WorldWideScience

Sample records for causing increased neurogenesis

  1. Taurine increases hippocampal neurogenesis in aging mice

    Directory of Open Access Journals (Sweden)

    Elias Gebara

    2015-05-01

    Full Text Available Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.

  2. D-serine increases adult hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Sebastien eSultan

    2013-08-01

    Full Text Available Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. The neurogenic niche regulates the stem cell proliferation and the differentiation and survival of new neurons and a major contributor to the neurogenic niche are astrocytes. Among the molecules secreted by astrocytes, D-serine is an important gliotransmitter and is a co-agonist of the glutamate, N-methyl-D-aspartate (NMDA receptor. D-serine has been shown to enhance the proliferation of neural stem cells in vitro, but its effect on adult neurogenesis in vivo is unknown. Here, we tested the effect of exogenous administration of D-serine on adult neurogenesis in the mouse dentate gyrus. We found that 1 week of treatment with D-serine increased cell proliferation in vivo and in vitro and increased the density of neural stem cells and transit amplifying progenitors. Furthermore, D-serine increased the survival of newborn neurons. Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

  3. Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior.

    Science.gov (United States)

    Deroche-Gamonet, Véronique; Revest, Jean-Michel; Fiancette, Jean-François; Balado, Eric; Koehl, Muriel; Grosjean, Noëlle; Abrous, Djoher Nora; Piazza, Pier-Vincenzo

    2018-03-05

    The hippocampus is the main locus for adult dentate gyrus (DG) neurogenesis. A number of studies have shown that aberrant DG neurogenesis correlates with many neuropsychiatric disorders, including drug addiction. Although clear causal relationships have been established between DG neurogenesis and memory dysfunction or mood-related disorders, evidence of the causal role of DG neurogenesis in drug-seeking behaviors has not been established. Here we assessed the role of new DG neurons in cocaine self-administration using an inducible transgenic approach that selectively depletes adult DG neurogenesis. Our results show that transgenic mice with decreased adult DG neurogenesis exhibit increased motivation to self-administer cocaine and a higher seeking response to cocaine-related cues. These results identify adult hippocampal neurogenesis as a key factor in vulnerability to cocaine addiction.

  4. Lack of potassium channel induces proliferation and survival causing increased neurogenesis and two-fold hippocampus enlargement

    DEFF Research Database (Denmark)

    Almgren, Malin; Persson, Ann-Sophie; Fenghua, Chen

    2007-01-01

    -fold within dentate gyrus (DG), CA2/3, and hilus of 12-week-old mceph/mceph versus wild type mice. In CA1, there was a tendency toward an increase in volume and in number of astrocytes. The volume estimates in newborn and p14 mice suggest that the overgrowth in mceph/mceph hippocampus starts between birth...

  5. Neurogenesis Inhibition Prevents Enriched Environment to Prolong and Strengthen Social Recognition Memory, But Not to Increase BDNF Expression.

    Science.gov (United States)

    Pereira-Caixeta, Ana Raquel; Guarnieri, Leonardo O; Pena, Roberta R; Dias, Thomáz L; Pereira, Grace Schenatto

    2017-07-01

    Hippocampus-dependent memories, such as social recognition (SRM), are modulated by neurogenesis. However, the precise role of newborn neurons in social memory processing is still unknown. We showed previously that 1 week of enriched environment (EE) is sufficient to increase neurogenesis in the hippocampus (HIP) and the olfactory bulb (OB) of mice. Here, we tested the hypothesis that 1 week of EE would enhance SRM persistence and strength. In addition, as brain-derived neurotrophic factor (BDNF) may mediate some of the neurogenesis effects on memory, we also tested if 1 week of EE would increase BDNF expression in the HIP and OB. We also predicted that neurogenesis inhibition would block the gain of function caused by EE on both SRM and BDNF expression. We found that EE increased BDNF expression in the HIP and OB of mice; at the same time, it allowed SRM to last longer. In addition, mice on EE had their SRM unaffected by memory consolidation interferences. As we predicted, treatment with the anti-mitotic drug AraC blocked EE effects on SRM. Surprisingly, neurogenesis inhibition did not affect the BDNF expression, increased by EE. Together, our results suggest that newborn neurons improve SRM persistence through a BDNF-independent mechanism. Interestingly, this study on social memory uncovered an unexpected dissociation between the effect of adult neurogenesis and BDNF expression on memory persistence, reassuring the idea that not all neurogenesis effects on memory are BDNF-dependent.

