in DRG neurons. These effects were blocked by extracellular signal-regulated protein kinase 1/2 (ERK1/2) inhibitor PD98059 but not phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or phospholipase C-γ (PLC-γ) inhibitor U73122. Etv4 siRNA and Etv5 siRNA effectively blocked the VGLUT3 expression and neurite elongation induced by BNDF. The overexpression of Etv4 or Etv5 potentiated the effects of BNDF-induced neurite elongation and growth-associated protein 43 (GAP-43), medium neurofilament (NF-M), and light neurofilament (NF-L) expression while these effects could be inhibited by Etv4 and Etv5 siRNA. These data imply that Etv4 and Etv5 are essential transcription factors in modulating BDNF/TrkB signaling-mediated VGLUT3 expression and neurite outgrowth. BDNF, through the ERK1/2 signaling pathway, activates Etv4 and Etv5 to initiate GAP-43 expression, promote neurofilament (NF) protein expression, induce neurite outgrowth, and mediate VGLUT3 expression for neuronal function improvement. The biological effects initiated by BDNF/TrkB signaling linked to E26 transformation-specific (ETS) transcription factors are important to elucidate neuronal differentiation, axonal regeneration, and repair in various pathological states.

  17. Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice.

    PubMed

    de Sousa Rodrigues, Maria Elizabeth; Bekhbat, Mandakh; Houser, Madelyn C; Chang, Jianjun; Walker, Douglas I; Jones, Dean P; Oller do Nascimento, Claudia M P; Barnum, Christopher J; Tansey, Malú G

    2017-01-01

    The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders.

  18. Campaign for the Brain.

    PubMed

    Marshall, Jolene

    2017-04-01

    A stroke alert is an emergency. An event in the brain can end in long-term deficits that may be prevented if attention is given to the signs. The message needs to be told. Be fast. This is a poem to promote code stroke.

  19. Love promotes health.

    PubMed

    Esch, Tobias; Stefano, George B

    2005-06-01

    Love has consequences for health and well-being. Engaging in joyful activities such as love may activate areas in the brain responsible for emotion, attention, motivation and memory (i.e., limbic structures), and it may further serve to control the autonomic nervous system, i.e., stress reduction. This specific CNS activity pattern appears to exert protective effects, even on the brain itself. Moreover, anxiolytic effects of pleasurable experiences may occur by promotion of an inhibitory tone in specific areas of the brain. Thus, love and pleasure clearly are capable of stimulating health, well-being and (re)productivity: This wonderful biological instrument makes procreation and maintenance of organisms and their species a deeply rewarding and pleasurable experience, thus ensuring survival, health, and perpetuation.

  20. Assessment of Students with Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Chesire, David J.; Buckley, Valerie A.; Canto, Angela I.

    2011-01-01

    The incidence of brain injuries, as well as their impact on individuals who sustain them, has received growing attention from American media in recent years. This attention is likely the result of high profile individuals suffering brain injuries. Greater public awareness of traumatic brain injuries (TBIs) has also been promoted by sources such as…

  1. Aquaporins and Brain Tumors

    PubMed Central

    Maugeri, Rosario; Schiera, Gabriella; Di Liegro, Carlo Maria; Fricano, Anna; Iacopino, Domenico Gerardo; Di Liegro, Italia

    2016-01-01

    Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood–brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs). PMID:27367682

  2. Targeted taste cell-specific overexpression of brain-derived neurotrophic factor in adult taste buds elevates phosphorylated TrkB protein levels in taste cells, increases taste bud size, and promotes gustatory innervation.

    PubMed

    Nosrat, Irina V; Margolskee, Robert F; Nosrat, Christopher A

    2012-05-11

    Brain-derived neurotrophic factor (BDNF) is the most potent neurotrophic factor in the peripheral taste system during embryonic development. It is also expressed in adult taste buds. There is a lack of understanding of the role of BDNF in the adult taste system. To address this, we generated novel transgenic mice in which transgene expression was driven by an α-gustducin promoter coupling BDNF expression to the postnatal expression of gustducin in taste cells. Immunohistochemistry revealed significantly stronger BDNF labeling in taste cells of high BDNF-expressing mouse lines compared with controls. We show that taste buds in these mice are significantly larger and have a larger number of taste cells compared with controls. To examine whether innervation was affected in Gust-BDNF mice, we used antibodies to neural cell adhesion molecule (NCAM) and ATP receptor P2X3. The total density of general innervation and specifically the gustatory innervation was markedly increased in high BDNF-expressing mice compared with controls. TrkB and NCAM gene expression in laser capture microdissected taste epithelia were significantly up-regulated in these mice. Up-regulation of TrkB transcripts in taste buds and elevated taste cell-specific TrkB phosphorylation in response to increased BDNF levels indicate that BDNF controls the expression and activation of its high affinity receptor in taste cells. This demonstrates a direct taste cell function for BDNF. BDNF also orchestrates and maintains taste bud innervation. We propose that the Gust-BDNF transgenic mouse models can be employed to further dissect the specific roles of BDNF in the adult taste system.

  3. Brain Diseases

    MedlinePlus

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  4. Brain Aneurysm

    MedlinePlus

    ... tests don't provide enough information. Screening for brain aneurysms The use of imaging tests to screen ... and occupational therapy to relearn skills. Treating unruptured brain aneurysms Surgical clipping or endovascular coiling can be ...

  5. Brain Development

    MedlinePlus

    ... developed the f… Series Healthy Minds: Nurturing Your Child's Development Each of these age-based handouts are based ... report from the National Academy of Sciences on child and brain development. Podcast Nurturing Brain Development From Birth to Three ...

  6. Brain Fog

    MedlinePlus

    ... friendships and relationships. • Take your body to the gym and don’t forget to visit the “BRAIN SPA” – both will improve brain function. • Recent scientific data show that longevity ...

  7. Brain Power.

    ERIC Educational Resources Information Center

    Albrecht, Karl

    2002-01-01

    Reviews significant findings of recent brain research, including the concept of five minds: automatic, subconscious, practical, creative, and spiritual. Suggests approaches to training the brain that are related to this hierarchy of thinking. (JOW)

  8. Health Promotion

    DTIC Science & Technology

    1986-03-11

    Department of Defense DIRECTIVEAD-A269 638 , , AD-A29 638March 11, 1986 IIIIii!IN 111111111,11 Ii1111,111111[NUMBER 1010.10 SUBJECT: Health Promotion ...34 March 13, 1985 INC A. URPOSE SThis Directive establishes a health promotion policy within the Department of Defense to improve and maintain military...civilian employees. C. DEFINITIONS 1. Health Promotion . Any combination of health education and related organizational, social, economic or health care

  9. Brain Aneurysm

    MedlinePlus

    A brain aneurysm is an abnormal bulge or "ballooning" in the wall of an artery in the brain. They are sometimes called berry aneurysms because they ... often the size of a small berry. Most brain aneurysms produce no symptoms until they become large, ...

  10. Brain Lesions

    MedlinePlus

    ... MRI scans, brain lesions appear as dark or light spots that don't look like normal brain tissue. Usually, a brain lesion is an incidental finding unrelated to the condition or symptom that led to the imaging test in the first place. ...

  11. The Brain.

    ERIC Educational Resources Information Center

    Hubel, David H.

    1979-01-01

    This article on the brain is part of an entire issue about neurobiology and the question of how the human brain works. The brain as an intricate tissue composed of cells is discussed based on the current knowledge and understanding of its composition and structure. (SA)

  12. Left Brain. Right Brain. Whole Brain

    ERIC Educational Resources Information Center

    Farmer, Lesley S. J.

    2004-01-01

    As the United States student population is becoming more diverse, library media specialists need to find ways to address these distinctive needs. However, some of these differences transcend culture, touching on variations in the brain itself. Most people have a dominant side of the brain, which can affect their personality and learning style.…

  13. Brain to music to brain!

    PubMed

    Azizi, S Ausim

    2009-07-31

    It has been implicitly understood that culture and music as collective products of human brain in turn influence the brain itself. Now, imaging and anatomical data add substance to this notion. The impact of playing piano on the brain of musicians and its possible effects on cultural and neurological evolution are briefly discussed.

  14. The potential of neural transplantation for brain repair and regeneration following traumatic brain injury

    PubMed Central

    Sun, Dong

    2016-01-01

    Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent development in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury. PMID:26981070

  15. Health Promotion

    PubMed Central

    Wilson, Ron

    1992-01-01

    How physicians address issues of disease prevention and health promotion is discussed and current standards of screening for disease and counseling practices are reviewed. Collaboration among all health professionals is necessary if preventive medicine is to be effective. PMID:21221259

  16. Brain surgery - discharge

    MedlinePlus

    ... to take these medicines. If you had a brain aneurysm , you may also have other symptoms or problems. ... chap 28. Read More Acoustic neuroma Brain abscess Brain aneurysm repair Brain surgery Brain tumor - children Brain tumor - ...

  17. Health Promotion

    PubMed Central

    Karmali-Rawji, Shameela; Kassim-Lakha, Shaheen; Taylor, Karmel

    1992-01-01

    Perceived lack or loss of control, stress, a rapidly again population and rising costs of health care necessitate effective health promotion and disease prevention in the elderly. In a collaborative health promotion effort, the private sector, public sector, and community partners have joined to increase the South Asian elders' sense of control over the decisions and circumstances that affect their everyday lives. The project was designed to help elders come to terms with the fragmentation of their extended families, cultural alienation, decreased autonomy, need for information, and greater risk of cardiovascular disease. Imagesp622-a

  18. Electroacupuncture stimulation of the brachial plexus trunk on the healthy side promotes brain-derived neurotrophic factor mRNA expression in the ischemic cerebral cortex of a rat model of cerebral ischemia/reperfusion injury.

    PubMed

    Guo, Zongjun; Wang, Lumin

    2012-07-25

    A rat model of cerebral ischemia/reperfusion was established by suture occlusion of the left middle cerebral artery. In situ hybridization results showed that the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic rat cerebral cortex increased after cerebral ischemia/ reperfusion injury. Low frequency continuous wave electroacupuncture (frequency 2-6 Hz, current intensity 2 mA) stimulation of the brachial plexus trunk on the healthy (right) side increased the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic cerebral cortex 14 days after cerebral ischemia/reperfusion injury. At the same time, electroacupuncture stimulation of the healthy brachial plexus truck significantly decreased neurological function scores and alleviated neurological function deficits. These findings suggest that electroacupuncture stimulation of the brachial plexus trunk on the healthy (right) side can greatly increase brain-derived neurotrophic factor mRNA expression and improve neurological function.

  19. Brain investigation and brain conceptualization

    PubMed Central

    Redolfi, Alberto; Bosco, Paolo; Manset, David; Frisoni, Giovanni B.

    Summary The brain of a patient with Alzheimer’s disease (AD) undergoes changes starting many years before the development of the first clinical symptoms. The recent availability of large prospective datasets makes it possible to create sophisticated brain models of healthy subjects and patients with AD, showing pathophysiological changes occurring over time. However, these models are still inadequate; representations are mainly single-scale and they do not account for the complexity and interdependence of brain changes. Brain changes in AD patients occur at different levels and for different reasons: at the molecular level, changes are due to amyloid deposition; at cellular level, to loss of neuron synapses, and at tissue level, to connectivity disruption. All cause extensive atrophy of the whole brain organ. Initiatives aiming to model the whole human brain have been launched in Europe and the US with the goal of reducing the burden of brain diseases. In this work, we describe a new approach to earlier diagnosis based on a multimodal and multiscale brain concept, built upon existing and well-characterized single modalities. PMID:24139654

  20. Interleukin-10 in the brain.

    PubMed

    Strle, K; Zhou, J H; Shen, W H; Broussard, S R; Johnson, R W; Freund, G G; Dantzer, R; Kelley, K W

    2001-01-01

    Interleukin (IL)-10 is synthesized in the central nervous system (CNS) and acts to limit clinical symptoms of stroke, multiple sclerosis, Alzheimer's disease, meningitis, and the behavioral changes that occur during bacterial infections. Expression of IL-10 is elevated during the course of most major diseases in the CNS and promotes survival of neurons and all glial cells in the brain by blocking the effects of proapoptotic cytokines and by promoting expression of cell survival signals. Stimulation of IL-10 receptors regulates numerous life- or death-signaling pathways--including Jak1/Stat3, PI 3-kinase, MAPK, SOCS, and NF-kappaB--ultimately promoting cell survival by inhibiting both ligand- and mitochondrial-induced apoptotic pathways. IL-10 also limits inflammation in the brain; it does so by three major pathways: (1) reducing synthesis of proinflammatory cytokines, (2) suppressing cytokine receptor expression, and (3) inhibiting receptor activation. Finally, IL-10 induces anergy in brain-infiltrating T cells by inhibiting cell signaling through the costimulatory CD28-CD80/86 pathway. The multiple functions of IL-10 in the brain will create new and intriguing vistas that will promote a better understanding of neurodegenerative diseases. These discoveries could lead to development of innovative approaches for the use of antiinflammatory cytokines in major debilitating diseases of the CNS.

  1. Linking Brain Research to Art.

    ERIC Educational Resources Information Center

    Rettig, Perry R.; Rettig, Janet L.

    1999-01-01

    Reviews recent brain research in education. Provides five implications for teaching in art: (1) use emotion; (2) use different sense; (3) promote student self-direction; (4) enable social learning; and (5) encourage pattern finding. Describes two sample art units demonstrating how the five implications and art instruction can be integrated. (CMK)

  2. [Brain concussion].

    PubMed

    Pälvimäki, Esa-Pekka; Siironen, Jari; Pohjola, Juha; Hernesniemi, Juha

    2011-01-01

    Brain concussion is a common disturbance caused by external forces or acceleration affecting the head. It may be accompanied by transient loss of consciousness and amnesia. Typical symptoms include headache, nausea and dizziness; these may remain for a week or two. Some patients may experience transient loss of inability to create new memories or other brief impairment of mental functioning. Treatment is symptomatic. Some patients may suffer from prolonged symptoms, the connection of which with brain concession is difficult to show. Almost invariably the prognosis of brain concussion is good.

  3. Brain radiation - discharge

    MedlinePlus

    Radiation - brain - discharge; Cancer-brain radiation; Lymphoma - brain radiation; Leukemia - brain radiation ... Decadron) while you are getting radiation to the brain. It may make you hungrier, cause leg swelling ...

  4. Brain Stimulation Therapies

    MedlinePlus

    ... Magnetic Seizure Therapy Deep Brain Stimulation Additional Resources Brain Stimulation Therapies Overview Brain stimulation therapies can play ... for a shorter recovery time than ECT Deep Brain Stimulation Deep brain stimulation (DBS) was first developed ...

  5. Brain tumor - primary - adults

    MedlinePlus

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  6. Right Hemisphere Brain Damage

    MedlinePlus

    ... Language and Swallowing / Disorders and Diseases Right Hemisphere Brain Damage [ en Español ] What is right hemisphere brain ... right hemisphere brain damage ? What is right hemisphere brain damage? Right hemisphere brain damage (RHD) is damage ...

  7. Anatomy of the Brain

    MedlinePlus

    ... Young Adult Guidelines For brain tumor information and support Call: 800-886-ABTA (2282) or Complete our contact form Brain Tumor Information Brain Anatomy Brain Structure Neuron Anatomy Brain Tumor Symptoms Diagnosis Types of ...

  8. Brain foods: the effects of nutrients on brain function

    PubMed Central

    Gómez-Pinilla, Fernando

    2009-01-01

    It has long been suspected that the relative abundance of specific nutrients can affect cognitive processes and emotions. Newly described influences of dietary factors on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that are responsible for the action of diet on brain health and mental function. Several gut hormones that can enter the brain, or that are produced in the brain itself, influence cognitive ability. In addition, well-established regulators of synaptic plasticity, such as brain-derived neurotrophic factor, can function as metabolic modulators, responding to peripheral signals such as food intake. Understanding the molecular basis of the effects of food on cognition will help us to determine how best to manipulate diet in order to increase the resistance of neurons to insults and promote mental fitness. PMID:18568016

  9. Fragile Brains.

    ERIC Educational Resources Information Center

    Jensen, Eric

    2001-01-01

    Describes three types of brain disorders: the sluggish, the oppositional, and the depressed. Explains how to identify these disorders and offers educators strategies for dealing with each. (Contains 11 references.) (PKP)

  10. Brain abscess

    MedlinePlus

    ... small abscess (less than 2 cm) An abscess deep in the brain An abscess and meningitis Several ... or MRI scan may be needed for a deep abscess. During this procedure, medicines may be injected ...

  11. Brain Basics

    MedlinePlus Videos and Cool Tools

    ... genes and epigenetics may one day lead to genetic testing for people at risk for mental disorders. ... brain. DNA —The "recipe of life," containing inherited genetic information that helps to define physical and some ...

  12. Brain Autopsy

    MedlinePlus

    ... Monthly Donation Named Funds Planned Giving Gifts of Stock Business Partnerships Host an Event AFTD-Team Races ... family members to reach a closure after a long struggle. Brain autopsy is often done in conjunction ...

  13. Brain-Based Education: Its Pedagogical Implications and Research Relevance

    ERIC Educational Resources Information Center

    Laxman, Kumar; Chin, Yap Kueh

    2010-01-01

    The brain, being the organ of learning, must be understood if classrooms are to be places of meaningful learning. Understanding the brain has the potential to alter the foundation of education, transform traditional classrooms to interactive learning environments and promote better instructional approaches amongst teachers. Brain-based education…

  14. Informal, Real-Life Play--Building Children's Brain Connections.

    ERIC Educational Resources Information Center

    Jambor, Tom

    2000-01-01

    Describes how children's play contributes to brain development. Details the importance of early experience for brain development, arguing that the optimal learning activities to promote brain development are complex, use many senses simultaneously, and are perceived as relevant, useful, emotionally engaging, and novel. Suggests that informal play…

  15. [Human brain resource--experience at the Brain Research Institute,University of Niigata].

    PubMed

    Kakita, Akiyoshi; Takahashi, Hitoshi

    2010-10-01

    Through 40 years of neuropathological practice,the Brain Research Institute, University of Niigata (BRI-Niigata), Japan has accumulated extensive human brain resource,including fresh-frozen brain slices,for scientific research. Over 30,000 slices obtained from consecutive autopsies have been systematically stored in 25 deep freezers. Establishment of effective networks between brain banks and institutional collections in Japan is essential for promoting scientific activities that require human brain resource. We at the BRI-Niigata are eager to contribute to the establishment of such networks.

  16. Brain imaging and brain function

    SciTech Connect

    Sokoloff, L.

    1985-01-01

    This book is a survey of the applications of imaging studies of regional cerebral blood flow and metabolism to the investigation of neurological and psychiatric disorders. Contributors review imaging techniques and strategies for measuring regional cerebral blood flow and metabolism, for mapping functional neural systems, and for imaging normal brain functions. They then examine the applications of brain imaging techniques to the study of such neurological and psychiatric disorders as: cerebral ischemia; convulsive disorders; cerebral tumors; Huntington's disease; Alzheimer's disease; depression and other mood disorders. A state-of-the-art report on magnetic resonance imaging of the brain and central nervous system rounds out the book's coverage.

