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Sample records for elevated insular glutamate

  1. Memory Trace Reactivation and Behavioral Response during Retrieval Are Differentially Modulated by Amygdalar Glutamate Receptors Activity: Interaction between Amygdala and Insular Cortex

    ERIC Educational Resources Information Center

    Osorio-Gómez, Daniel; Guzmán-Ramos, Kioko; Bermúdez-Rattoni, Federico

    2017-01-01

    The insular cortex (IC) is required for conditioned taste aversion (CTA) retrieval. However, it remains unknown which cortical neurotransmitters levels are modified upon CTA retrieval. Using in vivo microdialysis, we observed that there were clear elevations in extracellular glutamate, norepinephrine, and dopamine in and around the center of the…

  2. Disruptions in Serotonergic Regulation of Cortical Glutamate Release in Primate Insular Cortex in Response to Chronic Ethanol and Nursery Rearing

    PubMed Central

    Alexander, Georgia M.; Graef, John D.; Hammarback, James A.; Nordskog, Brian K.; Burnett, Elizabeth J.; Daunais, James B.; Bennett, Allyson J.; Friedman, David P.; Suomi, Stephen J.; Godwin, Dwayne W.

    2015-01-01

    Early-life stress has been shown to increase susceptibility to anxiety and substance abuse. Disrupted activity within the anterior insular cortex (AIC) has been shown to play a role in both of these disorders. Altered serotonergic processing is implicated in controlling the activity levels of the associated cognitive networks. We therefore investigated changes in both serotonin receptor expression and glutamatergic synaptic activity in the AIC of alcohol-drinking rhesus monkeys. We studied tissues from male rhesus monkeys raised under two conditions: Male rhesus monkeys 1) “Mother reared” (MR) by adult females (n=9), or; 2) “Nursery reared” (NR), i.e., separated from their mothers and reared as a separate group under surrogate/peer-reared conditions (n=9). The NR condition represents a long-standing and well-validated nonhuman primate model of early life stress. All monkeys were trained to self-administer ethanol (4% w/v) or an isocaloric maltose-dextrin control solution. Subsets from each rearing condition were then given daily access to either ethanol, water or maltose dextrin for 12 months. Tissues were collected at necropsy and were further analyzed. Using real time RT-PCR we found that ethanol-naïve, NR monkeys had lower AIC levels of 5-HT1A and 5-HT2A receptor mRNA compared to ethanol-naïve, MR animals. While NR monkeys consumed more ethanol over the 12-month period compared to MR animals, both MR and NR animals expressed greater 5-HT1A and 5-HT2A receptor mRNA levels following chronic alcohol self-administration. The interaction between nursery-rearing conditions and alcohol consumption resulted in a significant enhancement of both 5-HT1A and 5-HT2A receptor mRNA levels such that lower expression levels observed in nursery rearing conditions were not found in the alcohol self-administration group. Using voltage clamp recordings in the whole cell configuration we recorded excitatory postsynaptic currents in both ethanol-naïve and chronic self

  3. Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects

    PubMed Central

    Nam, H W; Karpyak, V M; Hinton, D J; Geske, J R; Ho, A M C; Prieto, M L; Biernacka, J M; Frye, M A; Weinshilboum, R M; Choi, D-S

    2015-01-01

    Acamprosate has been widely used since the Food and Drug Administration approved the medication for treatment of alcohol use disorders (AUDs) in 2004. Although the detailed molecular mechanism of acamprosate remains unclear, it has been largely known that acamprosate inhibits glutamate action in the brain. However, AUD is a complex and heterogeneous disorder. Thus, biomarkers are required to prescribe this medication to patients who will have the highest likelihood of responding positively. To identify pharmacometabolomic biomarkers of acamprosate response, we utilized serum samples from 120 alcohol-dependent subjects, including 71 responders (maintained continuous abstinence) and 49 non-responders (any alcohol use) during 12 weeks of acamprosate treatment. Notably, baseline serum glutamate levels were significantly higher in responders compared with non-responders. Importantly, serum glutamate levels of responders are normalized after acamprosate treatment, whereas there was no significant glutamate change in non-responders. Subsequent functional studies in animal models revealed that, in the absence of alcohol, acamprosate activates glutamine synthetase, which synthesizes glutamine from glutamate and ammonia. These results suggest that acamprosate reduces serum glutamate levels for those who have elevated baseline serum glutamate levels among responders. Taken together, our findings demonstrate that elevated baseline serum glutamate levels are a potential biomarker associated with positive acamprosate response, which is an important step towards development of a personalized approach to treatment for AUD. PMID:26285131

  4. Elevated systemic glutamic acid level in the non-obese diabetic mouse is Idd linked and induces beta cell apoptosis.

    PubMed

    Banday, Viqar Showkat; Lejon, Kristina

    2017-02-01

    Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic (NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a (NOD×B6)F2 cohort (n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl-tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2(-/-) Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy.

  5. Depletion of serotonin in the basolateral amygdala elevates glutamate receptors and facilitates fear-potentiated startle

    PubMed Central

    Tran, L; Lasher, B K; Young, K A; Keele, N B

    2013-01-01

    Our previous experiments demonstrated that systemic depletion of serotonin (5-hydroxytryptamine, 5-HT), similar to levels reported in patients with emotional disorders, enhanced glutamateric activity in the lateral nucleus of the amygdala (LA) and potentiated fear behaviors. However, the effects of isolated depletion of 5-HT in the LA, and the molecular mechanisms underlying enhanced glutamatergic activity are unknown. In the present study, we tested the hypothesis that depletion of 5-HT in the LA induces increased fear behavior, and concomitantly enhances glutamate receptor (GluR) expression. Bilateral infusions of 5,7-dihydroxytryptamine (4 μg per side) into the LA produced a regional reduction of serotonergic fibers, resulting in decreased 5-HT concentrations. The induction of low 5-HT in the LA elevated fear-potentiated startle, with a parallel increase in GluR1 mRNA and GluR1 protein expression. These findings suggest that low 5-HT concentrations in the LA may facilitate fear behavior through enhanced GluR-mediated mechanisms. Moreover, our data support a relationship between 5-HT and glutamate in psychopathologies. PMID:24002084

  6. Elevation of 2-AG by monoacylglycerol lipase inhibition in the visceral insular cortex interferes with anticipatory nausea in a rat model.

    PubMed

    Limebeer, Cheryl L; Rock, Erin M; Puvanenthirarajah, Nirushan; Niphakis, Micah J; Cravatt, Benjamin F; Parker, Linda A

    2016-04-01

    Anticipatory nausea (AN) is a conditioned nausea reaction experienced by chemotherapy patients upon returning to the clinic. Currently, there are no specific treatments for this phenomenon, with the classic antiemetic treatments (e.g., ondansetron) providing no relief. The rat model of AN, contextually elicited conditioned gaping reactions in rats, provides a tool for assessing potential treatments for this difficult to treat disorder. Systemically administered drugs which elevate the endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), by interfering with their respective degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) interfere with AN in the rat model. We have shown that MAGL inhibition within the visceral insular cortex (VIC) interferes with acute nausea in the gaping model (Sticht et al., 2015). Here we report that bilateral infusion of the MAGL inhibitor, MJN110 (but neither the FAAH inhibitor, PF3845, nor ondansetron) into the VIC suppressed contextually elicited conditioned gaping, and this effect was reversed by coadministration of the CB1 antagonist, AM251. These findings suggest that 2-AG within the VIC plays a critical role in the regulation of both acute nausea and AN. Because there are currently no specific therapeutics for chemotherapy patients that develop anticipatory nausea, MAGL inhibition by MJN110 may be a candidate treatment. (PsycINFO Database Record

  7. Selective effects of potassium elevations on glutamate signaling and action potential conduction in hippocampus.

    PubMed

    Meeks, Julian P; Mennerick, Steven

    2004-01-07

    High-frequency synaptic transmission is depressed by moderate rises in the extracellular potassium concentration ([K+]o). Previous reports have indicated that depression of action potential signaling may underlie the synaptic depression. Here, we investigated the specific contribution of K+-induced action potential changes to synaptic depression. We found that glutamatergic transmission in the hippocampal area CA1 was significantly depressed by 8-10 mM [K+]o, but that GABAergic transmission remained intact. Riluzole, a drug that slows recovery from inactivation of voltage-gated sodium channels (NaChs), interacts with subthreshold [K+]o to depress afferent volleys and EPSCs strongly. Thus, elevated [K+]o likely depresses synapses by slowing NaCh recovery from inactivation. It is unclear from previous studies whether [K+]o-induced action potential depression is caused by changes in initiation, reliability, or waveform. We investigated these possibilities explicitly. [K+]o-induced afferent volley depression was independent of stimulus strength, suggesting that changes in action potential initiation do not explain [K+]o-induced depression. Measurements of action potentials from single axons revealed that 8 mM [K+]o increased conduction failures in a subpopulation of fibers and depressed action potential amplitude in all fibers. Together, these changes quantitatively account for the afferent volley depression. We estimate that conduction failure explains more than half of the synaptic depression observed at 8 mM [K+]o, with the remaining depression likely explained by waveform changes. These mechanisms of selective sensitivity of glutamate release to [K+]o accumulation represent a unique neuromodulatory mechanism and a brake on runaway excitation.

  8. Elevated ammonium levels: differential acute effects on three glutamate transporter isoforms.

    PubMed

    Søgaard, Rikke; Novak, Ivana; MacAulay, Nanna

    2012-03-15

    Increased ammonium (NH(4)(+)/NH(3)) in the brain is a significant factor in the pathophysiology of hepatic encephalopathy, which involves altered glutamatergic neurotransmission. In glial cell cultures and brain slices, glutamate uptake either decreases or increases following acute ammonium exposure but the factors responsible for the opposing effects are unknown. Excitatory amino acid transporter isoforms EAAT1, EAAT2, and EAAT3 were expressed in Xenopus oocytes to study effects of ammonium exposure on their individual function. Ammonium increased EAAT1- and EAAT3-mediated [(3)H]glutamate uptake and glutamate transport currents but had no effect on EAAT2. The maximal EAAT3-mediated glutamate transport current was increased but the apparent affinities for glutamate and Na(+) were unaltered. Ammonium did not affect EAAT3-mediated transient currents, indicating that EAAT3 surface expression was not enhanced. The ammonium-induced stimulation of EAAT3 increased with increasing extracellular pH, suggesting that the gaseous form NH(3) mediates the effect. An ammonium-induced intracellular alkalinization was excluded as the cause of the enhanced EAAT3 activity because 1) ammonium acidified the oocyte cytoplasm, 2) intracellular pH buffering with MOPS did not reduce the stimulation, and 3) ammonium enhanced pH-independent cysteine transport. Our data suggest that the ammonium-elicited uptake stimulation is not caused by intracellular alkalinization or changes in the concentrations of cotransported ions but may be due to a direct effect on EAAT1/EAAT3. We predict that EAAT isoform-specific effects of ammonium combined with cell-specific differences in EAAT isoform expression may explain the conflicting reports on ammonium-induced changes in glial glutamate uptake.

  9. Glutamate receptor antagonism in inferior colliculus attenuates elevated startle response of high anxiety diazepam-withdrawn rats.

    PubMed

    Cabral, A; De Ross, J; Castilho, V M; Brandão, M L; Nobre, M J

    2009-07-07

    Rats segregated according to low (LA) or high (HA) anxiety levels have been used as an important tool in the study of fear and anxiety. Since the efficacy of an anxiolytic compound is a function of the animal's basal anxiety level, it is possible that chronic treatment with a benzodiazepine (Bzp) affects LA and HA animals differently. Based on these assumptions, this study aimed to provide some additional information on the influence of acute, chronic (18 days) and withdrawal effects (48 h) from diazepam (10 mg/kg), in rats with LA or HA levels, on startle response amplitude. For this purpose, the elevated plus-maze (EPM) test was used. In addition, the role of glutamate receptors of the central nucleus of the inferior colliculus (cIC), the most important mesencephalic tectum integrative structure of the auditory pathways and a brain region that is linked to the processing of auditory information of aversive nature, was also evaluated. Our results showed that, contrary to the results obtained in LA rats, long-term treatment with diazepam promoted anxiolytic and aversive effects in HA animals that were tested under chronic effects or withdrawal from this drug, respectively. In addition, since Bzp withdrawal may function as an unconditioned stressor, the negative affective states observed in HA rats could be a by-product of GABA-glutamate imbalance in brain systems that modulate unconditioned fear and anxiety behaviors, since the blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors in the cIC clearly reduced the aversion promoted by diazepam withdrawal.

  10. [Insular epilepsy: The Montreal experience].

    PubMed

    Nguyen, D K; Surbeck, W; Weil, A G; Villemure, J-G; Bouthillier, A

    2009-10-01

    In this article, we review recently published data on the role of the insula in refractory partial epilepsy and summarize our own experience in the investigation and treatment of this entity. Case studies and evoked responses obtained from insular cortical stimulation reveal a wide array of clinical manifestations which may mimic temporal, frontal or parietal lobe seizures. Clinicians should hence lower their threshold to sample the insula with intracerebral electrodes. Lack of recognition of insular seizures may explain part of epilepsy surgery failures. Advances in microneurosurgery open the way to safer insular resection.

  11. Glutamate-induced elevations in intracellular chloride concentration in hippocampal cell cultures derived from EYFP-expressing mice.

    PubMed

    Slemmer, Jennifer E; Matsushita, Shinichi; De Zeeuw, Chris I; Weber, John T; Knöpfel, Thomas

    2004-06-01

    The homeostasis of intracellular Cl(-) concentration ([Cl(-)](i)) is critical for neuronal function, including gamma-aminobutyric acid (GABA)ergic synaptic transmission. Here, we investigated activity-dependent changes in [Cl(-)](i) using a transgenetically expressed Cl(-)-sensitive enhanced yellow-fluorescent protein (EYFP) in cultures of mouse hippocampal neurons. Application of glutamate (100 microm for 3 min) in a bath perfusion to cell cultures of various days in vitro (DIV) revealed a decrease in EYFP fluorescence. The EYFP signal increased in amplitude with increasing DIV, reaching a maximal response after 7 DIV. Glutamate application resulted in a slight neuronal acidification. Although EYFP fluorescence is sensitive to pH, EYFP signals were virtually abolished in Cl(-)-free solution, demonstrating that the EYFP signal represented an increase in [Cl(-)](i). Similar to glutamate, a rise in [Cl(-)](i) was also induced by specific ionotropic glutamate receptor agonists and by increasing extracellular [K(+)], indicating that an increase in driving force for Cl(-) suffices to increase [Cl(-)](i). To elucidate the membrane mechanisms mediating the Cl(-) influx, a series of blockers of ion channels and transporters were tested. The glutamate-induced increase in [Cl(-)](i) was resistant to furosemide, bumetanide and 4,4'-diisothiocyanato-stilbene-2,2'-disulphonic acid (DIDS), was reduced by bicuculline to about 80% of control responses, and was antagonized by niflumic acid (NFA) and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We conclude that membrane depolarization increases [Cl(-)](i) via several pathways involving NFA- and NPPB-sensitive anion channels and GABA(A) receptors, but not through furosemide-, bumetanide- or DIDS-sensitive Cl(-) transporters. The present study highlights the vulnerability of [Cl(-)](i) homeostasis after membrane depolarization in neurons.

  12. Diffuse Brain Injury Elevates Tonic Glutamate Levels and Potassium-Evoked Glutamate Release in Discrete Brain Regions at Two Days Post-Injury: An Enzyme-Based Microelectrode Array Study

    PubMed Central

    Hinzman, Jason M.; Currier Thomas, Theresa; Burmeister, Jason J.; Quintero, Jorge E.; Huettl, Peter; Pomerleau, Francois; Gerhardt, Greg A.

    2010-01-01

    Abstract Traumatic brain injury (TBI) survivors often suffer from a wide range of post-traumatic deficits, including impairments in behavioral, cognitive, and motor function. Regulation of glutamate signaling is vital for proper neuronal excitation in the central nervous system. Without proper regulation, increases in extracellular glutamate can contribute to the pathophysiology and neurological dysfunction seen in TBI. In the present studies, enzyme-based microelectrode arrays (MEAs) that selectively measure extracellular glutamate at 2 Hz enabled the examination of tonic glutamate levels and potassium chloride (KCl)-evoked glutamate release in the prefrontal cortex, dentate gyrus, and striatum of adult male rats 2 days after mild or moderate midline fluid percussion brain injury. Moderate brain injury significantly increased tonic extracellular glutamate levels by 256% in the dentate gyrus and 178% in the dorsal striatum. In the dorsal striatum, mild brain injury significantly increased tonic glutamate levels by 200%. Tonic glutamate levels were significantly correlated with injury severity in the dentate gyrus and striatum. The amplitudes of KCl-evoked glutamate release were increased significantly only in the striatum after moderate injury, with a 249% increase seen in the dorsal striatum. Thus, with the MEAs, we measured discrete regional changes in both tonic and KCl-evoked glutamate signaling, which were dependent on injury severity. Future studies may reveal the specific mechanisms responsible for glutamate dysregulation in the post-traumatic period, and may provide novel therapeutic means to improve outcomes after TBI. PMID:20233041

  13. Newly-diagnosed pediatric epilepsy is associated with elevated autoantibodies to glutamic acid decarboxylase but not cardiolipin.

    PubMed

    Veri, Kadi; Uibo, Oivi; Talvik, Tiina; Talvik, Inga; Metsküla, Kaja; Napa, Aita; Vaher, Ulvi; Õiglane-Šlik, Eve; Rein, Reet; Kolk, Anneli; Traat, Aili; Uibo, Raivo

    2013-07-01

    Glutamic acid decarboxylase autoantibodies (GADA) and anti-cardiolipin autoantibodies (ACA) have been detected in adult subjects with epilepsy, though the functional implications of these findings are a matter of debate. This study aimed to determine the prevalence of GADA and ACA and to investigate their clinical significance in pediatric subjects with newly-diagnosed epilepsy. For this purpose GADA and ACA were assessed by enzyme-linked immunosorbent assays in 208 pediatric patients with newly-diagnosed epilepsy and 128 controls. The clinical data (results of electroencephalography, magnetic resonance imaging, 6-month outcome etc.) was compared to antibody test results. Our study revealed GADA in 14 (6.7%) patients with epilepsy and in 1 (0.8%) control, which was a statistically significant difference (P=0.010; Chi-square test). The GADA-positive and -negative patients had similar clinical characteristics. The prevalence of ACA in patients with epilepsy (6.3%) was not significantly different than controls (2.6%). These results suggest that GADA is associated with epilepsy in a subgroup of newly-diagnosed pediatric patients. Further studies are required to determine the prognostic significance and pathogenic role of GADA among pediatric subjects with epilepsy.

  14. Food related processes in the insular cortex

    PubMed Central

    Frank, Sabine; Kullmann, Stephanie; Veit, Ralf

    2013-01-01

    The insular cortex is a multimodal brain region with regional cytoarchitectonic differences indicating various functional specializations. As a multisensory neural node, the insular cortex integrates perception, emotion, interoceptive awareness, cognition, and gustation. Regarding the latter, predominantly the anterior part of the insular cortex is regarded as the primary taste cortex. In this review, we will specifically focus on the involvement of the insula in food processing and on multimodal integration of food-related items. Influencing factors of insular activation elicited by various foods range from calorie-content to the internal physiologic state, body mass index or eating behavior. Sensory perception of food-related stimuli including seeing, smelling, and tasting elicits increased activation in the anterior and mid-dorsal part of the insular cortex. Apart from the pure sensory gustatory processing, there is also a strong association with the rewarding/hedonic aspects of food items, which is reflected in higher insular activity and stronger connections to other reward-related areas. Interestingly, the processing of food items has been found to elicit different insular activation in lean compared to obese subjects and in patients suffering from an eating disorder (anorexia nervosa (AN), bulimia nervosa (BN)). The knowledge of functional differences in the insular cortex opens up the opportunity for possible noninvasive treatment approaches for obesity and eating disorders. To target brain functions directly, real-time functional magnetic resonance imaging neurofeedback offers a state-of-the-art tool to learn to control the anterior insular cortex activity voluntarily. First evidence indicates that obese adults have an enhanced ability to regulate the anterior insular cortex. PMID:23986683

  15. Pure dysarthria due to an insular infarction.

    PubMed

    Hiraga, Akiyuki; Tanaka, Saiko; Kamitsukasa, Ikuo

    2010-06-01

    Cortical infarction presenting with pure dysarthria is rarely reported. Previous studies have reported pure dysarthria due to cortical stroke at the precentral gyrus or middle frontal gyrus. We report a 72-year-old man who developed pure dysarthria caused by an acute cortical infarction in the insular cortex. The role of the insula in language has been difficult to assess clinically because of the rarity of pure insular strokes. Our patient showed pure dysarthria without aphasia, indicating that pure dysarthria can be the sole manifestation of insular infarctions.

  16. Prolonged continuous intravenous infusion of the dipeptide L-alanine- L-glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe traumatic brain injury

    PubMed Central

    2014-01-01

    .75 g/ kg/ d up to 5 days) increased plasma and brain glutamine and alanine levels. This was not associated with elevated glutamate or signs of potential glutamate-mediated cerebral injury. The increased nitrogen load should be considered in patients with renal and hepatic dysfunction. Trial registration Clinicaltrials.gov NCT02130674. Registered 5 April 2014 PMID:24992948

  17. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2014-04-01 2014-04-01 false Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  18. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2010-04-01 2010-04-01 false Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  19. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2011-04-01 2010-04-01 true Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  20. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2013-04-01 2013-04-01 false Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  1. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2012-04-01 2010-04-01 true Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  2. Extreme insular dwarfism evolved in a mammoth.

    PubMed

    Herridge, Victoria L; Lister, Adrian M

    2012-08-22

    The insular dwarfism seen in Pleistocene elephants has come to epitomize the island rule; yet our understanding of this phenomenon is hampered by poor taxonomy. For Mediterranean dwarf elephants, where the most extreme cases of insular dwarfism are observed, a key systematic question remains unresolved: are all taxa phyletic dwarfs of a single mainland species Palaeoloxodon antiquus (straight-tusked elephant), or are some referable to Mammuthus (mammoths)? Ancient DNA and geochronological evidence have been used to support a Mammuthus origin for the Cretan 'Palaeoloxodon' creticus, but these studies have been shown to be flawed. On the basis of existing collections and recent field discoveries, we present new, morphological evidence for the taxonomic status of 'P'. creticus, and show that it is indeed a mammoth, most probably derived from Early Pleistocene Mammuthus meridionalis or possibly Late Pliocene Mammuthus rumanus. We also show that Mammuthus creticus is smaller than other known insular dwarf mammoths, and is similar in size to the smallest dwarf Palaeoloxodon species from Sicily and Malta, making it the smallest mammoth species known to have existed. These findings indicate that extreme insular dwarfism has evolved to a similar degree independently in two elephant lineages.

  3. Extreme insular dwarfism evolved in a mammoth

    PubMed Central

    Herridge, Victoria L.; Lister, Adrian M.

    2012-01-01

    The insular dwarfism seen in Pleistocene elephants has come to epitomize the island rule; yet our understanding of this phenomenon is hampered by poor taxonomy. For Mediterranean dwarf elephants, where the most extreme cases of insular dwarfism are observed, a key systematic question remains unresolved: are all taxa phyletic dwarfs of a single mainland species Palaeoloxodon antiquus (straight-tusked elephant), or are some referable to Mammuthus (mammoths)? Ancient DNA and geochronological evidence have been used to support a Mammuthus origin for the Cretan ‘Palaeoloxodon’ creticus, but these studies have been shown to be flawed. On the basis of existing collections and recent field discoveries, we present new, morphological evidence for the taxonomic status of ‘P’. creticus, and show that it is indeed a mammoth, most probably derived from Early Pleistocene Mammuthus meridionalis or possibly Late Pliocene Mammuthus rumanus. We also show that Mammuthus creticus is smaller than other known insular dwarf mammoths, and is similar in size to the smallest dwarf Palaeoloxodon species from Sicily and Malta, making it the smallest mammoth species known to have existed. These findings indicate that extreme insular dwarfism has evolved to a similar degree independently in two elephant lineages. PMID:22572206

  4. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage

    PubMed Central

    Soria, Federico N.; Pérez-Samartín, Alberto; Martin, Abraham; Gona, Kiran Babu; Llop, Jordi; Szczupak, Boguslaw; Chara, Juan Carlos; Matute, Carlos; Domercq, María

    2014-01-01

    During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in pyramidal cortical neurons in brain slices from rodents in response to oxygen and glucose deprivation (OGD) as a real-time glutamate sensor to identify the source of glutamate release and determined the extent of neuronal damage. Blockade of excitatory amino acid transporters or vesicular glutamate release did not inhibit ischemia-gated currents or neuronal damage after OGD. In contrast, pharmacological inhibition of the cystine/glutamate antiporter dramatically attenuated ischemia-gated currents and cell death after OGD. Compared with control animals, mice lacking a functional cystine/glutamate antiporter exhibited reduced anoxic depolarization and neuronal death in response to OGD. Furthermore, glutamate released by the cystine/glutamate antiporter activated extrasynaptic, but not synaptic, NMDARs, and blockade of extrasynaptic NMDARs reduced ischemia-gated currents and cell damage after OGD. Finally, PET imaging showed increased cystine/glutamate antiporter function in ischemic rats. Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death. PMID:25036707

  5. Insular volume reduction in fragile X syndrome.

    PubMed

    Cohen, Jeremy D; Nichols, Taylor; Brignone, Laura; Hall, Scott S; Reiss, Allan L

    2011-06-01

    Fragile X syndrome (FraX) is the most common form of inherited mental deficit and is caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. While males and females with the full FMR1 mutation are affected differently because the disorder is X-linked, both suffer from varying degrees of cognitive impairment, attention deficits and social anxiety. The insula is a sensory integrative region that has been increasingly suggested as a critical area involved in anxiety manifestation. The current study was designed to examine possible changes in insular volume in FraX compared to age- and gender-matched typically developing healthy controls (HC) as well as age-, gender-, and intelligence-matched developmentally delayed controls (DD). An established native-space, manual morphometry method was utilized to quantify total and regional insular volumes using structural magnetic resonance imaging. Total, anterior and posterior insular volumes were found to be reduced in FraX compared to both HC and DD. The current data add to a growing literature concerning brain abnormalities in FraX and suggests that significant volume reduction of the insula is a component of the FraX neuroanatomical phenotype. This finding also provides an intriguing potential neural correlate for hyperarousal and gaze aversion, which are prominent behavioral symptoms of FraX.

  6. Insular Volume Reduction in Fragile X Syndrome

    PubMed Central

    Cohen, Jeremy D.; Nichols, Taylor; Brignone, Laura; Hall, Scott S.; Reiss, Allan L.

    2011-01-01

    Fragile X Syndrome (FraX) is the most common form of inherited mental deficit and is caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. While males and females with the full FMR1 mutation are affected differently because the disorder is X-linked, both suffer from varying degrees of cognitive impairment, attention deficits and social anxiety. The insula is a sensory integrative region that has been increasingly suggested as a critical area involved in anxiety manifestation. The current study was designed to examine possible changes in insular volume in FraX compared to age- and gender-matched typically developing healthy controls (HC) as well as age, gender-, and intelligence-matched developmentally delayed controls (DD). An established native-space, manual morphometry method was utilized to quantify total and regional insular volumes using structural magnetic resonance imaging. Total, anterior and posterior insular volumes were found to be reduced in FraX compared to both HC and DD. The current data add to a growing literature concerning brain abnormalities in FraX and suggests that significant volume reduction of the insula is a component of the FraX neuroanatomical phenotype. This finding also provides an intriguing potential neural correlate for hyperarousal and gaze aversion, which are prominent behavioral symptoms of FraX. PMID:21291994

  7. Glutamate Transporter-Mediated Glutamate Secretion in the Mammalian Pineal Gland

    PubMed Central

    Kim, Mean-Hwan; Uehara, Shunsuke; Muroyama, Akiko; Hille, Bertil; Moriyama, Yoshinori; Koh, Duk-Su

    2008-01-01

    Glutamate transporters are expressed throughout the central nervous system where their major role is to clear released glutamate from presynaptic terminals. Here we report a novel function of the transporter in rat pinealocytes. This electrogenic transporter conducted inward current in response to L-glutamate and L- or D-aspartate and depolarized the membrane in patch clamp experiments. Ca2+ imaging demonstrated that the transporter-mediated depolarization induced a significant Ca2+ influx through voltage-gated Ca2+ channels. The Ca2+ rise finally evoked glutamate exocytosis as detected by carbon-fiber amperometry and by high-performance liquid chromatography. In pineal slices with densely packed pinealocytes, glutamate released from the cells effectively activated glutamate transporters in neighboring cells. The Ca2+ signal generated by KCl depolarization or acetylcholine propagated through several cell layers by virtue of the regenerative ‘glutamate-induced glutamate release’. Therefore we suggest that glutamate transporters mediate synchronized elevation of L-glutamate and thereby efficiently down-regulate melatonin secretion via previously identified inhibitory metabotropic glutamate receptors in the pineal gland. PMID:18945893

  8. Deciphering arboviral emergence within insular ecosystems.

    PubMed

    Tortosa, Pablo; Pascalis, Hervé; Guernier, Vanina; Cardinale, Eric; Le Corre, Matthieu; Goodman, Steven M; Dellagi, Koussay

    2012-08-01

    The spatial dynamics of zoonotic arthropod-borne viruses is a fashionable though challenging topic. Inter-human local transmission of a given arbovirus during an outbreak and its spread over large distances are considered as key parameters of emergence. Here, we suggest that insular ecosystems provide ideal natural "laboratory" conditions to uncouple local transmission from long distance spread, and differentiate these two processes. Due to geographic isolation, often-limited land surface area and relatively homogenous ecosystems, oceanic islands display low species richness and often-high levels of endemism. These aspects provide the means for comprehensive entomological surveys and investigations of original host/pathogen interactions. In addition, islands are interconnected through discrete anthropogenic and non-anthropogenic exchanges: whilst islands maintain a substantial level of human and domestic animal exchange with other neighbouring or distant territories, they also comprise dispersal and migratory pathways of volant organisms (insects, birds and bats). Hence, both anthropogenic and non-anthropogenic exchanges in island systems are easier to identify and investigate than in continuous, continental systems. Finally, island ecosystems tend to be notably simpler, more prone to invasive taxa and, therefore, easier to document the colonization or displacement of vector species. These different aspects are presented and overlaid upon the spread of arboviruses within two distinct insular systems: islands of Polynesia and the south-western Indian Ocean. The former have been repeatedly affected by Dengue fever epidemics, while the latter recently suffered four successive epidemics, probably of east African origin, three of which involved the emerging viruses Chikungunya, Rift Valley and Dengue fever. Here, we review some new insights into arboviral spread and evolution associated with investigations that followed these epidemics, as well as several aspects that

  9. Morphometry of Human Insular Cortex and Insular Volume Reduction in Williams syndrome

    PubMed Central

    Cohen, Jeremy D.; Mock, Jeffrey R.; Nichols, Taylor; Zadina, Janet; Corey, David M.; Lemen, Lisa; Bellugi, Ursula; Galaburda, Albert; Reiss, Allan; Foundas, Anne L.

    2009-01-01

    Functional imaging in humans and anatomical data in monkeys have implicated the insula as a multimodal sensory integrative brain region. The topography of insular connections is organized by its cytoarchitectonic regions. Previous attempts to measure the insula have utilized either indirect or automated methods. This study was designed to develop a reliable method for obtaining volumetric magnetic resonance imaging (MRI) measurements of the human insular cortex, and to validate that method by examining the anatomy of insular cortex in adults with Williams syndrome (WS) and healthy age-matched controls. Statistical reliability was obtained among three raters for this method, supporting its reproducibility not only across raters, but within different software packages. The procedure described here utilizes native-space morphometry as well as a method for dividing the insula into connectivity-based sub-regions estimated from cytoarchitectonics. Reliability was calculated in both ANALYZE (n=3) and BrainImageJava (N=10) where brain scans were measured once in each hemisphere by each rater. This highly reliable method revealed total, anterior, and posterior insular volume reduction bilaterally (all p’s < .002) in WS, after accounting for reduced total brain volumes in these participants. Although speculative, the reduced insular volumes in WS may represent a neural risk for the development of hyperaffiliative social behavior with increased specific phobias, and implicate the insula as a critical limbic integrative region. Native-space quantification of the insula may be valuable in the study of neurodevelopmental or neuropsychiatric disorders related to anxiety and social behavior. PMID:19660766

  10. 38 CFR 3.40 - Philippine and Insular Forces.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Forces. 3.40 Section 3.40 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... Insular Forces. (a) Regular Philippine Scouts. Service in the Philippine Scouts (except that described in paragraph (b) of this section), the Insular Force of the Navy, Samoan Native Guard, and Samoan Native...

  11. 38 CFR 3.40 - Philippine and Insular Forces.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Forces. 3.40 Section 3.40 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... Insular Forces. (a) Regular Philippine Scouts. Service in the Philippine Scouts (except that described in paragraph (b) of this section), the Insular Force of the Navy, Samoan Native Guard, and Samoan Native...

  12. Anterior insular cortex is necessary for empathetic pain perception

    PubMed Central

    Gu, Xiaosi; Gao, Zhixian; Wang, Xingchao; Liu, Xun; Knight, Robert T.; Hof, Patrick R.

    2012-01-01

    Empathy refers to the ability to perceive and share another person’s affective state. Much neuroimaging evidence suggests that observing others’ suffering and pain elicits activations of the anterior insular and the anterior cingulate cortices associated with subjective empathetic responses in the observer. However, these observations do not provide causal evidence for the respective roles of anterior insular and anterior cingulate cortices in empathetic pain. Therefore, whether these regions are ‘necessary’ for empathetic pain remains unknown. Herein, we examined the perception of others’ pain in patients with anterior insular cortex or anterior cingulate cortex lesions whose locations matched with the anterior insular cortex or anterior cingulate cortex clusters identified by a meta-analysis on neuroimaging studies of empathetic pain perception. Patients with focal anterior insular cortex lesions displayed decreased discrimination accuracy and prolonged reaction time when processing others’ pain explicitly and lacked a typical interference effect of empathetic pain on the performance of a pain-irrelevant task. In contrast, these deficits were not observed in patients with anterior cingulate cortex lesions. These findings reveal that only discrete anterior insular cortex lesions, but not anterior cingulate cortex lesions, result in deficits in explicit and implicit pain perception, supporting a critical role of anterior insular cortex in empathetic pain processing. Our findings have implications for a wide range of neuropsychiatric illnesses characterized by prominent deficits in higher-level social functioning. PMID:22961548

  13. Anterior Insular Cortex and Emotional Awareness

    PubMed Central

    Gu, Xiaosi; Hof, Patrick R.; Friston, Karl J.; Fan, Jin

    2014-01-01

    This paper reviews the foundation for a role of the human anterior insular cortex (AIC) in emotional awareness, defined as the conscious experience of emotions. We first introduce the neuroanatomical features of AIC and existing findings on emotional awareness. Using empathy, the awareness and understanding of other people’s emotional states, as a test case, we then present evidence to demonstrate: 1) AIC and anterior cingulate cortex (ACC) are commonly coactivated as revealed by a meta-analysis, 2) AIC is functionally dissociable from ACC, 3) AIC integrates stimulus-driven and top-down information, and 4) AIC is necessary for emotional awareness. We propose a model in which AIC serves two major functions: integrating bottom-up interoceptive signals with top-down predictions to generate a current awareness state and providing descending predictions to visceral systems that provide a point of reference for autonomic reflexes. We argue that AIC is critical and necessary for emotional awareness. PMID:23749500

  14. Insular cortex mediates increased pain tolerance in yoga practitioners.

    PubMed

    Villemure, Chantal; Ceko, Marta; Cotton, Valerie A; Bushnell, M Catherine

    2014-10-01

    Yoga, an increasingly popular discipline among Westerners, is frequently used to improve painful conditions. We investigated possible neuroanatomical underpinnings of the beneficial effects of yoga using sensory testing and magnetic resonance imaging techniques. North American yogis tolerated pain more than twice as long as individually matched controls and had more gray matter (GM) in multiple brain regions. Across subjects, insular GM uniquely correlated with pain tolerance. Insular GM volume in yogis positively correlated with yoga experience, suggesting a causal relationship between yoga and insular size. Yogis also had increased left intrainsular white matter integrity, consistent with a strengthened insular integration of nociceptive input and parasympathetic autonomic regulation. Yogis, as opposed to controls, used cognitive strategies involving parasympathetic activation and interoceptive awareness to tolerate pain, which could have led to use-dependent hypertrophy of insular cortex. Together, these findings suggest that regular and long-term yoga practice improves pain tolerance in typical North Americans by teaching different ways to deal with sensory inputs and the potential emotional reactions attached to those inputs leading to a change in insular brain anatomy and connectivity.

  15. The Role of the Insular Cortex in Retaliation

    PubMed Central

    Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander Thomas

    2016-01-01

    The insular cortex has consistently been associated with various aspects of emotion regulation and social interaction, including anger processing and overt aggression. Aggression research distinguishes proactive or instrumental aggression from retaliation, i.e. aggression in response to provocation. Here, we investigated the specific role of the insular cortex during retaliation, employing a controlled behavioral aggression paradigm implementing different levels of provocation. Fifteen healthy male volunteers underwent whole brain functional magnetic resonance imaging (fMRI) to identify brain regions involved in interaction with either a provoking or a non-provoking opponent. FMRI group analyses were complemented by examining the parametric modulations of brain activity related to the individual level of displayed aggression. These analyses identified a hemispheric lateralization as well as an anatomical segregation of insular cortex with specifically the left posterior part being involved in retaliation. The left-lateralization of insular activity during retaliation is in accordance with evidence from electro-physiological studies, suggesting left-lateralized fronto-cortical dominance during anger processing and aggressive acts. The posterior localization of insular activity, on the other hand, suggests a spatial segregation within insular cortex with particularly the posterior part being involved in the processing of emotions that trigger intense bodily sensations and immediate action tendencies. PMID:27096431

  16. Insular ecosystems of the southeastern United States—A regional synthesis to support biodiversity conservation in a changing climate

    USGS Publications Warehouse

    Cartwright, Jennifer M.; Wolfe, William J.

    2016-08-11

    In the southeastern United States, insular ecosystems—such as rock outcrops, depression wetlands, high-elevation balds, flood-scoured riparian corridors, and insular prairies and barrens—occupy a small fraction of land area but constitute an important source of regional and global biodiversity, including concentrations of rare and endemic plant taxa. Maintenance of this biodiversity depends upon regimes of abiotic stress and disturbance, incorporating factors such as soil surface temperature, widely fluctuating hydrologic conditions, fires, flood scouring, and episodic droughts that may be subject to alteration by climate change. Over several decades, numerous localized, site-level investigations have yielded important information about the floristics, physical environments, and ecological dynamics of these insular ecosystems; however, the literature from these investigations has generally remained fragmented. This report consists of literature syntheses for eight categories of insular ecosystems of the southeastern United States, concerning (1) physical geography, (2) ecological determinants of community structures including vegetation dynamics and regimes of abiotic stress and disturbance, (3) contributions to regional and global biodiversity, (4) historical and current anthropogenic threats and conservation approaches, and (5) key knowledge gaps relevant to conservation, particularly in terms of climate-change effects on biodiversity. This regional synthesis was undertaken to discern patterns across ecosystems, identify knowledge gaps, and lay the groundwork for future analyses of climate-change vulnerability. Findings from this synthesis indicate that, despite their importance to regional and global biodiversity, insular ecosystems of the southeastern United States have been subjected to a variety of direct and indirect human alterations. In many cases, important questions remain concerning key determinants of ecosystem function. In particular, few

  17. Mechanisms of glutamate transport.

    PubMed

    Vandenberg, Robert J; Ryan, Renae M

    2013-10-01

    L-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the pathogenesis of many neurological disorders. The control of glutamate concentrations is critical to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concentrations to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystallized and its structure determined. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.

  18. [Risk taking and the insular cortex].

    PubMed

    Ishii, Hironori; Tsutsui, Ken-Ichiro; Iijima, Toshio

    2013-08-01

    Risk taking can lead to ruin, but sometimes, it can also provide great success. How does our brain make a decision on whether to take a risk or to play it safe? Recent studies have revealed the neural basis of risky decision making. In this review, we focus on the role of the anterior insular cortex (AIC) in risky decision making. Although human imaging studies have shown activations of the AIC in various gambling tasks, the causal involvement of the AIC in risky decision making was still unclear. Recently, we demonstrated a causality of the AIC in risky decision making by using a pharmacological approach in behaving rats-temporary inactivation of the AIC decreased the risk preference in gambling tasks, whereas temporary inactivation of the adjacent orbitofrontal cortex (OFC) increased the risk preference. The latter finding is consistent with a previous finding that patients with damage to the OFC take abnormally risky decisions in the Iowa gambling task. On the basis of these observations, we hypothesize that the intact AIC promotes risk-seeking behavior, and that the AIC and OFC are crucial for balancing the opposing motives of whether to take a risk or avoid it. However, the functional relationship between the AIC and OFC remains unclear. Future combinations of inactivation and electrophysiological studies may promote further understanding of risky decision making.

  19. Serum Glutamic-Oxaloacetic Transaminase (GOT) and Glutamic-Pyruvic Transaminase (GPT) Levels in Children and Adolescents with Intellectual Disabilities

    ERIC Educational Resources Information Center

    Lin, Jin-Ding; Lin, Pei-Ying; Chen, Li-Mei; Fang, Wen-Hui; Lin, Lan-Ping; Loh, Ching-Hui

    2010-01-01

    The elevated serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) rate among people with intellectual disabilities (ID) is unknown and have not been sufficiently studies. The present paper aims to provide the profile of GOT and GPT, and their associated relationship with other biochemical levels of children or…

  20. Repeated Binge Drinking Increases Perineuronal Nets in the Insular Cortex

    PubMed Central

    Chen, Hu; He, Donghong; Lasek, Amy W.

    2015-01-01

    Background Alcohol exposure leads to changes in the extracellular matrix (ECM) in the brain, which profoundly impacts neuronal plasticity. Perineuronal nets (PNs) are specialized ECM structures that enclose subpopulations of neurons in the cortex. Adolescent exposure to alcohol induces long-lasting increases in the expression of PN components in the cortex in adult mice. However, it has not been determined whether binge alcohol exposure in young adults alters PNs. Here, we examined PNs and their core components in the insula and primary motor cortex after repeated binge-like ethanol consumption in adult mice. Methods The 4 day drinking in the dark (DID) procedure was performed in mice for 1 or 6 weeks to model binge alcohol consumption. The impact of ethanol drinking on PNs was examined by fluorescent staining of brain sections using a marker for PNs, Wisteria floribunda agglutinin (WFA). In another set of experiments, cortex was dissected and Western blots and quantitative real-time PCR (qPCR) were performed to evaluate the expression of the PN proteins aggrecan, brevican, and phosphacan. Results Binge-like ethanol drinking for 6 weeks caused a significant increase in PNs in the insula, as measured by WFA binding. Aggrecan, brevican and phosphacan protein expression, and aggrecan mRNA expression, were also elevated in the insula after 6 weeks of ethanol drinking. In contrast, expression of PN components did not change after 1 week of DID. The increase in PNs appears to be specific to the insula, since alterations were not observed in the primary motor cortex. Conclusions Our results provide the first evidence that insular PNs increase after long-term binge drinking. The insula mediates compulsive alcohol use. Since PNs influence neuronal firing and plasticity, increased PNs in the insula after multiple binge cycles may contribute to restricted neuronal plasticity and lead to the development of compulsive alcohol use. PMID:26332441

  1. Report to Congress on Insular Area energy vulnerability

    SciTech Connect

    Not Available

    1994-05-01

    This report was prepared in response to Section 1406 of the Energy Policy Act of 1992 (Public Law 102-486), which directed the Department of Energy (DOE) to ``conduct a study of the implications of the unique vulnerabilities of the insular areas to an oil supply disruption,`` and to ``outline how the insular areas shall gain access to vital oil supplies during times of national emergency.`` The Act defines the insular areas to be the US Virgin Islands and Puerto Rico in the Caribbean, and Guam, American Samoa, the Commonwealth of the Northern Mariana Islands (CNMI), and Palau in the Pacific. In the study, ``unique vulnerabilities`` were defined as susceptibility to: (1) more frequent or more likely interruptions of oil supplies compared to the US Mainland, and/or (2) disproportionately larger or more likely economic losses in the event of an oil supply disruption. In order to assess unique vulnerabilities, the study examined the insular areas` experience during past global disruptions of oil supplies and during local emergencies caused by natural disasters. The effects of several possible future global disruptions and local emergencies were also analyzed. Analyses were based on historical data, simulations using energy and economic models, and interviews with officials in the insular governments and the energy industry.

  2. Lights and shadows in the evolutionary patterns of insular bovids.

    PubMed

    Rozzi, Roberto; Palombo, Maria Rita

    2014-03-01

    Endemic bovids are intriguing elements of insular faunas. The living species include the Japanese serow (Capricornis crispus) and the Formosan serow (C. swinhoei), the tamaraw from Mindoro, Philippines, (Bubalus mindorensis) and the anoas (B. depressicornis and B. quarlesi), 2 species of dwarf buffalos endemic to Sulawesi, Indonesia. Fossil endemic bovids are only recorded in some Asian, North American and Western Mediterranean islands. Here we present a comprehensive overview of the changes in body size and evolutionary patterns exhibited by both extant and extinct insular bovids. Our appraisal indicates that each insular representative of Bovidae shows its own peculiar evolutionary model, albeit some parallel trends exist (e.g. reduction in body size, allometric changes in limb bones, alteration of the life history traits). Some changes in morphology (e.g. the simplification of horn cores, the increase in hypsodonty, the acquisition of a 'low-gear' locomotion), for instance, appear as common, albeit not general, patterns triggered by a combination of selective forces. Body size patterns support the 'generality of the island rule' and suggest that biotic interaction had/have a major role in influencing body size evolution in these species, although in different ways on different islands. All things considered, available evidence suggest that a major role in the evolution of insular bovids is played by the structure of the insular community, the nature of available niches and by the dynamics of ecological interactions.

  3. Forest fires in the insular Caribbean.

    PubMed

    Robbins, A Marcus J; Eckelmann, Claus-Martin; Quiñones, Maya

    2008-12-01

    This paper presents a summary of the forest fire reports in the insular Caribbean derived from both management reports and an analysis of publicly available Moderate Resolution Imaging Spectrodiometer (MODIS) satellite active fire products from the region. A vast difference between the amount of fires reported by land managers and fire points in the MODIS Fire Information for Resource Management System data can be observed. Future research is recommended to better understand the nature of these differences. While there is a general lack of available statistical data on forest fires in the Caribbean, a few general observations can be made: Forest fires occur mainly in dry forest types (500 to 1000 mm of mean annual rainfall). These are also the areas where most human settlements are located. Lowland high forests and montane forests with higher rainfall (1000 and more mm y(-1)) are less susceptible to forest fire, but they can burn in exceptionally dry years. Most of the dry forest ecosystems in the Caribbean can be considered to be fire-sensitive ecosystems, while the pine forests in the Caribbean (Cuba, Dominican Republic, and the Bahamas) are maintained by wildfires. In fire-sensitive ecosystems, uncontrolled burning often encourages the spread of alien invasive species. A Caribbean Fire Management Cooperation Strategy was developed between 2005 and 2006 under auspices of the Food and Agriculture Organization of the United Nations. This regional strategy aims to strengthen Caribbean fire management networking by encouraging closer collaboration among countries with similar ecological conditions. The strategy for the Caribbean identifies a number of research, training, and management activities to improve wildfire management capacity in the Caribbean.

  4. Influence of glutamic acid enantiomers on C-mineralization.

    PubMed

    Formánek, Pavel; Vranová, Valerie; Lojková, Lea

    2015-02-01

    Seasonal dynamics in the mineralization of glutamic acid enantiomers in soils from selected ecosystems was determined and subjected to a range of treatments: ambient x elevated CO2 level and meadow x dense x thinned forest environment. Mineralization of glutamic acid was determined by incubation of the soil with 2 mg L- or D-glutamic acid g(-1) of dry soil to induce the maximum respiration rate. Mineralization of glutamic acid enantiomers in soils fluctuates over the course of a vegetation season, following a similar trend across a range of ecosystems. Mineralization is affected by environmental changes and management practices, including elevated CO2 level and thinning intensity. L-glutamic acid metabolism is more dependent on soil type as compared to metabolism of its D-enantiomer. The results support the hypothesis that the slower rate of D- compared to L- amino acid mineralization is due to different roles in anabolism and catabolism of the soil microbial community.

  5. SLC1 Glutamate Transporters

    PubMed Central

    Grewer, Christof; Gameiro, Armanda; Rauen, Thomas

    2014-01-01

    The plasma membrane transporters for the neurotransmitter glutamate belong to the solute carrier 1 (SLC1) family. They are secondary active transporters, taking up glutamate into the cell against a substantial concentration gradient. The driving force for concentrative uptake is provided by the cotransport of Na+ ions and the countertransport of one K+ in a step independent of the glutamate translocation step. Due to eletrogenicity of transport, the transmembrane potential can also act as a driving force. Glutamate transporters are expressed in many tissues, but are of particular importance in the brain, where they contribute to the termination of excitatory neurotransmission. Glutamate transporters can also run in reverse, resulting in glutamate release from cells. Due to these important physiological functions, glutamate transporter expression and, therefore, the transport rate, are tightly regulated. This review summarizes recent literature on the functional and biophysical properties, structure-function relationships, regulation, physiological significance, and pharmacology of glutamate transporters. Particular emphasis is on the insight from rapid kinetic and electrophysiological studies, transcriptional regulation of transporter expression, and reverse transport and its importance for pathophysiological glutamate release under ischemic conditions. PMID:24240778

  6. Insular cortex activity and the evocation of laughter.

    PubMed

    Wattendorf, Elise; Westermann, Birgit; Lotze, Martin; Fiedler, Klaus; Celio, Marco R

    2016-06-01

    The insular cortex is fundamentally involved in the processing of interoceptive information. It has been postulated that the integrative monitoring of the bodily responses to environmental stimuli is crucial for the recognition and experience of emotions. Because emotional arousal is known to be closely coupled to functions of the anterior insula, we suspected laughter to be associated primarily with neuronal activity in this region. An anatomically constrained re-analysis of our imaging data pertaining to ticklish laughter, to inhibited ticklish laughter, and to voluntary laughter revealed regional differences in the levels of neuronal activity in the posterior and mid-/anterior portions of the insula. Ticklish laughter was associated specifically with right ventral anterior insular activity, which was not detected under the other two conditions. Hence, apparently, only laughter that is evoked as an emotional response bears the signature of autonomic arousal in the insular cortex.

  7. Glutamate and Neurodegenerative Disease

    NASA Astrophysics Data System (ADS)

    Schaeffer, Eric; Duplantier, Allen

    As the main excitatory neurotransmitter in the mammalian central nervous system, glutamate is critically involved in most aspects of CNS function. Given this critical role, it is not surprising that glutamatergic dysfunction is associated with many CNS disorders. In this chapter, we review the literature that links aberrant glutamate neurotransmission with CNS pathology, with a focus on neurodegenerative diseases. The biology and pharmacology of the various glutamate receptor families are discussed, along with data which links these receptors with neurodegenerative conditions. In addition, we review progress that has been made in developing small molecule modulators of glutamate receptors and transporters, and describe how these compounds have helped us understand the complex pharmacology of glutamate in normal CNS function, as well as their potential for the treatment of neurodegenerative diseases.

  8. 24 CFR 570.405 - The insular areas.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 3 2011-04-01 2010-04-01 true The insular areas. 570.405 Section 570.405 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR COMMUNITY PLANNING AND DEVELOPMENT, DEPARTMENT OF HOUSING AND...

  9. Ideas on the Margins: Professional Counseling and Ideological Insularity

    ERIC Educational Resources Information Center

    Hansen, James

    2010-01-01

    Efforts to professionalize counseling practice have yielded extraordinary benefits to counselors. However, professionalization has also caused counselors to adopt strict definitions of their education, practices, and ethics. In order to combat the ideological insularity brought on by professionalization, several marginalized ideas are considered.…

  10. 38 CFR 3.40 - Philippine and Insular Forces.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Philippine and Insular Forces. 3.40 Section 3.40 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... under the law. All enlistments and reenlistments of Philippine Scouts in the Regular Army...

  11. 38 CFR 3.40 - Philippine and Insular Forces.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Philippine and Insular Forces. 3.40 Section 3.40 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... under the law. All enlistments and reenlistments of Philippine Scouts in the Regular Army...

  12. 38 CFR 3.40 - Philippine and Insular Forces.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Philippine and Insular Forces. 3.40 Section 3.40 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... under the law. All enlistments and reenlistments of Philippine Scouts in the Regular Army...

  13. 24 CFR 570.442 - Reallocations-Insular Areas.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HOUSING AND URBAN DEVELOPMENT COMMUNITY FACILITIES COMMUNITY DEVELOPMENT BLOCK GRANTS Small Cities, Non... according to population. (b) Any Insular Area grant funds for a fiscal year reserved for an applicant that... according to population. (c) No amounts shall be reallocated under this section in any fiscal year to...

  14. 24 CFR 35.940 - Special requirements for insular areas.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 1 2011-04-01 2011-04-01 false Special requirements for insular areas. 35.940 Section 35.940 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL...

  15. 24 CFR 35.940 - Special requirements for insular areas.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 1 2012-04-01 2012-04-01 false Special requirements for insular areas. 35.940 Section 35.940 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL...

  16. 24 CFR 35.940 - Special requirements for insular areas.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 1 2013-04-01 2013-04-01 false Special requirements for insular areas. 35.940 Section 35.940 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL...

  17. 24 CFR 35.940 - Special requirements for insular areas.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 1 2014-04-01 2014-04-01 false Special requirements for insular areas. 35.940 Section 35.940 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL...

  18. 24 CFR 35.940 - Special requirements for insular areas.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Special requirements for insular areas. 35.940 Section 35.940 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL...

  19. Insular Cortex Is Involved in Consolidation of Object Recognition Memory

    ERIC Educational Resources Information Center

    Bermudez-Rattoni, Federico; Okuda, Shoki; Roozendaal, Benno; McGaugh, James L.

    2005-01-01

    Extensive evidence indicates that the insular cortex (IC), also termed gustatory cortex, is critically involved in conditioned taste aversion and taste recognition memory. Although most studies of the involvement of the IC in memory have investigated taste, there is some evidence that the IC is involved in memory that is not based on taste. In…

  20. 24 CFR 570.405 - The insular areas.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 3 2010-04-01 2010-04-01 false The insular areas. 570.405 Section 570.405 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR COMMUNITY PLANNING AND DEVELOPMENT, DEPARTMENT OF HOUSING AND...

  1. Insular projections to the parahippocampal region in the rat.

    PubMed

    Mathiasen, Mathias L; Hansen, Lilliane; Witter, Menno P

    2015-06-15

    The insular cortex is involved in the perception of interoceptive signals, coding of emotional and affective states, and processing information from gustatory, olfactory, auditory, somatosensory, and nociceptive modalities. This information represents an important component of episodic memory, mediated by the parahippocampal-hippocampal region. A comprehensive description of insular projections to the latter region is lacking. Previous studies reported that insular projections do not target any of the subdivisions in the hippocampal formation (the dentate gyus, the cornu ammonis [CA] fields 1, 2, and 3 and the subiculum), but, in contrast, target the parahippocampal region (perirhinal, postrhinal, lateral and medial entorhinal cortices, and pre- and parasubiculum). The present study examined the topographical and laminar organization of insular projections to the parahippocampal region in the rat with the use of anterograde tracing. Notably, our results corroborated the absence of hippocampal projections. We further showed that the perirhinal and the lateral entorhinal cortices received extensive projections from the insular cortex, primarily from its agranular areas. With the exception of a weak projection to the postrhinal cortex, projections to the remaining parahippocampal areas were either absent or very sparse. The projections to the lateral entorhinal cortex displayed a preference for the deep layers of its most lateral subdivisions, known also to receive hippocampal inputs. Projections to the perirhinal cortex primarily targeted the superficial layers with a preference for its ventral subdivision, referred to as area 35. Our findings indicate that only processed information, reflecting emotional and affective states, but not primary gustatory and viscerosensory information, has direct access to the parahippocampal-hippocampal system.

  2. The cystine/glutamate antiporter system xc− drives breast tumor cell glutamate release and cancer-induced bone pain

    PubMed Central

    Slosky, Lauren M.; BassiriRad, Neemah M.; Symons, Ashley M.; Thompson, Michelle; Doyle, Timothy; Forte, Brittany L.; Staatz, William D.; Bui, Lynn; Neumann, William L.; Mantyh, Patrick W.; Salvemini, Daniela; Largent-Milnes, Tally M.; Vanderah, Todd W.

    2016-01-01

    Abstract Bone is one of the leading sites of metastasis for frequently diagnosed malignancies, including those arising in the breast, prostate and lung. Although these cancers develop unnoticed and are painless in their primary sites, bone metastases result in debilitating pain. Deeper investigation of this pain may reveal etiology and lead to early cancer detection. Cancer-induced bone pain (CIBP) is inadequately managed with current standard-of-care analgesics and dramatically diminishes patient quality of life. While CIBP etiology is multifaceted, elevated levels of glutamate, an excitatory neurotransmitter, in the bone-tumor microenvironment may drive maladaptive nociceptive signaling. Here, we establish a relationship between the reactive nitrogen species peroxynitrite, tumor-derived glutamate, and CIBP. In vitro and in a syngeneic in vivo model of breast CIBP, murine mammary adenocarcinoma cells significantly elevated glutamate via the cystine/glutamate antiporter system xc−. The well-known system xc− inhibitor sulfasalazine significantly reduced levels of glutamate and attenuated CIBP-associated flinching and guarding behaviors. Peroxynitrite, a highly reactive species produced in tumors, significantly increased system xc− functional expression and tumor cell glutamate release. Scavenging peroxynitrite with the iron and mangano-based porphyrins, FeTMPyP and SRI10, significantly diminished tumor cell system xc− functional expression, reduced femur glutamate levels and mitigated CIBP. In sum, we demonstrate how breast cancer bone metastases upregulate a cystine/glutamate co-transporter to elevate extracellular glutamate. Pharmacological manipulation of peroxynitrite or system xc− attenuates CIBP, supporting a role for tumor-derived glutamate in CIBP and validating the targeting of system xc− as a novel therapeutic strategy for the management of metastatic bone pain. PMID:27482630

  3. Body Size Evolution in Insular Speckled Rattlesnakes (Viperidae: Crotalus mitchellii)

    PubMed Central

    Meik, Jesse M.; Lawing, A. Michelle; Pires-daSilva, André

    2010-01-01

    Background Speckled rattlesnakes (Crotalus mitchellii) inhabit multiple islands off the coast of Baja California, Mexico. Two of the 14 known insular populations have been recognized as subspecies based primarily on body size divergence from putative mainland ancestral populations; however, a survey of body size variation from other islands occupied by these snakes has not been previously reported. We examined body size variation between island and mainland speckled rattlesnakes, and the relationship between body size and various island physical variables among 12 island populations. We also examined relative head size among giant, dwarfed, and mainland speckled rattlesnakes to determine whether allometric differences conformed to predictions of gape size (and indirectly body size) evolving in response to shifts in prey size. Methodology/Principal Findings Insular speckled rattlesnakes show considerable variation in body size when compared to mainland source subspecies. In addition to previously known instances of gigantism on Ángel de la Guarda and dwarfism on El Muerto, various degrees of body size decrease have occurred frequently in this taxon, with dwarfed rattlesnakes occurring mostly on small, recently isolated, land-bridge islands. Regression models using the Akaike information criterion (AIC) showed that mean SVL of insular populations was most strongly correlated with island area, suggesting the influence of selection for different body size optima for islands of different size. Allometric differences in head size of giant and dwarf rattlesnakes revealed patterns consistent with shifts to larger and smaller prey, respectively. Conclusions/Significance Our data provide the first example of a clear relationship between body size and island area in a squamate reptile species; among vertebrates this pattern has been previously documented in few insular mammals. This finding suggests that selection for body size is influenced by changes in community dynamics

  4. Activation of right insular cortex during imaginary speech articulation.

    PubMed

    Kato, Yutaka; Muramatsu, Taro; Kato, Motoichiro; Shintani, Masuro; Kashima, Haruo

    2007-03-26

    Human speech articulation is a complex process controlled by a form of 'programming' implemented in the brain. Analysis of speech articulation using neuroimaging techniques is difficult, however, because motor noise is time-locked to the articulatory events. The current magnetoencephalography study, in which 12 participants were required to imagine vocalizing a phonogram after a visual cue, was designed to visualize the prearticulatory 'automatic' processes corresponding to the motor initiation. Magnetic activity correlating with the preparation for articulation occurred in the insular cortices at about 160 ms after the visual cue, and had a relative dominance in the right hemisphere. This suggests that motor control of speech proceeds from the insular regions, although the 'automatic' nature of our task might have led to the observed right-sided dominance.

  5. A review of glutamate's role in traumatic brain injury mechanisms

    NASA Astrophysics Data System (ADS)

    Good, Cameron H.

    2013-05-01

    Glutamate is the primary excitatory neurotransmitter used by the central nervous system (CNS) for synaptic communication, and its extracellular concentration is tightly regulated by glutamate transporters located on nearby astrocytes. Both animal models and human clinical studies have demonstrated elevated glutamate levels immediately following a traumatic brain event, with the duration and severity of the rise corresponding to prognosis. This rise in extracellular glutamate likely results from a combination of excessive neurotransmitter release from damaged neurons and down regulation of uptake mechanisms in local astrocytes. The immediate results of a traumatic event can lead to necrotic tissue in severely injured regions, while prolonged increases in excitatory transmission can cause secondary excitotoxic injury through activation of delayed apoptotic pathways. Initial TBI animal studies utilized a variety of broad glutamate receptor antagonists to successfully combat secondary injury mechanisms, but unfortunately this same strategy has proven inconclusive in subsequent human trials due to deleterious side effects and heterogeneity of injuries. More recent treatment strategies have utilized specific glutamate receptor subunit antagonists in an effort to minimize side effects and have shown promising results. Future challenges will be detecting the concentration and kinetics of the glutamate rise following injury, determining which patient populations could benefit from antagonist treatment based on their extracellular glutamate concentrations and when drugs should be administered to maximize efficacy.

  6. Relation of the insular claustrum to the neocortex in Insectivora.

    PubMed

    Narkiewicz, O; Mamos, L

    1990-01-01

    The claustra of 9 species of Insectivora (Sorex araneus, Sorex minutus, Tenrec ecaudatus, Solenodon paradoxus, Neomys fodiens, Erinaceus europaeus, Talpa europaea, Desmana moschata, Potamogale velox) were investigated. In all examined animals we found two parts of the insular claustrum: the main part called by us the pars principalis and more medially situated lamina profunda claustri. In the "basal" Insectivora the main part is in close contact with the layer VIa of the neocortex. In some more developed "basal" and in all "progressive" Insectivora the area capsularis appears. Dorsolaterally it separates the main part of the insular claustrum from the neocortex and possesses, besides neurons, also numerous fibers of the extreme capsule. The above data strongly suggest that in the phylogenesis the insular claustrum originates from the cortex from which it gets separated by the extreme capsule. Lamina profunda claustri is rather a narrow band of neurons situated on the medial side of the pars principalis and mostly separated from it by a thin lamina of white substance. Lamina profunda is continuous with the layer VIb of the neocortex.

  7. Elevating your elevator talk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An important and often overlooked item that every early career researcher needs to do is compose an elevator talk. The elevator talk, named because the talk should not last longer than an average elevator ride (30 to 60 seconds), is an effective method to present your research and yourself in a clea...

  8. History of glutamate production.

    PubMed

    Sano, Chiaki

    2009-09-01

    In 1907 Kikunae Ikeda, a professor at the Tokyo Imperial University, began his research to identify the umami component in kelp. Within a year, he had succeeded in isolating, purifying, and identifying the principal component of umami and quickly obtained a production patent. In 1909 Saburosuke Suzuki, an entrepreneur, and Ikeda began the industrial production of monosodium l-glutamate (MSG). The first industrial production process was an extraction method in which vegetable proteins were treated with hydrochloric acid to disrupt peptide bonds. l-Glutamic acid hydrochloride was then isolated from this material and purified as MSG. Initial production of MSG was limited because of the technical drawbacks of this method. Better methods did not emerge until the 1950s. One of these was direct chemical synthesis, which was used from 1962 to 1973. In this procedure, acrylonitrile was the starting material, and optical resolution of dl-glutamic acid was achieved by preferential crystallization. In 1956 a direct fermentation method to produce glutamate was introduced. The advantages of the fermentation method (eg, reduction of production costs and environmental load) were large enough to cause all glutamate manufacturers to shift to fermentation. Today, total world production of MSG by fermentation is estimated to be 2 million tons/y (2 billion kg/y). However, future production growth will likely require further innovation.

  9. Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period.

    PubMed

    Zhao, Changjiu; Gammie, Stephen C

    2014-12-03

    Dramatic structural and functional remodeling occurs in the postpartum brain for the establishment of maternal care, which is essential for the growth and development of young offspring. Glutamate and GABA signaling are critically important in modulating multiple behavioral performances. Large scale signaling changes occur in the postpartum brain, but it is still not clear to what extent the neurotransmitters glutamate and GABA change and whether the ratio of glutamate/GABA remains balanced. In this study, we examined the glutamate/GABA-glutamine cycle in the lateral septum (LS) of postpartum female mice. In postpartum females (relative to virgins), tissue levels of glutamate and GABA were elevated in LS and increased mRNA was found for the respective enzymes producing glutamate and GABA, glutaminase (Gls) and glutamate decarboxylase 1 and 2 (Gad1 and Gad2). The common precursor, glutamine, was elevated as was the enzyme that produces it, glutamate-ammonia ligase (Glul). Additionally, glutamate, GABA, and glutamine were positively correlated and the glutamate/GABA ratio was almost identical in the postpartum and virgin females. Collectively, these findings indicate that glutamate and GABA signaling are increased and that the ratio of glutamate/GABA is well balanced in the maternal LS. The postpartum brain may provide a useful model system for understanding how glutamate and GABA are linked despite large signaling changes. Given that some mental health disorders, including depression and schizophrenia display dysregulated glutamate/GABA ratio, and there is increased vulnerability to mental disorders in mothers, it is possible that these postpartum disorders emerge when glutamate and GABA changes are not properly coordinated.

  10. Dysfunctional TCA-Cycle Metabolism in Glutamate Dehydrogenase Deficient Astrocytes.

    PubMed

    Nissen, Jakob D; Pajęcka, Kamilla; Stridh, Malin H; Skytt, Dorte M; Waagepetersen, Helle S

    2015-12-01

    Astrocytes take up glutamate in the synaptic area subsequent to glutamatergic transmission by the aid of high affinity glutamate transporters. Glutamate is converted to glutamine or metabolized to support intermediary metabolism and energy production. Glutamate dehydrogenase (GDH) and aspartate aminotransferase (AAT) catalyze the reversible reaction between glutamate and α-ketoglutarate, which is the initial step for glutamate to enter TCA cycle metabolism. In contrast to GDH, AAT requires a concomitant interconversion of oxaloacetate and aspartate. We have investigated the role of GDH in astrocyte glutamate and glucose metabolism employing siRNA mediated knock down (KD) of GDH in cultured astrocytes using stable and radioactive isotopes for metabolic mapping. An increased level of aspartate was observed upon exposure to [U-(13) C]glutamate in astrocytes exhibiting reduced GDH activity. (13) C Labeling of aspartate and TCA cycle intermediates confirmed that the increased amount of aspartate is associated with elevated TCA cycle flux from α-ketoglutarate to oxaloacetate, i.e. truncated TCA cycle. (13) C Glucose metabolism was elevated in GDH deficient astrocytes as observed by increased de novo synthesis of aspartate via pyruvate carboxylation. In the absence of glucose, lactate production from glutamate via malic enzyme was lower in GDH deficient astrocytes. In conclusions, our studies reveal that metabolism via GDH serves an important anaplerotic role by adding net carbon to the TCA cycle. A reduction in GDH activity seems to cause the astrocytes to up-regulate activity in pathways involved in maintaining the amount of TCA cycle intermediates such as pyruvate carboxylation as well as utilization of alternate substrates such as branched chain amino acids.