  6. Polysaccharides from Wolfberry Prevents Corticosterone-Induced Inhibition of Sexual Behavior and Increases Neurogenesis

    Science.gov (United States)

    Lau, Benson Wui-Man; Lee, Jada Chia-Di; Li, Yue; Fung, Sophia Man-Yuk; Sang, Yan-Hua; Shen, Jiangang; Chang, Raymond Chuen-Chung; So, Kwok-Fai

    2012-01-01

    Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of infertility and sexual dysfunction. However, there is still a scarcity of experimental evidence to support the pro-sexual effect of wolfberry. The aim of this study is to determine the effect of Lycium barbarum polysaccharides (LBP) on male sexual behavior of rats. Here we report that oral feeding of LBP for 21 days significantly improved the male copulatory performance including increase of copulatory efficiency, increase of ejaculation frequency and shortening of ejaculation latency. Furthermore, sexual inhibition caused by chronic corticosterone was prevented by LBP. Simultaneously, corticosterone suppressed neurogenesis in subventricular zone and hippocampus in adult rats, which could be reversed by LBP. The neurogenic effect of LBP was also shown in vitro. Significant correlation was found between neurogenesis and sexual performance, suggesting that the newborn neurons are associated with reproductive successfulness. Blocking neurogenesis in male rats abolished the pro-sexual effect of LBP. Taken together, these results demonstrate the pro-sexual effect of LBP on normal and sexually-inhibited rats, and LBP may modulate sexual behavior by regulating neurogenesis. PMID:22523540

  7. Implication of neuro-genesis during brain development in behavior disorders caused by depleted uranium

    International Nuclear Information System (INIS)

    Legrand, Marie

    2016-01-01

    Humans are continuously exposed to neurotoxic compounds in the environment. The developing brain is more susceptible to neurotoxic compounds and modifications in its growth could lead to disorders in adulthood. Uranium (U) is an environmental heavy metal and induces behavioral disorders as well as affects neurochemistry. The aim of my thesis was to investigate whether depleted uranium (DU) exposure affects neuro-genesis processes, which are implicated in brain development and in synaptic plasticity in adults. While DU increased cell proliferation in the hippocampal neuro-epithelium and decreased cell death at prenatal stages, DU lead to opposite effects in the dentate gyrus at postnatal stages. Moreover, DU had an inhibitory effect on the transition toward neuronal differentiation pathway during development. At adult stage, DU induced a decrease in neuronal differentiation but has no impact in cell proliferation. Finally, DU exposure during brain development caused depressive like behavior at late postnatal and adult stage, and decreased spatial memory at adult stage. Consequently, DU exposure during brain development caused modification in neuro-genesis processes associated to cognitive and emotional disorders at adult age. U could present a threat to human health, especially in pregnant women and children. (author)

  8. Increase in neurogenesis and behavioural benefit after chronic fluoxetine treatment in Wistar rats

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Flagstad, P; Kristjansen, P E G

    2008-01-01

    Disturbances in hippocampal neurogenesis may be involved in the pathophysiology of depression and it has been argued that an increase in the generation of new nerve cells in the hippocampus is involved in the mechanism of action of antidepressants.......Disturbances in hippocampal neurogenesis may be involved in the pathophysiology of depression and it has been argued that an increase in the generation of new nerve cells in the hippocampus is involved in the mechanism of action of antidepressants....

  9. Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly.

    Directory of Open Access Journals (Sweden)

    Hanqian Mao

    2016-09-01

    Full Text Available The exon junction complex (EJC is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis and microcephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employ mouse genetics, transcriptomic and proteomic analyses to demonstrate that haploinsufficiency for each of the 3 core EJC components causes microcephaly via converging regulation of p53 signaling. Using a new conditional allele, we first show that Eif4a3 haploinsufficiency phenocopies aberrant neurogenesis and microcephaly of Magoh and Rbm8a mutant mice. Transcriptomic and proteomic analyses of embryonic brains at the onset of neurogenesis identifies common pathways altered in each of the 3 EJC mutants, including ribosome, proteasome, and p53 signaling components. We further demonstrate all 3 mutants exhibit defective splicing of RNA regulatory proteins, implying an EJC dependent RNA regulatory network that fine-tunes gene expression. Finally, we show that genetic ablation of one downstream pathway, p53, significantly rescues microcephaly of all 3 EJC mutants. This implicates p53 activation as a major node of neurodevelopmental pathogenesis following EJC impairment. Altogether our study reveals new mechanisms to help explain how EJC mutations influence neurogenesis and underlie neurodevelopmental disease.