  17. Brain death.

    PubMed

    Wijdicks, Eelco F M

    2013-01-01

    The diagnosis of brain death should be based on a simple premise. If every possible confounder has been excluded and all possible treatments have been tried or considered, irreversible loss of brain function is clinically recognized as the absence of brainstem reflexes, verified apnea, loss of vascular tone, invariant heart rate, and, eventually, cardiac standstill. This condition cannot be reversed - not even partly - by medical or surgical intervention, and thus is final. Many countries in the world have introduced laws that acknowledge that a patient can be declared brain-dead by neurologic standards. The U.S. law differs substantially from all other brain death legislation in the world because the U.S. law does not spell out details of the neurologic examination. Evidence-based practice guidelines serve as a standard. In this chapter, I discuss the history of development of the criteria, the current clinical examination, and some of the ethical and legal issues that have emerged. Generally, the concept of brain death has been accepted by all major religions. But patients' families may have different ideas and are mostly influenced by cultural attitudes, traditional customs, and personal beliefs. Suggestions are offered to support these families.

  18. Skullduggery: A Case of Cranium Confusion. BrainLink: Brain Comparisons.

    ERIC Educational Resources Information Center

    Boyle, Grace

    The BrainLink project offers educational materials focusing on current neuroscience issues with the goal of promoting a deeper understanding of how the nervous system works and why the brain makes each individual special while conveying the excitement of "doing science" among upper elementary and middle school students. Project materials engage…

  19. Brain heterotopia.

    PubMed

    Modarresifar, Homayoun; Ho, Linh

    2009-03-01

    We present a case with intractable partial complex seizures in a 14-year-old girl who was found to have brain heterotopia on MRI and PET-CT. The patient presented with intractable partial complex seizures and a normal electroencephalogram. Her brain magnetic resonance imaging showed heterotopic gray matter lining the ventricular margin of the right occipital horn. Subsequent PET-CT demonstrated moderate tracer localization in the heterotopic gray matter surrounding the ventricular margin of the right occipital horn. Heterotopia may demonstrate normal or increased FDG uptake on PET, therefore its appearance may be deceiving when other pathologies are being considered.

  20. Long-term cognitive dysfunction in the rat following docetaxel treatment is ameliorated by the phosphodiesterase-4 inhibitor, rolipram.

    PubMed

    Callaghan, Charlotte K; O'Mara, Shane M

    2015-09-01

    Clinical studies report evidence of long-term cognitive and other deficits following adjunctive chemotherapy treatment, which is often termed "chemobrain" or "chemo-fog". The neurological bases of these impairments are poorly understood. Here, we hypothesize that systemic chemotherapy treatment causes long-term neurobehavioral deficits, and that these deficits are reversed by manipulation of cAMP by the PDE4 inhibitor, rolipram. Male han Wistar rats were treated with docetaxel (an adjunctive chemotherapeutic agent (1mg/kg i.v.)) or control solution (ethanol/Tween 20/0.9% Saline - 5/5/90) once per week for 4 weeks. They were allowed to recover for 4 weeks, administration of rolipram (0.5mg/kg po) or vehicle (maple syrup) then began and continued daily for 4 weeks. At the end of the treatment regime animals were tested for spatial and recognition memory deficits with the object exploration task and for depressive- and anxiety-like behavior in the forced swim test (FST) and open field exploration. We report docetaxel treatment impaired spatial memory but not object recognition memory, compared to control rats. Docetaxel-treated rats also spent significantly more time immobile than controls in the FST. Chronic rolipram treatment attenuated all of these docetaxel-associated changes, recovering spatial memory and reducing immobility. In conclusion, docetaxel-treated rats exhibit alterations in spatial memory and depressive-like behavior, which are reversed following chronic rolipram administration. These results detect long-term cognitive and mood changes following docetaxel treatment and identify PDE4 inhibition as a target treatment of neuropsychological changes associated with "chemobrain".

  1. Characterization of phosphodiesterase 4 in guinea-pig macrophages: multiple activities, association states and sensitivity to selective inhibitors

    PubMed Central

    Kelly, John J; Barnes, Peter J; Giembycz, Mark A

    1998-01-01

    The cyclic AMP phosphodiesterases (PDE) in guinea-pig peritoneal macrophages were isolated, partially characterized and their role in regulating the cyclic AMP content in intact cells evaluated.Differential centrifugation of macrophage lysates revealed that ∼90% of the PDE activity was membrane-bound and exclusively hydrolyzed cyclic AMP. This activity was not removed by KCl (200 mM) but was readily solubilized by the non-ionic detergent, Triton X-100 (1% v/v). Greater than 80% of the hydrolytic activity was suppressed by the PDE4 inhibitors, R-rolipram and nitraquazone with IC50s of 240 and 540 nM, respectively.Anion-exchange chromatography of the total protein extracted from macrophages resolved two major peaks of cyclic AMP PDE activity that were insensitive to cyclic GMP (10 μM), calmodulin (50 units plus 2 mM CaCl2) and a PDE3 inhibitor, SK&F 95654 (10 μM), but were markedly suppressed by RS-rolipram (10 μM). The two peaks of PDE activity were arbitrarily designated CPPDE4α and CPPDE4β with respect to the order from which they were eluted from the column where the prefix, CP, refers to the species, Cavia porcellus.The hydrolysis of cyclic AMP catalyzed by CPPDE4α and CPPDE4β conformed to Michaelis-Menten kinetic behaviour with similar Kms (13.4 and 6.4 μM, respectively).Thermal denaturation of membrane-bound PDE4 at 50°C followed bi-exponential kinetics with t1/2 values of 1.5 and 54.7 min for the first and second components, respectively. In contrast, CPPDE4α and CPPDE4β each decayed mono-exponentially with significantly different thermostabilities (t1/2=2.77 and 1.15 min, respectively).Gel filtration of CPPDE4β separated two peaks of rolipram-sensitive PDE activity. The main peak eluted at a volume indicative of a ∼180 kDa protein but was preceded by a much larger form of the enzyme that had an estimated weight of 750 kDa. Size exclusion chromatography of CPPDE4α resolved a broad peak of activity with molecular weights spanning 50 to 200 kDa.Of ten PDE inhibitors examined, none distinguished CPPDE4α from CPPDE4β with respect to their IC50 values or their rank order of potency. RS-rolipram acted as a purely competitive inhibitor of cyclic AMP hydrolysis with Kis of 2 μM and 1.5 μM for CPPDE4α and CPPDE4β, respectively. In contrast to the membrane-associated enzyme(s), R-rolipram and nitraquazone were 4 to 19 fold less potent as inhibitors of CPPDE4α and CPPDE4β.In intact macrophages, Ro 20-1724 and RS-rolipram potentiated isoprenaline-induced cyclic AMP accumulation under conditions where a PDE3 inhibitor, SK&F 94120, was essentially inactive.These data demonstrate that the predominant cyclic AMP hydrolyzing activity in guinea-pig macrophages is a PDE4. Moreover, thermostability studies and size exclusion chromatography indicates the possible expression of two intrinsic, membrane-associated isoenzymes which can regulate the cyclic AMP content in intact cells. The finding that soluble and particulate forms of the same enzyme exhibit different sensitivities to rolipram and nitraquazone implies that PDE4 can change conformation. Finally, the identification of multiple molecular weight species of CPPDE4 suggests that this enzyme(s) might form multimeric complexes of variable association states. PMID:9630352

  2. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor: A novel treatment option for nurse practitioners treating patients with psoriatic disease

    PubMed Central

    Roebuck, Heather L.

    2016-01-01

    Abstract Background and purpose Apremilast is an oral nonbiologic medication approved for the treatment of adult patients with active psoriatic arthritis and for patients with moderate to severe plaque psoriasis. This article summarizes the efficacy and safety of apremilast and provides characterization of the novel medication with clinical perspectives to successfully incorporate this therapy into practice for appropriate patients. Data sources A review and synthesis of the results from the ESTEEM (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis) phase 3 clinical studies evaluating the efficacy, safety, and tolerability of apremilast for the treatment of moderate to severe plaque psoriasis was conducted. Conclusions Results from the ESTEEM clinical trial program demonstrate that apremilast significantly reduces the severity of moderate to severe plaque psoriasis, has an acceptable safety profile, and is generally well tolerated. Implications for practice The novel mechanism of action, convenience of oral administration, and acceptable side effect profile make this medication an attractive choice for clinicians treating patients with plaque psoriasis. PMID:27869356

  3. UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

    PubMed Central

    Wang, Li; Burmeister, Brian T.; Johnson, Keven R.; Baillie, George S.; Karginov, Andrei V.; Skidgel, Randal A.; O’Bryan, John P.; Carnegie, Graeme K.

    2015-01-01

    Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3′, 5′-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-Kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity. PMID:25683917

  4. Estradiol and the Developing Brain

    PubMed Central

    McCarthy, Margaret M.

    2009-01-01

    Estradiol is the most potent and ubiquitous member of a class of steroid hormones called estrogens. Fetuses and newborns are exposed to estradiol derived from their mother, their own gonads, and synthesized locally in their brains. Receptors for estradiol are nuclear transcription factors that regulate gene expression but also have actions at the membrane, including activation of signal transduction pathways. The developing brain expresses high levels of receptors for estradiol. The actions of estradiol on developing brain are generally permanent and range from establishment of sex differences to pervasive trophic and neuroprotective effects. Cellular end points mediated by estradiol include the following: 1) apoptosis, with estradiol preventing it in some regions but promoting it in others; 2) synaptogenesis, again estradiol promotes in some regions and inhibits in others; and 3) morphometry of neurons and astrocytes. Estradiol also impacts cellular physiology by modulating calcium handling, immediate-early-gene expression, and kinase activity. The specific mechanisms of estradiol action permanently impacting the brain are regionally specific and often involve neuronal/glial cross-talk. The introduction of endocrine disrupting compounds into the environment that mimic or alter the actions of estradiol has generated considerable concern, and the developing brain is a particularly sensitive target. Prostaglandins, glutamate, GABA, granulin, and focal adhesion kinase are among the signaling molecules co-opted by estradiol to differentiate male from female brains, but much remains to be learned. Only by understanding completely the mechanisms and impact of estradiol action on the developing brain can we also understand when these processes go awry. PMID:18195084

  5. Smart Brains.

    ERIC Educational Resources Information Center

    Jones, Rebecca

    1995-01-01

    New techniques have opened windows to the brain. Although the biochemistry of learning remains largely a mystery, the following findings seem to have clear implications for education: (1) the importance of early-learning opportunities for the very young; (2) the connection between music and abstract reasoning; and (3) the importance of good…

  6. Animating Brains.

    PubMed

    Borck, Cornelius

    2016-07-01

    A recent paper famously accused the rising field of social neuroscience of using faulty statistics under the catchy title 'Voodoo Correlations in Social Neuroscience'. This Special Issue invites us to take this claim as the starting point for a cross-cultural analysis: in which meaningful ways can recent research in the burgeoning field of functional imaging be described as, contrasted with, or simply compared to animistic practices? And what light does such a reading shed on the dynamics and effectiveness of a century of brain research into higher mental functions? Reviewing the heated debate from 2009 around recent trends in neuroimaging as a possible candidate for current instances of 'soul catching', the paper will then compare these forms of primarily image-based brain research with older regimes, revolving around the deciphering of the brain's electrical activity. How has the move from a decoding paradigm to a representational regime affected the conceptualisation of self, psyche, mind and soul (if there still is such an entity)? And in what ways does modern technoscience provide new tools for animating brains?

  7. Brain Tumors (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Brain Tumors KidsHealth > For Parents > Brain Tumors Print A ... radiation therapy or chemotherapy, or both. Types of Brain Tumors There are many different types of brain ...

  8. Understanding Brain Tumors

    MedlinePlus

    ... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

  9. Brain tumor - children

    MedlinePlus

    ... children; Neuroglioma - children; Oligodendroglioma - children; Meningioma - children; Cancer - brain tumor (children) ... The cause of primary brain tumors is unknown. Primary brain tumors may ... (spread to nearby areas) Cancerous (malignant) Brain tumors ...

  10. Brain Tumors (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Brain Tumors KidsHealth > For Parents > Brain Tumors A A ... radiation therapy or chemotherapy, or both. Types of Brain Tumors There are many different types of brain ...

  11. Brain Tumor Diagnosis

    MedlinePlus

    ... Types of Brain Scans X-rays Laboratory Tests DNA Profiling Biopsy Procedure Malignant and Benign Brain Tumors Tumor ... Types of Brain Scans X-rays Laboratory Tests DNA Profiling Biopsy Procedure Malignant and Benign Brain Tumors Tumor ...

  12. Promoting Retention

    PubMed Central

    Hall, LaToya N.; Ficker, Lisa J.; Chadiha, Letha A.; Green, Carmen R.; Jackson, James S.; Lichtenberg, Peter A.

    2016-01-01

    Objectives: The objectives of this study were to evaluate the capability of a research volunteer registry to retain community-dwelling African American older adults, and to explore demographic and health factors associated with retention. Method: A logistic regression model was used to determine the influence of demographics, health factors, and registry logic model activities on retention in a sample of 1,730 older African American adults. Results: Almost 80% of participants active in the volunteer research registry between January 2012 and June 2015 were retained. Employment, being referred to research studies, a higher number of medical conditions, and more follow-up contacts were associated with an increased likelihood of retention. Older age, more months in the registry, and more mobility problems decreased the likelihood of retention. Discussion: These results suggest the Michigan Center for Urban African American Aging Research logic model promotes retention through involving older African American adults in research through study referrals and intensive follow-up. The loss of participants due to age- and mobility-related issues indicate the registry may be losing its most vulnerable participants. PMID:28138501

  13. The Creative Brain.

    ERIC Educational Resources Information Center

    Herrmann, Ned

    1982-01-01

    Outlines the differences between left-brain and right-brain functioning and between left-brain and right-brain dominant individuals, and concludes that creativity uses both halves of the brain. Discusses how both students and curriculum can become more "whole-brained." (Author/JM)

  14. A 252 bp upstream region of the rat spermatocyte-specific hst70 gene is sufficient to promote expression of the hst70-CAT hybrid gene in testis and brain of transgenic mice.

    PubMed

    Widłak, W; Markkula, M; Krawczyk, Z; Kananen, K; Huhtaniemi, I

    1995-11-07

    The rat hst70 gene belongs to a heat shock hsp70 multigene family and its expression has been detected so far solely in spermatocytes. To investigate the cis-elements responsible for testis-specific expression of the hst70 gene we produced several lines of transgenic mice carrying fragments of the 5'-flanking regions of the hst70 gene fused to the chloramphenicol acetyltransferase (CAT) reporter gene. Hybrid genes of series B were constructed such that, besides the 780 bp, 343 bp and 163 bp 5'-flanking region these plasmids contained no other sequences of the hst70 gene. In hybrid genes of series D the CAT gene was ligated to 343 bp and 252 bp 5'-flanking regions together with the 57 bp of the 5'-end nontranslated (leader) sequences of the hst70 gene. We found that in 780/B, 343/B, 343/D and 252/D adult mice the transgene was specifically and highly expressed in testes. In developing testes the high CAT activity appeared in transgenic mice aged 3 weeks and older. None of the three 163/B transgenic lines exhibited CAT activity in any tissue analyzed. In all CAT expressing lines a weak but significant CAT activity (up to 5% of that in testis) was detected also in the brain. RNase protection assay confirmed that the endogenous hst70 gene transcripts are present in testis as well as in brain of nontransgenic rats and mice. Our data show that the cis-regulatory sequences responsible for testis-specific and developmentally regulated expression of the hst70 gene are localized within the 252 bp region 5' to the gene and neither the 5'-end nor 3'-end nontranslated sequences of the gene are important for this specificity.

  15. Martian 'Brain'

    NASA Technical Reports Server (NTRS)

    2004-01-01

    5 May 2004 Most middle-latitude craters on Mars have strange landforms on their floors. Often, the floors have pitted and convoluted features that lack simple explanation. In this case, the central part of the crater floor shown in this 2004 Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) image bears some resemblance to the folded nature of a brain. Or not. It depends upon the 'eye of the beholder,' perhaps. The light-toned 'ring' around the 'brain' feature is more easily explained--windblown ripples and dunes. The crater occurs near 33.1oS, 91.2oW, and is illuminated from the upper left. The picture covers an area about 3 km (1.9 mi) across.

  16. Silicon Brains

    NASA Astrophysics Data System (ADS)

    Hoefflinger, Bernd

    Beyond the digital neural networks of Chap. 16, the more radical mapping of brain-like structures and processes into VLSI substrates has been pioneered by Carver Mead more than 30 years ago [1]. The basic idea was to exploit the massive parallelism of such circuits and to create low-power and fault-tolerant information-processing systems. Neuromorphic engineering has recently seen a revival with the availability of deep-submicron CMOS technology, which allows for the construction of very-large-scale mixed-signal systems combining local analog processing in neuronal cells with binary signalling via action potentials. Modern implementations are able to reach the complexity-scale of large functional units of the human brain, and they feature the ability to learn by plasticity mechanisms found in neuroscience. Combined with high-performance programmable logic and elaborate software tools, such systems are currently evolving into user-configurable non-von-Neumann computing systems, which can be used to implement and test novel computational paradigms. The chapter introduces basic properties of biological brains with up to 200 Billion neurons and their 1014 synapses, where action on a synapse takes ˜10 ms and involves an energy of ˜10 fJ. We outline 10x programs on neuromorphic electronic systems in Europe and the USA, which are intended to integrate 108 neurons and 1012 synapses, the level of a cat's brain, in a volume of 1 L and with a power dissipation <1 kW. For a balanced view on intelligence, we references Hawkins' view to first perceive the task and then design an intelligent technical response.

  17. Brain imaging

    SciTech Connect

    Bradshaw, J.R.

    1989-01-01

    This book presents a survey of the various imaging tools with examples of the different diseases shown best with each modality. It includes 100 case presentations covering the gamut of brain diseases. These examples are grouped according to the clinical presentation of the patient: headache, acute headache, sudden unilateral weakness, unilateral weakness of gradual onset, speech disorders, seizures, pituitary and parasellar lesions, sensory disorders, posterior fossa and cranial nerve disorders, dementia, and congenital lesions.