  11. Prefrontal glutamate correlates of methamphetamine sensitization and preference

    PubMed Central

    Lominac, Kevin D.; Quadir, Sema G.; Barrett, Hannah M.; McKenna, Courtney L.; Schwartz, Lisa M.; Ruiz, Paige N.; Wroten, Melissa G.; Campbell, Rianne R.; Miller, Bailey W.; Holloway, John J.; Travis, Katherine O.; Rajasekar, Ganesh; Maliniak, Dan; Thompson, Andrew B.; Urman, Lawrence E.; Kippin, Tod E.; Phillips, Tamara J.; Szumlinski, Karen K.

    2016-01-01

    Methamphetamine (MA) is a widely abused, highly addictive, psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo-functioning of the prefrontal cortex (PFC). Our understanding of how repeated methamphetamine impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relation between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of methamphetamine (10 injections of 2 mg/kg, IP) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high versus low MA-drinking selectively bred mouse lines (MAHDR versus MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated methamphetamine sensitized drug-induced glutamate release and lowered indices of NMDA receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or AMPA glutamate receptors. Elevated basal glutamate, blunted methamphetamine-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high versus low methamphetamine drinking, and Homer2a/b levels were inversely correlated with the motivational valence of methamphetamine in C57BL/6J mice. These data provide novel evidence that repeated, low-dose, methamphetamine is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in methamphetamine addiction vulnerability/resiliency. PMID:26742098

  12. Prefrontal glutamate correlates of methamphetamine sensitization and preference.

    PubMed

    Lominac, Kevin D; Quadir, Sema G; Barrett, Hannah M; McKenna, Courtney L; Schwartz, Lisa M; Ruiz, Paige N; Wroten, Melissa G; Campbell, Rianne R; Miller, Bailey W; Holloway, John J; Travis, Katherine O; Rajasekar, Ganesh; Maliniak, Dan; Thompson, Andrew B; Urman, Lawrence E; Kippin, Tod E; Phillips, Tamara J; Szumlinski, Karen K

    2016-03-01

    Methamphetamine (MA) is a widely misused, highly addictive psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo-functioning of the prefrontal cortex (PFC). Our understanding of how repeated MA impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relationship between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of MA (ten injections of 2 mg/kg, i.p.) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high vs. low MA-drinking selectively bred mouse lines (MAHDR vs. MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated MA sensitized drug-induced glutamate release and lowered indices of N-methyl-d-aspartate receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. Elevated basal glutamate, blunted MA-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high vs. low MA drinking, and Homer2a/b levels were inversely correlated with the motivational valence of MA in C57BL/6J mice. These data provide novel evidence that repeated, low-dose MA is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in MA addiction vulnerability/resiliency.

  13. Repeated exposure to moderate doses of ethanol augments hippocampal glutamate neurotransmission by increasing release

    PubMed Central

    Chefer, Vladimir; Meis, Jennifer; Wang, Grace; Kuzmin, Alexander; Bakalkin, Georgy; Shippenberg, Toni

    2013-01-01

    The present study used conventional and quantitative microdialysis to assess glutamatergic and GABAergic neurotransmission in the hippocampal CA3 area of the rat following a moderate-dose ethanol treatment regimen. Male Wistar rats received 3.4 g/kg of ethanol or water for 6 days via gastric gavage. Microdialysis experiments commenced 2 days later. Basal and depolarization-induced glutamate overflow were significantly elevated in ethanol-treated animals. Basal and depolarization-induced gamma-aminobutyric acid (GABA) overflow were unaltered. Quantitative no-net-flux microdialysis was used to determine if changes in dialysate glutamate levels following ethanol administration are due to an increase in release or a decrease in uptake.To confirm the validity of this method for quantifying basal glutamate dynamics, extracellular concentrations of glutamate and the extraction fraction, which reflects changes in analyte clearance, were quantified in response to retro-dialysis of the glutamate uptake blocker trans-pyrrolidine-2,4-dicarboxylic acid (tPDC). tPDC significantly decreased the extraction fraction for glutamate, resulting in augmented extracellular glutamate concentrations. Repeated ethanol administration did not alter the glutamate extraction fraction. However, extracellular glutamate concentrations were significantly elevated, indicating that glutamate release is increased as a consequence of repeated ethanol administration. These data demonstrate that repeated bouts of moderate ethanol consumption alter basal glutamate dynamics in the CA3 region of the dorsal hippocampus. Basal glutamate release is augmented, whereas glutamate uptake is unchanged. Furthermore, they suggest that dysregulation of glutamate transmission in this region may contribute to the previously documented deficits in cognitive function associated with moderate dose ethanol use. PMID:21182572

  14. Dietary Glutamate: Interactions With the Enteric Nervous System

    PubMed Central

    Wang, Guo-Du; Wang, Xi-Yu; Xia, Yun

    2014-01-01

    Background/Aims Digestion of dietary protein elevates intraluminal concentrations of glutamate in the small intestine, some of which gain access to the enteric nervous system (ENS). Glutamate, in the central nervous system (CNS), is an excitatory neurotransmitter. A dogma that glutamatergic neurophysiology in the ENS recapitulates CNS glutamatergic function persists. We reassessed the premise that glutamatergic signaling in the ENS recapitulates its neurotransmitter role in the CNS. Methods Pharmacological analysis of actions of receptor agonists and antagonists in concert with immunohistochemical localization of glutamate transporters and receptors was used. Analysis focused on intracellularly-recorded electrical and synaptic behavior of ENS neurons, on stimulation of mucosal secretion by secretomotor neurons in the submucosal plexus and on muscle contractile behavior mediated by musculomotor neurons in the myenteric plexus. Results Immunoreactivity for glutamate was expressed in ENS neurons. ENS neurons expressed immunoreactivity for the EAAC-1 glutamate transporter. Neither L-glutamate nor glutamatergic receptor agonists had excitatory actions on ENS neurons. Metabotropic glutamatergic receptor agonists did not directly stimulate neurogenic mucosal chloride secretion. Neither L-glutamate nor the metabotropic glutamatergic receptor agonist, aminocyclopentane-1,3-dicarboxylic acid (ACPD), changed the mean amplitude of spontaneously occurring contractions in circular or longitudinal strips of intestinal wall from either guinea pig or human small intestinal preparations. Conclusions Early discoveries, for excitatory glutamatergic neurotransmission in the CNS, inspired enthusiasm that investigation in the ENS would yield discoveries recapitulating the CNS glutamatergic story. We found this not to be the case. PMID:24466444

  15. Differential Responses of the Insular Cortex Gyri to Autonomic Challenges

    PubMed Central

    Macey, Paul M.; Wu, Paula; Kumar, Rajesh; Ogren, Jennifer A.; Richardson, Heidi L.; Woo, Mary A.; Harper, Ronald M.

    2014-01-01

    Determining insular functional topography is essential for assessing autonomic consequences of neural injury. We examined that topography in the five major insular cortex gyri to three autonomic challenges, the Valsalva, hand grip, and foot cold pressor, using functional magnetic resonance imaging (fMRI) procedures. Fifty-seven healthy subjects (age±std: 47±9 years) performed four 18 s Valsalva maneuvers (30 mmHg load pressure), four hand grip challenges (16 s at 80% effort), and a foot cold pressor (60 s, 4°C), with fMRI scans recorded every 2 s. Signal trends were compared across gyri using repeated measures ANOVA. Significantly (P<0.05) higher signals in left anterior versus posterior gyri appeared during Valsalva strain, and in the first 4 s of recovery. The right anterior gyri showed sustained higher signals up to 2 s post-challenge, relative to posterior gyri, with sub-gyral differentiation. Left anterior gyri signals were higher than posterior areas during the hand grip challenge. All right anterior gyri showed increased signals over posterior up to 12 s post-challenge, with decline in the most-anterior gyrus from 10–24 s during recovery. The left three anterior gyri showed relatively lower signals only during the 90 s recovery of the cold pressor, while the two most-anterior right gyri signals increased only during the stimulus. More-differentiated representation of autonomic signals appear in the anterior right insula for the Valsalva maneuver, a bilateral, more-posterior signal representation for hand grip, and preferentially right-sided, anterior-posterior representation for the cold pressor. The functional organization of the insular cortex is gyri-specific to unique autonomic challenges. PMID:22342370

  16. Insular primary glioblastomas with IDH mutations: Clinical and biological specificities.

    PubMed

    Hata, Nobuhiro; Hatae, Ryusuke; Yoshimoto, Koji; Murata, Hideki; Kuga, Daisuke; Akagi, Yojiro; Sangatsuda, Yuhei; Suzuki, Satoshi O; Iwaki, Toru; Mizoguchi, Masahiro; Iihara, Koji

    2017-01-24

    Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH-wildtype (IDH-wt) pGBMs. IDH-mutant (IDH-mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH-mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH-wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long-surviving case, but genetic alterations in the astrocyte-sGBM pathway were generally prevalent in IDH-mut pGBMs. Our results present a unique phenotype of IDH-mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs.

  17. Insular avian adaptations on two Neotropical continental islands

    PubMed Central

    Wright, Natalie A.; Steadman, David W.

    2012-01-01

    Aim Most studies of avian insular adaptations have focused on oceanic islands, which may not allow characters that are insular adaptations to be teased apart from those that benefit dispersal and colonization. Using birds on continental islands, we investigated characters that evolved in situ in response to insular environments created by late Pleistocene sea level rise. Location Trinidad and Tobago, nearby Caribbean islands and continental South America. Methods We weighed fresh flight muscles and measured museum skeletal specimens of seven species of birds common to the continental islands of Trinidad and Tobago. Results When corrected for body size, study species exhibited significantly smaller flight muscles, sterna and sternal keels on Tobago than on larger Trinidad and continental South America. Tobago populations were more ‘insular’ in their morphologies than conspecifics on Trinidad or the continent in other ways as well, including having longer bills, longer wings, longer tails and longer legs. Main conclusions We hypothesize that the longer bills enhance foraging diversity, the longer wings and tails compensate for the smaller pectoral assemblage (allowing for retention of volancy, but with a probable reduction in flight power and speed), and the longer legs expand perching ability. Each of these differences is likely to be related to the lower diversity and fewer potential predators and competitors on Tobago compared with Trinidad. These patterns of smaller flight muscles and larger bills, legs, wings and tails in island birds are not the results of selection for island dispersal and colonization, but probably arose from selection pressures acting on populations already inhabiting these islands. PMID:23066173

  18. 19 CFR 7.4 - Watches and watch movements from U.S. insular possessions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Watches and watch movements from U.S. insular... STATION § 7.4 Watches and watch movements from U.S. insular possessions. (a) The issuance of an... Watches and Watch Movements, by the Department of Commerce, authorizes a producer of watches in the...

  19. 19 CFR 7.4 - Watches and watch movements from U.S. insular possessions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Watches and watch movements from U.S. insular... STATION § 7.4 Watches and watch movements from U.S. insular possessions. (a) The issuance of an... Watches and Watch Movements, by the Department of Commerce, authorizes a producer of watches in the...

  20. 19 CFR 7.4 - Watches and watch movements from U.S. insular possessions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Watches and watch movements from U.S. insular... STATION § 7.4 Watches and watch movements from U.S. insular possessions. (a) The issuance of an... Watches and Watch Movements, by the Department of Commerce, authorizes a producer of watches in the...

  1. 19 CFR 7.4 - Watches and watch movements from U.S. insular possessions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 1 2013-04-01 2013-04-01 false Watches and watch movements from U.S. insular... STATION § 7.4 Watches and watch movements from U.S. insular possessions. (a) The issuance of an... Watches and Watch Movements, by the Department of Commerce, authorizes a producer of watches in the...

  2. 19 CFR 7.4 - Watches and watch movements from U.S. insular possessions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Watches and watch movements from U.S. insular... STATION § 7.4 Watches and watch movements from U.S. insular possessions. (a) The issuance of an... Watches and Watch Movements, by the Department of Commerce, authorizes a producer of watches in the...

  3. Isolated left posterior insular infarction and convergent roles in verbal fluency, language, memory, and executive function.

    PubMed

    Julayanont, Parunyou; Ruthirago, Doungporn; DeToledo, John C

    2016-07-01

    The posterior insular cortex-a complex structure interconnecting various brain regions for different functions-is a rare location for ischemic stroke. We report a patient with isolated left posterior insular infarction who presented with multiple cognitive impairment, including impairment in semantic and phonemic verbal fluency.

  4. Altered Functional Connectivity of the Insular Cortex across Prefrontal Networks in Cocaine Addiction

    PubMed Central

    Cisler, Josh M.; Elton, Amanda; Kennedy, Ashley P.; Young, Jonathan; Smitherman, Sonet; James, George Andrew; Kilts, Clinton D.

    2013-01-01

    Interoception is theorized to be an important process mediating substance use disorders, and the insular cortex is recognized as a core neural region supporting interoception. The purpose of this study was to compare the integration of the insular cortex into prefrontal-related resting-state networks between individuals with cocaine dependence and healthy controls. 41 participants with cocaine dependence and 19 control participants underwent a resting-state 3T fMRI scan. Individuals with cocaine dependence demonstrated altered functional connectivity of the insular cortex, predominantly the right insular cortex, with all eight prefrontal-related resting-state networks identified through Independent Component Analysis (ICA). A conjunction analysis demonstrated that the right insular cortex was the neural region with the highest number of common group differences across the networks. There was no evidence that insular cortex connectivity commonly differed between groups for non-prefrontal-related networks. Further, seed-based functional connectivity analyses extended the network analyses and indicated that cocaine dependence was associated with greater connectivity of the right insula with the dorsomedial PFC, inferior frontal gyrus, and bilateral dlPFC. These data support the hypothesis that cocaine dependence is related to altered functional interactions of the insular cortex with prefrontal networks. The results suggest possible neural mechanisms by which the insular cortex and interoceptive information influence cognitive control and decision-making processes presumably mediated by prefrontal networks in the cocaine dependence process. PMID:23684980

  5. The conversion of glutamate by glutamine synthase in neocortical astrocytes from juvenile rat is important to limit glutamate spillover and peri/extrasynaptic activation of NMDA receptors.

    PubMed

    Trabelsi, Yosra; Amri, Mohamed; Becq, Hélène; Molinari, Florence; Aniksztejn, Laurent

    2017-02-01

    Glutamate transporters (EAATs) are important to maintain spatial and temporal specificity of synaptic transmission. Their efficiency to uptake and transport glutamate into the intracellular space depends on several parameters including the intracellular concentrations of Na(+) and glutamate, the elevations of which may slow down the cycling rate of EAATs. In astrocytes, glutamate is maintained at low concentration due to the presence of specific enzymes such as glutamine synthase (GS). GS inhibition results in cytosolic accumulation of glutamate suggesting that the conversion of glutamate by GS is important for EAATs operation. Here we recorded astrocytes from juvenile rat neocortical slices and analyzed the consequences of elevated intracellular glutamate concentrations and of GS inhibition on the time course of synaptically evoked transporter current (STC). In slices from rats treated with methionine sulfoximine (MSO), a GS inhibitor, STC evoked by short burst of high frequency stimulation (HFS; 100 Hz for 100 ms) but not by low frequency stimulation (LFS; 0.1 Hz) was twice slower than STC evoked from saline injected rats. Same results were obtained for astrocytes recorded with pipette containing 3-10 mM glutamate and compared with cells recorded with 0 or1 mM glutamate in the patch pipette. We also showed that HFS elicited significantly larger NMDAR-excitatory postsynaptic currents (EPSCs) with a stronger peri/extrasynaptic component in pyramidal cells from MSO-treated compared with saline treated rats. Taken together our data demonstrate that the conversion of glutamate by GS is fundamental to ensure an efficient clearance of glutamate by EAATs and to prevent glutamate spillover. GLIA 2017;65:401-415.

  6. Left-Insular Damage, Autonomic Instability and Sudden Unexpected Death in Epilepsy

    PubMed Central

    Lacuey, Nuria; Zonjy, Bilal; Theerannaew, Wanchat; Loparo, Kenneth A.; Tatsuoka, Curtis; Sahadevan, Jayakumar; Lhatoo, Samden D.

    2015-01-01

    We analyzed the only two sudden unexpected death in epilepsy (SUDEP) cases from 320 prospectively recruited patients in the three-year Prevention and Risk Identification of SUDEP Mortality (PRISM) Project. Both patients had surgically refractory epilepsy, evidence of left insular damage following previous temporal/temporo-insular resections, and progressive changes in Heart Rate Variability (HRV) in monitored evaluations prior to death. Insular damage is known to cause autonomic dysfunction and increased mortality in acute stroke. This report suggests a possible role for the insula in the pathogenesis of SUDEP. The presence of intrinsic insular lesions or acquired insular damage in refractory epilepsy patients may be an additional risk factor for SUDEP. PMID:26797084

  7. Left-insular damage, autonomic instability, and sudden unexpected death in epilepsy.

    PubMed

    Lacuey, Nuria; Zonjy, Bilal; Theerannaew, Wanchat; Loparo, Kenneth A; Tatsuoka, Curtis; Sahadevan, Jayakumar; Lhatoo, Samden D

    2016-02-01

    We analyzed the only two sudden unexpected death in epilepsy (SUDEP) cases from 320 prospectively recruited patients in the three-year Prevention and Risk Identification of SUDEP Mortality (PRISM) project. Both patients had surgically refractory epilepsy, evidence of left insular damage following previous temporal/temporo-insular resections, and progressive changes in heart rate variability (HRV) in monitored evaluations prior to death. Insular damage is known to cause autonomic dysfunction and increased mortality in acute stroke. This report suggests a possible role for the insula in the pathogenesis of SUDEP. The presence of intrinsic insular lesions or acquired insular damage in patients with refractory epilepsy may be an additional risk factor for SUDEP.

  8. Glucose replaces glutamate as energy substrate to fuel glutamate uptake in glutamate dehydrogenase-deficient astrocytes.

    PubMed

    Pajęcka, Kamilla; Nissen, Jakob D; Stridh, Malin H; Skytt, Dorte M; Schousboe, Arne; Waagepetersen, Helle S

    2015-07-01

    Cultured astrocytes treated with siRNA to knock down glutamate dehydrogenase (GDH) were used to investigate whether this enzyme is important for the utilization of glutamate as an energy substrate. By incubation of these cells in media containing different concentrations of glutamate (range 100-500 µM) in the presence or in the absence of glucose, the metabolism of these substrates was studied by using tritiated glutamate or 2-deoxyglucose as tracers. In addition, the cellular contents of glutamate and ATP were determined. The astrocytes were able to maintain physiological levels of ATP regardless of the expression level of GDH and the incubation condition, indicating a high degree of flexibility with regard to regulatory mechanisms involved in maintaining an adequate energy level in the cells. Glutamate uptake was found to be increased in these cells when exposed to increasing levels of extracellular glutamate independently of the GDH expression level. Moreover, increased intracellular glutamate content was observed in the GDH-deficient cells after a 2-hr incubation in the presence of 100 µM glutamate. It is significant that GDH-deficient cells exhibited an increased utilization of glucose in the presence of 250 and 500 µM glutamate, monitored as an increase in the accumulation of tritiated 2-deoxyglucose-6-phosphate. These findings underscore the importance of the expression level of GDH for the ability to utilize glutamate as an energy source fueling its own energy-requiring uptake.

  9. Phylogeny and adaptation shape the teeth of insular mice.

    PubMed

    Ledevin, Ronan; Chevret, Pascale; Ganem, Guila; Britton-Davidian, Janice; Hardouin, Emilie A; Chapuis, Jean-Louis; Pisanu, Benoit; da Luz Mathias, Maria; Schlager, Stefan; Auffray, Jean-Christophe; Renaud, Sabrina

    2016-02-10

    By accompanying human travels since prehistorical times, the house mouse dispersed widely throughout the world, and colonized many islands. The origin of the travellers determined the phylogenetic source of the insular mice, which encountered diverse ecological and environmental conditions on the various islands. Insular mice are thus an exceptional model to disentangle the relative role of phylogeny, ecology and climate in evolution. Molar shape is known to vary according to phylogeny and to respond to adaptation. Using for the first time a three-dimensional geometric morphometric approach, compared with a classical two-dimensional quantification, the relative effects of size variation, phylogeny, climate and ecology were investigated on molar shape diversity across a variety of islands. Phylogeny emerged as the factor of prime importance in shaping the molar. Changes in competition level, mostly driven by the presence or absence of the wood mouse on the different islands, appeared as the second most important effect. Climate and size differences accounted for slight shape variation. This evidences a balanced role of random differentiation related to history of colonization, and of adaptation possibly related to resource exploitation.

  10. Phylogeny and adaptation shape the teeth of insular mice

    PubMed Central

    Ledevin, Ronan; Chevret, Pascale; Ganem, Guila; Britton-Davidian, Janice; Hardouin, Emilie A.; Chapuis, Jean-Louis; Pisanu, Benoit; da Luz Mathias, Maria; Schlager, Stefan; Auffray, Jean-Christophe; Renaud, Sabrina

    2016-01-01

    By accompanying human travels since prehistorical times, the house mouse dispersed widely throughout the world, and colonized many islands. The origin of the travellers determined the phylogenetic source of the insular mice, which encountered diverse ecological and environmental conditions on the various islands. Insular mice are thus an exceptional model to disentangle the relative role of phylogeny, ecology and climate in evolution. Molar shape is known to vary according to phylogeny and to respond to adaptation. Using for the first time a three-dimensional geometric morphometric approach, compared with a classical two-dimensional quantification, the relative effects of size variation, phylogeny, climate and ecology were investigated on molar shape diversity across a variety of islands. Phylogeny emerged as the factor of prime importance in shaping the molar. Changes in competition level, mostly driven by the presence or absence of the wood mouse on the different islands, appeared as the second most important effect. Climate and size differences accounted for slight shape variation. This evidences a balanced role of random differentiation related to history of colonization, and of adaptation possibly related to resource exploitation. PMID:26842576

  11. Structural Differences in Insular Cortex Reflect Vicarious Injustice Sensitivity

    PubMed Central

    Baumgartner, Thomas; Saulin, Anne; Hein, Grit; Knoch, Daria

    2016-01-01

    Sensitivity to injustice inflicted on others is a strong motivator of human social behavior. There are, however, enormous individual differences in vicarious injustice sensitivity. Some people are strongly affected when witnessing injustice, while others barely notice it, but the factors behind this heterogeneity are poorly understood. Here we examine the neuroanatomical basis of these differences using voxel-based morphometry and Freesurfer image analysis suite. Whole brain corrected analyses show that a person’s propensity to be vicariously affected by injustice to others is reflected by the gray matter volume and thickness of the bilateral mid insular cortex. The larger a person’s gray matter volume and thickness of the mid insula, the higher that person’s sensitivity to injustice experienced by others. These findings show that the individual neuroanatomy of the mid insular cortex captures a person’s predisposition to be vicariously affected by injustice, and thus adds a novel aspect to previous functional work that has linked this region to the processing of transient vicarious states. PMID:27930678

  12. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

    PubMed

    Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

    2016-12-01

    Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

  13. Visualization of glutamate as a volume transmitter.

    PubMed

    Okubo, Yohei; Iino, Masamitsu

    2011-02-01

    Glutamate is the major excitatory neurotransmitter in the central nervous system. Although glutamate mediates synaptically confined point-to-point transmission, it has been suggested that under certain conditions glutamate may escape from the synaptic cleft (glutamate spillover), accumulate in the extrasynaptic space, and mediate volume transmission to regulate important brain functions. However, the inability to directly measure glutamate dynamics around active synapses has limited our understanding of glutamatergic volume transmission. The recent development of a family of fluorescent glutamate indicators has enabled the visualization of extrasynaptic glutamate dynamics in brain tissues. In this topical review, we examine glutamate as a volume transmitter based on novel results of glutamate imaging in the brain.

  14. Dwarfism in insular sloths: biogeography, selection, and evolutionary rate.

    PubMed

    Anderson, Robert P; Handley, Charles O

    2002-05-01

    The islands of Bocas del Toro, Panama, were sequentially separated from the adjacent mainland by rising sea levels during the past 10,000 years. Three-toed sloths (Bradypus) from five islands are smaller than their mainland counterparts, and the insular populations themselves vary in mean body size. We first examine relationships between body size and physical characteristics of the islands, testing hypotheses regarding optimal body size, evolutionary equilibria, and the presence of dispersal in this system. To do so, we conduct linear regressions of body size onto island area, distance from the mainland, and island age. Second, we retroactively calculate two measures of the evolutionary rate of change in body size (haldanes and darwins) and the standardized linear selection differential, or selection intensity (i). We also test the observed morphological changes against models of evolution by genetic drift. The results indicate that mean body size decreases linearly with island age, explaining up to 97% of the variation among population means. Neither island area nor distance from the mainland is significant in multiple regressions that include island age. Thus, we find no evidence for differential optimal body size among islands, or for dispersal in the system. In contrast, the dependence of body size on island age suggests uniform directional selection for small body size in the insular populations. Although genetic drift cannot be discounted as the cause for this evolution in body size, the probability is small given the consistent direction of evolution (repeated dwarfism). The insular sloths show a sustained rate of evolution similar to those measured in haldanes over tens of generations, appearing to unite micro- and macroevolutionary time scales. Furthermore, the magnitude and rate of this example of rapid differentiation fall within predictions of theoretical models from population genetics. However, the linearity of the relationship between body size and

  15. Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress.

    PubMed

    Zhang, Chao; Wang, Chendan; Ren, Jianbo; Guo, Xiangjie; Yun, Keming

    2016-10-24

    Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca(2+) release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca(2+) release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca(2+) overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca(2+) release and ER stress.

  16. Metabotropic Glutamate Receptors

    PubMed Central

    Dillon, James; Franks, Christopher J.; Murray, Caitriona; Edwards, Richard J.; Calahorro, Fernando; Ishihara, Takeshi; Katsura, Isao; Holden-Dye, Lindy; O'Connor, Vincent

    2015-01-01

    Glutamatergic neurotransmission is evolutionarily conserved across animal phyla. A major class of glutamate receptors consists of the metabotropic glutamate receptors (mGluRs). In C. elegans, three mGluR genes, mgl-1, mgl-2, and mgl-3, are organized into three subgroups, similar to their mammalian counterparts. Cellular reporters identified expression of the mgls in the nervous system of C. elegans and overlapping expression in the pharyngeal microcircuit that controls pharyngeal muscle activity and feeding behavior. The overlapping expression of mgls within this circuit allowed the investigation of receptor signaling per se and in the context of receptor interactions within a neural network that regulates feeding. We utilized the pharmacological manipulation of neuronally regulated pumping of the pharyngeal muscle in the wild-type and mutants to investigate MGL function. This defined a net mgl-1-dependent inhibition of pharyngeal pumping that is modulated by mgl-3 excitation. Optogenetic activation of the pharyngeal glutamatergic inputs combined with electrophysiological recordings from the isolated pharyngeal preparations provided further evidence for a presynaptic mgl-1-dependent regulation of pharyngeal activity. Analysis of mgl-1, mgl-2, and mgl-3 mutant feeding behavior in the intact organism after acute food removal identified a significant role for mgl-1 in the regulation of an adaptive feeding response. Our data describe the molecular and cellular organization of mgl-1, mgl-2, and mgl-3. Pharmacological analysis identified that, in these paradigms, mgl-1 and mgl-3, but not mgl-2, can modulate the pharyngeal microcircuit. Behavioral analysis identified mgl-1 as a significant determinant of the glutamate-dependent modulation of feeding, further highlighting the significance of mGluRs in complex C. elegans behavior. PMID:25869139

  17. Gustatory insular cortex, aversive taste memory and taste neophobia.

    PubMed

    Lin, Jian-You; Arthurs, Joe; Reilly, Steve

    2015-03-01

    Prior research indicates a role for the gustatory insular cortex (GC) in taste neophobia. Rats with lesions of the GC show much weaker avoidance to a novel and potentially dangerous taste than do neurologically intact animals. The current study used the retention of conditioned taste aversion (CTA) as a tool to determine whether the GC modulates neophobia by processing taste novelty or taste danger. The results show that GC lesions attenuate CTA retention (Experiment 1) and impair taste neophobia (Experiment 2). Given that normal CTA retention does not involve the processing of taste novelty, the pattern of results suggests that the GC is involved in taste neophobia via its function in processing the danger conveyed by a taste stimulus.

  18. Auditory, Somatosensory, and Multisensory Insular Cortex in the Rat

    PubMed Central

    Rodgers, Krista M.; Benison, Alexander M.; Klein, Andrea

    2008-01-01

    Compared with other areas of the forebrain, the function of insular cortex is poorly understood. This study examined the unisensory and multisensory function of the rat insula using high-resolution, whole-hemisphere, epipial evoked potential mapping. We found the posterior insula to contain distinct auditory and somatotopically organized somatosensory fields with an interposed and overlapping region capable of integrating these sensory modalities. Unisensory and multisensory responses were uninfluenced by complete lesioning of primary and secondary auditory and somatosensory cortices, suggesting a high degree of parallel afferent input from the thalamus. In light of the established connections of the posterior insula with the amygdala, we propose that integration of auditory and somatosensory modalities reported here may play a role in auditory fear conditioning. PMID:18424777

  19. Insular Organization of Gene Space in Grass Genomes

    PubMed Central

    Massa, Alicia N.; Wanjugi, Humphrey; Deal, Karin R.; You, Frank M.; Xu, Xiangyang; Gu, Yong Q.; Luo, Ming-Cheng; Anderson, Olin D.; Chan, Agnes P.; Rabinowicz, Pablo

    2013-01-01

    Wheat and maize genes were hypothesized to be clustered into islands but the hypothesis was not statistically tested. The hypothesis is statistically tested here in four grass species differing in genome size, Brachypodium distachyon, Oryza sativa, Sorghum bicolor, and Aegilops tauschii. Density functions obtained under a model where gene locations follow a homogeneous Poisson process and thus are not clustered are compared with a model-free situation quantified through a non-parametric density estimate. A simple homogeneous Poisson model for gene locations is not rejected for the small O. sativa and B. distachyon genomes, indicating that genes are distributed largely uniformly in those species, but is rejected for the larger S. bicolor and Ae. tauschii genomes, providing evidence for clustering of genes into islands. It is proposed to call the gene islands “gene insulae” to distinguish them from other types of gene clustering that have been proposed. An average S. bicolor and Ae. tauschii insula is estimated to contain 3.7 and 3.9 genes with an average intergenic distance within an insula of 2.1 and 16.5 kb, respectively. Inter-insular distances are greater than 8 and 81 kb and average 15.1 and 205 kb, in S. bicolor and Ae. tauschii, respectively. A greater gene density observed in the distal regions of the Ae. tauschii chromosomes is shown to be primarily caused by shortening of inter-insular distances. The comparison of the four grass genomes suggests that gene locations are largely a function of a homogeneous Poisson process in small genomes. Nonrandom insertions of LTR retroelements during genome expansion creates gene insulae, which become less dense and further apart with the increase in genome size. High concordance in relative lengths of orthologous intergenic distances among the investigated genomes including the maize genome suggests functional constraints on gene distribution in the grass genomes. PMID:23326580

  20. Insular organization of gene space in grass genomes.

    PubMed

    Gottlieb, Andrea; Müller, Hans-Georg; Massa, Alicia N; Wanjugi, Humphrey; Deal, Karin R; You, Frank M; Xu, Xiangyang; Gu, Yong Q; Luo, Ming-Cheng; Anderson, Olin D; Chan, Agnes P; Rabinowicz, Pablo; Devos, Katrien M; Dvorak, Jan

    2013-01-01

    Wheat and maize genes were hypothesized to be clustered into islands but the hypothesis was not statistically tested. The hypothesis is statistically tested here in four grass species differing in genome size, Brachypodium distachyon, Oryza sativa, Sorghum bicolor, and Aegilops tauschii. Density functions obtained under a model where gene locations follow a homogeneous Poisson process and thus are not clustered are compared with a model-free situation quantified through a non-parametric density estimate. A simple homogeneous Poisson model for gene locations is not rejected for the small O. sativa and B. distachyon genomes, indicating that genes are distributed largely uniformly in those species, but is rejected for the larger S. bicolor and Ae. tauschii genomes, providing evidence for clustering of genes into islands. It is proposed to call the gene islands "gene insulae" to distinguish them from other types of gene clustering that have been proposed. An average S. bicolor and Ae. tauschii insula is estimated to contain 3.7 and 3.9 genes with an average intergenic distance within an insula of 2.1 and 16.5 kb, respectively. Inter-insular distances are greater than 8 and 81 kb and average 15.1 and 205 kb, in S. bicolor and Ae. tauschii, respectively. A greater gene density observed in the distal regions of the Ae. tauschii chromosomes is shown to be primarily caused by shortening of inter-insular distances. The comparison of the four grass genomes suggests that gene locations are largely a function of a homogeneous Poisson process in small genomes. Nonrandom insertions of LTR retroelements during genome expansion creates gene insulae, which become less dense and further apart with the increase in genome size. High concordance in relative lengths of orthologous intergenic distances among the investigated genomes including the maize genome suggests functional constraints on gene distribution in the grass genomes.

  1. ALTERED PREFRONTAL AND INSULAR CORTICAL THICKNESS IN ADOLESCENT MARIJUANA USERS

    PubMed Central

    Lopez-Larson, Melissa P.; Bogorodzki, Piotr; Rogowska, Jadwiga; McGlade, Erin; King, Jace B.; Terry, Janine; Yurgelun-Todd, Deborah

    2011-01-01

    Introduction There are limited data regarding the impact of marijuana (MJ) on cortical development during adolescence. Adolescence is a period of substantial brain maturation and cortical thickness abnormalities may be indicative of disruptions of normal cortical development. This investigation applied cortical-surface based techniques to compare cortical thickness measures in MJ using adolescents compared to non-using controls. Methods Eighteen adolescents with heavy MJ use and 18 non-using controls similar in age received MRI scans using a 3T Siemens scanner. Cortical reconstruction and volumetric segmentation was performed with FreeSurfer. Group differences in cortical thickness were assessed using statistical difference maps covarying for age and gender. Results Compared to non-users, MJ users had decreased cortical thickness in right caudal middle frontal, bilateral insula and bilateral superior frontal corticies. Marijuana users had increased cortical thickness in the bilateral lingual, right superior temporal, right inferior parietal and left paracentral regions. In the MJ users, negative correlations were found between frontal and lingual regions for urinary cannabinoid levels and between age of onset of use and the right superior frontal gyrus. Conclusion This is one of the first studies to evaluate cortical thickness in a group of adolescents with heavy MJ use compared to non-users. Our findings are consistent with prior studies that documented abnormalities in prefrontal and insular regions. Our results suggest that age of regular use may be associated with altered prefrontal cortical gray matter development in adolescents. Furthermore, reduced insular cortical thickness may be a biological marker for increased risk of substance dependence. PMID:21310189

  2. Caffeine promotes glutamate and histamine release in the posterior hypothalamus.

    PubMed

    John, Joshi; Kodama, Tohru; Siegel, Jerome M

    2014-09-15

    Histamine neurons are active during waking and largely inactive during sleep, with minimal activity during rapid-eye movement (REM) sleep. Caffeine, the most widely used stimulant, causes a significant increase of sleep onset latency in rats and humans. We hypothesized that caffeine increases glutamate release in the posterior hypothalamus (PH) and produces increased activity of wake-active histamine neurons. Using in vivo microdialysis, we collected samples from the PH after caffeine administration in freely behaving rats. HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 min. GABA levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 min. Immunostaining showed a significantly elevated number of c-Fos-labeled histamine neurons in caffeine-treated rats compared with saline-treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness.

  3. 24 CFR 570.440 - Application requirements for insular area grants funded under section 106.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR COMMUNITY PLANNING AND DEVELOPMENT, DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT COMMUNITY FACILITIES COMMUNITY... statement. The insular area jurisdiction shall submit to HUD a final statement describing its...

  4. 24 CFR 570.440 - Application requirements for insular area grants funded under section 106.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR COMMUNITY PLANNING AND DEVELOPMENT, DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT COMMUNITY FACILITIES COMMUNITY... statement. The insular area jurisdiction shall submit to HUD a final statement describing its...

  5. 24 CFR 570.440 - Application requirements for insular area grants funded under section 106.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR COMMUNITY PLANNING AND DEVELOPMENT, DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT COMMUNITY FACILITIES COMMUNITY... statement. The insular area jurisdiction shall submit to HUD a final statement describing its...

  6. 24 CFR 570.440 - Application requirements for insular area grants funded under section 106.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR COMMUNITY PLANNING AND DEVELOPMENT, DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT COMMUNITY FACILITIES COMMUNITY... statement. The insular area jurisdiction shall submit to HUD a final statement describing its...

  7. A quantitative analysis of L-glutamate-regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics.

    PubMed

    Chatton, J Y; Marquet, P; Magistretti, P J

    2000-11-01

    The mode of Na+ entry and the dynamics of intracellular Na+ concentration ([Na+]i) changes consecutive to the application of the neurotransmitter glutamate were investigated in mouse cortical astrocytes in primary culture by video fluorescence microscopy. An elevation of [Na+]i was evoked by glutamate, whose amplitude and initial rate were concentration dependent. The glutamate-evoked Na+ increase was primarily due to Na+-glutamate cotransport, as inhibition of non-NMDA ionotropic receptors by 6-cyano-7-nitroquinoxiline-2,3-dione (CNQX) only weakly diminished the response and D-aspartate, a substrate of the glutamate transporter, produced [Na+]i elevations similar to those evoked by glutamate. Non-NMDA receptor activation could nevertheless be demonstrated by preventing receptor desensitization using cyclothiazide. Thus, in normal conditions non-NMDA receptors do not contribute significantly to the glutamate-evoked Na+ response. The rate of Na+ influx decreased during glutamate application, with kinetics that correlate well with the increase in [Na+]i and which depend on the extracellular concentration of glutamate. A tight coupling between Na+ entry and Na+/K+ ATPase activity was revealed by the massive [Na+]i increase evoked by glutamate when pump activity was inhibited by ouabain. During prolonged glutamate application, [Na+]i remains elevated at a new steady-state where Na+ influx through the transporter matches Na+ extrusion through the Na+/K+ ATPase. A mathematical model of the dynamics of [Na+]i homeostasis is presented which precisely defines the critical role of Na+ influx kinetics in the establishment of the elevated steady state and its consequences on the cellular bioenergetics. Indeed, extracellular glutamate concentrations of 10 microM already markedly increase the energetic demands of the astrocytes.

  8. Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

    PubMed Central

    Xi, Qi; Tcheranova, Dilyara; Basuroy, Shyamali; Parfenova, Helena; Jaggar, Jonathan H.

    2011-01-01

    Glutamate-stimulated, astrocyte-derived carbon monoxide (CO) causes cerebral arteriole dilation by activating smooth muscle cell large-conductance Ca2+-activated K+ channels. Here, we examined the hypothesis that glutamate activates heme oxygenase (HO)-2 and CO production via the intracellular Ca2+ concentration ([Ca2+]i)/Ca2+-calmodulin signaling pathway in newborn pig astrocytes. The major findings are: 1) glutamate stimulated Ca2+ transients and increased steady-state [Ca2+]i in cerebral cortical astrocytes in primary culture, 2) in astrocytes permeabilized with ionomycin, elevation of [Ca2+]i concentration-dependently increased CO production, 3) glutamate did not affect CO production at any [Ca2+]i when the [Ca2+]i was held constant, 4) thapsigargin, a sarco/endoplasmic reticulum Ca2+-ATPase blocker, decreased basal CO production and blocked glutamate-induced increases in CO, and 5) calmidazolium, a calmodulin inhibitor, blocked CO production induced by glutamate and by [Ca2+]i elevation. Taken together, our data are consistent with the hypothesis that glutamate elevates [Ca2+]i in astrocytes, leading to Ca2+- and calmodulin-dependent HO-2 activation, and CO production. PMID:21572018

  9. The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors.

    PubMed

    Musazzi, Laura; Treccani, Giulia; Mallei, Alessandra; Popoli, Maurizio

    2013-06-15

    Recent compelling evidence has suggested that the glutamate system is a primary mediator of psychiatric pathology and also a target for rapid-acting antidepressants. Clinical research in mood and anxiety disorders has shown alterations in levels, clearance, and metabolism of glutamate and consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent stress and depression models have found dendritic remodeling and synaptic spines reduction in corresponding areas, suggesting these as major factors in psychopathology. Enhancement of glutamate release/transmission, in turn induced by stress/glucocorticoids, seems crucial for structural/functional changes. Understanding mechanisms of maladaptive plasticity may allow identification of new targets for drugs and therapies. Interestingly, traditional monoaminergic-based antidepressants have been repeatedly shown to interfere with glutamate system function, starting with modulation of N-methyl-D-aspartate (NMDA) receptors. Subsequently, it has been shown that antidepressants reduce glutamate release and synaptic transmission; in particular, it was found antidepressants prevent the acute stress-induced enhancement of glutamate release. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression models. Finally, a number of studies over the years have shown that these drugs regulate glutamate receptors, reducing the function of NMDA receptors, potentiating the function of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, and, more recently, exerting variable effects on different subtypes of metabotropic glutamate receptors. The development of NMDA receptor antagonists has opened new avenues for glutamatergic, rapid acting, antidepressants, while additional targets in the glutamate synapse await development of new compounds for better, faster antidepressant action.

  10. 1,25-Dihydroxyvitamin D induces the glutamate transporter SLC1A1 and alters glutamate handling in non-transformed mammary cells

    PubMed Central

    Beaudin, Sarah; Welsh, JoEllen

    2016-01-01

    Genomic profiling of immortalized human mammary epithelial (hTERT-HME1) cells identified several metabolic genes, including the membrane glutamate transporter, SLC1A1, as 1,25-dihydroxyvitamin D3 (1,25D) regulated. In these studies we have surveyed the effects of 1,25D on known glutamate transporters and evaluated its impact on cellular glutamate handling. We confirm that expression of SLC1A1 and all of its known transcript variants are significantly upregulated in hTERT-HME1 cells following 1,25D treatment. Expression of the full-length cognate protein, EAAT3 is correspondingly increased in 1,25D treated hTERT-HME1 cells. Under the same conditions, the expression of two other glutamate transporters - SLC1A6 (EAAT4) and SLC1A2 (EAAT2 or GLT-1) - is enhanced by 1,25D while that of SLC1A3 (EAAT1 or GLAST) and SLC7A11 (xCT) is decreased. Glutamate is not essential for growth of hTERT-HME1 cells, and supplemental glutamate (up to 0.5 mM) does not abrogate the growth inhibitory effects of 1,25D. These data suggest that extracellular glutamate is not a major contributor to cellular energy metabolism in hTERT-HME1 cells under basal conditions and that the growth inhibitory effects of 1,25D are not secondary to its effects on glutamate handling. Instead, the effects of 1,25D on glutamate transporters translated to a decrease in cellular glutamate concentration and an increase in media glutamate concentration, suggesting that one or more of these transporters functions to export glutamate in response to 1,25D exposure. The reduced cellular glutamate concentration may also reflect its incorporation into the cellular glutathione (GSH) pool, which is increased upon 1,25D treatment. In support of this concept, the expression of GCLC (which codes for the rate-limiting enzyme in GSH synthesis) and genes which generate reducing equivalents in the form of NADPH (ie, G6PD, PGD, IDH2) are elevated in 1,25D treated cells. Taken together, these data identify 1,25D as a physiological

  11. Distribution and biology of Indo-Pacific insular hypogeal shrimps

    USGS Publications Warehouse

    Maciolek, J.A.

    1983-01-01

    Ten species of caridean shrimps, representing nine genera in five families, have been found in exposures of the marine water table at 28 islands from Hawaii to the western Indian Ocean. Synthesis of literature information and personal observations indicate that, as a group, these shrimps are characterized by red body pigment, reduced but pigmented eyes, euryhalinity, a proclivity for interstitial seawater in limestone or lava rock, generalized food requirements, and probable pre-Pleistocene origins. The shrimps have not been found in waters cooler than about 20°C.Species are often solitary, but as many as five are known to coexist. Six of the species have widely scattered populations, some as far apart as Hawaii and the Red Sea. Passive oceanic dispersal is endorsed as a general explanation for such apparently disjunct distributions. On the basis of an assumed primary habitat requirement of interstitial marine water, which could include that in shallow submerged rock as well as that in emergent (insular) rock, I hypothesize a much more cosmopolitan distribution of these shrimps in the Indo-Pacific Tropical Zone.

  12. The anterior insular cortex represents breaches of taste identity expectation.

    PubMed

    Veldhuizen, Maria G; Douglas, Danielle; Aschenbrenner, Katja; Gitelman, Darren R; Small, Dana M

    2011-10-12

    Despite the importance of breaches of taste identity expectation for survival, its neural correlate is unknown. We used fMRI in 16 women to examine brain response to expected and unexpected receipt of sweet taste and tasteless/odorless solutions. During expected trials (70%), subjects heard "sweet" or "tasteless" and received the liquid indicated by the cue. During unexpected trials (30%), subjects heard sweet but received tasteless or they heard tasteless but received sweet. After delivery, subjects indicated stimulus identity by pressing a button. Reaction time was faster and more accurate after valid cuing, indicating that the cues altered expectancy as intended. Tasting unexpected versus expected stimuli resulted in greater deactivation in fusiform gyri, possibly reflecting greater suppression of visual object regions when orienting to, and identifying, an unexpected taste. Significantly greater activation to unexpected versus expected stimuli occurred in areas related to taste (thalamus, anterior insula), reward [ventral striatum (VS), orbitofrontal cortex], and attention [anterior cingulate cortex, inferior frontal gyrus, intraparietal sulcus (IPS)]. We also observed an interaction between stimulus and expectation in the anterior insula (primary taste cortex). Here response was greater for unexpected versus expected sweet compared with unexpected versus expected tasteless, indicating that this region is preferentially sensitive to breaches of taste expectation. Connectivity analyses confirmed that expectation enhanced network interactions, with IPS and VS influencing insular responses. We conclude that unexpected oral stimulation results in suppression of visual cortex and upregulation of sensory, attention, and reward regions to support orientation, identification, and learning about salient stimuli.

  13. Glutamic acid as anticancer agent: An overview.

    PubMed

    Dutta, Satyajit; Ray, Supratim; Nagarajan, K

    2013-10-01

    The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. It also possesses anticancer activity. So the transportation and metabolism of glutamine are also discussed for better understanding the role of glutamic acid. Glutamates are the carboxylate anions and salts of glutamic acid. Here the roles of various enzymes required for the metabolism of glutamates are also discussed.

  14. Computational Studies of Glutamate Transporters

    PubMed Central

    Setiadi, Jeffry; Heinzelmann, Germano; Kuyucak, Serdar

    2015-01-01

    Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of bacterial aspartate transporters has paved the way for computational investigation of their function and dynamics at the molecular level. Here, we review molecular dynamics and free energy calculation methods used in these computational studies and discuss the recent applications to glutamate transporters. The focus of the review is on the insights gained on the transport mechanism through computational methods, which otherwise is not directly accessible by experimental probes. Recent efforts to model the mammalian glutamate and other amino acid transporters, whose crystal structures have not been solved yet, are included in the review. PMID:26569328

  15. c-Fos positive nucleus reveals that contextual specificity of latent inhibition is dependent of insular cortex.

    PubMed

    Quintero, Esperanza; Vargas, Juan Pedro; Diaz, Estrella; Escarabajal, María Dolores; Carrasco, Manuel; López, Juan Carlos

    2014-09-01

    The present study analyzed the functional activity of granular and agranular insular cortices in contextual specificity of latent inhibition using a conditioned taste aversion paradigm. c-Fos immunolabeling was examined in insular cortex in preexposed and no preexposed groups under similar and different context conditions. Result showed that the exposition to a novel taste increased c-fos activity in insular cortex. However, a context shift caused an increase in immunolabeling in animals preexposed to saccharine. These results suggest insular cortex is part of a complex system to evaluate taste-response, and it may read the meaning of taste stimuli depending on the context.

  16. Subgroup characteristics of insular low-grade glioma based on clinical and molecular analysis of 42 cases.

    PubMed

    Tang, Chao; Zhang, Zhen-yu; Chen, Ling-chao; Sun, Zelin; Zhang, Yi; Qin, Zhiyong; Yao, Yu; Zhou, Liang-fu

    2016-02-01

    Although the classification of insular glioma has been established based on the anatomical location in order to facilitate personalized surgical resection, the diagnosis based on anatomical and functional characteristics becomes more complex when insular tumors extend into either the frontobasal brain region and/or the temporal lobe, as part of the limbic system. Moreover, prognosis of insular tumor resection is still controversial. Further analysis of subgroup characteristics of insular grade II gliomas based on clinical and molecular analysis is required to reliably determine patients' survival rates. In this retrospective study 20 purely insular grade II gliomas patients and 22 paralimbic grade II gliomas that involved frontal and/or temporal lobes were compared with regard to epidemiological and clinical characteristics. The molecular profiles including Isocitrate dehydrogenase 1 (IDH1), telomerase reverse transcriptase (TERT) promoter, and P53 mutations, 1p19q co-deletion were analyzed, and microRNA profiles were assessed by microarray and bioinformatics analysis. Purely insular grade II gliomas displayed a high frequency of IDH1 mutations with favorable outcome. IDH1 mutated paralimbic glioma shared many parameters with the purely insular glioma in respect to growth patterns, survival, and microRNA profile, but differed significantly from the IDH1 wild type paralimbic gliomas. Our findings suggest that IDH1 mutations can define subpopulations of insular gliomas with distinct disease entities regardless of tumor extension patterns. These findings could be useful to develop a customized treatment strategy for insular glioma patients.

  17. Glutamate pays its own way in astrocytes.

    PubMed

    McKenna, Mary C

    2013-12-16

    In vitro and in vivo studies have shown that glutamate can be oxidized for energy by brain astrocytes. The ability to harvest the energy from glutamate provides astrocytes with a mechanism to offset the high ATP cost of the uptake of glutamate from the synaptic cleft. This brief review focuses on oxidative metabolism of glutamate by astrocytes, the specific pathways involved in the complete oxidation of glutamate and the energy provided by each reaction.

  18. Prefrontal cortex glutamate and extraversion.

    PubMed

    Grimm, Simone; Schubert, Florian; Jaedke, Maren; Gallinat, Jürgen; Bajbouj, Malek

    2012-10-01

    Extraversion is considered one of the core traits of personality. Low extraversion has been associated with increased vulnerability to affective and anxiety disorders. Brain imaging studies have linked extraversion, approach behaviour and the production of positive emotional states to the dorsolateral prefrontal cortex (DLPFC) and glutamatergic neurotransmission. However, the relationship between extraversion and glutamate in the DLPFC has not been investigated so far. In order to address this issue, absolute glutamate concentrations in the DLPFC and the visual cortex as a control region were measured by 3-Tesla proton magnetic resonance spectroscopy (1H-MRS) in 29 subjects with high and low extraversion. We found increased glutamate levels in the DLPFC of introverts as compared with extraverts. The increased glutamate concentration was specific for the DLPFC and negatively associated with state anxiety. Although preliminary, results indicate altered top-down control of DLPFC due to reduced glutamate concentration as a function of extraversion. Glutamate measurement with 1H-MRS may facilitate the understanding of biological underpinnings of personality traits and psychiatric diseases associated with dysfunctions in approach behaviour and the production of positive emotional states.

  19. Genotoxicity of monosodium glutamate.

    PubMed

    Ataseven, Nazmiye; Yüzbaşıoğlu, Deniz; Keskin, Ayten Çelebi; Ünal, Fatma

    2016-05-01

    Monosodium glutamate (MSG) is one of the most widely used flavor enhancers throughout the world. The aim of this study is to investigate the genotoxic potential of MSG by using chromosome aberrations (CAs), sister-chromatid exchanges (SCEs), cytokinesis-blocked micronucleus (CBMN), and random amplified polymorphic DNA-polimerase chain reaction (RAPD-PCR) in cultured human lymphocytes and alkaline comet assays in isolated human lymphocytes, which were incubated with six concentrations (250, 500, 1000, 2000, 4000 and 8000 μg/mL) of MSG. The result of this study indicated that MSG significantly and dose dependently increased the frequencies of CAs, SCE and MN in all treatments and times, compared with control. However, the replication (RI) and nuclear division indices (NDI) were not affected. In this paper, in vitro genotoxic effects of the MSG was also investigated on human peripheral lymphocytes by analysing the RAPD-PCR with arbitrary 10-mer primers. The changes occurring in RAPD profiles after MSG treatment include increase or decrease in band intensity and gain or loss of bands. In the comet assay, this additive caused DNA damage at all concentrations in isolated human lymphocytes after 1-h in vitro exposure. Our results demonstrate that MSG is genotoxic to the human peripheral blood lymphocytes in vitro.

  20. Negative childhood experiences alter a prefrontal-insular-motor cortical network in healthy adults: A preliminary multimodal rsfMRI-fMRI-MRS-dMRI study

    PubMed Central

    Duncan, Niall W.; Hayes, Dave J.; Wiebking, Christine; Tiret, Brice; Pietruska, Karin; Chen, David Q.; Rainville, Pierre; Marjańska, Malgorzata; Mohammid, Omar; Doyon, Julien; Hodaie, Mojgan; Northoff, Georg

    2016-01-01

    Research in humans and animals has shown that negative childhood experiences (NCE) can have long-term effects on the structure and function of the brain. Alterations have been noted in grey and white matter, in the brain’s resting state, on the glutamatergic system, and on neural and behavioural responses to aversive stimuli. These effects can be linked to psychiatric disorder such as depression and anxiety disorders that are influenced by excessive exposure to early life stressors. The aim of the current study was to investigate the effect of NCEs on these systems. Resting state functional MRI (rsfMRI), aversion task fMRI, glutamate magnetic resonance spectroscopy (MRS), and diffusion magnetic resonance imaging (dMRI) were combined with the Childhood Trauma Questionnaire (CTQ) in healthy subjects to examine the impact of NCEs on the brain. Low CTQ scores, a measure of NCEs, were related to higher resting state glutamate levels and higher resting state entropy in the medial prefrontal cortex (mPFC). CTQ scores, mPFC glutamate and entropy, correlated with neural BOLD responses to the anticipation of aversive stimuli in regions throughout the aversion-related network, with strong correlations between all measures in the motor cortex and left insula. Structural connectivity strength, measured using mean fractional anisotropy, between the mPFC and left insula correlated to aversion-related signal changes in the motor cortex. These findings highlight the impact of NCEs on multiple inter-related brain systems. In particular, they highlight the role of a prefrontal-insular-motor cortical network in the processing and responsivity to aversive stimuli and its potential adaptability by NCEs. PMID:26287448

  1. Disrupted resting-state insular subregions functional connectivity in post-traumatic stress disorder

    PubMed Central

    Zhang, Youxue; Xie, Bing; Chen, Heng; Li, Meiling; Guo, Xiaonan; Chen, Huafu

    2016-01-01

    Abstract Post-traumatic stress disorder (PTSD) is suggested to be a structural and functional abnormality in the insula. The insula, which consists of distinct subregions with various patterns of connectivity, displays complex and diverse functions. However, whether these insular subregions have different patterns of connectivity in PTSD remains unclear. Investigating the abnormal functional connectivity of the insular subregions is crucial to reveal its potential effect on diseases specifically PTSD. This study uses a seed-based method to investigate the altered resting-state functional connectivity of insular subregions in PTSD. We found that patients with PTSD showed reduced functional connectivity compared with healthy controls (HCs) between the left ventral anterior insula and the anterior cingulate cortex. The patients with PTSD also exhibited decreased functional connectivity between the right posterior insula and left inferior parietal lobe, and the postcentral gyrus relative to HCs. These results suggest the involvement of altered functional connectivity of insular subregions in the abnormal regulation of emotion and processing of somatosensory information in patients with PTSD. Such impairments in functional connectivity patterns of the insular subregions may advance our understanding of the pathophysiological basis underlying PTSD. PMID:27399097

  2. Insular Area energy vulnerability, Puerto Rico, US Virgin Islands. Technical Appendix 1

    SciTech Connect

    Stern, M.; Willard, E.E.; Efferding, S.

    1994-05-01

    This report was prepared in response to Section 1406 of the Energy Policy Act of 1992 (P.L. 192-486). The Act directed the Department of Energy (DOE) to ``conduct a study of the implications of the unique vulnerabilities of the insular areas to an oil supply disruption,`` and to ``outline how the insular areas shall gain access to vital oil supplies during times of national emergency.`` The Act defines the insular areas to be the US Virgin Islands and Puerto Rico in the Caribbean, and Guam, American Samoa, the Commonwealth of the Northern Mariana Islands (CNMI), and Palau in the Pacific. This report is the analysis of Puerto Rico and the US Virgin Islands. In the study, ``unique vulnerabilities`` were defined as susceptibility to: (1) more frequent or more likely interruptions of oil supplies compared to the mainland, and/or (2) disproportionately larger or more likely economic losses in the event of an oil supply disruption. In order to asses unique vulnerabilities, the study examined in the insular areas` experience during past global disruptions of oil supplies and during local emergencies caused by natural disasters. The effects of several possible future global disruptions and local emergencies were also analyzed. Analyses were based on historical data, simulations using energy and economic models, and interviews with officials in the insular governments and the energy industry.

  3. Disrupted resting-state insular subregions functional connectivity in post-traumatic stress disorder.

    PubMed

    Zhang, Youxue; Xie, Bing; Chen, Heng; Li, Meiling; Guo, Xiaonan; Chen, Huafu

    2016-07-01

    Post-traumatic stress disorder (PTSD) is suggested to be a structural and functional abnormality in the insula. The insula, which consists of distinct subregions with various patterns of connectivity, displays complex and diverse functions. However, whether these insular subregions have different patterns of connectivity in PTSD remains unclear. Investigating the abnormal functional connectivity of the insular subregions is crucial to reveal its potential effect on diseases specifically PTSD. This study uses a seed-based method to investigate the altered resting-state functional connectivity of insular subregions in PTSD. We found that patients with PTSD showed reduced functional connectivity compared with healthy controls (HCs) between the left ventral anterior insula and the anterior cingulate cortex. The patients with PTSD also exhibited decreased functional connectivity between the right posterior insula and left inferior parietal lobe, and the postcentral gyrus relative to HCs. These results suggest the involvement of altered functional connectivity of insular subregions in the abnormal regulation of emotion and processing of somatosensory information in patients with PTSD. Such impairments in functional connectivity patterns of the insular subregions may advance our understanding of the pathophysiological basis underlying PTSD.

  4. Glutamate dysregulation in the trigeminal ganglion: a novel mechanism for peripheral sensitization of the craniofacial region.

    PubMed

    Laursen, J C; Cairns, B E; Dong, X D; Kumar, U; Somvanshi, R K; Arendt-Nielsen, L; Gazerani, P

    2014-01-03

    In the trigeminal ganglion (TG), satellite glial cells (SGCs) form a functional unit with neurons. It has been proposed that SGCs participate in regulating extracellular glutamate levels and that dysfunction of this SGC capacity can impact nociceptive transmission in craniofacial pain conditions. This study investigated whether SGCs release glutamate and whether elevation of TG glutamate concentration alters response properties of trigeminal afferent fibers. Immunohistochemistry was used to assess glutamate content and the expression of excitatory amino acid transporter (EAAT)1 and EAAT2 in TG sections. SGCs contained glutamate and expressed EAAT1 and EAAT2. Potassium chloride (10 mM) was used to evoke glutamate release from cultured rat SGCs treated with the EAAT1/2 inhibitor (3S)-3-[[3-[[4-(trifluoromethyl)ben zoyl]amino]phenyl]methoxy]-L-aspartic acid (TFB-TBOA) or control. Treatment with TFB-TBOA (1 and 10 μM) significantly reduced the glutamate concentration from 10.6 ± 1.1 to 5.8 ± 1.4 μM and 3.0 ± 0.8 μM, respectively (p<0.05). Electrophysiology experiments were conducted in anaesthetized rats to determine the effect of intraganglionic injections of glutamate on the response properties of ganglion neurons that innervated either the temporalis or masseter muscle. Intraganglionic injection of glutamate (500 mM, 3 μl) evoked afferent discharge and significantly reduced muscle afferent mechanical threshold. Glutamate-evoked discharge was attenuated bythe N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovalerate (APV) and increased by TFB-TBOA, whereas mechanical sensitization was only sensitive to APV. Antidromic invasion of muscle afferent fibers by electrical stimulation of the caudal brainstem (10 Hz) or local anesthesia of the brainstem with lidocaine did not alter glutamate-induced mechanical sensitization. These findings provide a novel mechanism whereby dysfunctional trigeminal SGCs could contribute to cranial muscle tenderness in

  5. Temporal prediction errors modulate cingulate-insular coupling.

    PubMed

    Limongi, Roberto; Sutherland, Steven C; Zhu, Jian; Young, Michael E; Habib, Reza

    2013-05-01

    Prediction error (i.e., the difference between the expected and the actual event's outcome) mediates adaptive behavior. Activity in the anterior mid-cingulate cortex (aMCC) and in the anterior insula (aINS) is associated with the commission of prediction errors under uncertainty. We propose a dynamic causal model of effective connectivity (i.e., neuronal coupling) between the aMCC, the aINS, and the striatum in which the task context drives activity in the aINS and the temporal prediction errors modulate extrinsic cingulate-insular connections. With functional magnetic resonance imaging, we scanned 15 participants when they performed a temporal prediction task. They observed visual animations and predicted when a stationary ball began moving after being contacted by another moving ball. To induced uncertainty-driven prediction errors, we introduced spatial gaps and temporal delays between the balls. Classical and Bayesian fMRI analyses provided evidence to support that the aMCC-aINS system along with the striatum not only responds when humans predict whether a dynamic event occurs but also when it occurs. Our results reveal that the insula is the entry port of a three-region pathway involved in the processing of temporal predictions. Moreover, prediction errors rather than attentional demands, task difficulty, or task duration exert an influence in the aMCC-aINS system. Prediction errors debilitate the effect of the aMCC on the aINS. Finally, our computational model provides a way forward to characterize the physiological parallel of temporal prediction errors elicited in dynamic tasks.

  6. Tuberculosis Epidemiology in Islands: Insularity, Hosts and Trade

    PubMed Central

    Acevedo, Pelayo; Romero, Beatriz; Vicente, Joaquin; Caracappa, Santo; Galluzzo, Paola; Marineo, Sandra; Vicari, Domenico; Torina, Alessandra; Casal, Carmen; de la Fuente, Jose; Gortazar, Christian

    2013-01-01

    Because of their relative simplicity and the barriers to gene flow, islands are ideal systems to study the distribution of biodiversity. However, the knowledge that can be extracted from this peculiar ecosystem regarding epidemiology of economically relevant diseases has not been widely addressed. We used information available in the scientific literature for 10 old world islands or archipelagos and original data on Sicily to gain new insights into the epidemiology of the Mycobacterium tuberculosis complex (MTC). We explored three nonexclusive working hypotheses on the processes modulating bovine tuberculosis (bTB) herd prevalence in cattle and MTC strain diversity: insularity, hosts and trade. Results suggest that bTB herd prevalence was positively correlated with island size, the presence of wild hosts, and the number of imported cattle, but neither with isolation nor with cattle density. MTC strain diversity was positively related with cattle bTB prevalence, presence of wild hosts and the number of imported cattle, but not with island size, isolation, and cattle density. The three most common spoligotype patterns coincided between Sicily and mainland Italy. However in Sicily, these common patterns showed a clearer dominance than on the Italian mainland, and seven of 19 patterns (37%) found in Sicily had not been reported from continental Italy. Strain patterns were not spatially clustered in Sicily. We were able to infer several aspects of MTC epidemiology and control in islands and thus in fragmented host and pathogen populations. Our results point out the relevance of the intensity of the cattle commercial networks in the epidemiology of MTC, and suggest that eradication will prove more difficult with increasing size of the island and its environmental complexity, mainly in terms of the diversity of suitable domestic and wild MTC hosts. PMID:23923053

  7. Tuberculosis epidemiology in islands: insularity, hosts and trade.

    PubMed

    Acevedo, Pelayo; Romero, Beatriz; Vicente, Joaquin; Caracappa, Santo; Galluzzo, Paola; Marineo, Sandra; Vicari, Domenico; Torina, Alessandra; Casal, Carmen; de la Fuente, Jose; Gortazar, Christian

    2013-01-01

    Because of their relative simplicity and the barriers to gene flow, islands are ideal systems to study the distribution of biodiversity. However, the knowledge that can be extracted from this peculiar ecosystem regarding epidemiology of economically relevant diseases has not been widely addressed. We used information available in the scientific literature for 10 old world islands or archipelagos and original data on Sicily to gain new insights into the epidemiology of the Mycobacterium tuberculosis complex (MTC). We explored three nonexclusive working hypotheses on the processes modulating bovine tuberculosis (bTB) herd prevalence in cattle and MTC strain diversity: insularity, hosts and trade. Results suggest that bTB herd prevalence was positively correlated with island size, the presence of wild hosts, and the number of imported cattle, but neither with isolation nor with cattle density. MTC strain diversity was positively related with cattle bTB prevalence, presence of wild hosts and the number of imported cattle, but not with island size, isolation, and cattle density. The three most common spoligotype patterns coincided between Sicily and mainland Italy. However in Sicily, these common patterns showed a clearer dominance than on the Italian mainland, and seven of 19 patterns (37%) found in Sicily had not been reported from continental Italy. Strain patterns were not spatially clustered in Sicily. We were able to infer several aspects of MTC epidemiology and control in islands and thus in fragmented host and pathogen populations. Our results point out the relevance of the intensity of the cattle commercial networks in the epidemiology of MTC, and suggest that eradication will prove more difficult with increasing size of the island and its environmental complexity, mainly in terms of the diversity of suitable domestic and wild MTC hosts.

  8. Biochemical and immunological changes on oral glutamate feeding in male albino rats

    NASA Astrophysics Data System (ADS)

    Kumar, D.; Bansal, Anju; Thomas, Pauline; Sairam, M.; Sharma, S. K.; Mongia, S. S.; Singh, R.; Selvamurthy, W.

    High altitude stress leads to lipid peroxidation and free radical formation which results in cell membrane damage in organs and tissues, and associated mountain diseases. This paper discusses the changes in biochemical parameters and antibody response on feeding glutamate to male albino Sprague Dawley rats under hypoxic stress. Exposure of rats to simulated hypoxia at 7576 m, for 6 h daily for 5 consecutive days, in an animal decompression chamber at 32+/-2° C resulted in an increase in plasma malondialdehyde level with a concomitant decrease in blood glutathione (reduced) level. Supplementation of glutamate orally at an optimal dose (27 mg/kg body weight) in male albino rats under hypoxia enhanced glutathione level and decreased malondialdehyde concentration significantly. Glutamate feeding improved total plasma protein and glucose levels under hypoxia. The activities of serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) and the urea level remained elevated on glutamate supplementation under hypoxia. Glutamate supplementation increased the humoral response against sheep red blood cells (antibody titre). These results indicate a possible utility of glutamate in the amelioration of hypoxia-induced oxidative stress.