  10. An Aminopropyl Carbazole Derivative Induces Neurogenesis by Increasing Final Cell Division in Neural Stem Cells.

    Science.gov (United States)

    Shin, Jae-Yeon; Kong, Sun-Young; Yoon, Hye Jin; Ann, Jihyae; Lee, Jeewoo; Kim, Hyun-Jung

    2015-07-01

    P7C3 and its derivatives, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol (1) and N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide (2), were previously reported to increase neurogenesis in rat neural stem cells (NSCs). Although P7C3 is known to increase neurogenesis by protecting newborn neurons, it is not known whether its derivatives also have protective effects to increase neurogenesis. In the current study, we examined how 1 induces neurogenesis. The treatment of 1 in NSCs increased numbers of cells in the absence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), while not affecting those in the presence of growth factors. Compound 1 did not induce astrocytogenesis during NSC differentiation. 5-Bromo-2'-deoxyuridine (BrdU) pulsing experiments showed that 1 significantly enhanced BrdU-positive neurons. Taken together, our data suggest that 1 promotes neurogenesis by the induction of final cell division during NSC differentiation.

  11. Delayed and transient increase of adult hippocampal neurogenesis by physical exercise in DBA/2 mice.

    Directory of Open Access Journals (Sweden)

    Rupert W Overall

    Full Text Available This study builds on the findings that physical activity, such as wheel running in mice, enhances cell proliferation and neurogenesis in the adult hippocampus of the common mouse strain C57BL/6, and that the baseline level of neurogenesis varies by strain, being considerably lower in DBA/2. Because C57BL/6 and DBA/2 are important as the parental strains of the BXD recombinant inbred cross which allows the detection of genetic loci regulating phenotypes such as adult neurogenesis, we performed the current study to investigate the gene x environment interactions regulating neurogenesis. At equal distances and times run DBA/2J mice lacked the acute increase in precursor cell proliferation known from C57BL/6. In DBA/2J proliferation even negatively correlated with the distance run. This was neither due to a stress response (to running itself or single housing nor differences in estrous cycle. DBA/2 animals exhibited a delayed and weaker pro-neurogenic response with a significant increase in numbers of proliferating cells first detectable after more than a week of wheel running. The proliferative response to running was transient in both strains, the effect being undetectable by 6 weeks. There was also a small transient increase in the production of new neurons in DBA/2J, although these extra cells did not survive. These findings indicate that the comparison between C57BL/6 and DBA/2, and by extension the BXD genetic reference population derived from these strains, should provide a powerful tool for uncovering the complex network of modifier genes affecting the activity-dependent regulation of adult hippocampal neurogenesis. More generally, our findings also describe how the external physical environment interacts with the internal genetic environment to produce different responses to the same behavioral stimuli.

  12. Voluntary resistance running induces increased hippocampal neurogenesis in rats comparable to load-free running.

    Science.gov (United States)

    Lee, Min Chul; Inoue, Koshiro; Okamoto, Masahiro; Liu, Yu Fan; Matsui, Takashi; Yook, Jang Soo; Soya, Hideaki