  18. Animating Brains

    PubMed Central

    Borck, Cornelius

    2016-01-01

    A recent paper famously accused the rising field of social neuroscience of using faulty statistics under the catchy title ‘Voodoo Correlations in Social Neuroscience’. This Special Issue invites us to take this claim as the starting point for a cross-cultural analysis: in which meaningful ways can recent research in the burgeoning field of functional imaging be described as, contrasted with, or simply compared to animistic practices? And what light does such a reading shed on the dynamics and effectiveness of a century of brain research into higher mental functions? Reviewing the heated debate from 2009 around recent trends in neuroimaging as a possible candidate for current instances of ‘soul catching’, the paper will then compare these forms of primarily image-based brain research with older regimes, revolving around the deciphering of the brain’s electrical activity. How has the move from a decoding paradigm to a representational regime affected the conceptualisation of self, psyche, mind and soul (if there still is such an entity)? And in what ways does modern technoscience provide new tools for animating brains? PMID:27292322

  19. Neurorestorative Treatments for Traumatic Brain Injury

    PubMed Central

    Xiong, Ye; Mahmood, Asim; Chopp, Michael

    2011-01-01

    Traumatic brain injury (TBI) remains a major cause of death and permanent disability worldwide, especially in children and young adults. A total of 1.5 million people experience head trauma each year in the United States, with an annual economic cost exceeding $56 billion. Unfortunately, almost all Phase III TBI clinical trials have yet to yield a safe and effective neuroprotective treatment, raising questions regarding the use of neuroprotective strategies as the primary therapy for acute brain injuries. Recent preclinical data suggest that neurorestorative strategies that promote angiogenesis (formation of new blood vessels from pre-existing endothelial cells), axonal remodeling (axonal sprouting and pruning), neurogenesis (generation of new neurons) and synaptogenesis (formation of new synapses) provide promising opportunities for the treatment of TBI. This review discusses select cell-based and pharmacological therapies that activate and amplify these endogenous restorative brain plasticity processes to promote both repair and regeneration of injured brain tissue and functional recovery after TBI. PMID:21122475

  20. Gtx: a novel murine homeobox-containing gene, expressed specifically in glial cells of the brain and germ cells of testis, has a transcriptional repressor activity in vitro for a serum-inducible promoter.

    PubMed Central

    Komuro, I; Schalling, M; Jahn, L; Bodmer, R; Jenkins, N A; Copeland, N G; Izumo, S

    1993-01-01

    Although it is likely that a highly complex network of transcription factors acts in concert during mammalian brain development, relatively few such genes have been characterized to date. We describe here a novel murine homeobox gene, denoted Gtx, which in adult animals is specifically expressed within glial cells of the central nervous system, including the forebrain, and in germ cells of the testis. Gtx resides on chromosome 7 and does not cosegregate with any previously mapped homeobox gene. The amino acid sequence of the predicted protein encoded by Gtx is highly divergent from that of any other known homeobox genes. The Gtx homeodomain contains unique residues at positions predicted to contact DNA bases. It did not bind to known target sites for other homeobox genes in vitro but bound with high affinity to the MEF-2 motif, a binding site for the serum response factor-related proteins. GTX efficiently competed with RSRF to bind the MEF-2 element in vitro. Co-transfection of Gtx prevented the serum-induced activation of the MEF-2-containing reporter genes. Although the true biological role of Gtx is not known, these results suggest that Gtx is a novel cell-type specific homeobox gene that has the potential to act as a transcriptional repressor for a subset of serum-inducible genes. Images PMID:8096811

  1. Brain Imaging

    PubMed Central

    Racine, Eric; Bar-Ilan, Ofek; Illes, Judy

    2007-01-01

    Advances in neuroscience are increasingly intersecting with issues of ethical, legal, and social interest. This study is an analysis of press coverage of an advanced technology for brain imaging, functional magnetic resonance imaging, that has gained significant public visibility over the past ten years. Discussion of issues of scientific validity and interpretation dominated over ethical content in both the popular and specialized press. Coverage of research on higher order cognitive phenomena specifically attributed broad personal and societal meaning to neuroimages. The authors conclude that neuroscience provides an ideal model for exploring science communication and ethics in a multicultural context. PMID:17330151

  2. Fortress brain.

    PubMed

    Royall, Donald R

    2013-02-01

    Neurodegenerative diseases are associated with neuronal inclusions, comprised of protein aggregates. In Alzheimer's Disease (AD) and Lewy Body Disease (LBD) such lesions are distributed in a hierarchical retrograde transynaptic spatial pattern. This implies a retrograde transynaptic temporal propagation as well. There can be few explanations for this other than infectious agents (prions and viruses). This suggests that AD and LBD (at least) may have infectious origins. Transynaptic infiltration of the CNS along cranial nerve or other major projections, by one or more infectious agents has important implications. The clinical syndrome and natural history of each neurodegenerative disorder will reflect its portal of entry. There may be a different neurodegenerative syndrome for each cranial nerve or other portal of entry, and not all may manifest as "dementia". Each syndrome may be associated with more than one pathological lesion. Each pathology may be associated with several clinical syndromes. Host-parasite interactions are species specific. This may explain the rarity of AD-like pathology in most other older mammals. Over evolutionary timescales, the human brain should be adapted to predation by neurotropic agents. Viewed from this perspective, the prion-like pro-inflammatory and pro-apoptotic properties of β-amyloid and other proteins may be adaptive, and anti-microbial. Reductions in synaptic density may slow the progress of invading pathogens, while perineuronal nets and other structures may guard the gates. This suggests a defense in depth of a structure, the brain, that is inherently vulnerable to invasion along its neural networks.

  3. Entrainment of perceptually relevant brain oscillations by non-invasive rhythmic stimulation of the human brain.

    PubMed

    Thut, Gregor; Schyns, Philippe G; Gross, Joachim

    2011-01-01

    The notion of driving brain oscillations by directly stimulating neuronal elements with rhythmic stimulation protocols has become increasingly popular in research on brain rhythms. Induction of brain oscillations in a controlled and functionally meaningful way would likely prove highly beneficial for the study of brain oscillations, and their therapeutic control. We here review conventional and new non-invasive brain stimulation protocols as to their suitability for controlled intervention into human brain oscillations. We focus on one such type of intervention, the direct entrainment of brain oscillations by a periodic external drive. We review highlights of the literature on entraining brain rhythms linked to perception and attention, and point out controversies. Behaviourally, such entrainment seems to alter specific aspects of perception depending on the frequency of stimulation, informing models on the functional role of oscillatory activity. This indicates that human brain oscillations and function may be promoted in a controlled way by focal entrainment, with great potential for probing into brain oscillations and their causal role.

  4. Brain aneurysm repair - discharge

    MedlinePlus

    ... gov/pubmed/22556195 . Szeder V, Tateshima S, Duckwiler GR. Intracranial aneurysms and subarachnoid hemorrhage. In: Daroff RB, Jankovic J, ... chap 67. Read More Aneurysm in the brain Brain aneurysm repair Brain surgery Recovering after stroke Seizures Smoking - ...

  5. Traumatic Brain Injury

    MedlinePlus

    Traumatic brain injury (TBI) happens when a bump, blow, jolt, or other head injury causes damage to the brain. Every year, millions of people in the U.S. suffer brain injuries. More than half are bad enough that ...

  6. Pediatric Brain Tumor Foundation

    MedlinePlus

    ... you insights into your child's treatment. LEARN MORE Brain tumors and their treatment can be deadly so ... Pediatric Brain Tumor Foundation Board Read more >> Pediatric Brain Tumor Foundation 302 Ridgefield Court, Asheville, NC 28806 ...

  7. Brain-based Learning.

    ERIC Educational Resources Information Center

    Weiss, Ruth Palombo

    2000-01-01

    Discusses brain research and how new imaging technologies allow scientists to explore how human brains process memory, emotion, attention, patterning, motivation, and context. Explains how brain research is being used to revise learning theories. (JOW)

  8. Special Report: Brain Chemistry.

    ERIC Educational Resources Information Center

    Krassner, Michael B.

    1983-01-01

    Chemical actions in the brain result in cognitive, emotional, neuroendocrine, neuromuscular, and/or neurocirculatory effects. Developments in understanding brain chemistry are discussed, considering among others, neurotransmitter chemistry, neuropeptides, drugs and the brain, antidepressants, and actions of minor tranquilizers. (JN)

  9. Mild Traumatic Brain Injury

    MedlinePlus

    ... Questions Glossary Contact Us Visitor Feedback mild Traumatic Brain Injury mild Traumatic Brain Injury VIDEO STORIES What is TBI Measuring Severity ... most common deployment injuries is a mild Traumatic Brain Injury (TBI). A mild TBI is an injury ...

  10. Traumatic Brain Injury

    MedlinePlus

    ... brain to bump against the inside of your skull. Common TBIs, such as concussions, can happen during ... an object, like a bullet or piece of skull, pierces your brain. Symptoms of a traumatic brain ...

  11. That's Using Your Brain!

    ERIC Educational Resources Information Center

    Visser, Dana R.

    1996-01-01

    Discusses new adult learning theories, including those of Roger Sperry (left brain/right brain), Paul McLean (triune brain), and Howard Gardner (multiple intelligences). Relates adult learning theory to training. (JOW)

  12. American Brain Tumor Association

    MedlinePlus

    ... Molecule Read More ABTA News April 6, 2017 Chicago-Based American Brain Tumor Association’s Breakthrough for Brain ... Association 8550 W. Bryn Mawr Ave. Ste 550 Chicago, IL 60631 © 2014 American Brain Tumor Association Phone: ...

  13. Nourish Your Brain

    MedlinePlus

    ... Tags: brain, brain-healthy, cognitive decline, dementia, diet, exercise, health, lifestyle Family Health, Prevention and Wellness, Seniors, Staying Healthy December 2010 Copyright © American Academy of ...

  14. The Changed Brain: Teacher Awareness of Traumatic Brain Injury and Instruction Methods to Enhance Cognitive Processing in Mathematics

    ERIC Educational Resources Information Center

    Stahl, Judith M.

    2008-01-01

    Traumatic brain injury (TBI) has come to subjugate and exert its authority on education as some survivors re-enter the academic arena. A key component of a TBI student's academic success is dependent upon a teacher's awareness of the TBI learner and a willingness to modify curriculum to promote the uniqueness of the changed brain and therefore,…

  15. Designing Schools Based on Brain Research.

    ERIC Educational Resources Information Center

    Chermayeff, Peter; Townsend, Ted

    An audiotape explains an Iowa rainforest project that promotes experiential learning for children, and explores the effects of the physical environment on the brain. The project is a one-of-a-kind private/partnership that has created a fully integrated, seamless educational facility that combines a public school (prekindergarten through fifth…

  16. School Reentry Following Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Deidrick, Kathleen K. M.; Farmer, Janet E.

    2005-01-01

    Successful school reentry following traumatic brain injury (TBI) is critical to recovery. Physical, cognitive, behavioral, academic, and social problems can affect a child's school performance after a TBI. However, early intervention has the potential to improve child academic outcomes and promote effective coping with any persistent changes in…

  17. Left brain, right brain: facts and fantasies.

    PubMed

    Corballis, Michael C

    2014-01-01

    Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the "norm" of right-handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal.

  18. The shopping brain: math anxiety modulates brain responses to buying decisions.

    PubMed

    Jones, William J; Childers, Terry L; Jiang, Yang

    2012-01-01

    Metacognitive theories propose that consumers track fluency feelings when buying, which may have biological underpinnings. We explored this using event-related potential (ERP) measures as twenty high-math anxiety (High MA) and nineteen low-math anxiety (Low MA) consumers made buying decisions for promoted (e.g., 15% discount) and non-promoted products. When evaluating prices, ERP correlates of higher perceptual and conceptual fluency were associated with buys, however only for High MA females under no promotions. In contrast, High MA females and Low MA males demonstrated greater FN400 amplitude, associated with enhanced conceptual processing, to prices of buys relative to non-buys under promotions. Concurrent late positive component (LPC) differences under no promotions suggest discrepant retrieval processes during price evaluations between consumer groups. When making decisions to buy or not, larger (smaller) P3, sensitive to outcome responses in the brain, was associated with buying for High MA females (Low MA females) under promotions, an effect also present for males under no promotions. Thus, P3 indexed decisions to buy differently between anxiety groups, but only for promoted items among females and for no promotions among males. Our findings indicate that perceptual and conceptual processes interact with anxiety and gender to modulate brain responses during consumer choices.

  19. Healthy Aging Promotion through Neuroscientific Information-Based Strategies.

    PubMed

    Seinfeld, Sofia; Sanchez-Vives, Maria V

    2015-09-28

    To ensure the well-being of a rapidly growing elderly population, it is fundamental to find strategies to foster healthy brain aging. With this intention, we designed a program of scientific-based lectures aimed at dissemination by established neuroscientists about brain function, brain plasticity and how lifestyle influences the brain. We also carried out a pilot study on the impact of the lectures on attendees. The objective was to provide information to elderly people in order to encourage them to identify unhealthy and healthy daily habits, and more importantly, to promote behavioral changes towards healthy brain aging. Here we report on our experience. In order to determine the impact of the lectures in the daily routine of the attendees, we asked them to fill out questionnaires. Preliminary results indicate that neuroscientific information-based strategies can be a useful method to have a positive impact on the lives of elderly, increase their awareness on how to improve brain function and promote positive lifestyle modifications. Furthermore, based on self-reported data, we also found that through this strategy it is possible to promote behavioral changes related to nutrition, sleep, and realization of physical and cognitively stimulating activities. Finally, based on the results obtained, the importance of promoting self-efficacy and the empowerment of the older populations is highlighted.

  20. Healthy Aging Promotion through Neuroscientific Information-Based Strategies

    PubMed Central

    Seinfeld, Sofia; Sanchez-Vives, Maria V.

    2015-01-01

    To ensure the well-being of a rapidly growing elderly population, it is fundamental to find strategies to foster healthy brain aging. With this intention, we designed a program of scientific-based lectures aimed at dissemination by established neuroscientists about brain function, brain plasticity and how lifestyle influences the brain. We also carried out a pilot study on the impact of the lectures on attendees. The objective was to provide information to elderly people in order to encourage them to identify unhealthy and healthy daily habits, and more importantly, to promote behavioral changes towards healthy brain aging. Here we report on our experience. In order to determine the impact of the lectures in the daily routine of the attendees, we asked them to fill out questionnaires. Preliminary results indicate that neuroscientific information-based strategies can be a useful method to have a positive impact on the lives of elderly, increase their awareness on how to improve brain function and promote positive lifestyle modifications. Furthermore, based on self-reported data, we also found that through this strategy it is possible to promote behavioral changes related to nutrition, sleep, and realization of physical and cognitively stimulating activities. Finally, based on the results obtained, the importance of promoting self-efficacy and the empowerment of the older populations is highlighted. PMID:26426029

  1. Imaging brain development: the adolescent brain.

    PubMed

    Blakemore, Sarah-Jayne

    2012-06-01

    The past 15 years have seen a rapid expansion in the number of studies using neuroimaging techniques to investigate maturational changes in the human brain. In this paper, I review MRI studies on structural changes in the developing brain, and fMRI studies on functional changes in the social brain during adolescence. Both MRI and fMRI studies point to adolescence as a period of continued neural development. In the final section, I discuss a number of areas of research that are just beginning and may be the subject of developmental neuroimaging in the next twenty years. Future studies might focus on complex questions including the development of functional connectivity; how gender and puberty influence adolescent brain development; the effects of genes, environment and culture on the adolescent brain; development of the atypical adolescent brain; and implications for policy of the study of the adolescent brain.

  2. The plastic brain: neoliberalism and the neuronal self.

    PubMed

    Pitts-Taylor, Victoria

    2010-11-01

    Neuroscience-based representations and practices of the brain aimed at lay populations present the brain in ways that both affirm biological determinism and also celebrate plasticity, or the brain's ability to change structure and function. Popular uses of neuroscientific theories of brain plasticity are saturated with a neoliberal vision of the subject. Against more optimistic readings of plasticity, I view the popular deployment of plasticity through the framework of governmentality. I describe how popular brain discourse on plasticity opens up the brain to personal techniques of enhancement and risk avoidance, and how it promotes a neuronal self. I situate brain plasticity in a context of biomedical neoliberalism, where the engineering and modification of biological life is positioned as essential to selfhood and citizenship.

  3. Brain AVM (Arteriovenous Malformation)

    MedlinePlus

    ... a brain scan for another health issue or after the blood vessels rupture and cause bleeding in the brain (hemorrhage). Once diagnosed, a brain AVM can often be treated successfully to prevent complications, such as brain damage or stroke. Find out why Mayo Clinic is the best ...

  4. Exercise, nutrition and the brain.

    PubMed

    Meeusen, Romain

    2014-05-01

    Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related health disorders and can improve cognitive function. Exercise has been promoted as a possible prevention for neurodegenerative diseases. Exercise will have a positive influence on cognition and it increases the brain-derived neurotrophic factor, an essential neurotrophin. Several dietary components have been identified as having effects on cognitive abilities. In particular, polyphenols have been reported to exert their neuroprotective actions through the potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning, and cognitive function. Dietary factors can affect multiple brain processes by regulating neurotransmitter pathways, synaptic transmission, membrane fluidity, and signal-transduction pathways. Flavonols are part of the flavonoid family that is found in various fruits, cocoa, wine, tea and beans. Although the antioxidant effects of flavonols are well established in vitro, there is general agreement that flavonols have more complex actions in vivo. Several cross-sectional and longitudinal studies have shown that a higher intake of flavonoids from food may be associated with a better cognitive evolution. Whether this reflects a causal association remains to be elucidated. Several studies have tried to 'manipulate' the brain in order to postpone central fatigue. Most studies have clearly shown that in normal environmental circumstances these interventions are not easy to perform. There is accumulating evidence that rinsing the mouth with a carbohydrate solution will improve endurance performance. There is a need for additional well controlled studies to explore the possible impact of diet and nutrition on brain functioning.

  5. Lighting up the Brain with Songs and Stories

    ERIC Educational Resources Information Center

    Cooper, Shelly

    2010-01-01

    Songs and stories have a strong relationship to each other and have the capacity to boost brain development, increase vocabulary, and promote future academic success. The sounds and foundational structures of reading and singing provide young children with successful pathways for advancing language skills, increasing memory, and promoting emerging…

  6. Brain evolution by brain pathway duplication

    PubMed Central

    Chakraborty, Mukta; Jarvis, Erich D.

    2015-01-01

    Understanding the mechanisms of evolution of brain pathways for complex behaviours is still in its infancy. Making further advances requires a deeper understanding of brain homologies, novelties and analogies. It also requires an understanding of how adaptive genetic modifications lead to restructuring of the brain. Recent advances in genomic and molecular biology techniques applied to brain research have provided exciting insights into how complex behaviours are shaped by selection of novel brain pathways and functions of the nervous system. Here, we review and further develop some insights to a new hypothesis on one mechanism that may contribute to nervous system evolution, in particular by brain pathway duplication. Like gene duplication, we propose that whole brain pathways can duplicate and the duplicated pathway diverge to take on new functions. We suggest that one mechanism of brain pathway duplication could be through gene duplication, although other mechanisms are possible. We focus on brain pathways for vocal learning and spoken language in song-learning birds and humans as example systems. This view presents a new framework for future research in our understanding of brain evolution and novel behavioural traits. PMID:26554045

  7. Astrocytes in the epileptic brain.

    PubMed

    Wetherington, Jonathon; Serrano, Geidy; Dingledine, Ray

    2008-04-24

    The roles that astrocytes play in the evolution of abnormal network excitability in chronic neurological disorders involving brain injury, such as acquired epilepsy, are receiving renewed attention due to improved understanding of the molecular events underpinning the physiological functions of astrocytes. In epileptic tissue, evidence is pointing to enhanced chemical signaling and disrupted linkage between water and potassium balance by reactive astrocytes, which together conspire to enhance local synchrony in hippocampal microcircuits. Reactive astrocytes in epileptic tissue both promote and oppose seizure development through a variety of specific mechanisms; the new findings suggest several novel astrocyte-related targets for drug development.