  9. Downregulation of postsynaptic density-95-interacting regulator of spine morphogenesis reduces glutamate-induced excitotoxicity by differentially regulating glutamate receptors in rat cortical neurons.

    PubMed

    Luo, Peng; Yang, Yuefan; Liu, Wei; Rao, Wei; Bian, Huan; Li, Xin; Chen, Tao; Liu, Mengdong; Zhao, Yongbo; Dai, Shuhui; Yan, Xu; Fei, Zhou

    2013-12-01

    Glutamate-induced excitotoxicity is involved in many neurological diseases. Preso, a novel postsynaptic scaffold protein, mediates excitatory synaptic transmission and various synaptic functions. In this study, we investigated the role of Preso in the regulation of glutamate-induced excitotoxicity in rat cortical neurons. Knockdown of Preso with small interfering RNA improved neuronal viability and attenuated the elevation of lactate dehydrogenase (LDH) release after glutamate treatment. Downregulation of Preso also inhibited an increase in the BAX/Bcl-2 ratio and cleavage of caspase-9 and caspase-3. Although the expression and distribution of metabotropic glutamate receptor (mGluR) 1/5, NR1, NR2A and NR2B were not changed by knockdown of Preso, downregulation of Preso protected neurons from glutamate-induced excitotoxicity by inhibiting mGluR and N-methyl-D-aspartate receptor function. However, downregulation of Preso neither affected the expression of GluR1 and GluR2 nor influenced the function of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor after glutamate treatment. Furthermore, intracellular Ca(2+) was an important downstream effector of Preso in the regulation of excitotoxicity. These results suggest that expression of Preso promotes the induction of excitotoxicity by facilitating different glutamate receptor signaling pathways. Therefore, Preso might be a potential pharmacological target for preventing and treating neurological diseases.

  10. Abnormalities in glutamate metabolism and excitotoxicity in the retinal diseases.

    PubMed

    Ishikawa, Makoto

    2013-01-01

    In the physiological condition, glutamate acts as an excitatory neurotransmitter in the retina. However, excessive glutamate can be toxic to retinal neurons by overstimulation of the glutamate receptors. Glutamate excess is primarily attributed to perturbation in the homeostasis of the glutamate metabolism. Major pathway of glutamate metabolism consists of glutamate uptake by glutamate transporters followed by enzymatic conversion of glutamate to nontoxic glutamine by glutamine synthetase. Glutamate metabolism requires energy supply, and the energy loss inhibits the functions of both glutamate transporters and glutamine synthetase. In this review, we describe the present knowledge concerning the retinal glutamate metabolism under the physiological and pathological conditions.

  11. Metabotropic glutamate receptors in cancer.

    PubMed

    Yu, Lumeng J; Wall, Brian A; Wangari-Talbot, Janet; Chen, Suzie

    2016-02-16

    Metabotropic glutamate receptors (mGluRs) are widely known for their roles in synaptic signaling. However, accumulating evidence suggests roles of mGluRs in human malignancies in addition to synaptic transmission. Somatic cell homeostasis presents intriguing possibilities of mGluRs and glutamate signaling as novel targets for human cancers. More recently, aberrant glutamate signaling has been shown to participate in the transformation and maintenance of various cancer types, including glioma, melanoma skin cancer, breast cancer, and prostate cancer, indicating that genes encoding mGluRs, GRMs, can function as oncogenes. Here, we provide a review on the interactions of mGluRs and their ligand, glutamate, in processes that promote the growth of tumors of neuronal and non-neuronal origins. Further, we discuss the evolution of riluzole, a glutamate release inhibitor approved for amyotrophic lateral sclerosis (ALS), but now fashioned as an mGluR1 inhibitor for melanoma therapy and as a radio-sensitizer for tumors that have metastasized to the brain. With the success of riluzole, it is not far-fetched to believe that other drugs that may act directly or indirectly on other mGluRs can be beneficial for multiple applications.

  12. Dyscalculia, dysgraphia, and left-right confusion from a left posterior peri-insular infarct.

    PubMed

    Bhattacharyya, S; Cai, X; Klein, J P

    2014-01-01

    The Gerstmann syndrome of dyscalculia, dysgraphia, left-right confusion, and finger agnosia is generally attributed to lesions near the angular gyrus of the dominant hemisphere. A 68-year-old right-handed woman presented with sudden difficulty completing a Sudoku grid and was found to have dyscalculia, dysgraphia, and left-right confusion. Magnetic resonance imaging (MRI) showed a focus of abnormal reduced diffusivity in the left posterior insula and temporoparietal operculum consistent with acute infarct. Gerstmann syndrome from an insular or peri-insular lesion has not been described in the literature previously. Pathological and functional imaging studies show connections between left posterior insular region and inferior parietal lobe. We postulate that the insula and operculum lesion disrupted key functional networks resulting in a pseudoparietal presentation.

  13. Dyscalculia, Dysgraphia, and Left-Right Confusion from a Left Posterior Peri-Insular Infarct

    PubMed Central

    Bhattacharyya, S.; Cai, X.; Klein, J. P.

    2014-01-01

    The Gerstmann syndrome of dyscalculia, dysgraphia, left-right confusion, and finger agnosia is generally attributed to lesions near the angular gyrus of the dominant hemisphere. A 68-year-old right-handed woman presented with sudden difficulty completing a Sudoku grid and was found to have dyscalculia, dysgraphia, and left-right confusion. Magnetic resonance imaging (MRI) showed a focus of abnormal reduced diffusivity in the left posterior insula and temporoparietal operculum consistent with acute infarct. Gerstmann syndrome from an insular or peri-insular lesion has not been described in the literature previously. Pathological and functional imaging studies show connections between left posterior insular region and inferior parietal lobe. We postulate that the insula and operculum lesion disrupted key functional networks resulting in a pseudoparietal presentation. PMID:24817791

  14. Feelings of warmth correlate with neural activity in right anterior insular cortex.

    PubMed

    Olausson, H; Charron, J; Marchand, S; Villemure, C; Strigo, I A; Bushnell, M C

    2005-11-25

    The neural coding of perception can differ from that for the physical attributes of a stimulus. Recent studies suggest that activity in right anterior insular cortex may underlie thermal perception, particularly that of cold. We now examine whether this region is also important for the perception of warmth. We applied cutaneous warm stimuli on the left leg (warmth) in normal subjects (n = 7) during functional magnetic resonance imaging (fMRI). After each stimulus, subjects rated their subjective intensity of the stimulus using a visual analogue scale (VAS), and correlations were determined between the fMRI signal and the VAS ratings. We found that intensity ratings of warmth correlated with the fMRI signal in the right (contralateral to stimulation) anterior insular cortex. These results, in conjunction with previous reports, suggest that the right anterior insular cortex is important for different types of thermal perception.

  15. Putamen involvement and survival outcomes in patients with insular low-grade gliomas.

    PubMed

    Wang, Yongheng; Wang, Yinyan; Fan, Xing; Li, Shaowu; Liu, Xing; Wang, Jiangfei; Jiang, Tao

    2016-08-26

    OBJECTIVE Insular glioma has a unique origin and biological behavior; however, the associations between its anatomical features and prognosis have not been well established. The object of this study was to propose a classification system of insular low-grade gliomas based on preoperative MRI findings and to assess the system's association with survival outcome. METHODS A total of 211 consecutively collected patients diagnosed with low-grade insular gliomas was analyzed. All patients were classified according to whether tumor involved the putamen on MR images. The prognostic role of this novel putaminal classification, as well as that of Yaşargil's classification, was examined using multivariate analyses. RESULTS Ninety-nine cases (46.9%) of insular gliomas involved the putamen. Those tumors involving the putamen, as compared with nonputaminal tumors, were larger (p < 0.001), less likely to be associated with a history of seizures (p = 0.04), more likely to have wild-type IDH1 (p = 0.003), and less likely to be totally removed (p = 0.02). Significant favorable predictors of overall survival on univariate analysis included a high preoperative Karnofsky Performance Scale score (p = 0.02), a history of seizures (p = 0.04), gross-total resection (p = 0.006), nonputaminal tumors (p < 0.001), and an IDH1 mutation (p < 0.001). On multivariate analysis, extent of resection (p = 0.035), putamen classification (p = 0.014), and IDH1 mutation (p = 0.026) were independent predictors of overall survival. No prognostic role was found for Yaşargil's classification. CONCLUSIONS The current study's findings suggest that the putamen classification is an independent predictor of survival outcome in patients with insular low-grade gliomas. This newly proposed classification allows preoperative survival prediction for patients with insular gliomas.

  16. A role for the anterior insular cortex in the global neuronal workspace model of consciousness.

    PubMed

    Michel, Matthias

    2017-03-01

    According to the global neuronal workspace model of consciousness, consciousness results from the global broadcast of information throughout the brain. The global neuronal workspace is mainly constituted by a fronto-parietal network. The anterior insular cortex is part of this global neuronal workspace, but the function of this region has not yet been defined within the global neuronal workspace model of consciousness. In this review, I hypothesize that the anterior insular cortex implements a cross-modal priority map, the function of which is to determine priorities for the processing of information and subsequent entrance in the global neuronal workspace.

  17. Impaired executive functioning after left anterior insular stroke: a case report.

    PubMed

    Markostamou, Ioanna; Rudolf, Jobst; Tsiptsios, Iakovos; Kosmidis, Mary H

    2015-01-01

    Given the insular's anatomic complexity and functional interconnectivity, acute lesions may result in varied clinical presentations, including autonomic, somatosensory, perceptual, motor, affective, and cognitive deficits. Although functional neuroimaging studies have demonstrated its role in executive functions, no clinical manifestations have been reported to date. We present the case of a woman with an acute left anterior insular infarction leading to executive (i.e., word and design fluency, mental flexibility, sustained attention, inhibitory control), but not language, visuoperceptual, or memory impairment. This case confirms the left anterior insula's involvement in executive functioning and suggests that an infarction may result in executive impairment.

  18. Increasing Our Insular World View: Interoception and Psychopathology for Psychotherapists

    PubMed Central

    Duquette, Patrice

    2017-01-01

    Interoception has been determined to be an elemental aspect of the neural foundations of physiological homeostasis, subjective experience, and motivated behavior. This paper reviews current neuroscience research regarding interoception and forms of interoceptive dysfunction that may result in psychopathology, focusing on depression, and anxiety, in a manner conducive to psychotherapists engaging with it to consider clinical applications. Pertinent aspects of interoceptive system processes in relation to psychopathology are addressed: Functional interoceptive ability and the forms of its expression, the difficulty of accurate measurement of such within an individual or group, interoceptive inference processes and perturbations. Predictive coding, considered in this context as interoceptive inference, a process that integrates bottom-up and top down lines of neural information emerging from the multitude of bidirectional, anatomically hierarchical connections the insular cortex makes with other cortical, and subcortical structures, will be addressed regarding its place in psychopathological formulations. Clinical vignettes will elucidate how interoceptive disturbances might present in the therapeutic relationship, supporting the evaluation and application of scientific theory, and research findings by psychotherapists. The clinical implications of this neuroscientific research have received little attention in the psychotherapeutic setting. Increasing the knowledge base of psychotherapists and furthering awareness of the functional interactions of body and brain toward the creation of healthy and psychopathological experience benefits the patient. There is immediate need for the translational expression of scientific findings into the psychological evaluation of patients, therapeutic process, and treatment. While it may seem distant and unrelated to the affective processes that occur within the psychotherapeutic exchange, neuroscience adds a unique perspective from

  19. Glutamate receptors at atomic resolution

    SciTech Connect

    Mayer, Mark L.

    2010-12-03

    At synapses throughout the brain and spinal cord, the amino-acid glutamate is the major excitatory neurotransmitter. During evolution, a family of glutamate-receptor ion channels seems to have been assembled from a kit consisting of discrete ligand-binding, ion-channel, modulatory and cytoplasmic domains. Crystallographic studies that exploit this unique architecture have greatly aided structural analysis of the ligand-binding core, but the results also pose a formidable challenge, namely that of resolving the allosteric mechanisms by which individual domains communicate and function in an intact receptor.

  20. A dynamic network involving M1-S1, SII-insular, medial insular, and cingulate cortices controls muscular activity during an isometric contraction reaction time task.

    PubMed

    Jouanin, Jean-Claude; Pérès, Michel; Ducorps, Antoine; Renault, Bernard

    2009-02-01

    Magnetoencephalographic, electromyographic (EMG), work, and reaction time (RT) were recorded from nine subjects during visually triggered intermittent isometric contractions of the middle finger under two conditions: unloaded and loaded (30% of maximal voluntary contraction). The effect of muscle fatigue was studied over three consecutive periods under both conditions. In the loaded condition, the motor evoked field triggered by the EMG onset decreased with fatigue, whereas movement-evoked fields (MEFs) increased (P < 0.01). Fatigue was demonstrated in the loaded condition, since (i) RT increased due to an increase in the electromechanical delay (P < 0.002); (ii) work decreased from Periods 1 to 3 (P < 0.005), while (iii) the myoelectric RMS amplitude of both flexor digitorum superficialis and extensor muscles increased (P < 0.003) and (iv) during Period 3, the spectral deflection of the EMG median frequency of the FDS muscle decreased (P < 0.001). In the unloaded condition and at the beginning of the loaded condition, a parallel network including M1-S1, posterior SII-insular, and posterior cingulate cortices accounted for the MEF activities. However, under the effect of fatigue, medial insular and posterior cingulate cortices drove this network. Moreover, changes in the location of insular and M1-S1 activations were significantly correlated with muscle fatigue (increase of RMS-EMG; P < 0.03 and P < 0.01, respectively). These results demonstrate that a plastic network controls the strength of the motor command as fatigue occurs: sensory information, pain, and exhaustion act through activation of the medial insular and posterior cingulate cortices to decrease the motor command in order to preserve muscle efficiency and integrity.

  1. ELEVATING MECHANISM

    DOEpatents

    Frederick, H.S.; Kinsella, M.A.

    1959-02-24

    An elevator is described, which is arranged for movement both in a horizontal and in a vertical direction so that the elevating mechanism may be employed for servicing equipment at separated points in a plant. In accordance with the present invention, the main elevator chassis is suspended from a monorail. The chassis, in turn supports a vertically moveable carriage, a sub- carriage vertically moveable on the carriage, and a turntable carried by the sub- carriage and moveable through an arc of 90 with the equipment attached thereto. In addition, the chassis supports all the means required to elevate or rotate the equipment.

  2. Deletion of genes involved in glutamate metabolism to improve poly-gamma-glutamic acid production in B. amyloliquefaciens LL3.

    PubMed

    Zhang, Wei; He, Yulian; Gao, Weixia; Feng, Jun; Cao, Mingfeng; Yang, Chao; Song, Cunjiang; Wang, Shufang

    2015-02-01

    Here, we attempted to elevate poly-gamma-glutamic acid (γ-PGA) production by modifying genes involved in glutamate metabolism in Bacillus amyloliquefaciens LL3. Products of rocR, rocG and gudB facilitate the conversion from glutamate to 2-oxoglutarate in Bacillus subtillis. The gene odhA is responsible for the synthesis of a component of the 2-oxoglutarate dehydrogenase complex that catalyzes the oxidative decarboxylation of 2-oxoglutarate to succinyl coenzyme A. In-frame deletions of these four genes were performed. In shake flask experiments the gudB/rocG double mutant presented enhanced production of γ-PGA, a 38 % increase compared with wild type. When fermented in a 5-L fermenter with pH control, the γ-PGA yield of the rocR mutant was increased to 5.83 g/L from 4.55 g/L for shake flask experiments. The gudB/rocG double mutant produced 5.68 g/L γ-PGA compared with that of 4.03 g/L for the wild type, a 40 % increase. Those results indicated the possibility of improving γ-PGA production by modifying glutamate metabolism, and identified potential genetic targets to improve γ-PGA production.

  3. 21 CFR 582.1500 - Monoammonium glutamate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Monoammonium glutamate. 582.1500 Section 582.1500 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1500 Monoammonium glutamate. (a) Product. Monoammonium glutamate. (b) Conditions of...

  4. 21 CFR 182.1500 - Monoammonium glutamate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Monoammonium glutamate. 182.1500 Section 182.1500 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD... Substances § 182.1500 Monoammonium glutamate. (a) Product. Monoammonium glutamate. (b) Conditions of...

  5. 21 CFR 582.1516 - Monopotassium glutamate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Monopotassium glutamate. 582.1516 Section 582.1516 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1516 Monopotassium glutamate. (a) Product. Monopotassium glutamate. (b) Conditions of...

  6. 21 CFR 182.1516 - Monopotassium glutamate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Monopotassium glutamate. 182.1516 Section 182.1516 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD... Substances § 182.1516 Monopotassium glutamate. (a) Product. Monopotassium glutamate. (b) Conditions of...

  7. 21 CFR 182.1045 - Glutamic acid.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Glutamic acid. 182.1045 Section 182.1045 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN....1045 Glutamic acid. (a) Product. Glutamic acid. (b) (c) Limitations, restrictions, or explanation....

  8. 21 CFR 182.1045 - Glutamic acid.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Glutamic acid. 182.1045 Section 182.1045 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN....1045 Glutamic acid. (a) Product. Glutamic acid. (b) (c) Limitations, restrictions, or explanation....

  9. 21 CFR 182.1045 - Glutamic acid.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Glutamic acid. 182.1045 Section 182.1045 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN....1045 Glutamic acid. (a) Product. Glutamic acid. (b) (c) Limitations, restrictions, or explanation....

  10. 21 CFR 182.1045 - Glutamic acid.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glutamic acid. 182.1045 Section 182.1045 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN....1045 Glutamic acid. (a) Product. Glutamic acid. (b) (c) Limitations, restrictions, or explanation....

  11. 21 CFR 182.1045 - Glutamic acid.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Glutamic acid. 182.1045 Section 182.1045 Food and... GENERALLY RECOGNIZED AS SAFE Multiple Purpose GRAS Food Substances § 182.1045 Glutamic acid. (a) Product. Glutamic acid. (b) (c) Limitations, restrictions, or explanation. This substance is generally recognized...

  12. Modes of glutamate receptor gating

    PubMed Central

    Popescu, Gabriela K

    2012-01-01

    Abstract The time course of excitatory synaptic currents, the major means of fast communication between neurons of the central nervous system, is encoded in the dynamic behaviour of post-synaptic glutamate-activated channels. First-pass attempts to explain the glutamate-elicited currents with mathematical models produced reaction mechanisms that included only the most basic functionally defined states: resting vs. liganded, closed vs. open, responsive vs. desensitized. In contrast, single-molecule observations afforded by the patch-clamp technique revealed an unanticipated kinetic multiplicity of transitions: from microseconds-lasting flickers to minutes-long modes. How these kinetically defined events impact the shape of the synaptic response, how they relate to rearrangements in receptor structure, and whether and how they are physiologically controlled represent currently active research directions. Modal gating, which refers to the slowest, least frequently observed ion-channel transitions, has been demonstrated for representatives of all ion channel families. However, reaction schemes have been largely confined to the short- and medium-range time scales. For glutamate receptors as well, modal gating has only recently come under rigorous scrutiny. This article reviews the evidence for modal gating of glutamate receptors and the still developing hypotheses about the mechanism(s) by which modal shifts occur and the ways in which they may impact the time course of synaptic transmission. PMID:22106181

  13. Synaptic modulation by astrocytes via Ca2+-dependent glutamate release.

    PubMed

    Santello, M; Volterra, A

    2009-01-12

    In the past 15 years the classical view that astrocytes play a relatively passive role in brain function has been overturned and it has become increasingly clear that signaling between neurons and astrocytes may play a crucial role in the information processing that the brain carries out. This new view stems from two seminal observations made in the early 1990s: 1. astrocytes respond to neurotransmitters released during synaptic activity with elevation of their intracellular Ca2+ concentration ([Ca2+]i); 2. astrocytes release chemical transmitters, including glutamate, in response to [Ca2+]i elevations. The simultaneous recognition that astrocytes sense neuronal activity and release neuroactive agents has been instrumental for understanding previously unknown roles of these cells in the control of synapse formation, function and plasticity. These findings open a conceptual revolution, leading to rethink how brain communication works, as they imply that information travels (and is processed) not just in the neuronal circuitry but in an expanded neuron-glia network. In this review we critically discuss the available information concerning: 1. the characteristics of the astrocytic Ca2+ responses to synaptic activity; 2. the basis of Ca2+-dependent glutamate exocytosis from astrocytes; 3. the modes of action of astrocytic glutamate on synaptic function.

  14. Node Detection Using High-Dimensional Fuzzy Parcellation Applied to the Insular Cortex

    PubMed Central

    Vercelli, Ugo; Diano, Matteo; Costa, Tommaso; Nani, Andrea; Duca, Sergio; Geminiani, Giuliano; Vercelli, Alessandro; Cauda, Franco

    2016-01-01

    Several functional connectivity approaches require the definition of a set of regions of interest (ROIs) that act as network nodes. Different methods have been developed to define these nodes and to derive their functional and effective connections, most of which are rather complex. Here we aim to propose a relatively simple “one-step” border detection and ROI estimation procedure employing the fuzzy c-mean clustering algorithm. To test this procedure and to explore insular connectivity beyond the two/three-region model currently proposed in the literature, we parcellated the insular cortex of 20 healthy right-handed volunteers scanned in a resting state. By employing a high-dimensional functional connectivity-based clustering process, we confirmed the two patterns of connectivity previously described. This method revealed a complex pattern of functional connectivity where the two previously detected insular clusters are subdivided into several other networks, some of which are not commonly associated with the insular cortex, such as the default mode network and parts of the dorsal attentional network. Furthermore, the detection of nodes was reliable, as demonstrated by the confirmative analysis performed on a replication group of subjects. PMID:26881093

  15. Evidence of correlated evolution of hypsodonty and exceptional longevity in endemic insular mammals.

    PubMed

    Jordana, Xavier; Marín-Moratalla, Nekane; DeMiguel, Daniel; Kaiser, Thomas M; Köhler, Meike

    2012-08-22

    Here, we test whether the increase in tooth height in insular endemics results from the expansion of the dietary niche under resource limitation, as widely considered, or whether it represents an investment in dental durability in response to the selection for extended longevity under low levels of extrinsic mortality. We tested these hypotheses in the extremely hypsodont fossil bovid Myotragus balearicus from the Balearic Islands, an ideal model to study the evolutionary trends on islands. Dental abrasion was significantly lower in the insular bovid than in highly hypsodont continental artiodactyls, suggesting that feeding habits are not the sole driving force behind increased crown height. However, the estimated longevity for M. balearicus based on dental durability was two times that predicted from body mass. Survivorship curves confirm that an extraordinarily large number of individuals approached the longevity of the species. Our results, hence, provide evidence that hypsodonty in insular endemics is the outcome of selection for increased durability of the permanent dentition in association with an extended lifespan. In the context of insularity, our results lend additional support to the disposable soma theory of ageing confirming the dependency of somatic maintenance and repair on lifespan, and its control by resource availability and extrinsic mortality.

  16. 47 CFR 54.101 - Supported services for rural, insular and high cost areas.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... extent the local government in an eligible carrier's service area has implemented 911 or enhanced 911... cost areas. 54.101 Section 54.101 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... services for rural, insular and high cost areas. (a) Services designated for support. The...

  17. 47 CFR 54.101 - Supported services for rural, insular and high cost areas.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ..., to the extent the local government in an eligible carrier's service area has implemented 911 or... cost areas. 54.101 Section 54.101 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... services for rural, insular and high cost areas. (a) Services designated for support. Voice...

  18. 47 CFR 54.101 - Supported services for rural, insular and high cost areas.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., to the extent the local government in an eligible carrier's service area has implemented 911 or... cost areas. 54.101 Section 54.101 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... services for rural, insular and high cost areas. (a) Services designated for support. Voice...

  19. Population size and time since island isolation determine genetic diversity loss in insular frog populations.

    PubMed

    Wang, Supen; Zhu, Wei; Gao, Xu; Li, Xianping; Yan, Shaofei; Liu, Xuan; Yang, Ji; Gao, Zengxiang; Li, Yiming

    2014-02-01

    Understanding the factors that contribute to loss of genetic diversity in fragmented populations is crucial for conservation measurements. Land-bridge archipelagoes offer ideal model systems for identifying the long-term effects of these factors on genetic variations in wild populations. In this study, we used nine microsatellite markers to quantify genetic diversity and differentiation of 810 pond frogs (Pelophylax nigromaculatus) from 24 islands of the Zhoushan Archipelago and three sites on nearby mainland China and estimated the effects of the island area, population size, time since island isolation, distance to the mainland and distance to the nearest larger island on reduced genetic diversity of insular populations. The mainland populations displayed higher genetic diversity than insular populations. Genetic differentiations and no obvious gene flow were detected among the frog populations on the islands. Hierarchical partitioning analysis showed that only time since island isolation (square-root-transformed) and population size (log-transformed) significantly contributed to insular genetic diversity. These results suggest that decreased genetic diversity and genetic differentiations among insular populations may have been caused by random genetic drift following isolation by rising sea levels during the Holocene. The results provide strong evidence for a relationship between retained genetic diversity and population size and time since island isolation for pond frogs on the islands, consistent with the prediction of the neutral theory for finite populations. Our study highlights the importance of the size and estimated isolation time of populations in understanding the mechanisms of genetic diversity loss and differentiation in fragmented wild populations.

  20. Differential Effects of Insular and Ventromedial Prefrontal Cortex Lesions on Risky Decision-Making

    ERIC Educational Resources Information Center

    Clark, L.; Bechara, A.; Damasio, H.; Aitken, M. R. F.; Sahakian, B. J.; Robbins, T. W.

    2008-01-01

    The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear…

  1. The biogeography of threatened insular iguanas and opportunities for invasive vertebrate management

    USGS Publications Warehouse

    Tershy, Bernie R.; Newton, Kelly M.; Spatz, Dena R.; Swinnerton, Kirsty; Iverson, John B.; Fisher, Robert N.; Harlow, Peter S.; Holmes, Nick D.; Croll, Donald A.; Iverson, J.B.; Grant, T. D.; Knapp, C. R.; Pasachnik, S. A.

    2016-01-01

    Iguanas are a particularly threatened group of reptiles, with 61% of species at risk of extinction. Primary threats to iguanas include habitat loss, direct and indirect impacts by invasive vertebrates, overexploitation, and human disturbance. As conspicuous, charismatic vertebrates, iguanas also represent excellent flagships for biodiversity conservation. To assist planning for invasive vertebrate management and thus benefit threatened iguana recovery, we identified all islands with known extant or extirpated populations of Critically Endangered and Endangered insular iguana taxa as recognized by the International Union for Conservation of Nature (IUCN) Red List of Threatened Species. For each island, we determined total area, sovereignty, the presence of invasive alien vertebrates, and human population. For the 23 taxa of threatened insular iguanas we identified 230 populations, of which iguanas were extant on 185 islands and extirpated from 45 islands. Twenty-one iguana taxa (91% of all threatened insular iguana taxa) occurred on at least one island with invasive vertebrates present; 16 taxa had 100% of their population(s) on islands with invasive vertebrates present. Rodents, cats, ungulates, and dogs were the most common invasive vertebrates. We discuss biosecurity, eradication, and control of invasive vertebrates to benefit iguana recovery: (1) on islands already free of invasive vertebrates; (2) on islands with high iguana endemicity; and (3) for species and subspecies with small total populations occurring across multiple small islands. Our analyses provide an important first step toward understanding how invasive vertebrate management can be planned effectively to benefit threatened insular iguanas.

  2. Rapid changes in expression of glutamate transporters after spinal cord injury.

    PubMed

    Vera-Portocarrero, Louis P; Mills, Charles D; Ye, Zaiming; Fullwood, Steven D; McAdoo, David J; Hulsebosch, Claire E; Westlund, Karin N

    2002-02-08

    Glutamate is a major excitatory neurotransmitter in the mammalian CNS. After its release, specific transporter proteins rapidly remove extracellular glutamate from the synaptic cleft. The clearance of excess extracellular glutamate prevents accumulation under normal conditions; however, CNS injury elevates extracellular glutamate concentrations to neurotoxic levels. The purpose of this study was to examine changes in expression and in spatial localization of glial glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) and the neuronal glutamate transporter EAAC1 (EAAT3) after spinal cord contusion injury (SCI). The levels of all three transporters significantly increased at the epicenter of injury (T10) and in segments rostral and caudal to the epicenter as determined by Western blot analysis. Quantitative immunohistochemistry demonstrated an increase in GLAST staining in laminae I-V and lamina X both rostral and caudal to the epicenter of injury. Staining for GLT-1 increased significantly in lamina I rostral to the injury site and in the entire gray matter caudal to the injury site. A significant increase in EAAC1 staining was observed in laminae I-IV rostral to the epicenter of injury and throughout the gray matter caudal to the injury site. The results suggest that upregulation of these high affinity transporters occurs rapidly and is important in regulating glutamate homeostasis after SCI.

  3. Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex

    PubMed Central

    Sticht, Martin A.; Limebeer, Cheryl L.; Rafla, Benjamin R.; Abdullah, Rehab A.; Poklis, Justin L.; Ho, Winnie; Niphakis, Micah J.; Cravatt, Benjamin F.; Sharkey, Keith A.; Lichtman, Aron H.; Parker, Linda A.

    2015-01-01

    Cannabinoid (CB) agonists suppress nausea in humans and animal models; yet, their underlying neural substrates remain largely unknown. Evidence suggests that the visceral insular cortex (VIC) plays a critical role in nausea. Given the expression of CB1 receptors and the presence of endocannabinoids in this brain region, we hypothesized that the VIC endocannabinoid system regulates nausea. In the present study, we assessed whether inhibiting the primary endocannabinoid hydrolytic enzymes in the VIC reduces acute lithium chloride (LiCl)-induced conditioned gaping, a rat model of nausea. We also quantified endocannabinoid levels during an episode of nausea, and assessed VIC neuronal activation using the marker, c-Fos. Local inhibition of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of 2-arachidonylglycerol (2-AG), reduced acute nausea through a CB1 receptor mechanism, whereas inhibition of fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of anandamide (AEA), was without effect. Levels of 2-AG were also selectively elevated in the VIC during an episode of nausea. Inhibition of MAGL robustly increased 2-AG in the VIC, while FAAH inhibition had no effect on AEA. Finally, we demonstrated that inhibition of MAGL reduced VIC Fos immunoreactivity in response to LiCl treatment. Taken together, these findings provide compelling evidence that acute nausea selectively increases 2-AG in the VIC, and suggests that 2-AG signaling within the VIC regulates nausea by reducing neuronal activity in this forebrain region. PMID:26541329

  4. Effect of ambient extracellular glutamate on Drosophila glutamate receptor trafficking and function.

    PubMed

    Chen, Kaiyun; Augustin, Hrvoje; Featherstone, David E

    2009-01-01

    Measurements suggest that the hemolymph glutamate concentrations in Drosophila are relatively high. This raises the possibility that extracellular glutamate could be an important regulator of glutamatergic transmission in vivo. Using voltage clamp electrophysiology, we found that synaptic currents in D. melanogaster larval neuromuscular junctions are reduced by extracellular glutamate (EC50: approximately 0.4 mM), such that only 10-30% of receptors were functionally available in 1 mM extracellular glutamate. The kinetics of synaptic currents were also slowed in a dose-dependent fashion (EC50: approximately 1 mM), consistent with the idea that extracellular glutamate preferentially removes the fastest-desensitizing receptors from the functional pool. Prolonged exposure (several hours) to extracellular glutamate also triggers loss of glutamate receptor immunoreactivity from neuromuscular junctions. To determine whether this receptor loss requires that glutamate bind directly to the lost receptors, we examined glutamate-dependent loss of receptor immunoreactivity in larvae with glutamate receptor ligand binding mutations. Our results suggest that glutamate-dependent receptor loss requires binding of glutamate directly to the lost receptors. To determine whether lost receptor protein is degraded or merely redistributed, we used immunoblots. Results suggest that glutamate receptor protein is redistributed, but not degraded, after prolonged exposure to high extracellular glutamate.

  5. Inducible Glutamate Oxaloacetate Transaminase as a Therapeutic Target Against Ischemic Stroke

    PubMed Central

    Khanna, Savita; Briggs, Zachary

    2015-01-01

    Abstract Significance: Glutamate serves multi-faceted (patho)physiological functions in the central nervous system as the most abundant excitatory neurotransmitter and under pathological conditions as a potent neurotoxin. Regarding the latter, elevated extracellular glutamate is known to play a central role in ischemic stroke brain injury. Recent Advances: Glutamate oxaloacetate transaminase (GOT) has emerged as a new therapeutic target in protecting against ischemic stroke injury. Oxygen-sensitive induction of GOT expression and activity during ischemic stroke lowers glutamate levels at the stroke site while sustaining adenosine triphosphate levels in brain. The energy demands of the brain are among the highest of all organs underscoring the need to quickly mobilize alternative carbon skeletons for metabolism in the absence of glucose during ischemic stroke. Recent work builds on the important observation of Hans Krebs that GOT-mediated metabolism of glutamate generates tri-carboxylic acid (TCA) cycle intermediates in brain tissue. Taken together, outcomes suggest GOT may enable the transformative switch of otherwise excitotoxic glutamate into life-sustaining TCA cycle intermediates during ischemic stroke. Critical Issues: Neuroprotective strategies that focus solely on blocking mechanisms of glutamate-mediated excitotoxicity have historically failed in clinical trials. That GOT can enable glutamate to assume the role of a survival factor represents a paradigm shift necessary to develop the overall significance of glutamate in stroke biology. Future Directions: Ongoing efforts are focused to develop the therapeutic significance of GOT in stroke-affected brain. Small molecules that target induction of GOT expression and activity in the ischemic penumbra are the focus of ongoing studies. Antioxid. Redox Signal. 22, 175–186. PMID:25343301

  6. Ligands for Ionotropic Glutamate Receptors

    PubMed Central

    Swanson, Geoffrey T.; Sakai, Ryuichi

    2010-01-01

    Marine-derived small molecules and peptides have played a central role in elaborating pharmacological specificities and neuronal functions of mammalian ionotropic glutamate receptors (iGluRs), the primary mediators of excitatory synaptic transmission in the central nervous system (CNS). As well, the pathological sequelae elicited by one class of compounds (the kainoids) constitute a widely-used animal model for human mesial temporal lobe epilepsy (mTLE). New and existing molecules could prove useful as lead compounds for the development of therapeutics for neuropathologies that have aberrant glutamatergic signaling as a central component. In this chapter we discuss natural source origins and pharmacological activities of those marine compounds that target ionotropic glutamate receptors. PMID:19184587

  7. Transient mitochondrial permeability transition mediates excitotoxicity in glutamate-sensitive NSC34D motor neuron-like cells

    PubMed Central

    Liu, Xiaoyun; Xu, Shangcheng; Wang, Pei; Wang, Wang

    2015-01-01

    Excitotoxicity plays a critical role in neurodegenerative disease. Cytosolic calcium overload and mitochondrial dysfunction are among the major mediators of high level glutamate-induced neuron death. Here, we show that the transient opening of mitochondrial permeability transition pore (tMPT) bridges cytosolic calcium signaling and mitochondrial dysfunction and mediates glutamate-induced neuron death. Incubation of the differentiated motor neuron-like NSC34D cells with glutamate (1 mM) acutely induces cytosolic calcium transient (30% increase). Glutamate also stimulates tMPT opening, as reflected by a 2-fold increase in the frequency of superoxide flash, a bursting superoxide production event in individual mitochondria coupled to tMPT opening. The glutamate-induced tMPT opening is attenuated by suppressing cytosolic calcium influx and abolished by inhibiting mitochondrial calcium uniporter (MCU) with Ru360 (100 µM) or MCU shRNA. Further, increased cytosolic calcium is sufficient to induce tMPT in a mitochondrial calcium dependent manner. Finally, chronic glutamate incubation (24 hr) persistently elevates the probability of tMPT opening, promotes oxidative stress and induces neuron death. Attenuating tMPT activity or inhibiting MCU protects NSC34D cells from glutamate-induced cell death. These results indicate that high level glutamate-induced neuron toxicity is mediated by tMPT, which connects increased cytosolic calcium signal to mitochondrial dysfunction. PMID:26024861

  8. Impaired anterior insular activation during risky decision making in young adults with internet gaming disorder.

    PubMed

    Lee, Deokjong; Lee, Junghan; Yoon, Kang Joon; Kee, Namkoong; Jung, Young-Chul

    2016-05-25

    Internet gaming disorder is defined as excessive and compulsive use of the internet to engage in games that leads to clinically significant psychosocial impairment. We tested the hypothesis that individuals with internet gaming disorder would be less sensitive to high-risk situations and show aberrant brain activation related to risk prediction processing. Young adults with internet gaming disorder underwent functional MRI while performing a risky decision-making task. The healthy control group showed stronger activations within the dorsal attention network and the anterior insular cortex, which were not found in the internet gaming disorder group. Our findings imply that young adults with internet gaming disorder show impaired anterior insular activation during risky decision making, which might make them vulnerable when they need to adapt new behavioral strategies in high-risk situations.

  9. G-protein coupled receptor-evoked glutamate exocytosis from astrocytes: role of prostaglandins.

    PubMed

    Cali, Corrado; Lopatar, Jan; Petrelli, Francesco; Pucci, Luca; Bezzi, Paola

    2014-01-01

    Astrocytes are highly secretory cells, participating in rapid brain communication by releasing glutamate. Recent evidences have suggested that this process is largely mediated by Ca(2+)-dependent regulated exocytosis of VGLUT-positive vesicles. Here by taking advantage of VGLUT1-pHluorin and TIRF illumination, we characterized mechanisms of glutamate exocytosis evoked by endogenous transmitters (glutamate and ATP), which are known to stimulate Ca(2+) elevations in astrocytes. At first we characterized the VGLUT1-pHluorin expressing vesicles and found that VGLUT1-positive vesicles were a specific population of small synaptic-like microvesicles containing glutamate but which do not express VGLUT2. Endogenous mediators evoked a burst of exocytosis through activation of G-protein coupled receptors. Subsequent glutamate exocytosis was reduced by about 80% upon pharmacological blockade of the prostaglandin-forming enzyme, cyclooxygenase. On the other hand, receptor stimulation was accompanied by extracellular release of prostaglandin E2 (PGE2). Interestingly, administration of exogenous PGE2 produced per se rapid, store-dependent burst exocytosis of glutamatergic vesicles in astrocytes. Finally, when PGE2-neutralizing antibody was added to cell medium, transmitter-evoked exocytosis was again significantly reduced (by about 50%). Overall these data indicate that cyclooxygenase products are responsible for a major component of glutamate exocytosis in astrocytes and that large part of such component is sustained by autocrine/paracrine action of PGE2.

  10. Evidence of Genetic Differentiation for Hawaii Insular False Killer Whales (Pseudorca crassidens)

    DTIC Science & Technology

    2010-05-01

    derived from beluga whales (Delphinapterus leucas) (Buchanan et al., 1996), EV94t derived from humpback whales (Megaptera novaenglia) (Valsecchi and Amos...Buchanan, F. C., Friesen, M. K., Littlejohn, R. P., and Clayton, J. W. 1996. Microsatellites from the beluga whale Delphinapterus leucas. Mol. Ecol. 5:571...Schultz, Janet L. Thieleking and Daniel L. Webster EVIDENCE OF GENETIC DIFFERENTIATION FOR HAWAI I INSULAR FALSE KILLER WHALES ` (Pseudorca crassidens

  11. Probabilistic Tractography Recovers a Rostrocaudal Trajectory of Connectivity Variability in the Human Insular Cortex

    PubMed Central

    Cerliani, Leonardo; Thomas, Rajat M; Jbabdi, Saad; Siero, Jeroen CW; Nanetti, Luca; Crippa, Alessandro; Gazzola, Valeria; D'Arceuil, Helen; Keysers, Christian

    2012-01-01

    The insular cortex of macaques has a wide spectrum of anatomical connections whose distribution is related to its heterogeneous cytoarchitecture. Although there is evidence of a similar cytoarchitectural arrangement in humans, the anatomical connectivity of the insula in the human brain has not yet been investigated in vivo. In the present work, we used in vivo probabilistic white-matter tractography and Laplacian eigenmaps (LE) to study the variation of connectivity patterns across insular territories in humans. In each subject and hemisphere, we recovered a rostrocaudal trajectory of connectivity variation ranging from the anterior dorsal and ventral insula to the dorsal caudal part of the long insular gyri. LE suggested that regional transitions among tractography patterns in the insula occur more gradually than in other brain regions. In particular, the change in tractography patterns was more gradual in the insula than in the medial premotor region, where a sharp transition between different tractography patterns was found. The recovered trajectory of connectivity variation in the insula suggests a relation between connectivity and cytoarchitecture in humans resembling that previously found in macaques: tractography seeds from the anterior insula were mainly found in limbic and paralimbic regions and in anterior parts of the inferior frontal gyrus, while seeds from caudal insular territories mostly reached parietal and posterior temporal cortices. Regions in the putative dysgranular insula displayed more heterogeneous connectivity patterns, with regional differences related to the proximity with either putative granular or agranular regions. Hum Brain Mapp 33:2005–2034, 2012. © 2011 Wiley Periodicals, Inc. PMID:21761507

  12. Esophageal Acid Stimulation Alters Insular Cortex Functional Connectivity in Gastroesophageal Reflux Disease

    PubMed Central

    Siwiec, Robert M.; Babaei, Arash; Kern, Mark; Samuel, Erica A.; Li, Shi-Jiang; Shaker, Reza

    2014-01-01

    Background The insula plays a significant role in the interoceptive processing of visceral stimuli. We have previously shown that GERD patients have increased insular cortex activity during esophageal stimulation, suggesting a sensitized esophago-cortical neuraxis. However, information regarding the functional connectivity (FC) of the insula during visceral stimulation is lacking. The primary aim of this study was to investigate the FC of insular subregions during esophageal acid stimulation. Methods Functional imaging data was obtained from 12 GERD patients and 14 healthy subjects during four steady state conditions: (1) presence of transnasal esophageal catheter (pre-infusion); (2) neutral solution; (3) acid infusion; (4) presence of transnasal esophageal catheter following infusions (post-infusion). The insula was parcellated into 6 regions of interest (ROI). FC maps between each insular ROI and interoceptive regions were created. Differences in FC between GERD patients and healthy subjects were determined across the 4 study conditions. Key Results All GERD patients experienced heartburn during and after esophageal acidification. Significant differences between GERD patients and healthy subjects were seen in: (1) insula-thalamic FC (neutral solution infusion, acid infusion, post-infusion); (2) insula-amygdala FC (acid infusion, post-infusion); (3) insula-hippocampus and insula-cingulate FC (post-infusion). Conclusions & Inferences Esophageal stimulation in GERD patients revealed significant insular cortex FC differences with regions involved in viscerosensation and interoception. The results of our study provide further evidence that the insula, located at the transition of afferent physiologic information to human feelings, is essential for both visceral homeostasis and the experience of heartburn in GERD patients. PMID:25367277

  13. The shore fishes of the Trindade-Martin Vaz insular complex: an update.

    PubMed

    Simon, T; Macieira, R M; Joyeux, J-C

    2013-06-01

    A compilation of historical and recent collections and observations of shore fishes yielded 154 recorded species for Trindade and 67 for Martin Vaz. Twelve taxa, mostly small cryptobenthic species with limited dispersal capabilities and low ecological amplitude, are endemic to this insular complex. In several cases, the seamounts of the Vitória-Trindade Chain appear to have acted as stepping stones between the mainland and islands in periods of low sea level.

  14. The Many Roles of Glutamate in Metabolism

    PubMed Central

    Walker, Mark C.

    2015-01-01

    The amino acid glutamate is a major metabolic hub in many organisms and as such is involved in diverse processes in addition to its role in protein synthesis. Nitrogen assimilation, nucleoside, amino acid, and cofactor biosynthesis, as well as secondary natural product formation all utilize glutamate in some manner. Glutamate also plays a role in the catabolism of certain amines. Understanding glutamate's role in these various processes can aid in genome mining for novel metabolic pathways or the engineering of pathways for bioremediation or chemical production of valuable compounds. PMID:26323613

  15. Delta and gamma oscillations in operculo-insular cortex underlie innocuous cold thermosensation.

    PubMed

    Fardo, Francesca; Vinding, Mikkel C; Allen, Micah; Jensen, Troels Staehelin; Finnerup, Nanna Brix

    2017-03-01

    Cold-sensitive and nociceptive neural pathways interact to shape the quality and intensity of thermal and pain perception. Yet, the central processing of cold-thermosensation in the human brain has not yet been extensively studied. Here, we used magnetoencephalography (MEG) and electroencephalography (EEG) in healthy volunteers, to investigate the time course (evoked fields and potentials) and oscillatory activity associated with the perception of cold temperature changes. Non-noxious cold stimuli consisting of Δ3°C and Δ5°C decrements from an adapting temperature of 35°C were delivered on the dorsum of the left hand via a contact thermode. Cold-evoked fields peaked at around 240 and 500 ms, at similar peak latencies as the N1 and P2 cold-evoked potentials. Importantly, cold-related changes in oscillatory power indicated that innocuous thermosensation is mediated by oscillatory activity in the range of delta (1-4 Hz) and gamma (55-90 Hz) rhythms, originating in operculo-insular cortical regions. We suggest that delta rhythms coordinate functional integration between operculo-insular and fronto-parietal regions, while gamma rhythms reflect local sensory processing in operculo-insular areas.

  16. A volumetric comparison of the insular cortex and its subregions in primates

    PubMed Central

    Bauernfeind, Amy L.; de Sousa, Alexandra A.; Avasthi, Tanvi; Dobson, Seth D.; Raghanti, Mary Ann; Lewandowski, Albert H.; Zilles, Karl; Semendeferi, Katerina; Allman, John M.; (Bud) Craig, Arthur D.; Hof, Patrick R.; Sherwood, Chet C.

    2013-01-01

    The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body’s homeostatic state. We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent = 1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent = 1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee. PMID:23466178

  17. Insular neural system controls decision-making in healthy and methamphetamine-treated rats

    PubMed Central

    Mizoguchi, Hiroyuki; Katahira, Kentaro; Inutsuka, Ayumu; Fukumoto, Kazuya; Nakamura, Akihiro; Wang, Tian; Nagai, Taku; Sato, Jun; Sawada, Makoto; Ohira, Hideki; Yamanaka, Akihiro; Yamada, Kiyofumi

    2015-01-01

    Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making. PMID:26150496

  18. Variable temporo-insular cortex neuroanatomy in primates suggests a bottleneck effect in eastern gorillas

    PubMed Central

    Barks, Sarah K.; Bauernfeind, Amy L.; Bonar, Christopher J.; Cranfield, Michael R.; de Sousa, Alexandra A.; Erwin, Joseph M.; Hopkins, William D.; Lewandowski, Albert H.; Mudakikwa, Antoine; Phillips, Kimberley A.; Raghanti, Mary Ann; Stimpson, Cheryl D.; Hof, Patrick R.; Zilles, Karl; Sherwood, Chet C.

    2013-01-01

    In this study, we describe an atypical neuroanatomical feature present in several primate species that involves a fusion between the temporal lobe (often including Heschl’s gyrus in great apes) and the posterior dorsal insula, such that a portion of insular cortex forms an isolated pocket medial to the Sylvian fissure. We assessed the frequency of this fusion in 56 primate species (including apes, Old World monkeys, New World monkeys, and strepsirrhines) using either magnetic resonance images or histological sections. A fusion between temporal cortex and posterior insula was present in 22 species (7 apes, 2 Old World monkeys, 4 New World monkeys, and 9 strepsirrhines). The temporo-insular fusion was observed in most eastern gorilla (Gorilla beringei beringei and G. b. graueri) specimens (62% and 100% of cases, respectively) but less frequently in other great apes and was never found in humans. We further explored the histology of this fusion in eastern gorillas by examining the cyto- and myeloarchitecture within this region, and observed that the degree to which deep cortical layers and white matter are incorporated into the fusion varies among individuals within a species. We suggest that fusion between temporal and insular cortex is an example of a relatively rare neuroanatomical feature that has become more common in eastern gorillas, possibly as the result of a population bottleneck effect. Characterizing the phylogenetic distribution of this morphology highlights a derived feature of these great apes. PMID:23939630

  19. Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse

    PubMed Central

    Scofield, Michael D.; Boger, Heather; Hensley, Megan; Kalivas, Peter W.

    2014-01-01

    Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration. PMID:24741055

  20. Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse.

    PubMed

    Shen, Hao-wei; Scofield, Michael D; Boger, Heather; Hensley, Megan; Kalivas, Peter W

    2014-04-16

    Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration.

  1. Effects of phosphoenolpyruvate carboxylase desensitization on glutamic acid production in Corynebacterium glutamicum ATCC 13032.

    PubMed

    Wada, Masaru; Sawada, Kazunori; Ogura, Kotaro; Shimono, Yuta; Hagiwara, Takuya; Sugimoto, Masakazu; Onuki, Akiko; Yokota, Atsushi

    2016-02-01

    Phosphoenolpyruvate carboxylase (PEPC) in Corynebacterium glutamicum ATCC13032, a glutamic-acid producing actinobacterium, is subject to feedback inhibition by metabolic intermediates such as aspartic acid and 2-oxoglutaric acid, which implies the importance of PEPC in replenishing oxaloacetic acid into the TCA cycle. Here, we investigated the effects of feedback-insensitive PEPC on glutamic acid production. A single amino-acid substitution in PEPC, D299N, was found to relieve the feedback control by aspartic acid, but not by 2-oxoglutaric acid. A simple mutant, strain R1, having the D299N substitution in PEPC was constructed from ATCC 13032 using the double-crossover chromosome replacement technique. Strain R1 produced glutamic acid at a concentration of 31.0 g/L from 100 g/L glucose in a jar fermentor culture under biotin-limited conditions, which was significantly higher than that of the parent, 26.0 g/L (1.19-fold), indicative of the positive effect of desensitized PEPC on glutamic acid production. Another mutant, strain DR1, having both desensitized PEPC and PYK-gene deleted mutations, was constructed in a similar manner using strain D1 with a PYK-gene deleted mutation as the parent. This mutation had been shown to enhance glutamic acid production in our previous study. Although marginal, strain D1 produced higher glutamic acid, 28.8 g/L, than ATCC13032 (1.11-fold). In contrast, glutamic acid production by strain DR-1 was elevated up to 36.9 g/L, which was 1.42-fold higher than ATCC13032 and significantly higher than the other three strains. The results showed a synergistic effect of these two mutations on glutamic acid production in C. glutamicum.

  2. Two insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA.

    PubMed

    Mandelli, Maria Luisa; Vitali, Paolo; Santos, Miguel; Henry, Maya; Gola, Kelly; Rosenberg, Lynne; Dronkers, Nina; Miller, Bruce; Seeley, William W; Gorno-Tempini, Maria Luisa

    2016-01-01

    The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and the behavioral variant frontotemporal dementia (bvFTD) are focal neurodegenerative disorders belonging to the FTD-spectrum clinical syndromes. NfvPPA is characterized by effortful speech and/or agrammatism and left frontal atrophy, while bvFTD is characterized by social-emotional dysfunction often accompanied by right-lateralized frontal damage. Despite their contrasting clinical presentations, both disorders show prominent left anterior insula atrophy. We investigated differential patterns of insular sub-region atrophy in nfvPPA and bvFTD. Based on knowledge of insular connectivity and physiology, we hypothesized that the left superior precentral region of the dorsal anterior insula (SPGI) would be more atrophic in nvfPPA due to its critical role in motor speech, whereas the ventral anterior region would be more atrophied in bvFTD reflecting its known role in social-emotional-autonomic functions. Early stage nfvPPA and bvFTD patients matched for disease severity, age, gender and education and healthy controls participated in the study. Detailed clinical history, neurological examination, neuropsychological screening evaluation, and high-resolution T1-weighted brain magnetic resonance imaging (MRI) were collected. Voxel-based morphometry (VBM) was applied to perform group comparisons across the whole brain and in bilateral insula region of interest (ROI). Correlation analyses between insular sub-region atrophy and relevant clinical features were performed. Whole brain group comparisons between nfvPPA and bvFTD showed the expected predominantly left or right anterior insular atrophy pattern. ROI analysis of bilateral insula showed that the left SPGI was significantly more atrophied in nfvPPA compared to bvFTD, while the bilateral ventral anterior and right dorsal anterior insula sub-regions were more atrophied in bvFTD than nfvPPA. Only left SPGI volume correlated with speech production

  3. Two insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA

    PubMed Central

    Mandelli, Maria Luisa; Vitali, Paolo; Santos, Miguel; Henry, Maya; Gola, Kelly; Rosenberg, Lynne; Dronkers, Nina; Miller, Bruce; Seeley, William W.; Gorno-Tempini, Maria Luisa

    2016-01-01

    The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and the behavioral variant frontotemporal dementia (bvFTD) are focal neurodegenerative disorders belonging to the FTD-spectrum clinical syndromes. NfvPPA is characterized by effortful speech and/or agrammatism and left frontal atrophy, while bvFTD is characterized by social-emotional dysfunction often accompanied by right-lateralized frontal damage. Despite their contrasting clinical presentations, both disorders show prominent left anterior insula atrophy. We investigated differential patterns of insular subregion atrophy in nfvPPA and bvFTD. Based on knowledge of insular connectivity and physiology, we hypothesized that the left superior precentral region of the dorsal anterior insula (SPGI) would be more atrophic in nvfPPA due to its critical role in motor speech, whereas the ventral anterior region would be more atrophied in bvFTD reflecting its known role in social-emotional-autonomic functions. Early stage nfvPPA and bvFTD patients matched for disease severity, age, gender and education and healthy controls participated in the study. Detailed clinical history, neurological examination, neuropsychological screening evaluation, and high-resolution T1-weighted brain magnetic resonance images (MRI) were collected. Voxel-based morphometry (VBM) was applied to perform group comparisons across the whole brain and in bilateral insula region of interest (ROI). Correlation analyses between insular subregion atrophy and relevant clinical features were performed. Whole brain group comparisons between nfvPPA and bvFTD showed the expected predominantly left or right anterior insular atrophy pattern. ROI analysis of bilateral insula showed that the left SPGI was significantly more atrophied in nfvPPA compared to bvFTD, while the bilateral ventral anterior and right dorsal anterior insula subregions were more atrophied in bvFTD than nfvPPA. Only left SPGI volume correlated with speech production

  4. Effects of Prolonged Exposure to Hypobaric Hypoxia on Oxidative Stress, Inflammation and Gluco-Insular Regulation: The Not-So-Sweet Price for Good Regulation

    PubMed Central

    Siervo, Mario; Riley, Heather L.; Fernandez, Bernadette O.; Leckstrom, Carl A.; Martin, Daniel S.; Mitchell, Kay; Levett, Denny Z. H.; Montgomery, Hugh E.; Mythen, Monty G.

    2014-01-01

    Objectives The mechanisms by which low oxygen availability are associated with the development of insulin resistance remain obscure. We thus investigated the relationship between such gluco-insular derangements in response to sustained (hypobaric) hypoxemia, and changes in biomarkers of oxidative stress, inflammation and counter-regulatory hormone responses. Methods After baseline testing in London (75 m), 24 subjects ascended from Kathmandu (1,300 m) to Everest Base Camp (EBC;5,300 m) over 13 days. Of these, 14 ascended higher, with 8 reaching the summit (8,848 m). Assessments were conducted at baseline, during ascent to EBC, and 1, 6 and 8 week(s) thereafter. Changes in body weight and indices of gluco-insular control were measured (glucose, insulin, C-Peptide, homeostasis model assessment of insulin resistance [HOMA-IR]) along with biomarkers of oxidative stress (4-hydroxy-2-nonenal-HNE), inflammation (Interleukin-6 [IL-6]) and counter-regulatory hormones (glucagon, adrenalin, noradrenalin). In addition, peripheral oxygen saturation (SpO2) and venous blood lactate concentrations were determined. Results SpO2 fell significantly from 98.0% at sea level to 82.0% on arrival at 5,300 m. Whilst glucose levels remained stable, insulin and C-Peptide concentrations increased by >200% during the last 2 weeks. Increases in fasting insulin, HOMA-IR and glucagon correlated with increases in markers of oxidative stress (4-HNE) and inflammation (IL-6). Lactate levels progressively increased during ascent and remained significantly elevated until week 8. Subjects lost on average 7.3 kg in body weight. Conclusions Sustained hypoxemia is associated with insulin resistance, whose magnitude correlates with the degree of oxidative stress and inflammation. The role of 4-HNE and IL-6 as key players in modifying the association between sustained hypoxia and insulin resistance merits further investigation. PMID:24733551

  5. Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol-preferring (P) rats.

    PubMed

    Ding, Zheng-Ming; Rodd, Zachary A; Engleman, Eric A; Bailey, Jason A; Lahiri, Debomoy K; McBride, William J

    2013-03-01

    The present study determined the effects of voluntary ethanol drinking and deprivation on basal extracellular glutamate concentrations and clearance in the mesolimbic system and tested the hypothesis that chronic ethanol drinking would persistently increase basal glutamate neurotransmission. Three groups of alcohol-preferring (P) rats were used: 'water group (WG),' 'ethanol maintenance group (MG; 24-hour free choice water versus 15% ethanol)' and 'ethanol deprivation group (DG; 2 weeks of deprivation).' Quantitative microdialysis and Western blots were conducted to measure basal extracellular glutamate concentrations, clearance and proteins associated with glutamate clearance. Chronic alcohol drinking produced a 70-100% increase of basal extracellular glutamate concentrations in the posterior ventral tegmental area (4.0 versus 7.0 μM) and nucleus accumbens shell (3.0 versus 6.0 μM). Glutamate clearances were reduced by 30-40% in both regions of MG rats compared with WG rats. In addition, Western blots revealed a 40-45% decrease of excitatory amino transporter 1 (EAAT1) protein, but no significant changes in the levels of EAAT2 or cystine-glutamate antiporter in these regions of MG versus WG rats. The enhanced glutamate concentrations returned to control levels, accompanied by a recovery of glutamate clearance following deprivation. These results indicated that chronic alcohol drinking enhanced extracellular glutamate concentrations in the mesolimbic system, as a result, in part, of reduced clearance, suggesting that enhanced glutamate neurotransmission may contribute to the maintenance of alcohol drinking. However, because the increased glutamate levels returned to normal after deprivation, elevated glutamate neurotransmission may not contribute to the initiation of relapse drinking.

  6. Glutamate Fermentation-2: Mechanism of L-Glutamate Overproduction in Corynebacterium glutamicum.

    PubMed

    Hirasawa, Takashi; Wachi, Masaaki

    2016-12-03

    The nonpathogenic coryneform bacterium, Corynebacterium glutamicum, was isolated as an L-glutamate-overproducing microorganism by Japanese researchers and is currently utilized in various amino acid fermentation processes. L-Glutamate production by C. glutamicum is induced by limitation of biotin and addition of fatty acid ester surfactants and β-lactam antibiotics. These treatments affect the cell surface structures of C. glutamicum. After the discovery of C. glutamicum, many researchers have investigated the underlying mechanism of L-glutamate overproduction with respect to the cell surface structures of this organism. Furthermore, metabolic regulation during L-glutamate overproduction by C. glutamicum, particularly, the relationship between central carbon metabolism and L-glutamate biosynthesis, has been investigated. Recently, the role of a mechanosensitive channel protein in L-glutamate overproduction has been reported. In this chapter, mechanisms of L-glutamate overproduction by C. glutamicum have been reviewed.

  7. Glutamate-based antidepressants: preclinical psychopharmacology.

    PubMed

    Pilc, Andrzej; Wierońska, Joanna M; Skolnick, Phil

    2013-06-15

    Over the past 20 years, converging lines of evidence have both linked glutamatergic dysfunction to the pathophysiology of depression and demonstrated that the glutamatergic synapse presents multiple targets for developing novel antidepressants. The robust antidepressant effects of the N-methyl-D-aspartate receptor antagonists ketamine and traxoprodil provide target validation for this family of ionotropic glutamate receptors. This article reviews the preclinical evidence that it may be possible to develop glutamate-based antidepressants by not only modulating ionotropic (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and metabotropic glutamate (mGlu) receptors, including mGlu2/3, mGLu5 and mGlu7 receptors, but also by altering synaptic concentrations of glutamate via specialized transporters such as glial glutamate transporter 1 (excitatory amino-acid transporter 2).

  8. Kanamycin ototoxicity in glutamate transporter knockout mice.

    PubMed

    Shimizu, Yoshitaka; Hakuba, Nobuhiro; Hyodo, Jun; Taniguchi, Masafumi; Gyo, Kiyofumi

    2005-06-03

    Glutamate-aspartate transporter (GLAST), a powerful glutamate uptake system, removes released glutamate from the synaptic cleft and facilitates the re-use of glutamate as a neurotransmitter recycling system. Aminoglycoside-induced hearing loss is mediated via a glutamate excitotoxic process. We investigated the effect of aminoglycoside ototoxicity in GLAST knockout mice using the recorded auditory brainstem response (ABR) and number of hair cells in the cochlea. Kanamycin (100 mg/mL) was injected directly into the posterior semicircular canal of mice. Before the kanamycin treatment, there was no difference in the ABR threshold average between the wild-type and knockout mice. Kanamycin injection aggravated the ABR threshold in the GLAST knockout mice compared with the wild-type mice, and the IHC degeneration was more severe in the GLAST knockout mice. These findings suggest that GLAST plays an important role in preventing the degeneration of inner hair cells in aminoglycoside ototoxicity.

  9. Nanomolar vitamin E alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A2 and causes neuroprotection.

    PubMed

    Khanna, Savita; Parinandi, Narasimham L; Kotha, Sainath R; Roy, Sashwati; Rink, Cameron; Bibus, Douglas; Sen, Chandan K

    2010-03-01

    Our previous works have elucidated that the 12-lipoxygenase pathway is directly implicated in glutamate-induced neural cell death, and that such that toxicity is prevented by nM concentrations of the natural vitamin E alpha-tocotrienol (TCT). In the current study we tested the hypothesis that phospholipase A(2) (PLA(2)) activity is sensitive to glutamate and mobilizes arachidonic acid (AA), a substrate for 12-lipoxygenase. Furthermore, we examined whether TCT regulates glutamate-inducible PLA(2) activity in neural cells. Glutamate challenge induced the release of [(3)H]AA from HT4 neural cells. Such response was attenuated by calcium chelators (EGTA and BAPTA), cytosolic PLA(2) (cPLA(2))-specific inhibitor (AACOCF(3)) as well as TCT at 250 nM. Glutamate also caused the elevation of free polyunsaturated fatty acid (AA and docosahexaenoic acid) levels and disappearance of phospholipid-esterified AA in neural cells. Furthermore, glutamate induced a time-dependent translocation and enhanced serine phosphorylation of cPLA(2) in the cells. These effects of glutamate on fatty acid levels and on cPLA(2) were significantly attenuated by nM TCT. The observations that AACOCF(3), transient knock-down of cPLA(2) as well as TCT significantly protected against the glutamate-induced death of neural cells implicate cPLA(2) as a TCT-sensitive mediator of glutamate induced neural cell death. This work presents first evidence recognizing glutamate-induced changes in cPLA(2) as a novel mechanism responsible for neuroprotection observed in response to nanomolar concentrations of TCT.

  10. Using glutamate homeostasis as a target for treating addictive disorders

    PubMed Central

    Reissner, Kathryn J.; Kalivas, Peter W.

    2010-01-01

    Well-developed cellular mechanisms exist to preserve glutamate homeostasis and regulate extrasynaptic glutamate levels. Accumulating evidence indicates that disruptions in glutamate homeostasis are associated with addictive disorders. The disruptions in glutamate concentrations observed following prolonged exposure to drugs of abuse are associated with changes in the function and activity of several key components within the homeostatic control mechanism, including the cystine/glutamate exchanger xc− and the glial glutamate transporter EAAT2/GLT-1. Changes in the balance between synaptic and extrasynaptic glutamate levels in turn influence signaling through pre- and postsynaptic glutamate receptors, and thus affect synaptic plasticity and circuit-level activity. In this review we describe the evidence for impaired glutamate homestasis as a critical mediator of long-term drug-seeking behaviors, how chronic neuroadaptations in xc− and GLT-1 mediate a disruption in glutamate homeostasis, and how targeting these components restores glutamate levels and inhibits drug-seeking behaviors. PMID:20634691

  11. ASIC1a regulates insular long-term depression and is required for the extinction of conditioned taste aversion

    PubMed Central

    Li, Wei-Guang; Liu, Ming-Gang; Deng, Shining; Liu, Yan-Mei; Shang, Lin; Ding, Jing; Hsu, Tsan-Ting; Jiang, Qin; Li, Ying; Li, Fei; Zhu, Michael Xi; Xu, Tian-Le

    2016-01-01

    Acid-sensing ion channel 1a (ASIC1a) has been shown to play important roles in synaptic plasticity, learning and memory. Here we identify a crucial role for ASIC1a in long-term depression (LTD) at mouse insular synapses. Genetic ablation and pharmacological inhibition of ASIC1a reduced the induction probability of LTD without affecting that of long-term potentiation in the insular cortex. The disruption of ASIC1a also attenuated the extinction of established taste aversion memory without altering the initial associative taste learning or its long-term retention. Extinction of taste aversive memory led to the reduced insular synaptic efficacy, which precluded further LTD induction. The impaired LTD and extinction learning in ASIC1a null mice were restored by virus-mediated expression of wild-type ASIC1a, but not its ion-impermeable mutant, in the insular cortices. Our data demonstrate the involvement of an ASIC1a-mediated insular synaptic depression mechanism in extinction learning, which raises the possibility of targeting ASIC1a to manage adaptive behaviours. PMID:27924869

  12. Status of ammonia, glutamate, lactate and pyruvate during Plasmodium yoelii infection and pyrimethamine treatment in mice.

    PubMed

    Agarwal, A; Tripathi, L M; Pandey, V C

    1997-09-01

    Ammonia, lactate, glutamate and pyruvate levels in blood, liver, brain, spleen and kidney were determined during Plasmodium yoelii infection and pyrimethamine treatment in mice. Ammonia and lactate levels showed significant increase with rise in parasitaemia except in spleen where decrease in the lactate levels was observed. The glutamate level displayed a marked decrease in blood, liver and splenic tissues, whereas, significant increase in glutamate level in kidney was observed, although its level in cerebral tissue remained unaltered. The pyruvate level in blood and liver showed a noticeable decrease but brain, spleen and kidney registered an elevation of the same due to the parasitic infection. Pyrimethamine (oral) treatment (10 mg/kg body weight) to infected mice (5-10%) for four days brought back the altered levels of the above cellular constituents in different tissues to normal, a week after cessation of drug treatment.

  13. Modulation of pineal melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through NF-κB activation.

    PubMed

    Villela, Darine; Atherino, Victoria Fairbanks; Lima, Larissa de Sá; Moutinho, Anderson Augusto; do Amaral, Fernanda Gaspar; Peres, Rafael; Martins de Lima, Thais; Torrão, Andréa da Silva; Cipolla-Neto, José; Scavone, Cristóforo; Afeche, Solange Castro

    2013-01-01

    The glutamatergic modulation of melatonin synthesis is well known, along with the importance of astrocytes in mediating glutamatergic signaling in the central nervous system. Pinealocytes and astrocytes are the main cell types in the pineal gland. The objective of this work was to investigate the interactions between astrocytes and pinealocytes as a part of the glutamate inhibitory effect on melatonin synthesis. Rat pinealocytes isolated or in coculture with astrocytes were incubated with glutamate in the presence of norepinephrine, and the melatonin content, was quantified. The expression of glutamate receptors, the intracellular calcium content and the NF- κ B activation were analyzed in astrocytes and pinealocytes. TNF- α 's possible mediation of the effect of glutamate was also investigated. The results showed that glutamate's inhibitory effect on melatonin synthesis involves interactions between astrocytes and pinealocytes, possibly through the release of TNF- α . Moreover, the activation of the astrocytic NF- κ B seems to be a necessary step. In astrocytes and pinealocytes, AMPA, NMDA, and group I metabotropic glutamate receptors were observed, as well as the intracellular calcium elevation. In conclusion, there is evidence that the modulation of melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through the activation of the astrocytic NF- κ B transcription factor and possibly by subsequent TNF- α release.