    2013-03-14

    Recently, we reported that voluntary resistance wheel running with a resistance of 30% of body weight (RWR), which produces shorter distances but higher work levels, enhances spatial memory associated with hippocampal brain-derived neurotrophic factor (BDNF) signaling compared to wheel running without a load (WR) [17]. We thus hypothesized that RWR promotes adult hippocampal neurogenesis (AHN) as a neuronal substrate underlying this memory improvement. Here we used 10-week-old male Wistar rats divided randomly into sedentary (Sed), WR, and RWR groups. All rats were injected intraperitoneally with the thymidine analogue 5-Bromo-2'-deoxuridine (BrdU) for 3 consecutive days before wheel running. We found that even when the average running distance decreased by about half, the average work levels significantly increased in the RWR group, which caused muscular adaptation (oxidative capacity) for fast-twitch plantaris muscle without causing any negative stress effects. Additionally, immunohistochemistry revealed that the total BrdU-positive cells and newborn mature cells (BrdU/NeuN double-positive) in the dentate gyrus increased in both the WR and RWR groups. These results provide new evidence that RWR has beneficial effects on AHN comparable to WR, even with short running distances. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Postpartum estrogen withdrawal impairs hippocampal neurogenesis and causes depression- and anxiety-like behaviors in mice.

    Science.gov (United States)

    Zhang, Zhuan; Hong, Juan; Zhang, Suyun; Zhang, Tingting; Sha, Sha; Yang, Rong; Qian, Yanning; Chen, Ling

    2016-04-01

    Postpartum estrogen withdrawal is known to be a particularly vulnerable time for depressive symptoms. Ovariectomized adult mice (OVX-mice) treated with hormone-simulated pregnancy (HSP mice) followed by a subsequent estradiol benzoate (EB) withdrawal (EW mice) exhibited depression- and anxiety-like behaviors, as assessed by forced swim, tail suspension and elevated plus-maze, while HSP mice, OVX mice or EB-treated OVX mice (OVX/EB mice) did not. The survival and neurite growth of newborn neurons in hippocampal dentate gyrus were examined on day 5 after EW. Compared with controls, the numbers of 28-day-old BrdU(+) and BrdU(+)/NeuN(+) cells were increased in HSP mice but significantly decreased in EW mice; the numbers of 10-day-old BrdU(+) cells were increased in HSP mice and OVX/EB mice; and the density of DCX(+) fibers was reduced in EW mice and OVX mice. The phosphorylation of hippocampal NMDA receptor (NMDAr) NR2B subunit or Src was increased in HSP mice but decreased in EW mice. NMDAr agonist NMDA prevented the loss of 28-day-old BrdU(+) cells and the depression- and anxiety-like behaviors in EW mice. NR2B inhibitor Ro25-6981 or Src inhibitor dasatinib caused depression- and anxiety-like behaviors in HSP mice with the reduction of 28-day-old BrdU(+) cells. The hippocampal BDNF levels were reduced in EW mice and OVX mice. TrkB receptor inhibitor K252a reduced the density of DCX(+) fibers in HSP mice without the reduction of 28-day-old BrdU(+) cells, or the production of affective disorder. Collectively, these results indicate that postpartum estrogen withdrawal impairs hippocampal neurogenesis in mice that show depression- and anxiety-like behaviors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition.

    Science.gov (United States)

    Meyers, Emily A; Gobeske, Kevin T; Bond, Allison M; Jarrett, Jennifer C; Peng, Chian-Yu; Kessler, John A

    2016-02-01

    Aging is associated with decreased neurogenesis in the hippocampus and diminished hippocampus-dependent cognitive functions. Expression of bone morphogenetic protein 4 (BMP4) increases with age by more than 10-fold in the mouse dentate gyrus while levels of the BMP inhibitor, noggin, decrease. This results in a profound 30-fold increase in phosphorylated-SMAD1/5/8, the effector of canonical BMP signaling. Just as observed in mice, a profound increase in expression of BMP4 is observed in the dentate gyrus of humans with no known cognitive abnormalities. Inhibition of BMP signaling either by overexpression of noggin or transgenic manipulation not only increases neurogenesis in aging mice, but remarkably, is associated with a rescue of cognitive deficits to levels comparable to young mice. Additive benefits are observed when combining inhibition of BMP signaling and environmental enrichment. These findings indicate that increased BMP signaling contributes significantly to impairments in neurogenesis and to cognitive decline associated with aging, and identify this pathway as a potential druggable target for reversing age-related changes in cognition. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Intermittent fasting attenuates increases in neurogenesis after ischemia and reperfusion and improves recovery.