  8. Astrocytes in the Epileptic Brain

    PubMed Central

    Wetherington, Jonathon; Serrano, Geidy; Dingledine, Ray

    2014-01-01

    The roles that astrocytes play in the evolution of abnormal network excitability in chronic neurological disorders involving brain injury, such as acquired epilepsy, are receiving renewed attention due to improved understanding of the molecular events underpinning the physiological functions of astrocytes. In epileptic tissue, evidence is pointing to enhanced chemical signaling and disrupted linkage between water and potassium balance by reactive astrocytes, which together conspire to enhance local synchrony in hippocampal microcircuits. Reactive astrocytes in epileptic tissue both promote and oppose seizure development through a variety of specific mechanisms; the new findings suggest several novel astrocyte-related targets for drug development. PMID:18439402

  9. Dysfunction of brain pericytes in chronic neuroinflammation.

    PubMed

    Persidsky, Yuri; Hill, Jeremy; Zhang, Ming; Dykstra, Holly; Winfield, Malika; Reichenbach, Nancy L; Potula, Raghava; Mukherjee, Abir; Ramirez, Servio H; Rom, Slava

    2016-04-01

    Brain pericytes are uniquely positioned within the neurovascular unit to provide support to blood brain barrier (BBB) maintenance. Neurologic conditions, such as HIV-1-associated neurocognitive disorder, are associated with BBB compromise due to chronic inflammation. Little is known about pericyte dysfunction during HIV-1 infection. We found decreased expression of pericyte markers in human brains from HIV-1-infected patients (even those on antiretroviral therapy). Using primary human brain pericytes, we assessed expression of pericyte markers (α1-integrin, α-smooth muscle actin, platelet-derived growth factor-B receptor β, CX-43) and found their downregulation after treatment with tumor necrosis factor-α (TNFα) or interleukin-1 β (IL-1β). Pericyte exposure to virus or cytokines resulted in decreased secretion of factors promoting BBB formation (angiopoietin-1, transforming growth factor-β1) and mRNA for basement membrane components. TNFα and IL-1β enhanced expression of adhesion molecules in pericytes paralleling increased monocyte adhesion to pericytes. Monocyte migration across BBB models composed of human brain endothelial cells and pericytes demonstrated a diminished rate in baseline migration compared to constructs composed only of brain endothelial cells. However, exposure to the relevant chemokine, CCL2, enhanced the magnitude of monocyte migration when compared to BBB models composed of brain endothelial cells only. These data suggest an important role of pericytes in BBB regulation in neuroinflammation.

  10. Epidemiology of Brain Tumors.

    PubMed

    McNeill, Katharine A

    2016-11-01

    Brain tumors are the commonest solid tumor in children, leading to significant cancer-related mortality. Several hereditary syndromes associated with brain tumors are nonfamilial. Ionizing radiation is a well-recognized risk factor for brain tumors. Several industrial exposures have been evaluated for a causal association with brain tumor formation but the results are inconclusive. A casual association between the common mutagens of tobacco, alcohol, or dietary factors has not yet been established. There is no clear evidence that the incidence of brain tumors has changed over time. This article presents the descriptive epidemiology of the commonest brain tumors of children and adults.

  11. Alternative promoters of Peg3 with maternal specificity

    PubMed Central

    Perera, Bambarendage P. U.; Kim, Joomyeong

    2016-01-01

    Peg3 (paternally expressed gene 3) is an imprinted gene localized within an evolutionarily conserved 500-kb domain in human chromosome 19q13.4 and mouse proximal chromosome 7. In the current study, we have identified three alternative promoters for mouse Peg3 and one alternative promoter for human PEG3. These alternative promoters are localized within the 200-kb upstream region of human and mouse PEG3, which is well conserved and thus predicted to harbor several cis-regulatory elements for the PEG3 domain. In the mouse, two of these alternative promoters drive maternal-specific expression of Peg3 specifically in the hypothalamus of the adult brain, while the remaining third promoter drives bi-allelic expression of Peg3 with a paternal bias only in the neonatal-stage brain. In human, an alternative transcript is also detected at relatively very low levels in adult brain and placenta. Overall, the identification of alternative promoters in both mouse and human models suggests that these alternative promoters may be functionally selected features for the PEG3 imprinted domain during mammalian evolution. PMID:27075691

  12. Developing a Promotional Video

    ERIC Educational Resources Information Center

    Epley, Hannah K.

    2014-01-01

    There is a need for Extension professionals to show clientele the benefits of their program. This article shares how promotional videos are one way of reaching audiences online. An example is given on how a promotional video has been used and developed using iMovie software. Tips are offered for how professionals can create a promotional video and…

  13. Yawning and Stretching Predict Brain Temperature Changes in Rats: Support for the Thermoregulatory Hypothesis

    PubMed Central

    Shoup-Knox, Melanie L.; Gallup, Andrew C.; Gallup, Gordon G.; McNay, Ewan C.

    2010-01-01

    Recent research suggests that yawning is an adaptive behavior that functions to promote brain thermoregulation among homeotherms. To explore the relationship between brain temperature and yawning we implanted thermocoupled probes in the frontal cortex of rats to measure brain temperature before, during and after yawning. Temperature recordings indicate that yawns and stretches occurred during increases in brain temperature, with brain temperatures being restored to baseline following the execution of each of these behaviors. The circulatory changes that accompany yawning and stretching may explain some of the thermal similarities surrounding these events. These results suggest that yawning and stretching may serve to maintain brain thermal homeostasis. PMID:21031034

  14. Understanding brain networks and brain organization

    NASA Astrophysics Data System (ADS)

    Pessoa, Luiz

    2014-09-01

    What is the relationship between brain and behavior? The answer to this question necessitates characterizing the mapping between structure and function. The aim of this paper is to discuss broad issues surrounding the link between structure and function in the brain that will motivate a network perspective to understanding this question. However, as others in the past, I argue that a network perspective should supplant the common strategy of understanding the brain in terms of individual regions. Whereas this perspective is needed for a fuller characterization of the mind-brain, it should not be viewed as panacea. For one, the challenges posed by the many-to-many mapping between regions and functions is not dissolved by the network perspective. Although the problem is ameliorated, one should not anticipate a one-to-one mapping when the network approach is adopted. Furthermore, decomposition of the brain network in terms of meaningful clusters of regions, such as the ones generated by community-finding algorithms, does not by itself reveal "true" subnetworks. Given the hierarchical and multi-relational relationship between regions, multiple decompositions will offer different "slices" of a broader landscape of networks within the brain. Finally, I described how the function of brain regions can be characterized in a multidimensional manner via the idea of diversity profiles. The concept can also be used to describe the way different brain regions participate in networks.

  15. NONINVASIVE BRAIN STIMULATION IN TRAUMATIC BRAIN INJURY

    PubMed Central

    Demirtas-Tatlidede, Asli; Vahabzadeh-Hagh, Andrew M.; Bernabeu, Montserrat; Tormos, Jose M.; Pascual-Leone, Alvaro

    2012-01-01

    Brain stimulation techniques have evolved in the last few decades with more novel methods capable of painless, noninvasive brain stimulation. While the number of clinical trials employing noninvasive brain stimulation continues to increase in a variety of medication-resistant neurological and psychiatric diseases, studies evaluating their diagnostic and therapeutic potential in traumatic brain injury (TBI) are largely lacking. This review introduces different techniques of noninvasive brain stimulation, which may find potential use in TBI. We cover transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), low-level laser therapy (LLLT) and transcranial doppler sonography (TCD) techniques. We provide a brief overview of studies to date, discuss possible mechanisms of action, and raise a number of considerations when thinking about translating these methods to clinical use. PMID:21691215

  16. Modulating brain oscillations to drive brain function.

    PubMed

    Thut, Gregor

    2014-12-01

    Do neuronal oscillations play a causal role in brain function? In a study in this issue of PLOS Biology, Helfrich and colleagues address this long-standing question by attempting to drive brain oscillations using transcranial electrical current stimulation. Remarkably, they were able to manipulate visual perception by forcing brain oscillations of the left and right visual hemispheres into synchrony using oscillatory currents over both hemispheres. Under this condition, human observers more often perceived an inherently ambiguous visual stimulus in one of its perceptual instantiations. These findings shed light on the mechanisms underlying neuronal computation. They show that it is the neuronal oscillations that drive the visual experience, not the experience driving the oscillations. And they indicate that synchronized oscillatory activity groups brain areas into functional networks. This points to new ways for controlled experimental and possibly also clinical interventions for the study and modulation of brain oscillations and associated functions.

  17. Modulating Brain Oscillations to Drive Brain Function

    PubMed Central

    Thut, Gregor

    2014-01-01

    Do neuronal oscillations play a causal role in brain function? In a study in this issue of PLOS Biology, Helfrich and colleagues address this long-standing question by attempting to drive brain oscillations using transcranial electrical current stimulation. Remarkably, they were able to manipulate visual perception by forcing brain oscillations of the left and right visual hemispheres into synchrony using oscillatory currents over both hemispheres. Under this condition, human observers more often perceived an inherently ambiguous visual stimulus in one of its perceptual instantiations. These findings shed light on the mechanisms underlying neuronal computation. They show that it is the neuronal oscillations that drive the visual experience, not the experience driving the oscillations. And they indicate that synchronized oscillatory activity groups brain areas into functional networks. This points to new ways for controlled experimental and possibly also clinical interventions for the study and modulation of brain oscillations and associated functions. PMID:25549340

  18. Left Brain, Right Brain: Facts and Fantasies

    PubMed Central

    Corballis, Michael C.

    2014-01-01

    Summary Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the “norm” of right-handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal. PMID:24465175

  19. Brain aneurysm repair

    MedlinePlus

    ... aneurysm repair; Dissecting aneurysm repair; Endovascular aneurysm repair - brain; Subarachnoid hemorrhage - aneurysm ... Your scalp, skull, and the coverings of the brain are opened. A metal clip is placed at ...

  20. Children's Brain Tumor Foundation

    MedlinePlus

    ... CBTF Justin's Hope Fund Grant Recipients Grants Children’s Brain Tumor Foundation, A non-profit organization, was founded ... and the long term outlook for children with brain and spinal cord tumors through research, support, education, ...

  1. Genetic Brain Disorders

    MedlinePlus

    A genetic brain disorder is caused by a variation or a mutation in a gene. A variation is a different form ... mutation is a change in a gene. Genetic brain disorders affect the development and function of the ...

  2. Childhood Brain Tumors

    MedlinePlus

    Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

  3. Brain cancer spreads.

    PubMed

    Perryman, Lara; Erler, Janine T

    2014-07-30

    The discovery that ~20% of patients with brain cancer have circulating tumor cells breaks the dogma that these cells are confined to the brain and has important clinical implications (Müller et al., this issue).

  4. Biophysics: Unfolding the brain

    NASA Astrophysics Data System (ADS)

    Kuhl, Ellen

    2016-06-01

    The folded surface of the human brain, although striking, continues to evade understanding. Experiments with swelling gels now fuel the notion that brain folding is modulated by physical forces, and not by genetic, biological or chemical events alone.

  5. Brain Training for Seniors

    MedlinePlus

    ... than 65, stimulating your brain with activities and games can keep your mind sharp later in life ( ... you currently have some form of dementia, brain games and “active mind” activity can still help.There ...

  6. Regulation of the nascent brain vascular network by neural progenitors.

    PubMed

    Santhosh, Devi; Huang, Zhen

    2015-11-01

    Neural progenitors are central players in the development of the brain neural circuitry. They not only produce the diverse neuronal and glial cell types in the brain, but also guide their migration in this process. Recent evidence indicates that neural progenitors also play a critical role in the development of the brain vascular network. At an early stage, neural progenitors have been found to facilitate the ingression of blood vessels from outside the neural tube, through VEGF and canonical Wnt signaling. Subsequently, neural progenitors directly communicate with endothelial cells to stabilize nascent brain vessels, in part through down-regulating Wnt pathway activity. Furthermore, neural progenitors promote nascent brain vessel integrity, through integrin αvβ8-dependent TGFβ signaling. In this review, we will discuss the evidence for, as well as questions that remain, regarding these novel roles of neural progenitors and the underlying mechanisms in their regulation of the nascent brain vascular network.

  7. Operation Brain Trauma Therapy

    DTIC Science & Technology

    2014-10-01

    et al. Statins and neuroprotectants: A comparatife in vitro study of lipopholicity, blood-brain barrier penetration, lowering of brain cholesterol ...heterogeneous disease involving multiple brain injury phenotypes and that success of an agent tested across multiple established TBI models using an...coenzyme A (HMG CoA) reductase inhibitor Simvastatin reduces serum cholesterol but also inhibits neuro-inflammation and has possible effects on brain

  8. NASA Robot Brain Surgeon

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Mechanical Engineer Michael Guerrero works on the Robot Brain Surgeon testbed in the NeuroEngineering Group at the Ames Research Center, Moffett Field, California. Principal investigator Dr. Robert W. Mah states that potentially the simple robot will be able to feel brain structures better than any human surgeon, making slow, very precise movements during an operation. The brain surgery robot that may give surgeons finer control of surgical instruments during delicate brain operations is still under development.

  9. Brain Death Determination.

    PubMed

    Spinello, Irene M

    2015-09-01

    In the United States, each year 1% to 2% of deaths are brain deaths. Considerable variation in the practice of determining brain death still remains, despite the publication of practice parameters in 1995 and an evidence-based guideline update in 2010. This review is intended to give bedside clinicians an overview of definition, the causes and pitfalls of misdiagnosing brain death, and a focus on the specifics of the brain death determination process.

  10. Your Brain and Nervous System

    MedlinePlus

    ... los dientes Video: Getting an X-ray Your Brain & Nervous System KidsHealth > For Kids > Your Brain & Nervous ... The coolest wetsuit? Nope — he needs his cerebellum! Brain Stem Keeps You Breathing — and More Another brain ...

  11. Primary lymphoma of the brain

    MedlinePlus

    Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

  12. Your Brain and Nervous System

    MedlinePlus

    ... Room? What Happens in the Operating Room? Your Brain & Nervous System KidsHealth > For Kids > Your Brain & Nervous ... The coolest wetsuit? Nope — he needs his cerebellum! Brain Stem Keeps You Breathing — and More Another brain ...

  13. Brain and Language.

    ERIC Educational Resources Information Center

    Damasio, Antonio R., Damasio, Hanna

    1992-01-01

    Discusses the advances made in understanding the brain structures responsible for language. Presents findings made using magnetic resonance imaging (MRI) and positron emission tomographic (PET) scans to study brain activity. These findings map the structures in the brain that manipulate concepts and those that turn concepts into words. (MCO)

  14. Brain Migration Revisited

    ERIC Educational Resources Information Center

    Vinokur, Annie

    2006-01-01

    The "brain drain/brain gain" debate has been going on for the past 40 years, with irresolvable theoretical disputes and unenforceable policy recommendations that economists commonly ascribe to the lack of reliable empirical data. The recent report of the World Bank, "International migration, remittances and the brain drain", documents the…

  15. Our Amazing Brains

    ERIC Educational Resources Information Center

    Bath, Howard

    2005-01-01

    This article begins a regular series on how brain research can help us understand young people and ourselves as well. The intent is to alert the reader to important information from recent research on the brain. This initial installment explores the concept of the triune brain, a term coined by neuroscientist Paul MacLean. This refers to three…

  16. Australian Brain Alliance.

    PubMed

    2016-11-02

    A proposal for an Australian Brain Initiative (ABI) is under development by members of the Australian Brain Alliance. Here we discuss the goals of the ABI, its areas of research focus, its context in the Australian research setting, and its necessity for ensuring continued success for Australian brain research.

  17. Brain Research and Learning.

    ERIC Educational Resources Information Center

    Claycomb, Mary

    Current research on brain activity has many implications for educators. The triune brain concept and the left and right hemisphere concepts are among the many complex theories evolving from experimentation and observation. The triune brain concept suggests that the human forebrain has expanded while retaining three structurally unique formations…

  18. Whither brain death?

    PubMed

    Bernat, James L

    2014-01-01

    The publicity surrounding the recent McMath and Muñoz cases has rekindled public interest in brain death: the familiar term for human death determination by showing the irreversible cessation of clinical brain functions. The concept of brain death was developed decades ago to permit withdrawal of therapy in hopeless cases and to permit organ donation. It has become widely established medical practice, and laws permit it in all U.S. jurisdictions. Brain death has a biophilosophical justification as a standard for determining human death but remains poorly understood by the public and by health professionals. The current controversies over brain death are largely restricted to the academy, but some practitioners express ambivalence over whether brain death is equivalent to human death. Brain death remains an accepted and sound concept, but more work is necessary to establish its biophilosophical justification and to educate health professionals and the public.

  19. Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brain-related disorders.

    PubMed

    Sibille, Etienne

    2013-03-01

    The increased risk for neurodegenerative and neuropsychiatric disorders associated with extended lifespan has long suggested mechanistic links between chronological age and brain-related disorders, including depression, Recent characterizations of age-dependent gene expression changes now show that aging of the human brain engages a specific set of biological pathways along a continuous lifelong trajectory, and that the same genes that are associated with normal brain aging are also frequently and similarly implicated in depression and other brain-related disorders. These correlative observations suggest a model of age-by-disease molecular interactions, in which brain aging promotes biological changes associated with diseases, and additional environmental factors and genetic variability contribute to defining disease risk or resiliency trajectories. Here we review the characteristic features of brain aging in terms of changes in gene function over time, and then focus on evidence supporting accelerated molecular aging in depression. This proposed age-by-disease biological interaction model addresses the current gap in research between "normal" brain aging and its connection to late-life diseases. The implications of this model are profound, as it provides an investigational framework for identifying critical moderating factors, outlines opportunities for early interventions or preventions, and may form the basis for a dimensional definition of diseases that goes beyond the current categorical system.

  20. Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer.

    PubMed

    Wu, Kerui; Fukuda, Koji; Xing, Fei; Zhang, Yingyu; Sharma, Sambad; Liu, Yin; Chan, Michael D; Zhou, Xiaobo; Qasem, Shadi A; Pochampally, Radhika; Mo, Yin-Yuan; Watabe, Kounosuke

    2015-04-10

    Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.