  14. Glutamate and Brain Glutaminases in Drug Addiction.

    PubMed

    Márquez, Javier; Campos-Sandoval, José A; Peñalver, Ana; Matés, José M; Segura, Juan A; Blanco, Eduardo; Alonso, Francisco J; de Fonseca, Fernando Rodríguez

    2017-03-01

    Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.

  15. Elevation changes

    USGS Publications Warehouse

    Jayko, A. S.; Marshall, G.A.; Carver, G.A.

    1992-01-01

    Elevation changes, as well as horizontal displacements of the Earth's surface, are an expected consequence of dip-slip displacement on earthquake faults. the rock surrounding and overlying the fault is forced to stretch and bend to accommodate fault slip. Slip in the case of the April 25 mainshock is thought to have occurred on a gently inclined plane dipping to the northeast at a small angle (see article on preliminary seismological results in this issue).The associated fault-plane solution implies that rock overlying the fault plane (the hanging-wall block west and south of the epicenter) rose and shifted to the northeast. The map on the next page shows the location of the epicenter and approximate extent of uplift and subsidence derived from estimates of the geometry, location. and slip on the buried fault plane. 

  16. The effects of feral cats on insular wildlife: the Club-Med syndrome

    USGS Publications Warehouse

    Hess, Steve C.; Danner, Raymond M.; Timm, R.M.

    2012-01-01

    Domestic cats have been introduced to many of the world‘s islands where they have been particularly devastating to insular wildlife which, in most cases, evolved in the absence of terrestrial predatory mammals and feline diseases. We review the effects of predation, feline diseases, and the life history characteristics of feral cats and their prey that have contributed to the extirpation and extinction of many insular vertebrate species. The protozoan Toxoplasma gondii is a persistent land-based zoonotic pathogen hosted by cats that is known to cause mortality in several insular bird species. It also enters marine environments in cat feces where it can cause the mortality of marine mammals. Feral cats remain widespread on islands throughout the world and are frequently subsidized in colonies which caretakers often assert have little negative effect on native wildlife. However, population genetics, home range, and movement studies all suggest that there are no locations on smaller islands where these cats cannot penetrate within two generations. While the details of past vertebrate extinctions were rarely documented during contemporary time, a strong line of evidence is emerging that the removal of feral cats from islands can rapidly facilitate the recolonization of extirpated species, particularly seabirds. Islands offer unique, mostly self-contained ecosystems in which to conduct controlled studies of the effects of feral cats on wildlife, having implications for continental systems. The response of terrestrial wildlife such as passerine birds, small mammals, and herptiles still needs more thorough long-term monitoring and documentation after the removal of feral cats.

  17. Effects of Ceftriaxone on Glial Glutamate Transporters in Wistar Rats Administered Sequential Ethanol and Methamphetamine

    PubMed Central

    Althobaiti, Yusuf S.; Alshehri, Fahad S.; Almalki, Atiah H.; Sari, Youssef

    2016-01-01

    Methamphetamine (METH) is one of the psychostimulants that is co-abused with ethanol. Repeated exposure to high dose of METH has been shown to cause increases in extracellular glutamate concentration. We have recently reported that ethanol exposure can also increase the extracellular glutamate concentration and downregulate the expression of glutamate transporter subtype 1 (GLT-1). GLT-1 is a glial transporter that regulates the majority of extracellular glutamate. A Wistar rat model of METH and ethanol co-abuse was used to examine the expression of GLT-1 as well as other glutamate transporters such as cystine/glutamate exchanger (xCT) and glutamate aspartate transporter (GLAST). We also examined the body temperature in rats administered METH, ethanol or both drugs. We further investigated the effects of ceftriaxone (CEF), a β-lactam antibiotic known to upregulate GLT-1, in this METH/ethanol co-abuse rat model. After 7 days of either ethanol (6 g/kg) or water oral gavage, Wistar rats received either saline or METH (10 mg/kg i.p. every 2 h × 4), followed by either saline or CEF (200 mg/kg) posttreatment. METH administered alone decreased GLT-1 expression in the nucleus accumbens (NAc) and prefrontal cortex (PFC) and increased body temperature, but did not reduce either xCT or GLAST expression in ethanol and water-pretreated rats. Interestingly, ethanol and METH were found to have an additive effect on the downregulation of GLT-1 expression in the NAc but not in the PFC. Moreover, ethanol alone caused GLT-1 downregulation in the NAc and elevated body temperature compared to control. Finally, CEF posttreatment significantly reversed METH-induced hyperthermia, restored GLT-1 expression, and increased xCT expression. These findings suggest the potential therapeutic role of CEF against METH- or ethanol/METH-induced hyperglutamatergic state and hyperthermia. PMID:27713684

  18. Peripheral nerve injury produces a sustained shift in the balance between glutamate release and uptake in the dorsal horn of the spinal cord

    PubMed Central

    Inquimbert, Perrine; Bartels, Karsten; Babaniyi, Olusegun B.; Barrett, Lee B.; Tegeder, Irmgard; Scholz, Joachim

    2012-01-01

    Peripheral nerve injury provokes heightened excitability of primary sensory afferents including nociceptors, and elicits ectopic activity in lesioned and neighboring intact nerve fibers. The major transmitter released by sensory afferents in the superficial dorsal horn of the spinal cord is glutamate. Glutamate is critically involved in nociceptive signaling and the development of neuropathic pain. We recorded miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II of the rat dorsal horn to assess spontaneous synaptic activity after spared nerve injury (SNI), a model of chronic neuropathic pain. Following SNI, the frequency of mEPSCs doubled, indicating heightened glutamate release from primary afferents or spinal interneurons. Consistent with this finding, glutamate concentrations in the cerebrospinal fluid were elevated at one and four weeks after SNI. Transmitter uptake was insufficient to prevent the rise in extracellular glutamate as the expression of glutamate transporters remained unchanged or decreased. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor 5 (mGluR5), reduced the frequency of mEPSCs to its preinjury level, suggesting a positive feedback mechanism that involves facilitation of transmitter release by mGluR5 activation in the presence of high extracellular glutamate. Treatment with the β-lactam antibiotic ceftriaxone increased the expression of glutamate transporter 1 (Glt1) in the dorsal horn after SNI, raised transmitter uptake and lowered extracellular glutamate. Improving glutamate clearance prevented the facilitation of transmitter release by mGluR5 and attenuated neuropathic pain-like behavior. Balancing glutamate release and uptake after nerve injury should be an important target in the management of chronic neuropathic pain. PMID:23021150

  19. CB1 receptor antagonism in the granular insular cortex or somatosensory area facilitates consolidation of object recognition memory.

    PubMed

    O'Brien, Lesley D; Sticht, Martin A; Mitchnick, Krista A; Limebeer, Cheryl L; Parker, Linda A; Winters, Boyer D

    2014-08-22

    Cannabinoid agonists typically impair memory, whereas CB1 receptor antagonists enhance memory performance under specific conditions. The insular cortex has been implicated in object memory consolidation. Here we show that infusions of the CB1 receptor antagonist SR141716 enhances long-term object recognition memory in rats in a dose-dependent manner (facilitation with 1.5, but not 0.75 or 3 μg/μL) when administered into the granular insular cortex; the SR141716 facilitation was seen with a memory delay of 72 h, but not when the delay was shorter (1 h), consistent with enhancement of memory consolidation. Moreover, a sub-group of rats with cannulas placed in the somatosensory area were also facilitated. These results highlight the robust potential of cannabinoid antagonists to facilitate object memory consolidation, as well as the capacity for insular and somatosensory cortices to contribute to object processing, perhaps through enhancement of tactile representation.

  20. Mutism and auditory agnosia due to bilateral insular damage--role of the insula in human communication.

    PubMed

    Habib, M; Daquin, G; Milandre, L; Royere, M L; Rey, M; Lanteri, A; Salamon, G; Khalil, R

    1995-03-01

    We report a case of transient mutism and persistent auditory agnosia due to two successive ischemic infarcts mainly involving the insular cortex on both hemispheres. During the 'mutic' period, which lasted about 1 month, the patient did not respond to any auditory stimuli and made no effort to communicate. On follow-up examinations, language competences had re-appeared almost intact, but a massive auditory agnosia for non-verbal sounds was observed. From close inspection of lesion site, as determined with brain resonance imaging, and from a study of auditory evoked potentials, it is concluded that bilateral insular damage was crucial to both expressive and receptive components of the syndrome. The role of the insula in verbal and non-verbal communication is discussed in the light of anatomical descriptions of the pattern of connectivity of the insular cortex.

  1. Apigenin, a natural flavonoid, inhibits glutamate release in the rat hippocampus.

    PubMed

    Chang, Chia Ying; Lin, Tzu Yu; Lu, Cheng Wei; Wang, Chia Chuan; Wang, Ying Chou; Chou, Shang Shing Peter; Wang, Su Jane

    2015-09-05

    The purpose of this study was to examine the effect and mechanism of apigenin, a natural flavonoid, on glutamate release in the rat hippocampus. In rat hippocampal nerve terminals (synaptosomes), apigenin inhibited glutamate release and the elevation of the cytosolic free Ca(2+) concentration evoked by 4-aminopyridine, whereas it had no effect on 4-aminopyridine-mediated depolarization and Na(+) influx. The apigenin-mediated inhibition of evoked glutamate release was prevented by chelating the extracellular Ca(2+) ions and blocking Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel activity. Furthermore, we determined that gamma-aminobutyric acid type A (GABAA) receptors are present in the hippocampal nerve terminals because they are colocalized with the presynaptic marker synaptophysin. However, the effect of apigenin on 4-aminopyridine-evoked glutamate release from synaptosomes was unaffected by the GABAA receptor antagonists SR95531 and bicuculline. Furthermore, in slice preparations, whole-cell patch-clamp experiments showed that apigenin reduced the frequency of spontaneous excitatory postsynaptic currents without affecting their amplitude, suggesting a presynaptic mechanism. On the basis of these results, we suggested that apigenin exerts its presynaptic inhibition probably by reducing Ca(2+) entry mediated by the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, thereby inhibiting glutamate release from the rat hippocampal nerve terminals.

  2. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction

    PubMed Central

    Rao, PSS; Yallapu, Murali M.; Sari, Youssef; Fisher, Paul B.; Kumar, Santosh

    2015-01-01

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described. PMID:26635971

  3. Xanthohumol-induced presynaptic reduction of glutamate release in the rat hippocampus.

    PubMed

    Chang, Yi; Lin, Tzu Yu; Lu, Cheng Wei; Huang, Shu Kuei; Wang, Ying Chou; Wang, Su Jane

    2016-01-01

    This study examined whether xanthohumol, a hop-derived prenylated flavonoid present in beer, affects glutamate release in the rat hippocampus. In the rat hippocampal nerve terminals (synaptosomes), xanthohumol inhibited the release of 4-aminopyridine (4-AP)-evoked glutamate and the elevation of cytosolic Ca(2+) concentration, whereas it had no effect on 4-AP-mediated depolarization. The inhibitory effect of xanthohumol on the evoked glutamate release was prevented by removing extracellular Ca(2+), using the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-CgTX MVIIC, the calmodulin antagonists W7 and calmidazolium, and the protein kinase A inhibitor H89; however, no such effect was observed when the G-protein inhibitor N-ethylmaleimide was used. In addition, immunocytochemical data demonstrated that GABAA receptors are present in the hippocampal synaptosomes and that the xanthohumol effect on evoked glutamate release was antagonized by the GABAA receptor antagonist SR95531. Furthermore, in slice preparations, xanthohumol reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude. We conclude that xanthohumol acts at GABAA receptors present in the hippocampal nerve terminals to decrease the Ca(2+) influx through N- and P/Q-type Ca(2+) channels, which subsequently suppresses the Ca(2+)-calmodulin/PKA cascade to decrease the evoked glutamate release.

  4. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    PubMed

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  5. Vesicular Glutamate Transport Promotes Dopamine Storage and Glutamate Corelease In Vivo

    PubMed Central

    Hnasko, Thomas S.; Chuhma, Nao; Zhang, Hui; Goh, Germaine Y.; Sulzer, David; Palmiter, Richard D.; Rayport, Stephen; Edwards, Robert H.

    2010-01-01

    SUMMARY Dopamine neurons in the ventral tegmental area (VTA) play an important role in the motivational systems underlying drug addiction, and recent work has suggested that they also release the excitatory neurotransmitter glutamate. To assess a physiological role for glutamate corelease, we disrupted the expression of vesicular glutamate transporter 2 selectively in dopamine neurons. The conditional knockout abolishes glutamate release from midbrain dopamine neurons in culture and severely reduces their excitatory synaptic output in mesoaccumbens slices. Baseline motor behavior is not affected, but stimulation of locomotor activity by cocaine is impaired, apparently through a selective reduction of dopamine stores in the projection of VTA neurons to ventral striatum. Glutamate co-entry promotes monoamine storage by increasing the pH gradient that drives vesicular monoamine transport. Remarkably, low concentrations of glutamate acidify synaptic vesicles more slowly but to a greater extent than equimolar Cl−, indicating a distinct, presynaptic mechanism to regulate quantal size. PMID:20223200

  6. Metabolic fate and function of dietary glutamate in the gut

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glutamate is a major constituent of dietary protein and is also consumed in many prepared foods as an additive in the form of monosodium glutamate. Evidence from human and animal studies indicates that glutamate is a major oxidative fuel for the gut and that dietary glutamate is extensively metabol...

  7. Emerging aspects of dietary glutamate metabolism in the developing gut

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glutamate is a major constituent of dietary protein and is also consumed in many prepared foods as a flavour additive in the form of monosodium glutamate (MSG). Evidence from human and animal studies indicates that glutamate is the major oxidative fuel for the gut and that dietary glutamate is exten...

  8. GABA-Mediated Inactivation of Medial Prefrontal and Agranular Insular Cortex in the Rat: Contrasting Effects on Hunger- and Palatability-Driven Feeding

    PubMed Central

    Baldo, Brian A; Spencer, Robert C; Sadeghian, Ken; Mena, Jesus D

    2016-01-01

    A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-mediated inactivation of two frontal regions in rats, the agranular/dysgranular insular cortex (AIC) and the ventromedial prefrontal cortex (vmPFC). Food and water intake, feeding microstructure, and general motor activity were measured under two motivational conditions: food-deprived rats given standard chow or ad libitum-fed rats given a palatable chocolate shake. Muscimol infusions into the AIC diminished intake, total feeding duration, and average feeding bout duration for the palatable-food condition only but failed to alter exploratory-like behavior (ambulation or rearing). In contrast, intra-vmPFC muscimol infusions did not alter the overall intake of chow or chocolate shake. However, these infusions markedly increased mean feeding bout duration for both food types and produced a modest but significant reduction of exploratory-like behavior. The lengthening of feeding-bout duration and reduction in rearing were mimicked by intra-vmPFC blockade of AMPA-type but not NMDA-type glutamate receptors. Neither water consumption nor the microstructure of water drinking was affected by inactivation of either site. These results indicate a regional heterogeneity in frontal control of feeding behavior. Neural processing in AIC supports palatability-driven feeding but is not necessary for intake of a standard food under a food-restriction condition, whereas ventromedial prefrontal cortex, and AMPA signaling therein, modulates the duration of individual feeding bouts regardless of motivational context. Results are discussed in the context of regionally heterogeneous frontal modulation of two distinct components of feeding behavior: reward valuation based upon taste perception (AIC) vs switching between ingestive and non-ingestive (eg, exploratory-like) behavioral repertoires (vmPFC). PMID:26202102

  9. GABA-Mediated Inactivation of Medial Prefrontal and Agranular Insular Cortex in the Rat: Contrasting Effects on Hunger- and Palatability-Driven Feeding.

    PubMed

    Baldo, Brian A; Spencer, Robert C; Sadeghian, Ken; Mena, Jesus D

    2016-03-01

    A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-mediated inactivation of two frontal regions in rats, the agranular/dysgranular insular cortex (AIC) and the ventromedial prefrontal cortex (vmPFC). Food and water intake, feeding microstructure, and general motor activity were measured under two motivational conditions: food-deprived rats given standard chow or ad libitum-fed rats given a palatable chocolate shake. Muscimol infusions into the AIC diminished intake, total feeding duration, and average feeding bout duration for the palatable-food condition only but failed to alter exploratory-like behavior (ambulation or rearing). In contrast, intra-vmPFC muscimol infusions did not alter the overall intake of chow or chocolate shake. However, these infusions markedly increased mean feeding bout duration for both food types and produced a modest but significant reduction of exploratory-like behavior. The lengthening of feeding-bout duration and reduction in rearing were mimicked by intra-vmPFC blockade of AMPA-type but not NMDA-type glutamate receptors. Neither water consumption nor the microstructure of water drinking was affected by inactivation of either site. These results indicate a regional heterogeneity in frontal control of feeding behavior. Neural processing in AIC supports palatability-driven feeding but is not necessary for intake of a standard food under a food-restriction condition, whereas ventromedial prefrontal cortex, and AMPA signaling therein, modulates the duration of individual feeding bouts regardless of motivational context. Results are discussed in the context of regionally heterogeneous frontal modulation of two distinct components of feeding behavior: reward valuation based upon taste perception (AIC) vs switching between ingestive and non-ingestive (eg, exploratory-like) behavioral repertoires (vmPFC).

  10. Susceptibility to Infection and Immune Response in Insular and Continental Populations of Egyptian Vulture: Implications for Conservation

    PubMed Central

    Gangoso, Laura; Grande, Juan M.; Lemus, Jesús A.; Blanco, Guillermo; Grande, Javier; Donázar, José A.

    2009-01-01

    Background A generalized decline in populations of Old World avian scavengers is occurring on a global scale. The main cause of the observed crisis in continental populations of these birds should be looked for in the interaction between two factors - changes in livestock management, including the increased use of pharmaceutical products, and disease. Insular vertebrates seem to be especially susceptible to diseases induced by the arrival of exotic pathogens, a process often favored by human activities, and sedentary and highly dense insular scavengers populations may be thus especially exposed to infection by such pathogens. Here, we compare pathogen prevalence and immune response in insular and continental populations of the globally endangered Egyptian vulture under similar livestock management scenarios, but with different ecological and evolutionary perspectives. Methods/Principal Findings Adult, immature, and fledgling vultures from the Canary Islands and the Iberian Peninsula were sampled to determine a) the prevalence of seven pathogen taxa and b) their immunocompetence, as measured by monitoring techniques (white blood cells counts and immunoglobulins). In the Canarian population, pathogen prevalence was higher and, in addition, an association among pathogens was apparent, contrary to the situation detected in continental populations. Despite that, insular fledglings showed lower leukocyte profiles than continental birds and Canarian fledglings infected by Chlamydophila psittaci showed poorer cellular immune response. Conclusions/Significance A combination of environmental and ecological factors may contribute to explain the high susceptibility to infection found in insular vultures. The scenario described here may be similar in other insular systems where populations of carrion-eaters are in strong decline and are seriously threatened. Higher susceptibility to infection may be a further factor contributing decisively to the extinction of island scavengers

  11. Monocular Elevation Deficiency - Double Elevator Palsy

    MedlinePlus

    ... sucking thus creating a "wink" when chewing or sucking. Is Monocular Elevation Deficiency associated with other diseases or developmental problems? There is no known association between Monocular Elevation ...

  12. DNA nanopore translocation in glutamate solutions

    NASA Astrophysics Data System (ADS)

    Plesa, C.; van Loo, N.; Dekker, C.

    2015-08-01

    Nanopore experiments have traditionally been carried out with chloride-based solutions. Here we introduce silver/silver-glutamate-based electrochemistry as an alternative, and study the viscosity, conductivity, and nanopore translocation characteristics of potassium-, sodium-, and lithium-glutamate solutions. We show that it has a linear response at typical voltages and can be used to detect DNA translocations through a nanopore. The glutamate anion also acts as a redox-capable thickening agent, with high-viscosity solutions capable of slowing down the DNA translocation process by up to 11 times, with a corresponding 7 time reduction in signal. These results demonstrate that glutamate can replace chloride as the primary anion in nanopore resistive pulse sensing.

  13. Mechanism for the activation of glutamate receptors

    Cancer.gov

    Scientists at the NIH have used a technique called cryo-electron microscopy to determine a molecular mechanism for the activation and desensitization of ionotropic glutamate receptors, a prominent class of neurotransmitter receptors in the brain and spina

  14. DNA nanopore translocation in glutamate solutions.

    PubMed

    Plesa, C; van Loo, N; Dekker, C

    2015-08-28

    Nanopore experiments have traditionally been carried out with chloride-based solutions. Here we introduce silver/silver-glutamate-based electrochemistry as an alternative, and study the viscosity, conductivity, and nanopore translocation characteristics of potassium-, sodium-, and lithium-glutamate solutions. We show that it has a linear response at typical voltages and can be used to detect DNA translocations through a nanopore. The glutamate anion also acts as a redox-capable thickening agent, with high-viscosity solutions capable of slowing down the DNA translocation process by up to 11 times, with a corresponding 7 time reduction in signal. These results demonstrate that glutamate can replace chloride as the primary anion in nanopore resistive pulse sensing.

  15. Glutamate and dopamine components in schizophrenia

    PubMed Central

    Seeman, Philip

    2009-01-01

    The treatment of schizophrenia for the last half century has been with dopamine (DA) D2 receptor blockers, implicating a hyperdopamine basis for psychosis. However, a 2007 report found that the glutamate agonist LY404039 was effective in schizophrenia, suggesting a hypoglutamate state for the illness. Although phencyclidine psychosis also supports a hypoglutamate cause, assessing the basic and clinical findings shows that phencyclidine has DA D2 agonist actions as well. Accurate Dreiding models of phencyclidine and the LY glutamate agonists precisely fit the known tetrahedral model of the D2 receptor that accommodates all DA agonists. A further view is that metabotropic glutamate agonists also exert D2 agonism, and their antipsychotic doses (about 100 mg/d) are predicted by their dissociation constants (about 20 nM) for D2. Hence, the clinical antipsychotic action of a glutamate agonist may depend on its ability to interfere with DA neurotransmission by its DA partial agonism. PMID:19270765

  16. Glutamate Receptor Dynamics in Dendritic Microdomains

    PubMed Central

    Newpher, Thomas M.; Ehlers, Michael D.

    2008-01-01

    Among diverse factors regulating excitatory synaptic transmission, the abundance of postsynaptic glutamate receptors figures prominently in molecular memory and learning-related synaptic plasticity. To allow for both long-term maintenance of synaptic transmission and acute changes in synaptic strength, the relative rates of glutamate receptor insertion and removal must be tightly regulated. Interactions with scaffolding proteins control the targeting and signaling properties of glutamate receptors within the postsynaptic membrane. In addition, extrasynaptic receptor populations control the equilibrium of receptor exchange at synapses and activate distinct signaling pathways involved in plasticity. Here, we review recent findings that have shaped our current understanding of receptor mobility between synaptic and extrasynaptic compartments at glutamatergic synapses, focusing on AMPA and NMDA receptors. We also examine the cooperative relationship between intracellular trafficking and surface diffusion of glutamate receptors that underlies the expression of learning-related synaptic plasticity. PMID:18498731

  17. [Glutamate neurotransmission, stress and hormone secretion].

    PubMed

    Jezová, D; Juránková, E; Vigas, M

    1995-11-01

    Glutamate neurotransmission has been investigated in relation to several physiological processes (learning, memory) as well as to neurodegenerative and other disorders. Little attention has been paid to its involvement in neuroendocrine response during stress. Penetration of excitatory amino acids from blood to the brain is limited by the blood-brain barrier. As a consequence, several toxic effects but also bioavailability for therapeutic purposes are reduced. A free access to circulating glutamate is possible only in brain structures lacking the blood-brain barrier or under conditions of its increased permeability. Excitatory amino acids were shown to stimulate the pituitary hormone release, though the mechanism of their action is still not fully understood. Stress exposure in experimental animals induced specific changes in mRNA levels coding the glutamate receptor subunits in the hippocampus and hypothalamus. The results obtained with the use of glutamate receptor antagonists indicate that a number of specific receptor subtypes contribute to the stimulation of ACTH release during stress. The authors provided also data on the role of NMDA receptors in the control of catecholamine release, particularly in stress-induced secretion of epinephrine. These results were the first piece of evidence on the involvement of endogenous excitatory amino acids in neuroendocrine activation during stress. Neurotoxic effects of glutamate in animals are well described, especially after its administration in the neonatal period. In men, glutamate toxicity and its use as a food additive are a continuous subject of discussions. The authors found an increase in plasma cortisol and norepinephrine, but not epinephrine and prolactin, in response to the administration of a high dose of glutamate. It cannot be excluded that these effects might be induced even by lower doses in situations with increased vulnerability to glutamate action (age, individual variability). (Tab. 1, Fig. 6, Ref. 44.).

  18. Structural basis of empathy and the domain general region in the anterior insular cortex

    PubMed Central

    Mutschler, Isabella; Reinbold, Céline; Wankerl, Johanna; Seifritz, Erich; Ball, Tonio

    2013-01-01

    Empathy is key for healthy social functioning and individual differences in empathy have strong implications for manifold domains of social behavior. Empathy comprises of emotional and cognitive components and may also be closely linked to sensorimotor processes, which go along with the motivation and behavior to respond compassionately to another person's feelings. There is growing evidence for local plastic change in the structure of the healthy adult human brain in response to environmental demands or intrinsic factors. Here we have investigated changes in brain structure resulting from or predisposing to empathy. Structural MRI data of 101 healthy adult females was analyzed. Empathy in fictitious as well as real-life situations was assessed using a validated self-evaluation measure. Furthermore, empathy-related structural effects were also put into the context of a functional map of the anterior insular cortex (AIC) determined by activation likelihood estimate (ALE) meta-analysis of previous functional imaging studies. We found that gray matter (GM) density in the left dorsal AIC correlates with empathy and that this area overlaps with the domain general region (DGR) of the anterior insula that is situated in-between functional systems involved in emotion–cognition, pain, and motor tasks as determined by our meta-analysis. Thus, we propose that this insular region where we find structural differences depending on individual empathy may play a crucial role in modulating the efficiency of neural integration underlying emotional, cognitive, and sensorimotor information which is essential for global empathy. PMID:23675334

  19. Molecular systematics of Hispaniolan pupfishes (Cyprinodontidae: Cyprinodon): implications for the biogeography of insular Caribbean fishes.

    PubMed

    Echelle, Anthony A; Fuselier, Linda; Van Den Bussche, Ronald A; Rodriguez, Carlos M L; Smith, Michael L

    2006-06-01

    We used sequence variation in the mtDNA control-region and ND2 and cyt b genes to assess the systematics and biogeography of the five species of pupfish (Cyprinodon) on Hispaniola. These include four endemics, the relatively large-bodied Cyprinodon bondi, Cyprinodon nichollsi, and Cyprinodon sp., each from a separate lake in southwestern Hispaniola, and Cyprinodon higuey from a coastal lake in eastern Hispaniola. The fifth species consists of coastal populations referable to Cyprinodon variegatus riverendi. The results indicate that Hispaniola has been invaded by at least two forms, first by a late Pliocene progenitor of Cyprinodon variegatus ovinus and the large-bodied Hispaniolan species, and, more recently, by one or more ancestral forms allied with Cyprinodon variegatus variegatus and C. v. riverendi. Levels of divergence indicate that large expanses of open sea have not acted as long-term barriers to inter-island dispersal of cyprinodontiform fishes. This study, together with the molecular systematics of other insular Caribbean fishes, indicates that most insular groups originated from late Neogene dispersal from the mainland. The patterns of mtDNA variation in Cyprinodon showed little congruence with the species/subspecies taxonomy.

  20. A role for the interoceptive insular cortex in the consolidation of learned fear.

    PubMed

    Casanova, José Patricio; Madrid, Carlos; Contreras, Marco; Rodríguez, María; Vasquez, Mónica; Torrealba, Fernando

    2016-01-01

    A growing body of evidence suggests that learned fear may be related to the function of the interoceptive insular cortex. Using an auditory fear conditioning paradigm in rats, we show that the inactivation of the posterior insular cortex (pIC), the target of the interoceptive thalamus, prior to training produced a marked reduction in fear expression tested 24h later. Accordingly, post-training anisomycin infused immediately, but not 6h after, also reduced fear expression tested the following day, supporting a role for the pIC in consolidation of fear memory. The long-term (ca. a week) and reversible inactivation of the pIC with the sodium channel blocker neosaxitoxin, immediately after fear memory reactivation induced a progressive decrease in the behavioral expression of conditioned fear. In turn, we observed that fear memory reactivation is accompanied by an enhanced expression of Fos and Zif268, early genes involved in neural activity and plasticity. Taken together these data indicate that the pIC is involved in the regulation of fear memories.

  1. Involvement of the rostral agranular insular cortex in nicotine self-administration in rats.

    PubMed

    Pushparaj, Abhiram; Kim, Aaron S; Musiol, Martin; Trigo, Jose M; Le Foll, Bernard

    2015-09-01

    Our prior work demonstrated the involvement of the caudal granular subregion of the insular cortex in a rat model of nicotine self-administration. Recent studies in various animal models of addiction for nicotine and other drugs have identified a role for the rostral agranular subregion (RAIC). The current research was undertaken to examine the involvement of the RAIC in a rat model of nicotine self-administration. We investigated the inactivating effects of local infusions of a γ-aminobutyric acid agonist mixture (baclofen/muscimol) into the RAIC on nicotine self-administration under a fixed-ratio 5 (FR-5) schedule and on reinstatement of nicotine seeking induced by nicotine-associated cues in rats. We also evaluated the effects of RAIC inactivation on food self-administration under an FR5 schedule as a control. Inactivation of the RAIC decreased nicotine, but not food, self-administration. RAIC inactivation also prevented the reinstatement, after extinction, of nicotine seeking induced by nicotine-associated cues. Our study indicates that the RAIC is involved in nicotine-taking and nicotine-seeking in rats. Modulating insular cortex function appears to be a promising approach for nicotine dependence treatment.

  2. The Cortical Signature of Central Poststroke Pain: Gray Matter Decreases in Somatosensory, Insular, and Prefrontal Cortices.

    PubMed

    Krause, T; Asseyer, S; Taskin, B; Flöel, A; Witte, A V; Mueller, K; Fiebach, J B; Villringer, K; Villringer, A; Jungehulsing, G J

    2016-01-01

    It has been proposed that cortical structural plasticity plays a crucial role in the emergence and maintenance of chronic pain. Various distinct pain syndromes have accordingly been linked to specific patterns of decreases in regional gray matter volume (GMV). However, it is not known whether central poststroke pain (CPSP) is also associated with cortical structural plasticity. To determine this, we employed T1-weighted magnetic resonance imaging at 3 T and voxel-based morphometry in 45 patients suffering from chronic subcortical sensory stroke with (n = 23) and without CPSP (n = 22), and healthy matched controls (n = 31). CPSP patients showed decreases in GMV in comparison to healthy controls, involving secondary somatosensory cortex (S2), anterior as well as posterior insular cortex, ventrolateral prefrontal and orbitofrontal cortex, temporal cortex, and nucleus accumbens. Comparing CPSP patients to nonpain patients revealed a similar but more restricted pattern of atrophy comprising S2, ventrolateral prefrontal and temporal cortex. Additionally, GMV in the ventromedial prefrontal cortex negatively correlated to pain intensity ratings. This shows for the first time that CPSP is accompanied by a unique pattern of widespread structural plasticity, which involves the sensory-discriminative areas of insular/somatosensory cortex, but also expands into prefrontal cortex and ventral striatum, where emotional aspects of pain are processed.

  3. Island colonization and evolution of the insular woody habit in Echium L. (Boraginaceae).

    PubMed Central

    Böhle, U R; Hilger, H H; Martin, W F

    1996-01-01

    Numerous island-inhabiting species of predominantly herbaceous angiosperm genera are woody shrubs or trees. Such "insular woodiness" is strongly manifested in the genus Echium, in which the continental species of circummediterranean distribution are herbaceous, whereas endemic species of islands along the Atlantic coast of north Africa are woody perennial shrubs. The history of 37 Echium species was traced with 70 kb of noncoding DNA determined from both chloroplast and nuclear genomes. In all, 239 polymorphic positions with 137 informative sites, in addition to 27 informative indels, were found. Island-dwelling Echium species are shown to descend from herbaceous continental ancestors via a single island colonization event that occurred < 20 million years ago. Founding colonization appears to have taken place on the Canary Islands, from which the Madeira and Cape Verde archipelagos were invaded. Colonization of island habitats correlates with a recent origin of perennial woodiness from herbaceous habit and was furthermore accompanied by intense speciation, which brought forth remarkable diversity of forms among contemporary island endemics. We argue that the origin of insular woodiness involved response to counter-selection of inbreeding depression in founding island colonies. Images Fig. 1 Fig. 3 PMID:8876207

  4. Activation of Pedunculopontine Glutamate Neurons Is Reinforcing.

    PubMed

    Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan; Punta, Cindy; Ramajayam, Nivedita; Shen, Xinyi; Faget, Lauren; Lilascharoen, Varoth; Lim, Byung Kook; Hnasko, Thomas S

    2017-01-04

    Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders.

  5. Ionotropic Glutamate Receptors & CNS Disorders

    PubMed Central

    Bowie, Derek

    2008-01-01

    Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although etiology is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual’s susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor trafficking are important to Fragile X mental retardation and ectopic expression of kainate (KA) receptor synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms. PMID:18537642

  6. Glutamate formation via the leucine-to-glutamate pathway of rat pancreas.

    PubMed

    Schachter, David; Buteau, Jean

    2014-06-01

    The leucine-to-glutamate (Leu→Glu) pathway, which metabolizes the carbon atoms of l-leucine to form l-glutamate, was studied by incubation of rat tissue segments with l-[U-(14)C]leucine and estimation of the [(14)C]glutamate formed. Metabolism of the leucine carbon chain occurs in most rat tissues, but maximal activity of the Leu→Glu pathway for glutamate formation is limited to the thoracic aorta and pancreas. In rat aorta, the Leu→Glu pathway functions to relax the underlying smooth muscle; its functions in the pancreas are unknown. This report characterizes the Leu→Glu pathway of rat pancreas and develops methods to examine its functions. Pancreatic segments effect net formation of glutamate on incubation with l-leucine, l-glutamine, or a mix of 18 other plasma amino acids at their concentrations in normal rat plasma. Glutamate formed from leucine remains mainly in the tissue, whereas that from glutamine enters the medium. The pancreatic Leu→Glu pathway uses the leucine carbons for net glutamate formation; the α-amino group is not used; the stoichiometry is as follows: 1 mol of leucine yields 2 mol of glutamate (2 leucine carbons per glutamate) plus 2 mol of CO2. Comparison of the Leu→Glu pathway in preparations of whole pancreatic segments, isolated acini, and islets of Langerhans localizes it in the acini; relatively high activity is found in cultures of the AR42J cell line and very little in the INS-1 832/13 cell line. Pancreatic tissue glutamate concentration is homeostatically regulated in the range of ∼1-3 μmol/g wet wt. l-Valine and leucine ethyl, benzyl, and tert-butyl esters inhibit the Leu→Glu pathway without decreasing tissue total glutamate.

  7. The Degradation of 14C-Glutamic Acid by L-Glutamic Acid Decarboxylase.

    ERIC Educational Resources Information Center

    Dougherty, Charles M; Dayan, Jean

    1982-01-01

    Describes procedures and semi-micro reaction apparatus (carbon dioxide trap) to demonstrate how a particular enzyme (L-Glutamic acid decarboxylase) may be used to determine the site or sites of labeling in its substrate (carbon-14 labeled glutamic acid). Includes calculations, solutions, and reagents used. (Author/SK)

  8. "There Are No Housewives on 'Star Trek'": A Reexamination of Exit Rights for the Children of Insular Fundamentalist Parents

    ERIC Educational Resources Information Center

    McAvoy, Paula

    2012-01-01

    In this essay, Paula McAvoy addresses the problem caused by the liberal state's necessary tolerance of insular fundamentalist groups and the concern that children raised in such groups do not have a fair opportunity to evaluate their inherited beliefs. This tension comes to the fore around disagreements over schooling and requests for religious…

  9. Decreased Functional Connectivity of Insular Cortex in Drug Naïve First Episode Schizophrenia: In Relation to Symptom Severity

    PubMed Central

    Pang, Lijuan; Kennedy, David; Wei, Qinling; Lv, Luxian; Gao, Jinsong; Li, Hong; Quan, Meina; Li, Xue; Yang, Yongfeng; Fan, Xiaoduo; Song, Xueqin

    2017-01-01

    Background This study was to examine the insular cortical functional connectivity in drug naïve patients with first episode schizophrenia and to explore the relationship between the connectivity and the severity of clinical symptoms. Methods Thirty-seven drug naïve patients with schizophrenia and 25 healthy controls were enrolled in this study. A seed-based approach was used to analyze the resting-state functional imaging data. Insular cortical connectivity maps were bilaterally extracted for group comparison and validated by voxel-based morphometry (VBM) analysis. Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Results There were significant reductions in the right insular cortical connectivity with the Heschl’s gyrus, anterior cingulate cortex (ACC), and caudate (p’s<0.001) in the patient group compared with the healthy control (HC) group. Reduced right insular cortical connectivity with the Heschl’s gyrus was further confirmed in the VBM analysis (FDR corrected p<0.05). Within the patient group, there was a significant positive relationship between the right insula-Heschl’s connectivity and PANSS general psychopathology scores (r = 0.384, p = 0.019). Conclusion Reduced insula-Heschl’s functional connectivity is present in drug naïve patients with first episode schizophrenia, which might be related to the manifestation of clinical symptoms. PMID:28107346

  10. Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex.

    PubMed

    Muschamp, John W; Regina, Meredith J; Hull, Elaine M; Winter, Jerrold C; Rabin, Richard A

    2004-10-08

    The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT(2A) antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT(2A/C) agonist [-]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 microM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was observed. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.

  11. How can an inert gas counterbalance a NMDA-induced glutamate release?

    PubMed

    Vallee, Nicolas; Rostain, Jean-Claude; Risso, Jean-Jacques

    2009-12-01

    Previous neurochemical studies performed in rats have revealed a decrease of striatal dopamine and glutamate induced by inert gas narcosis. We sought to establish the hypothetical role of glutamate and its main receptor, the N-methyl-d-aspartate (NMDA) receptor, in this syndrome. We aimed to counteract the nitrogen narcosis-induced glutamate and dopamine decreases by stimulating the NMDA receptor in the striatum. We used bilateral retrodialysis on awake rats, submitted to nitrogen under pressure (3 MPa). Continuous infusion of 2 mM of NMDA under normobaric conditions (0.01 MPa) (n = 8) significantly increased extracellular average levels of glutamate, aspartate, glutamine, and asparagine by 241.8%, 292.5%, 108.3%, and 195.3%, respectively. The same infusion conducted under nitrogen at 3 MPa (n = 6) revealed significant lower levels of these amino acids (n = 8/6, P > 0.001). In opposition, the NMDA-induced effects on dopamine, dihydrophenylacetic acid (DOPAC), and homovanillic acid (HVA) levels were statistically not affected by the nitrogen at 3 MPa exposure (n = 8/6, P > 0.05). Dopamine was increased by >240% on average. HVA was decreased (down to 40%), and there was no change in DOPAC levels, in both conditions. Results highlight that the NMDA receptor is not directly affected by nitrogen under pressure as indicated by the elevation in NMDA-induced dopamine release under hyperbaric nitrogen. On the other hand, the NMDA-evoked glutamate increase is counteracted by nitrogen narcosis. No improvement in motor and locomotor disturbances was observed with high striatal concentration in dopamine. Further experiments have to be done to specify why the striatal glutamate pathways, in association with the inhibition of its metabolism, only are affected by nitrogen narcosis in this study.

  12. Sex Differences in Insular Cortex Gyri Responses to the Valsalva Maneuver

    PubMed Central

    Macey, Paul M.; Rieken, Nicholas S.; Kumar, Rajesh; Ogren, Jennifer A.; Middlekauff, Holly R.; Wu, Paula; Woo, Mary A.; Harper, Ronald M.

    2016-01-01

    Sex differences in autonomic regulation may underlie cardiovascular disease variations between females and males. One key autonomic brain region is the insular cortex, which typically consists of five main gyri in each hemisphere, and shows a topographical organization of autonomic function across those gyri. The present study aims to identify possible sex differences in organization of autonomic function in the insula. We studied brain functional magnetic resonance imaging (fMRI) responses to a series of four 18-s Valsalva maneuvers in 22 healthy females (age ± SD: 50.0 ± 7.9 years) and 36 healthy males (45.3 ± 9.2 years). Comparisons of heart rate (HR) and fMRI signals were performed with repeated measures ANOVA (threshold P < 0.05 for all findings). All subjects achieved the target 30 mmHg expiratory pressure for all challenges. Typical HR responses were elicited by the maneuver, including HR increases from ~4 s into the strain period (Phase II) and rapid declines to below baseline 5–10 s, following strain release (Phase IV). Small, but significant, sex differences in HR percent change occurred during the sympathetic-dominant Phase II (female < male) and parasympathetic-dominant Phase IV (female > male, i.e., greater undershoot in males). The insular cortices showed similar patterns in all gyri, with greater signal decreases in males than females. Both sexes exhibited an anterior–posterior topographical organization of insular responses during Phase II, with anterior gyri showing higher responses than more posterior gyri. The exception was the right anterior-most gyrus in females, which had lower responses than the four other right gyri. Responses were lateralized, with right-sided dominance during Phase II in both sexes, except the right anterior-most gyrus in females, which showed lower responses than the left. The findings confirm the anterior and right-sided sympathetic dominance of the insula. Although sex

  13. Right insular damage decreases heartbeat awareness and alters cardio-visual effects on bodily self-consciousness.

    PubMed

    Ronchi, Roberta; Bello-Ruiz, Javier; Lukowska, Marta; Herbelin, Bruno; Cabrilo, Ivan; Schaller, Karl; Blanke, Olaf

    2015-04-01

    Recent evidence suggests that multisensory integration of bodily signals involving exteroceptive and interoceptive information modulates bodily aspects of self-consciousness such as self-identification and self-location. In the so-called Full Body Illusion subjects watch a virtual body being stroked while they perceive tactile stimulation on their own body inducing illusory self-identification with the virtual body and a change in self-location towards the virtual body. In a related illusion, it has recently been shown that similar changes in self-identification and self-location can be observed when an interoceptive signal is used in association with visual stimulation of the virtual body (i.e., participants observe a virtual body illuminated in synchrony with their heartbeat). Although brain imaging and neuropsychological evidence suggest that the insular cortex is a core region for interoceptive processing (such as cardiac perception and awareness) as well as for self-consciousness, it is currently not known whether the insula mediates cardio-visual modulation of self-consciousness. Here we tested the involvement of insular cortex in heartbeat awareness and cardio-visual manipulation of bodily self-consciousness in a patient before and after resection of a selective right neoplastic insular lesion. Cardio-visual stimulation induced an abnormally enhanced state of bodily self-consciousness; in addition, cardio-visual manipulation was associated with an experienced loss of the spatial unity of the self (illusory bi-location and duplication of his body), not observed in healthy subjects. Heartbeat awareness was found to decrease after insular resection. Based on these data we propose that the insula mediates interoceptive awareness as well as cardio-visual effects on bodily self-consciousness and that insular processing of interoceptive signals is an important mechanism for the experienced unity of the self.

  14. Late Miocene insular mice from the Tusco-Sardinian palaeobioprovince provide new insights on the palaeoecology of the Oreopithecus faunas.

    PubMed

    Casanovas-Vilar, Isaac; van Dam, Jan A; Moyà-Solà, Salvador; Rook, Lorenzo

    2011-07-01

    Oreopithecus bambolii is one of the few hominoids that evolved under insular conditions, resulting in the development of unique adaptations that have fueled an intensive debate. The palaeoenvironment associated with this great ape has been the subject of great controversy as well. On the one hand, palaeobotanical data indicate that Oreopithecus likely inhabited mixed mesophytic forests interrupted by swamps; on the other hand, an abundance of hypsodont bovids points towards the existence of dry and open environments. Here, we provide a new approach based on the ecomorphology of the extinct endemic Muridae (rats and mice) of the so-called Oreopithecus faunas. Our results show that the successive species of endemic insular murids (Huerzelerimys and Anthracomys) evolved a number of adaptations observed only in extant family members that include significant proportions of grass in their diet. While this fits the pattern exhibited by large mammals, it contrasts with the available palaeobotanical information, which indicates that grasses were minor components of the vegetation. This contradiction may be explained because these endemic murids may have been adapted to the consumption of particular food items such as hard parts of aquatic plants (as shown by some extant murid species). However, because it is unlikely that the remaining herbivore mammals were adapted to this diet as well, we favour an alternative hypothesis that takes into account the peculiar ecological conditions of insular ecosystems leading to a density-dependent selective regime with strong competition. Such a regime would promote the selection of dental adaptations to increase feeding efficiency and durability of the dentition (such as hypsodonty) as seen in some fossil insular ruminants. This hypothesis requires further testing, but may partly account for parallel evolution of dental traits in phylogenetically unrelated insular mammals.

  15. Glutamate Metabolism in Major Depressive Disorder

    PubMed Central

    Abdallah, Chadi G.; Jiang, Lihong; De Feyter, Henk M.; Fasula, Madonna; Krystal, John H.; Rothman, Douglas L.; Mason, Graeme F.; Sanacora, Gerard

    2015-01-01

    Objective Emerging evidence suggests abnormalities in amino acid neurotransmitter function and impaired energy metabolism contribute to the underlying pathophysiology of Major Depressive Disorder (MDD). To test whether impairments in energetics and glutamate neurotransmitter cycling are present in MDD we used in vivo 13C magnetic resonance spectroscopy (13C MRS) to measure these fluxes in individuals diagnosed with MDD relative to non-depressed subjects. Method 1H MRS and 13C MRS data were collected on 23 medication-free MDD and 17 healthy subjects. 1H MRS provided total glutamate and GABA concentrations, and 13C MRS, coupled with intravenous infusion of [1-13C]-glucose, provided measures of the neuronal tricarboxylic acid cycle (VTCAN) for mitochondrial energy production, GABA synthesis, and glutamate/glutamine cycling, from voxels placed in the occipital cortex. Results Our main finding was that mitochondrial energy production of glutamatergic neurons was reduced by 26% in MDD subjects (t = 2.57, p = 0.01). Paradoxically we found no difference in the rate of glutamate/glutamine cycle (Vcycle). We also found a significant correlation between glutamate concentrations and Vcycle considering the total sample. Conclusions We interpret the reduction in mitochondrial energy production as being due to either mitochondrial dysfunction or a reduction in proper neuronal input or synaptic strength. Future MRS studies could help distinguish these possibilities. PMID:25073688

  16. Presynaptic glutamate receptors: physiological functions and mechanisms of action.

    PubMed

    Pinheiro, Paulo S; Mulle, Christophe

    2008-06-01

    Glutamate acts on postsynaptic glutamate receptors to mediate excitatory communication between neurons. The discovery that additional presynaptic glutamate receptors can modulate neurotransmitter release has added complexity to the way we view glutamatergic synaptic transmission. Here we review evidence of a physiological role for presynaptic glutamate receptors in neurotransmitter release. We compare the physiological roles of ionotropic and metabotropic glutamate receptors in short- and long-term regulation of synaptic transmission. Furthermore, we discuss the physiological conditions that are necessary for their activation, the source of the glutamate that activates them, their mechanisms of action and their involvement in higher brain function.

  17. Acute Stress Increases Depolarization-Evoked Glutamate Release in the Rat Prefrontal/Frontal Cortex: The Dampening Action of Antidepressants

    PubMed Central

    Farisello, Pasqualina; Zappettini, Simona; Tardito, Daniela; Barbiero, Valentina S.; Bonifacino, Tiziana; Mallei, Alessandra; Baldelli, Pietro; Racagni, Giorgio; Raiteri, Maurizio; Benfenati, Fabio; Bonanno, Giambattista; Popoli, Maurizio

    2010-01-01

    Background Behavioral stress is recognized as a main risk factor for neuropsychiatric diseases. Converging evidence suggested that acute stress is associated with increase of excitatory transmission in certain forebrain areas. Aim of this work was to investigate the mechanism whereby acute stress increases glutamate release, and if therapeutic drugs prevent the effect of stress on glutamate release. Methodology/Findings Rats were chronically treated with vehicle or drugs employed for therapy of mood/anxiety disorders (fluoxetine, desipramine, venlafaxine, agomelatine) and then subjected to unpredictable footshock stress. Acute stress induced marked increase in depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex in superfusion, and the chronic drug treatments prevented the increase of glutamate release. Stress induced rapid increase in the circulating levels of corticosterone in all rats (both vehicle- and drug-treated), and glutamate release increase was blocked by previous administration of selective antagonist of glucocorticoid receptor (RU 486). On the molecular level, stress induced accumulation of presynaptic SNARE complexes in synaptic membranes (both in vehicle- and drug-treated rats). Patch-clamp recordings of pyramidal neurons in the prefrontal cortex revealed that stress increased glutamatergic transmission through both pre- and postsynaptic mechanisms, and that antidepressants may normalize it by reducing release probability. Conclusions/Significance Acute footshock stress up-regulated depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex. Stress-induced increase of glutamate release was dependent on stimulation of glucocorticoid receptor by corticosterone. Because all drugs employed did not block either elevation of corticosterone or accumulation of SNARE complexes, the dampening action of the drugs on glutamate release must be downstream of these processes. This novel effect of

  18. A possible role for nitric oxide in glutamate (MSG)-induced Chinese restaurant syndrome, glutamate-induced asthma, 'hot-dog headache', pugilistic Alzheimer's disease, and other disorders.

    PubMed

    Scher, W; Scher, B M

    1992-07-01

    Endogenous glutamate is thought to be a major neurotransmitter. After binding to a cell membrane receptor there can be a stimulation of what can be called the nitric oxide (NO)-mediated neurotransmission pathway (NO-MNP). The activity of the enzyme that produces NO from arginine, NO synthase, and the level of NO become elevated. NO has little activity within the cell in which it is produced, but it rapidly leaks out of that cell and produces effects in neighboring cells. The NO-MNP can be activated to release NO in endothelial cells which in turn acts on neighboring vascular smooth muscle cells to induce vasodilation. Therefore, we suggest that exogenous, ingested glutamate, like endogenous glutamate, can lead to the same stimulation of the NO-MNP in sensitive individuals which would then cause the symptoms of the Chinese restaurant syndrome and/or glutamate-induced asthma. Further, since ingested nitrite and related compounds can be metabolized to NO, NO may more directly cause the symptoms of 'hot dog headache'. In addition, it has been suggested that NO production can also be controlled in endothelial cells by fluid forces that stimulate pressure receptors. Therefore, elevations of NO and stimulation of the NO-MNP may occur due to sudden, local, alterations of blood pressure during pugilistic activities and play a role in the symptoms of pugilistic Alzheimer's disease. If these ideas are correct, then inhibitors of the NO-MNP and/or temporary reduction of the plasma level of arginine may be useful in preventing at least some of the symptoms of these disorders.

  19. Taste-potentiated odor aversion learning in rats with lesions of the insular cortex.

    PubMed

    Lin, Jian-You; Roman, Christopher; Reilly, Steve

    2009-11-10

    The current study assessed the influence of excitotoxic lesions of the insular cortex (IC) on taste-potentiated odor aversion (TPOA) learning. Water-deprived rats initially received a single odor-toxicosis or odor/taste-toxicosis pairing and were subsequently tested, in separate trials, with the odor and the taste stimulus. Indicating TPOA, neurologically intact rats conditioned with the odor/taste compound stimulus acquired significantly stronger odor aversions than normal rats conditioned with the odor stimulus. IC lesions disrupted TPOA, conditioned taste aversion and taste neophobia. The finding that taste did not potentiate odor aversion learning in the IC-lesioned rats provides support for the "within-compound association" analysis but is inconsistent with the "sensory-and-gate" account of TPOA learning.

  20. Forest cover of insular Southeast Asia mapped from recent satellite images of coarse spatial resolution.

    PubMed

    Stibig, Hans-Jürgen; Malingreau, Jean-Paul

    2003-11-01

    The study provides an example of mapping tropical forest cover from SPOT-Vegetation satellite images of coarse spatial resolution (1 km) for the subregion of insular Southeast Asia. A satellite image mosaic has been generated from satellite images acquired for the period 1998 to 2000. Forest cover has been mapped by unsupervised digital classification. The mapping result has then been compared to selected forest maps from the subregion, demonstrating the potential to provide basic information on forest area extent and distribution, but also on massive forest cover change in the subregional context. Forest area estimates derived from the map for the subregion have been found comparable to those compiled by FAO. The results indicate that many of the remaining tropical forests in Southeast Asia, rich in timber resources and biodiversity, may be lost in the near future if deforestation continues at present or previous rates.

  1. Reduction of brain and sense organs in the fossil insular bovid Myotragus.

    PubMed

    Köhler, Meike; Moyà-Solà, Salvador

    2004-01-01

    Our study of the fossil rupicaprine bovid Myotragus [Bate, 1909] from the Mediterranean island Majorca (Spain) provides evidence that this animal underwent significant changes (reduction) in the relative size of brain and sense organs after geographic isolation at the end of the Messinian Salinity Crisis (Miocene-Pliocene boundary, 5.2 Mya). The changes in the central nervous system of Myotragus parallel the pattern reported for domesticated animals, in which decrease in relative brain size is accompanied by a decrease in the relative size of their sense organs. We interpret the important size reduction of brain and sense organs in Myotragus as an adaptive strategy for more efficient energy use under the special environmental conditions of the insular ecosystem, characterized by absence of predation and limitation of trophic resources.

  2. Relationship between rainfall and Aedes larval population at two insular sites in Pulau Ketam, Selangor, Malaysia.

    PubMed

    Wee, Lim Kwee; Weng, Sit Nam; Raduan, Norzahira; Wah, Sing Kong; Ming, Wong Hong; Shi, Chew Hwai; Rambli, Firdaus; Ahok, Cheryl Jacyln; Marlina, Suria; Ahmad, Nazni Wasi; Mckemy, Andrew; Vasan, S S; Lim, Lee Han

    2013-03-01

    Two insular settlements (Kampung Pulau Ketam and Kampung Sungai Lima) were selected to study the population dynamics of Aedes aegypti and Aedes albopictus mosquitoes, vectors of dengue and chikungunya infections. Ovitrap surveillance was conducted between October 2007 and October 2008. There was an inverse negative association between ovitrap index and rainfall at the time of collection, probably because rainfall increased the number of available oviposition sites. Rainfall and ovitrap index were positively associates the 25th day after rainfall occurred. A minor, second peak was observed from the 38th to the 42nd day. The first peak was consistent with the minimum 18-day period between the hatching of eggs to the first oviposition. The second minor peak could be due to the second gonotrophic cycle of the female mosquitoes. Rainfall is an important environmental factor associated with Aedes breeding at the study sites.

  3. Dengue vector surveillance in insular settlements of Pulau Ketam, Selangor, Malaysia.

    PubMed

    Lim, K W; Sit, N W; Norzahira, R; Sing, K W; Wong, H M; Chew, H S; Firdaus, R; Cheryl, J A; Suria, M; Mahathavan, M; Nazni, W A; Lee, H L; McKemy, A; Vasan, S S

    2010-08-01

    A year-long ovitrap surveillance was conducted between November 2007 and October 2008 in two insular settlements (Kampung Pulau Ketam and Kampung Sungai Lima) within the Malaysian island of Pulau Ketam. Eighty standard ovitraps were placed indoors and outdoors of randomly selected houses/locations. Results demonstrated an endemic baseline Aedes population throughout the year without weekly large fluctuations. Kampung Pulau Ketam has high Aedes aegypti and Aedes albopictus population, but only Ae. aegypti was found in Kampung Sungai Lima. Aedes aegypti showed no preference for ovitraps placed indoor versus outdoor. However, as expected, significantly more outdoor ovitraps were positive for Ae. albopictus (p<0.05). Trends in Ae. albopictus and Ae. aegypti populations mirrored each other suggesting that common factors influenced these two populations.

  4. Conjoint activity of anterior insular and anterior cingulate cortex: awareness and response

    PubMed Central

    Critchley, Hugo D.

    2010-01-01

    There is now a wealth of evidence that anterior insular and anterior cingulate cortices have a close functional relationship, such that they may be considered together as input and output regions of a functional system. This system is typically engaged across cognitive, affective, and behavioural contexts, suggesting that it is of fundamental importance for mental life. Here, we review the literature and reinforce the case that these brain regions are crucial, firstly, for the production of subjective feelings and, secondly, for co-ordinating appropriate responses to internal and external events. This model seeks to integrate higher-order cortical functions with sensory representation and autonomic control: it is argued that feeling states emerge from the raw data of sensory (including interoceptive) inputs and are integrated through representations in conscious awareness. Correspondingly, autonomic nervous system reactivity is particularly important amongst the responses that accompany conscious experiences. Potential clinical implications are also discussed. PMID:20512367

  5. A new insular species of Rock Gecko (Cnemaspis Boulenger) from Pulau Langkawi, Kedah, Peninsular Malaysia.

    PubMed

    Grismer, L Lee; Wood, P L Jr; Quah, Evan S H; Anuar, Shahrul; Ngadi, Ehwan; Ahmad, Norhayati

    2015-07-10

    A new, diminutive species of Rock Gecko Cnemaspis mahsuriae sp. nov. of the affinis group, is described from Gunung Raya on Pulau Langkawi, Kedah, Peninsular Malaysia and is differentiated from all other species in the affinis group by having a unique combination of characters including a maximum SVL of 36.6 mm; keeled subtibials and ventrals; 21-24 paravertebral tubercles; no tubercles in the lateral caudal furrows; caudal tubercles not encircling tail; no precloacal pores; 23-26 subdigital lamellae on the fourth toe; no white ocelli in the shoulder region; no yellow postscapular band; and faint yellow bars on the flanks. Cnemaspis mahsuriae sp. nov. is a forest-dwelling species living in close sympatry or paraptry with the insular endemic C. roticanai Grismer & Chan. The Langkawi Archipelago harbors a unique mix of Malaysian and Indochinese taxa and the frequency of new discoveries from this group of islands is increasing.

  6. Cigarette smoking is associated with thinner cingulate and insular cortices in patients with severe mental illness

    PubMed Central

    Jørgensen, Kjetil Nordbø; Psychol, Cand; Skjærvø, Ingeborg; Mørch-Johnsen, Lynn; Haukvik, Unn Kristin; Lange, Elisabeth Heffermehl; Melle, Ingrid; Andreassen, Ole Andreas; Agartz, Ingrid

    2015-01-01

    Background Magnetic resonance imaging (MRI) studies show reduced cortical thickness in patients with schizophrenia and bipolar disorder. These subtle brain abnormalities may provide insight into illness mechanisms. However, environmental and lifestyle-related factors, such as cigarette smoking, may contribute to brain structure changes. Cigarette smoking is highly prevalent in patients with severe mental illness. In nonpsychiatric samples, smoking has been associated with reduced thickness in the anterior (ACC) and posterior cingulate cortices, the insular cortex (INS), the dorsolateral prefrontal cortex and the orbitofrontal cortex. Methods We examined MRI scans from patients with schizophrenia, other psychotic disorders or bipolar disorder and healthy controls using FreeSurfer. Results We included 506 patients (49% smokers) and 237 controls (20% smokers) in our study. We found reduced cortical thickness in the left rostral ACC and the left INS in smoking patients compared with nonsmoking patients, but this difference was not found among healthy controls. No dose–response relationship was found between amount of smoking and cortical thickness in these regions. Among patients, maps of thickness along the whole cortical surface revealed reduced insular thickness but no effects in other regions. Among healthy controls, similar analyses revealed increased age-related cortical thinning in the left occipital lobe among smokers compared with nonsmokers. Limitations The causal direction could not be determined owing to the cross-sectional design and lack of detailed data on smoking addiction and smoking history. Conclusion The effect of cigarette smoking should be considered in MRI studies of patients with severe mental illness. PMID:25672482

  7. Predictive coding accounts of shared representations in parieto-insular networks.

    PubMed

    Ishida, Hiroaki; Suzuki, Keisuke; Grandi, Laura Clara

    2015-04-01

    The discovery of mirror neurons in the ventral premotor cortex (area F5) and inferior parietal cortex (area PFG) in the macaque monkey brain has provided the physiological evidence for direct matching of the intrinsic motor representations of the self and the visual image of the actions of others. The existence of mirror neurons implies that the brain has mechanisms reflecting shared self and other action representations. This may further imply that the neural basis self-body representations may also incorporate components that are shared with other-body representations. It is likely that such a mechanism is also involved in predicting other's touch sensations and emotions. However, the neural basis of shared body representations has remained unclear. Here, we propose a neural basis of body representation of the self and of others in both human and non-human primates. We review a series of behavioral and physiological findings which together paint a picture that the systems underlying such shared representations require integration of conscious exteroception and interoception subserved by a cortical sensory-motor network involving parieto-inner perisylvian circuits (the ventral intraparietal area [VIP]/inferior parietal area [PFG]-secondary somatosensory cortex [SII]/posterior insular cortex [pIC]/anterior insular cortex [aIC]). Based on these findings, we propose a computational mechanism of the shared body representation in the predictive coding (PC) framework. Our mechanism proposes that processes emerging from generative models embedded in these specific neuronal circuits play a pivotal role in distinguishing a self-specific body representation from a shared one. The model successfully accounts for normal and abnormal shared body phenomena such as mirror-touch synesthesia and somatoparaphrenia. In addition, it generates a set of testable experimental predictions.

  8. Sediment dynamics and their potential influence on insular-slope mesophotic coral ecosystems

    NASA Astrophysics Data System (ADS)

    Sherman, C.; Schmidt, W.; Appeldoorn, R.; Hutchinson, Y.; Ruiz, H.; Nemeth, M.; Bejarano, I.; Motta, J. J. Cruz; Xu, H.

    2016-10-01

    Although sediment dynamics exert a fundamental control on the character and distribution of reefs, data on sediment dynamics in mesophotic systems are scarce. In this study, sediment traps and benthic photo-transects were used to document spatial and temporal patterns of suspended-sediment and bed-load dynamics at two geomorphically distinct mesophotic coral ecosystems (MCEs) on the upper insular slope of southwest Puerto Rico. Trap accumulation rates of suspended sediment were relatively low and spatiotemporally uniform, averaging <1 mg cm-2 d-1 and never exceeding 3 mg cm-2 d-1 over the sampled period. In contrast, trap accumulation rates of downslope bed-load movement were orders of magnitude higher than suspended-sediment accumulation rates and highly variable, by orders of magnitude, both spatially and temporally. Percent sand cover within photo-transects varied over time from 10% to more than 40% providing further evidence of downslope sediment movement. In general, the more exposed, lower gradient site had higher rates of downslope sediment movement, higher sand cover and lower coral cover than the more sheltered and steep site that exhibited lower rates of downslope sediment movement, lower sand cover and higher coral cover. In most cases, trap accumulation rates of suspended sediment and bed load varied together and peaks in trap accumulation rates correspond to peaks in SWAN-modeled wave-orbital velocities, suggesting that surface waves may influence sediment dynamics even in mesophotic settings. Though variable, off-shelf transport of sediment is a continuous process occurring even during non-storm conditions. Continuous downslope sediment movement in conjunction with degree of exposure to prevailing seas and slope geomorphology are proposed to exert an important influence on the character and distribution of insular-slope MCEs.

  9. Parental Praise Correlates with Posterior Insular Cortex Gray Matter Volume in Children and Adolescents

    PubMed Central

    Matsudaira, Izumi; Yokota, Susumu; Hashimoto, Teruo; Takeuchi, Hikaru; Asano, Kohei; Asano, Michiko; Sassa, Yuko; Taki, Yasuyuki; Kawashima, Ryuta

    2016-01-01

    A positive parenting style affects psychological and cognitive development in children. Neuroimaging studies revealed that a positive parenting style influenced brain structure in children. Parental praise is a concrete behavior observed in positive parenting. Although previous psychological studies revealed a positive effect of parental praise on children, little is known about the relationship between parental praise and brain structure in children. Thus, the purpose of the present study was to determine whether there was a correlation between the parental attitude towards praising their child and gray matter volume in the children (116 boys and 109 girls; mean age, 10.6 years old). We examined the correlation between regional gray matter volume and parental praise using voxel-based morphometry (VBM) following magnetic resonance imaging (MRI). In addition, to confirm the positive effects of parental praise, we analyzed the correlation between the frequency of parental praise and personality traits in children. We showed that the parental attitude towards praising their child was significantly and positively correlated with the gray matter volume of the left posterior insular cortex in children. Moreover, we found a significant positive correlation between parental attitude towards praising their child and the personality traits of conscientiousness and openness to experience in the children. Prior studies said that gray matter volume in the posterior insula was correlated with empathy, and the functional connectivity between this area and the amygdala was associated with emotional regulation. Furthermore, the posterior insula relates to auditory function, and therefore, was likely involved in the processing of parental praise. Considering the possibility of experience-dependent plasticity, frequent parental praise would lead to increased posterior insular gray matter volume in children. Our study is the first to elucidate the relationship between a specific

  10. Pain and emotion in the insular cortex: evidence for functional reorganization in major depression.

    PubMed

    Mutschler, Isabella; Ball, Tonio; Wankerl, Johanna; Strigo, Irina A

    2012-06-29

    Major Depressive Disorder (MDD) is among the top causes of disability worldwide and many patients with depression experience pain symptoms. Little is known regarding what makes depressed persons feel like they are in pain. An increasing number of neuroimaging studies show that both physical pain and depression involve the insular cortex. The present study aimed to investigate whether emotional processing in MDD patients is topologically shifted towards the insular area(s) involved in pain processing in healthy individuals. To achieve this aim, we investigated the functional organization of the insula by conducting meta-analyses of previously published neuroimaging studies on: (1) emotion in patients with MDD, (2) emotion in healthy subjects, and (3) physical pain in healthy subjects. Our results show that the dorsal part of the insula is reproducibly activated during experimental pain in healthy individuals, with multiple separate pain-related areas aligned along its dorsal border. Regions with maximal pain-related activation likelihood estimate (ALE) were located in the posterior (left) and dorsal mid-anterior insula (left and right). Furthermore, emotion-related peaks in healthy subjects were found both in its ventral (as shown in a previous meta-analysis) and dorsal anterior part. Importantly, emotion-related peaks in depressed patients were shifted to the dorsal anterior insula, where regions related to physical pain in healthy subjects are located. This shift was reflected in the observation that median z-coordinates of emotion-related responses in the left hemisphere were significantly larger in depressed patients than in healthy controls. This shift of emotion-related responses to the dorsal insula, i.e., where pain-processing takes place in healthy subjects, may play a role in "emotional allodynia" - a notion that individuals with MDD experience pain in response to stimuli that are normally not painful.