    Science.gov (United States)

    Manzanero, Silvia; Erion, Joanna R; Santro, Tomislav; Steyn, Frederik J; Chen, Chen; Arumugam, Thiruma V; Stranahan, Alexis M

    2014-05-01

    Intermittent fasting (IF) is neuroprotective across a range of insults, but the question of whether extending the interval between meals alters neurogenesis after ischemia remains unexplored. We therefore measured cell proliferation, cell death, and neurogenesis after transient middle cerebral artery occlusion (MCAO) or sham surgery (SHAM) in mice fed ad libitum (AL) or maintained on IF for 3 months. IF was associated with twofold reductions in circulating levels of the adipocyte cytokine leptin in intact mice, but also prevented further reductions in leptin after MCAO. IF/MCAO mice also exhibit infarct volumes that were less than half those of AL/MCAO mice. We observed a 30% increase in basal cell proliferation in the hippocampus and subventricular zone (SVZ) in IF/SHAM, relative to AL/SHAM mice. However, cell proliferation after MCAO was limited in IF mice, which showed twofold increases in cell proliferation relative to IF/SHAM, whereas AL/MCAO mice exhibit fivefold increases relative to AL/SHAM. Attenuation of stroke-induced neurogenesis was correlated with reductions in cell death, with AL/MCAO mice exhibiting twice the number of dying cells relative to IF/MCAO mice. These observations indicate that IF protects against neurological damage in ischemic stroke, with circulating leptin as one possible mediator.

  16. Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia.

    Science.gov (United States)

    Moraga, Ana; Pradillo, Jesús M; García-Culebras, Alicia; Palma-Tortosa, Sara; Ballesteros, Ivan; Hernández-Jiménez, Macarena; Moro, María A; Lizasoain, Ignacio

    2015-05-10

    Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young- (2 to 3 months) and middle-aged mice (13 to 14 months). Aging increased both microglial proliferation, as shown by a higher number of BrdU(+) cells and BrdU/Iba1(+) cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1(+)/epidermal growth factor receptor (EGFR)(+)/nestin(+)/glial fibrillary acidic protein (GFAP)(+) cells) and type-C cells (prominin-1(+)/EGFR(+)/nestin(-)/Mash1(+) cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX(+) cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN(+)/BrdU(+) and GAD67(+) cells) in the peri-infarct cortical area 14 days after stroke. Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in

  17. Retinoic acid-treated pluripotent stem cells undergoing neurogenesis present increased aneuploidy and micronuclei formation.

    Directory of Open Access Journals (Sweden)

    Rafaela C Sartore

    Full Text Available The existence of loss and gain of chromosomes, known as aneuploidy, has been previously described within the central nervous system. During development, at least one-third of neural progenitor cells (NPCs are aneuploid. Notably, aneuploid NPCs may survive and functionally integrate into the mature neural circuitry. Given the unanswered significance of this phenomenon, we tested the hypothesis that neural differentiation induced by all-trans retinoic acid (RA in pluripotent stem cells is accompanied by increased levels of aneuploidy, as previously described for cortical NPCs in vivo. In this work we used embryonal carcinoma (EC cells, embryonic stem (ES cells and induced pluripotent stem (iPS cells undergoing differentiation into NPCs. Ploidy analysis revealed a 2-fold increase in the rate of aneuploidy, with the prevalence of chromosome loss in RA primed stem cells when compared to naïve cells. In an attempt to understand the basis of neurogenic aneuploidy, micronuclei formation and survivin expression was assessed in pluripotent stem cells exposed to RA. RA increased micronuclei occurrence by almost 2-fold while decreased survivin expression by 50%, indicating possible mechanisms by which stem cells lose their chromosomes during neural differentiation. DNA fragmentation analysis demonstrated no increase in apoptosis on embryoid bodies treated with RA, indicating that cell death is not the mandatory fate of aneuploid NPCs derived from pluripotent cells. In order to exclude that the increase in aneuploidy was a spurious consequence of RA treatment, not related to neurogenesis, mouse embryonic fibroblasts were treated with RA under the same conditions and no alterations in chromosome gain or loss were observed. These findings indicate a correlation amongst neural differentiation, aneuploidy, micronuclei formation and survivin downregulation in pluripotent stem cells exposed to RA, providing evidence that somatically generated chromosomal

  18. Post-stroke gaseous hypothermia increases vascular density but not neurogenesis in the ischemic penumbra of aged rats