  1. Brain pathways to recovery from alcohol dependence.

    PubMed

    Cui, Changhai; Noronha, Antonio; Warren, Kenneth R; Koob, George F; Sinha, Rajita; Thakkar, Mahesh; Matochik, John; Crews, Fulton T; Chandler, L Judson; Pfefferbaum, Adolf; Becker, Howard C; Lovinger, David; Everitt, Barry J; Egli, Mark; Mandyam, Chitra D; Fein, George; Potenza, Marc N; Harris, R Adron; Grant, Kathleen A; Roberto, Marisa; Meyerhoff, Dieter J; Sullivan, Edith V

    2015-08-01

    This article highlights the research presentations at the satellite symposium on "Brain Pathways to Recovery from Alcohol Dependence" held at the 2013 Society for Neuroscience Annual Meeting. The purpose of this symposium was to provide an up to date overview of research efforts focusing on understanding brain mechanisms that contribute to recovery from alcohol dependence. A panel of scientists from the alcohol and addiction research field presented their insights and perspectives on brain mechanisms that may underlie both recovery and lack of recovery from alcohol dependence. The four sessions of the symposium encompassed multilevel studies exploring mechanisms underlying relapse and craving associated with sustained alcohol abstinence, cognitive function deficit and recovery, and translational studies on preventing relapse and promoting recovery. Gaps in our knowledge and research opportunities were also discussed.

  2. Brain Pathways to Recovery from Alcohol Dependence

    PubMed Central

    Cui, Changhai; Noronha, Antonio; Warren, Kenneth; Koob, George F.; Sinha, Rajita; Thakkar, Mahesh; Matochik, John; Crews, Fulton T.; Chandler, L. Judson; Pfefferbaum, Adolf; Becker, Howard C.; Lovinger, David; Everitt, Barry; Egli, Mark; Mandyam, Chitra; Fein, George; Potenza, Marc N.; Harris, R. Adron; Grant, Kathleen A.; Roberto, Marisa; Meyerhoff, Dieter J.; Sullivan, Edith V.

    2015-01-01

    This article highlights the research presentations at the satellite symposium on “Brain Pathways to Recovery from Alcohol Dependence” held at the 2013 Society for Neuroscience Annual Meeting. The purpose of this symposium was to provide an up to date overview of research efforts focusing on understanding brain mechanisms that contribute to recovery from alcohol dependence. A panel of scientists from the alcohol and addiction research field presented their insights and perspectives on brain mechanisms that may underlie both recovery and lack of recovery from alcohol dependence. The four sessions of the symposium encompassed multilevel studies exploring mechanisms underlying relapse and craving associated with sustained alcohol abstinence, cognitive function deficit and recovery, and translational studies on preventing relapse and promoting recovery. Gaps in our knowledge and research opportunities were also discussed. PMID:26074423

  3. Health promotion in Brazil.

    PubMed

    Buss, Paulo Marchiori; de Carvalho, Antonio Ivo

    2007-01-01

    The evolution of health promotion within the Brazilian health system is examined, including an assessment of the intersectoral and development policies that have influenced the process. Particular attention is paid to the legal characteristics of the Unified Health System. Human resources formation and research initiatives in health promotion are outlined, with a summary of the obstacles that need to be overcome in order to ensure the effective implementation of health promotion in the future. Up to the end of the 20th Century health promotion was not used as a term in the Brazilian public heath context. Health promoting activities were concentrated in the area of health education, although targeting the social determinants of health and the principle of intersectoral action were part of the rhetoric. The situation has changed during the last decade, with the publication of a national policy of health promotion, issued by the Ministry of Health and jointly implemented with the States and Municipals Health Secretaries. More recently there has been a re-emergence of the discourse on the social determinants of health and the formation of intersectoral public policies as the basis of a comprehensive health promotion. Health promotion infrastructure, particularly around human resources and financing, requires strengthening in order to ensure capacity and sustainability in health promotion practice.

  4. Brain plasticity in the developing brain.

    PubMed

    Kolb, Bryan; Mychasiuk, Richelle; Muhammad, Arif; Gibb, Robbin

    2013-01-01

    The developing normal brain shows a remarkable capacity for plastic change in response to a wide range of experiences including sensory and motor experience, psychoactive drugs, parent-child relationships, peer relationships, stress, gonadal hormones, intestinal flora, diet, and injury. The effects of injury vary with the precise age-at-injury, with the general result being that injury during cell migration and neuronal maturation has a poor functional outcome, whereas similar injury during synaptogenesis has a far better outcome. A variety of factors influence functional outcome including the nature of the behavior in question and the age at behavioral assessment as well as pre- and postinjury experiences. Here, we review the phases of brain development, how factors influence brain, and behavioral development in both the normal and perturbed brain, and propose mechanisms that may underlie these effects.

  5. High expression Zymomonas promoters

    DOEpatents

    Viitanen, Paul V.; Tao, Luan; Zhang, Yuying; Caimi, Perry G.; McCole, Laura : Zhang, Min; Chou, Yat-Chen; McCutchen, Carol M.; Franden, Mary Ann

    2011-08-02

    Identified are mutants of the promoter of the Z. mobilis glyceraldehyde-3-phosphate dehydrogenase gene, which direct improved expression levels of operably linked heterologous nucleic acids. These are high expression promoters useful for expression of chimeric genes in Zymomonas, Zymobacter, and other related bacteria.

  6. Health Promotion Program.

    ERIC Educational Resources Information Center

    McClary, Cheryl

    The Health Promotion Program began with establishment of a one-credit course in health promotion and wellness and the training of family practice residents at the Mountain Area Health Education Center to serve as lab leaders in the course. The course later became part of the university's general education requirements. In addition, a health…

  7. Promoting Resilience in Children.

    ERIC Educational Resources Information Center

    Rolfe, Sharne A.

    2002-01-01

    This booklet invites reflection on ways in which childhood resilience can be promoted, thereby helping children to adapt effectively in the face of adversity. The attributes of resilient children are described, as is the importance of protective factors in building or promoting resilience. The booklet discusses the complex interplay between risk…

  8. Brain iron homeostasis.

    PubMed

    Moos, Torben

    2002-11-01

    Iron is essential for virtually all types of cells and organisms. The significance of the iron for brain function is reflected by the presence of receptors for transferrin on brain capillary endothelial cells. The transport of iron into the brain from the circulation is regulated so that the extraction of iron by brain capillary endothelial cells is low in iron-replete conditions and the reverse when the iron need of the brain is high as in conditions with iron deficiency and during development of the brain. Whereas there is good agreement that iron is taken up by means of receptor-mediated uptake of iron-transferrin at the brain barriers, there are contradictory views on how iron is transported further on from the brain barriers and into the brain extracellular space. The prevailing hypothesis for transport of iron across the BBB suggests a mechanism that involves detachment of iron from transferrin within barrier cells followed by recycling of apo-transferrin to blood plasma and release of iron as non-transferrin-bound iron into the brain interstitium from where the iron is taken up by neurons and glial cells. Another hypothesis claims that iron-transferrin is transported into the brain by means of transcytosis through the BBB. This thesis deals with the topic "brain iron homeostasis" defined as the attempts to maintain constant concentrations of iron in the brain internal environment via regulation of iron transport through brain barriers, cellular iron uptake by neurons and glia, and export of iron from brain to blood. The first part deals with transport of iron-transferrin complexes from blood to brain either by transport across the brain barriers or by uptake and retrograde axonal transport in motor neurons projecting beyond the blood-brain barrier. The transport of iron and transport into the brain was examined using radiolabeled iron-transferrin. Intravenous injection of [59Fe-125]transferrin led to an almost two-fold higher accumulation of 59Fe than of

  9. Experimental traumatic brain injury

    PubMed Central

    2010-01-01

    Traumatic brain injury, a leading cause of death and disability, is a result of an outside force causing mechanical disruption of brain tissue and delayed pathogenic events which collectively exacerbate the injury. These pathogenic injury processes are poorly understood and accordingly no effective neuroprotective treatment is available so far. Experimental models are essential for further clarification of the highly complex pathology of traumatic brain injury towards the development of novel treatments. Among the rodent models of traumatic brain injury the most commonly used are the weight-drop, the fluid percussion, and the cortical contusion injury models. As the entire spectrum of events that might occur in traumatic brain injury cannot be covered by one single rodent model, the design and choice of a specific model represents a major challenge for neuroscientists. This review summarizes and evaluates the strengths and weaknesses of the currently available rodent models for traumatic brain injury. PMID:20707892

  10. Brain evolution triggers increased diversification of electric fishes.

    PubMed

    Carlson, Bruce A; Hasan, Saad M; Hollmann, Michael; Miller, Derek B; Harmon, Luke J; Arnegard, Matthew E

    2011-04-29

    Communication can contribute to the evolution of biodiversity by promoting speciation and reinforcing reproductive isolation between existing species. The evolution of species-specific signals depends on the ability of individuals to detect signal variation, which in turn relies on the capability of the brain to process signal information. Here, we show that evolutionary change in a region of the brain devoted to the analysis of communication signals in mormyrid electric fishes improved detection of subtle signal variation and resulted in enhanced rates of signal evolution and species diversification. These results show that neural innovations can drive the diversification of signals and promote speciation.

  11. Brain 'imaging' in the Renaissance.

    PubMed

    Paluzzi, Alessandro; Belli, Antonio; Bain, Peter; Viva, Laura

    2007-12-01

    During the Renaissance, a period of 'rebirth' for humanities and science, new knowledge and speculation began to emerge about the function of the human body, replacing ancient religious and philosophical dogma. The brain must have been a fascinating mystery to a Renaissance artist, but some speculation existed at that time on the function of its parts. Here we show how revived interest in anatomy and life sciences may have influenced the figurative work of Italian and Flemish masters, such as Rafael, Michelangelo and David. We present a historical perspective on the artists and the period in which they lived, their fascination for human anatomy and its symbolic use in their art. Prior to the 16th century, knowledge of the brain was limited and influenced in a dogmatic way by the teachings of Galen(1) who, as we now know, conducted his anatomical studies not on humans but on animals.(2) Nemesus, Bishop of Emesa, in around the year 400 was one of the first to attribute mental faculties to the brain, specifically to the ventricles. He identified two anterior (lateral) ventricles, to which he assigned perception, a middle ventricle responsible for cognition and a posterior ventricle for memory.(2,3) After a long period of stasis in the Middle Ages, Renaissance scholars realized the importance of making direct observations on dissected cadavers. Between 1504 and 1507, Leonardo da Vinci conducted experiments to reveal the anatomy of the ventricular system in the brain. He injected hot wax through a tube thrust into the ventricular cavities of an ox and then scraped the overlying brain off, thus obtaining, in a simple but ingenious way, an accurate cast of the ventricles.(2,4) Leonardo shared the belief promoted by scholarly Christians that the ventricles were the abode of rational soul. We have several examples of hidden symbolism in Renaissance paintings, but the influence of phrenology and this rudimentary knowledge of neuroanatomy on artists of that period is under

  12. Sex and Tissue Specificity of Peg3 Promoters

    PubMed Central

    Perera, Bambarendage P. U.; Kim, Joomyeong

    2016-01-01

    The expression of mouse Peg3 (Paternally expressed gene 3) is driven by 4 promoters, including its main and three alternative promoters. The sexual, temporal and spatial specificity of these promoters was characterized in the current study. According to the results, the main promoter displays ubiquitous expression patterns throughout different stages and tissues. In contrast, the expression of Peg3 driven by the alternative promoter U2 was detected mainly in muscle and skin, but not in brain, starting from the late embryonic stage, revealing its tissue and stage specificity. The expression levels of both the main and U2 promoters are also sexually biased: the levels in females start higher but become lower than those in males during early postnatal stages. As an imprinted locus, the paternal alleles of these promoters are active whereas the maternal alleles are silent. Interestingly, deletion of the repressed maternal allele of the main promoter has an unusual effect on the opposite paternal allele, causing the up-regulation of both the main and U2 promoters. Overall, the promoters of Peg3 derive sexually biased and tissue-specific expression patterns. PMID:27711129

  13. Left Brain, Right Brain, Super Brain: The Holistic Model.

    ERIC Educational Resources Information Center

    Yellin, David

    Recent discoveries about the whole brain seem to call for a holistic approach to learning, one in which educators would teach the whole person, including physical and emotional states as well as cognitive abilities. Three holistic techniques are particularly relevant to education: (1) biofeedback; (2) yoga; and (3) the Lozanov method. Biofeedback…

  14. [Effectiveness of music in brain rehabilitation. A systematic review].

    PubMed

    Sihvonen, Aleksi J; Leo, Vera; Särkämö, Teppo; Soinila, Seppo

    2014-01-01

    There is no curative treatment for diseases causing brain injury. Music causes extensive activation of the brain, promoting the repair of neural systems. Addition of music listening to rehabilitation enhances the regulation or motor functions in Parkinson and stroke patients, accelerates the recovery of speech disorder and cognitive injuries after stroke, and decreases the behavioral disorders of dementia patients. Music enhances the ability to concentrate and decreases mental confusion. The effect of music can also be observed as structural and functional changes of the brain. The effect is based, among other things, on lessening of physiologic stress and depression and on activation of the dopaminergic mesolimbic system.

  15. Can we observe epigenetic effects on human brain function?

    PubMed

    Nikolova, Yuliya S; Hariri, Ahmad R

    2015-07-01

    Imaging genetics has identified many contributions of DNA sequence variation to individual differences in brain function, behavior, and risk for psychopathology. Recent studies have extended this work beyond the genome by mapping epigenetic differences, specifically gene methylation in peripherally assessed DNA, onto variability in behaviorally and clinically relevant brain function. These data have generated understandable enthusiasm for the potential of such research to illuminate biological mechanisms of risk. We use our research on the effects of genetic and epigenetic variation in the human serotonin transporter on brain function to generate a guardedly optimistic opinion that the available data encourage continued research in this direction, and suggest strategies to promote faster progress.

  16. Mechanisms of action of brain insulin against neurodegenerative diseases.

    PubMed

    Ramalingam, Mahesh; Kim, Sung-Jin

    2014-06-01

    Insulin, a pancreatic hormone, is best known for its peripheral effects on the metabolism of glucose, fats and proteins. There is a growing body of evidence linking insulin action in the brain to neurodegenerative diseases. Insulin present in central nervous system is a regulator of central glucose metabolism nevertheless this glucoregulation is not the main function of insulin in the brain. Brain is known to be specifically vulnerable to oxidative products relative to other organs and altered brain insulin signaling may cause or promote neurodegenerative diseases which invalidates and reduces the quality of life. Insulin located within the brain is mostly of pancreatic origin or is produced in the brain itself crosses the blood-brain barrier and enters the brain via a receptor-mediated active transport system. Brain Insulin, insulin receptor and insulin receptor substrate-mediated signaling pathways play important roles in the regulation of peripheral metabolism, feeding behavior, memory and maintenance of neural functions such as neuronal growth and differentiation, neuromodulation and neuroprotection. In the present review, we would like to summarize the novel biological and pathophysiological roles of neuronal insulin in neurodegenerative diseases and describe the main signaling pathways in use for therapeutic strategies in the use of insulin to the cerebral tissues and their biological applications to neurodegenerative diseases.

  17. FACS purification of immunolabeled cell types from adult rat brain.

    PubMed

    Guez-Barber, Danielle; Fanous, Sanya; Harvey, Brandon K; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G; Picciotto, Marina R; Hope, Bruce T

    2012-01-15

    Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience.

  18. Consciousness, brain, neuroplasticity

    PubMed Central

    Askenasy, Jean; Lehmann, Joseph

    2013-01-01

    Subjectivity, intentionality, self-awareness and will are major components of consciousness in human beings. Changes in consciousness and its content following different brain processes and malfunction have long been studied. Cognitive sciences assume that brain activities have an infrastructure, but there is also evidence that consciousness itself may change this infrastructure. The two-way influence between brain and consciousness has been at the center of philosophy and less so, of science. This so-called bottom-up and top-down interrelationship is controversial and is the subject of our article. We would like to ask: how does it happen that consciousness may provoke structural changes in the brain? The living brain means continuous changes at the synaptic level with every new experience, with every new process of learning, memorizing or mastering new and existing skills. Synapses are generated and dissolved, while others are preserved, in an ever-changing process of so-called neuroplasticity. Ongoing processes of synaptic reinforcements and decay occur during wakefulness when consciousness is present, but also during sleep when it is mostly absent. We suggest that consciousness influences brain neuroplasticity both during wakefulness as well as sleep in a top-down way. This means that consciousness really activates synaptic flow and changes brain structures and functional organization. The dynamic impact of consciousness on brain never stops despite the relative stationary structure of the brain. Such a process can be a target for medical intervention, e.g., by cognitive training. PMID:23847580

  19. Brain Stimulation in Addiction.

    PubMed

    Salling, Michael C; Martinez, Diana

    2016-11-01

    Localized stimulation of the human brain to treat neuropsychiatric disorders has been in place for over 20 years. Although these methods have been used to a greater extent for mood and movement disorders, recent work has explored brain stimulation methods as potential treatments for addiction. The rationale behind stimulation therapy in addiction involves reestablishing normal brain function in target regions in an effort to dampen addictive behaviors. In this review, we present the rationale and studies investigating brain stimulation in addiction, including transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Overall, these studies indicate that brain stimulation has an acute effect on craving for drugs and alcohol, but few studies have investigated the effect of brain stimulation on actual drug and alcohol use or relapse. Stimulation therapies may achieve their effect through direct or indirect modulation of brain regions involved in addiction, either acutely or through plastic changes in neuronal transmission. Although these mechanisms are not well understood, further identification of the underlying neurobiology of addiction and rigorous evaluation of brain stimulation methods has the potential for unlocking an effective, long-term treatment of addiction.

  20. Consciousness, brain, neuroplasticity.

    PubMed

    Askenasy, Jean; Lehmann, Joseph

    2013-01-01

    Subjectivity, intentionality, self-awareness and will are major components of consciousness in human beings. Changes in consciousness and its content following different brain processes and malfunction have long been studied. Cognitive sciences assume that brain activities have an infrastructure, but there is also evidence that consciousness itself may change this infrastructure. The two-way influence between brain and consciousness has been at the center of philosophy and less so, of science. This so-called bottom-up and top-down interrelationship is controversial and is the subject of our article. We would like to ask: how does it happen that consciousness may provoke structural changes in the brain? The living brain means continuous changes at the synaptic level with every new experience, with every new process of learning, memorizing or mastering new and existing skills. Synapses are generated and dissolved, while others are preserved, in an ever-changing process of so-called neuroplasticity. Ongoing processes of synaptic reinforcements and decay occur during wakefulness when consciousness is present, but also during sleep when it is mostly absent. We suggest that consciousness influences brain neuroplasticity both during wakefulness as well as sleep in a top-down way. This means that consciousness really activates synaptic flow and changes brain structures and functional organization. The dynamic impact of consciousness on brain never stops despite the relative stationary structure of the brain. Such a process can be a target for medical intervention, e.g., by cognitive training.