  11. Hetero-oligomerization of neuronal glutamate transporters.

    PubMed

    Nothmann, Doreen; Leinenweber, Ariane; Torres-Salazar, Delany; Kovermann, Peter; Hotzy, Jasmin; Gameiro, Armanda; Grewer, Christof; Fahlke, Christoph

    2011-02-04

    Excitatory amino acid transporters (EAATs) mediate the uptake of glutamate into neuronal and glial cells of the mammalian central nervous system. Two transporters expressed primarily in glia, EAAT1 and EAAT2, are crucial for glutamate homeostasis in the adult mammalian brain. Three neuronal transporters (EAAT3, EAAT4, and EAAT5) appear to have additional functions in regulating and processing cellular excitability. EAATs are assembled as trimers, and the existence of multiple isoforms raises the question of whether certain isoforms can form hetero-oligomers. Co-expression and pulldown experiments of various glutamate transporters showed that EAAT3 and EAAT4, but neither EAAT1 and EAAT2, nor EAAT2 and EAAT3 are capable of co-assembling into heterotrimers. To study the functional consequences of hetero-oligomerization, we co-expressed EAAT3 and the serine-dependent mutant R501C EAAT4 in HEK293 cells and Xenopus laevis oocytes and studied glutamate/serine transport and anion conduction using electrophysiological methods. Individual subunits transport glutamate independently of each other. Apparent substrate affinities are not affected by hetero-oligomerization. However, polarized localization in Madin-Darby canine kidney cells was different for homo- and hetero-oligomers. EAAT3 inserts exclusively into apical membranes of Madin-Darby canine kidney cells when expressed alone. Co-expression with EAAT4 results in additional appearance of basolateral EAAT3. Our results demonstrate the existence of heterotrimeric glutamate transporters and provide novel information about the physiological impact of EAAT oligomerization.

  12. Towards a glutamate hypothesis of depression

    PubMed Central

    Sanacora, Gerard; Treccani, Giulia; Popoli, Maurizio

    2011-01-01

    Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way ‘involved’ in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel

  13. Combining Ca2+ imaging with -glutamate photorelease

    PubMed Central

    Canepari, Marco; De Waard, Michel; Ogden, David

    2013-01-01

    We describe simple configurations and methods to measure optical Ca2+ signals in response to photorelease of L-glutamate. This photostimulation allows activation of postsynaptic glutamate receptors without activation of voltage-gated Ca2+ channels permitting the separation and the analysis of different Ca2+ components. We give details of basic microscopy configurations and of tools to efficiently illuminate the preparation while preserving the healthy conditions of the tissues. We also suggest methodological procedures and we discuss protocols of linear optics to achieve simultaneous imaging and uncaging in relation to protocols using two photon illumination. PMID:24298028

  14. Metabolism of Proline, Glutamate, and Ornithine in Proline Mutant Root Tips of Zea mays (L.)

    PubMed Central

    Dierks-Ventling, Christa; Tonelli, Chiara

    1982-01-01

    In excised pro1-1 mutant and corresponding normal type roots of Zea mays L. the uptake and interconversion of [14C]proline, [14C]glutamic acid, [14C]glutamine, and [14C]ornithine and their utilization for protein synthesis was measured with the intention of finding an explanation for the proline requirement of the mutant. Uptake of these four amino acids, with the exception of proline, was the same in mutant and normal roots, but utilization differed. Higher than normal utilization rates for proline and glutamic acid were noted in mutant roots leading to increased CO2 production, free amino acid interconversion, and protein synthesis. Proline was synthesized from either glutamic acid (or glutamine) or ornithine in both mutant and normal roots; it did not accumulate but rather was used for protein synthesis. Ornithine was not a good precursor for proline in either system, but was preferentially converted to arginine and glutamine, particularly in mutant roots. The pro1-1 mutant was thus not deficient in its ability to make proline. Based on these findings, and on the fact that ornithine, arginine, glutamic acid and aspartic acid are elevated as free amino acids in mutant roots, it is suggested that in the pro1-1 mutant proline catabolism prevails over proline synthesis. PMID:16662144

  15. Anterior Cingulate Glutamate Is Reduced by Acamprosate Treatment in Patients With Alcohol Dependence.

    PubMed

    Frye, Mark A; Hinton, David J; Karpyak, Victor M; Biernacka, Joanna M; Gunderson, Lee J; Feeder, Scott E; Choi, Doo-Sup; Port, John D

    2016-12-01

    Although the precise drug mechanism of action of acamprosate remains unclear, its antidipsotropic effect is mediated in part through glutamatergic neurotransmission. We evaluated the effect of 4 weeks of acamprosate treatment in a cohort of 13 subjects with alcohol dependence (confirmed by a structured interview, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) on proton magnetic resonance spectroscopy glutamate levels in the midline anterior cingulate cortex (MACC). We compared levels of metabolites with a group of 16 healthy controls. The Pennsylvania Alcohol Craving Scale was used to assess craving intensity. At baseline, before treatment, the mean cerebrospinal fluid-corrected MACC glutamate (Glu) level was significantly elevated in subjects with alcohol dependence compared with controls (P = 0.004). Four weeks of acamprosate treatment reduced glutamate levels (P = 0.025), an effect that was not observed in subjects who did not take acamprosate. At baseline, there was a significant positive correlation between cravings, measured by the Pennsylvania Alcohol Craving Scale, and MACC (Glu) levels (P = 0.019). Overall, these data would suggest a normalizing effect of acamprosate on a hyperglutamatergic state observed in recently withdrawn patients with alcohol dependence and a positive association between MACC glutamate levels and craving intensity in early abstinence. Further research is needed to evaluate the use of these findings for clinical practice, including monitoring of craving intensity and individualized selection of treatment with antidipsotropic medications in subjects with alcohol dependence.

  16. Corticotrigeminal Projections from the Insular Cortex to the Trigeminal Caudal Subnucleus Regulate Orofacial Pain after Nerve Injury via Extracellular Signal-Regulated Kinase Activation in Insular Cortex Neurons.

    PubMed

    Wang, Jian; Li, Zhi-Hua; Feng, Ban; Zhang, Ting; Zhang, Han; Li, Hui; Chen, Tao; Cui, Jing; Zang, Wei-Dong; Li, Yun-Qing

    2015-01-01

    Cortical neuroplasticity alterations are implicated in the pathophysiology of chronic orofacial pain. However, the relationship between critical cortex excitability and orofacial pain maintenance has not been fully elucidated. We recently demonstrated a top-down corticospinal descending pain modulation pathway from the anterior cingulate cortex (ACC) to the spinal dorsal horn that could directly regulate nociceptive transmission. Thus, we aimed to investigate possible corticotrigeminal connections that directly influence orofacial nociception in rats. Infraorbital nerve chronic constriction injury (IoN-CCI) induced significant orofacial nociceptive behaviors as well as pain-related negative emotions such as anxiety/depression in rats. By combining retrograde and anterograde tract tracing, we found powerful evidence that the trigeminal caudal subnucleus (Vc), especially the superficial laminae (I/II), received direct descending projections from granular and dysgranular parts of the insular cortex (IC). Extracellular signal-regulated kinase (ERK), an important signaling molecule involved in neuroplasticity, was significantly activated in the IC following IoN-CCI. Moreover, in IC slices from IoN-CCI rats, U0126, an inhibitor of ERK activation, decreased both the amplitude and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and reduced the paired-pulse ratio (PPR) of Vc-projecting neurons. Additionally, U0126 also reduced the number of action potentials in the Vc-projecting neurons. Finally, intra-IC infusion of U0126 obviously decreased Fos expression in the Vc, accompanied by the alleviation of both nociceptive behavior and negative emotions. Thus, the corticotrigeminal descending pathway from the IC to the Vc could directly regulate orofacial pain, and ERK deactivation in the IC could effectively alleviate neuropathic pain as well as pain-related negative emotions in IoN-CCI rats, probably through this top-down pathway. These findings may help

  17. Corticotrigeminal Projections from the Insular Cortex to the Trigeminal Caudal Subnucleus Regulate Orofacial Pain after Nerve Injury via Extracellular Signal-Regulated Kinase Activation in Insular Cortex Neurons

    PubMed Central

    Wang, Jian; Li, Zhi-Hua; Feng, Ban; Zhang, Ting; Zhang, Han; Li, Hui; Chen, Tao; Cui, Jing; Zang, Wei-Dong; Li, Yun-Qing

    2015-01-01

    Cortical neuroplasticity alterations are implicated in the pathophysiology of chronic orofacial pain. However, the relationship between critical cortex excitability and orofacial pain maintenance has not been fully elucidated. We recently demonstrated a top-down corticospinal descending pain modulation pathway from the anterior cingulate cortex (ACC) to the spinal dorsal horn that could directly regulate nociceptive transmission. Thus, we aimed to investigate possible corticotrigeminal connections that directly influence orofacial nociception in rats. Infraorbital nerve chronic constriction injury (IoN-CCI) induced significant orofacial nociceptive behaviors as well as pain-related negative emotions such as anxiety/depression in rats. By combining retrograde and anterograde tract tracing, we found powerful evidence that the trigeminal caudal subnucleus (Vc), especially the superficial laminae (I/II), received direct descending projections from granular and dysgranular parts of the insular cortex (IC). Extracellular signal-regulated kinase (ERK), an important signaling molecule involved in neuroplasticity, was significantly activated in the IC following IoN-CCI. Moreover, in IC slices from IoN-CCI rats, U0126, an inhibitor of ERK activation, decreased both the amplitude and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and reduced the paired-pulse ratio (PPR) of Vc-projecting neurons. Additionally, U0126 also reduced the number of action potentials in the Vc-projecting neurons. Finally, intra-IC infusion of U0126 obviously decreased Fos expression in the Vc, accompanied by the alleviation of both nociceptive behavior and negative emotions. Thus, the corticotrigeminal descending pathway from the IC to the Vc could directly regulate orofacial pain, and ERK deactivation in the IC could effectively alleviate neuropathic pain as well as pain-related negative emotions in IoN-CCI rats, probably through this top–down pathway. These findings may

  18. Environmental drivers of megafaunal assemblage composition and biomass distribution over mainland and insular slopes of the Balearic Basin (Western Mediterranean)

    NASA Astrophysics Data System (ADS)

    Fanelli, E.; Cartes, J. E.; Papiol, V.; López-Pérez, C.

    2013-08-01

    The influence of mesoscale physical and trophic variables on deep-sea megafauna, a scale of variation often neglected in deep-sea studies, is crucial for understanding their role in the ecosystem. Drivers of megafaunal assemblage composition and biomass distribution have been investigated in two contrasting areas of the Balearic basin in the NW Mediterranean: on the mainland slope (Catalonian coasts) and on the insular slope (North of Mallorca, Balearic Islands). An experimental bottom trawl survey was carried out during summer 2010, at stations in both sub-areas located between 450 and 2200 m water depth. Environmental data were collected simultaneously: near-bottom physical parameters, and the elemental and isotopic composition of sediments. Initially, data were analysed along the whole depth gradient, and then assemblages from the two areas were compared. Analysis of the trawls showed the existence of one group associated with the upper slope (US=450-690 m), another with the middle slope (MS=1000-1300 m) and a third with the lower slope (LS=1400-2200 m). Also, significant differences in the assemblage composition were found between mainland and insular slopes at MS. Dominance by different species was evident when the two areas were compared by SIMPER analysis. The greatest fish biomass was recorded in both areas at 1000-1300 m, a zone linked to minimum temperature and maximum O2 concentration on the bottom. Near the mainland, fish assemblages were best explained (43% of total variance, DISTLM analysis) by prey availability (gelatinous zooplankton biomass). On the insular slope, trophic webs seemed less complex and were based on vertical input of surface primary production. Decapods, which reached their highest biomass values on the upper slope, were correlated with salinity and temperature in both the areas. However, while hydrographic conditions (temperature and salinity) seemed to be the most important variables over the insular slope, resource availability

  19. Elevated Liver Enzymes

    MedlinePlus

    Symptoms Elevated liver enzymes By Mayo Clinic Staff Elevated liver enzymes may indicate inflammation or damage to cells in the liver. Inflamed or ... than normal amounts of certain chemicals, including liver enzymes, into the bloodstream, which can result in elevated ...

  20. 21 CFR 182.1047 - Glutamic acid hydrochloride.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glutamic acid hydrochloride. 182.1047 Section 182.1047 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Food Substances § 182.1047 Glutamic acid hydrochloride. (a) Product. Glutamic acid hydrochloride....

  1. 21 CFR 182.1047 - Glutamic acid hydrochloride.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Glutamic acid hydrochloride. 182.1047 Section 182.1047 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Food Substances § 182.1047 Glutamic acid hydrochloride. (a) Product. Glutamic acid hydrochloride....

  2. 21 CFR 182.1047 - Glutamic acid hydrochloride.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Glutamic acid hydrochloride. 182.1047 Section 182...) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Multiple Purpose GRAS Food Substances § 182.1047 Glutamic acid hydrochloride. (a) Product. Glutamic acid hydrochloride. (b) (c) Limitations, restrictions, or explanation....

  3. 21 CFR 182.1047 - Glutamic acid hydrochloride.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Glutamic acid hydrochloride. 182.1047 Section 182.1047 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Food Substances § 182.1047 Glutamic acid hydrochloride. (a) Product. Glutamic acid hydrochloride....

  4. Glutamate Transmission Enhancement for Treatment of PTSD

    DTIC Science & Technology

    2010-09-01

    sessions or more of approximately 1h each to achieve significant beneficial effects. Thus, treatments that enhance the efficacy of extinction therapies...term medication. Preclinical studies have demonstrated that glutamate transmission in the amygdala is necessary for long term extinction of...fearmemories. Furthermore, d-cycloserine (DCS), a partial NMDA receptor agonist acting on the glycine modulator site, significantly enhances fear extinction

  5. Direct effect of neuroleptics on glutamate release.

    PubMed

    Sherman, A D; Mott, J

    1984-11-01

    In studies designed to assess the pre-synaptic effects of neuroleptics in vitro, synaptosomes were prepared from several regions of rat brain. These preparations were incubated in the presence of a representative of each of the major classes of neuroleptic--chlorpromazine, haloperidol, or clozapine, or with (+) or (-)butaclamol. The calcium-specific release of endogenous glutamic acid was reduced only in synaptosomes derived from the amygdala. In this area, each of these agents [except (-)butaclamol] reduced the release of glutamic acid to a maximum of 40% in a concentration-dependent manner. When [3H]glutamine was included in the incubation media, a reduction in the released [3H]glutamate was present with 10(-8) M haloperidol, and 5 X 10(-8) M (+)butaclamol, clozapine, or chlorpromazine. (-)Butaclamol was inactive at 10(-5) M, a concentration producing complete blockade of the release of [3H]glutamic acid when active agents were included. Again, the effects were observed only in the amygdala. All agents, including (-)butaclamol blocked the uptake of [3H]glutamine into depolarized synaptosomes.

  6. Does the thrifty phenotype result from chronic glutamate intoxication? A hypothesis.

    PubMed

    Hermanussen, Michael; Tresguerres, Jesus A F

    2003-01-01

    The thrifty phenotype hypothesis proposes that the epidemiological associations between poor fetal and infant growth and the subsequent development of the metabolic syndrome, result from the effects of poor nutrition in early life. The present review however, considers an opposite explanation. We hypothesize that fetal over-nutrition plays a major role in the development of the metabolic syndrome. We found evidence that the thrifty phenotype may be the consequence of fetal hyperglutamatemia. Maternal glutamate (GLU) reaches the fetal circulation, as part of the materno-fetal glutamine-glutamate exchange. Glutamine is absorbed from the maternal circulation, and deaminated for nitrogen utilization, resulting in a fetal production of GLU. GLU is extracted as it returns to the placenta. When the umbilical plasma flow is low, GLU may be trapped in the fetal circulation, and reaches neurotoxic levels. Administering GLU to newborn rodents completely destructs arcuate nucleus neurons, and results in permanently elevated plasma leptin levels that fail to adequately counter-regulate food intake. Chronic fetal exposure to elevated levels of GLU may be caused by chronic maternal over-nutrition or by reduced umbilical plasma flow. We strongly suggest abandoing the flavoring agent monosodium glutamate and reconsidering the recommended daily allowances of protein and amino acids during pregnancy.

  7. ¹³C-metabolic enrichment of glutamate in glutamate dehydrogenase mutants of Saccharomyces cerevisiae.

    PubMed

    Tang, Yijin; Sieg, Alex; Trotter, Pamela J

    2011-10-20

    Glutamate dehydrogenases (GDH) interconvert α-ketoglutarate and glutamate. In yeast, NADP-dependent enzymes, encoded by GDH1 and GDH3, are reported to synthesize glutamate from α-ketoglutarate, while an NAD-dependent enzyme, encoded by GDH2, catalyzes the reverse. Cells were grown in acetate/raffinose (YNAceRaf) to examine the role(s) of these enzymes during aerobic metabolism. In YNAceRaf the doubling time of wild type, gdh2Δ, and gdh3Δ cells was comparable at ∼4 h. NADP-dependent GDH activity (Gdh1p+Gdh3p) in wild type, gdh2Δ, and gdh3Δ was decreased ∼80% and NAD-dependent activity (Gdh2p) in wild type and gdh3Δ was increased ∼20-fold in YNAceRaf as compared to glucose. Cells carrying the gdh1Δ allele did not divide in YNAceRaf, yet both the NADP-dependent (Gdh3p) and NAD-dependent (Gdh2p) GDH activity was ∼3-fold higher than in glucose. Metabolism of [1,2-(13)C]-acetate and analysis of carbon NMR spectra were used to examine glutamate metabolism. Incorporation of (13)C into glutamate was nearly undetectable in gdh1Δ cells, reflecting a GDH activity at <15% of wild type. Analysis of (13)C-enrichment of glutamate carbons indicates a decreased rate of glutamate biosynthesis from acetate in gdh2Δ and gdh3Δ strains as compared to wild type. Further, the relative complexity of (13)C-isotopomers at early time points was noticeably greater in gdh3Δ as compared to wild type and gdh2Δ cells. These in vivo data show that Gdh1p is the primary GDH enzyme and Gdh2p and Gdh3p play evident roles during aerobic glutamate metabolism.

  8. Amperometric L-glutamate biosensor based on bacterial cell-surface displayed glutamate dehydrogenase.

    PubMed

    Liang, Bo; Zhang, Shu; Lang, Qiaolin; Song, Jianxia; Han, Lihui; Liu, Aihua

    2015-07-16

    A novel L-glutamate biosensor was fabricated using bacteria surface-displayed glutamate dehydrogenase (Gldh-bacteria). Here the cofactor NADP(+)-specific dependent Gldh was expressed on the surface of Escherichia coli using N-terminal region of ice nucleation protein (INP) as the anchoring motif. The cell fractionation assay and SDS-PAGE analysis indicated that the majority of INP-Gldh fusion proteins were located on the surface of cells. The biosensor was fabricated by successively casting polyethyleneimine (PEI)-dispersed multi-walled carbon nanotubes (MWNTs), Gldh-bacteria and Nafion onto the glassy carbon electrode (Nafion/Gldh-bacteria/PEI-MWNTs/GCE). The MWNTs could not only significantly lower the oxidation overpotential towards NAPDH, which was the product of NADP(+) involving in the oxidation of glutamate by Gldh, but also enhanced the current response. Under the optimized experimental conditions, the current-time curve of the Nafion/Gldh-bacteria/PEI-MWNTs/GCE was performed at +0.52 V (vs. SCE) by amperometry varying glutamate concentration. The current response was linear with glutamate concentration in two ranges (10 μM-1 mM and 2-10 mM). The low limit of detection was estimated to be 2 μM glutamate (S/N=3). Moreover, the proposed biosensor is stable, specific, reproducible and simple, which can be applied to real samples detection.

  9. Effects of insularity on digestion: living on islands induces shifts in physiological and morphological traits in island reptiles.

    PubMed

    Sagonas, Kostas; Pafilis, Panayiotis; Valakos, Efstratios D

    2015-10-01

    Living on islands entails numerous challenges for animals, among which resource scarcity stands out. In order to survive, animals have to optimize energy acquisition. We examined the impact of insularity on digestion comparing a series of physiological and morphological traits of adult males between insular and mainland populations of the Balkan green lizard. Island lizards had longer gastrointestinal tracts and gut passage times and higher digestive efficiencies. The dissection of the hindgut revealed an unexpected finding, the presence of cecal valves that were more frequent in island lizards. Thanks to all above islanders retain food for longer periods and thus maximize energy income and increase the amount of the extracted nutrients. That way, they secure energy income from the limited, in time and quantity, food resources of the islands.

  10. A new species of insular Rock Gecko (Genus Cnemaspis Strauch, 1887) from the Bidong Archipelago, Terengganu, Peninsular Malaysia.

    PubMed

    Grismer, L Lee; Wood, Perry L; Ahmad, Amirrudin B; Sumarli, Alexandra S-I; Vazquez, Jessika J; Ismail, Lukman H B; Nance, Ronald; Mohd-Amin, Muhammad Afif B; Othman, Mohamad N A B; Rizaijessika, Syed A; Kuss, Maria; Murdoch, Matthew; Cobos, Anthony

    2014-01-24

    A new insular species Cnemaspis bidongensis sp. nov. (Squamata: Gekkonidae), is described from Pulau Bidong, Terengganu, Peninsular Malaysia and bears a unique suite of morphological and color pattern characters that differentiate it from all other congeners. Cnemaspis bidongensis sp. nov. is the sister species to C. kendallii (Gray) and represents the fifth insular endemic species of Cnemaspis on archipelagos along the east coast of Peninsular Malaysia. This species survived massive deforestation of the small island of Bidong (260 ha) from the mid 1970s to the early 1990s when the island served as a Vietnamese refugee camp and harbored as many as 40,000 people at one time. We hypothesize that this species' generalized lifestyle contributed to its survival, allowing it to seek refuge in rocky microhabitats.

  11. Effects of insularity on digestion: living on islands induces shifts in physiological and morphological traits in island reptiles

    NASA Astrophysics Data System (ADS)

    Sagonas, Kostas; Pafilis, Panayiotis; Valakos, Efstratios D.

    2015-10-01

    Living on islands entails numerous challenges for animals, among which resource scarcity stands out. In order to survive, animals have to optimize energy acquisition. We examined the impact of insularity on digestion comparing a series of physiological and morphological traits of adult males between insular and mainland populations of the Balkan green lizard. Island lizards had longer gastrointestinal tracts and gut passage times and higher digestive efficiencies. The dissection of the hindgut revealed an unexpected finding, the presence of cecal valves that were more frequent in island lizards. Thanks to all above islanders retain food for longer periods and thus maximize energy income and increase the amount of the extracted nutrients. That way, they secure energy income from the limited, in time and quantity, food resources of the islands.

  12. Building and Applying "Insularity Theory": Review on Knapp's Prehistoric and Protohistoric Cyprus, 2008.

    NASA Astrophysics Data System (ADS)

    Katsarou-Tzeveleki, Stella

    listing of external factors (colonization, invasions) originating in the Near East and the Aegean as sequential narrative history, and the descriptive, systemic analysis of 'materiality, production, trade, migration and colonization which have for long been the cornerstones of Cypriot archaeology' (p. 11). In contrast, he turns his attention towards the internal processes within the island society of Bronze Age Cyprus, which shape its insularity and give it a distinctive identity at this specific period, processes that lead to contextual history and formative tradition. 'To study how any society changes, at any time, it is crucial first to look at internal rather than external factors' (p. 1). Defining the concept of insularity is his aim; therefore, he begins with a number of very apposite rhetorical questions (p. 13) and identifies several individual parameters (connectivity, islandscape, social identity, ethnicity, migration, acculturation, hybridization) to which he assigns collective and individual meanings. The eight chapters that follow may be assigned, broadly, to three general units: in the first of these (ch. 1-2), Knapp offers a synthesis of these parameters in the form of a 'theory of insularity'. In the second (ch. 3-7) he formulates his revised narrative of the prehistory and social identity of the island, which involves a presentation of social and economic, rather than stylistic categories, on the basis of the parameters laid down in his theoretical scheme. Finally, in the third unit (ch. 8), he records his overall conclusions, the new cognitive experiences and concerns that have emerged from the application of his theory, both to Cyprus and to insular archaeology in the Mediterranean and on a world scale. Knapp's synthesis of the theory of insularity in the first unit is a major contribution to Mediterranean archaeology, and makes this book a seminal work. Continuing and broadening Broodbank's (2000) reasoning about the Cyclades, Knapp, with Cyprus as his

  13. A Role for the Insular Cortex in Long-Term Memory for Context-Evoked Drug Craving in Rats

    PubMed Central

    Contreras, Marco; Billeke, Pablo; Vicencio, Sergio; Madrid, Carlos; Perdomo, Guetón; González, Marcela; Torrealba, Fernando

    2012-01-01

    Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamine-conditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise. PMID:22534623

  14. Major histocompatibility complex variation in insular populations of the Egyptian vulture: inferences about the roles of genetic drift and selection.

    PubMed

    Agudo, Rosa; Alcaide, Miguel; Rico, Ciro; Lemus, Jesus A; Blanco, Guillermo; Hiraldo, Fernando; Donázar, Jose A

    2011-06-01

    Insular populations have attracted the attention of evolutionary biologists because of their morphological and ecological peculiarities with respect to their mainland counterparts. Founder effects and genetic drift are known to distribute neutral genetic variability in these demes. However, elucidating whether these evolutionary forces have also shaped adaptive variation is crucial to evaluate the real impact of reduced genetic variation in small populations. Genes of the major histocompatibility complex (MHC) are classical examples of evolutionarily relevant loci because of their well-known role in pathogen confrontation and clearance. In this study, we aim to disentangle the partial roles of genetic drift and natural selection in the spatial distribution of MHC variation in insular populations. To this end, we integrate the study of neutral (22 microsatellites and one mtDNA locus) and MHC class II variation in one mainland (Iberia) and two insular populations (Fuerteventura and Menorca) of the endangered Egyptian vulture (Neophron percnopterus). Overall, the distribution of the frequencies of individual MHC alleles (n=17 alleles from two class II B loci) does not significantly depart from neutral expectations, which indicates a prominent role for genetic drift over selection. However, our results point towards an interesting co-evolution of gene duplicates that maintains different pairs of divergent alleles in strong linkage disequilibrium on islands. We hypothesize that the co-evolution of genes may counteract the loss of genetic diversity in insular demes, maximize antigen recognition capabilities when gene diversity is reduced, and promote the co-segregation of the most efficient allele combinations to cope with local pathogen communities.

  15. Effect of systemic monosodium glutamate (MSG) on headache and pericranial muscle sensitivity.

    PubMed

    Baad-Hansen, L; Cairns, Be; Ernberg, M; Svensson, P

    2010-01-01

    We conducted a double-blinded, placebo-controlled, crossover study to investigate the occurrence of adverse effects such as headache as well as pain and mechanical sensitivity in pericranial muscles after oral administration of monosodium glutamate (MSG). In three sessions, 14 healthy men drank sugar-free soda that contained either MSG (75 or 150 mg/kg) or NaCl (24 mg/kg, placebo). Plasma glutamate level, pain, pressure pain thresholds and tolerance levels, blood pressure (BP), heart rate and reported adverse effects were assessed for 2 h. No muscle pain or robust changes in mechanical sensitivity were detected, but there was a significant increase in reports of headache and subjectively reported pericranial muscle tenderness after MSG. Systolic BP was elevated in the high MSG session compared with low MSG and placebo. These findings add new information to the concept of MSG headache and craniofacial pain sensitivity.

  16. Nitric Oxide Mediates Glutamate-Linked Enhancement of cGMP Levels in the Cerebellum

    NASA Astrophysics Data System (ADS)

    Bredt, David S.; Snyder, Solomon H.

    1989-11-01

    Nitric oxide, which mediates influences of numerous neurotransmitters and modulators on vascular smooth muscle and leukocytes, can be formed in the brain from arginine by an enzymatic activity that stoichiometrically generates citrulline. We show that glutamate and related amino acids, such as N-methyl-D-aspartate, markedly stimulate arginine-citrulline transformation in cerebellar slices stoichiometrically with enhancement of cGMP levels. Nω-monomethyl-L-arginine blocks the augmentation both of citrulline and cGMP with identical potencies. Arginine competitively reverses both effects of Nω-monomethyl-L-arginine with the same potencies. Hemoglobin, which complexes nitric oxide, prevents the stimulation by N-methyl-D-aspartate of cGMP levels, and superoxide dismutase, which elevates nitric oxide levels, increases cGMP formation. These data establish that nitric oxide mediates the stimulation by glutamate of cGMP formation.

  17. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum.

    PubMed

    Bredt, D S; Snyder, S H

    1989-11-01

    Nitric oxide, which mediates influences of numerous neurotransmitters and modulators on vascular smooth muscle and leukocytes, can be formed in the brain from arginine by an enzymatic activity that stoichiometrically generates citrulline. We show that glutamate and related amino acids, such as N-methyl-D-aspartate, markedly stimulate arginine--citrulline transformation in cerebellar slices stoichiometrically with enhancement of cGMP levels. N omega-monomethyl-L-arginine blocks the augmentation both of citrulline and cGMP with identical potencies. Arginine competitively reverses both effects of N omega-monomethyl-L-arginine with the same potencies. Hemoglobin, which complexes nitric oxide, prevents the stimulation by N-methyl-D-aspartate of cGMP levels, and superoxide dismutase, which elevates nitric oxide levels, increases cGMP formation. These data establish that nitric oxide mediates the stimulation by glutamate of cGMP formation.

  18. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum

    SciTech Connect

    Bredt, D.S.; Snyder, S.H. )

    1989-11-01

    Nitric oxide, which mediates influences of numerous neurotransmitters and modulators on vascular smooth muscle and leukocytes, can be formed in the brain from arginine by an enzymatic activity that stoichiometrically generates citrulline. The authors show that glutamate and related amino acids, such as N-methyl-D-aspartate, markedly stimulate arginine-citrulline transformation in cerebellar slices stoichiometrically with enhancement of cGMP levels. N{sup {omega}}-monomethyl-L-arginine blocks the augmentation both of citrulline and cGMP with identical potencies. Arginine competitively reverses both effects of N{sup {omega}}-monomethyl-L-arginine with the same potencies. Hemoglobin, which complexes nitric oxide, prevents the stimulation by N-methyl-D-aspartate of cGMP levels, and superoxide dismutase, which elevates nitric oxide levels, increases cGMP formation. These data establish that nitric oxide mediates the stimulation by glutamate of cGMP formation.

  19. K+ depolarization evokes ATP, adenosine and glutamate release from glia in rat hippocampus: a microelectrode biosensor study

    PubMed Central

    Heinrich, A; Andó, RD; Túri, G; Rózsa, B; Sperlágh, B

    2012-01-01

    BACKGROUND AND PURPOSE This study was undertaken to characterize the ATP, adenosine and glutamate outflow evoked by depolarization with high K+ concentrations, in slices of rat hippocampus. EXPERIMENTAL APPROACH We utilized the microelectrode biosensor technique and extracellular electrophysiological recording for the real-time monitoring of the efflux of ATP, adenosine and glutamate. KEY RESULTS ATP, adenosine and glutamate sensors exhibited transient and reversible current during depolarization with 25 mM K+, with distinct kinetics. The ecto-ATPase inhibitor ARL67156 enhanced the extracellular level of ATP and inhibited the prolonged adenosine efflux, suggesting that generation of adenosine may derive from the extracellular breakdown of ATP. Stimulation-evoked ATP, adenosine and glutamate efflux was inhibited by tetrodotoxin, while exposure to Ca2+-free medium abolished ATP and adenosine efflux from hippocampal slices. Extracellular elevation of ATP and adenosine were decreased in the presence of NMDA receptor antagonists, D-AP-5 and ifenprodil, whereas non-NMDA receptor blockade by CNQX inhibited glutamate but not ATP and adenosine efflux. The gliotoxin fluoroacetate and P2X7 receptor antagonists inhibited the K+-evoked ATP, adenosine and glutamate efflux, while carbenoxolone in low concentration and probenecid decreased only the adenosine efflux. CONCLUSIONS AND IMPLICATIONS Our results demonstrated activity-dependent gliotransmitter release in the hippocampus in response to ongoing neuronal activity. ATP and glutamate were released by P2X7 receptor activation into extracellular space. Although the increased extracellular levels of adenosine did derive from released ATP, adenosine might also be released directly via pannexin hemichannels. LINKED ARTICLE This article is commented on by Sershen, pp. 1000–1002 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02072.x PMID:22394324

  20. HIF-1α triggers long-lasting glutamate excitotoxicity via system xc(-) in cerebral ischaemia-reperfusion.

    PubMed

    Hsieh, Chia-Hung; Lin, Yu-Jung; Chen, Wei-Ling; Huang, Yen-Chih; Chang, Chi-Wei; Cheng, Fu-Chou; Liu, Ren-Shyan; Shyu, Woei-Cherng

    2017-02-01

    Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-d-aspartate receptor (NMDAR) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF-1α mainly regulates the cystine-glutamate transporter (system xc(-) ) subunit xCT by directly binding to its promoter; xCT and its function are up-regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR) or CIR-mediated glutamate excitotoxicity in vitro and in vivo. Pharmaceutical inhibition of system xc(-) by a clinically approved anti-cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF-1α plays a role in CIR-induced glutamate excitotoxicity via the long-lasting activation of system xc(-) -dependent glutamate outflow and suggest that system xc(-) is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  1. Cytoarchitecture-Dependent Decrease in Propagation Velocity of Cortical Spreading Depression in the Rat Insular Cortex Revealed by Optical Imaging.

    PubMed

    Fujita, Satoshi; Mizoguchi, Naoko; Aoki, Ryuhei; Cui, Yilong; Koshikawa, Noriaki; Kobayashi, Masayuki

    2016-04-01

    Cortical spreading depression (SD) is a self-propagating wave of depolarization accompanied by a substantial disturbance of the ionic distribution between the intra- and extracellular compartments. Glial cells, including astrocytes, play critical roles in maintenance of the extracellular environment, including ionic distribution. Therefore, SD propagation in the cerebral cortex may depend on the density of astrocytes. The present study aimed to examine the profile of SD propagation in the insular cortex (IC), which is located between the neocortex and paleocortex and is where the density of astrocytes gradually changes. The velocity of SD propagation in the neocortex, including the somatosensory, motor, and granular insular cortices (5.7 mm/min), was higher than that (2.8 mm/min) in the paleocortex (agranular insular and piriform cortices). Around thick vessels, including the middle cerebral artery, SD propagation was frequently delayed and sometimes disappeared. Immunohistological analysis of glial fibrillary acidic protein (GFAP) demonstrated the sparse distribution of astrocytes in the somatosensory cortex and the IC dorsal to the rhinal fissure, whereas the ventral IC showed a higher density of astrocytes. These results suggest that cortical cytoarchitectonic features, which possibly involve the distribution of astrocytes, are crucial for regulating the velocity of SD propagation in the cerebral cortex.

  2. Targeting glutamate homeostasis for potential treatment of nicotine dependence

    PubMed Central

    Alasmari, Fawaz; Al-Rejaie, Salim S.; AlSharari, Shakir D.; Sari, Youssef

    2015-01-01

    Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with downregulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence. PMID:26589642

  3. Microsensors for in vivo Measurement of Glutamate in Brain Tissue

    PubMed Central

    Qin, Si; van der Zeyden, Miranda; Oldenziel, Weite H.; Cremers, Thomas I.F.H.; Westerink, Ben H.C.

    2008-01-01

    Several immobilized enzyme-based electrochemical biosensors for glutamate detection have been developed over the last decade. In this review, we compare first and second generation sensors. Structures, working mechanisms, interference prevention, in vitro detection characteristics and in vivo performance are summarized here for those sensors that have successfully detected brain glutamate in vivo. In brief, first generation sensors have a simpler structure and are faster in glutamate detection. They also show a better sensitivity to glutamate during calibration in vitro. For second generation sensors, besides their less precise detection, their fabrication is difficult to reproduce, even with a semi-automatic dip-coater. Both generations of sensors can detect glutamate levels in vivo, but the reported basal levels are different. In general, second generation sensors detect higher basal levels of glutamate compared with the results obtained from first generation sensors. However, whether the detected glutamate is indeed from synaptic sources is an issue that needs further attention. PMID:27873904

  4. Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.

    PubMed

    Gheni, Ghupurjan; Ogura, Masahito; Iwasaki, Masahiro; Yokoi, Norihide; Minami, Kohtaro; Nakayama, Yasumune; Harada, Kazuo; Hastoy, Benoit; Wu, Xichen; Takahashi, Harumi; Kimura, Kazushi; Matsubara, Toshiya; Hoshikawa, Ritsuko; Hatano, Naoya; Sugawara, Kenji; Shibasaki, Tadao; Inagaki, Nobuya; Bamba, Takeshi; Mizoguchi, Akira; Fukusaki, Eiichiro; Rorsman, Patrik; Seino, Susumu

    2014-10-23

    Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion.

  5. Acetylated Chitosan Oligosaccharides Act as Antagonists against Glutamate-Induced PC12 Cell Death via Bcl-2/Bax Signal Pathway

    PubMed Central

    Hao, Cui; Gao, Lixia; Zhang, Yiran; Wang, Wei; Yu, Guangli; Guan, Huashi; Zhang, Lijuan; Li, Chunxia

    2015-01-01

    Chitosan oligosaccharides (COSs), depolymerized products of chitosan composed of β-(1→4) d-glucosamine units, have broad range of biological activities such as antitumour, antifungal, and antioxidant activities. In this study, peracetylated chitosan oligosaccharides (PACOs) and N-acetylated chitosan oligosaccharides (NACOs) were prepared from the COSs by chemcal modification. The structures of these monomers were identified using NMR and ESI-MS spectra. Their antagonist effects against glutamate-induced PC12 cell death were investigated. The results showed that pretreatment of PC12 cells with the PACOs markedly inhibited glutamate-induced cell death in a concentration-dependent manner. The PACOs were better glutamate antagonists compared to the COSs and the NACOs, suggesting the peracetylation is essential for the neuroprotective effects of chitosan oligosaccharides. In addition, the PACOs pretreatment significantly reduced lactate dehydrogenase release and reactive oxygen species production. It also attenuated the loss of mitochondrial membrane potential. Further studies indicated that the PACOs inhibited glutamate-induced cell death by preventing apoptosis through depressing the elevation of Bax/Bcl-2 ratio and caspase-3 activation. These results suggest that PACOs might be promising antagonists against glutamate-induced neural cell death. PMID:25775423

  6. Glutamate Acts as a Key Signal Linking Glucose Metabolism to Incretin/cAMP Action to Amplify Insulin Secretion

    PubMed Central

    Gheni, Ghupurjan; Ogura, Masahito; Iwasaki, Masahiro; Yokoi, Norihide; Minami, Kohtaro; Nakayama, Yasumune; Harada, Kazuo; Hastoy, Benoit; Wu, Xichen; Takahashi, Harumi; Kimura, Kazushi; Matsubara, Toshiya; Hoshikawa, Ritsuko; Hatano, Naoya; Sugawara, Kenji; Shibasaki, Tadao; Inagaki, Nobuya; Bamba, Takeshi; Mizoguchi, Akira; Fukusaki, Eiichiro; Rorsman, Patrik; Seino, Susumu

    2014-01-01

    Summary Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion. PMID:25373904

  7. In situ fluorescence imaging of glutamate-evoked mitochondrial Na+ responses in astrocytes.

    PubMed

    Bernardinelli, Yann; Azarias, Guillaume; Chatton, Jean-Yves

    2006-10-01

    Astrocytes can experience large intracellular Na+ changes following the activation of the Na+-coupled glutamate transport. The present study investigated whether cytosolic Na+ changes are transmitted to mitochondria, which could therefore influence their function and contribute to the overall intracellular Na+ regulation. Mitochondrial Na+ (Na+(mit)) changes were monitored using the Na+-sensitive fluorescent probe CoroNa Red (CR) in intact primary cortical astrocytes, as opposed to the classical isolated mitochondria preparation. The mitochondrial localization and Na+ sensitivity of the dye were first verified and indicated that it can be safely used as a selective Na+(mit) indicator. We found by simultaneously monitoring cytosolic and mitochondrial Na+ using sodium-binding benzofuran isophthalate and CR, respectively, that glutamate-evoked cytosolic Na+ elevations are transmitted to mitochondria. The resting Na+(mit) concentration was estimated at 19.0 +/- 0.8 mM, reaching 30.1 +/- 1.2 mM during 200 microM glutamate application. Blockers of conductances potentially mediating Na+ entry (calcium uniporter, monovalent cation conductances, K+(ATP) channels) were not able to prevent the Na+(mit) response to glutamate. However, Ca2+ and its exchange with Na+ appear to play an important role in mediating mitochondrial Na+ entry as chelating intracellular Ca2+ with BAPTA or inhibiting Na+/Ca2+ exchanger with CGP-37157 diminished the Na+(mit) response. Moreover, intracellular Ca2+ increase achieved by photoactivation of caged Ca2+ also induced a Na+(mit) elevation. Inhibition of mitochondrial Na/H antiporter using ethylisopropyl-amiloride caused a steady increase in Na+(mit) without increasing cytosolic Na+, indicating that Na+ extrusion from mitochondria is mediated by these exchangers. Thus, mitochondria in intact astrocytes are equipped to efficiently sense cellular Na+ signals and to dynamically regulate their Na+ content.

  8. Glutamate alteration of glutamic acid decarboxylase (GAD) in GABAergic neurons: the role of cysteine proteases.

    PubMed

    Monnerie, Hubert; Le Roux, Peter D

    2008-09-01

    Brain cell vulnerability to neurologic insults varies greatly, depending on their neuronal subpopulation. Among cells that survive a pathological insult such as ischemia or brain trauma, some may undergo morphological and/or biochemical changes that could compromise brain function. We previously reported that surviving cortical GABAergic neurons exposed to glutamate in vitro displayed an NMDA receptor (NMDAR)-mediated alteration in the levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67) [Monnerie, H., Le Roux, P., 2007. Reduced dendrite growth and altered glutamic acid decarboxylase (GAD) 65- and 67-kDa isoform protein expression from mouse cortical GABAergic neurons following excitotoxic injury in vitro. Exp. Neurol. 205, 367-382]. In this study, we examined the mechanisms by which glutamate excitotoxicity caused a change in cortical GABAergic neurons' GAD protein levels. Removing extracellular calcium prevented the NMDAR-mediated decrease in GAD protein levels, measured using Western blot techniques, whereas inhibiting calcium entry through voltage-gated calcium channels had no effect. Glutamate's effect on GAD protein isoforms was significantly attenuated by preincubation with the cysteine protease inhibitor N-Acetyl-L-Leucyl-L-Leucyl-L-norleucinal (ALLN). Using class-specific protease inhibitors, we observed that ALLN's effect resulted from the blockade of calpain and cathepsin protease activities. Cell-free proteolysis assay confirmed that both proteases were involved in glutamate-induced alteration in GAD protein levels. Together these results suggest that glutamate-induced excitotoxic stimulation of NMDAR in cultured cortical neurons leads to altered GAD protein levels from GABAergic neurons through intracellular calcium increase and protease activation including calpain and cathepsin. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation

  9. Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors.

    PubMed

    Mahler, Stephen V; Hensley-Simon, Megan; Tahsili-Fahadan, Pouya; LaLumiere, Ryan T; Thomas, Charles; Fallon, Rebecca V; Kalivas, Peter W; Aston-Jones, Gary

    2014-01-01

    Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties.

  10. Multiarchitectonic characterization of insular, perirhinal and related regions in a basal mammal, Echinops telfairi.

    PubMed

    Künzle, H; Radtke-Schuller, S

    2000-12-01

    The rhinal cortex was investigated in the Madagascan lesser hedgehog tenrec, a basal placental mammal. This region parallels the rhinal indentation and presumably contains the equivalents of the insular and perirhinal cortices. Using cyto- and myeloarchitectural, enzyme- and immunohistochemical criteria as well as data on the connections with the olfactory bulb, the rhinal cortex was subdivided tentatively along its rostrocaudal and dorsoventral planes. An area caudally adjacent to the rhinal cortex received a prominent input from the olfactory bulb and was also preliminarily characterized in this study. Because previous studies in insectivores remained controversial with regard to the identification of the claustrum, special attention was paid to the laminar organization of the rhinal cortex and its deep cell groups. The tenrec's claustrum was identified and delineated cytoarchitecturally and by its negative acetylcholinesterase stain. Latexin, a molecular marker for characterizing infragranular and claustral cells, also helped to differentiate the claustrum from the cell groups subjacent to it. Thus, the data indicate that in poorly differentiated mammals the claustrum occupies an intermediate deep position within the width of the rhinal cortex, i.e., it is separated from the subcortical white matter by additional, still unidentified, cell groups.

  11. [Performance of entero-insular axis in an athletic population: diet and exercise influence].

    PubMed

    Rodriguez, Carmen; Quezada-Feijoo, Maribel; Toro, Carmen; Barón-Esquivias, Gonzalo; Segura, Eduardo; Mangas, Alipio; Toro, Rocio

    2015-05-01

    Introducción: La relación existente entre el ejercicio físico y la regulación del apetito puede conducir a una mejora del rendimiento competitivo de los deportistas. Los mediadores del eje entero-insular generan señales neurohumorales que influyen en la regulación del apetito y la homeostasis energética. Objetivo: Determinar la influencia de la dieta y el ejercicio prolongado sobre los péptidos intestinales, grelina, resistina, leptina, e incretinas (GLP-1 y GIP) en una población deportista. MÉTODOS: Este es un estudio prospectivo, de intervención desarrollado desde Octubre 2012 a Marzo 2013. Se incluyeron 32 jugadores de rugby sanos. Se tomaron medidas antropométricas y muestras de sangre en el momento 0 y a los seis meses del estudio. Se distribuyeron aleatoriamente a una dieta bien proteica (DP) o mediterránea (DM) y estudiamos los niveles plasmáticos de adipoquinas e incretinas. Resultados: Las concentraciones plasmáticas de GLP- 1 y GIP presentaron un descenso (p.

  12. A molecular mechanism underlying gustatory memory trace for an association in the insular cortex

    PubMed Central

    Adaikkan, Chinnakkaruppan; Rosenblum, Kobi

    2015-01-01

    Events separated in time are associatively learned in trace conditioning, recruiting more neuronal circuits and molecular mechanisms than in delay conditioning. However, it remains unknown whether a given sensory memory trace is being maintained as a unitary item to associate. Here, we used conditioned taste aversion learning in the rat model, wherein animals associate a novel taste with visceral nausea, and demonstrate that there are two parallel memory traces of a novel taste: a short-duration robust trace, lasting approximately 3 hr, and a parallel long-duration weak one, lasting up to 8 hr, and dependent on the strong trace for its formation. Moreover, only the early robust trace is maintained by a NMDAR-dependent CaMKII- AMPAR pathway in the insular cortex. These findings suggest that a memory trace undergoes rapid modifications, and that the mechanisms underlying trace associative learning differ when items in the memory are experienced at different time points. DOI: http://dx.doi.org/10.7554/eLife.07582.001 PMID:26452094

  13. Increased cellular activity in rat insular cortex after water and salt ingestion induced by fluid depletion.

    PubMed

    Pastuskovas, Cinthia V; Cassell, Martin D; Johnson, Alan Kim; Thunhorst, Robert L

    2003-04-01

    Insular cortex (IC) receives inputs from multiple sensory systems, including taste, and from receptors that monitor body electrolyte and fluid balance and blood pressure. This work analyzed metabolic activity of IC cells after water and sodium ingestion induced by sodium depletion. Rats were injected with the diuretic furosemide (10 mg/kg body wt), followed 5 min later by injections of the angiotensin-converting enzyme inhibitor captopril (5 mg/kg body wt). After 90 min, some rats received water and 0.3 M NaCl to drink for 2 h while others did not. A third group had access to water and saline but was not depleted of fluids. All rats were killed for processing of brain tissue for Fos-immunoreactivity (Fos-ir). Nondepleted animals had weak-to-moderate levels of Fos-ir within subregions of IC. Fluid-depleted rats without fluid access had significantly increased Fos-ir in all areas of IC. Levels of Fos-ir were highest in fluid-depleted rats that drank water and sodium. Fos-ir levels were highest in anterior regions of IC and lowest in posterior regions of IC. These results implicate visceral, taste, and/or postingestional factors in the increased metabolic activity of cells in IC.

  14. The avian fossil record in Insular Southeast Asia and its implications for avian biogeography and palaeoecology

    PubMed Central

    2014-01-01

    Excavations and studies of existing collections during the last decades have significantly increased the abundance as well as the diversity of the avian fossil record for Insular Southeast Asia. The avian fossil record covers the Eocene through the Holocene, with the majority of bird fossils Pleistocene in age. Fossil bird skeletal remains represent at least 63 species in 54 genera and 27 families, and two ichnospecies are represented by fossil footprints. Birds of prey, owls and swiftlets are common elements. Extinctions seem to have been few, suggesting continuity of avian lineages since at least the Late Pleistocene, although some shifts in species ranges have occurred in response to climatic change. Similarities between the Late Pleistocene avifaunas of Flores and Java suggest a dispersal route across southern Sundaland. Late Pleistocene assemblages of Niah Cave (Borneo) and Liang Bua (Flores) support the rainforest refugium hypothesis in Southeast Asia as they indicate the persistence of forest cover, at least locally, throughout the Late Pleistocene and Holocene. PMID:24688871

  15. Genetic drift and rapid evolution of viviparity in insular fire salamanders (Salamandra salamandra)

    PubMed Central

    Velo-Antón, G; Zamudio, K R; Cordero-Rivera, A

    2012-01-01

    Continental islands offer an excellent opportunity to investigate adaptive processes and to time microevolutionary changes that precede macroevolutionary events. We performed a population genetic study of the fire salamander (Salamandra salamandra), a species that displays unique intraspecific diversity of reproductive strategies, to address the microevolutionary processes leading to phenotypic and genetic differentiation of island, coastal and interior populations. We used eight microsatellite markers to estimate genetic diversity, population structure and demographic parameters in viviparous insular populations and ovoviviparous coastal and interior populations. Our results show considerable genetic differentiation (FST range: 0.06–0.27), and no clear signs of gene flow among populations, except between the large and admixed interior populations. We find no support for island colonization by rafting or intentional/accidental anthropogenic introductions, indicating that rising sea levels were responsible for isolation of the island populations approximately 9000 years ago. Our study provides evidence of rapid genetic differentiation between island and coastal populations, and rapid evolution of viviparity driven by climatic selective pressures on island populations, geographic isolation with genetic drift, or a combination of these factors. Studies of these viviparous island populations in early stages of divergence help us better understand the microevolutionary processes involved in rapid phenotypic shifts. PMID:22086081

  16. Differential role of insular cortex muscarinic and NMDA receptors in one-trial appetitive taste learning.

    PubMed

    Parkes, Shauna L; De la Cruz, Vanesa; Bermúdez-Rattoni, Federico; Coutureau, Etienne; Ferreira, Guillaume

    2014-12-01

    Our current understanding of the neurobiology of taste learning and memory has been greatly facilitated by the use of a reliable behavioural model, conditioned taste aversion (CTA). This model has revealed that the insular cortex (IC), specifically muscarinic and N-methyl-d-aspartate (NMDA) receptor activation in the IC, is critical for the formation of aversive taste memories. In contrast, current models of appetitive taste learning are less adequate, relying on the use of neophobic tastes (attenuation of neophobia) or on the integration of appetitive and aversive taste memories (latent inhibition of CTA). While these models have implicated IC muscarinic receptors, the involvement of NMDA receptors in the IC remains unclear. Here, we examined the role of both muscarinic and NMDA receptors in appetitive taste learning using a simple paradigm that is independent of neophobic and aversive components. First, we demonstrated that a single exposure to a novel taste, saccharin 0.1%, is sufficient to promote an appetitive taste memory as revealed by an increase in saccharin consumption during the second presentation. This increase was blocked by bilateral infusion in the IC of the muscarinic receptor antagonist, scopolamine. In contrast, infusion of the NMDA receptor antagonist, AP5, did not block appetitive taste learning but did abolish CTA. Therefore, common and distinct molecular substrates within the IC mediate appetitive versus aversive learning about the same taste.

  17. Differential coding of uncertain reward in rat insular and orbitofrontal cortex

    PubMed Central

    Jo, Suhyun; Jung, Min Whan

    2016-01-01

    Anterior insular and orbitofrontal cortex (AIC and OFC, respectively) are known to play important roles in decision making under risk. However, risk-related AIC neural activity has not been investigated and it is controversial whether the rodent OFC conveys genuine risk signals. To address these issues, we examined AIC and OFC neuronal activity in rats responding to five distinct auditory cues predicting water reward with different probabilities. Both structures conveyed significant neural signals for reward, value and risk, with value and risk signals conjunctively coded. However, value signals were stronger and appeared earlier in the OFC, and many risk-coding OFC neurons responded only to the cue predicting certain (100%) reward. Also, AIC neurons tended to increase their activity for a prolonged time following a negative outcome and according to previously expected value. These results show that both the AIC and OFC convey neural signals related to reward uncertainty, but in different ways. The OFC might play an important role in encoding certain reward-biased, risk-modulated subjective value, whereas the AIC might convey prolonged negative outcome and disappointment signals. PMID:27052943

  18. Chromosomal inversion patterning and population differentiation in a young insular species, Drosophila silvestris.

    PubMed Central

    Craddock, E M; Carson, H L

    1989-01-01

    The recently evolved Hawaiian species Drosophila silvestris has a subdivided population structure and shows great spatial heterogeneity in chromosome inversion distributions and frequencies within its extremely limited geographic range. Pattern analysis of the 11 chromosomal polymorphisms in the context of the recently discovered morphological and behavioral divergence within the species has elucidated the history of the chromosomal differentiation. We identify four chronological groups of inversions and their probable sites of origin. Spread of the derived "3-row" bristle morphotype on the Hilo side of the Island of Hawaii has been accompanied by the acquisition of six new inversion polymorphisms. Three phylogenetically old inversions show correlations with altitude, and there are multiple cross-correlations between inversions on the same and different chromosomes, reflecting complex interaction systems. Quantification of the genetic population structure of D. silvestris by hierarchical F statistics reveals a dramatic level of genetic differentiation for an evolutionarily new species of such restricted range. This level exceeds that of older, continental Drosophila species. There is, however, minimal concordance between the chromosomal variation and the morphological-behavioral discontinuity, a consequence of the extensive cytological variation within each morphotype. Such a fragmented gene pool favors the rapid evolution and continued divergence of this insular species. PMID:2734320

  19. Energy expenditure in Crocidurinae shrews (Insectivora): is metabolism a key component of the insular syndrome?

    PubMed

    Magnanou, Elodie; Fons, Roger; Blondel, Jacques; Morand, Serge

    2005-11-01

    A cascade of morphological, ecological, demographical and behavioural changes operates within island communities compared to mainland. We tested whether metabolic rates change on islands. Using a closed circuit respirometer, we investigated resting metabolic rate (RMR) of three species of Crocidurinae shrews: Suncus etruscus, Crocidura russula, and C. suaveolens. For the latter, we compared energy expenditure of mainland and island populations. Our measurements agree with those previously reported for others Crocidurinae: the interspecific comparison (ANCOVA) demonstrated an allometric relation between energy requirements and body mass. Energy expenditure also scaled with temperature. Island populations (Corsica and Porquerolles) of C. suaveolens differed in size from mainland (gigantism). A GLM showed a significant relationship between energy expenditure, temperature, body mass and locality. Mass specific RMR allometrically scales body mass, but total RMR does not significantly differ between mainland and island, although island shrews are giant. Our results are consistent with other studies: that demonstrated that the evolution of mammalian metabolism on islands is partially independent of body mass. In relation to the insular syndrome, we discuss how island selective forces (changes in resource availability, decrease in competition and predation pressures) can operate in size and physiological adjustments.

  20. Volumetric growth analysis of an insular dysembryoplastic neuroepithelial tumor over a 10-year follow-up

    PubMed Central

    Uno, Takehiro; Kinoshita, Masashi; Furuta, Takuya; Miyashita, Katsuyoshi; Sabit, Hemragul; Nakada, Mitsutoshi

    2016-01-01

    Background: Dysembryoplastic neuroepithelial tumors (DNETs) are benign tumors characterized by a cortical location; they result in symptoms of drug-resistant partial seizures in children. The development of DNETs is poorly understood because most of them are resected immediately upon diagnosis without any observation period owing to the intractable seizures. Case Description: We report the first DNET case with the growth rate analyzed in the natural course of development for a period of 10 years. The patient was a right-handed man who was initially referred to another hospital with mild head injury when he was 8 years old. A tumor located in the right insular cortex was incidentally detected on magnetic resonance imaging (MRI) and followed-up with annual MRI for 10 years. Conclusion: In this case, the volume of the DNET increased in direct proportion to the length of time in its clinical course. The tumor doubling time was approximately 10 years. This case suggests DNET is a slow-growing but not stable tumor. PMID:28194304

  1. Household waste compositional analysis variation from insular communities in the framework of waste prevention strategy plans

    SciTech Connect

    Zorpas, Antonis A.; Lasaridi, Katia; Voukkali, Irene; Loizia, Pantelitsa; Chroni, Christina

    2015-04-15

    Highlights: • Waste framework directive has set clear waste prevention procedures. • Household Compositional analysis. • Waste management plans. • Zero waste approach. • Waste generation. - Abstract: Waste management planning requires reliable data regarding waste generation, affecting factors on waste generation and forecasts of waste quantities based on facts. In order to decrease the environmental impacts of waste management the choice of prevention plan as well as the treatment method must be based on the features of the waste that are produced in a specific area. Factors such as culture, economic development, climate, and energy sources have an impact on waste composition; composition influences the need of collecting waste more or less frequently of waste collection and disposition. The research question was to discover the main barriers concerning the compositional analysis in Insular Communities under warm climate conditions and the findings from this study enabled the main contents of a waste management plan to be established. These included advice to residents on waste minimisation, liaison with stakeholders and the expansion of kerbside recycling schemes.

  2. AxIOM: Amphipod crustaceans from insular Posidonia oceanica seagrass meadows

    PubMed Central

    Heughebaert, André; Lepoint, Gilles

    2016-01-01

    Abstract Background The Neptune grass, Posidonia oceanica (L.) Delile, 1813, is the most widespread seagrass of the Mediterranean Sea. This foundation species forms large meadows that, through habitat and trophic services, act as biodiversity hotspots. In Neptune grass meadows, amphipod crustaceans are one of the dominant groups of vagile invertebrates, forming an abundant and diverse taxocenosis. They are key ecological components of the complex, pivotal, yet critically endangered Neptune grass ecosystems. Nevertheless, comprehensive qualitative and quantitative data about amphipod fauna found in Mediterranean Neptune grass meadows remain scarce, especially in insular locations. New information Here, we provide in-depth metadata about AxIOM, a sample-based dataset published on the GBIF portal. AxIOM is based on an extensive and spatially hierarchized sampling design with multiple years, seasons, day periods, and methods. Samples were taken along the coasts of Calvi Bay (Corsica, France) and of the Tavolara-Punta Coda Cavallo Marine Protected Area (Sardinia, Italy). In total, AxIOM contains 187 samples documenting occurrence (1775 records) and abundance (10720 specimens) of amphipod crustaceans belonging to 72 species spanning 29 families. The dataset is available at http://ipt.biodiversity.be/resource?r=axiom. PMID:27660521

  3. Genetic structure in insular and mainland populations of house sparrows (Passer domesticus) and their hemosporidian parasites

    PubMed Central

    Bichet, Coraline; Moodley, Yoshan; Penn, Dustin J; Sorci, Gabriele; Garnier, Stéphane

    2015-01-01

    Small and isolated populations usually exhibit low levels of genetic variability, and thus, they are expected to have a lower capacity to adapt to changes in environmental conditions, such as exposure to pathogens and parasites. Comparing the genetic variability of selectively neutral versus functional loci allows one to assess the evolutionary history of populations and their future evolutionary potential. The genes of the major histocompatibility complex (MHC) control immune recognition of parasites, and their unusually high diversity is genes which is likely driven by parasite-mediated balancing selection. Here, we examined diversity and differentiation of neutral microsatellite loci and functional MHC class I genes in house sparrows (Passer domesticus), living in six insular and six mainland populations, and we aimed to determine whether their diversity or differentiation correlates with the diversity and the prevalence of infection of hemosporidian parasites. We found that island bird populations tended to have lower neutral genetic variability, whereas MHC variability gene was similar between island and mainland populations. Similarly, island populations tended to show greater genetic differentiation than mainland populations, especially at microsatellite markers. The maintenance of MHC genetic diversity and its less marked structure in the island populations could be attributed to balancing-selection. The greater MHC differentiation among populations was negatively correlated with similarity in blood parasites (prevalence and diversity of parasite strains) between populations. Even at low prevalence and small geographical scale, haemosporidian parasites might contribute to structure the variability of immune genes among populations of hosts. PMID:25937907

  4. Genetic drift and rapid evolution of viviparity in insular fire salamanders (Salamandra salamandra).

    PubMed

    Velo-Antón, G; Zamudio, K R; Cordero-Rivera, A

    2012-04-01

    Continental islands offer an excellent opportunity to investigate adaptive processes and to time microevolutionary changes that precede macroevolutionary events. We performed a population genetic study of the fire salamander (Salamandra salamandra), a species that displays unique intraspecific diversity of reproductive strategies, to address the microevolutionary processes leading to phenotypic and genetic differentiation of island, coastal and interior populations. We used eight microsatellite markers to estimate genetic diversity, population structure and demographic parameters in viviparous insular populations and ovoviviparous coastal and interior populations. Our results show considerable genetic differentiation (F(ST) range: 0.06-0.27), and no clear signs of gene flow among populations, except between the large and admixed interior populations. We find no support for island colonization by rafting or intentional/accidental anthropogenic introductions, indicating that rising sea levels were responsible for isolation of the island populations approximately 9000 years ago. Our study provides evidence of rapid genetic differentiation between island and coastal populations, and rapid evolution of viviparity driven by climatic selective pressures on island populations, geographic isolation with genetic drift, or a combination of these factors. Studies of these viviparous island populations in early stages of divergence help us better understand the microevolutionary processes involved in rapid phenotypic shifts.

  5. Altered Insular Function during Aberrant Salience Processing in Relation to the Severity of Psychotic Symptoms

    PubMed Central

    Walter, Anna; Suenderhauf, Claudia; Smieskova, Renata; Lenz, Claudia; Harrisberger, Fabienne; Schmidt, André; Vogel, Tobias; Lang, Undine E.; Riecher-Rössler, Anita; Eckert, Anne; Borgwardt, Stefan

    2016-01-01

    There is strong evidence for abnormal salience processing in patients with psychotic experiences. In particular, there are indications that the degree of aberrant salience processing increases with the severity of positive symptoms. The aim of the present study was to elucidate this relationship by means of brain imaging. Functional magnetic resonance imaging was acquired to assess hemodynamic responses during the Salience Attribution Test, a paradigm for reaction time that measures aberrant salience to irrelevant stimulus features. We included 42 patients who were diagnosed as having a psychotic disorder and divided them into two groups according to the severity of their positive symptoms. Whole brain analysis was performed using Statistical Parametric Mapping. We found no significant behavioral differences with respect to task performance. Patients with more positive symptoms showed increased hemodynamic responses in the left insula corresponding to aberrant salience than in patients with less positive symptoms. In addition, left insula activation correlated negatively with cumulative antipsychotic medication. Aberrant salience processing in the insula may be increased in psychosis, depending on the severity of positive symptoms. This study indicates that clinically similar psychosis manifestations share the same functional characteristics. In addition, our results suggest that antipsychotic medication can modulate insular function. PMID:27933003

  6. Assemblage of Necrophagous Diptera in Atlantic Insular Environments and Response to Different Levels of Human Presence.

    PubMed

    Carmo, R F R; Vasconcelos, S D

    2016-10-01

    Islands act as natural laboratories for ecological studies to explain bioinvasion processes and, in this scenario, necrophagous Diptera have never been used as model organisms. This study aimed to (i) describe assemblages of necrophagous Diptera (Calliphoridae and Sarcophagidae) in two insular environments of different origins and distances from mainland, (ii) investigate the effect of anthropogenic impact on the assemblage of carrion flies, (iii) to quantify the establishment of invasive species in the two islands, and (iv) to infer about the conservation status of the islands based on the ecological parameters. Sampling was performed in 2011-2012, in the dry and rainy season. Insects were collected by using traps with chicken liver or sardine baits. In each island, environments exposed to different degrees of human impact were sampled. Ecological analyses were carried out to characterize the assemblages of Calliphoridae and Sarcophagidae, with emphasis on the relation between native and invasive species. In total, 99,862 adults of 21 species of blow flies and flesh flies were collected. Overall abundance in the oceanic island was higher than in the continental island, although the richness of species was higher in the latter. The type of bait did not influence diversity of species sampled in either island. No difference was observed in total richness of both families according to the gradient of anthropogenic impact, in both islands. The invasive species Chrysomya megacephala (Fabricius) was classified as dominant in all environments, irrespective of the anthropogenic impact, which raises concern about the conservation status of each island.

  7. Local enhancement and social foraging in a non-social insular lizard.

    PubMed

    Pérez-Cembranos, Ana; Pérez-Mellado, Valentín

    2015-05-01

    Even in solitary foragers, conspecifics can provide reliable information about food location. The insular lizard Podarcis lilfordi is a solitary species with high population densities that sometimes aggregate around rich food patches. Its diet includes novel and unpredictable resources, such as carcasses or plants, whose exploitation quickly became widespread among the population. We tested the use of social information by lizards through some field experiments in which they had to choose one of the two pieces of fruit. Probably due to local enhancement, lizards preferred to feed on the piece of fruit where conspecifics or lizard-shaped models were already present. Conspecifics' behaviour, but also their mere presence, seems to be a valuable source of information to decide where to feed. Lizards also showed a strong attraction to conspecifics, even in the absence of food. Maybe the presence of a group is interpreted as an indirect cue for the presence of food. The group size was not important to females, but males had a significantly higher attraction towards groups with three conspecifics. We discuss some characteristics of P. lilfordi at Aire Island that can explain the development of the observed social foraging, as well as their possible consequences.

  8. Central role for the insular cortex in mediating conditioned responses to anticipatory cues

    PubMed Central

    Kusumoto-Yoshida, Ikue; Liu, Haixin; Chen, Billy T.; Fontanini, Alfredo; Bonci, Antonello

    2015-01-01

    Reward-related circuits are fundamental for initiating feeding on the basis of food-predicting cues, whereas gustatory circuits are believed to be involved in the evaluation of food during consumption. However, accumulating evidence challenges such a rigid separation. The insular cortex (IC), an area largely studied in rodents for its role in taste processing, is involved in representing anticipatory cues. Although IC responses to anticipatory cues are well established, the role of IC cue-related activity in mediating feeding behaviors is poorly understood. Here, we examined the involvement of the IC in the expression of cue-triggered food approach in mice trained with a Pavlovian conditioning paradigm. We observed a significant change in neuronal firing during presentation of the cue. Pharmacological silencing of the IC inhibited food port approach. Such a behavior could be recapitulated by temporally selective inactivation during the cue. These findings represent the first evidence, to our knowledge, that cue-evoked neuronal activity in the mouse IC modulates behavioral output, and demonstrate a causal link between cue responses and feeding behaviors. PMID:25583486

  9. How large are the extinct giant insular rodents? New body mass estimations from teeth and bones.

    PubMed

    Moncunill-Solé, Blanca; Jordana, Xavier; Marín-Moratalla, Nekane; Moyà-Solà, Salvador; Köhler, Meike

    2014-03-01

    The island rule entails a modification of the body size of insular mammals, a character related with numerous biological and ecological variables. From the Miocene to human colonization (Holocene), Mediterranean and Canary Islands were unaltered natural ecosystems, with paleofaunas formed with endemic giant rodents among other mammals. Our aim is to create methods to estimate the body masses of fossil island rodents and address the nature of ecological pressures driving the island rule. We created regression equations based on extant rodent data and used these to estimate the body masses of the extinct species. Our results show strong correlations between teeth, cranial and postcranial measurements and body mass, except for the length of the long bones, the transversal diameter of the distal tibia and the anteroposterior diameter of the proximal tibia, where the equations were less reliable. The use of equations obtained from a more homogeneous group (suborder and family) is preferable when analyzing the area of the first molar. The new regressions were applied to estimate the body masses of some Mediterranean and Canarian fossil rodents (Canariomys, C. bravoi 1.5 kg and C. tamarani 1 kg; Hypnomys, H. morpheus 230 g and H. onicensis 200 g; and Muscardinus cyclopeus 100 g). Our results indicate that under absence of predation, resource availability (island area) is the key factor that determines the size of the Canariomys sp. However, under presence of specialized predators (birds of prey), body size evolution is less pronounced (Hypnomys sp.).