    DEFF Research Database (Denmark)

    Sandu, Raluca Elena; Uzoni, Adriana; Ciobanu, Ovidiu

    2016-01-01

    of several genes involved in protein degradation, thereby leading to better preservation of infarcted tissue. Further, hypothermia increased the density of newly formed blood vessels in the peri-lesional cortex did not enhance neurogenesis in the infarcted area of aged rats. Likewise, there was improved......-PCR and immunofluorescence, we assessed infarct size, vascular density, neurogenesis and as well as the expression of genes coding for proteasomal proteins as well as in post-stroke aged Sprague-Dawley rats exposed to H2S- induced hypothermia. Results: Two days exposure to mild hypothermia diminishes the expression...

  19. The evidence for increased L1 activity in the site of human adult brain neurogenesis.

    Directory of Open Access Journals (Sweden)

    Alexey A Kurnosov

    Full Text Available Retroelement activity is a common source of polymorphisms in human genome. The mechanism whereby retroelements contribute to the intraindividual genetic heterogeneity by inserting into the DNA of somatic cells is gaining increasing attention. Brain tissues are suspected to accumulate genetic heterogeneity as a result of the retroelements somatic activity. This study aims to expand our understanding of the role retroelements play in generating somatic mosaicism of neural tissues. Whole-genome Alu and L1 profiling of genomic DNA extracted from the cerebellum, frontal cortex, subventricular zone, dentate gyrus, and the myocardium revealed hundreds of somatic insertions in each of the analyzed tissues. Interestingly, the highest concentration of such insertions was detected in the dentate gyrus-the hotspot of adult neurogenesis. Insertions of retroelements and their activity could produce genetically diverse neuronal subsets, which can be involved in hippocampal-dependent learning and memory.

  20. Implantation of Neuronal Stem Cells Enhances Object Recognition without Increasing Neurogenesis after Lateral Fluid Percussion Injury in Mice

    Directory of Open Access Journals (Sweden)

    Laura B. Ngwenya

    2018-01-01

    Full Text Available Cognitive deficits after traumatic brain injury (TBI are debilitating and contribute to the morbidity and loss of productivity of over 10 million people worldwide. Cell transplantation has been linked to enhanced cognitive function after experimental traumatic brain injury, yet the mechanism of recovery is poorly understood. Since the hippocampus is a critical structure for learning and memory, supports adult neurogenesis, and is particularly vulnerable after TBI, we hypothesized that stem cell transplantation after TBI enhances cognitive recovery by modulation of endogenous hippocampal neurogenesis. We performed lateral fluid percussion injury (LFPI in adult mice and transplanted embryonic stem cell-derived neural progenitor cells (NPC. Our data confirm an injury-induced cognitive deficit in novel object recognition, a hippocampal-dependent learning task, which is reversed one week after NPC transplantation. While LFPI alone promotes hippocampal neurogenesis, as revealed by doublecortin immunolabeling of immature neurons, subsequent NPC transplantation prevents increased neurogenesis and is not associated with morphological maturation of endogenous injury-induced immature neurons. Thus, NPC transplantation enhances cognitive recovery early after LFPI without a concomitant increase in neuron numbers or maturation.

  1. Increased radial glia quiescence, decreased reactivation upon injury and unaltered neuroblast behavior underlie decreased neurogenesis in the aging zebrafish telencephalon.

    Science.gov (United States)

    Edelmann, Kathrin; Glashauser, Lena; Sprungala, Susanne; Hesl, Birgit; Fritschle, Maike; Ninkovic, Jovica; Godinho, Leanne; Chapouton, Prisca