  1. The anatomical problem posed by brain complexity and size: a potential solution.

    PubMed

    DeFelipe, Javier

    2015-01-01

    Over the years the field of neuroanatomy has evolved considerably but unraveling the extraordinary structural and functional complexity of the brain seems to be an unattainable goal, partly due to the fact that it is only possible to obtain an imprecise connection matrix of the brain. The reasons why reaching such a goal appears almost impossible to date is discussed here, together with suggestions of how we could overcome this anatomical problem by establishing new methodologies to study the brain and by promoting interdisciplinary collaboration. Generating a realistic computational model seems to be the solution rather than attempting to fully reconstruct the whole brain or a particular brain region.

  2. The anatomical problem posed by brain complexity and size: a potential solution

    PubMed Central

    DeFelipe, Javier

    2015-01-01

    Over the years the field of neuroanatomy has evolved considerably but unraveling the extraordinary structural and functional complexity of the brain seems to be an unattainable goal, partly due to the fact that it is only possible to obtain an imprecise connection matrix of the brain. The reasons why reaching such a goal appears almost impossible to date is discussed here, together with suggestions of how we could overcome this anatomical problem by establishing new methodologies to study the brain and by promoting interdisciplinary collaboration. Generating a realistic computational model seems to be the solution rather than attempting to fully reconstruct the whole brain or a particular brain region. PMID:26347617

  3. Does sleep promote false memories?

    PubMed

    Darsaud, Annabelle; Dehon, Hedwige; Lahl, Olaf; Sterpenich, Virginie; Boly, Mélanie; Dang-Vu, Thanh; Desseilles, Martin; Gais, Stephen; Matarazzo, Luca; Peters, Frédéric; Schabus, Manuel; Schmidt, Christina; Tinguely, Gilberte; Vandewalle, Gilles; Luxen, André; Maquet, Pierre; Collette, Fabienne

    2011-01-01

    Memory is constructive in nature so that it may sometimes lead to the retrieval of distorted or illusory information. Sleep facilitates accurate declarative memory consolidation but might also promote such memory distortions. We examined the influence of sleep and lack of sleep on the cerebral correlates of accurate and false recollections using fMRI. After encoding lists of semantically related word associates, half of the participants were allowed to sleep, whereas the others were totally sleep deprived on the first postencoding night. During a subsequent retest fMRI session taking place 3 days later, participants made recognition memory judgments about the previously studied associates, critical theme words (which had not been previously presented during encoding), and new words unrelated to the studied items. Sleep, relative to sleep deprivation, enhanced accurate and false recollections. No significant difference was observed in brain responses to false or illusory recollection between sleep and sleep deprivation conditions. However, after sleep but not after sleep deprivation (exclusive masking), accurate and illusory recollections were both associated with responses in the hippocampus and retrosplenial cortex. The data suggest that sleep does not selectively enhance illusory memories but rather tends to promote systems-level consolidation in hippocampo-neocortical circuits of memories subsequently associated with both accurate and illusory recollections. We further observed that during encoding, hippocampal responses were selectively larger for items subsequently accurately retrieved than for material leading to illusory memories. The data indicate that the early organization of memory during encoding is a major factor influencing subsequent production of accurate or false memories.

  4. 77 FR 47820 - Invention Promoters/Promotion Firms Complaints

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-10

    ... United States Patent and Trademark Office Invention Promoters/Promotion Firms Complaints ACTION: Proposed... participate in any legal proceedings against invention promoters or promotion firms. Complaints submitted to... promotion firm, explain the basis for the complaint, and include the signature of the complainant....

  5. The blood-brain barrier as a regulatory interface in the gut-brain axes.

    PubMed

    Banks, William A

    2006-11-30

    The blood-brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation. Insulin transport is also regulated. For example, treatment of mice with lipopolysaccharide (LPS) increases insulin transport across the BBB by about threefold. Since many of the actions of CNS insulin oppose those of peripheral insulin and since LPS releases proinflammatory cytokines, enhanced transport of insulin across the BBB could be a mechanism which promotes insulin resistance in sepsis. The brain endothelial cells which comprise the BBB secrete many substances including cytokines. Such secretion can be stimulated from one side of the BBB with release into the other side. For example, it appears that adiponectin can inhibit release of interleukin-6 from brain endothelial cells. Overall, the BBB represents an important interface in mediating gut-brain axes.

  6. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases.

    PubMed

    Saraiva, Cláudia; Praça, Catarina; Ferreira, Raquel; Santos, Tiago; Ferreira, Lino; Bernardino, Liliana

    2016-08-10

    The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed.

  7. Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence

    PubMed Central

    Li, Shasha; Zaninotto, Ana Luiza; Neville, Iuri Santana; Paiva, Wellingson Silva; Nunn, Danuza; Fregni, Felipe

    2015-01-01

    Traumatic brain injury (TBI) remains the main cause of disability and a major public health problem worldwide. This review focuses on the neurophysiology of TBI, and the rationale and current state of evidence of clinical application of brain stimulation to promote TBI recovery, particularly on consciousness, cognitive function, motor impairments, and psychiatric conditions. We discuss the mechanisms of different brain stimulation techniques including major noninvasive and invasive stimulations. Thus far, most noninvasive brain stimulation interventions have been nontargeted and focused on the chronic phase of recovery after TBI. In the acute stages, there is limited available evidence of the efficacy and safety of brain stimulation to improve functional outcomes. Comparing the studies across different techniques, transcranial direct current stimulation is the intervention that currently has the higher number of properly designed clinical trials, though total number is still small. We recognize the need for larger studies with target neuroplasticity modulation to fully explore the benefits of brain stimulation to effect TBI recovery during different stages of recovery. PMID:26170670

  8. Novelty and Promotional Items

    EPA Pesticide Factsheets

    Small novelty or promotional products, primarily used for outreach and educational purposes, must effectively convey a message, and their purchase will only be allowed if the item will contribute to the accomplishment of the Agency's mission.

  9. Promoting "Global" Attitudes.

    ERIC Educational Resources Information Center

    Case, Roland

    1996-01-01

    Discusses and illustrates three ways to promote prosocial attitudes towards global issues among students. Includes classroom environments that reinforce desired attitudes; facilitating direct "emotional" experiences that influence attitudes; and engaging students in thoughtful deliberation about global issues. Offers illustrative…

  10. Promoting Successful Cognitive Aging: A Comprehensive Review

    PubMed Central

    Daffner, Kirk R.

    2010-01-01

    Promoting successful cognitive aging is a topic of major importance to individuals and the field of public health. This review presents a coherent framework not only for evaluating factors, protective activities, and enhancing agents that have already been proposed, but also ones that will be put forward in the future. The promotion of successful cognitive aging involves the dual goals of preventing loss of information processing capacity and cognitive reserve, and enhancing brain capacity and cognitive reserve. Four major lines of evidence are available for evaluating whether a proposed factor promotes successful cognitive aging: 1) epidemiologic/cohort studies; 2) animal/basic science studies; 3) human “proof-of-concept” studies; and 4) human intervention studies. Each line of evidence has advantages and limitations that will be discussed. Through illustrative examples, we trace the ways in which each method informs us about the potential value of several proposed factors. Currently, lines of converging evidence allow the strongest case to be made for physical and cognitively stimulating activities. Although epidemiological data seem to favor the use of statins to lower the risk of dementia, more definitive recommendations await further randomized controlled studies. There is presently no clear evidence that antioxidants or Ginkgo biloba promote successful cognitive aging. The impact of resveratrol, fish oil, and a long list of other proposed agents needs to be determined. Clinicians remain well-positioned to identify and aggressively treat vascular risk factors, diabetes, sleep disorders, and other conditions that may reduce brain capacity, and to encourage activities that can build cognitive reserve. PMID:20308777

  11. Brain Pressure Monitoring

    NASA Technical Reports Server (NTRS)

    1977-01-01

    A transducer originally used to measure air pressure in aircraft wind tunnel tests is the basis for a development important in diagnosis and treatment of certain types of brain damage. A totally implantable device, tbe intracranial pressure monitor measures and reports brain pressure by telemetry.

  12. Split Brain Functioning.

    ERIC Educational Resources Information Center

    Cassel, Russell N.

    1978-01-01

    Summarizing recent research, this article defines the functions performed by the left and right sides of the human brain. Attention is given to the right side, or the nondominant side, of the brain and its potential in terms of perception of the environment, music, art, geometry, and the aesthetics. (JC)

  13. The Emerging Scholarly Brain

    NASA Astrophysics Data System (ADS)

    Kurtz, Michael J.

    It is now a commonplace observation that human society is becoming a coherent super-organism, and that the information infrastructure forms its emerging brain. Perhaps, as the underlying technologies are likely to become billions of times more powerful than those we have today, we could say that we are now building the lizard brain for the future organism.

  14. Brain and Nervous System

    MedlinePlus

    ... other regions of the brain (such as the hippocampus and amygdala) for long-term storage and retrieval. As these messages travel through the brain, they too create pathways that serve as the basis of our memory. Movement. Different parts of the cerebrum are responsible ...

  15. Demystifying the Adolescent Brain

    ERIC Educational Resources Information Center

    Steinberg, Laurence

    2011-01-01

    Understanding the nature of brain development in adolescence helps explain why adolescents can vacillate so often between mature and immature behavior. Early and middle adolescence, in particular, are times of heightened vulnerability to risky and reckless behavior because the brain's reward center is easily aroused, but the systems that control…

  16. Brain Friendly School Libraries

    ERIC Educational Resources Information Center

    Sykes, Judith Anne

    2006-01-01

    This title gives concrete practical examples of how to align school library programs and instructional practice with the six key concepts of brain-compatible learning: increasing input to the brain; increasing experiential data; multiple source feedback; reducing threat; involving students in learning decision making; and interdisciplinary unit…

  17. Inside the Adolescent Brain

    ERIC Educational Resources Information Center

    Drury, Stacy S.

    2009-01-01

    Dr. Jay Giedd says that the main alterations in the adolescent brain are the inverted U-shaped developmental trajectories with late childhood/early teen peaks for gray matter volume among others. Giedd adds that the adolescent brain is vulnerable to substances that artificially modulate dopamine levels since its reward system is in a state of flux.

  18. Imaging the Working Brain.

    ERIC Educational Resources Information Center

    Swithenby, S. J.

    1996-01-01

    Very sensitive SQUID (superconducting quantum interference device) detectors are used in the technique known as magnetoencephalography to provide dynamic images of the brain. This can help our fundamental understanding of the way the brain works and may be of particular use in treating disorders such as epilepsy. (Author/MKR)

  19. Drugs and the Brain.

    ERIC Educational Resources Information Center

    National Institutes of Health (DHHS), Bethesda, MD.

    This booklet explores various aspects of drug addiction, with a special focus on drugs' effects on the brain. A brief introduction presents information on the rampant use of drugs in society and elaborates the distinction between drug abuse and drug addiction. Next, a detailed analysis of the brain and its functions is given. Drugs target the more…

  20. Measuring brain lipids.

    PubMed

    Dawson, Glyn

    2015-08-01

    The rapid development of analytical technology has made lipidomics an exciting new area and this review will focus more on modern approaches to lipidomics than on earlier technology. Although not fully comprehensive for all possible brain lipids, the intent is to at least provide a reference for the analysis of classes of lipids found in brain and nervous tissue. We will discuss problems posed by the brain because of its structural and functional heterogeneity, the development changes it undergoes (myelination, aging, pathology etc.) and its cellular heterogeneity (neurons, glia etc.). Section 2 will discuss the various ways in which brain tissue can be extracted to yield lipids for analysis and section 3 will cover a wide range of techniques used to analyze brain lipids such as chromatography and mass-spectrometry. In Section 4 we will discuss ways of analyzing some of the specific biologically active brain lipids found in very small amounts except in pathological conditions and section 5 looks to the future of experimental lipidomic modification in the brain. This article is part of a Special Issue entitled Brain Lipids.

  1. What a Brain!

    ERIC Educational Resources Information Center

    Love, Kim

    1997-01-01

    Outlines basic concepts about how the brain develops and considers how Head Start teachers and parents can take full advantage of the brain's multisensory learning approach to develop more effective ways to interact with children. Focuses on the critical developmental period for stimulating neurons and developing neural connections. Suggests…

  2. [Brain death diagnosis].

    PubMed

    Escudero, Dolores

    2009-05-01

    Brain death has been recognized by the scientific community as the person's death, and accepted in the legislation of different countries. Brain death is defined as the irreversible ending of the functions of all the intracranial neurological structure in both the brain and brain stem. This clinical situation appears when intracranial pressure exceeds the patient's systolic blood pressure, leading to brain circulatory arrest. The most frequent are cerebral hemorrhage and cranioencephalic trauma. Clinical diagnostic must be done by doctors with expertise in neurocritical patient treatment. This diagnosis is based on a systematic, complete and extremely rigorous clinical examination that confirms a non-reactive coma, absence of brain stem reflex, and absence of spontaneous breathing. Instrumental tests may be obligatory in some cases, this depending on each country. Electroencephalogram and evoked potentials are the electrophysiological tests used. In patients treated with sedative drugs, cerebral blood flow evaluation tests, such as cerebral angiography, transcranial Doppler or 99Tc-HMPAO scintigraphy, will be used. More than 92% of the transplants performed in Spain are performed with brain death donor organs. Brain death confirmation is a high responsibility act, with medical, ethical and legal significance since it requires removal of all artificial support, or organs extraction for transplant. Extensive knowledge on its diagnostic and correct decision making avoid unnecessary use of resources and improves management of organs for transplant.

  3. The Resilient Brain

    ERIC Educational Resources Information Center

    Brendtro, Larry K.; Longhurst, James E.

    2005-01-01

    Brain research opens new frontiers in working with children and youth experiencing conflict in school and community. Blending this knowledge with resilience science offers a roadmap for reclaiming those identified as "at risk." This article applies findings from resilience research and recent brain research to identify strategies for reaching…

  4. Feed Your Brain!

    ERIC Educational Resources Information Center

    Failmezger, Tammie L.

    2006-01-01

    Language arts teachers and library media specialists bear the responsibility of teaching students how to properly feed their brains. In this article, the author describes how she teaches her students to make wise choices when selecting books. Furthermore, she presents the "Brain Food Pyramid" model that looks similar to the food pyramid but it…

  5. Brain imaging in psychiatry

    SciTech Connect

    Morihisa, J.M.

    1984-01-01

    This book contains the following five chapters: Positron Emission Tomography (PET) in Psychiatry; Regional Cerebral Blood Flow (CBF) in Psychiatry: Methodological Issues; Regional Cerebral Blood Flow in Psychiatry: Application to Clinical Research; Regional Cerebral Blood Flow in Psychiatry: The Resting and Activated Brains of Schizophrenic Patients; and Brain Electrical Activity Mapping (BEAM) in Psychiatry.

  6. A Child's Brain. Part I.

    ERIC Educational Resources Information Center

    Sylwester, Robert

    1982-01-01

    The first of a series of articles on the human brain focuses on the cyclic nature of brain development. Educational and social issues evolving from current discoveries about the brain are also discussed. (CJ)

  7. Traumatic Brain Injury and Dystonia

    MedlinePlus

    Traumatic Brain Injury & Dystonia Traumatic brain injury (TBI) occurs when a sudden trauma damages to the brain. TBI can occur when the head suddenly and violently hits an object, or when an object pierces the skull and ...

  8. Brain Vascular Imaging Techniques

    PubMed Central

    Laviña, Bàrbara

    2016-01-01

    Recent major improvements in a number of imaging techniques now allow for the study of the brain in ways that could not be considered previously. Researchers today have well-developed tools to specifically examine the dynamic nature of the blood vessels in the brain during development and adulthood; as well as to observe the vascular responses in disease situations in vivo. This review offers a concise summary and brief historical reference of different imaging techniques and how these tools can be applied to study the brain vasculature and the blood-brain barrier integrity in both healthy and disease states. Moreover, it offers an overview on available transgenic animal models to study vascular biology and a description of useful online brain atlases. PMID:28042833

  9. Familiality in brain tumors

    PubMed Central

    Blumenthal, Deborah T.; Cannon-Albright, Lisa A.

    2008-01-01

    Background: Familiality in brain tumors is not definitively substantiated. Methods: We used the Utah Population Data Base (UPDB), a genealogy representing the Utah pioneers and their descendants, record-linked to statewide cancer records, to describe the familial nature of primary brain cancer. We examined the familial clustering of primary brain tumors, including subgroups defined by histologic type and age at diagnosis. The UPDB includes 1,401 primary brain tumor cases defined as astrocytoma or glioblastoma, all with at least three generations of genealogy data. We tested the hypothesis of excess relatedness of brain tumor cases using the Genealogical Index of Familiality method. We estimated relative risks for brain tumors in relatives using rates of brain tumors estimated internally. Results: Significant excess relatedness was observed for astrocytomas and glioblastomas considered as a group (n = 1,401), for astrocytomas considered separately (n = 744), but not for glioblastomas considered separately (n = 658). Significantly increased risks to first- and second-degree relatives for astrocytomas were identified for relatives of astrocytomas considered separately. Significantly increased risks to first-degree relatives, but not second degree, were observed for astrocytoma and glioblastoma cases considered together, and for glioblastoma cases considered separately. Conclusions: This study provides strong evidence for a familial contribution to primary brain cancer risk. There is evidence that this familial aspect includes not only shared environment, but also a heritable component. Extended high-risk brain tumor pedigrees identified in the UPDB may provide the opportunity to identify predisposition genes responsible for familial brain tumors. GLOSSARY GBM = glioblastoma; GIF = Genealogical Index of Familiality; HGG = high-grade gliomas; ICD-O = International Classification of Disease–Oncology; LGG = low-grade gliomas; RR = relative risks; SEER = Surveillance

  10. Intraoperative virtual brain counseling

    NASA Astrophysics Data System (ADS)

    Jiang, Zhaowei; Grosky, William I.; Zamorano, Lucia J.; Muzik, Otto; Diaz, Fernando

    1997-06-01

    Our objective is to offer online real-tim e intelligent guidance to the neurosurgeon. Different from traditional image-guidance technologies that offer intra-operative visualization of medical images or atlas images, virtual brain counseling goes one step further. It can distinguish related brain structures and provide information about them intra-operatively. Virtual brain counseling is the foundation for surgical planing optimization and on-line surgical reference. It can provide a warning system that alerts the neurosurgeon if the chosen trajectory will pass through eloquent brain areas. In order to fulfill this objective, tracking techniques are involved for intra- operativity. Most importantly, a 3D virtual brian environment, different from traditional 3D digitized atlases, is an object-oriented model of the brain that stores information about different brain structures together with their elated information. An object-oriented hierarchical hyper-voxel space (HHVS) is introduced to integrate anatomical and functional structures. Spatial queries based on position of interest, line segment of interest, and volume of interest are introduced in this paper. The virtual brain environment is integrated with existing surgical pre-planning and intra-operative tracking systems to provide information for planning optimization and on-line surgical guidance. The neurosurgeon is alerted automatically if the planned treatment affects any critical structures. Architectures such as HHVS and algorithms, such as spatial querying, normalizing, and warping are presented in the paper. A prototype has shown that the virtual brain is intuitive in its hierarchical 3D appearance. It also showed that HHVS, as the key structure for virtual brain counseling, efficiently integrates multi-scale brain structures based on their spatial relationships.This is a promising development for optimization of treatment plans and online surgical intelligent guidance.