  10. Sertraline reduces glutamate uptake in human platelets.

    PubMed

    Rodrigues, Débora Olmedo; Bristot, Ivi Juliana; Klamt, Fábio; Frizzo, Marcos Emílio

    2015-12-01

    Mitochondrial damage and declines in ATP levels have been recently attributed to sertraline. The effects of sertraline on different parameters were investigated in washed platelets from 18 healthy male volunteers, after 24h of drug exposure. Sertraline toxicity was observed only at the highest concentrations, 30 and 100 μM, which significantly reduced platelet viability to 76 ± 3% and 20 ± 2%, respectively. The same concentrations significantly decreased total ATP to 73 ± 3% and 13 ± 2%, respectively. Basal values of glycogen were not significantly affected by sertraline treatment. Glutamate uptake was significantly reduced after treatment with 3, 30 and 100 μM, by 28 ± 6%, 32 ± 5% and 54 ± 4%, respectively. Our data showed that sertraline at therapeutic concentrations does not compromise platelet viability and ATP levels, but they suggest that in a situation where extracellular glutamate levels are potentially increased, sertraline might aggravate an excitotoxic condition.

  11. Striatal glutamate antagonism induces contralateral neglect.

    PubMed

    Schuller, J J; Tran, D D; Marshall, J F

    1998-03-30

    To assess the role of striatal glutamatergic synapses in mediating sensorimotor orientation behavior, glutamate receptor antagonists were infused into the left striatum of awake rats and behavioral orientation to contralateral and ipsilateral stimuli were quantified. The AMPA-kainate antagonist, DNQX, and the NMDA antagonist, CPP, both induced a large asymmetry in responding, such that the rats oriented much less to stimuli presented contralateral to the antagonist infusions. Furthermore, intrastriatal glutamate antagonist infusions increased the occurrence of incorrect responses, or turning away from a contralaterally-presented stimulus. In a separate experiment, intrastriatal DNQX was shown to block kainic acid (KA)-induced Fos expression in the striatum, but not in adjacent cerebral cortex, suggesting that the diffusion of this drug is restricted to the striatum.

  12. Three Distinct Glutamate Decarboxylase Genes in Vertebrates

    PubMed Central

    Grone, Brian P.; Maruska, Karen P.

    2016-01-01

    Gamma-aminobutyric acid (GABA) is a widely conserved signaling molecule that in animals has been adapted as a neurotransmitter. GABA is synthesized from the amino acid glutamate by the action of glutamate decarboxylases (GADs). Two vertebrate genes, GAD1 and GAD2, encode distinct GAD proteins: GAD67 and GAD65, respectively. We have identified a third vertebrate GAD gene, GAD3. This gene is conserved in fishes as well as tetrapods. We analyzed protein sequence, gene structure, synteny, and phylogenetics to identify GAD3 as a homolog of GAD1 and GAD2. Interestingly, we found that GAD3 was lost in the hominid lineage. Because of the importance of GABA as a neurotransmitter, GAD3 may play important roles in vertebrate nervous systems. PMID:27461130

  13. Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease

    PubMed Central

    Niswender, Colleen M.; Conn, P. Jeffrey

    2010-01-01

    The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer’s disease, Parkinson’s disease, anxiety, depression, and schizophrenia. PMID:20055706

  14. Mechanism of glutamate uptake in Zymomonas mobilis.

    PubMed Central

    Ruhrmann, J; Krämer, R

    1992-01-01

    The energetics of the anaerobic gram-negative bacterium Zymomonas mobilis, a well-known ethanol-producing organism, is based solely on synthesis of 1 mol of ATP per mol of glucose by the Entner-Doudoroff pathway. When grown in the presence of glucose as a carbon and energy source, Z. mobilis had a cytosolic ATP content of 3.5 to 4 mM. Because of effective pH homeostasis, the components of the proton motive force strongly depended on the external pH. At pH 5.5, i.e., around the optimal pH for growth, the proton motive force was about -135 mV and was composed of a pH gradient of 0.6 pH units (internal pH 6.1) and a membrane potential of about -100 mV. Measurement of these parameters was complicated since ionophores and lipophilic probes were ineffective in this organism. So far, only glucose transport by facilitated diffusion is well characterized for Z. mobilis. We investigated a constitutive secondary glutamate uptake system. Glutamate can be used as a nitrogen source for Z. mobilis. Transport of glutamate at pH 5.5 shows a relatively high Vmax of 40 mumol.min-1.g (dry mass) of cells-1 and a low affinity (Km = 1.05 mM). Glutamate is taken up by a symport with two H+ ions, leading to substantial accumulation in the cytosol at low pH values. PMID:1332937

  15. Glutamate dehydrogenase (RocG) in Bacillus licheniformis WX-02: Enzymatic properties and specific functions in glutamic acid synthesis for poly-γ-glutamic acid production.

    PubMed

    Tian, Guangming; Wang, Qin; Wei, Xuetuan; Ma, Xin; Chen, Shouwen

    2017-04-01

    Poly-γ-glutamic acid (γ-PGA), a natural biopolymer, is widely used in cosmetics, medicine, food, water treatment, and agriculture owing to its features of moisture sequestration, cation chelation, non-toxicity and biodegradability. Intracellular glutamic acid, the substrate of γ-PGA, is a limiting factor for high yield in γ-PGA production. Bacillus subtilis and Bacillus licheniformis are both important γ-PGA producing strains, and B. subtilis synthesizes glutamic acid in vivo using the unique GOGAT/GS pathway. However, little is known about the glutamate synthesis pathway in B. licheniformis. The aim of this work was to characterize the glutamate dehydrogenase (RocG) in glutamic acid synthesis from B. licheniformis with both in vivo and in vitro experiments. By re-directing the carbon flux distribution, the rocG gene deletion mutant WX-02ΔrocG produced intracellular glutamic acid with a concentration of 90ng/log(CFU), which was only 23.7% that of the wild-type WX-02 (380ng/log(CFU)). Furthermore, the γ-PGA yield of mutant WX-02ΔrocG was 5.37g/L, a decrease of 45.3% compared to the wild type (9.82g/L). In vitro enzymatic assays of RocG showed that RocG has higher affinity for 2-oxoglutarate than glutamate, and the glutamate synthesis rate was far above degradation. This is probably the first study to reveal the glutamic acid synthesis pathway and the specific functions of RocG in B. licheniformis. The results indicate that γ-PGA production can be enhanced through improving intracellular glutamic acid synthesis.

  16. Ketamine and other potential glutamate antidepressants.

    PubMed

    Dutta, Arpan; McKie, Shane; Deakin, J F William

    2015-01-30

    The need for rapid acting antidepressants is widely recognised. There has been much interest in glutamate mechanisms in major depressive disorder (MDD) as a promising target for the development of new antidepressants. A single intravenous infusion of ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist anaesthetic agent, can alleviate depressive symptoms in patients within hours of administration. The mechanism of action appears to be in part through glutamate release onto non-NMDA receptors including α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic receptors. However these are also reported effects on 5-HT, dopamine and intracellular effects on the mammalian target of rapamycin (mTOR) pathway. The effects of SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants may also involve alterations in NMDA function. The article reviews the effect of current antidepressants on NMDA and examines the efficacy and mechanism of ketamine. Response to ketamine is also discussed and comparison with other glutamate drugs including lamotrigine, amantadine, riluzole, memantine, traxoprodil, GLYX-13, MK-0657, RO4917523, AZD2066 and Coluracetam. Future studies need to link the rapid antidepressant effects seen with ketamine to inflammatory theories in MDD.

  17. Efferent connections of an auditory area in the caudal insular cortex of the rat: anatomical nodes for cortical streams of auditory processing and cross-modal sensory interactions.

    PubMed

    Kimura, A; Imbe, H; Donishi, T

    2010-04-14

    In the rat cortex, the two non-primary auditory areas, posterodorsal and ventral auditory areas, may constitute the two streams of auditory processing in their distinct projections to the posterior parietal and insular cortices. The posterior parietal cortex is considered crucial for auditory spatial processing and directed attention, while possible auditory function of the insular cortex is largely unclear. In this study, we electrophysiologically delineated an auditory area in the caudal part of the granular insular cortex (insular auditory area, IA) and examined efferent connections of IA with anterograde tracer biocytin to deduce the functional significance of IA. IA projected to the rostral agranular insular cortex, a component of the lateral prefrontal cortex. IA also projected to the adjacent dysgranular insular cortex and the caudal agranular insular cortex and sent feedback projections to cortical layer I of the primary and secondary somatosensory areas. Corticofugal projections terminated in auditory, somatosensory and visceral thalamic nuclei, and the bottom of the thalamic reticular nucleus that could overlap the visceral sector. The ventral part of the caudate putamen, the external cortex of the inferior colliculus and the central amygdaloid nucleus were also the main targets. IA exhibited neural response to transcutaneous electrical stimulation of the forepaw in addition to acoustic stimulation (noise bursts and pure tones). The results suggest that IA subserves diverse functions associated with somatosensory, nociceptive and visceral processing that may underlie sound-driven emotional and autonomic responses. IA, being potentially involved in such extensive cross-modal sensory interactions, could also be an important anatomical node of auditory processing linked to higher neural processing in the prefrontal cortex.

  18. A novel glutamate transport system in poly(γ-glutamic acid)-producing strain Bacillus subtilis CGMCC 0833.

    PubMed

    Wu, Qun; Xu, Hong; Zhang, Dan; Ouyang, Pingkai

    2011-08-01

    Bacillus subtilis CGMCC 0833 is a poly(γ-glutamic acid) (γ-PGA)-producing strain. It has the capacity to tolerate high concentration of extracellular glutamate and to utilize glutamate actively. Such a high uptake capacity was owing to an active transport system for glutamate. Therefore, a specific transport system for L-glutamate has been observed in this strain. It was a novel transport process in which glutamate was symported with at least two protons, and an inward-directed sodium gradient had no stimulatory effect on it. K(m) and V(m) for glutamate transport were estimated to be 67 μM and 152 nmol⁻¹ min⁻¹ mg⁻¹ of protein, respectively. The transport system showed structural specificity and stereospecificity and was strongly dependent on extracellular pH. Moreover, it could be stimulated by Mg²⁺, NH₄⁺, and Ca²⁺. In addition, the glutamate transporter in this strain was studied at the molecular level. As there was no important mutation of the transporter protein, it appeared that the differences of glutamate transporter properties between this strain and other B. subtilis strains were not due to the differences of the amino acid sequence and the structure of transporter protein. This is the first extensive report on the properties of glutamate transport system in γ-PGA-producing strain.

  19. From the Cover: Glutamate antagonists limit tumor growth

    NASA Astrophysics Data System (ADS)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  20. [Determination of glutamic acid in biological material by capillary electrophoresis].

    PubMed

    Narezhnaya, E; Krukier, I; Avrutskaya, V; Degtyareva, A; Igumnova, E A

    2015-01-01

    The conditions for the identification and determination of Glutamic acid by capillary zone electrophoresis without their preliminary derivatization have been optimized. The effect of concentration of buffer electrolyte and pH on determination of Glutamic acid has been investigated. It is shown that the 5 Mm borate buffer concentration and a pH 9.15 are optimal. Quantitative determination of glutamic acid has been carried out using a linear dependence between the concentration of the analyte and the area of the peak. The accuracy and reproducibility of the determination are confirmed by the method "introduced - found". Glutamic acid has been determined in the placenta homogenate. The duration of analysis doesn't exceed 30 minutes. The results showed a decrease in the level of glutamic acid in cases of pregnancy complicated by placental insufficiency compared with the physiological, and this fact allows to consider the level of glutamic acid as a possible marker of complicated pregnancy.

  1. Increased plasma concentrations of aspartate, glutamate and glycine in Parkinson's disease.

    PubMed

    Iwasaki, Y; Ikeda, K; Shiojima, T; Kinoshita, M

    1992-10-12

    We measured fasting plasma amino acids in 20 patients with Parkinson's disease (PD) and 20 controls matched for age and sex. PD patients had significant elevations in plasma levels of aspartate, glutamate and glycine. The levels of other amino acids were not significantly different from those found in controls. No correlation was noted between PD severity and the degree of abnormality of plasma amino acids. We conclude that excitatory amino acids may be altered in patients with PD, and raise the possibility that neuroexcitotoxic mechanisms may be involved in the neurodegeneration of PD.

  2. Exercise increases mitochondrial glutamate oxidation in the mouse cerebral cortex.

    PubMed

    Herbst, Eric A F; Holloway, Graham P

    2016-07-01

    The present study investigated the impact of acute exercise on stimulating mitochondrial respiratory function in mouse cerebral cortex. Where pyruvate-stimulated respiration was not affected by acute exercise, glutamate respiration was enhanced following the exercise bout. Additional assessment revealed that this affect was dependent on the presence of malate and did not occur when substituting glutamine for glutamate. As such, our results suggest that glutamate oxidation is enhanced with acute exercise through activation of the malate-aspartate shuttle.

  3. Ketosis and brain handling of glutamate, glutamine, and GABA.

    PubMed

    Yudkoff, Marc; Daikhin, Yevgeny; Horyn, Oksana; Nissim, Ilana; Nissim, Itzhak

    2008-11-01

    We hypothesize that one mechanism of the anti-epileptic effect of the ketogenic diet is to alter brain handling of glutamate. According to this formulation, in ketotic brain astrocyte metabolism is more active, resulting in enhanced conversion of glutamate to glutamine. This allows for: (a) more efficient removal of glutamate, the most important excitatory neurotransmitter; and (b) more efficient conversion of glutamine to GABA, the major inhibitory neurotransmitter.

  4. Relationship between Increase in Astrocytic GLT-1 Glutamate Transport and Late-LTP

    ERIC Educational Resources Information Center

    Pita-Almenar, Juan D.; Zou, Shengwei; Colbert, Costa M.; Eskin, Arnold

    2012-01-01

    Na[superscript +]-dependent high-affinity glutamate transporters have important roles in the maintenance of basal levels of glutamate and clearance of glutamate during synaptic transmission. Interestingly, several studies have shown that basal glutamate transport displays plasticity. Glutamate uptake increases in hippocampal slices during early…

  5. Late Quaternary seismic stratigraphy and structure of the western insular shelf margin of Puerto Rico

    NASA Astrophysics Data System (ADS)

    Hanzlik, M.; Mann, P.; Abrams, L.; Grindlay, N.

    2005-12-01

    725 km of high-resolution seismic data were collected over the insular shelf of western Puerto Rico to better understand its late Quaternary depositional and structural history. Due to low tectonic uplift rates of onshore areas in this region, well dated late Quaternary sediments and corals have only been identified in a few scattered onland localities around Puerto Rico. Seismic data from the Rio Anasco delta area of western Puerto Rico reveals four main units with characteristic stratal reflection terminations that total about 25 m in thickness. Because of a lack of well information, age estimates of these late Quaternary units are based on correlations with sea level curves derived from dated coral samples from Puerto Rico, St. Croix, and Antigua. Units include: Unit 1 - a gently folded and faulted basal section correlated to the Oliogene-early Pliocene? carbonate shelf of Puerto Rico; deeper penetration, industry MCS lines show that these rocks are deformed in a broad EW-trenching arch; Unit 2 - chaotic channel fill deposits in incisions related to the lowstand equivalent of the Rio Anasco likely formed during the Last Glacial Maximum about 25-15 ka; Unit 3 - roughly stratified deposits onlapping the top of Unit 2; these are interpreted as an estuarine facies deposited during Holocene sea level transgression; Unit 4 - highly stratified deposits related to progradation of the Anasco delta during sea level rise. The base of unit 4 is a downlap surface interpreted as a maximum flooding surface likely formed about 6 ka. East-northeast-striking faults are observed breaking the younger late Quaternary units in three separate zones off the west coast of Puerto Rico. Onland continuations of these faults have not been identified likely due to cultural overprint of natural scarps on late Quaternary floodplains.

  6. Macaque Parieto-Insular Vestibular Cortex: Responses to self-motion and optic flow

    PubMed Central

    Chen, Aihua; DeAngelis, Gregory C.; Angelaki, Dora E.

    2011-01-01

    The parieto-insular vestibular cortex (PIVC) is thought to contain an important representation of vestibular information. Here we describe responses of macaque PIVC neurons to three-dimensional (3D) vestibular and optic flow stimulation. We found robust vestibular responses to both translational and rotational stimuli in the retroinsular (Ri) and adjacent secondary somatosensory (S2) cortices. PIVC neurons did not respond to optic flow stimulation, and vestibular responses were similar in darkness and during visual fixation. Cells in the upper bank and tip of the lateral sulcus (Ri and S2) responded to sinusoidal vestibular stimuli with modulation at the first harmonic frequency, and were directionally tuned. Cells in the lower bank of the lateral sulcus (mostly Ri) often modulated at the second harmonic frequency, and showed either bimodal spatial tuning or no tuning at all. All directions of 3D motion were represented in PIVC, with direction preferences distributed roughly uniformly for translation, but showing a preference for roll rotation. Spatio-temporal profiles of responses to translation revealed that half of PIVC cells followed the linear velocity profile of the stimulus, one-quarter carried signals related to linear acceleration (in the form of two peaks of direction selectivity separated in time), and a few neurons followed the derivative of linear acceleration (jerk). In contrast, mainly velocity-coding cells were found in response to rotation. Thus, PIVC comprises a large functional region in macaque areas Ri and S2, with robust responses to 3D rotation and translation, but is unlikely to play a significant role in visual/vestibular integration for self-motion perception. PMID:20181599

  7. Mindfulness training modulates value signals in ventromedial prefrontal cortex through input from insular cortex.

    PubMed

    Kirk, Ulrich; Gu, Xiaosi; Harvey, Ann H; Fonagy, Peter; Montague, P Read

    2014-10-15

    Neuroimaging research has demonstrated that ventromedial prefrontal cortex (vmPFC) encodes value signals that can be modulated by top-down cognitive input such as semantic knowledge, price incentives, and monetary favors suggesting that such biases may have an identified biological basis. It has been hypothesized that mindfulness training (MT) provides one path for gaining control over such top-down influences; yet, there have been no direct tests of this hypothesis. Here, we probe the behavioral and neural effects of MT on value signals in vmPFC in a randomized longitudinal design of 8 weeks of MT on an initially naïve subject cohort. The impact of this within-subject training was assessed using two paradigms: one that employed primary rewards (fruit juice) in a simple conditioning task and another that used a well-validated art-viewing paradigm to test bias of monetary favors on preference. We show that MT behaviorally censors the top-down bias of monetary favors through a measurable influence on value signals in vmPFC. MT also modulates value signals in vmPFC to primary reward delivery. Using a separate cohort of subjects we show that 8 weeks of active control training (ACT) generates the same behavioral impact also through an effect on signals in the vmPFC. Importantly, functional connectivity analyses show that value signals in vmPFC are coupled with bilateral posterior insula in the MT groups in both paradigms, but not in the ACT groups. These results suggest that MT integrates interoceptive input from insular cortex in the context of value computations of both primary and secondary rewards.

  8. Evidence that remodeling of insular cortex neurovascular unit contributes to hypertension-related sympathoexcitation.

    PubMed

    Marins, Fernanda R; Iddings, Jennifer A; Fontes, Marco A P; Filosa, Jessica A

    2017-03-01

    The intermediate region of the posterior insular cortex (intermediate IC) mediates sympathoexcitatory responses to the heart and kidneys. Previous studies support hypertension-evoked changes to the structure and function of neurons, blood vessels, astrocytes and microglia, disrupting the organization of the neurovascular unit (NVU). In this study, we evaluated the functional and anatomical integrity of the NVU at the intermediate IC in the spontaneously hypertensive rat (SHR) and its control the Wistar-Kyoto (WKY). Under urethane anesthesia, NMDA microinjection (0.2 mmol/L/100 nL) was performed at the intermediate IC with simultaneous recording of renal sympathetic nerve activity (RSNA), heart rate (HR) and mean arterial pressure (MAP). Alterations in NVU structure were investigated by immunofluorescence for NMDA receptors (NR1), blood vessels (70 kDa FITC-dextran), astrocytes (GFAP), and microglia (Iba1). Injections of NMDA into intermediate IC of SHR evoked higher amplitude responses of RSNA, MAP, and HR On the other hand, NMDA receptor blockade decreased baseline RSNA, MAP and HR in SHR, with no changes in WKY Immunofluorescence data from SHR intermediate IC showed increased NMDA receptor density, contributing to the SHR enhanced sympathetic responses, and increased in vascular density (increased number of branches and endpoints, reduced average branch length), suggesting angiogenesis. Additionally, IC from SHR presented increased GFAP immunoreactivity and contact between astrocyte processes and blood vessels. In SHR, IC microglia skeleton analysis supports their activation (reduced number of branches, junctions, endpoints and process length), suggesting an inflammatory process in this region. These findings indicate that neurogenic hypertension in SHR is accompanied by marked alterations to the NVU within the IC and enhanced NMDA-mediated sympathoexcitatory responses likely contributors of the maintenance of hypertension.

  9. Interhemispheric insular and inferior frontal connectivity are associated with substance abuse in a psychiatric population.

    PubMed

    Viswanath, Humsini; Velasquez, Kenia M; Savjani, Ricky; Molfese, David L; Curtis, Kaylah; Molfese, Peter J; Eagleman, David M; Baldwin, Philip R; Frueh, B Christopher; Fowler, J Christopher; Salas, Ramiro

    2015-05-01

    Substance abuse is highly comorbid with major psychiatric disorders. While the neural underpinnings of drug abuse have been studied extensively, most existing studies compare drug users without comorbidities and healthy, non-user controls. Such studies do not generalize well to typical patients with substance abuse disorders. Therefore, we studied a population of psychiatric inpatients (n = 151) with a range of mental illnesses. Psychiatric disorders were diagnosed via structured interviews. Sixty-five percent of patients met criteria for at least one substance use disorder. Patients were recruited for resting state functional connectivity (RSFC) and diffusion tensor imaging (DTI) experiments to examine the interhemispheric connectivity between brain regions hypothesized to be involved in drug addiction, namely: the inferior, medial, and superior frontal gyri; insula; striatum; and anterior cingulate cortex. The World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test (WHOA) questionnaire was used to further assess drug use. An association between use of tobacco, alcohol, cocaine, sedatives, and hallucinogens with increased insular interhemispheric connectivity was observed. In addition, increased inferior frontal gyrus interhemispheric connectivity was associated with amphetamine and inhalant use. Our results suggest that increased inter-hemispheric insula connectivity is associated with the use of several drugs of abuse. Importantly, psychiatric inpatients without a history of drug dependence were used as an ecologically valid control group rather than the more typical comparison between "mentally ill vs. healthy control" populations. We suggest that dysfunction of interhemispheric connectivity of the insula and to a lesser extent of the inferior frontal gyrus, are related to drug abuse in psychiatric populations.

  10. Differential structural and resting state connectivity between insular subdivisions and other pain-related brain regions.

    PubMed

    Wiech, K; Jbabdi, S; Lin, C S; Andersson, J; Tracey, I

    2014-10-01

    Functional neuroimaging studies suggest that the anterior, mid, and posterior division of the insula subserve different functions in the perception of pain. The anterior insula (AI) has predominantly been associated with cognitive-affective aspects of pain, while the mid and posterior divisions have been implicated in sensory-discriminative processing. We examined whether this functional segregation is paralleled by differences in (1) structural and (2) resting state connectivity and (3) in correlations with pain-relevant psychological traits. Analyses were restricted to the 3 insular subdivisions and other pain-related brain regions. Both type of analyses revealed largely overlapping results. The AI division was predominantly connected to the ventrolateral prefrontal cortex (structural and resting state connectivity) and orbitofrontal cortex (structural connectivity). In contrast, the posterior insula showed strong connections to the primary somatosensory cortex (SI; structural connectivity) and secondary somatosensory cortex (SII; structural and resting state connectivity). The mid insula displayed a hybrid connectivity pattern with strong connections with the ventrolateral prefrontal cortex, SII (structural and resting state connectivity) and SI (structural connectivity). Moreover, resting state connectivity revealed strong connectivity of all 3 subdivisions with the thalamus. On the behavioural level, AI structural connectivity was related to the individual degree of pain vigilance and awareness that showed a positive correlation with AI-amygdala connectivity and a negative correlation with AI-rostral anterior cingulate cortex connectivity. In sum, our findings show a differential structural and resting state connectivity for the anterior, mid, and posterior insula with other pain-relevant brain regions, which might at least partly explain their different functional profiles in pain processing.

  11. Decoupling of ENSO and fires in insular Southeast Asia from 2001-2010

    NASA Astrophysics Data System (ADS)

    Fuller, D. O.

    2010-12-01

    Eight-day active fire time series (2001-May 2010) in western, insular Southeast Asia were analyzed to evaluate whether the relationship between the El Niño Southern Oscillation (ENSO) and fires has changed through time consistent with the hypothesis that fires and climate forcings are becoming decoupled as deforestation has continued in the region. The study period was marked by three major fire peaks in 2002, 2006 and 2009-2010 coinciding with three El Niño events. Maximum cross correlation coefficients (MCC) between lagged ENSO sea-surface temperature indices and fire counts (raw and seasonally detrended) were modest (≤ 0.50) and showed a general decrease for most land cover types from 2001-2006 to 2007-May 2010. A notable exception was peat swamp forest where the MCC increased slightly between the two periods for all indices except Niño3. A measure of annual seasonality also revealed that fires in peat swamp forest, lowland forest and secondary formations from 2007-May 2010 were more seasonal than fires during 2001-2006. Overall, the evidence suggests that fires and ENSO are becoming decoupled in the region and that forest types such as peat swamp and lowland forest may be experiencing more seasonal fires. We hypothesize that the decoupling occurs because of a stabilization in land use and establishment of permanent crops. We thus expect that fires will diminish in these areas as permanent plantations (primarily oil palm) are established and incentives to protect valuable crops outweigh incentives to convert land for cultivation.

  12. From carbon sink to carbon source: extensive peat oxidation in insular Southeast Asia since 1990

    NASA Astrophysics Data System (ADS)

    Miettinen, Jukka; Hooijer, Aljosja; Vernimmen, Ronald; Liew, Soo Chin; Page, Susan E.

    2017-02-01

    Tropical peatlands of the western part of insular Southeast Asia have experienced extensive land cover changes since 1990. Typically involving drainage, these land cover changes have resulted in increased peat oxidation in the upper peat profile. In this paper we provide current (2015) and cumulative carbon emissions estimates since 1990 from peat oxidation in Peninsular Malaysia, Sumatra and Borneo, utilizing newly published peatland land cover information and the recently agreed Intergovernmental Panel on Climate Change (IPCC) peat oxidation emission values for tropical peatland areas. Our results highlight the change of one of the Earth’s most efficient long-term carbon sinks to a short-term emission source, with cumulative carbon emissions since 1990 estimated to have been in the order of 2.5 Gt C. Current (2015) levels of emissions are estimated at around 146 Mt C yr‑1, with a range of 132–159 Mt C yr‑1 depending on the selection of emissions factors for different land cover types. 44% (or 64 Mt C yr‑1) of the emissions come from industrial plantations (mainly oil palm and Acacia pulpwood), followed by 34% (49 Mt C yr‑1) of emissions from small-holder areas. Thus, altogether 78% of current peat oxidation emissions come from managed land cover types. Although based on the latest information, these estimates may still include considerable, yet currently unquantifiable, uncertainties (e.g. due to uncertainties in the extent of peatlands and drainage networks) which need to be focused on in future research. In comparison, fire induced carbon dioxide emissions over the past ten years for the entire equatorial Southeast Asia region have been estimated to average 122 Mt C yr‑1 (www.globalfiredata.org/_index.html). The results emphasise that whilst reducing emissions from peat fires is important, urgent efforts are also needed to mitigate the constantly high level of emissions arising from peat drainage, regardless of fire occurrence.

  13. Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation.

    PubMed

    Lekander, Mats; Karshikoff, Bianka; Johansson, Emilia; Soop, Anne; Fransson, Peter; Lundström, Johan N; Andreasson, Anna; Ingvar, Martin; Petrovic, Predrag; Axelsson, John; Nilsonne, Gustav

    2016-08-01

    Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.

  14. Maps Showing Composition of Surficial Sediments on the Insular Shelf of Southwestern Puerto Rico

    USGS Publications Warehouse

    Shideler, Gerald L.

    1980-01-01

    The limited availability of onshore sand deposits for use in construction appears to be a future major problem in Puerto Rico (U.S. Bureau of Mines, 1972; Committee on Puerto Rico and the Sea, 1974). Consequently, the mining of offshore sand deposits as supplemental sources of construction aggregate may becom e necessary. For this reason, the U.S. Geological Survey and the Department of Natural Resources of the Commonwealth of Puerto Rico have conducted investigations of potential offshore sand deposits on the Puerto Rico insular shelf. This report provides information on the composition of surficial sediments on the southwestern Puerto Rico shelf (fig. 1), an area that may be one of the more favorable potential sites for offshore sand resources. Water depths over most of the study area are less than 22 meters (m). The sea floor is composed of live and dead patch and fringing reefs, areas of rock exposures, and sedim ent-covered areas. The adjacent coastline includes prominent embaym ents and a conspicuous rock promontory (Cabo Rojo) connected by a tombolo to the mainland of Puerto Rico. The study area is in the belt of northeast trade winds. Waves approach the coast predominantly from the southeast, resulting in a predominantly westward littoral drift along the south coast (Grove and Trumbull, 1978). Local sand movement on the southern shelf is shown by an active sand wave field south of Bah1a Sucia in which the sand wave crests have migrated toward the southwest (Grove and Trumbull, 1978). The presence of the sand wave field suggests that large volumes of sand having potential for mining are locally present in the study area.

  15. Selective changes in inhibition as determinants for limited hyperexcitability in the insular cortex of epileptic rats

    PubMed Central

    Bortel, Aleksandra; Longo, Daniela; de Guzman, Philip; Dubeau, François; Biagini, Giuseppe; Avoli, Massimo

    2016-01-01

    The insular cortex (IC) is involved in the generalization of epileptic discharges in temporal lobe epilepsy (TLE), whereas seizures originating in the IC can mimic the epileptic phenotype seen in some patients with TLE. However, few studies have addressed the changes occurring in the IC in TLE animal models. Here, we analyzed the immunohistochemical and electrophysiological properties of IC networks in non-epileptic control and pilocarpine-treated epileptic rats. Neurons identified with a neuron-specific nuclear protein antibody showed similar counts in the two types of tissue but parvalbumin- and neuropeptide Y-positive interneurons were significantly decreased (parvalbumin, approximately −35%; neuropeptide Y, approximately −38%; P < 0.01) in the epileptic IC. Nonadapting neurons were seen more frequently in the epileptic IC during intracellular injection of depolarizing current pulses. In addition, single-shock electrical stimuli elicited network-driven epileptiform responses in 87% of epileptic and 22% of non-epileptic control neurons (P < 0.01) but spontaneous postsynaptic potentials had similar amplitude, duration and intervals of occurrence in the two groups. Finally, pharmacologically isolated, GABAA receptor-mediated inhibitory postsynaptic potentials had more negative reversal potential (P < 0.01) and higher peak conductance (P < 0.05) in epileptic tissue. These data reveal moderate increased network excitability in the IC of pilocarpine-treated epileptic rats. We propose that this limited degree of hyperexcitability originates from the loss of parvalbumin- and neuropeptide Y-positive interneurons that is compensated by an increased drive for GABAA receptor-mediated inhibition. PMID:20497472

  16. Tuning the ion selectivity of glutamate transporter–associated uncoupled conductances

    PubMed Central

    Cater, Rosemary J.; Vandenberg, Robert J.

    2016-01-01

    The concentration of glutamate within a glutamatergic synapse is tightly regulated by excitatory amino acid transporters (EAATs). In addition to their primary role in clearing extracellular glutamate, the EAATs also possess a thermodynamically uncoupled Cl− conductance. This conductance is activated by the binding of substrate and Na+, but the direction of Cl− flux is independent of the rate or direction of substrate transport; thus, the two processes are thermodynamically uncoupled. A recent molecular dynamics study of the archaeal EAAT homologue GltPh (an aspartate transporter from Pyrococcus horikoshii) identified an aqueous pore at the interface of the transport and trimerization domains, through which anions could permeate, and it was suggested that an arginine residue at the most restricted part of this pathway might play a role in determining anion selectivity. In this study, we mutate this arginine to a histidine in the human glutamate transporter EAAT1 and investigate the role of the protonation state of this residue on anion selectivity and transporter function. Our results demonstrate that a positive charge at this position is crucial for determining anion versus cation selectivity of the uncoupled conductance of EAAT1. In addition, because the nature of this residue influences the turnover rate of EAAT1, we reveal an intrinsic link between the elevator movement of the transport domain and the Cl− channel. PMID:27296367

  17. Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication

    PubMed Central

    Ruban, Angela; Mohar, Boaz; Jona, Ghil; Teichberg, Vivian I

    2014-01-01

    Organophosphate-induced brain damage is an irreversible neuronal injury, likely because there is no pharmacological treatment to prevent or block secondary damage processes. The presence of free glutamate (Glu) in the brain has a substantial role in the propagation and maintenance of organophosphate-induced seizures, thus contributing to the secondary brain damage. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity. We demonstrated that BGS treatment significantly prevented the peripheral benzodiazepine receptor (PBR) density elevation, after PO exposure. Furthermore, we showed that BGS was able to rescue neurons in the piriform cortex of the treated rats. In conclusion, these results suggest that treatment with BGS has a neuroprotective effect in the PO intoxication. This is the first time that this approach is used in PO intoxication and it may be of high clinical significance for the future treatment of the secondary neurologic damage post organophosphates exposure. PMID:24149933

  18. AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo.

    PubMed

    Corona, Juan Carlos; Tapia, Ricardo

    2004-05-01

    The mechanisms of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS) are unknown, but glutamate-mediated excitotoxicity may be involved. To examine directly this idea in vivo, we have used microdialysis in the rat lumbar spinal cord and showed that four- to fivefold increases in the concentration of endogenous extracellular glutamate during at least 1 h, by perfusion with the glutamate transport inhibitor L-2,4-trans-pyrrolidine-dicarboxylate, elicited no motor alterations or MN damage. Stimulation of glutamate release with 4-aminopyridine induced transitory ipsilateral hindlimb muscular twitches but no MN damage. In contrast, perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) did not modify glutamate levels but produced intense muscular spasms, followed by ipsilateral permanent hindlimb paralysis and a remarkable loss of MNs. These effects of AMPA were prevented by co-perfusion with the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline. Perfusion with NMDA or kainate produced no motor effects or MN damage. Thus, the elevation of endogenous extracellular glutamate in vivo due to blockade of its transport is innocuous for spinal MNs. Because this resistance is observed under the same experimental conditions in which MNs are highly vulnerable to AMPA, these results indicate that excitotoxicity due to this mechanism might not be an important factor in the pathogenesis of ALS.

  19. Synthesis and biological activity of glutamic acid derivatives.

    PubMed

    Receveur, J M; Guiramand, J; Récasens, M; Roumestant, M L; Viallefont, P; Martinez, J

    1998-01-20

    In order to develop new specific glutamate analogues at metabotropic glutamate receptors, Diels-Alder, 1-4 ionic and radical reactions were performed starting from (2S)-4-methyleneglutamic acid. Preliminary pharmacological evaluation by measuring IP accumulation using rat forebrain synaptoneurosomes has shown that (2S)-4-(2-phthalimidoethyl)glutamic acid (3a), (2S)-4-(4-phthalimidobutyl)glutamic acid (3b) and 1-[(S)-2-amino-2-carboxyethyl]-3,4-dimethylcyclohex-3-ene-1-carbox ylic acid (8) presented moderate antagonist activities.

  20. Diagnostic and pathogenic significance of glutamate receptor autoantibodies.

    PubMed

    Pleasure, David

    2008-05-01

    Autoantibodies against glutamate receptors, first reported in Rasmussen encephalitis, have been observed in other focal epilepsies, central nervous system ischemic infarcts, transient ischemic attacks, sporadic olivopontocerebellar atrophy, systemic lupus erythematosus, and paraneoplastic encephalopathies. The detection of glutamate receptor autoantibodies is not useful in the evaluation of Rasmussen encephalitis but may be a biomarker for brain ischemia, and it is helpful in diagnosing certain paraneoplastic encephalopathies. Passive transfer of glutamate receptor autoantibodies from patients with systemic lupus erythematosus or paraneoplastic encephalopathy suggests that glutamate receptor autoantibodies can actively contribute to neurologic dysfunction.

  1. D-Glutamate is metabolized in the heart mitochondria

    PubMed Central

    Ariyoshi, Makoto; Katane, Masumi; Hamase, Kenji; Miyoshi, Yurika; Nakane, Maiko; Hoshino, Atsushi; Okawa, Yoshifumi; Mita, Yuichiro; Kaimoto, Satoshi; Uchihashi, Motoki; Fukai, Kuniyoshi; Ono, Kazunori; Tateishi, Syuhei; Hato, Daichi; Yamanaka, Ryoetsu; Honda, Sakiko; Fushimura, Yohei; Iwai-Kanai, Eri; Ishihara, Naotada; Mita, Masashi; Homma, Hiroshi; Matoba, Satoaki

    2017-01-01

    D-Amino acids are enantiomers of L-amino acids and have recently been recognized as biomarkers and bioactive substances in mammals, including humans. In the present study, we investigated functions of the novel mammalian mitochondrial protein 9030617O03Rik and showed decreased expression under conditions of heart failure. Genomic sequence analyses showed partial homology with a bacterial aspartate/glutamate/hydantoin racemase. Subsequent determinations of all free amino acid concentrations in 9030617O03Rik-deficient mice showed high accumulations of D-glutamate in heart tissues. This is the first time that a significant amount of D-glutamate was detected in mammalian tissue. Further analysis of D-glutamate metabolism indicated that 9030617O03Rik is a D-glutamate cyclase that converts D-glutamate to 5-oxo-D-proline. Hence, this protein is the first identified enzyme responsible for mammalian D-glutamate metabolism, as confirmed in cloning analyses. These findings suggest that D-glutamate and 5-oxo-D-proline have bioactivities in mammals through the metabolism by D-glutamate cyclase. PMID:28266638

  2. CONTROL OF GLUTAMATE OXIDATION IN BRAIN AND LIVER MITOCHONDRIAL SYSTEMS.

    PubMed

    BALAZS, R

    1965-05-01

    1. Glutamate oxidation in brain and liver mitochondrial systems proceeds mainly through transamination with oxaloacetate followed by oxidation of the alpha-oxoglutarate formed. Both in the presence and absence of dinitrophenol in liver mitochondria this pathway accounted for almost 80% of the uptake of glutamate. In brain preparations the transamination pathway accounted for about 90% of the glutamate uptake. 2. The oxidation of [1-(14)C]- and [5-(14)C]-glutamate in brain preparations is compatible with utilization through the tricarboxylic acid cycle, either after the formation of alpha-oxoglutarate or after decarboxylation to form gamma-aminobutyrate. There is no indication of gamma-decarboxylation of glutamate. 3. The high respiratory control ratio obtained with glutamate as substrate in brain mitochondrial preparations is due to the low respiration rate in the absence of ADP: this results from the low rate of formation of oxaloacetate under these conditions. When oxaloacetate is made available by the addition of malate or of NAD(+), the respiration rate is increased to the level obtained with other substrates. 4. When the transamination pathway of glutamate oxidation was blocked with malonate, the uptake of glutamate was inhibited in the presence of ADP or ADP plus dinitrophenol by about 70 and 80% respectively in brain mitochondrial systems, whereas the inhibition was only about 50% in dinitrophenol-stimulated liver preparations. In unstimulated liver mitochondria in the presence of malonate there was a sixfold increase in the oxidation of glutamate by the glutamate-dehydrogenase pathway. Thus the operating activity of glutamate dehydrogenase is much less than the ;free' (non-latent) activity. 5. The following explanation is put forward for the control of glutamate metabolism in liver and brain mitochondrial preparations. The oxidation of glutamate by either pathway yields alpha-oxoglutarate, which is further metabolized. Since aspartate aminotransferase is

  3. How Glutamate Is Managed by the Blood–Brain Barrier

    PubMed Central

    Hawkins, Richard A.; Viña, Juan R.

    2016-01-01

    A facilitative transport system exists on the blood–brain barrier (BBB) that has been tacitly assumed to be a path for glutamate entry to the brain. However, glutamate is a non-essential amino acid whose brain content is much greater than plasma, and studies in vivo show that glutamate does not enter the brain in appreciable quantities except in those small regions with fenestrated capillaries (circumventricular organs). The situation became understandable when luminal (blood facing) and abluminal (brain facing) membranes were isolated and studied separately. Facilitative transport of glutamate and glutamine exists only on the luminal membranes, whereas Na+-dependent transport systems for glutamate, glutamine, and some other amino acids are present only on the abluminal membrane. The Na+-dependent cotransporters of the abluminal membrane are in a position to actively transport amino acids from the extracellular fluid (ECF) into the endothelial cells of the BBB. These powerful secondary active transporters couple with the energy of the Na+-gradient to move glutamate and glutamine into endothelial cells, whereupon glutamate can exit to the blood on the luminal facilitative glutamate transporter. Glutamine may also exit the brain via separate facilitative transport system that exists on the luminal membranes, or glutamine can be hydrolyzed to glutamate within the BBB, thereby releasing ammonia that is freely diffusible. The γ-glutamyl cycle participates indirectly by producing oxoproline (pyroglutamate), which stimulates almost all secondary active transporters yet discovered in the abluminal membranes of the BBB. PMID:27740595

  4. Ciproxifan, a histamine H3 receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus.

    PubMed

    Lu, Cheng-Wei; Lin, Tzu-Yu; Chang, Chia-Ying; Huang, Shu-Kuei; Wang, Su-Jane

    2017-03-15

    Ciproxifan is an H3 receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca(2+)-dependent glutamate release and cytosolic Ca(2+) concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca(2+)-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A2 (PLA2) inhibitor OBAA, prostaglandin E2 (PGE2), PGE2 subtype 2 (EP2) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H3 receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca(2+) entry by diminishing PLA2/PGE2/EP2 receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.

  5. Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons.

    PubMed

    Mao, Xiao-Yuan; Cao, Yong-Gang; Ji, Zhong; Zhou, Hong-Hao; Liu, Zhao-Qian; Sun, Hong-Li

    2015-07-03

    Topiramate (TPM) was previously found to have neuroprotection against neuronal injury in epileptic and ischemic models. However, whether TPM protects against glutamate-induced excitotoxicity in hippocampal neurons is elusive. Our present work aimed to evaluate the protective effect of TPM against glutamate toxicity in hippocampal neurons and further figure out the potential molecular mechanisms. The in vitro glutamate excitotoxic model was prepared with 125μM glutamate for 20min. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) analysis and Hoechst 33342 staining were conducted to detect neuronal survival. The protein expressions of brain-derived neurotrophic factor (BDNF), TrkB, mitogen-activated protein kinase (MAPK) cascade (including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK), cyclic AMP response element binding protein (CREB), Bcl-2, Bax and β-actin were detected via Western blot assay. Our results demonstrated that TPM protected hippocampal neurons from glutamate toxicity. Meanwhile, the pretreatment of TPM for 10min significantly prevented the down-regulation of BDNF and the phosphorylation of TrkB. Furthermore, the elevation of phosphorylated EKR expression was significantly inhibited after blockade of TrkB by TrkB IgG, while no alterations of phosphorylated JNK and p38 MAPK were found in the cultured hippocampal neurons. Besides, it was also found that the enhanced phosphorylation of CREB was evidently reversed under excitotoxic conditions after treating with U0126 (the selective inhibitor of ERK). The protein level of Bcl-2 was also observed to be remarkably increased after TPM treatment. In conclusion, these findings implicate that TPM exerts neuroprotective effects against glutamate excitotoxicity in hippocampal neurons and its protection may be modulated through BDNF/TrkB-dependent ERK pathway.

  6. Monosodium glutamate-associated alterations in open field, anxiety-related and conditioned place preference behaviours in mice.

    PubMed

    Onaolapo, Olakunle James; Aremu, Olaleye Samuel; Onaolapo, Adejoke Yetunde

    2017-03-29

    The present study investigated changes in behaviour associated with oral monosodium glutamate (a flavouring agent), using the open field, elevated plus maze and conditioned place preference (CPP) paradigms, respectively. Mice were assigned to two groups for CPP [monosodium glutamate (MSG)-naïve (n = 40) and MSG-pretreated (n = 40)] and two groups for open field (OF) and elevated plus maze (EPM) tests [n = 40 each], respectively. Animals in respective groups were then divided into four subgroups (n = 10) (vehicle or MSG (80, 160 and 320 mg/kg)). MSG-naïve mice were observed in the CPP box in three phases (pre-conditioning, conditioning and post-conditioning). Mice were conditioned to MSG or an equivalent volume of saline. The MSG pretreatment group received vehicle or respective doses of MSG daily for 21 days, prior to conditioning. Mice in the OF or EPM groups received vehicle or doses of MSG (orally) for 21 days, at 10 ml/kg. Open field or EPM behaviours were assessed on days 1 and 21. At the end of the experiments, mice in the OF groups were sacrificed and brain homogenates used to assay glutamate and glutamine. Results showed that administration of MSG was associated with a decrease in rearing, dose-related mixed horizontal locomotor, grooming and anxiety-related response and an increase in brain glutamate/glutamine levels. Following exposure to the CPP paradigm, MSG-naïve and MSG-pretreated mice both showed 'drug-paired' chamber preference. The study concluded that MSG (at the administered doses) was associated with changes in open field activities, anxiety-related behaviours and brain glutamate/glutamine levels; its ingestion also probably leads to a stimulation of the brain reward system.

  7. Learning touch preferences with a tactile robot using dopamine modulated STDP in a model of insular cortex.

    PubMed

    Chou, Ting-Shuo; Bucci, Liam D; Krichmar, Jeffrey L

    2015-01-01

    Neurorobots enable researchers to study how behaviors are produced by neural mechanisms in an uncertain, noisy, real-world environment. To investigate how the somatosensory system processes noisy, real-world touch inputs, we introduce a neurorobot called CARL-SJR, which has a full-body tactile sensory area. The design of CARL-SJR is such that it encourages people to communicate with it through gentle touch. CARL-SJR provides feedback to users by displaying bright colors on its surface. In the present study, we show that CARL-SJR is capable of learning associations between conditioned stimuli (CS; a color pattern on its surface) and unconditioned stimuli (US; a preferred touch pattern) by applying a spiking neural network (SNN) with neurobiologically inspired plasticity. Specifically, we modeled the primary somatosensory cortex, prefrontal cortex, striatum, and the insular cortex, which is important for hedonic touch, to process noisy data generated directly from CARL-SJR's tactile sensory area. To facilitate learning, we applied dopamine-modulated Spike Timing Dependent Plasticity (STDP) to our simulated prefrontal cortex, striatum, and insular cortex. To cope with noisy, varying inputs, the SNN was tuned to produce traveling waves of activity that carried spatiotemporal information. Despite the noisy tactile sensors, spike trains, and variations in subject hand swipes, the learning was quite robust. Further, insular cortex activities in the incremental pathway of dopaminergic reward system allowed us to control CARL-SJR's preference for touch direction without heavily pre-processed inputs. The emerged behaviors we found in this model match animal's behaviors wherein they prefer touch in particular areas and directions. Thus, the results in this paper could serve as an explanation on the underlying neural mechanisms for developing tactile preferences and hedonic touch.

  8. Pentameric assembly of a neuronal glutamate transporter.

    PubMed

    Eskandari, S; Kreman, M; Kavanaugh, M P; Wright, E M; Zampighi, G A

    2000-07-18

    Freeze-fracture electron microscopy was used to study the structure of a human neuronal glutamate transporter (EAAT3). EAAT3 was expressed in Xenopus laevis oocytes, and its function was correlated with the total number of transporters in the plasma membrane of the same cells. Function was assayed as the maximum charge moved in response to a series of transmembrane voltage pulses. The number of transporters in the plasma membrane was determined from the density of a distinct 10-nm freeze-fracture particle, which appeared in the protoplasmic face only after EAAT3 expression. The linear correlation between EAAT3 maximum carrier-mediated charge and the total number of the 10-nm particles suggested that this particle represented functional EAAT3 in the plasma membrane. The cross-sectional area of EAAT3 in the plasma membrane (48 +/- 5 nm(2)) predicted 35 +/- 3 transmembrane alpha-helices in the transporter complex. This information along with secondary structure models (6-10 transmembrane alpha-helices) suggested an oligomeric state for EAAT3. EAAT3 particles were pentagonal in shape in which five domains could be identified. They exhibited fivefold symmetry because they appeared as equilateral pentagons and the angle at the vertices was 110 degrees. Each domain appeared to contribute to an extracellular mass that projects approximately 3 nm into the extracellular space. Projections from all five domains taper toward an axis passing through the center of the pentagon, giving the transporter complex the appearance of a penton-based pyramid. The pentameric structure of EAAT3 offers new insights into its function as both a glutamate transporter and a glutamate-gated chloride channel.

  9. Red nucleus glutamate facilitates neuropathic allodynia induced by spared nerve injury through non-NMDA and metabotropic glutamate receptors.

    PubMed

    Yu, Jing; Ding, Cui-Ping; Wang, Jing; Wang, Ting; Zhang, Tao; Zeng, Xiao-Yan; Wang, Jun-Yang

    2015-12-01

    Previous studies have demonstrated that glutamate plays an important role in the development of pathological pain. This study investigates the expression changes of glutamate and the roles of different types of glutamate receptors in the red nucleus (RN) in the development of neuropathic allodynia induced by spared nerve injury (SNI). Immunohistochemistry indicated that glutamate was constitutively expressed in the RN of normal rats. After SNI, the expression levels of glutamate were significantly increased in the RN at 1 week and reached the highest level at 2 weeks postinjury compared with sham-operated and normal rats. The RN glutamate was colocalized with neurons, oligodendrocytes, and astrocytes but not microglia under physiological and neuropathic pain conditions. To elucidate further the roles of the RN glutamate and different types of glutamate receptors in the development of neuropathic allodynia, antagonists to N-methyl-D-aspartate (NMDA), non-NMDA, or metabotropic glutamate receptors (mGluRs) were microinjected into the RN contralateral to the nerve-injury side of rats with SNI, and the paw withdrawal threshold (PWT) was dynamically assessed with von Frey filaments. Microinjection of the NMDA receptor antagonist MK-801 into the RN did not show any effect on SNI-induced mechanical allodynia. However, microinjection of the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3(1H,4H)-dione or the mGluR antagonist (±)-α-methyl-(4-carboxyphenyl) glycine into the RN significantly increased the PWT and alleviated SNI-induced mechanical allodynia. These findings suggest that RN glutamate is involved in regulating neuropathic pain and facilitates the development of SNI-induced neuropathic allodynia. The algesic effect of glutamate is transmitted by the non-NMDA glutamate receptor and mGluRs.

  10. Anti glutamate-decarboxylase antibodies: a liaison between localisation related epilepsy, stiff-person syndrome and type-1 diabetes mellitus.

    PubMed

    Szűcs, Anna; Barcs, Gábor; Winkler, Gábor; Soós, Zsuzsanna; Folyovich, András; Kelemen, Anna; Várallyay, Péter; Kamondi, Anita

    2014-07-30

    We present two patients with partial epilepsy, type-1 diabetes and stiff person syndrome associated with high serum auto-antibody levels to glutamate-decarboxylase (anti-GAD). Both patients were or have suffered from additional autoimmune conditions. The presence of stiff person syndrome and elevated anti-GAD levels have to make clinicians look for additional autoimmune conditions including type-1 diabetes. On the other hand, the co-morbidity of partial epilepsy with autoimmune conditions in patients with elevated serum anti-GAD suggests an autoimmune mechanism of partial epilepsy in these cases.

  11. Extracellular glutamate diffusion determines the occupancy of glutamate receptors at CA1 synapses in the hippocampus.

    PubMed Central

    Kullmann, D M; Min, M Y; Asztely, F; Rusakov, D A

    1999-01-01

    Following exocytosis at excitatory synapses in the brain, glutamate binds to several subtypes of postsynaptic receptors. The degree of occupancy of AMPA and NMDA receptors at hippocampal synapses is, however, not known. One approach to estimate receptor occupancy is to examine quantal amplitude fluctuations of postsynaptic signals in hippocampal neurons studied in vitro. The results of such experiments suggest that NMDA receptors at CA1 synapses are activated not only by glutamate released from the immediately apposed presynaptic terminals, but also by glutamate spillover from neighbouring terminals. Numerical simulations point to the extracellular diffusion coefficient as a critical parameter that determines the extent of activation of receptors positioned at different distances from the release site. We have shown that raising the viscosity of the extracellular medium can modulate the diffusion coefficient, providing an experimental tool to investigate the role of diffusion in activation of synaptic and extrasynaptic receptors. Whether intersynaptic cross-talk mediated by NMDA receptors occurs in vivo remains to be determined. The theoretical and experimental approaches described here also promise to shed light on the roles of metabotropic and kainate receptors, which often occur in an extrasynaptic distribution, and are therefore positioned to sense glutamate escaping from the synaptic cleft. PMID:10212489

  12. Glutamate-based therapeutic approaches: ampakines.

    PubMed

    Lynch, Gary

    2006-02-01

    Ampakines are a structurally diverse family of small molecules that positively modulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, and thereby enhance fast, excitatory transmission throughout the brain. Surprisingly, ampakines have discrete effects on brain activity and behavior. Because their excitatory synaptic targets mediate communication between cortical regions, serve as sites of memory encoding, and regulate the production of growth factors, ampakines have a broad range of potential therapeutic applications. Several of these possibilities have been tested with positive results in preclinical models; preliminary clinical work has also been encouraging.

  13. Inhibitory effects of (2S, 3S)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (TFB-TBOA) on the astrocytic sodium responses to glutamate.

    PubMed

    Bozzo, Luigi; Chatton, Jean-Yves

    2010-02-26

    Astrocytes are responsible for the majority of the clearance of extracellular glutamate released during neuronal activity. dl-threo-beta-benzyloxyaspartate (TBOA) is extensively used as inhibitor of glutamate transport activity, but suffers from relatively low affinity for the transporter. Here, we characterized the effects of (2S, 3S)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (TFB-TBOA), a recently developed inhibitor of the glutamate transporter on mouse cortical astrocytes in primary culture. The glial Na(+)-glutamate transport system is very efficient and its activation by glutamate causes rapid intracellular Na(+) concentration (Na(+)(i)) changes that enable real time monitoring of transporter activity. Na(+)(i) was monitored by fluorescence microscopy in single astrocytes using the fluorescent Na(+)-sensitive probe sodium-binding benzofuran isophtalate. When applied alone, TFB-TBOA, at a concentration of 1 microM, caused small alterations of Na(+)(i). TFB-TBOA inhibited the Na(+)(i) response evoked by 200 microM glutamate in a concentration-dependent manner with IC(50) value of 43+/-9 nM, as measured on the amplitude of the Na(+)(i) response. The maximum inhibition of glutamate-evoked Na(+)(i) increase by TFB-TBOA was >80%, but was only partly reversible. The residual response persisted in the presence of the AMPA/kainate receptor antagonist CNQX. TFB-TBOA also efficiently inhibited Na(+)(i) elevations caused by the application of d-aspartate, a transporter substrate that does not activate non-NMDA ionotropic receptors. TFB-TBOA was found not to influence the membrane properties of cultured cortical neurons recorded in whole-cell patch clamp. Thus, TFB-TBOA, with its high potency and its apparent lack of neuronal effects, appears to be one of the most useful pharmacological tools available so far for studying glial glutamate transporters.

  14. Costimulation of AMPA and metabotropic glutamate receptors underlies phospholipase C activation by glutamate in hippocampus.

    PubMed

    Kim, Hye-Hyun; Lee, Kyu-Hee; Lee, Doyun; Han, Young-Eun; Lee, Suk-Ho; Sohn, Jong-Woo; Ho, Won-Kyung

    2015-04-22

    Glutamate, a major neurotransmitter in the brain, activates ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs, respectively). The two types of glutamate receptors interact with each other, as exemplified by the modulation of iGluRs by mGluRs. However, the other way of interaction (i.e., modulation of mGluRs by iGluRs) has not received much attention. In this study, we found that group I mGluR-specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) alone is not sufficient to activate phospholipase C (PLC) in rat hippocampus, while glutamate robustly activates PLC. These results suggested that additional mechanisms provided by iGluRs are involved in group I mGluR-mediated PLC activation. A series of experiments demonstrated that glutamate-induced PLC activation is mediated by mGluR5 and is facilitated by local Ca(2+) signals that are induced by AMPA-mediated depolarization and L-type Ca(2+) channel activation. Finally, we found that PLC and L-type Ca(2+) channels are involved in hippocampal mGluR-dependent long-term depression (mGluR-LTD) induced by paired-pulse low-frequency stimulation, but not in DHPG-induced chemical LTD. Together, we propose that AMPA receptors initiate Ca(2+) influx via the L-type Ca(2+) channels that facilitate mGluR5-PLC signaling cascades, which underlie mGluR-LTD in rat hippocampus.

  15. At the boundary of the self: the insular cortex in patients with childhood-onset schizophrenia, their healthy siblings, and normal volunteers.

    PubMed

    Moran, Marcel E; Weisinger, Brian; Ludovici, Katharine; McAdams, Harrison; Greenstein, Deanna; Gochman, Pete; Miller, Rachel; Clasen, Liv; Rapoport, Judith; Gogtay, Nitin

    2014-02-01

    The insular cortex (insula), whose normal function involves delineating the boundary between self and non-self stimuli, has been implicated in the pathophysiology of the positive symptoms of schizophrenia, including hallucinations and delusions. Childhood-onset schizophrenia (COS), that includes the onset of psychosis before age 13, is a severe and continuous form of the illness which shows profound and global progressive cortical brain abnormalities during adolescence which merge in the adult pattern with age. Using prospectively acquired anatomic brain magnetic resonance imaging (MRI) scans, a matched sample of COS patients, their nonpsychotic full siblings and healthy volunteers, we measured insular volume using the FreeSurfer automated software. COS patients (n=98; 234 scans) had significantly lower right (p=0.003), left (p<0.001), and total (p<0.001) insular volumes than healthy volunteers (n=100; 248 scans). Right insular volume negatively correlated with positive symptoms as measured by the Scale for the Assessment of Positive Symptoms (SAPS) (p=0.02), while both left (p=0.01) and right (p=0.006) insula volumes were positively correlated with overall functioning, as measured by the Children's Global Assessment Scale (CGAS) scores. COS siblings (n=71; 153 scans), on the other hand, did not differ significantly from normal volunteers suggesting that the insular deficits are more related to the illness state than a familial endophenotype. These results also highlight the salience of the insula in positive symptoms of schizophrenia perhaps resulting from the inability to discriminate between self from the non-self in COS. Further work to connect insular deficits to other neurocircuitries is warranted.

  16. New threshold temperatures for the development of a North American diamondback moth (Lepidoptera: Plutellidae) population and its larval parasitoid, Diadegma insulare (Hymenoptera: Ichneumonidae).

    PubMed

    Bahar, M H; Soroka, J J; Grenkow, L; Dosdall, L M

    2014-10-01

    The currently accepted lower threshold temperature for the development of diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae), the world's most destructive insect pest of cruciferous crops, is around 6.0°C, and there is no known upper threshold temperature. Neither are there established threshold temperatures for diamondback moth's major natural enemy, Diadegma insulare (Hymenoptera: Ichneumonidae). Laboratory studies were undertaken to determine the survival and development of a North American diamondback moth population and its parasitoid D. insulare at 20 constant temperatures ranging from 2.0 to 38.0°C. Diamondback moth completed development from second instar to adult within a temperature range of 4.0-37°C, and D. insulare completed its life cycle from egg to adult within a temperature range of 4.0-33°C. The developmental data were fitted into one linear and four nonlinear models. Using goodness-of-fit and the ability to estimate parameters of biological significance as selection criteria, the Wang model was the most acceptable among the nonlinear models to describe the relationship between temperature and development of both species. According to this model, the lower and upper threshold temperatures for diamondback moth were 2.1 and 38.0°C, respectively, and for D. insulare they were 2.1 and 34.0°C, respectively. Based on the Degree Day model, diamondback moth required 143 d above the lower threshold of 4.23°C to complete the life cycle, while D. insulare required 286 d above the lower threshold of 2.57°C. This study suggests that temperatures during the crop-growing seasons in North America are not limiting factors for development of either diamondback moth or D. insulare.

  17. Therapeutic promise and principles: metabotropic glutamate receptors.

    PubMed

    Maiese, Kenneth; Chong, Zhao Zhong; Shang, Yan Chen; Hou, Jinling

    2008-01-01

    For a number of disease entities, oxidative stress becomes a significant factor in the etiology and progression of cell dysfunction and injury. Therapeutic strategies that can identify novel signal transduction pathways to ameliorate the toxic effects of oxidative stress may lead to new avenues of treatment for a spectrum of disorders that include diabetes, Alzheimer's disease, Parkinson's disease and immune system dysfunction. In this respect, metabotropic glutamate receptors (mGluRs) may offer exciting prospects for several disorders since these receptors can limit or prevent apoptotic cell injury as well as impact upon cellular development and function. Yet the role of mGluRs is complex in nature and may require specific mGluR modulation for a particular disease entity to maximize clinical efficacy and limit potential disability. Here we discuss the potential clinical translation of mGluRs and highlight the role of novel signal transduction pathways in the metabotropic glutamate system that may be vital for the clinical utility of mGluRs.

  18. Localization of neuronal and glial glutamate transporters.

    PubMed

    Rothstein, J D; Martin, L; Levey, A I; Dykes-Hoberg, M; Jin, L; Wu, D; Nash, N; Kuncl, R W

    1994-09-01

    The cellular and subcellular distributions of the glutamate transporter subtypes EAAC1, GLT-1, and GLAST in the rat CNS were demonstrated using anti-peptide antibodies that recognize the C-terminal domains of each transporter. On immunoblots, the antibodies specifically recognize proteins of 65-73 kDa in total brain homogenates. Immunocytochemistry shows that glutamate transporter subtypes are distributed differentially within neurons and astroglia. EAAC1 is specific for certain neurons, such as large pyramidal cortical neurons and Purkinje cells, but does not appear to be selective for glutamatergic neurons. GLT-1 is localized only to astroglia. GLAST is found in both neurons and astroglia. The regional localizations are unique to each transporter subtype. EAAC1 is highly enriched in the cortex, hippocampus, and caudate-putamen and is confined to pre- and postsynaptic elements. GLT-1 is distributed in astrocytes throughout the brain and spinal cord. GLAST is most abundant in Bergmann glia in the cerebellar molecular layer brain, but is also present in the cortex, hippocampus, and deep cerebellar nuclei.

  19. Effect of Bt broccoli and resistant genotype of Plutella xylostella (Lepidoptera: Plutellidae) on development and host acceptance of the parasitoid Diadegma insulare (Hymenoptera: Ichneumonidae).

    PubMed

    Liu, Xiaoxia; Chen, Mao; Onstad, David; Roush, Rick; Shelton, Anthony M

    2011-08-01

    The ecological implications on biological control of insecticidal transgenic plants, which produce crystal (Cry) proteins from the soil bacterium Bacillus thuringiensis (Bt), remain a contentious issue and affect risk assessment decisions. In this study, we used a unique system of resistant insects, Bt plants and a parasitoid to critically evaluate this issue. The effects of broccoli type (normal or expressing Cry1Ac protein) and insect genotype (susceptible or Cry1Ac-resistant) of Plutella xylostella L. (Lepidoptera: Plutellidae) were examined for their effects on the development and host foraging behavior of the parasitoid, Diadegma insulare (Cresson) (Hymenoptera: Ichneumonidae) over two generations. Parasitism rate and development of D. insulare were not significantly different when different genotypes (Bt-resistant or susceptible) of insect host larvae fed on non-Bt broccoli plants. D. insulare could not discriminate between resistant and susceptible genotypes of P. xylostella, nor between Bt and normal broccoli plants with different genotypes of P. xylostella feeding on them. No D. insulare could emerge from Bt broccoli-fed susceptible and heterozygous P. xylostella larvae because these larvae were unable to survive on Bt broccoli. The parasitism rate, developmental period, pupal and adult weights of D. insulare that had developed on Bt broccoli-fed Cry1Ac-resistant P. xylostella larvae were not significantly different from those that developed on non-Bt broccoli-fed larvae. Female D. insulare emerged from Cry1Ac-resistant P. xylostella that fed on Bt plants could successfully parasitize P. xylostella larvae. The life parameters of the subsequent generation of D. insulare from P. xylostella reared on Bt broccoli were not significantly different from those from non-Bt broccoli. The Cry1Ac protein was detected in P. xylostella and in D. insulare when hosts fed on Bt broccoli. These results are the first to indicate that Cry1Ac did not harm the development or

  20. EFFECT OF INTERFERON-α ON CORTICAL GLUTAMATE IN PATIENTS WITH HEPATITIS C: A PROTON MRS STUDY

    PubMed Central

    Taylor, Matthew J; Godlewska, Beata; Near, Jamie; Christmas, David; Potokar, John; Collier, Jane; Klenerman, Paul; Barnes, Eleanor; Cowen, Philip J

    2013-01-01

    Background The development of depressive symptomatology is a recognised complication of treatment with the cytokine, interferon-α, and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of interferon-induced depression have implicated neurotoxic influences which could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure both glutamate and its major metabolite, glutamine in patients with hepatitis C who received treatment with pegylated-interferon-α and ribavirin. Methods MRS measurements of glutamate and glutamine were taken from a 25×20×20mm voxel including pregenual anterior cingulate cortex in 12 patients before and after 4-6 weeks treatment with interferon. Results Interferon treatment led to an increase in cortical levels of glutamine (p= 0.02) and a significant elevation in the ratio of glutamine to glutamate (p<.01). Further, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan. Conclusions We conclude that treatment with interferon-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression which suggests that the pathophysiology of interferon-induced depression may be distinct from that of major depression more generally. PMID:23659574

  1. Abnormal Expression of Glutamate Transporter and Transporter Interacting Molecules in Prefrontal Cortex in Elderly Patients with Schizophrenia

    PubMed Central

    Bauer, Deborah; Gupta, Daya; Harotunian, Vahram; Meador-Woodruff, James H.; McCullumsmith, Robert E.

    2008-01-01

    Glutamate cycling is critically important for neurotransmission, and may be altered in schizophrenia. The excitatory amino acid transporters (EAATs) facilitate the reuptake of glutamate from the synaptic cleft and have a key role in glutamate cycling. We hypothesized that expression of the EAATs and the EAAT regulating proteins ARHGEF11, JWA, G protein suppressor pathway 1 (GPS1), and KIAA0302 are altered in the brain in schizophrenia. To test this, we measured expression of EAAT1, EAAT2, EAAT3, and EAAT interacting proteins in postmortem tissue from the dorsolateral prefrontal and anterior cingulate cortex of patients with schizophrenia and a comparison group using in situ hybridization and Western blot analysis. We found increased EAAT1 transcripts and decreased protein expression, increased EAAT3 transcripts and protein, and elevated protein expression of both GPS1 and KIAA0302 protein. We did not find any changes in expression of EAAT2. These data indicate that proteins involved in glutamate reuptake and cycling are altered in the cortex in schizophrenia, and may provide potential targets for future treatment strategies. PMID:18678470

  2. Effect of biotin on transcription levels of key enzymes and glutamate efflux in glutamate fermentation by Corynebacterium glutamicum.