    2013-09-01

    The zebrafish has recently become a source of new data on the mechanisms of neural stem cell (NSC) maintenance and ongoing neurogenesis in adult brains. In this vertebrate, neurogenesis occurs at high levels in all ventricular regions of the brain, and brain injuries recover successfully, owing to the recruitment of radial glia, which function as NSCs. This new vertebrate model of adult neurogenesis is thus advancing our knowledge of the molecular cues in use for the activation of NSCs and fate of their progeny. Because the regenerative potential of somatic stem cells generally weakens with increasing age, it is important to assess the extent to which zebrafish NSC potential decreases or remains unaltered with age. We found that neurogenesis in the ventricular zone, in the olfactory bulb, and in a newly identified parenchymal zone of the telencephalon indeed declines as the fish ages and that oligodendrogenesis also declines. In the ventricular zone, the radial glial cell population remains largely unaltered morphologically but enters less frequently into the cell cycle and hence produces fewer neuroblasts. The neuroblasts themselves do not change their behavior with age and produce the same number of postmitotic neurons. Thus, decreased neurogenesis in the physiologically aging zebrafish brain is correlated with an increasing quiescence of radial glia. After injuries, radial glia in aged brains are reactivated, and the percentage of cell cycle entry is increased in the radial glia population. However, this reaction is far less pronounced than in younger animals, pointing to irreversible changes in aging zebrafish radial glia. Copyright © 2013 Wiley Periodicals, Inc.

  2. The Histamine H1 Receptor Participates in the Increased Dorsal Telencephalic Neurogenesis in Embryos from Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Karina H. Solís

    2017-12-01

    Full Text Available Increased neuron telencephalic differentiation during deep cortical layer formation has been reported in embryos from diabetic mice. Transitory histaminergic neurons within the mesencephalon/rhombencephalon are responsible for fetal histamine synthesis during development, fibers from this system arrives to the frontal and parietal cortex at embryo day (E 15. Histamine is a neurogenic factor for cortical neural stem cells in vitro through H1 receptor (H1R which is highly expressed during corticogenesis in rats and mice. Furthermore, in utero administration of an H1R antagonist, chlorpheniramine, decreases the neuron markers microtubuline associated protein 2 (MAP2 and forkhead box protein 2. Interestingly, in the diabetic mouse model of diabetes induced with streptozotocin, an increase in fetal neurogenesis in terms of MAP2 expression in the telencephalon is reported at E11.5. Because of the reported effects on cortical neuron differentiation of maternal diabetes in one hand and of histamine in the other, here the participation of histamine and H1R on the increased dorsal telencephalic neurogenesis was explored. First, the increased neurogenesis in the dorsal telencephalon at E14 in diabetic rats was corroborated by immunohistochemistry and Western blot. Then, changes during corticogenesis in the level of histamine was analyzed by ELISA and in H1R expression by qRT-PCR and Western blot and, finally, we tested H1R participation in the increased dorsal telencephalic neurogenesis by the systemic administration of chlorpheniramine. Our results showed a significant increase of histamine at E14 and in the expression of the receptor at E12. The administration of chlorpheniramine to diabetic rats at E12 prevented the increased expression of βIII-tubulin and MAP2 mRNAs (neuron markers and partially reverted the increased level of MAP2 protein at E14, concluding that H1R have an important role in the increased neurogenesis within the dorsal telencephalon

  3. Neurogenesis and Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Philippe Taupin

    2006-01-01

    Full Text Available Alzheimer’s disease (AD is a neurodegenerative disease, characterized in the brain by amyloid plaque deposits and neurofibrillary tangles. It is the most common form of dementia among older people. There is at present no cure for AD, and current treatments consist mainly in drug therapy. Potential therapies for AD involve gene and cellular therapy. The recent confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs reside in the adult central nervous system (CNS provide new opportunities for cellular therapy in the CNS, particularly for AD, and to better understand brain physiopathology. Hence, researchers have aimed at characterizing neurogenesis in patients with AD. Studies show that neurogenesis is increased in these patients, and in animal models of AD. The effect of drugs used to treat AD on neurogenesis is currently being investigated, to identify whether neurogenesis contributes to their therapeutic activities.

  4. Neurogenesis and Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Philippe Taupin

    2006-01-01

    Full Text Available Alzheimer's disease (AD is a neurodegenerative disease, characterized in the brain by amyloid plaque deposits and neurofibrillary tangles. It is the most common form of dementia among older people. There is at present no cure for AD, and current treatments consist mainly in drug therapy. Potential therapies for AD involve gene and cellular therapy. The recent confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs reside in the adult central nervous system (CNS provide new opportunities for cellular therapy in the CNS, particularly for AD, and to better understand brain physiopathology. Hence, researchers have aimed at characterizing neurogenesis in patients with AD. Studies show that neurogenesis is increased in these patients, and in animal models of AD. The effect of drugs used to treat AD on neurogenesis is currently being investigated, to identify whether neurogenesis contributes to their therapeutic activities.