  11. Peers Increase Adolescent Risk Taking by Enhancing Activity in the Brain's Reward Circuitry

    ERIC Educational Resources Information Center

    Chein, Jason; Albert, Dustin; O'Brien, Lia; Uckert, Kaitlyn; Steinberg, Laurence

    2011-01-01

    The presence of peers increases risk taking among adolescents but not adults. We posited that the presence of peers may promote adolescent risk taking by sensitizing brain regions associated with the anticipation of potential rewards. Using fMRI, we measured brain activity in adolescents, young adults, and adults as they made decisions in a…

  12. Identification of a set of genes showing regionally enriched expression in the mouse brain

    PubMed Central

    D'Souza, Cletus A; Chopra, Vikramjit; Varhol, Richard; Xie, Yuan-Yun; Bohacec, Slavita; Zhao, Yongjun; Lee, Lisa LC; Bilenky, Mikhail; Portales-Casamar, Elodie; He, An; Wasserman, Wyeth W; Goldowitz, Daniel; Marra, Marco A; Holt, Robert A; Simpson, Elizabeth M; Jones, Steven JM

    2008-01-01

    Background The Pleiades Promoter Project aims to improve gene therapy by designing human mini-promoters (< 4 kb) that drive gene expression in specific brain regions or cell-types of therapeutic interest. Our goal was to first identify genes displaying regionally enriched expression in the mouse brain so that promoters designed from orthologous human genes can then be tested to drive reporter expression in a similar pattern in the mouse brain. Results We have utilized LongSAGE to identify regionally enriched transcripts in the adult mouse brain. As supplemental strategies, we also performed a meta-analysis of published literature and inspected the Allen Brain Atlas in situ hybridization data. From a set of approximately 30,000 mouse genes, 237 were identified as showing specific or enriched expression in 30 target regions of the mouse brain. GO term over-representation among these genes revealed co-involvement in various aspects of central nervous system development and physiology. Conclusion Using a multi-faceted expression validation approach, we have identified mouse genes whose human orthologs are good candidates for design of mini-promoters. These mouse genes represent molecular markers in several discrete brain regions/cell-types, which could potentially provide a mechanistic explanation of unique functions performed by each region. This set of markers may also serve as a resource for further studies of gene regulatory elements influencing brain expression. PMID:18625066

  13. Danger at Rocky River: A Memorable Misadventure. BrainLink: Memory & Learning.

    ERIC Educational Resources Information Center

    Chetkovich, Dane

    The BrainLink project offers educational materials focusing on current neuroscience issues with the goal of promoting a deeper understanding of how the nervous system works and why the brain makes each individual special while conveying the excitement of "doing science" among upper elementary and middle school students. Project materials engage…

  14. Trouble at Tsavo: The Tale of the Black Rhino. BrainLink: Motor Highways.

    ERIC Educational Resources Information Center

    Boyle, Grace

    The BrainLink project offers educational materials that focus on current neuroscience issues with the goal of promoting a deeper understanding of how the nervous system works and why the brain makes each individual special while conveying the excitement of "doing science" among upper elementary and middle school students. Project materials engage…

  15. The Cookie Crumbles: A Case of Sensory Sleuthing. BrainLink: Sensory Signals.

    ERIC Educational Resources Information Center

    Boyle, Grace

    The BrainLink project offers educational materials focusing on current neuroscience issues with the goal of promoting a deeper understanding of how the nervous system works and why the brain makes each individual special while conveying the excitement of "doing science" among upper elementary and middle school students. Project materials engage…

  16. Infant Brain Development: Making the Research Work for Early Childhood Programs.

    ERIC Educational Resources Information Center

    Wiggins, Paula

    2000-01-01

    Surveys early brain development research. Discusses the importance of attachment, windows of opportunity, and the importance of quality in care. Suggests 6 ways to promote healthy development, lists 10 things every child needs, and poses 12 questions to ask about early brain development. (DLH)

  17. Monte Carlo simulation of quantum Zeno effect in the brain

    NASA Astrophysics Data System (ADS)

    Georgiev, Danko

    2015-12-01

    Environmental decoherence appears to be the biggest obstacle for successful construction of quantum mind theories. Nevertheless, the quantum physicist Henry Stapp promoted the view that the mind could utilize quantum Zeno effect to influence brain dynamics and that the efficacy of such mental efforts would not be undermined by environmental decoherence of the brain. To address the physical plausibility of Stapp's claim, we modeled the brain using quantum tunneling of an electron in a multiple-well structure such as the voltage sensor in neuronal ion channels and performed Monte Carlo simulations of quantum Zeno effect exerted by the mind upon the brain in the presence or absence of environmental decoherence. The simulations unambiguously showed that the quantum Zeno effect breaks down for timescales greater than the brain decoherence time. To generalize the Monte Carlo simulation results for any n-level quantum system, we further analyzed the change of brain entropy due to the mind probing actions and proved a theorem according to which local projections cannot decrease the von Neumann entropy of the unconditional brain density matrix. The latter theorem establishes that Stapp's model is physically implausible but leaves a door open for future development of quantum mind theories provided the brain has a decoherence-free subspace.

  18. Lutein and Brain Function

    PubMed Central

    Erdman, John W.; Smith, Joshua W.; Kuchan, Matthew J.; Mohn, Emily S.; Johnson, Elizabeth J.; Rubakhin, Stanislav S.; Wang, Lin; Sweedler, Jonathan V.; Neuringer, Martha

    2015-01-01

    Lutein is one of the most prevalent carotenoids in nature and in the human diet. Together with zeaxanthin, it is highly concentrated as macular pigment in the foveal retina of primates, attenuating blue light exposure, providing protection from photo-oxidation and enhancing visual performance. Recently, interest in lutein has expanded beyond the retina to its possible contributions to brain development and function. Only primates accumulate lutein within the brain, but little is known about its distribution or physiological role. Our team has begun to utilize the rhesus macaque (Macaca mulatta) model to study the uptake and bio-localization of lutein in the brain. Our overall goal has been to assess the association of lutein localization with brain function. In this review, we will first cover the evolution of the non-human primate model for lutein and brain studies, discuss prior association studies of lutein with retina and brain function, and review approaches that can be used to localize brain lutein. We also describe our approach to the biosynthesis of 13C-lutein, which will allow investigation of lutein flux, localization, metabolism and pharmacokinetics. Lastly, we describe potential future research opportunities. PMID:26566524

  19. The Brain from Within

    PubMed Central

    di Porzio, Umberto

    2016-01-01

    Functional magnetic resonance imaging (fMRI) provides a powerful way to visualize brain functions and observe brain activity in response to tasks or thoughts. It allows displaying brain damages that can be quantified and linked to neurobehavioral deficits. fMRI can potentially draw a new cartography of brain functional areas, allow us to understand aspects of brain function evolution or even breach the wall into cognition and consciousness. However, fMRI is not deprived of pitfalls, such as limitation in spatial resolution, poor reproducibility, different time scales of fMRI measurements and neuron action potentials, low statistical values. Thus, caution is needed in the assessment of fMRI results and conclusions. Additional diagnostic techniques based on MRI such as arterial spin labeling (ASL) and the measurement of diffusion tensor imaging (DTI) provide new tools to assess normal brain development or disruption of anatomical networks in diseases. A cutting edge of recent research uses fMRI techniques to establish a “map” of neural connections in the brain, or “connectome”. It will help to develop a map of neural connections and thus understand the operation of the network. New applications combining fMRI and real time visualization of one’s own brain activity (rtfMRI) could empower individuals to modify brain response and thus could enable researchers or institutions to intervene in the modification of an individual behavior. The latter in particular, as well as the concern about the confidentiality and storage of sensitive information or fMRI and lie detectors forensic use, raises new ethical questions. PMID:27375460

  20. Bilirubin oxidation in brain.

    PubMed

    Hansen, T W

    2000-01-01

    Bilirubin is a product of heme catabolism which by virtue of its lipid solubility can cross the blood-brain barrier and enter the brain. Neonatal jaundice is a common transitional phenomenon which is due to the combination of increased heme catabolism and rate limitations as far as hepatic conjugation and biliary excretion of bilirubin. In the great majority of cases this is an innocuous condition, which is even posited to have some beneficial effects due to the ability of bilirubin to quench free oxygen radicals. However, because bilirubin is neurotoxic, hyperbilirubinemia in the newborn may exceptionally result in death in the neonatal period, or survival with severe neurological sequelae (kernicterus). Bilirubin enters the brain through an intact blood-brain barrier. Clearance of bilirubin from brain partly involves retro-transfer through the blood-brain barrier, and possibly also through the brain-CSF barrier into CSF. Work in our lab during the past 5 years has substantiated earlier work which had suggested that bilirubin may also be metabolized in brain. The responsible enzyme is found on the inner mitochondrial membrane, and oxidizes bilirubin at a rate of 100-300 pmol bilirubin/mg protein/minute. The enzyme activity is lower in the newborn compared with the mature animal, and is also lower in neurons compared with glia. Studies of different rat strains have documented genetic variability. The enzyme is cytochrome-c-dependent, but has as yet not been unequivocally identified. The rate of oxidation of bilirubin is such that this enzyme probably contributes meaningfully to the clearance of bilirubin from brain.

  1. Evaluation of a Health Education Programme about Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Garcia, Jane Mertz; Sellers, Debra M.; Hilgendorf, Amy E.; Burnett, Debra L.

    2014-01-01

    Objective: Our aim was to evaluate a health education programme (TBIoptions: Promoting Knowledge) designed to increase public awareness and understanding about traumatic brain injury (TBI) through in-person (classroom) and computer-based (electronic) learning environments. Design: We used a pre-post survey design with randomization of participants…

  2. How Brain Research Has Changed Our Understanding of Giftedness

    ERIC Educational Resources Information Center

    Clark, Barbara

    2009-01-01

    Understanding brain development and its relationship to intelligence promotes a clearer understanding of giftedness. Children are born with unique patterns and pathways which provide potential for high levels of intelligence. Parents and teachers contribute to the development of giftedness with experiences that are appropriately stimulating. It is…

  3. Breastfeeding, Brain Activation to Own Infant Cry, and Maternal Sensitivity

    ERIC Educational Resources Information Center

    Kim, Pilyoung; Feldman, Ruth; Mayes, Linda C.; Eicher, Virginia; Thompson, Nancy; Leckman, James F.; Swain, James E.

    2011-01-01

    Background: Research points to the importance of breastfeeding for promoting close mother-infant contact and social-emotional development. Recent functional magnetic resonance imaging (fMRI) studies have identified brain regions related to maternal behaviors. However, little research has addressed the neurobiological mechanisms underlying the…

  4. Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings.

    PubMed

    Zhou, Zhong-Zhen; Ge, Bing-Chen; Zhong, Qiu-Ping; Huang, Chang; Cheng, Yu-Fang; Yang, Xue-Mei; Wang, Hai-Tao; Xu, Jiang-Ping

    2016-11-29

    In this study, catecholamides (7a-l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.

  5. Involvement of cyclic AMP systems in morphine physical dependence in mice: prevention of development of morphine dependence by rolipram, a phosphodiesterase 4 inhibitor

    PubMed Central

    Mamiya, Takayoshi; Noda, Yukihiro; Ren, Xiuhai; Hamdy, Moustafa; Furukawa, Shoei; Kameyama, Tsutomu; Yamada, Kiyofumi; Nabeshima, Toshitaka

    2001-01-01

    In this study, we examined whether morphine dependence was inhibited by rolipram, a cyclic AMP selective phosphodiesterase inhibitor in mice, since a role for the cyclic AMP systems in the development of morphine dependence has been reported. Mice, which received morphine (10 mg kg−1 s.c.) twice a day for 5 days showed withdrawal syndromes such as jumping, rearing and forepaw tremor following naloxone challenge (5 mg kg−1 i.p.) on the 6th day. Such mice exhibited a significant elevation of cyclic AMP levels in the thalamus compared to control mice. However, co-administration of rolipram (1 mg kg−1 i.p.) with morphine for 5 days significantly attenuated the severity of the withdrawal syndrome and the increase in the cyclic AMP levels after the administration of naloxone. In naïve mice, acute morphine treatment (10 mg kg−1 s.c.) decreased cyclic AMP levels in the thalamus and cerebral cortex 10 min later. The decrease of cyclic AMP levels induced by acute morphine treatment was blocked by co-administration of rolipram (1 mg kg−1 i.p.). However, acute rolipram did not affect the naloxone-precipitated morphine withdrawal syndrome. These results suggest that the elevation of the cyclic AMP levels is involved in the development of morphine withdrawal syndrome and that blockade of the morphine-induced reduction of cyclic AMP levels by chronic rolipram inhibits the development of dependence and the behavioural and biochemical changes induced by naloxone. Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence. PMID:11226142

  6. Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia

    PubMed Central

    Chiu, Simon; Farina-Woodbury, Michel; Terpstra, Kristen; Antongiorgi, Joalex; Bureau, Yves; Cernovsky, Zack; Hou, Jirui; Sanchez, Veronica; Williams, Marissa; Copen, John; Husni, Mariwan; Goble, Liz

    2014-01-01

    Introduction. Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB). Objective. The primary endpoint was to examine the neurocognitive effects of extract Sceletium tortuosum (Zembrin) and to assess the safety and tolerability of Zembrin in cognitively healthy control subjects. Method. We chose the randomized double-blind placebo-controlled cross-over design in our study. We randomized normal healthy subjects (total n = 21) to receive either 25 mg capsule Zembrin or placebo capsule once daily for 3 weeks, in a randomized placebo-controlled 3-week cross-over design. We administered battery of neuropsychological tests: CNS Vital Signs and Hamilton depression rating scale (HAM-D) at baseline and regular intervals and monitored side effects with treatment emergent adverse events scale. Results. 21 subjects (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) entered the study. Zembrin at 25 mg daily dosage significantly improved cognitive set flexibility (P < 0.032) and executive function (P < 0.022), compared with the placebo group. Positive changes in mood and sleep were found. Zembrin was well tolerated. Conclusion. The promising cognitive enhancing effects of Zembrin likely implicate the PDE-4-cAMP-CREB cascade, a novel drug target in the potential treatment of early Alzheimer's dementia. This trial is registered with ClinicalTrials.gov NCT01805518. PMID:25389443

  7. Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia.

    PubMed

    Chiu, Simon; Gericke, Nigel; Farina-Woodbury, Michel; Badmaev, Vladimir; Raheb, Hana; Terpstra, Kristen; Antongiorgi, Joalex; Bureau, Yves; Cernovsky, Zack; Hou, Jirui; Sanchez, Veronica; Williams, Marissa; Copen, John; Husni, Mariwan; Goble, Liz

    2014-01-01

    Introduction. Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB). Objective. The primary endpoint was to examine the neurocognitive effects of extract Sceletium tortuosum (Zembrin) and to assess the safety and tolerability of Zembrin in cognitively healthy control subjects. Method. We chose the randomized double-blind placebo-controlled cross-over design in our study. We randomized normal healthy subjects (total n = 21) to receive either 25 mg capsule Zembrin or placebo capsule once daily for 3 weeks, in a randomized placebo-controlled 3-week cross-over design. We administered battery of neuropsychological tests: CNS Vital Signs and Hamilton depression rating scale (HAM-D) at baseline and regular intervals and monitored side effects with treatment emergent adverse events scale. Results. 21 subjects (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) entered the study. Zembrin at 25 mg daily dosage significantly improved cognitive set flexibility (P < 0.032) and executive function (P < 0.022), compared with the placebo group. Positive changes in mood and sleep were found. Zembrin was well tolerated. Conclusion. The promising cognitive enhancing effects of Zembrin likely implicate the PDE-4-cAMP-CREB cascade, a novel drug target in the potential treatment of early Alzheimer's dementia. This trial is registered with ClinicalTrials.gov NCT01805518.

  8. Building Brains for Bodies

    DTIC Science & Technology

    1993-08-01

    34dU UAI:5 L.OVERED August 1993 memorandum 4. TITLE ANg SUBTITLn S. FUNDING NUMBERS Building Brains for Bodies N00014-91-J-4038 6. AUTHOR(S) Rodney...FIrS INSTfIflTE OF TEI( ’IINOL()( ;Y ARTIFI(’IAL INTLLWEII ,N’iE L,11OHXIOtlY A.I. Memo No. 1439 August. 1993 Building Brains for Bodies Rodney A...atioiial Ali enabling technology such as lie brain t hat we will power simply has not previously been available. build- has thle abilityv to revol itt onize

  9. Radioresistance of Brain Tumors

    PubMed Central

    Kelley, Kevin; Knisely, Jonathan; Symons, Marc; Ruggieri, Rosamaria

    2016-01-01

    Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation. PMID:27043632

  10. Brain Organization and Psychodynamics

    PubMed Central

    Peled, Avi; Geva, Amir B.

    1999-01-01

    Any attempt to link brain neural activity and psychodynamic concepts requires a tremendous conceptual leap. Such a leap may be facilitated if a common language between brain and mind can be devised. System theory proposes formulations that may aid in reconceptualizing psychodynamic descriptions in terms of neural organizations in the brain. Once adopted, these formulations can help to generate testable predictions about brain–psychodynamic relations and thus significantly affect the future of psychotherapy. (The Journal of Psychotherapy Practice and Research 1999; 8:24–39) PMID:9888105

  11. Brain Drain: A Child's Brain on Poverty. Poverty Fact Sheet

    ERIC Educational Resources Information Center

    Damron, Neil

    2015-01-01

    "Brain Drain: A Child's Brain on Poverty," released in March 2015 and prepared by intern Neil Damron, explores the brain's basic anatomy and recent research findings suggesting that poverty affects the brain development of infants and young children and the potential lifelong effects of the changes. The sheet draws from a variety of…

  12. Brain Gym. Simple Activities for Whole Brain Learning.

    ERIC Educational Resources Information Center

    Dennison, Paul E.; Dennison, Gail E.

    This booklet contains simple movements and activities that are used with students in Educational Kinesiology to enhance their experience of whole brain learning. Whole brain learning through movement repatterning and Brain Gym activities enable students to access those parts of the brain previously unavailable to them. These movements of body and…

  13. Brain Imaging and Behavioral Outcome in Traumatic Brain Injury.

    ERIC Educational Resources Information Center

    Bigler, Erin D.