    PubMed

    Cao, Yan; Duan, Zuoying; Shi, Zhongping

    2014-02-01

    Biotin is an important factor affecting the performance of glutamate fermentation by biotin auxotrophic Corynebacterium glutamicum and glutamate is over-produced only when initial biotin content is controlled at suitable levels or initial biotin is excessive but with Tween 40 addition during fermentation. The transcription levels of key enzymes at pyruvate, isocitrate and α-ketoglutarate metabolic nodes, as well as transport protein (TP) of glutamate were investigated under the conditions of varied biotin contents and Tween 40 supplementation. When biotin was insufficient, the genes encoding key enzymes and TP were down-regulated in the early production phase, in particular, the transcription level of isocitrate dehydrogenase (ICDH) which was only 2% of that of control. Although the cells' morphology transformation and TP level were not affected, low transcription level of ICDH led to lower final glutamate concentration (64 g/L). When biotin was excessive, the transcription levels of key enzymes were at comparable levels as those of control with ICDH as an exception, which was only 3-22% of control level throughout production phase. In this case, little intracellular glutamate accumulation (1.5 mg/g DCW) and impermeable membrane resulted in non glutamate secretion into broth, even though the quantity of TP was more than 10-folds of control level. Addition of Tween 40 when biotin was excessive stimulated the expression of all key enzymes and TP, intracellular glutamate content was much higher (10-12 mg/g DCW), and final glutamate concentration reached control level (75-80 g/L). Hence, the membrane alteration and TP were indispensable in glutamate secretion. Biotin and Tween 40 influenced the expression level of ICDH and glutamate efflux, thereby influencing glutamate production.

  3. 78 FR 76321 - Monosodium Glutamate From China and Indonesia

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-17

    ... COMMISSION Monosodium Glutamate From China and Indonesia Determinations On the basis of the record \\1... injured by reason of imports from China and Indonesia of monosodium glutamate, provided for in subheading... United States at less than fair value (LTFV) and subsidized by the Governments of China and Indonesia....

  4. Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease

    PubMed Central

    Mattson, Mark P.

    2008-01-01

    Glutamate’s role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis and neuron survival in the developing and adult mammalian nervous system. Cell surface glutamate receptors are coupled to Ca2+ influx and release from endoplasmic reticulum stores which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF) which, in turn, modifies neuronal glutamate sensitivity, Ca2+ homeostasis and plasticity. Neurotrophic factors may modify glutamate signalling directly, by changing the expression of glutamate receptor subunits and Ca2+-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins and anti-apoptotic Bcl2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer’s disease to psychiatric disorders. By enhancing neurotrophic factor signalling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signalling and protect against neurological disorders. PMID:19076369

  5. 21 CFR 522.1125 - Hemoglobin glutamer-200 (bovine).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Hemoglobin glutamer-200 (bovine). 522.1125 Section... § 522.1125 Hemoglobin glutamer-200 (bovine). (a) Specifications. Each 125 milliliter bag contains 13 grams per deciliter of polymerized hemoglobin of bovine origin in modified Lactated Ringer's...

  6. 21 CFR 522.1125 - Hemoglobin glutamer-200 (bovine).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Hemoglobin glutamer-200 (bovine). 522.1125 Section... § 522.1125 Hemoglobin glutamer-200 (bovine). (a) Specifications. Each 125 milliliter bag contains 13 grams per deciliter of polymerized hemoglobin of bovine origin in modified Lactated Ringer's...

  7. 21 CFR 522.1125 - Hemoglobin glutamer-200 (bovine).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Hemoglobin glutamer-200 (bovine). 522.1125 Section... § 522.1125 Hemoglobin glutamer-200 (bovine). (a) Specifications. Each 125 milliliter bag contains 13 grams per deciliter of polymerized hemoglobin of bovine origin in modified Lactated Ringer's...

  8. 21 CFR 522.1125 - Hemoglobin glutamer-200 (bovine).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Hemoglobin glutamer-200 (bovine). 522.1125 Section... § 522.1125 Hemoglobin glutamer-200 (bovine). (a) Specifications. Each 125 milliliter bag contains 13 grams per deciliter of polymerized hemoglobin of bovine origin in modified Lactated Ringer's...

  9. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  10. Aerosol optical, microphysical and radiative properties at regional background insular sites in the western Mediterranean

    NASA Astrophysics Data System (ADS)

    Sicard, Michaël; Barragan, Rubén; Dulac, François; Alados-Arboledas, Lucas; Mallet, Marc

    2016-09-01

    In the framework of the ChArMEx (the Chemistry-Aerosol Mediterranean Experiment; http://charmex.lsce.ipsl.fr/) program, the seasonal variability of the aerosol optical, microphysical and radiative properties derived from AERONET (Aerosol Robotic Network; http://aeronet.gsfc.nasa.gov/) is examined in two regional background insular sites in the western Mediterranean Basin: Ersa (Corsica Island, France) and Palma de Mallorca (Mallorca Island, Spain). A third site, Alborán (Alborán Island, Spain), with only a few months of data is considered for examining possible northeast-southwest (NE-SW) gradients of the aforementioned aerosol properties. The AERONET dataset is exclusively composed of level 2.0 inversion products available during the 5-year period 2011-2015. AERONET solar radiative fluxes are compared with ground- and satellite-based flux measurements. To the best of our knowledge this is the first time that AERONET fluxes are compared with measurements at the top of the atmosphere. Strong events (with an aerosol optical depth at 440 nm greater than 0.4) of long-range transport aerosols, one of the main drivers of the observed annual cycles and NE-SW gradients, are (1) mineral dust outbreaks predominant in spring and summer in the north and in summer in the south and (2) European pollution episodes predominant in autumn. A NE-SW gradient exists in the western Mediterranean Basin for the aerosol optical depth and especially its coarse-mode fraction, which all together produces a similar gradient for the aerosol direct radiative forcing. The aerosol fine mode is rather homogeneously distributed. Absorption properties are quite variable because of the many and different sources of anthropogenic particles in and around the western Mediterranean Basin: North African and European urban areas, the Iberian and Italian peninsulas, most forest fires and

  11. Combined adverse effects of cascading events on systems' functionality: an insular case study, French West Indies

    NASA Astrophysics Data System (ADS)

    Desramaut, Nicolas; Wang, Justin; Gehl, Pierre; Marti, Jose; Baills, Audrey; Reveillere, Arnaud

    2013-04-01

    In our modern societies, lifelines play a vital role, even in normal conditions. Therefore, during crises, the dependency to critical infrastructures is likely to be exacerbated. Indeed, in order to provide quick emergency services to the population, systems have to be functional. However, even if not directly damaged, in order to be functional, elements of the different systems have to receive enough resources but also to be able to supply their own services. In a multi-risk approach, this necessity to take into account systemic vulnerability to assess the real impact of natural hazards on society is even made more obvious. For example, impacts of one hazard, taken separately, might not significantly affect societies, but might reduce redundancy, and therefore could increase functional vulnerability to other hazards. The present study aims at analyzing the effects of cascading events on the behaviour of interdependent systems and on the capacities of the health care system to treat the victims. In order to work on a close system, an insular context (Guadeloupe, French West Indies) has been selected. The hazard cascading scenario consists of a M6.3 earthquake striking Basse-Terre, and triggering landslides in the mountainous areas where antecedent precipitations have made the area prone to slide. Damages due to earthquakes have been estimated for the 5 considered systems (buildings, healthcare system, electrical network, water supply network and transportation). Due to their localization in mountainous areas, landslides would affect only transportation networks, with closure of roads. The inter- and intra-dependencies of systems have been modeled thanks to the I2Sim platform developed at UBC. The functionality of each element is therefore the consequence of the physical (direct damage) but also functional (indirect) damage. Analyses are performed for different strategies of resources allocations, and one of the final results is the impact of the induced landslides

  12. Rapid and repeated origin of insular gigantism and dwarfism in Australian tiger snakes.

    PubMed

    Keogh, J Scott; Scott, Ian A W; Hayes, Christine

    2005-01-01

    It is a well-known phenomenon that islands can support populations of gigantic or dwarf forms of mainland conspecifics, but the variety of explanatory hypotheses for this phenomenon have been difficult to disentangle. The highly venomous Australian tiger snakes (genus Notechis) represent a well-known and extreme example of insular body size variation. They are of special interest because there are multiple populations of dwarfs and giants and the age of the islands and thus the age of the tiger snake populations are known from detailed sea level studies. Most are 5000-7000 years old and all are less than 10,000 years old. Here we discriminate between two competing hypotheses with a molecular phylogeography dataset comprising approximately 4800 bp of mtDNA and demonstrate that populations of island dwarfs and giants have evolved five times independently. In each case the closest relatives of the giant or dwarf populations are mainland tiger snakes, and in four of the five cases, the closest relatives are also the most geographically proximate mainland tiger snakes. Moreover, these body size shifts have evolved extremely rapidly and this is reflected in the genetic divergence between island body size variants and mainland snakes. Within south eastern Australia, where populations of island giants, populations of island dwarfs, and mainland tiger snakes all occur, the maximum genetic divergence is only 0.38%. Dwarf tiger snakes are restricted to prey items that are much smaller than the prey items of mainland tiger snakes and giant tiger snakes are restricted to seasonally available prey items that are up three times larger than the prey items of mainland tiger snakes. We support the hypotheses that these body size shifts are due to strong selection imposed by the size of available prey items, rather than shared evolutionary history, and our results are consistent with the notion that adaptive plasticity also has played an important role in body size shifts. We suggest

  13. Exchange transamination and the metabolism of glutamate in brain

    PubMed Central

    Balázs, R.; Haslam, R. J.

    1965-01-01

    1. Experiments were performed to throw light on why the incorporation of 14C from labelled carbohydrate precursors into glutamate has been found to be more marked in brain than in other tissues. 2. Rapid isotope exchange between labelled glutamate and unlabelled α-oxoglutarate was demonstrated in brain and liver mitochondrial preparations. In the presence but not in the absence of α-oxoglutarate the yield of 14CO2 from [1-14C]glutamate exceeded the net glutamate removal, and the final relative specific activities of the two substrates indicated that complete isotopic equilibration had occurred. Also, when in a brain preparation net glutamate removal was inhibited by malonate, isotope exchange between [1-14C]glutamate and α-oxoglutarate and the formation of 14CO2 were unaffected. 3. The time-course of isotope exchange between labelled glutamate and unlabelled α-oxoglutarate was followed in uncoupled brain and liver mitochondrial fractions, and the rate of exchange calculated by a computer was found to be 3–8 times more rapid than the maximal rate of utilization of the two substrates. 4. The physiological situation was imitated by the continuous infusion of small amounts of α-oxo[1-14C]glutarate into brain homogenate containing added glutamate. The fraction of 14C infused that was retained in the glutamate pool depended on the size of the latter, and the final relative specific activities of the two substrates indicated almost complete isotope exchange. Isotopic equilibration also occurred when α-oxoglutarate was generated from pyruvate through the tricarboxylic acid cycle in a brain mitochondrial preparation containing [1-14C]glutamate. 5. The differences in the incorporation of 14C from labelled glucose into the glutamate of brain and liver are discussed in terms of the rates of isotope exchange, the glutamate pool sizes and the rates of formation of labelled α-oxoglutarate in the two tissues. It is concluded that the differences between tissues in the

  14. EXCHANGE TRANSAMINATION AND THE METABOLISM OF GLUTAMATE IN BRAIN.

    PubMed

    BALAZS, R; HASLAM, J

    1965-01-01

    1. Experiments were performed to throw light on why the incorporation of (14)C from labelled carbohydrate precursors into glutamate has been found to be more marked in brain than in other tissues. 2. Rapid isotope exchange between labelled glutamate and unlabelled alpha-oxoglutarate was demonstrated in brain and liver mitochondrial preparations. In the presence but not in the absence of alpha-oxoglutarate the yield of (14)CO(2) from [1-(14)C]glutamate exceeded the net glutamate removal, and the final relative specific activities of the two substrates indicated that complete isotopic equilibration had occurred. Also, when in a brain preparation net glutamate removal was inhibited by malonate, isotope exchange between [1-(14)C]glutamate and alpha-oxoglutarate and the formation of (14)CO(2) were unaffected. 3. The time-course of isotope exchange between labelled glutamate and unlabelled alpha-oxoglutarate was followed in uncoupled brain and liver mitochondrial fractions, and the rate of exchange calculated by a computer was found to be 3-8 times more rapid than the maximal rate of utilization of the two substrates. 4. The physiological situation was imitated by the continuous infusion of small amounts of alpha-oxo[1-(14)C]glutarate into brain homogenate containing added glutamate. The fraction of (14)C infused that was retained in the glutamate pool depended on the size of the latter, and the final relative specific activities of the two substrates indicated almost complete isotope exchange. Isotopic equilibration also occurred when alpha-oxoglutarate was generated from pyruvate through the tricarboxylic acid cycle in a brain mitochondrial preparation containing [1-(14)C]glutamate. 5. The differences in the incorporation of (14)C from labelled glucose into the glutamate of brain and liver are discussed in terms of the rates of isotope exchange, the glutamate pool sizes and the rates of formation of labelled alpha-oxoglutarate in the two tissues. It is concluded that

  15. The effect of lesions of the insular cortex on instrumental conditioning: evidence for a role in incentive memory.

    PubMed

    Balleine, B W; Dickinson, A

    2000-12-01

    In three experiments, we assessed the effect of lesions aimed at the gustatory region of the insular cortex on instrumental conditioning in rats. In experiment 1, the lesion had no effect on the acquisition of either lever pressing or chain pulling in food-deprived rats whether these actions earned food pellets or a maltodextrin solution. The lesion did, however, attenuate the impact of outcome devaluation, induced by sensory-specific satiety, on instrumental performance but only when assessed in an extinction test. This effect was not secondary to an impairment in instrumental learning; in experiment 2, no evidence was found to suggest that the lesioned rats differed from shams in their ability to encode the specific action-outcome contingencies to which they were exposed during training. In experiment 3, however, lesioned rats were found to be insensitive to the impact of an incentive learning treatment conducted when they were undeprived; although, again, this deficit was confined to a test conducted in extinction. These results are consistent with the view that, in instrumental conditioning, the gustatory region of the insular cortex is involved in encoding the taste of food outcomes in memory and, hence, in encoding the incentive value assigned to these outcomes on the basis of prevailing motivational conditions.

  16. Intersectional gene flow between insular endemics of Ilex (Aquifoliaceae) on the Bonin Islands and the Ryukyu Islands.

    PubMed

    Setoguchi, H; Watanabe, I

    2000-06-01

    Hybridization and introgression play important roles in plant evolution, and their occurrence on the oceanic islands provides good examples of plant speciation and diversification. Restriction fragment length polymorphisms (RFLPs) and trnL (UAA) 3'exon-trnF (GAA) intergenic spacer (IGS) sequences of chloroplast DNA (cpDNA), and the sequences of internal transcribed spacer (ITS) of nuclear ribosomal DNA were examined to investigate the occurrence of gene transfer in Ilex species on the Bonin Islands and the Ryukyu Islands in Japan. A gene phylogeny for the plastid genome is in agreement with the morphologically based taxonomy, whereas the nuclear genome phylogeny clusters putatively unrelated endemics both on the Bonin and the Ryukyu Islands. Intersectional hybridization and nuclear gene flow were independently observed in insular endemics of Ilex on both sets of islands without evidence of plastid introgression. Gene flow observed in these island systems can be explained by ecological features of insular endemics, i.e., limits of distribution range or sympatric distribution in a small land area.

  17. Nowhere safe? Exploring the influence of urbanization across mainland and insular seashores in continental Portugal and the Azorean Archipelago.

    PubMed

    Bertocci, Iacopo; Arenas, Francisco; Cacabelos, Eva; Martins, Gustavo M; Seabra, Maria I; Álvaro, Nuno V; Fernandes, Joana N; Gaião, Raquel; Mamede, Nuno; Mulas, Martina; Neto, Ana I

    2017-01-30

    Differences in the structure and functioning of intensively urbanized vs. less human-affected systems are reported, but such evidence is available for a much larger extent in terrestrial than in marine systems. We examined the hypotheses that (i) urbanization was associated to different patterns of variation of intertidal assemblages between urban and extra-urban environments; (ii) such patterns were consistent across mainland and insular systems, spatial scales from 10scm to 100skm, and a three months period. Several trends emerged: (i) a more homogeneous distribution of most algal groups in the urban compared to the extra-urban condition and the opposite pattern of most invertebrates; (ii) smaller/larger variances of most organisms where these were, respectively, less/more abundant; (iii) largest variability of most response variables at small scale; (iv) no facilitation of invasive species by urbanization and larger cover of canopy-forming algae in the insular extra-urban condition. Present findings confirm the acknowledged notion that future management strategies will require to include representative assemblages and their relevant scales of variation associated to urbanization gradients on both the mainland and the islands.

  18. Impulsivity is Associated with Increased Metabolism in the Fronto-Insular Network in Parkinson’s Disease

    PubMed Central

    Tahmasian, Masoud; Rochhausen, Luisa; Maier, Franziska; Williamson, Kim L.; Drzezga, Alexander; Timmermann, Lars; Van Eimeren, Thilo; Eggers, Carsten

    2015-01-01

    Various neuroimaging studies demonstrated that the fronto-insular network is implicated in impulsive behavior. We compared glucose metabolism (as a proxy measure of neural activity) among 24 patients with Parkinson’s disease (PD) who presented with low or high levels of impulsivity based on the Barratt Impulsiveness Scale 11 (BIS) scores. Subjects underwent 18-fluorodeoxyglucose positron emission tomography (FDG-PET) and the voxel-wise group difference of FDG-metabolism was analyzed in Statistical Parametric Mapping (SPM8). Subsequently, we performed a partial correlation analysis between the FDG-metabolism and BIS scores, controlling for covariates (i.e., age, sex, severity of disease and levodopa equivalent daily doses). Voxel-wise group comparison revealed higher FDG-metabolism in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and right insula in patients with higher impulsivity scores. Moreover, there was a positive correlation between the FDG-metabolism and BIS scores. Our findings provide evidence that high impulsivity is associated with increased FDG-metabolism within the fronto-insular network in PD. PMID:26648853

  19. Functional reconstitution of Drosophila melanogaster NMJ glutamate receptors

    DOE PAGES

    Han, Tae Hee; Dharkar, Poorva; Mayer, Mark L.; ...

    2015-04-27

    The Drosophila larval neuromuscular junction (NMJ), at which glutamate acts as the excitatory neurotransmitter, is a widely used model for genetic analysis of synapse function and development. Despite decades of study, the inability to reconstitute NMJ glutamate receptor function using heterologous expression systems has complicated the analysis of receptor function, such that it is difficult to resolve the molecular basis for compound phenotypes observed in mutant flies. In this paper, we find that Drosophila Neto functions as an essential component required for the function of NMJ glutamate receptors, permitting analysis of glutamate receptor responses in Xenopus oocytes. Finally, in combinationmore » with a crystallographic analysis of the GluRIIB ligand binding domain, we use this system to characterize the subunit dependence of assembly, channel block, and ligand selectivity for Drosophila NMJ glutamate receptors.« less

  20. Cortical neurons exposed to glutamate rapidly leak preloaded chromium 51

    SciTech Connect

    Maulucci-Gedde, M.; Choi, D.W.

    1987-05-01

    The acute toxic effects of excess glutamate exposure on cortical neurons in culture was followed using a novel adaptation of the /sup 51/Cr efflux assay. Although the acute, sodium-dependent phase of glutamate neurotoxicity may contribute to several acute disease settings, including sustained seizures and stroke, functional aspects of the phenomenon have not been previously studied. We report here that the earliest morphologic sign of glutamate neurotoxicity, neuronal swelling, is accompanied by a large efflux of complexed /sup 51/Cr from preloaded neurons in the first hour after exposure, and that this efflux is detectable as early as 15 min after the onset of glutamate exposure. We suggest that this pathological burst of /sup 51/Cr may result from glutamate-induced leakiness of neuronal cell membranes.

  1. The National Map - Elevation

    USGS Publications Warehouse

    Gesch, Dean; Evans, Gayla; Mauck, James; Hutchinson, John; Carswell, William J.

    2009-01-01

    The National Elevation Dataset (NED) is the primary elevation data product produced and distributed by the USGS. The NED provides seamless raster elevation data of the conterminous United States, Alaska, Hawaii, and the island territories. The NED is derived from diverse source data sets that are processed to a specification with a consistent resolution, coordinate system, elevation units, and horizontal and vertical datums. The NED is the logical result of the maturation of the long-standing USGS elevation program, which for many years concentrated on production of topographic map quadrangle-based digital elevation models. The NED serves as the elevation layer of The National Map, and provides basic elevation information for earth science studies and mapping applications in the United States. The NED is a multi-resolution dataset that is updated bimonthly to integrate newly available, improved elevation source data. NED data are available nationally at grid spacings of 1 arc-second (approximately 30 meters) for the conterminous United States, and at 1/3 and 1/9 arc-seconds (approximately 10 and 3 meters, respectively) for parts of the United States. Most of the NED for Alaska is available at 2-arc-second (about 60 meters) grid spacing, where only lower resolution source data exist. Part of Alaska is available at the 1/3-arc-second resolution, and plans are in development for a significant upgrade in elevation data coverage of the State over the next 5 years. Specifications for the NED include the following: *Coordinate system: Geographic (decimal degrees of latitude and longitude), *Horizontal datum: North American Datum of 1983 (NAD 83), *Vertical datum: North American Vertical Datum of 1988 (NAVD 88) over the conterminous United States and varies in other areas, and *Elevation units: Decimal meters.

  2. Morphine Induces Ubiquitin-Proteasome Activity and Glutamate Transporter Degradation*

    PubMed Central

    Yang, Liling; Wang, Shuxing; Sung, Backil; Lim, Grewo; Mao, Jianren

    2008-01-01

    Glutamate transporters play a crucial role in physiological glutamate homeostasis, neurotoxicity, and glutamatergic regulation of opioid tolerance. However, how the glutamate transporter turnover is regulated remains poorly understood. Here we show that chronic morphine exposure induced posttranscriptional down-regulation of the glutamate transporter EAAC1 in C6 glioma cells with a concurrent decrease in glutamate uptake and increase in proteasome activity, which were blocked by the selective proteasome inhibitor MG-132 or lactacystin but not the lysosomal inhibitor chloroquin. At the cellular level, chronic morphine induced the PTEN (phosphatase and tensin homolog deleted on chromosome Ten)-mediated up-regulation of the ubiquitin E3 ligase Nedd4 via cAMP/protein kinase A signaling, leading to EAAC1 ubiquitination and proteasomal degradation. Either Nedd4 or PTEN knockdown with small interfering RNA prevented the morphine-induced EAAC1 degradation and decreased glutamate uptake. These data indicate that cAMP/protein kinase A signaling serves as an intracellular regulator upstream to the activation of the PTEN/Nedd4-mediated ubiquitin-proteasome system activity that is critical for glutamate transporter turnover. Under an in vivo condition, chronic morphine exposure also induced posttranscriptional down-regulation of the glutamate transporter EAAC1, which was prevented by MG-132, and transcriptional up-regulation of PTEN and Nedd4 within the spinal cord dorsal horn. Thus, inhibition of the ubiquitin-proteasome-mediated glutamate transporter degradation may be an important mechanism for preventing glutamate overexcitation and may offer a new strategy for treating certain neurological disorders and improving opioid therapy in chronic pain management. PMID:18539596

  3. Expression of glutamate receptor subunits in human cancers.

    PubMed

    Stepulak, Andrzej; Luksch, Hella; Gebhardt, Christine; Uckermann, Ortrud; Marzahn, Jenny; Sifringer, Marco; Rzeski, Wojciech; Staufner, Christian; Brocke, Katja S; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2009-10-01

    Emerging evidence suggests a role for glutamate and its receptors in the biology of cancer. This study was designed to systematically analyze the expression of ionotropic and metabotropic glutamate receptor subunits in various human cancer cell lines, compare expression levels to those in human brain tissue and, using electrophysiological techniques, explore whether cancer cells respond to glutamate receptor agonists and antagonists. Expression analysis of glutamate receptor subunits NR1-NR3B, GluR1-GluR7, KA1, KA2 and mGluR1-mGluR8 was performed by means of RT-PCR in human rhabdomyosarcoma/medulloblastoma (TE671), neuroblastoma (SK-NA-S), thyroid carcinoma (FTC 238), lung carcinoma (SK-LU-1), astrocytoma (MOGGCCM), multiple myeloma (RPMI 8226), glioma (U87-MG and U343), lung carcinoma (A549), colon adenocarcinoma (HT 29), T cell leukemia cells (Jurkat E6.1), breast carcinoma (T47D) and colon adenocarcinoma (LS180). Analysis revealed that all glutamate receptor subunits were differentially expressed in the tumor cell lines. For the majority of tumors, expression levels of NR2B, GluR4, GluR6 and KA2 were lower compared to human brain tissue. Confocal imaging revealed that selected glutamate receptor subunit proteins were expressed in tumor cells. By means of patch-clamp analysis, it was shown that A549 and TE671 cells depolarized in response to application of glutamate agonists and that this effect was reversed by glutamate receptor antagonists. This study reveals that glutamate receptor subunits are differentially expressed in human tumor cell lines at the mRNA and the protein level, and that their expression is associated with the formation of functional channels. The potential role of glutamate receptor antagonists in cancer therapy is a feasible goal to be explored in clinical trials.

  4. House: Southeast/Front Elevation, Northeast/Side Elevation, Northwest/Rear Elevation, Southwest/Side Elevation, House ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    House: Southeast/Front Elevation, Northeast/Side Elevation, Northwest/Rear Elevation, Southwest/Side Elevation, House Plan - Driapsa Centennial Farm, Potts Hill European Community, 4511 Potts Hill Road, Bainbridge, Ross County, OH

  5. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment

    PubMed Central

    Rojas, Donald C.

    2014-01-01

    Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder. PMID:24752754

  6. Glutamate-induced glutamate release: A proposed mechanism for calcium bursting in astrocytes

    NASA Astrophysics Data System (ADS)

    Larter, Raima; Craig, Melissa Glendening

    2005-12-01

    Here we present a new model for the generation of complex calcium-bursting patterns in astrocytes, a type of brain cell recently implicated in a variety of neural functions including memory formation. The model involves two positive feedback processes, in which the key feedback species are calcium ion and glutamate. The latter is the most abundant excitatory neurotransmitter in the brain and has been shown to be involved in bidirectional communication between astrocytes and nearby neurons. The glutamate feedback process considered here is shown to be critical for the generation of complex bursting oscillations in the astrocytes and to, perhaps, code for information which may be passed from neuron to neuron via the astrocyte. These processes may be involved in memory storage and formation as well as in mechanisms which lead to dynamical diseases such as epilepsy.

  7. Mars elevation distribution

    NASA Technical Reports Server (NTRS)

    Wu, Sherman S. C.; Howington-Kraus, Annie E.; Ablin, Karyn K.

    1991-01-01

    A Digital Terrain Model (DTM) of Mars was derived with both Mercator and Sinusoidal Equal-Area projections from the global topographic map of Mars (scale 1:15 million, contour interval 1 km). Elevations on the map are referred to Mars' topographic datum that is defined by the gravity field at a 6.1-millibar pressure surface with respect to the center of mass of Mars. The DTM has a resolution at the equator of 1/59.226 degrees (exactly 1 km) per pixel. By using the DTM, the volumetric distribution of Mars topography above and below the datum has previously been calculated. Three types of elevation distributions of Mars' topography were calculated from the same DTM: (1) the frequency distribution of elevations at the pixel resolution; (2) average elevations in increments of 6 degrees in both longitude and latitude; and (3) average elevations in 36 separate blocks, each covering 30 degrees of latitude and 60 degrees of longitude.

  8. Translating Glutamate: From Pathophysiology to Treatment

    PubMed Central

    Javitt, Daniel C.; Schoepp, Darryle; Kalivas, Peter W.; Volkow, Nora D.; Zarate, Carlos; Merchant, Kalpana; Bear, Mark F.; Umbricht, Daniel; Hajos, Mihaly; Potter, William Z.; Lee, Chi-Ming

    2012-01-01

    The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders—including schizophrenia, drug abuse and addiction, autism, and depression—that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration–approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine–sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development. PMID:21957170

  9. Group II metabotropic glutamate receptors and schizophrenia.

    PubMed

    Moreno, José L; Sealfon, Stuart C; González-Maeso, Javier

    2009-12-01

    Schizophrenia is one of the most common mental illnesses, with hereditary and environmental factors important for its etiology. All antipsychotics have in common a high affinity for monoaminergic receptors. Whereas hallucinations and delusions usually respond to typical (haloperidol-like) and atypical (clozapine-like) monoaminergic antipsychotics, their efficacy in improving negative symptoms and cognitive deficits remains inadequate. In addition, devastating side effects are a common characteristic of monoaminergic antipsychotics. Recent biochemical, preclinical and clinical findings support group II metabotropic glutamate receptors (mGluR2 and mGluR3) as a new approach to treat schizophrenia. This paper reviews the status of general knowledge of mGluR2 and mGluR3 in the psychopharmacology, genetics and neuropathology of schizophrenia.

  10. Glutamate and GABA in Appetite Regulation

    PubMed Central

    Delgado, Teresa C.

    2013-01-01

    Appetite is regulated by a coordinated interplay between gut, adipose tissue, and brain. A primary site for the regulation of appetite is the hypothalamus where interaction between orexigenic neurons, expressing Neuropeptide Y/Agouti-related protein, and anorexigenic neurons, expressing Pro-opiomelanocortin cocaine/Amphetamine-related transcript, controls energy homeostasis. Within the hypothalamus, several peripheral signals have been shown to modulate the activity of these neurons, including the orexigenic peptide ghrelin and the anorexigenic hormones insulin and leptin. In addition to the accumulated knowledge on neuropeptide signaling, presence and function of amino acid neurotransmitters in key hypothalamic neurons brought a new light into appetite regulation. Therefore, the principal aim of this review will be to describe the current knowledge of the role of amino acid neurotransmitters in the mechanism of neuronal activation during appetite regulation and the associated neuronal-astrocytic metabolic coupling mechanisms. Glutamate and GABA dominate synaptic transmission in the hypothalamus and administration of their receptors agonists into hypothalamic nuclei stimulates feeding. By using 13C High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance spectroscopy based analysis, the Cerdán group has shown that increased neuronal firing in mice hypothalamus, as triggered by appetite during the feeding-fasting paradigm, may stimulate the use of lactate as neuronal fuel leading to increased astrocytic glucose consumption and glycolysis. Moreover, fasted mice showed increased hypothalamic [2-13C]GABA content, which may be explained by the existence of GABAergic neurons in key appetite regulation hypothalamic nuclei. Interestingly, increased [2-13C]GABA concentration in the hypothalamus of fasted animals appears to result mainly from reduction in GABA metabolizing pathways, rather than increased GABA synthesis by augmented activity of the glutamate

  11. Glutamate and GABA in Appetite Regulation.

    PubMed

    Delgado, Teresa C

    2013-01-01

    Appetite is regulated by a coordinated interplay between gut, adipose tissue, and brain. A primary site for the regulation of appetite is the hypothalamus where interaction between orexigenic neurons, expressing Neuropeptide Y/Agouti-related protein, and anorexigenic neurons, expressing Pro-opiomelanocortin cocaine/Amphetamine-related transcript, controls energy homeostasis. Within the hypothalamus, several peripheral signals have been shown to modulate the activity of these neurons, including the orexigenic peptide ghrelin and the anorexigenic hormones insulin and leptin. In addition to the accumulated knowledge on neuropeptide signaling, presence and function of amino acid neurotransmitters in key hypothalamic neurons brought a new light into appetite regulation. Therefore, the principal aim of this review will be to describe the current knowledge of the role of amino acid neurotransmitters in the mechanism of neuronal activation during appetite regulation and the associated neuronal-astrocytic metabolic coupling mechanisms. Glutamate and GABA dominate synaptic transmission in the hypothalamus and administration of their receptors agonists into hypothalamic nuclei stimulates feeding. By using (13)C High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance spectroscopy based analysis, the Cerdán group has shown that increased neuronal firing in mice hypothalamus, as triggered by appetite during the feeding-fasting paradigm, may stimulate the use of lactate as neuronal fuel leading to increased astrocytic glucose consumption and glycolysis. Moreover, fasted mice showed increased hypothalamic [2-(13)C]GABA content, which may be explained by the existence of GABAergic neurons in key appetite regulation hypothalamic nuclei. Interestingly, increased [2-(13)C]GABA concentration in the hypothalamus of fasted animals appears to result mainly from reduction in GABA metabolizing pathways, rather than increased GABA synthesis by augmented activity of the glutamate

  12. Allosteric Modulation of Metabotropic Glutamate Receptors

    PubMed Central

    Sheffler, Douglas J.; Gregory, Karen J.; Rook, Jerri M.; Conn, P. Jeffrey

    2013-01-01

    The development of receptor subtype-selective ligands by targeting allosteric sites of G protein-coupled receptors (GPCRs) has proven highly successful in recent years. One GPCR family that has greatly benefited from this approach is the metabotropic glutamate receptors (mGlus). These family C GPCRs participate in the neuromodulatory actions of glutamate throughout the CNS, where they play a number of key roles in regulating synaptic transmission and neuronal excitability. A large number of mGlu subtype-selective allosteric modulators have been identified, the majority of which are thought to bind within the transmembrane regions of the receptor. These modulators can either enhance or inhibit mGlu functional responses and, together with mGlu knockout mice, have furthered the establishment of the physiologic roles of many mGlu subtypes. Numerous pharmacological and receptor mutagenesis studies have been aimed at providing a greater mechanistic understanding of the interaction of mGlu allosteric modulators with the receptor, which have revealed evidence for common allosteric binding sites across multiple mGlu subtypes and the presence for multiple allosteric sites within a single mGlu subtype. Recent data have also revealed that mGlu allosteric modulators can display functional selectivity toward particular signal transduction cascades downstream of an individual mGlu subtype. Studies continue to validate the therapeutic utility of mGlu allosteric modulators as a potential therapeutic approach for a number of disorders including anxiety, schizophrenia, Parkinson’s disease, and Fragile X syndrome. PMID:21907906

  13. Enhancement of Inhibitory Avoidance and Conditioned Taste Aversion Memory with Insular Cortex Infusions of 8-Br-cAMP: Involvement of the Basolateral Amygdala

    ERIC Educational Resources Information Center

    Miranda, Maria I.; McGaugh, James L.

    2004-01-01

    There is considerable evidence that in rats, the insular cortex (IC) and amygdala are involved in the learning and memory of aversively motivated tasks. The present experiments examined the effects of 8-Br-cAMP, an analog of cAMP, and oxotremorine, a muscarinic agonist, infused into the IC after inhibitory avoidance (IA) training and during the…

  14. Anxious personality and functional efficiency of the insular-opercular network: A graph-analytic approach to resting-state fMRI.

    PubMed

    Markett, Sebastian; Montag, Christian; Melchers, Martin; Weber, Bernd; Reuter, Martin

    2016-12-01

    The brain is an intricate network, not only structurally but also functionally. On the functional level, connectivity in the brain is organized in separable yet interacting networks that support information processing by maintaining a ready state, even in the absence of external stimulation. It has been hypothesized that an insular-opercular network underlies the processing of emotionally salient information and that individual differences in functional connectivity within this network correspond to individual differences in trait anxiety. Here, we tested this relationship by applying graph analysis to multiple regions of interests delineating the insular-opercular network to estimate the characteristic path length that quantifies the overall information exchange efficiency within a given network. We found that people scoring high on the anxiety-related temperament-dimension harm avoidance had decreased insular-opercular network efficiency in the resting state, as indicated by a higher characteristic path length. Furthermore, people scoring high on harm avoidance showed generally reduced functional connectivity between brain regions; the relationship between harm avoidance and insular-opercular network efficiency remained significant when controlling for mean connectivity within this network. No such results were found for other resting-state networks. The results provide insights into how personality is organized in the human brain and point toward clinically relevant endophenotypes for affective and mood disorders.

  15. Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase.

    PubMed

    Hertz, Leif; Rothman, Douglas L

    2017-02-24

    The glutamine-glutamate cycle provides neurons with astrocyte-generated glutamate/γ-aminobutyric acid (GABA) and oxidizes glutamate in astrocytes, and it returns released transmitter glutamate/GABA to neurons after astrocytic uptake. This review deals primarily with the glutamate/GABA generation/oxidation, although it also shows similarity between metabolic rates in cultured astrocytes and intact brain. A key point is identification of the enzyme(s) converting astrocytic α-ketoglutarate to glutamate and vice versa. Most experiments in cultured astrocytes, including those by one of us, suggest that glutamate formation is catalyzed by aspartate aminotransferase (AAT) and its degradation by glutamate dehydrogenase (GDH). Strongly supported by results shown in Table 1 we now propose that both reactions are primarily catalyzed by AAT. This is possible because the formation occurs in the cytosol and the degradation in mitochondria and they are temporally separate. High glutamate/glutamine concentrations abolish the need for glutamate production from α-ketoglutarate and due to metabolic coupling between glutamate synthesis and oxidation these high concentrations render AAT-mediated glutamate oxidation impossible. This necessitates the use of GDH under these conditions, shown by insensitivity of the oxidation to the transamination inhibitor aminooxyacetic acid (AOAA). Experiments using lower glutamate/glutamine concentration show inhibition of glutamate oxidation by AOAA, consistent with the coupled transamination reactions described here.

  16. Cultures of rat astrocytes challenged with a steady supply of glutamate: new model to study flux distribution in the glutamate-glutamine cycle.

    PubMed

    Fonseca, Luís L; Monteiro, Miguel A R; Alves, Paula M; Carrondo, Manuel J T; Santos, Helena

    2005-09-01

    Glutamate metabolism in astrocytes was studied using an experimental setup that simulates the role of neurons (glutamate producers and glutamine consumers) by the addition of glutaminase to the culture medium. Thereby, a steady supply of glutamate was imposed at the expense of glutamine, and the stress intensity was manipulated by changing the glutaminase concentration. Glutamate supply rates in the range 8-23 nmol/min/mg protein were examined for periods of up to 48 h. When the glutamate supply rate exceeded the uptake rate of this amino acid, a transient increase in the extracellular concentration of glutamate was observed. In response to this stress, the fluxes through the glutamate transporter and glutamine synthetase were increased considerably, and the extracellular concentration of glutamate was eventually restored to a low level. The increased levels of glutamine synthetase were demonstrated by immunoblotting analysis. The effect on glutamate metabolism of the transaminase inhibitor, aminooxyacetic acid (AOAA), and of NH4Cl was also investigated. The supply of glutamate caused a concomitant reduction in the levels of phosphocreatine, phosphoethanolamine, and phosphocholine without affecting the ATP pool. Glutamine synthetase was shown to be is a key element in the control of glutamate metabolism in astrocytic cultures. The metabolic fate of glutamate depends greatly on the time of endurance to the challenge: in naive cells, glutamate was primarily metabolized through the transaminase pathway, while in well-adapted cells glutamate was converted almost exclusively through glutamine synthetase.

  17. Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase

    PubMed Central

    Hertz, Leif; Rothman, Douglas L

    2017-01-01

    The glutamine-glutamate cycle provides neurons with astrocyte-generated glutamate/γ-aminobutyric acid (GABA) and oxidizes glutamate in astrocytes, and it returns released transmitter glutamate/GABA to neurons after astrocytic uptake. This review deals primarily with the glutamate/GABA generation/oxidation, although it also shows similarity between metabolic rates in cultured astrocytes and intact brain. A key point is identification of the enzyme(s) converting astrocytic α-ketoglutarate to glutamate and vice versa. Most experiments in cultured astrocytes, including those by one of us, suggest that glutamate formation is catalyzed by aspartate aminotransferase (AAT) and its degradation by glutamate dehydrogenase (GDH). Strongly supported by results shown in Table 1 we now propose that both reactions are primarily catalyzed by AAT. This is possible because the formation occurs in the cytosol and the degradation in mitochondria and they are temporally separate. High glutamate/glutamine concentrations abolish the need for glutamate production from α-ketoglutarate and due to metabolic coupling between glutamate synthesis and oxidation these high concentrations render AAT-mediated glutamate oxidation impossible. This necessitates the use of GDH under these conditions, shown by insensitivity of the oxidation to the transamination inhibitor aminooxyacetic acid (AOAA). Experiments using lower glutamate/glutamine concentration show inhibition of glutamate oxidation by AOAA, consistent with the coupled transamination reactions described here. PMID:28245547

  18. Evidence for Glutamate as a Neuroglial Transmitter within Sensory Ganglia

    PubMed Central

    Kung, Ling-Hsuan; Gong, Kerui; Adedoyin, Mary; Ng, Johnson; Bhargava, Aditi; Ohara, Peter T.; Jasmin, Luc

    2013-01-01

    This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold. PMID:23844184

  19. Small molecule glutaminase inhibitors block glutamate release from stimulated microglia.

    PubMed

    Thomas, Ajit G; O'Driscoll, Cliona M; Bressler, Joseph; Kaufmann, Walter; Rojas, Camilo J; Slusher, Barbara S

    2014-01-03

    Glutaminase plays a critical role in the generation of glutamate, a key excitatory neurotransmitter in the CNS. Excess glutamate release from activated macrophages and microglia correlates with upregulated glutaminase suggesting a pathogenic role for glutaminase. Both glutaminase siRNA and small molecule inhibitors have been shown to decrease excess glutamate and provide neuroprotection in multiple models of disease, including HIV-associated dementia (HAD), multiple sclerosis and ischemia. Consequently, inhibition of glutaminase could be of interest for treatment of these diseases. Bis-2-(5-phenylacetimido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and 6-diazo-5-oxo-l-norleucine (DON), two most commonly used glutaminase inhibitors, are either poorly soluble or non-specific. Recently, several new BPTES analogs with improved physicochemical properties were reported. To evaluate these new inhibitors, we established a cell-based microglial activation assay measuring glutamate release. Microglia-mediated glutamate levels were significantly augmented by tumor necrosis factor (TNF)-α, phorbol 12-myristate 13-acetate (PMA) and Toll-like receptor (TLR) ligands coincident with increased glutaminase activity. While several potent glutaminase inhibitors abrogated the increase in glutamate, a structurally related analog devoid of glutaminase activity was unable to block the increase. In the absence of glutamine, glutamate levels were significantly attenuated. These data suggest that the in vitro microglia assay may be a useful tool in developing glutaminase inhibitors of therapeutic interest.

  20. Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight

    PubMed Central

    Savaskan, Nicolai E.; Fan, Zheng; Broggini, Thomas; Buchfelder, Michael; Eyüpoglu, Ilker Y.

    2015-01-01

    Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets. PMID:26411769

  1. Evidence for glutamate as a neuroglial transmitter within sensory ganglia.

    PubMed

    Kung, Ling-Hsuan; Gong, Kerui; Adedoyin, Mary; Ng, Johnson; Bhargava, Aditi; Ohara, Peter T; Jasmin, Luc

    2013-01-01

    This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold.

  2. Accumbal and pallidal dopamine, glutamate and GABA overflow during cocaine self-administration and its extinction in rats.

    PubMed

    Wydra, Karolina; Golembiowska, Krystyna; Zaniewska, Magdalena; Kamińska, Katarzyna; Ferraro, Luca; Fuxe, Kjell; Filip, Małgorzata

    2013-03-01

    We investigated the changes in dopamine (DA), glutamate and γ-aminobutyric acid (GABA) during cocaine self-administration in rats implanted with guide cannulae into the nucleus accumbens and ventral pallidum. After stabilized cocaine self-administration, separate groups of rats underwent extinction (10 days) procedure in which cocaine infusion was replaced by saline injections. With using a 'yoked' procedure, the effects of cocaine or its withdrawal on the level of neurotransmitters were evaluated by dual-probe microdialysis. Repeated cocaine administration reduced basal glutamate levels in the nucleus accumbens and ventral pallidum, whereas it did not affect basal accumbal DA levels. Only rats that self-administered cocaine had increased basal GABA overflow in both examined brain structures. Active or passive cocaine administration elevated extracellular accumbal DA, however, the extent of cocaine-evoked DA level was significantly higher in rats that self-administered cocaine while both groups of animals showed also an attenuation of GABA level in the nucleus accumbens. On day 10 of extinction training, rats previously given cocaine revealed decreases in the basal accumbal concentration of glutamate while the basal GABA levels were significantly enhanced as compared with baseline of saline-yoked controls. Potassium depolarization delayed the reduction of the accumbal and pallidal extracellular glutamate levels in the active and passive cocaine groups. The present data indicate that changes in DA and GABA neurotransmission during maintenance phase mirror the motivational aspects of cocaine intake. Depending on acute (24 hours) or late (10 days) cocaine withdrawal, different neurotransmitter systems (i.e. glutamate or GABA) seem to be involved.

  3. The Cystine/Glutamate Antiporter System xc− in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

    PubMed Central

    Hewett, Sandra J.; Huang, Ying; Lambros, Maria; Gout, Peter W.; Kalivas, Peter W.; Massie, Ann; Smolders, Ilse; Methner, Axel; Pergande, Mathias; Smith, Sylvia B.; Ganapathy, Vadivel; Maher, Pamela

    2013-01-01

    Abstract The antiporter system xc− imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system xc− is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system xc−, including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system xc−. Moreover, the roles of system xc− in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system xc− inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System xc− is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system xc− in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS. Antioxid. Redox Signal. 18, 522–555. PMID:22667998

  4. Expression cloning of a human cDNA encoding folylpoly(gamma-glutamate) synthetase and determination of its primary structure.

    PubMed Central

    Garrow, T A; Admon, A; Shane, B

    1992-01-01

    A human cDNA for folypoly(gamma-glutamate) synthetase [FPGS; tetrahydrofolate:L-glutamate gamma-ligase (ADP forming), EC 6.3.2.17] has been cloned by functional complementation of an Escherichia coli folC mutant. The cDNA encodes a 545-residue protein of M(r) 60,128. The deduced sequence has regions that are highly homologous to peptide sequences obtained from purified pig liver FPGS and shows limited homology to the E. coli and Lactobacillus casei FPGSs. Expression of the cDNA in E. coli results in elevated expression of an enzyme with characteristics of mammalian FPGS. Expression of the cDNA in AUXB1, a mammalian cell lacking FPGS activity, overcomes the cell's requirement for thymidine and purines but does not overcome the cell's glycine auxotrophy, consistent with expression of the protein in the cytosol but not the mitochondria. PMID:1409616

  5. GDH3 encodes a glutamate dehydrogenase isozyme, a previously unrecognized route for glutamate biosynthesis in Saccharomyces cerevisiae.

    PubMed

    Avendaño, A; Deluna, A; Olivera, H; Valenzuela, L; Gonzalez, A

    1997-09-01

    It has been considered that the yeast Saccharomyces cerevisiae, like many other microorganisms, synthesizes glutamate through the action of NADP+-glutamate dehydrogenase (NADP+-GDH), encoded by GDH1, or through the combined action of glutamine synthetase and glutamate synthase (GOGAT), encoded by GLN1 and GLT1, respectively. A double mutant of S. cerevisiae lacking NADP+-GDH and GOGAT activities was constructed. This strain was able to grow on ammonium as the sole nitrogen source and thus to synthesize glutamate through an alternative pathway. A computer search for similarities between the GDH1 nucleotide sequence and the complete yeast genome was carried out. In addition to identifying its cognate sequence at chromosome XIV, the search found that GDH1 showed high identity with a previously recognized open reading frame (GDH3) of chromosome I. Triple mutants impaired in GDH1, GLT1, and GDH3 were obtained. These were strict glutamate auxotrophs. Our results indicate that GDH3 plays a significant physiological role, providing glutamate when GDH1 and GLT1 are impaired. This is the first example of a microorganism possessing three pathways for glutamate biosynthesis.

  6. The Influence of Glutamate on Axonal Compound Action Potential In Vitro

    PubMed Central

    Abouelela, Ahmed; Wieraszko, Andrzej

    2016-01-01

    Background Our previous experiments demonstrated modulation of the amplitude of the axonal compound action potential (CAP) by electrical stimulation. To verify assumption that glutamate released from axons could be involved in this phenomenon, the modification of the axonal CAP induced by glutamate was investigated. Objectives The major objective of this research is to verify the hypothesis that axonal activity would trigger the release of glutamate, which in turn would interact with specific axonal receptors modifying the amplitude of the action potential. Methods Segments of the sciatic nerve were exposed to exogenous glutamate in vitro, and CAP was recorded before and after glutamate application. In some experiments, the release of radioactive glutamate analog from the sciatic nerve exposed to exogenous glutamate was also evaluated. Results The glutamate-induced increase in CAP was blocked by different glutamate receptor antagonists. The effect of glutamate was not observed in Ca-free medium, and was blocked by antagonists of calcium channels. Exogenous glutamate, applied to the segments of sciatic nerve, induced the release of radioactive glutamate analog, demonstrating glutamate-induced glutamate release. Immunohistochemical examination revealed that axolemma contains components necessary for glutamatergic neurotransmission. Conclusion The proteins of the axonal membrane can under the influence of electrical stimulation or exogenous glutamate change membrane permeability and ionic conductance, leading to a change in the amplitude of CAP. We suggest that increased axonal activity leads to the release of glutamate that results in changes in the amplitude of CAPs. PMID:28077958

  7. Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke.

    PubMed

    Rink, Cameron; Gnyawali, Surya; Peterson, Laura; Khanna, Savita

    2011-05-15

    This work rests on our previous report (J Cereb Blood Flow Metab 30: 1275-1287, 2010) recognizing that glutamate (Glu) oxaloacetate transaminase (GOT) is induced when brain tissue hypoxia is corrected during acute ischemic stroke (AIS). GOT can metabolize Glu into tricarboxylic acid cycle intermediates and may therefore be useful to harness excess neurotoxic extracellular Glu during AIS as a metabolic substrate. We report that in cultured neural cells challenged with hypoglycemia, extracellular Glu can support cell survival as long as there is sufficient oxygenation. This effect is abrogated by GOT knockdown. In a rodent model of AIS, supplemental oxygen (100% O(2) inhaled) during ischemia significantly increased GOT expression and activity in the stroke-affected brain tissue and prevented loss of ATP. Biochemical analyses and in vivo magnetic resonance spectroscopy during stroke demonstrated that such elevated GOT decreased Glu levels at the stroke-affected site. In vivo lentiviral gene delivery of GOT minimized lesion volume, whereas GOT knockdown worsened stroke outcomes. Thus, brain tissue GOT emerges as a novel target in managing stroke outcomes. This work demonstrates that correction of hypoxia during AIS can help clear extracellular neurotoxic Glu by enabling utilization of this amino acid as a metabolic fuel to support survival of the hypoglycemic brain tissue. Strategies to mitigate extracellular Glu-mediated neurodegeneration via blocking receptor-mediated excitotoxicity have failed in clinical trials. We introduce the concept that under hypoglycemic conditions extracellular Glu can be transformed from a neurotoxin to a survival factor by GOT, provided there is sufficient oxygen to sustain cellular respiration.

  8. The Oldest Gibbon Fossil (Hylobatidae) from Insular Southeast Asia: Evidence from Trinil, (East Java, Indonesia), Lower/Middle Pleistocene

    PubMed Central

    Ingicco, Thomas; de Vos, John; Huffman, O. Frank

    2014-01-01

    A fossil femur excavated by Eugène Dubois between 1891–1900 in the Lower/Middle Pleistocene bonebed of the Trinil site (Java, Indonesia) was recognised by us as that of a Hylobatidae. The specimen, Trinil 5703 of the Dubois Collection (Leiden, The Netherlands), has the same distinctive form of fossilization that is seen in many of the bonebed fossils from Trinil in the collection. Anatomical comparison of Trinil 5703 to a sample of carnivore and primate femora, supported by morphometric analyses, lead to the attribution of the fossil to gibbon. Trinil 5703 therefore provides the oldest insular record of this clade, one of the oldest known Hylobatidae fossils from Southeast Asia. Because living Hylobatidae only inhabit evergreen rain forests, the paleoenvironment within the river drainage in the greater Trinil area evidently included forests of this kind during the Lower/Middle Pleistocene as revealed here. PMID:24914951

  9. The extreme insular adaptation of Garganornis ballmanni Meijer, 2014: a giant Anseriformes of the Neogene of the Mediterranean Basin

    NASA Astrophysics Data System (ADS)

    Pavia, Marco; Meijer, Hanneke J. M.; Rossi, Maria Adelaide; Göhlich, Ursula B.

    2017-01-01

    New skeletal elements of the recently described endemic giant anseriform Garganornis ballmanni Meijer, 2014 are presented, coming from the type-area of the Gargano and from Scontrone, southern and central Italy, respectively. The new remains represent the first bird remains found at Scontrone so far, and another shared element between these two localities, both part of the Apulia-Abruzzi Palaeobioprovince. The presence of a very reduced carpometacarpus confirms its flightlessness, only previously supposed on the basis of the very large size, while the morphologies of tarsometatarsus and posterior phalanges clearly indicate the adaptation of G. ballmanni to a terrestrial, non-aquatic, lifestyle. Its very large body size is similar to that observed in different, heavily modified, insular waterfowl and has been normally interpreted as the response to the absence of terrestrial predators and a protection from the aerial ones. The presence of a carpal knob in the proximal carpometacarpus also indicates a fighting behaviour for this large terrestrial bird species.

  10. The extreme insular adaptation of Garganornis ballmanni Meijer, 2014: a giant Anseriformes of the Neogene of the Mediterranean Basin.

    PubMed

    Pavia, Marco; Meijer, Hanneke J M; Rossi, Maria Adelaide; Göhlich, Ursula B

    2017-01-01

    New skeletal elements of the recently described endemic giant anseriform Garganornis ballmanni Meijer, 2014 are presented, coming from the type-area of the Gargano and from Scontrone, southern and central Italy, respectively. The new remains represent the first bird remains found at Scontrone so far, and another shared element between these two localities, both part of the Apulia-Abruzzi Palaeobioprovince. The presence of a very reduced carpometacarpus confirms its flightlessness, only previously supposed on the basis of the very large size, while the morphologies of tarsometatarsus and posterior phalanges clearly indicate the adaptation of G. ballmanni to a terrestrial, non-aquatic, lifestyle. Its very large body size is similar to that observed in different, heavily modified, insular waterfowl and has been normally interpreted as the response to the absence of terrestrial predators and a protection from the aerial ones. The presence of a carpal knob in the proximal carpometacarpus also indicates a fighting behaviour for this large terrestrial bird species.

  11. Molecular detection of Rickettsia, Borrelia, and Babesia species in Ixodes ricinus sampled in northeastern, central, and insular areas of Italy.

    PubMed

    Castro, Lyda R; Gabrielli, Simona; Iori, Albertina; Cancrini, Gabriella

    2015-07-01

    The aim of the present study was to provide insight into the diversity of tick-borne pathogens circulating in Italy, carried/transmitted by Ixodes ricinus, one of the most abundant tick species in the country. A total of 447 specimens sampled in five areas of northeastern, central and insular Italy were analysed by polymerase chain reaction and sequencing for the presence of rickettsiae, borreliae and babesiae. Several rickettsial species of the spotted fever group of zoonotic concern and other zoonotic pathogens were found, such as Borrelia burgdorferi s.s., Borrelia afzelii, Borrelia garinii, and Babesia venatorum. These findings confirm a wide distribution of tick-borne bacterial and protozoan species in Italy, and highlight the sanitary importance of I. ricinus, often recorded as feeding on humans.

  12. Roles of the Different Sub-Regions of the Insular Cortex in Various Phases of the Decision-Making Process

    PubMed Central

    Droutman, Vita; Bechara, Antoine; Read, Stephen J.

    2015-01-01

    This paper presents a coherent account of the role of the insular cortex (IC) in decision-making. We follow a conceptualization of decision-making that is very close to one previously proposed by Ernst and Paulus (2005): that the decision process is a progression of four phases: (1) re-focusing attention; (2) evaluation; (3) action; and (4) outcome processing, and we present evidence for the insula’s role in all these phases. We review the existing work on insula’s functional anatomy that subdivides the IC into posterior, dorsal anterior and ventral anterior regions. We re-map the results provided by the existing literature into these subdivisions wherever possible, to identify the components’ role in each decision making phase. In addition, we identify a self-regulating quality of the IC focused on harm avoidance. PMID:26635559

  13. The oldest gibbon fossil (Hylobatidae) from insular Southeast Asia: evidence from Trinil, (East Java, Indonesia), Lower/Middle Pleistocene.

    PubMed

    Ingicco, Thomas; de Vos, John; Huffman, O Frank

    2014-01-01

    A fossil femur excavated by Eugène Dubois between 1891-1900 in the Lower/Middle Pleistocene bonebed of the Trinil site (Java, Indonesia) was recognised by us as that of a Hylobatidae. The specimen, Trinil 5703 of the Dubois Collection (Leiden, The Netherlands), has the same distinctive form of fossilization that is seen in many of the bonebed fossils from Trinil in the collection. Anatomical comparison of Trinil 5703 to a sample of carnivore and primate femora, supported by morphometric analyses, lead to the attribution of the fossil to gibbon. Trinil 5703 therefore provides the oldest insular record of this clade, one of the oldest known Hylobatidae fossils from Southeast Asia. Because living Hylobatidae only inhabit evergreen rain forests, the paleoenvironment within the river drainage in the greater Trinil area evidently included forests of this kind during the Lower/Middle Pleistocene as revealed here.

  14. Tick species, tick-borne pathogens and symbionts in an insular environment off the coast of Western France.

    PubMed

    Michelet, Lorraine; Joncour, Guy; Devillers, Elodie; Torina, Alessandra; Vayssier-Taussat, Muriel; Bonnet, Sarah I; Moutailler, Sara

    2016-10-01

    Insular environments provide ideal natural conditions to study disease ecology, especially emerging diseases, due to clear differentiation between local and long-distance transmission. Such environments are of particular interest regarding tick-borne pathogens (TBP), since animal exchange with the mainland (along with any ticks they carry) is limited, and because such locations could lie on migratory routes for birds carrying ticks. Therefore both tick species and TBP may display different prevalence than those observed on the continent. As such, an epidemiological survey was performed on Belle-Ile-en-Mer, an island off the coast of Western France, in order to estimate the prevalence of tick species and the microorganisms they carried. Three tick species, Dermacentor marginatus, D. reticulatus, and Haemaphysalis punctata were collected at five different sites in 2010 and 2011. All ticks were tested for pathogen's and symbiont's DNA by (i) PCR for Anaplasma spp., Borrelia spp., Rickettsia spp.; (ii) real-time PCR for Francisella tularensis, Francisella-like endosymbionts (FLE) and Coxiella spp. and (iii) PCR-RLB for Babesia-Theileria spp. Pathogen DNA detected in D. marginatus including Borrelia spp. (18%), Rickettsia spp. (13%) which was identified as R. slovaca, Babesia spp. (8%), and Theileria spp. (1%). Pathogens detected in D. reticulatus including Rickettsia spp. (31%) identified as R. raoulti, Francisella-like endosymbiont (86%), and Babesia spp (21%). Pathogens detected in H. punctata including Rickettsia spp. (1%) identified as R. aeschlimannii, FLE (0.4%), Babesia spp. (18%), and Theileria spp. (7%). Anaplasma spp., F. tularensis, or Coxiella spp. were not detected in any of the collected ticks. This study represents the first epidemiological survey of the insular Belle-Ile-en-Mer environment. It demonstrated the presence of expected pathogens, consistent with reports from island veterinarians or physicians, as well as unexpected pathogens, raising

  15. Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium.

    PubMed

    Bannai, Hiroko; Niwa, Fumihiro; Sherwood, Mark W; Shrivastava, Amulya Nidhi; Arizono, Misa; Miyamoto, Akitoshi; Sugiura, Kotomi; Lévi, Sabine; Triller, Antoine; Mikoshiba, Katsuhiko

    2015-12-29

    GABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses.

  16. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

    NASA Astrophysics Data System (ADS)

    Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.

    1993-06-01

    Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

  17. Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium

    PubMed Central

    Bannai, Hiroko; Niwa, Fumihiro; Sherwood, Mark W.; Shrivastava, Amulya Nidhi; Arizono, Misa; Miyamoto, Akitoshi; Sugiura, Kotomi; Lévi, Sabine; Triller, Antoine; Mikoshiba, Katsuhiko

    2015-01-01

    Summary GABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses. PMID:26711343

  18. location map, floor plan, north elevation, north elevation with porch ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    location map, floor plan, north elevation, north elevation with porch removed, south elevation, building section - Chopawamsic Recreational Demonstration Area - Cabin Camp 1, Help's Quarters, Prince William Forest Park, Triangle, Prince William County, VA

  19. Light: Isometric Casing with Lens, South Elevation, North Elevation, Top ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Light: Isometric Casing with Lens, South Elevation, North Elevation, Top Plan, Base Plan; Fresnel Lens: Isometric, Elevation, Plan - Fort Washington, Fort Washington Light, Northeast side of Potomac River at Fort Washington Park, Fort Washington, Prince George's County, MD

  20. Ammonia mediates methamphetamine-induced increases in glutamate and excitotoxicity.

    PubMed

    Halpin, Laura E; Northrop, Nicole A; Yamamoto, Bryan K

    2014-03-01

    Ammonia has been identified to have a significant role in the long-term damage to dopamine and serotonin terminals produced by methamphetamine (METH), but how ammonia contributes to this damage is unknown. Experiments were conducted to identify whether increases in brain ammonia affect METH-induced increases in glutamate and subsequent excitotoxicity. Increases in striatal glutamate were measured using in vivo microdialysis. To examine the role of ammonia in mediating changes in extracellular glutamate after METH exposure, lactulose was used to decrease plasma and brain ammonia. Lactulose is a non-absorbable disaccharide, which alters the intestinal lumen through multiple mechanisms that lead to the increased peripheral excretion of ammonia. METH caused a significant increase in extracellular glutamate that was prevented by lactulose. Lactulose had no effect on METH-induced hyperthermia. To determine if ammonia contributed to excitotoxicity, the effect of METH and lactulose treatment on calpain-mediated spectrin proteolysis was measured. METH significantly increased calpain-specific spectrin breakdown products, and this increase was prevented with lactulose treatment. To examine if ammonia-induced increases in extracellular glutamate were mediated by excitatory amino-acid transporters, the reverse dialysis of ammonia, the glutamate transporter inhibitor, DL-threo-β-benzyloxyaspartic acid (TBOA), or the combination of the two directly into the striatum of awake, freely moving rats was conducted. TBOA blocked the increases in extracellular glutamate produced by the reverse dialysis of ammonia. These findings demonstrate that ammonia mediates METH-induced increases in extracellular glutamate through an excitatory amino-acid transporter to cause excitotoxicity.

  1. Glutamic Acid Selective Chemical Cleavage of Peptide Bonds.

    PubMed

    Nalbone, Joseph M; Lahankar, Neelam; Buissereth, Lyssa; Raj, Monika

    2016-03-04

    Site-specific hydrolysis of peptide bonds at glutamic acid under neutral aqueous conditions is reported. The method relies on the activation of the backbone amide chain at glutamic acid by the formation of a pyroglutamyl (pGlu) imide moiety. This activation increases the susceptibility of a peptide bond toward hydrolysis. The method is highly specific and demonstrates broad substrate scope including cleavage of various bioactive peptides with unnatural amino acid residues, which are unsuitable substrates for enzymatic hydrolysis.

  2. Hyperglycemia Reduces Functional Expression of Astrocytic Kir4.1 Channels and Glial Glutamate Uptake

    PubMed Central

    Rivera-Aponte, David E.; Méndez-González, Miguel P.; Rivera-Pagán, Aixa F.; Kucheryavykh, Yuriy V.; Kucheryavykh, Lilia Y.; Skatchkov, Serguei N.; Eaton, Misty J.

    2015-01-01

    Diabetics are at risk for a number of serious health complications including an increased incidence of epilepsy and poorer recovery after ischemic stroke. Astrocytes play a critical role in protecting neurons by maintaining extracellular homeostasis and preventing neurotoxicity through glutamate uptake and potassium buffering. These functions are aided by the presence of potassium channels, such as Kir4.1 inwardly rectifying potassium channels, in the membranes of astrocytic glial cells. The purpose of the present study was to determine if hyperglycemia alters Kir4.1 potassium channel expression and homeostatic functions of astrocytes. We used q-PCR, Western blot, patch-clamp electrophysiology studying voltage and potassium step responses and a colorimetric glutamate clearance assay to assess Kir4.1 channel levels and homeostatic functions of astrocytes grown in normal and high glucose conditions. We found that astrocytes grown in high glucose (25 mM) had an approximately 50% reduction in Kir4.1 mRNA and protein expression as compared with those grown in normal glucose (5 mM). These reductions occurred within 4 to 7 days of exposure to hyperglycemia, whereas reversal occurred between 7 to 14 days after return to normal glucose. The decrease in functional Kir channels in the astrocytic membrane was confirmed using barium to block Kir channels. In the presence of 100 μm barium, the currents recorded from astrocytes in response to voltage steps were reduced by 45%. Furthermore, inward currents induced by stepping extracellular [K+]o from 3 to 10 mM (reflecting potassium uptake) were 50% reduced in astrocytes grown in high glucose. In addition, glutamate clearance by astrocytes grown in high glucose was significantly impaired. Taken together, our results suggest that down-regulation of astrocytic Kir4.1 channels by elevated glucose may contribute to the underlying pathophysiology of diabetes-induced CNS disorders and contribute to the poor prognosis after stroke. PMID

  3. Glutamate and GABA imbalance promotes neuronal apoptosis in hippocampus after stress

    PubMed Central

    Gao, Jie; Wang, He; Liu, Yuan; Li, Ying-yu; Chen, Can; Liu, Liang-ming; Wu, Ya-min; Li, Sen; Yang, Ce

    2014-01-01

    Background People who experience traumatic events have an increased risk of post-traumatic stress disorder (PTSD). However, PTSD-related pathological changes in the hippocampus and prefrontal cortex remain poorly understood. Material/Methods We investigated the effect of a PTSD-like animal model induced by severe stress. The experimental rats received 20 inescapable electric foot shocks in an enclosed box for a total of 6 times in 3 days. The physiological state (body weight and plasma corticosterone concentrations), emotion, cognitive behavior, brain morphology, apoptosis, and balance of gamma-aminobutyric acid (GABA) and glutamate in the hippocampus and prefrontal cortex were observed. Cell damages were examined with histological staining (HE, Nissl, and silver impregnation), while apoptosis was analyzed with flow cytometry using an Annexin V and propidium iodide (PI) binding and terminal deoxynucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) method. Results In comparison with the sham litter-mates, the stressed rats showed decreased body weight, inhibition of hypothalamic-pituitary-adrenal (HPA) axis activation, increase in freezing response to trauma reminder, hypoactivity and anxiety-like behaviors in elevated plus maze and open field test, poor learning in Morris water maze, and shortened latency in hot-plate test. There were significant damages in the hippocampus but not in the prefrontal cortex. Imbalance between glutamate and GABA was more evident in the hippocampus than in the prefrontal cortex. Conclusions These results suggest that neuronal apoptosis in the hippocampus after severe traumatic stress is related to the imbalance between glutamate and GABA. Such modifications may resemble the profound changes observed in PTSD patients. PMID:24675061

  4. Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

    PubMed Central

    2011-01-01

    Background Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target. Methods The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated. Results No growth defect under low and elevated oxygen tension, no up- or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10Δgdha parasite lines. Further, the fate of the carbon skeleton of [13C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of α-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites. Conclusions First, the data support the conclusion that D10Δgdha parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)-dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite

  5. Glutamate Receptor Ion Channels: Structure, Regulation, and Function

    PubMed Central

    Wollmuth, Lonnie P.; McBain, Chris J.; Menniti, Frank S.; Vance, Katie M.; Ogden, Kevin K.; Hansen, Kasper B.; Yuan, Hongjie; Myers, Scott J.; Dingledine, Ray

    2010-01-01

    The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors. PMID:20716669

  6. Reactivation of substrate-inactivated brain glutamate decarboxylase.

    PubMed

    Meeley, M P; Martin, D L

    1983-03-01

    The effects of ATP and inorganic phosphate (Pi) on the reactivation of glutamate apodecarboxylase by its cofactor pyridoxal-5'-phosphate (pyridoxal-P) was studied. Apoenzyme was prepared by preincubation with glutamate. Apoenzyme prepared with glutamate alone was reactivated slowly and incompletely by adding a saturating concentration of pyridoxal-P (20 microM). Reactivation was slightly enhanced by 1-10 mM Pi. Reactivation by pyridoxal-P plus Pi was greatly enhanced by the presence of low concentrations (less than 100 microM) of ATP during the preparation of apoenzyme with glutamate. Reactivation was much lower if Pi was omitted. Enhancement of reactivation by ATP was due to its effect during apoenzyme formation, since ATP did not enhance reactivation if added only during reactivation and since the enhancing effect persisted after the removal of free ATP by chromatography on Sephadex G-25 after apoenzyme preparation and before reactivation. Reactivation was inhibited by high concentrations of ATP (greater than 100 microM), possibly by competition of ATP for the cofactor binding site. Four factors (glutamate, pyridoxal-P, ATP, and Pi) control a cycle of inactivation and reactivation that appears to be important in the regulation of brain glutamate decarboxylase.