    1996-01-01

    This review explores the cellular pathology associated with traumatic brain injury (TBI) and its relation to neurobehavioral outcomes, the relationship of brain imaging findings to underlying pathology, brain imaging techniques, various image analysis procedures and how they relate to neuropsychological testing, and the importance of brain imaging…

  14. A Right Brain/Left Brain Model of Acting.

    ERIC Educational Resources Information Center

    Bowlen, Clark

    Using current right brain/left brain research, this paper develops a model that explains acting's underlying quality--the actor is both himself and the character. Part 1 presents (1) the background of the right brain/left brain theory, (2) studies showing that propositional communication is a left hemisphere function while affective communication…

  15. Successful brain aging: plasticity, environmental enrichment, and lifestyle.

    PubMed

    Mora, Francisco

    2013-03-01

    Aging is a physiological process that can develop without the appearance of concurrent diseases. However, very frequently, older people suffer from memory loss and an accelerated cognitive decline. Studies of the neurobiology of aging are beginning to decipher the mechanisms underlying not only the physiology of aging of the brain but also the mechanisms that make people more vulnerable to cognitive dysfunction and neurodegenerative diseases. Today we know that the aging brain retains a considerable functional plasticity, and that this plasticity is positively promoted by genes activated by different lifestyle factors. In this article some of these lifestyle factors and their mechanisms of action are reviewed, including environmental enrichment and the importance of food intake and some nutrients. Aerobic physical exercise and reduction of chronic stress are also briefly reviewed. It is proposed that lifestyle factors are powerful instruments to promote healthy and successful aging of the brain and delay the appearance of age-related cognitive deficits in elderly people.

  16. Novel Neuroimaging Methods to Understand How HIV Affects the Brain

    PubMed Central

    Thompson, Paul

    2015-01-01

    In much of the developed world, the HIV epidemic has largely been controlled by anti-retroviral treatment. Even so, there is growing concern that HIV-infected individuals may be at risk for accelerated brain aging, and a range of cognitive impairments. What promotes or resists these changes is largely unknown. There is also interest in discovering factors that promote resilience to HIV, and combat its adverse effects in children. Here we review recent developments in brain imaging that reveal how the virus affects the brain. We relate these brain changes to changes in blood markers, cognitive function, and other patient outcomes or symptoms, such as apathy or neuropathic pain. We focus on new and emerging techniques, including new variants of brain MRI. Diffusion tensor imaging, for example, can map the brain’s structural connections while fMRI can uncover functional connections. Finally, we suggest how large-scale global research alliances, such as ENIGMA, may resolve controversies over effects where evidence is now lacking. These efforts pool scans from tens of thousands of individuals, and offer a source of power not previously imaginable for brain imaging studies. PMID:25902966

  17. Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment.

    PubMed

    Wang, Jun; Ferruzzi, Mario G; Ho, Lap; Blount, Jack; Janle, Elsa M; Gong, Bing; Pan, Yong; Gowda, G A Nagana; Raftery, Daniel; Arrieta-Cruz, Isabel; Sharma, Vaishali; Cooper, Bruce; Lobo, Jessica; Simon, James E; Zhang, Chungfen; Cheng, Alice; Qian, Xianjuan; Ono, Kenjiro; Teplow, David B; Pavlides, Constantine; Dixon, Richard A; Pasinetti, Giulio M

    2012-04-11

    While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-β-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.

  18. Nutrients, Microglia Aging, and Brain Aging.

    PubMed

    Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

    2016-01-01

    As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of "microglia aging." This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

  19. Nutrients, Microglia Aging, and Brain Aging

    PubMed Central

    Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

    2016-01-01

    As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of “microglia aging.” This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging. PMID:26941889

  20. Prolactin and blood-brain barrier permeability.

    PubMed

    Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Hamilton, W Ryan; Ramirez-Lee, Manuel A; Ali, Syed F; Gonzalez, Carmen

    2013-11-01

    The blood-brain barrier (BBB) consists in part of a highly specialized set of cells which separates the brain from the vascular system. The BBB controls the entry and exit of substances from the brain tissue through tight junctions (TJs) between endothelial cells. It is known that the hormone prolactin (PRL) is able to regulate endothelial-dependent processes, like the balance between proliferation and apoptosis and the mammary epithelial permeability. However, the effects of PRL and the role it plays in the BBB permeability are still not well understood. A primary culture of bovine brain microvessel endothelial cells was used as in vitro model of BBB. Cells were treated with PRL (0.1, 1, 10 and 100 nM) for 24 hours. PRL significantly increased cellular proliferation at 10 and 100 nM, but did not modify basal apoptosis. These effects were dependent on the production of the mitogenic factor nitric oxide (NO). PRL significantly decreased the permeability and promoted an increase in trans-endothelial electrical resistance in a NO-independent way. PRL also increased the expression of the TJs proteins claudin-5 and occludin. The short form of the PRL receptor was detected in these cells but its expression was not modified by PRL. Together, these results suggest that PRL has the ability to increase cellular proliferation associated with a decrease on BBB permeability by increasing the expression of TJs proteins.

  1. Protection by Neuroglobin Expression in Brain Pathologies

    PubMed Central

    Baez, Eliana; Echeverria, Valentina; Cabezas, Ricardo; Ávila-Rodriguez, Marco; Garcia-Segura, Luis Miguel; Barreto, George E.

    2016-01-01

    Astrocytes play an important role in physiological, metabolic, and structural functions, and when impaired, they can be involved in various pathologies including Alzheimer, focal ischemic stroke, and traumatic brain injury. These disorders involve an imbalance in the blood flow and nutrients such as glucose and lactate, leading to biochemical and molecular changes that cause neuronal damage, which is followed by loss of cognitive and motor functions. Previous studies have shown that astrocytes are more resilient than neurons during brain insults as a consequence of their more effective antioxidant systems, transporters, and enzymes, which made them less susceptible to excitotoxicity. In addition, astrocytes synthesize and release different protective molecules for neurons, including neuroglobin, a member of the globin family of proteins. After brain injury, neuroglobin expression is induced in astrocytes. Since neuroglobin promotes neuronal survival, its increased expression in astrocytes after brain injury may represent an endogenous neuroprotective mechanism. Here, we review the role of neuroglobin in the central nervous system, its relationship with different pathologies, and the role of different factors that regulate its expression in astrocytes. PMID:27672379

  2. Embolization of Brain Aneurysms and Fistulas

    MedlinePlus

    ... Resources Professions Site Index A-Z Embolization of Brain Aneurysms and Arteriovenous Malformations/Fistulas Embolization of brain ... Brain Aneurysms and Fistulas? What is Embolization of Brain Aneurysms and Fistulas? Embolization of brain aneurysms and ...

  3. Undiagnosed amebic brain abscess.

    PubMed

    Viriyavejakul, Parnpen; Riganti, Mario

    2009-11-01

    We report a case of amebic brain abscess due to Entamoeba histolytica. The patient was a 31-year-old man who presented with amebic liver abscess. His clinical course deteriorated in spite of proper drainage and treatment. He developed delirium, lethargy and then expired. With a history of heroin addiction, withdrawal syndrome from heroin was suspected. At autopsy, amebic abscesses were detected in the liver, large intestine, meninges and brain. A 19 cm amebic liver abscess was found in the right lobe of the liver. A 4 cm amebic brain abscess was found in the right occipital lobe. Microscopically, the tissue sections from the affected organs were confirmed to have degenerated E. histolytica trophozoites. Involvement of the brain in amebic liver abscess should be suspected in patients with neurological signs and symptoms.

  4. Metastatic brain tumor

    MedlinePlus

    ... them create an advance directive and power of attorney for health care. Support Groups You can ease ... surgery Brain tumor - children Breast cancer Increased intracranial pressure Lung cancer - small cell Melanoma Renal cell carcinoma ...

  5. Organic brain syndrome

    MedlinePlus

    ... the skull causing pressure on brain ( subdural hematoma ) Concussion BREATHING CONDITIONS Low oxygen in the body (hypoxia) ... disease Arrhythmias Chronic subdural hematoma CO2 blood test Concussion Confusion Creutzfeldt-Jakob disease Dementia due to metabolic ...

  6. Brain and Addiction

    MedlinePlus

    ... reward circuit” of the brain Some drugs, like marijuana and heroin , have chemical structures that mimic that ... Pleasure Effect Most drugs of abuse— nicotine , cocaine , marijuana , and others—affect the brain’s “reward” circuit, which ...

  7. Brain injury - discharge

    MedlinePlus

    ... But usually there is improvement. Behavior and Social Interaction People may display inappropriate behavior after a brain ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  8. Brain PET scan

    MedlinePlus

    ... Tell the difference between Parkinson disease and other movement disorders Several PET scans may be taken to determine ... identify where the seizures start in your brain Movement disorders (such as Parkinson disease )

  9. Brain Tumor Statistics

    MedlinePlus

    ... About Us Our Founders Board of Directors Staff Leadership Strategic Plan Financials News Press Releases Headlines Newsletter ... About Us Our Founders Board of Directors Staff Leadership Strategic Plan Financials News Careers Brain Tumor Information ...

  10. Brains on video games.

    PubMed

    Bavelier, Daphne; Green, C Shawn; Han, Doug Hyun; Renshaw, Perry F; Merzenich, Michael M; Gentile, Douglas A

    2011-11-18

    The popular press is replete with stories about the effects of video and computer games on the brain. Sensationalist headlines claiming that video games 'damage the brain' or 'boost brain power' do not do justice to the complexities and limitations of the studies involved, and create a confusing overall picture about the effects of gaming on the brain. Here, six experts in the field shed light on our current understanding of the positive and negative ways in which playing video games can affect cognition and behaviour, and explain how this knowledge can be harnessed for educational and rehabilitation purposes. As research in this area is still in its early days, the contributors of this Viewpoint also discuss several issues and challenges that should be addressed to move the field forward.

  11. Genetics and the Brain

    MedlinePlus

    ... Find us on YouTube Follow us on Instagram Genetics and the Brain by Carl Sherman September 10, ... effects that may be responsible. How Much Is Genetic? [x] , [xi] , [xii] , [xiii] A basic question in ...

  12. Modular Brain Networks

    PubMed Central

    Sporns, Olaf; Betzel, Richard F.

    2016-01-01

    The development of new technologies for mapping structural and functional brain connectivity has led to the creation of comprehensive network maps of neuronal circuits and systems. The architecture of these brain networks can be examined and analyzed with a large variety of graph theory tools. Methods for detecting modules, or network communities, are of particular interest because they uncover major building blocks or subnetworks that are particularly densely connected, often corresponding to specialized functional components. A large number of methods for community detection have become available and are now widely applied in network neuroscience. This article first surveys a number of these methods, with an emphasis on their advantages and shortcomings; then it summarizes major findings on the existence of modules in both structural and functional brain networks and briefly considers their potential functional roles in brain evolution, wiring minimization, and the emergence of functional specialization and complex dynamics. PMID:26393868

  13. Brain catechol synthesis - Control by brain tyrosine concentration

    NASA Technical Reports Server (NTRS)

    Wurtman, R. J.; Larin, F.; Mostafapour, S.; Fernstrom, J. D.

    1974-01-01

    Brain catechol synthesis was estimated by measuring the rate at which brain dopa levels rose following decarboxylase inhibition. Dopa accumulation was accelerated by tyrosine administration, and decreased by treatments that lowered brain tyrosine concentrations (for example, intraperitoneal tryptophan, leucine, or parachlorophenylalanine). A low dose of phenylalanine elevated brain tyrosine without accelerating dopa synthesis. Our findings raise the possibility that nutritional and endocrine factors might influence brain catecholamine synthesis by controlling the availability of tyrosine.

  14. Management of brain metastases.

    PubMed

    Soffietti, Riccardo; Rudā, Roberta; Mutani, Roberto

    2002-10-01

    Brain metastases occur in 20-40% of patients with cancer and their frequency has increased over time. Lung, breast and skin (melanoma) are the commonest sources of brain metastases, and in up to 15% of patients the primary site remains unknown. After the introduction of MRI, multiple lesions have outnumbered single lesions. Contrast-enhanced MRI is the gold standard for the diagnosis. There are no pathognomonic features on CT or MRI that distinguish brain metastases from primary malignant brain tumors or nonneoplastic conditions: therefore a tissue diagnosis by biopsy should be always obtained in patients with unknown primary tumor before undergoing radiotherapy and/or chemotherapy. Some factors are prognostically important: a high Performance Status, a solitary brain metastasis, an absence of systemic metastases, a controlled primary tumor and a younger age. Based on these factors, subgroups of patients with different prognosis have been identified (RPA class I, II, III). Symptomatic therapy includes corticosteroids to reduce vasogenic cerebral edema and anticonvulsants to control seizures. In patients with newly diagnosed brain metastases prophylactic anticonvulsants should not be used routinely. The combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. Complete surgical resection allows a relief of intracranial hypertension, seizures and focal neurological deficits. Radiosurgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that lesion's diameter does not exceed 3-3.5 cm. Radiosurgery offers the potential of treating patients with surgically inaccessible metastases. Still controversial is the need for WBRT after surgery or radiosurgery: local control seems better with the combined approach, but overall survival does not

  15. Brain Tumor Epidemiology: Consensus from the Brain Tumor Epidemiology Consortium (BTEC)

    PubMed Central

    Bondy, Melissa L.; Scheurer, Michael E.; Malmer, Beatrice; Barnholtz-Sloan, Jill S.; Davis, Faith G.; Il’yasova, Dora; Kruchko, Carol; McCarthy, Bridget J.; Rajaraman, Preetha; Schwartzbaum, Judith A.; Sadetzki, Siegal; Schlehofer, Brigitte; Tihan, Tarik; Wiemels, Joseph L.; Wrensch, Margaret; Buffler, Patricia A.

    2010-01-01

    Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings possibly due to small sample sizes in individual studies and differences between studies in subjects, tumor types, and methods of classification. Individual studies have generally lacked sufficient sample size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups such as pediatric brain tumors, the etiology of rare glioma subtypes, such as oligodendroglioma, and meningioma, which not uncommon, has only recently been systematically registered in the US. There is also a pressing need to bring more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. We review the group’s consensus on the current state of scientific findings and present a consensus on research priorities to identify the important areas the science should move to address. PMID:18798534

  16. Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development.

    PubMed

    Goyal, Manu S; Venkatesh, Siddarth; Milbrandt, Jeffrey; Gordon, Jeffrey I; Raichle, Marcus E

    2015-11-17

    The human gut contains a microbial community composed of tens of trillions of organisms that normally assemble during the first 2-3 y of postnatal life. We propose that brain development needs to be viewed in the context of the developmental biology of this "microbial organ" and its capacity to metabolize the various diets we consume. We hypothesize that the persistent cognitive abnormalities seen in children with undernutrition are related in part to their persistent gut microbiota immaturity and that specific regions of the brain that normally exhibit persistent juvenile (neotenous) patterns of gene expression, including those critically involved in various higher cognitive functions such as the brain's default mode network, may be particularly vulnerable to the effects of microbiota immaturity in undernourished children. Furthermore, we postulate that understanding the interrelationships between microbiota and brain metabolism in childhood undernutrition could provide insights about responses to injury seen in adults. We discuss approaches that can be used to test these hypotheses, their ramifications for optimizing nutritional recommendations that promote healthy brain development and function, and the potential societal implications of this area of investigation.

  17. Embryonal brain tumors and developmental control genes

    SciTech Connect

    Aguzzi, A.

    1995-12-31

    Cell proliferation in embryogenesis and neoplastic transformation is thought to be controlled by similar sets of regulatory genes. This is certainly true for tumors of embryonic origin, such as Ewing sarcoma, Wilms` tumor and retinoblastoma, in which developmental control genes are either activated as oncogenes to promote proliferation, or are inactivated to eliminate their growth suppressing function. However, to date little is known about the genetic events underlying the pathogenesis of medulloblastoma, the most common brain tumor in children, which still carries an unfavourable prognosis. None of the common genetic alterations identified in other neuroectodermal tumors, such as mutation of the p53 gene or amplification of tyrosine kinase receptor genes, could be uncovered as key events in the formation of medulloblastoma. The identification of regulatory genes which are expressed in this pediatric brain tumor may provide an alternative approach to gain insight into the molecular aspects of tumor formation.

  18. Is Brain Emulation Dangerous?

    NASA Astrophysics Data System (ADS)

    Eckersley, Peter; Sandberg, Anders

    2013-12-01

    Brain emulation is a hypothetical but extremely transformative technology which has a non-zero chance of appearing during the next century. This paper investigates whether such a technology would also have any predictable characteristics that give it a chance of being catastrophically dangerous, and whether there are any policy levers which might be used to make it safer. We conclude that the riskiness of brain emulation probably depends on the order of the preceding research trajectory. Broadly speaking, it appears safer for brain emulation to happen sooner, because slower CPUs would make the technology`s impact more gradual. It may also be safer if brains are scanned before they are fully understood from a neuroscience perspective, thereby increasing the initial population of emulations, although this prediction is weaker and more scenario-dependent. The risks posed by brain emulation also seem strongly connected to questions about the balance of power between attackers and defenders in computer security contests. If economic property rights in CPU cycles1 are essentially enforceable, emulation appears to be comparatively safe; if CPU cycles are ultimately easy to steal, the appearance of brain emulation is more likely to be a destabilizing development for human geopolitics. Furthermore, if the computers used to run emulations can be kept secure, then it appears that making brain emulation technologies ―open‖ would make them safer. If, however, computer insecurity is deep and unavoidable, openness may actually be more dangerous. We point to some arguments that suggest the former may be true, tentatively implying that it would be good policy to work towards brain emulation using open scientific methodology and free/open source software codebases

  19. Evolution of brain elaboration

    PubMed Central

    Farris, Sarah M.

    2015-01-01

    Large, complex brains have evolved independently in several lineages of protostomes and deuterostomes. Sensory centres in the brain increase in size and complexity in proportion to the importance of a particular sensory modality, yet often share circuit architecture because of constraints in processing sensory inputs. The selective pressures driving enlargement of higher, integrative brain centres has been more difficult to determine, and may differ across taxa. The capacity for flexible, innovative behaviours, including learning and memory and other cognitive abilities, is commonly observed in animals with large higher brain centres. Other factors, such as social grouping and interaction, appear to be important in a more limited range of taxa, while the importance of spatial learning may be a common feature in insects with large higher brain centres. Despite differences in the exact behaviours under selection, evolutionary increases in brain size tend to derive from common modifications in development and generate common architectural features, even when comparing widely divergent groups such as vertebrates and insects. These similarities may in part be influenced by the deep homology of the brains of all Bilateria, in which shared patterns of developmental gene expression give rise to positionally, and perhaps functionally, homologous domains. Other shared modifications of development appear to be the result of homoplasy, such as the repeated, independent expansion of neuroblast numbers through changes in genes regulating cell division. The common features of large brains in so many groups of animals suggest that given their common ancestry, a limited set of mechanisms exist for increasing structural and functional diversity, resulting in many instances of homoplasy in bilaterian nervous systems. PMID:26554044

  20. Promoting La Cultura Hispana

    ERIC Educational Resources Information Center

    Pluviose, David

    2007-01-01

    Launched in 1985 at Arizona State University, the Hispanic Research Center's (HRC) efforts to promote Latino and Chicano art and issues have flourished in recent years. In 2004, the HRC hosted the Arizona International Latina/o Arts Festival in collaboration with the Mesa Southwest Museum. The HRC has also founded a mentoring institute for…