  7. Glutamate affects dendritic morphology of neurons grown on compliant substrates.

    PubMed

    Previtera, Michelle L; Firestein, Bonnie L

    2015-01-01

    Brain stiffness changes in response to injury or disease. As a secondary consequence, glutamate is released from neurons and astroglia. Two types of glutamate receptors, N-methyl-d-aspartate (NMDA) and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, sense mechanotransduction, leading to downstream signaling in neurons. Recently, our group reported that these two receptors affect dendrite morphology in hippocampal neurons grown on compliant substrates. Blocking receptor activity has distinct effects on dendrites, depending on whether neurons are grown on soft or stiff gels. In the current study, we examine whether exposure to glutamate itself alters stiffness-mediated changes to dendrites in hippocampal neurons. We find that glutamate augments changes seen when neurons are grown on soft gels of 300 or 600 Pa, but in contrast, glutamate attenuates changes seen when neurons are grown on stiff gels of 3,000 Pa. These results suggest that there is interplay between mechanosensing and glutamate receptor activation in determining dendrite morphology in neurons.

  8. Mapping of glutamic acid decarboxylase (GAD) genes

    SciTech Connect

    Edelhoff, S.; Adler, D.A.; Disteche, C.M.; Grubin, C.E.; Karlsen, A.E.; Lernmark, A.; Foster, D. )

    1993-07-01

    Glutamic acid decarboxylase (GAD) catalyzes the synthesis of [gamma]-aminobutyric acid (GABA), which is known as a major inhibitory neurotransmitter in the central nervous system (CNS), but is also present outside the CNS. Recent studies showed that GAD is the major target of autoantibodies associated with the development of insulin-dependent diabetes mellitus and of the rare stiff man syndrome. Studies of GAD expression have demonstrated multiple transcripts, suggesting several isoforms of GAD. In this study, three different genes were mapped by in situ hybridization to both human and mouse chromosomes. The GAD1 gene was mapped to human chromosome 2q31 and to mouse chromosome 2D in a known region of conservation between human and mouse. GAD2, previously mapped to human chromosome 10p11.2-p12, was mapped to mouse chromosome 2A2-B, which identifies a new region of conservation between human and mouse chromosomes. A potential GAD3 transcript was mapped to human chromosome 22q13 and to mouse chromosome 15E in a known region of conservation between human and mouse. It is concluded that the GAD genes may form a family with as many as three related members. 30 refs., 5 figs.

  9. [Glutamic acid as a universal extracellular signal].

    PubMed

    Yoneda, Yukio

    2015-08-01

    The prevailing view is that both glutamic (Glu) and gamma-aminobutyric (GABA) acids play a role as an amino acid neurotransmitter released from neurons. However, little attention has been paid to the possible expression and functionality of signaling machineries required for amino acidergic neurotransmission in cells other than central neurons. In line with our first demonstration of the presence of Glu receptors outside the brain, in this review I will outline our recent findings accumulated since then on the physiological and pathological significance of neuronal amino acids as an extracellular signal essential for homeostasis in a variety of phenotypic cells. In undifferentiated neural progenitor cells, for instance, functional expression is seen with different signaling machineries used for glutamatergic and GABAergic neurotransmission in neurons. Moreover, Glu plays a role in mechanisms underlying suppression of proliferation for self-replication in undifferentiated mesenchymal stem cells. There is more accumulating evidence for neuronal amino acids playing a role as an extracellular autocrine or paracrine signal commonly used in different phenotypic cells. Evaluation of drugs currently used could be thus beneficial for the efficient prophylaxis and/or the therapy of a variety of diseases relevant to disturbance of amino acid signaling in diverse organs.

  10. Comparative evaluation of glutamate-sensitive radiopharmaceuticals: Technetium-99m-glutamic acid and technetium-99m-diethylenetriaminepentaacetic acid-bis(glutamate) conjugate for tumor imaging.

    PubMed

    Kakkar, Dipti; Tiwari, Anjani K; Chuttani, Krishna; Kaul, Ankur; Singh, Harpal; Mishra, Anil K

    2010-12-01

    Single-photon emission computed tomography has become a significant imaging modality with huge potential to visualize and provide information of anatomic dysfunctions that are predictive of future diseases. This imaging tool is complimented by radiopharmaceuticals/radiosubstrates that help in imaging specific physiological aspects of the human body. The present study was undertaken to explore the utility of technetium-99m (⁹⁹(m)Tc)-labeled glutamate conjugates for tumor scintigraphy. As part of our efforts to further utilize the application of chelating agents, glutamic acid was conjugated with a multidentate ligand, diethylenetriaminepentaacetic acid (DTPA). The DTPA-glutamate conjugate [DTPA-bis(Glu)] was well characterized by IR, NMR, and mass spectroscopy. The biological activity of glutamic acid was compared with its DTPA conjugate by radiocomplexation with ⁹⁹(m)Tc (labeling efficiency ≥98%). In vivo studies of both the radiolabeled complexes ⁹⁹(m)Tc-Glu and ⁹⁹(m)Tc-DTPA-bis(Glu) were then carried out, followed by gamma scintigraphy in New Zealand albino rabbits. Improved serum stability of ⁹⁹(m)Tc-labeled DTPA conjugate indicated that ⁹⁹(m)Tc remained bound to the conjugate up to 24 hours. Blood clearance showed a relatively slow washout of the DTPA conjugate when compared with the labeled glutamate. Biodistribution characteristics of the conjugate in Balb/c mice revealed that DTPA conjugation of glutamic acid favors less accumulation in the liver and bone and rapid renal clearance. Tumor scintigraphy in mice showed increasing tumor accumulation, stable up to 4 hours. These preliminary studies show that ⁹⁹(m)Tc-DTPA-bis(Glu) can be a useful radiopharmaceutical for diagnostic applications in single-photon emission computed tomography imaging.

  11. Effects of ammonia on high affinity glutamate uptake and glutamate transporter EAAT3 expression in cultured rat cerebellar granule cells.

    PubMed

    Chan, Helen; Zwingmann, Claudia; Pannunzio, Marc; Butterworth, Roger F

    2003-07-01

    Increased levels of extracellular glutamate are a consistent feature of hepatic encephalopathy (HE) associated with liver failure and other hyperammonemic pathologies. Reduction of glutamate uptake has been described in ammonia-exposed cultured astrocytes, synaptosomes, and in animal models of hyperammonemia. In the present study, we examine the effects of pathophysiological concentrations of ammonia on D-aspartate (a non-metabolizable analog of glutamate) uptake by cultured rat cerebellar granule neurons. Exposure of these cells to ammonia resulted in time-dependent (24% reduction at 24h and 60% reduction at 5 days, P<0.001) and dose-dependent (21, 37, and 57% reduction at 1, 2.5, and 5mM for 5 days, P<0.01) suppression of D-aspartate uptake. Kinetic analyses revealed significant decreases in the velocity of uptake (V(max)) (37% decrease at 2.5mM NH(4)Cl, P<0.05 and 52% decrease at 5mM NH(4)Cl, P<0.001) as well as significant reductions in K(m) values (25% reduction at 2.5mM NH(4)Cl, P<0.05 and 45% reduction at 5mM NH(4)Cl, P<0.001). Western blotting, on the other hand, showed no significant changes in the neuronal glutamate transporter EAAC1/EAAT3 protein, the only glutamate transporter currently known to be expressed by these cells. In addition, 1H combined with 13C-NMR spectroscopy studies using the stable isotope [1-13C]-glucose demonstrated a significant increase in intracellular glutamate levels derived from the oxidative metabolism of glucose, rather than from the deamidation of exogenous glutamine in cultured granule neurons exposed to ammonia. The present study provides evidence that the effects of ammonia on glutamate uptake are not solely an astrocytic phenomenon and that unlike the astrocytic glutamate transporter counterpart, EAAT3 protein expression in cultured cerebellar granule cells is not down-regulated when exposed to ammonia. Decrease of glutamate uptake in these cellular preparations may afford an additional regulatory mechanism aimed at

  12. National Elevation Dataset

    USGS Publications Warehouse

    ,

    2002-01-01

    The National Elevation Dataset (NED) is a new raster product assembled by the U.S. Geological Survey. NED is designed to provide National elevation data in a seamless form with a consistent datum, elevation unit, and projection. Data corrections were made in the NED assembly process to minimize artifacts, perform edge matching, and fill sliver areas of missing data. NED has a resolution of one arc-second (approximately 30 meters) for the conterminous United States, Hawaii, Puerto Rico and the island territories and a resolution of two arc-seconds for Alaska. NED data sources have a variety of elevation units, horizontal datums, and map projections. In the NED assembly process the elevation values are converted to decimal meters as a consistent unit of measure, NAD83 is consistently used as horizontal datum, and all the data are recast in a geographic projection. Older DEM's produced by methods that are now obsolete have been filtered during the NED assembly process to minimize artifacts that are commonly found in data produced by these methods. Artifact removal greatly improves the quality of the slope, shaded-relief, and synthetic drainage information that can be derived from the elevation data. Figure 2 illustrates the results of this artifact removal filtering. NED processing also includes steps to adjust values where adjacent DEM's do not match well, and to fill sliver areas of missing data between DEM's. These processing steps ensure that NED has no void areas and artificial discontinuities have been minimized. The artifact removal filtering process does not eliminate all of the artifacts. In areas where the only available DEM is produced by older methods, then "striping" may still occur.

  13. Elevated BP after AKI.

    PubMed

    Hsu, Chi-yuan; Hsu, Raymond K; Yang, Jingrong; Ordonez, Juan D; Zheng, Sijie; Go, Alan S

    2016-03-01

    The connection between AKI and BP elevation is unclear. We conducted a retrospective cohort study to evaluate whether AKI in the hospital is independently associated with BP elevation during the first 2 years after discharge among previously normotensive adults. We studied adult members of Kaiser Permanente Northern California, a large integrated health care delivery system, who were hospitalized between 2008 and 2011, had available preadmission serum creatinine and BP measures, and were not known to be hypertensive or have BP>140/90 mmHg. Among 43,611 eligible patients, 2451 experienced AKI defined using observed changes in serum creatinine concentration measured during hospitalization. Survivors of AKI were more likely than those without AKI to have elevated BP--defined as documented BP>140/90 mmHg measured during an ambulatory, nonemergency department visit--during follow-up (46.1% versus 41.2% at 730 days; P<0.001). This difference was evident within the first 180 days (30.6% versus 23.1%; P<0.001). In multivariable models, AKI was independently associated with a 22% (95% confidence interval, 12% to 33%) increase in the odds of developing elevated BP during follow-up, with higher adjusted odds with more severe AKI. Results were similar in sensitivity analyses when elevated BP was defined as having at least two BP readings of >140/90 mmHg or those with evidence of CKD were excluded. We conclude that AKI is an independent risk factor for subsequent development of elevated BP. Preventing AKI during a hospitalization may have clinical and public health benefits beyond the immediate hospitalization.

  14. Elevated BP after AKI

    PubMed Central

    Hsu, Raymond K.; Yang, Jingrong; Ordonez, Juan D.; Zheng, Sijie; Go, Alan S.

    2016-01-01

    The connection between AKI and BP elevation is unclear. We conducted a retrospective cohort study to evaluate whether AKI in the hospital is independently associated with BP elevation during the first 2 years after discharge among previously normotensive adults. We studied adult members of Kaiser Permanente Northern California, a large integrated health care delivery system, who were hospitalized between 2008 and 2011, had available preadmission serum creatinine and BP measures, and were not known to be hypertensive or have BP>140/90 mmHg. Among 43,611 eligible patients, 2451 experienced AKI defined using observed changes in serum creatinine concentration measured during hospitalization. Survivors of AKI were more likely than those without AKI to have elevated BP—defined as documented BP>140/90 mmHg measured during an ambulatory, nonemergency department visit—during follow-up (46.1% versus 41.2% at 730 days; P<0.001). This difference was evident within the first 180 days (30.6% versus 23.1%; P<0.001). In multivariable models, AKI was independently associated with a 22% (95% confidence interval, 12% to 33%) increase in the odds of developing elevated BP during follow-up, with higher adjusted odds with more severe AKI. Results were similar in sensitivity analyses when elevated BP was defined as having at least two BP readings of >140/90 mmHg or those with evidence of CKD were excluded. We conclude that AKI is an independent risk factor for subsequent development of elevated BP. Preventing AKI during a hospitalization may have clinical and public health benefits beyond the immediate hospitalization. PMID:26134154

  15. American pikas (Ochotona princeps) in northwestern Nevada: A newly discovered population at a low-elevation site

    USGS Publications Warehouse

    Beever, E.A.; Wilkening, J.L.; McIvor, D.E.; Weber, S.S.; Brussard, P.F.

    2008-01-01

    The central tenet of island biogeography theory - that species assemblages on islands are functions of island area, isolation from mainlands, and vicariance - has been altered by the demonstrable effects that rapid climate change is imposing on insular faunas, at least in isolated mountaintops. Although populations of American pikas (Ochotona princeps) continue to suffer extirpations, and although the lower bounds of the pika's elevational distribution are shifting upslope across the Great Basin, we report here on the new discovery of a low-elevation population of pikas in a mountain range from which they had not been reported previously. This discovery, particularly in the context of relatively rapid ecological change, highlights the importance of seeking out original sources of information and performing spatially extensive fieldwork. Results presented here further illustrate that although thermal influences appear to be the single strongest determinant of pika distribution currently, such influences interact with a number of other factors to determine persistence.

  16. Elevated metabolites within dorsolateral prefrontal cortex in rapid cycling bipolar disorder.

    PubMed

    Michael, Nikolaus; Erfurth, Andreas; Pfleiderer, Bettina

    2009-04-30

    Metabolites within the left dorsolateral prefrontal cortex (DLPFC) of six inpatients with bipolar II rapid cycling (RC) during various mood states (depressed, hypomanic, and euthymic), six depressed inpatients with non-RC bipolar disorder (BIPD), and six healthy controls (HC) were assessed by proton magnetic resonance spectroscopy (MRS). We hypothesized that glutamate/glutamine levels should be altered in RC compared with HC. Patients with RC in contrast to BIPD and HC exhibited elevated levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and glutamate/glutamine (Glx) during all mood states. The Glx levels of BIPD compared with HC did not differ significantly; the other metabolites were increased, though less than in RC patients. Our findings of elevated metabolites in patients with RC, especially Glx as a possible marker of cortical activity, indicate that increased neuronal activity may constitute an important neurobiological feature of RC.

  17. Reduced Insular Glutamine and N-Acetylaspartate in Systemic Lupus Erythematosus

    PubMed Central

    Cagnoli, Patricia; Harris, Richard E.; Frechtling, Dan; Berkis, George; Gracley, Richard H.; Graft, Courtney C.; Lowe, Suzan E.; Chenevert, Thomas L.; McCune, William J.; Gebarski, Stephen; Sundgren, Pia C.

    2017-01-01

    Rationale and Objectives To investigate for differences in metabolic concentrations and ratios between patients with systemic lupus erythematosus (SLE) without (group SLE) and those with neurological symptoms (group NPSLE) compared to a healthy control (group HC) in three normal-appearing brain regions: the frontal white matter, right insula (RI), and occipital gray matter and whether changes in any of the metabolites or metabolic ratios are correlated to disease activity and other clinical parameters. Materials and Methods Twenty patients with SLE (18 women and 2 men, age range 23.4–64.6 years, mean age 43.9 years), 23 NPSLE patients (23 women, age range 23.7–69.8 years, mean age 42.4 years), and 21 HC (19 women and 2 men, age range 21.0–65.7 years, mean age 43.4 years) were included. All subjects had conventional brain magnetic resonance imaging and 1H single-voxel spectroscopy, clinical assessment, and laboratory testing. Results NPSLE patients had significantly reduced N-acetylaspartate (NAA)/creatine compared to HC (P = .02) and SLE patients (P = .01) in the RI. Lower glutamine/creatine levels were also detected in RI in both patient groups and in frontal white matter in NPSLE patients compared to HC (P = .01, P = .02). NAA/Cr ratio in the RI was significantly negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index (r = −0.41; P = .008), and patients with active SLE symptoms also had a trend toward lower NAA/creatine ratios (1.02 vs 1.12; P = .07). Conclusions The present data support previous findings of abnormal metabolic changes in normal-appearing regions in the brain of both SLE and NPSLE patients and raise the possibility that especially NAA, glutamine, and glutamate may be additional biomarkers for cerebral disease activity in SLE patients as these early metabolic changes occur in the brain of SLE patients before neurologic and imaging manifestations become apparent. PMID:24029061

  18. 60. FORWARD AIRPLANE ELEVATOR PIT WITH ELEVATOR IN RAISED POSITION ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    60. FORWARD AIRPLANE ELEVATOR PIT WITH ELEVATOR IN RAISED POSITION AFT LOOKING FORWARD ON CENTERLINE SHOWING ELEVATOR GUIDES, WIREWAYS, SHEAVES, HYDRAULIC OIL TANKS AND ELEVATOR LANDING PADS. - U.S.S. HORNET, Puget Sound Naval Shipyard, Sinclair Inlet, Bremerton, Kitsap County, WA

  19. Metabotropic glutamate receptor type 1 autoimmunity

    PubMed Central

    Lopez-Chiriboga, A. Sebastian; Komorowski, Lars; Kümpfel, Tania; Probst, Christian; Hinson, Shannon R.; Pittock, Sean J.

    2016-01-01

    Objective: To describe retrospectively the clinical associations of immunoglobulin G (IgG) targeting metabotropic glutamate receptor 1 (mGluR1-IgG). Methods: Specimens of 9 patients evaluated on a service basis in the Mayo Clinic Neuroimmunology Laboratory by tissue-based immunofluorescence assay (IFA) yielded a robust, synaptic immunostaining pattern consistent with mGluR1-IgG (serum, 9; CSF, 2 available). Transfected HEK293 cell-based assay (CBA) confirmed mGluR1 specificity in all 11 specimens. A further 2 patients were detected in Germany primarily by CBA. Results: The median symptom onset age for the 11 patients was 58 years (range 33–81 years); 6 were male. All 9 Mayo Clinic patients had subacute onset of cerebellar ataxia, 4 had dysgeusia, 1 had psychiatric symptoms, and 1 had cognitive impairment. All were evaluated for malignancy, but only 1 was affected (cutaneous T-cell lymphoma). One developed ataxia post–herpes zoster infection. Head MRIs were generally atrophic or normal-appearing, and CSF was inflammatory in just 1 of 5 tested, though mGluR1-IgG was detected in both specimens submitted. Five patients improved (attributable to immunotherapy in 4, spontaneously in 1), 3 stabilized (attributable to immunotherapy in 2, cancer therapy in 1), and 1 progressively declined (untreated). The 2 German patients had ataxia, but fulfilled multiple sclerosis diagnostic criteria (1 relapsing-remitting, 1 progressive). However, both had histories of hematologic malignancy (acute lymphocytic leukemia and mantle cell lymphoma), and had mGluR1-IgG detected in serum by CBA (weakly positive on tissue-based IFA). Conclusions: mGluR1 autoimmunity represents a treatable form of cerebellar ataxia. Dysgeusia may be a diagnostic clue. Paraneoplastic, parainfectious, or idiopathic causes may occur. PMID:26888994

  20. Therapeutic Effects of Glutamic Acid in Piglets Challenged with Deoxynivalenol

    PubMed Central

    Ren, Wenkai; Yin, Jie; Tan, Bie; Liu, Gang; Li, Lili; Nyachoti, Charles Martin; Xiong, Xia; Wu, Guoyao

    2014-01-01

    The mycotoxin deoxynivalenol (DON), one of the most common food contaminants, primarily targets the gastrointestinal tract to affect animal and human health. This study was conducted to examine the protective function of glutamic acid on intestinal injury and oxidative stress caused by DON in piglets. Twenty-eight piglets were assigned randomly into 4 dietary treatments (7 pigs/treatment): 1) uncontaminated control diet (NC), 2) NC+DON at 4 mg/kg (DON), 3) NC+2% glutamic acid (GLU), and 4) NC+2% glutamic acid + DON at 4 mg/kg (DG). At day 15, 30 and 37, blood samples were collected to determine serum concentrations of CAT (catalase), T-AOC (total antioxidant capacity), H2O2 (hydrogen peroxide), NO (nitric oxide), MDA (maleic dialdehyde), DAO (diamine oxidase) and D-lactate. Intestinal morphology, and the activation of Akt/mTOR/4EBP1 signal pathway, as well as the concentrations of H2O2, MDA, and DAO in kidney, liver and small intestine, were analyzed at day 37. Results showed that DON significantly (P<0.05) induced oxidative stress in piglets, while this stress was remarkably reduced with glutamic acid supplementation according to the change of oxidative parameters in blood and tissues. Meanwhile, DON caused obvious intestinal injury from microscopic observations and permeability indicators, which was alleviated by glutamic acid supplementation. Moreover, the inhibition of DON on Akt/mTOR/4EBP1 signal pathway was reduced by glutamic acid supplementation. Collectively, these data suggest that glutamic acid may be a useful nutritional regulator for DON-induced damage manifested as oxidative stress, intestinal injury and signaling inhibition. PMID:24984001

  1. Therapeutic effects of glutamic acid in piglets challenged with deoxynivalenol.

    PubMed

    Wu, Miaomiao; Xiao, Hao; Ren, Wenkai; Yin, Jie; Tan, Bie; Liu, Gang; Li, Lili; Nyachoti, Charles Martin; Xiong, Xia; Wu, Guoyao

    2014-01-01

    The mycotoxin deoxynivalenol (DON), one of the most common food contaminants, primarily targets the gastrointestinal tract to affect animal and human health. This study was conducted to examine the protective function of glutamic acid on intestinal injury and oxidative stress caused by DON in piglets. Twenty-eight piglets were assigned randomly into 4 dietary treatments (7 pigs/treatment): 1) uncontaminated control diet (NC), 2) NC+DON at 4 mg/kg (DON), 3) NC+2% glutamic acid (GLU), and 4) NC+2% glutamic acid + DON at 4 mg/kg (DG). At day 15, 30 and 37, blood samples were collected to determine serum concentrations of CAT (catalase), T-AOC (total antioxidant capacity), H2O2 (hydrogen peroxide), NO (nitric oxide), MDA (maleic dialdehyde), DAO (diamine oxidase) and D-lactate. Intestinal morphology, and the activation of Akt/mTOR/4EBP1 signal pathway, as well as the concentrations of H2O2, MDA, and DAO in kidney, liver and small intestine, were analyzed at day 37. Results showed that DON significantly (P<0.05) induced oxidative stress in piglets, while this stress was remarkably reduced with glutamic acid supplementation according to the change of oxidative parameters in blood and tissues. Meanwhile, DON caused obvious intestinal injury from microscopic observations and permeability indicators, which was alleviated by glutamic acid supplementation. Moreover, the inhibition of DON on Akt/mTOR/4EBP1 signal pathway was reduced by glutamic acid supplementation. Collectively, these data suggest that glutamic acid may be a useful nutritional regulator for DON-induced damage manifested as oxidative stress, intestinal injury and signaling inhibition.

  2. Metabotropic glutamate receptor ligands as potential therapeutics for addiction

    PubMed Central

    Olive, M. F.

    2009-01-01

    There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials. PMID:19630739

  3. Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring

    PubMed Central

    Cassella, Sarah N.; Hemmerle, Ann M.; Lundgren, Kerstin H.; Kyser, Tara L.; Ahlbrand, Rebecca; Bronson, Stefanie L.; Richtand, Neil M.; Seroogy, Kim B.

    2016-01-01

    Activation of the maternal innate immune system, termed “maternal immune activation” (MIA), represents a common environmental risk factor for schizophrenia. Whereas evidence suggests dysregulation of GABA systems may underlie the pathophysiology of schizophrenia, a role for MIA in alteration of GABAergic systems is less clear. Here, pregnant rats received either the viral mimetic polyriboinosinic-polyribocytidilic acid or vehicle injection on gestational day 14. Glutamic acid decarboxylase-67 (GAD67) mRNA expression was examined in male offspring at postnatal day (P)14, P30 and P60. At P60, GAD67 mRNA was elevated in hippocampus and thalamus and decreased in prefrontal cortex of MIA offspring. MIA-induced alterations in GAD expression could contribute to the pathophysiology of schizophrenia. PMID:26830319

  4. Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

    PubMed Central

    Griffin III, William C; Haun, Harold L; Hazelbaker, Callan L; Ramachandra, Vorani S; Becker, Howard C

    2014-01-01

    ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence. PMID:24067300

  5. The influence of ionotropic and metabotropic glutamate receptor ligands on anxiety-like effect of amphetamine withdrawal in rats.

    PubMed

    Koltunowska, D; Gibula-Bruzda, E; Kotlinska, J H

    2013-08-01

    Chronic amphetamine use results in anxiety-like states after drug cessation. The aim of the study was to determine a role of ionotropic and metabotropic glutamate receptor ligands in amphetamine-evoked withdrawal anxiety in the elevated plus-maze test in rats. In our study memantine (8 and 12 mg/kg), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist did not reduce amphetamine withdrawal anxiety. Acamprosate (NMDA and metabotropic glutamate 5 receptor (mGluR5) antagonist) at the dose 200 and 400mg/kg showed anxiolytic-like effect, thus increasing the percent of time spent in open arms and a number of open arm entries. mGluR5 selective antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine hydrochloride) and mGluR2/3 agonist, LY354740 (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid), caused effects similar to acamprosate at doses 1.25-5mg/kg and 2.5-5mg/kg, respectively. None of the glutamate ligands influenced locomotor activity of rats when given to the saline-treated group. Taking into account the positive correlation between amphetamine withdrawal-induced anxiety and relapse to amphetamine taking, our results suggest that modulation of mGluRs may prevent relapse to amphetamine and might pose a new direction in amphetamine abuse therapy.

  6. Intra-amygdala microinjection of TNF-α impairs the auditory fear conditioning of rats via glutamate toxicity.

    PubMed

    Jing, He; Hao, Yongxin; Bi, Qiang; Zhang, Jiaozhen; Yang, Pingting

    2015-02-01

    During an inflammatory or infectious process, innate immune cells produce large amount of pro-inflammatory cytokines that act on the brain to cause cognitive dysfunctions. Tumor necrosis factor alpha (TNF-α) is one of the main pro-inflammatory cytokines. Thus, it is important to study how the excessive TNF-α affects the cognitive functions of central nervous system and possible antagonists to its effects. In the present study, we conducted behavioral experiments of rats to determine whether murine TNF-α administered directly into the brain would elicit behavioral effects related to learning and memory impairments. Rats subjected to single-dose intra-amygdala TNF-α infusion showed a significant delay in the acquisition and extinction of auditory fear conditioning. Accordingly, the glutamate level of the tissue samples from amygdala was elevated after the TNF-α treatment. Furthermore, pharmacological blockade of NMDAR before the TNF-α treatment reversed the TNF-α induced impairments in fear learning. Our findings suggest that TNF-α can impair the learning and memory functions through glutamate-NMDAR neurotoxicity, and present the possibility to develop therapeutic modalities directing at glutamate transmission for the treatment of neuro-inflammative dysfunctions.

  7. Dietary taurine supplementation ameliorates diabetic retinopathy via anti-excitotoxicity of glutamate in streptozotocin-induced Sprague-Dawley rats.

    PubMed

    Yu, Xiaoping; Xu, Zhaoxia; Mi, Mantian; Xu, Hongxia; Zhu, Jundong; Wei, Na; Chen, Ka; Zhang, Qianyong; Zeng, Kaihong; Wang, Jian; Chen, Fang; Tang, Yong

    2008-03-01

    The purpose of this study was to investigate whether taurine ameliorate the diabetic retinopathy, and to further explore the underlying mechanisms. The Sprague-Dawley rats were injected with streptozotocin to establish experimental diabetic model, then fed without or with 1.2% taurine for additional 4-12 weeks. After that, the protective effects of dietary taurine supplementation on diabetic retinopathy were estimated. Our results showed that chronic taurine supplement effectively improved diabetic retinopathy as changes of histopathology and ultrastructure. The supplementation could not lower plasma glucose concentration (P > 0.05), but caused an elevation in taurine content and a decline in levels of glutamate and gamma-aminobutyric acid (GABA) in diabetic retina (P < 0.05). Moreover, chronic taurine supplementation increased glutamate transporter (GLAST) expression (P < 0.05), decreased intermediate filament glial fibrillary acidic protein (GFAP) and N-methyl-D: -aspartate receptor subunit 1 (NR1) expression in diabetic retina (P < 0.05). These results demonstrated that chronic taurine supplementation ameliorates diabetic retinopathy via anti-excitotoxicity of glutamate in rats.

  8. A NADP-glutamate dehydrogenase mutant of the petit-negative yeast Kluyveromyces lactis uses the glutamine synthetase-glutamate synthase pathway for glutamate biosynthesis.

    PubMed

    Valenzuela, L; Guzmán-León, S; Coria, R; Ramírez, J; Aranda, C; González, A

    1995-10-01

    The activities of the enzymes involved in ammonium assimilation and glutamate biosynthesis were determined in wild-type and NADP-glutamate dehydrogenase (GDH) null mutant strains of Kluyveromyces lactis. The specific NADP-GDH activity from K. lactis was fivefold lower than that found in Saccharomyces cerevisiae. The glutamine synthetase (GS) and glutamate synthase (GOGAT) activities were similar to those reported in S. cerevisiae. The NADP-GDH null mutant was obtained by transforming the uraA strain MD2/1 with a linearized integrative yeast vector harbouring a 390 bp fragment of the NADP-GDH structural gene. This mutant grew as well as the parent strain on ammonium, but showed GS and GOGAT activities higher that those found in the wild-type strain, implying that the GS-GOGAT pathway could play a leading role in glutamate biosynthesis in K. lactis. Southern blotting analysis of K. lactis chromosomes separated by contour-clamped homogeneous electric field electrophoresis, indicated that the NADP-GDH structural gene is localized on chromosome VI.

  9. Rewarding effects of electrical stimulation of the insular cortex: decayed effectiveness after repeated tests and subsequent increase in vertical behavioral activity and conditioned place aversion after naloxone administration.

    PubMed

    García, Raquel; Zafra, Maria A; Puerto, Amadeo

    2015-02-01

    The insular cortex has been associated with various aversive and rewarding sensory, regulatory, and learning processes. The objective of this study was to examine the characteristics of the reinforcement induced by electrical stimulation of this brain area in rats. Results obtained confirm that electrical stimulation of the insular cortex may induce conditioned place and flavor preferences but the learning acquired is not transferred in a reversal test. Unexpectedly, they also demonstrate that this rewarding effect diminishes after repeated tests. In follow-up experiments, locomotor activity tests revealed an increased number of rearings (a sensitization index) in stimulated animals. Furthermore, in these same animals, administration of low doses of naloxone, an opiate antagonist, developed place aversion toward the maze compartment for which the animals had previously shown preference. These results are interpreted in relation to the effects induced by the repeated administration of natural and artificial rewarding stimuli.

  10. α2-adrenergic receptors in spiral ganglion neurons may mediate protective effects of brimonidine and yohimbine against glutamate and hydrogen peroxide toxicity.

    PubMed

    Cai, J; Li, J; Liu, W; Han, Y; Wang, H

    2013-01-03

    Brimonidine, an alpha2-adrenergic receptor (α(2)-AR) agonist, is thought to be neuroprotective in some types of neurons via the activation of α(2)-AR. However, it is still unknown whether the α(2)-ARs exist in cochlear spiral ganglion neurons (SGNs). The authors aimed to demonstrate the presence and localization of α(2)-ARs in rat-cultured SGNs and to investigate the effect of brimonidine on glutamate- and hydrogen peroxide (H(2)O(2))-induced damage in the primary-cultured rat SGNs. The expression of α(2)-ARs was determined by reverse transcription-polymerase chain reaction, Western blot analysis and immunofluorescence. Then SGNs were exposed to glutamate or H(2)O(2) respectively with or without brimonidine. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Apoptosis was determined by acridine orange and Hoechst 33342/propidium iodide double staining. The protein expressions of α(2)-ARs, Bax, Bcl-2, Caspase-9, Caspase-3, p-ERK1/2, iNOS, and artemin were determined by Western blot respectively. The cell viability was markedly reduced after exposure of glutamate (1mM) or H(2)O(2) (300 μM) to SGNs. Treatment with brimonidine protected SGNs against glutamate- or H(2)O(2)-induced cell damage, enhanced SGNs survival, decreased the elevation of Bax, Caspase-9, Caspase-3, p-ERK1/2, and artemin triggered by glutamate or H(2)O(2), and altered the expressions of Bcl-2 and iNOS. These protective effects of brimonidine can be reversed by yohimbine. Overall, the study describes the localization of α(2)-ARs in rat-cultured SGNs and indicates that brimonidine, which may work directly via interaction with α(2)-ARs, attenuates glutamate- and H(2)O(2)-induced damage in SGNs by Caspase-dependent modes as well as Caspase-independent modes.

  11. Increasing influence of the glutamate transporter inhibitor on glutamate release in low [Na +] media under extremal conditions.

    NASA Astrophysics Data System (ADS)

    Borisova, T.; Krisanova, N.; Himmelreich, N.

    The effect of the competitive nontransportable inhibitor DL-threo-beta-benzyloxyaspartate DL-TBOA on the release of glutamate in Ca 2 -free Na - and NMDG-supplemented media was evaluated after exposure of rats to extremal conditions 6 min incubation of synaptosomes with 10 mu M DL-TBOA in low Na media resulted in the increase in extracellular L- 14 C glutamate level for control animals by 2 0 pm 0 5 of total accumulated label and 100 mu M DL-TBOA - 3 5 pm 0 5 respectively The experimental data for animals subjected to centrifuge-induced hypergravity showed 4 0 pm 1 0 and 9 0 pm 2 0 increase in L- 14 C glutamate level for 10 mu M and 100 mu M DL-TBOA respectively D le 0 05 The enhancement of the extracellular level of L- 14 C glutamate after application of DL-TBOA would be expected to connect with the inhibition of L- 14 C glutamate uptake process It appears that DL-TBOA inhibited uptake more potently after hypergravity The effect of DL-TBOA on depolarization-induced carrier-mediated L- 14 C glutamate release increased after hypergravity loading in Na - and low Na NMDG- supplemented media 10 mu M DL-TBOA-induced decrease in L- 14 C glutamate release in Na - supplemented medium was 15 2 pm 2 2 in the control experiments and 26 2 pm 3 9 after loading D le 0 05 and in low Na medium was 37 0 pm 2 5 and 45 0 pm 3 4 respectively DL-TBOA was demonstrated to better inhibit the transporter-mediated

  12. GLUTAMATE ABNORMALITIES IN OBSESSIVE COMPULSIVE DISORDER: NEUROBIOLOGY, PATHOPHYSIOLOGY, AND TREATMENT

    PubMed Central

    Pittenger, Christopher; Bloch, Michael H.; Williams, Kyle

    2011-01-01

    Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics. PMID:21963369

  13. A novel mechanism of neuroprotection: Blood glutamate grabber

    PubMed Central

    Loza, María Isabel; Mirelman, David; Brea, José; Blanco, Miguel; Sobrino, Tomás; Campos, Francisco

    2015-01-01

    Glutamate excitotoxicity is a primary contributor of ischemic neuronal death and other cellular components of the neurovascular unit. Several strategies have been developed against glutamate excitotoxicity, however none of them have not shown positive results in the clinical practice so far. Nowadays, the concept of blood/brain glutamate grabbing or scavenging is well recognized as a novel and attractive protective strategy to reduce the excitotoxic effect of excess extracellular glutamate that accumulates in the brain following an ischemic stroke. The main advantage of this novel therapeutic strategy is that it occurs in the blood circulation and therefore does not affect the normal brain neurophysiology, as it has been described for other drug treatments used against glutamate excitotoxicity. In this work we report all experimental data from the beginning of our studies, focused on stroke pathology, and we describe new findings about the potential application of this therapy. Future clinical trials will allow to know the real efficacy of this novel therapeutic strategy in stroke patients. PMID:26661174

  14. Ghrelin Regulates Glucose and Glutamate Transporters in Hypothalamic Astrocytes

    PubMed Central

    Fuente-Martín, Esther; García-Cáceres, Cristina; Argente-Arizón, Pilar; Díaz, Francisca; Granado, Miriam; Freire-Regatillo, Alejandra; Castro-González, David; Ceballos, María L.; Frago, Laura M.; Dickson, Suzanne L.; Argente, Jesús; Chowen, Julie A.

    2016-01-01

    Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons. PMID:27026049

  15. Zinc signaling through glucocorticoid and glutamate signaling in stressful circumstances.

    PubMed

    Takeda, Atsushi; Tamano, Haruna

    2010-11-01

    Humans and animals are constantly exposed to environmental stress. The hypothalamic-pituitary-adrenal (HPA) axis responds to stress, followed by glucocorticoid secretion from the adrenal glands. This response serves to maintain homeostasis in the living body through energy mobilization or to restore it. The brain is an important target for glucocorticoids. The hippocampus participates in the regulation of the HPA axis. Stress activates glutamatergic neurons in the hippocampus, and serious stress induces dyshomeostasis of extracellular glutamate. This dyshomeostasis, which is potentiated by glucocorticoids, modifies cognitive and emotional behavior. On the other hand, zinc is necessary for glucocorticoid signaling and is released from glutamatergic (zincergic) neurons to modulate synaptic glutamate signaling. Stress also induces dyshomeostasis of extracellular zinc, which may be linked to dyshomeostasis of extracellular glutamate. Thus, glucocorticoid signaling might also contribute to dyshomeostasis of extracellular zinc. It is likely that zinc signaling participates in cognitive and emotional behavior through glucocorticoid and glutamate signaling under stressful circumstances. This Mini-Review analyzes the relationship among signals of glucocorticoid, glutamate, and zinc under stressful circumstances to elucidate the significance of the zinc signaling in response to stress.

  16. Glutamate regulates the activity of topoisomerase I in mouse cerebellum.

    PubMed

    Zehorai, Eldar; Eitan, Erez; Hershfinkel, Michal; Sekler, Israel; Priel, Esther

    2008-12-01

    Topoisomerase I (topo I) is a nuclear enzyme which participates in most DNA transactions. It was shown to be inhibited in depolarized neurons by poly adenosine diphosphate (ADP)-ribosylation of the enzyme protein. We demonstrated previously an age and sex dependent topo I activity and enzyme protein level in the various regions of mouse brain. A specific distribution pattern of topo I was observed and the inhibitory neurons exhibited the highest enzyme activity and protein level in both the nucleus and the cytoplasm. Here, we show that neurotransmitters (glutamate and gamma-aminobutyric acid (GABA)) regulate the activity of topo I in mouse cerebellum sections. Glutamate exhibited a significant time-dependent inhibition of topo I activity but no effect of the enzyme protein level. GABA in contrary only slightly and transiently inhibited topo I activity. The inhibitory effect of glutamate was mediated by Ca(+2) and by ADP-ribosylation of topo I protein and the glutamate ionotropic receptors were involved. Glutamate also diminished the inhibitory effect of topotecan on topo I. These results point to distinct and highly specific effects of the major neurotransmitters on topo I activity in the cerebellum suggesting that topo I possesses a specific role in the brain which differs from its known biological functions.

  17. Ghrelin Regulates Glucose and Glutamate Transporters in Hypothalamic Astrocytes.

    PubMed

    Fuente-Martín, Esther; García-Cáceres, Cristina; Argente-Arizón, Pilar; Díaz, Francisca; Granado, Miriam; Freire-Regatillo, Alejandra; Castro-González, David; Ceballos, María L; Frago, Laura M; Dickson, Suzanne L; Argente, Jesús; Chowen, Julie A

    2016-03-30

    Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons.

  18. Distribution of vesicular glutamate transporters in the human brain

    PubMed Central

    Vigneault, Érika; Poirel, Odile; Riad, Mustapha; Prud'homme, Josée; Dumas, Sylvie; Turecki, Gustavo; Fasano, Caroline; Mechawar, Naguib; El Mestikawy, Salah

    2015-01-01

    Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3) are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe) while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains. PMID:25798091

  19. Stress, glucocorticoids and glutamate release: effects of antidepressant drugs.

    PubMed

    Musazzi, Laura; Racagni, Giorgio; Popoli, Maurizio

    2011-08-01

    Stressful life events impact on memory, cognition and emotional responses, and are known to precipitate mood/anxiety disorders. It is increasingly recognized that stress and its neurochemical and endocrine mediators induce changes in glutamate synapses and circuitry, and this in turn modify mental states. Half a century after the monoamine hypothesis, it is widely accepted that maladaptive changes in excitatory/inhibitory circuitry have a primary role in the pathophysiology of mood/anxiety disorders. The neuroplasticity hypothesis posits that volumetric changes consistently found in limbic and cortical areas of depressed subjects are in good part due to remodeling of neuronal dendritic arbors and loss of synaptic spines. A considerable body of work, carried out with in vivo microdialysis as well as alternative methodologies, has shown that both stress and corticosterone treatment induce enhancement of activity-dependent glutamate release. Accordingly, results from preclinical studies suggest that stress- and glucocorticoid-induced enhancement of glutamate release and transmission plays a main role in the induction of maladaptive cellular effects, in turn responsible for dendritic remodeling. Additional recent work has showed that drugs employed for therapy of mood/anxiety disorders (antidepressants) prevent the enhancement of glutamate release induced by stress. Understanding the action of traditional drugs on glutamate transmission could be of great help in developing drugs that may work directly at this level.

  20. A novel mechanism of neuroprotection: Blood glutamate grabber.

    PubMed

    Castillo, José; Loza, María Isabel; Mirelman, David; Brea, José; Blanco, Miguel; Sobrino, Tomás; Campos, Francisco

    2016-02-01

    Glutamate excitotoxicity is a primary contributor of ischemic neuronal death and other cellular components of the neurovascular unit. Several strategies have been developed against glutamate excitotoxicity, however none of them have not shown positive results in the clinical practice so far. Nowadays, the concept of blood/brain glutamate grabbing or scavenging is well recognized as a novel and attractive protective strategy to reduce the excitotoxic effect of excess extracellular glutamate that accumulates in the brain following an ischemic stroke. The main advantage of this novel therapeutic strategy is that it occurs in the blood circulation and therefore does not affect the normal brain neurophysiology, as it has been described for other drug treatments used against glutamate excitotoxicity. In this work we report all experimental data from the beginning of our studies, focused on stroke pathology, and we describe new findings about the potential application of this therapy. Future clinical trials will allow to know the real efficacy of this novel therapeutic strategy in stroke patients.

  1. Methylphenidate Increases Glutamate Uptake in Bergmann Glial Cells.

    PubMed

    Guillem, Alain M; Martínez-Lozada, Zila; Hernández-Kelly, Luisa C; López-Bayghen, Esther; López-Bayghen, Bruno; Calleros, Oscar A; Campuzano, Marco R; Ortega, Arturo

    2015-11-01

    Glutamate, the main excitatory transmitter in the vertebrate brain, exerts its actions through the activation of specific membrane receptors present in neurons and glial cells. Over-stimulation of glutamate receptors results in neuronal death, phenomena known as excitotoxicity. A family of glutamate uptake systems, mainly expressed in glial cells, removes the amino acid from the synaptic cleft preventing an excessive glutamatergic stimulation and thus neuronal damage. Autism spectrum disorders comprise a group of syndromes characterized by impaired social interactions and anxiety. One or the most common drugs prescribed to treat these disorders is Methylphenidate, known to increase dopamine extracellular levels, although it is not clear if its sedative effects are related to a plausible regulation of the glutamatergic tone via the regulation of the glial glutamate uptake systems. To gain insight into this possibility, we used the well-established model system of cultured chick cerebellum Bergmann glia cells. A time and dose-dependent increase in the activity and protein levels of glutamate transporters was detected upon Methylphenidate exposure. Interestingly, this increase is the result of an augmentation of both the synthesis as well as the insertion of these protein complexes in the plasma membrane. These results favour the notion that glial cells are Methylphenidate targets, and that by these means could regulate dopamine turnover.

  2. Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

    PubMed Central

    Cooper, Arthur J. L.; Jeitner, Thomas M.

    2016-01-01

    Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate

  3. Distinctive Roles of 5-aza-2′-deoxycytidine in Anterior Agranular Insular and Basolateral Amygdala in Reconsolidation of Aversive Memory Associated with Morphine in Rats

    PubMed Central

    Liu, Peng; Zhang, JianJun; Li, Ming; Sui, Nan

    2016-01-01

    5-aza-2′-deoxycytidine (5-aza), an inhibitor of DNA methyltransferases (DNMTs), has been implicated in aversive memory and the function of brain region involved in processing emotion. However, little is known about the role of 5-aza in the reconsolidation of opiate withdrawal memory. In the present study, using the morphine-naloxone induced conditioned place aversion (CPA) model in rats, we injected 5-aza into agranular insular (AI), granular insular (GI), basolateral amygdala (BLA) and central amygdala (CeA) immediately after the memory retrieval and tested the behavioral consequences at 24 h, 7 and 14 days after retrieval test. We found that 5-aza injection into AI disrupted the reconsolidation of morphine-associated withdrawal memory, but 5-aza injection into GI had no impact on the reconsolidation. Meanwhile, 5-aza injection into BLA but not CeA attenuated the withdrawal memory trace 14 days later. However, 5-aza administration to rats, in the absence of memory reactivation, had no effect on morphine-associated withdrawal memory. These findings suggest that 5-aza interferes with the reconsolidation of opiate withdrawal memory, and the roles of insular and amygdala in reconsolidation are distinctive. PMID:27014010

  4. Elevated temperature crack growth

    NASA Technical Reports Server (NTRS)

    Yau, J. F.; Malik, S. N.; Kim, K. S.; Vanstone, R. H.; Laflen, J. H.

    1985-01-01

    The objective of the Elevated Temperature Crack Growth Project is to evaluate proposed nonlinear fracture mechanics methods for application to combustor liners of aircraft gas turbine engines. During the first year of this program, proposed path-independent (P-I) integrals were reviewed for such applications. Several P-I integrals were implemented into a finite-element postprocessor which was developed and verified as part of the work. Alloy 718 was selected as the analog material for use in the forthcoming experimental work. A buttonhead, single-edge notch specimen was designed and verified for use in elevated-temperature strain control testing with significant inelastic strains. A crack mouth opening displacement measurement device was developed for further use.

  5. Elevated temperature envelope forming

    NASA Technical Reports Server (NTRS)

    Burg, Bruce M. (Inventor); Gane, David H. (Inventor); Starowski, Robert M. (Inventor)

    1992-01-01

    Elevated temperature envelope forming includes enclosing a part blank and form tool within an envelope sealed against the atmosphere, heat treating the combination while forming pressure holds the envelope and part against the form tool, and allowing part cool down to occur in an inert atmosphere with forming pressure removed. The forming pressure is provided by evacuating the envelope and may be aided by differential force applied between the envelope and the form tool.

  6. [PECULIARITIES OF THE CEREBROVASCULAR EFFECTS OF GLUTAMIC ACID].

    PubMed

    Gan'shina, T S; Kurza, E V; Kurdyumov, I N; Maslennikov, D V; Mirzoyan, R S

    2016-01-01

    Experiments on nonlinear rats subjected to global transient cerebral ischemia revealed the ability of glutamic acid to improve cerebral circulation. Consequently, the excitatory amino acid can produce adverse (neurotoxic) and positive (anti-ischemic) effects in cerebral ischemia. The cerebrovascular effect of glutamic acid in cerebral ischemia is attenuated on the background action of the MNDA receptor blocker MK-801 (0.5 mg/kg intravenously) and eliminated by bicuculline. When glutamic acid is combined with the non-competitive MNDA receptor antagonist MK-801, neither one nor another drug shows its vasodilator effect. The results are indicative of the interaction between excitatory and inhibitory systems on the level of cerebral vessels and once again confirm our previous conclusion about the decisive role of GABA(A) receptors in brain vessels in the implementation of anti-ischemic activity of endogenous compounds (melatonin) and well-known pharmacological substances (mexidol, afobazole), and new chemical compounds based on GABA-containing lipid derivatives.

  7. A noncanonical release of GABA and glutamate modulates neuronal migration.

    PubMed

    Manent, Jean-Bernard; Demarque, Michaël; Jorquera, Isabel; Pellegrino, Christophe; Ben-Ari, Yehezkel; Aniksztejn, Laurent; Represa, Alfonso

    2005-05-11

    Immature neurons express GABA and glutamate receptors before synapse formation, and both transmitters are released at an early developmental stage. We have now tested the hypothesis that the ongoing release of GABA and glutamate modulates neuronal migration. Using 5-bromo-2'-deoxyuridine labeling and cocultures of hippocampal slices obtained from naive and green fluorescent protein-transgenic mice, we report that migration is severely affected by GABA(A) or NMDA receptor antagonist treatments. These effects were also present in munc18-1 knock-out slices in which soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent vesicular secretion of transmitters has been deleted. GABA(A) antagonists were more efficient than NMDA antagonists to reduce cell migration, in keeping with the earlier maturation of GABAergic mechanisms. We conclude that GABA and, to a lesser degree, glutamate released in a SNARE-independent mechanism exert a paracrine action on neuronal migration.

  8. Glutamate transporters in brain ischemia: to modulate or not?

    PubMed Central

    Krzyżanowska, Weronika; Pomierny, Bartosz; Filip, Małgorzata; Pera, Joanna

    2014-01-01

    In this review, we briefly describe glutamate (Glu) metabolism and its specific transports and receptors in the central nervous system (CNS). Thereafter, we focus on excitatory amino acid transporters, cystine/glutamate antiporters (system xc-) and vesicular glutamate transporters, specifically addressing their location and roles in CNS and the molecular mechanisms underlying the regulation of Glu transporters. We provide evidence from in vitro or in vivo studies concerning alterations in Glu transporter expression in response to hypoxia or ischemia, including limited human data that supports the role of Glu transporters in stroke patients. Moreover, the potential to induce brain tolerance to ischemia through modulation of the expression and/or activities of Glu transporters is also discussed. Finally we present strategies involving the application of ischemic preconditioning and pharmacological agents, eg β-lactam antibiotics, amitriptyline, riluzole and N-acetylcysteine, which result in the significant protection of nervous tissues against ischemia. PMID:24681894

  9. Enzymatic production of α-ketoglutaric acid from l-glutamic acid via l-glutamate oxidase.

    PubMed

    Niu, Panqing; Dong, Xiaoxiang; Wang, Yuancai; Liu, Liming

    2014-06-10

    In this study, a novel strategy for α-ketoglutaric acid (α-KG) production from l-glutamic acid using recombinant l-glutamate oxidase (LGOX) was developed. First, by analyzing the molecular structure characteristics of l-glutamic acid and α-KG, LGOX was found to be the best catalyst for oxidizing the amino group of l-glutamic acid to a ketonic group without the need for exogenous cofactor. Then the LGOX gene was expressed in Escherichia coli BL21 (DE3) in a soluble and active form, and the recombinant LGOX activity reached to a maximum value of 0.59U/mL at pH 6.5, 30°C. Finally, the maximum α-KG concentration reached 104.7g/L from 110g/L l-glutamic acid in 24h, under the following optimum conditions: 1.5U/mL LGOX, 250U/mL catalase, 3mM MnCl2, 30°C, and pH 6.5.

  10. Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence?

    PubMed Central

    Lewerenz, Jan; Maher, Pamela

    2015-01-01

    Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases. PMID:26733784

  11. Genetic structure of introduced populations: 120-year-old DNA footprint of historic introduction in an insular small mammal population

    PubMed Central

    Simpson, Siobhan; Blampied, Nick; Peniche, Gabriela; Dozières, Anne; Blackett, Tiffany; Coleman, Stephen; Cornish, Nina; Groombridge, Jim J

    2013-01-01

    Wildlife populations have been introduced to new areas by people for centuries, but this human-mediated movement can disrupt natural patterns of genetic structure by altering patterns of gene flow. Insular populations are particularly prone to these influences due to limited opportunities for natural dispersal onto islands. Consequently, understanding how genetic patterns develop in island populations is important, particularly given that islands are frequently havens for protected wildlife. We examined the evolutionary origins and extent of genetic structure within the introduced island population of red squirrels (Sciurus vulgaris) on the Channel Island of Jersey using mitochondrial DNA (mtDNA) control region sequence and nuclear microsatellite genotypes. Our findings reveal two different genetic origins and a genetic architecture reflective of the introductions 120 years ago. Genetic structure is marked within the maternally inherited mtDNA, indicating slow dispersal of female squirrels. However, nuclear markers detected only weak genetic structure, indicating substantially greater male dispersal. Data from both mitochondrial and nuclear markers support historic records that squirrels from England were introduced to the west of the island and those from mainland Europe to the east. Although some level of dispersal and introgression across the island between the two introductions is evident, there has not yet been sufficient gene flow to erase this historic genetic “footprint.” We also investigated if inbreeding has contributed to high observed levels of disease, but found no association. Genetic footprints of introductions can persist for considerable periods of time and beyond traditional timeframes of wildlife management. PMID:23532702

  12. Signatures of volcanism and aridity in the evolution of an insular pine (Pinus canariensis Chr. Sm. Ex DC in Buch)

    PubMed Central

    López de Heredia, U; López, R; Collada, C; Emerson, B C; Gil, L

    2014-01-01

    Oceanic islands of volcanic origin provide useful templates for the study of evolution because they are subjected to recurrent perturbations that generate steep environmental gradients that may promote adaptation. Here we combine population genetic data from nuclear genes with the analysis of environmental variation and phenotypic data from common gardens to disentangle the confounding effects of demography and selection to identify the factors of importance for the evolution of the insular pine P. canariensis. Eight nuclear genes were partially sequenced in a survey covering the entire species range, and phenotypic traits were measured in four common gardens from contrasting environments. The explanatory power of population substrate age and environmental indices were assessed against molecular and phenotypic diversity estimates. In addition, neutral genetic variability (FST) and the genetic differentiation of phenotypic variation (QST) were compared in order to identify the evolutionary forces acting on these traits. Two key factors in the evolution of the species were identified: (1) recurrent volcanic activity has left an imprint in the genetic diversity of the nuclear genes; (2) aridity in southern slopes promotes local adaptation in the driest localities of P. canariensis, despite high levels of gene flow among populations. PMID:24619181

  13. The sensory insular cortex mediates the stress-buffering effects of safety signals but not behavioral control

    PubMed Central

    Christianson, J.P.; Benison, A.M.; Jennings, J.; Sandsmark, E.K.; Amat, J.; Kaufman, R.D.; Baratta, M.V.; Paul., E.D.; Campeau, S.; Watkins, L.R.; Barth, D.S.; Maier, S.F.

    2009-01-01

    Safety signals are learned cues that predict stress-free periods while behavioral control is the ability to modify a stressor by behavioral actions. Both serve to attenuate the effects of stressors such as uncontrollable shocks. Internal and external cues produced by a controlling behavior are followed by a stressor-free interval, and so it is possible that safety learning is fundamental to the effect of control. If this is the case then behavioral control and safety should recruit the same neural machinery. Interestingly, safety signals that prevented a behavioral outcome of stressor exposure that is also blocked by control (reduced social exploration) failed to inhibit activity in the dorsal raphé nucleus or utilize the ventromedial prefrontal cortex, the mechanisms by which behavioral control operates. However, bilateral lesions to a region of posterior insular cortex, termed the “sensory insula,” prevented the effect of safety but not of behavioral control, providing a double-dissociation. These results indicate that stressor-modulators can recruit distinct neural circuitry and imply a critical role of the sensory insula in safety learning. PMID:19074043

  14. Interaction of insular cortex and ventral striatum mediates the effect of incentive memory on choice between goal-directed actions.

    PubMed

    Parkes, Shauna L; Bradfield, Laura A; Balleine, Bernard W

    2015-04-22

    The anterior insular cortex (IC) and the nucleus accumbens (NAc) core have been separately implicated in the selection and performance of actions based on the incentive value of the instrumental outcome. Here, we examined the role of connections between the IC and the NAc core in the performance of goal-directed actions. Rats were trained on two actions for distinct outcomes, after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed the projection from the IC to the NAc core and then disconnected these structures via asymmetrical excitotoxic lesions before training. Contralateral, but not ipsilateral, disconnection of the IC and NAc core disrupted outcome devaluation. We hypothesized that communication between the IC and NAc core is necessary for the retrieval of incentive value at test. To test this, we infused the GABAA agonist muscimol into the IC and the μ-opioid receptor antagonist CTAP into the contralateral NAc before the choice extinction test. As expected, inactivation of the IC in one hemisphere and blocking μ-opioid receptors in the contralateral NAc core abolished outcome-selective devaluation. These results suggest that the IC and NAc core form part of a circuit mediating the retrieval of outcome values and the subsequent choice between goal-directed actions based on those values.

  15. The extreme insular adaptation of Garganornis ballmanni Meijer, 2014: a giant Anseriformes of the Neogene of the Mediterranean Basin

    PubMed Central

    Meijer, Hanneke J. M.; Rossi, Maria Adelaide; Göhlich, Ursula B.

    2017-01-01

    New skeletal elements of the recently described endemic giant anseriform Garganornis ballmanni Meijer, 2014 are presented, coming from the type-area of the Gargano and from Scontrone, southern and central Italy, respectively. The new remains represent the first bird remains found at Scontrone so far, and another shared element between these two localities, both part of the Apulia-Abruzzi Palaeobioprovince. The presence of a very reduced carpometacarpus confirms its flightlessness, only previously supposed on the basis of the very large size, while the morphologies of tarsometatarsus and posterior phalanges clearly indicate the adaptation of G. ballmanni to a terrestrial, non-aquatic, lifestyle. Its very large body size is similar to that observed in different, heavily modified, insular waterfowl and has been normally interpreted as the response to the absence of terrestrial predators and a protection from the aerial ones. The presence of a carpal knob in the proximal carpometacarpus also indicates a fighting behaviour for this large terrestrial bird species. PMID:28280574

  16. Neuroprotective effects of adenosine isolated from Cordyceps cicadae against oxidative and ER stress damages induced by glutamate in PC12 cells.

    PubMed

    Olatunji, Opeyemi J; Feng, Yan; Olatunji, Oyenike O; Tang, Jian; Ouyang, Zhen; Su, Zhaoliang; Wang, Dujun; Yu, Xiaofeng

    2016-06-01

    Glutamate has been proven to induce oxidative stress through the formation of reactive oxygen species (ROS) and increased calcium overload which results in neuronal injury, development of neurodegenerative diseases and death. Adenosine is one of the bioactive nucleosides found in Cordyceps cicadae and it has displayed several pharmacological activities including neuroprotection. In this study, the protective effects of adenosine from C. cicadae against glutamate-induce oxidative stress in PC12 cells were evaluated. The exposure of PC12 cells to glutamate (5mM) induced the formation of ROS, increased Ca(2+) influx, endoplasmic reticulum (ER) stress and up regulated the expression of pro-apoptotic factor Bax. However, pretreatment with adenosine markedly increased cell viability, decreased the elevated levels of ROS and Ca(2+) induced by glutamate. Furthermore adenosine increased the activities of GSH-Px and SOD, as well as retained mitochondria membrane potential (MMP), increased Bcl-2/Bax ratio, and reduced the expression of ERK, p38, and JNK. Overall, our results suggest that adenosine may be a promising potential therapeutic agent for the prevention and treatment of neurodegenerative disorders.

  17. VIEW SOUTHWEST, EAST GABLE ELEVATIONS AND NORTH ELEVATIONS OF ENGINE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW SOUTHWEST, EAST GABLE ELEVATIONS AND NORTH ELEVATIONS OF ENGINE HOUSE IN FOREGROUND AND ECCENTRIC HOUSE IN REAR NOTE ROD LINES IN FOREGROUND RIGHT. - Golden Oil Company, Lot 410 Lease, Sheffield Field, Donaldson, Warren County, PA

  18. 21. Interior of elevator, view from upper elevator room. Lyon ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    21. Interior of elevator, view from upper elevator room. Lyon - Whiteman Air Force Base, Oscar O-1 Minuteman Missile Alert Facility, Southeast corner of Twelfth & Vendenberg Avenues, Knob Noster, Johnson County, MO

  19. location plan, floor plan, building section, north elevation, west elevation, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    location plan, floor plan, building section, north elevation, west elevation, louver window detail, mechanical room door profile, partition profile - Chopawamsic Recreational Demonstration Area - Cabin Camp 1, Staff Bath House, Prince William Forest Park, Triangle, Prince William County, VA

  20. first floor plan, building section, west elevation, south elevation, baseboard ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    first floor plan, building section, west elevation, south elevation, baseboard profile, crown molding profile, window and door details - Cedar Pass Lodge, Cabin 22, 20681 South Dakota Highway 240, Interior, Jackson County, SD

  1. View to southwest showing facade (east elevation) and north elevation ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View to southwest showing facade (east elevation) and north elevation - Portsmouth Naval Hospital, Service Building, Between Williamson Drive & Green Street, adjacent to northern driveway behind Medical Officer's Quarters C, Portsmouth, Portsmouth, VA

  2. 33. Coal Fuel Elevator (diagonal in foreground), Fuel Elevator (left), ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    33. Coal Fuel Elevator (diagonal in foreground), Fuel Elevator (left), Fuel Storage Bins (center), and Power Plant (right) Photographs taken by Joseph E.B. Elliot - Huber Coal Breaker, 101 South Main Street, Ashley, Luzerne County, PA

  3. Refrigeration Plant, North Elevation, Second Floor Plan, East Elevation, Ground ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Refrigeration Plant, North Elevation, Second Floor Plan, East Elevation, Ground Floor Plan, Section A-A - Kennecott Copper Corporation, On Copper River & Northwestern Railroad, Kennicott, Valdez-Cordova Census Area, AK

  4. 3. A general elevation view looking west highlights the Elevator ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. A general elevation view looking west highlights the Elevator and Silo Complex C, commonly known as the 'Landmark' (1940). - Quaker Oats Cereal Factory, Southeast corner of Broadway & Mill Streets, Akron, Summit County, OH

  5. [Enzymatic production of α-ketoglutaric acid by L-glutamate oxidase from L-glutamic acid].

    PubMed

    Niu, Panqing; Zhang, Zhenyu; Liu, Liming

    2014-08-01

    We produced α-ketoglutaric acid (α-KG) from L-glutamic acid, using enzymatic transformation approach with L-glutamate oxidase (LGOX). First, wild strain Streptomyces sp. FMME066 was mutated with NTG, a genetically stable mutant Streptomyces sp. FMME067 was obtained. Under the optimal nutrition conditions with fructose 10 g/L, peptone 7.5 g/L, KH2PO4 1 g/L and CaCl2 0.05 g/L, the maximum LGOX activity reached 0.14 U/mL. The LGOX was stable to pH and temperature, and Mn2+ had a stimulating effect. Finally, after 24 h enzymatic conversion under the optimal conditions, the maximum titer of α-KG reached 38.1 g/L from 47 g/L L-glutamic acid. Enzymatic transformation by LGOX is a potential approach for α-KG production.

  6. Receptor-mediated glutamate release from volume sensitive channels in astrocytes

    NASA Astrophysics Data System (ADS)

    Takano, Takahiro; Kang, Jian; Jaiswal, Jyoti K.; Simon, Sanford M.; Lin, Jane H.-C.; Yu, Yufei; Li, Yuxing; Yang, Jay; Dienel, Gerald; Zielke, H. Ronald; Nedergaard, Maiken

    2005-11-01

    Several lines of work have shown that astrocytes release glutamate in response to receptor activation, which results in a modulation of local synaptic activity. Astrocytic glutamate release is Ca2+-dependent and occurs in conjunction with exocytosis of glutamate containing vesicles. However, astrocytes contain a millimolar concentration of cytosolic glutamate and express channels permeable to small anions, such as glutamate. Here, we tested the idea that astrocytes respond to receptor stimulation by dynamic changes in cell volume, resulting in volume-sensitive channel activation, and efflux of cytosolic glutamate. Confocal imaging and whole-cell recordings demonstrated that astrocytes exhibited a transient Ca2+-dependent cell volume increase, which activated glutamate permeable channels. HPLC analysis revealed that glutamate was released in conjunction with other amino acid osmolytes. Our observations indicate that volume-sensitive channel may constitute a previously uncharacterized target for modulation of astrocyte-neuronal interactions. electrophysiology | exocytosis | neurotransmitters | osmolarity | synapses

  7. Dopamine denervation of the prefrontal cortex increases expression of the astrocytic glutamate transporter GLT-1

    PubMed Central

    Vollbrecht, Peter J.; Simmler, Linda D.; Blakely, Randy D.; Deutch, Ariel Y.

    2014-01-01

    Both dopamine and glutamate are critically involved in cognitive processes such as working memory. Astrocytes, which express dopamine receptors, are essential elements in the termination of glutamatergic signaling: the astrocytic glutamate transporter GLT-1 is responsible for >90% of cortical glutamate uptake. The effect of dopamine depletion on glutamate transporters in the prefrontal cortex (PFC) is unknown. In an effort to determine if astrocytes are a locus of cortical dopamine-glutamate interactions, we examined the effects of chronic dopamine denervation on PFC protein and mRNA levels of glutamate transporters. PFC dopamine denervation elicited a marked increase in GLT-1 protein levels, but had no effect on levels of other glutamate transporters; high affinity glutamate transport was positively correlated with the extent of dopamine depletion. GLT-1 gene expression was not altered. Our data suggests that dopamine depletion may lead to post-translational modifications that result in increased expression and activity of GLT-1 in PFC astrocytes. PMID:24611756

  8. Glutamate Clearance Is Locally Modulated by Presynaptic Neuronal Activity in the Cerebral Cortex

    PubMed Central

    Armbruster, Moritz; Hanson, Elizabeth

    2016-