  5. Fluoxetine Increases Hippocampal Neurogenesis and Induces Epigenetic Factors But Does Not Improve Functional Recovery after Traumatic Brain Injury

    Science.gov (United States)

    Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Noble-Haeusslein, Linda J.

    2011-01-01

    Abstract The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits. PMID:21175261

  6. Neurogenesis and Increase in Differentiated Neural Cell Survival via Phosphorylation of Akt1 after Fluoxetine Treatment of Stem Cells

    Directory of Open Access Journals (Sweden)

    Anahita Rahmani

    2013-01-01

    Full Text Available Fluoxetine (FLX is a selective serotonin reuptake inhibitor (SSRI. Its action is possibly through an increase in neural cell survival. The mechanism of improved survival rate of neurons by FLX may relate to the overexpression of some kinases such as Akt protein. Akt1 (a serine/threonine kinase plays a key role in the modulation of cell proliferation and survival. Our study evaluated the effects of FLX on mesenchymal stem cell (MSC fate and Akt1 phosphorylation levels in MSCs. Evaluation tests included reverse transcriptase polymerase chain reaction, western blot, and immunocytochemistry assays. Nestin, MAP-2, and β-tubulin were detected after neurogenesis as neural markers. Ten μM of FLX upregulated phosphorylation of Akt1 protein in induced hEnSC significantly. Also FLX did increase viability of these MSCs. Continuous FLX treatment after neurogenesis elevated the survival rate of differentiated neural cells probably by enhanced induction of Akt1 phosphorylation. This study addresses a novel role of FLX in neurogenesis and differentiated neural cell survival that may contribute to explaining the therapeutic action of fluoxetine in regenerative pharmacology.

  7. Enrichment increases hippocampal neurogenesis independent of blood monocyte-derived microglia presence following high-dose total body irradiation.

    Science.gov (United States)

    Ruitenberg, Marc J; Wells, Julia; Bartlett, Perry F; Harvey, Alan R; Vukovic, Jana

    2017-06-01

    Birth of new neurons in the hippocampus persists in the brain of adult mammals and critically underpins optimal learning and memory. The process of adult neurogenesis is significantly reduced following brain irradiation and this correlates with impaired cognitive function. In this study, we aimed to compare the long-term effects of two environmental paradigms (i.e. enriched environment and exercise) on adult neurogenesis following high-dose (10Gy) total body irradiation. When housed in standard (sedentary) conditions, irradiated mice revealed a long-lasting (up to 4 months) deficit in neurogenesis in the granule cell layer of the dentate gyrus, the region that harbors the neurogenic niche. This depressive effect of total body irradiation on adult neurogenesis was partially alleviated by exposure to enriched environment but not voluntary exercise, where mice were single-housed with unlimited access to a running wheel. Exposure to voluntary exercise, but not enriched environment, did lead to significant increases in microglia density in the granule cell layer of the hippocampus; our study shows that these changes result from local microglia proliferation rather than recruitment and infiltration of circulating Cx 3 cr1 +/gfp blood monocytes that subsequently differentiate into microglia-like cells. In summary, latent neural precursor cells remain present in the neurogenic niche of the adult hippocampus up to 8 weeks following high-dose total body irradiation. Environmental enrichment can partially restore the adult neurogenic process in this part of the brain following high-dose irradiation, and this was found to be independent of blood monocyte-derived microglia presence. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  8. Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation.

    Science.gov (United States)

    Kodali, Maheedhar; Parihar, Vipan K; Hattiangady, Bharathi; Mishra, Vikas; Shuai, Bing; Shetty, Ashok K

    2015-01-28

    Greatly waned neurogenesis, diminished microvasculature, astrocyte hypertrophy and activated microglia are among the most conspicuous structural changes in the aged hippocampus. Because these alterations can contribute to age-related memory and mood impairments, strategies efficacious for mitigating these changes may preserve cognitive and mood function in old age. Resveratrol, a phytoalexin found in the skin of red grapes having angiogenic and antiinflammatory properties, appears ideal for easing these age-related changes. Hence, we examined the efficacy of resveratrol for counteracting age-related memory and mood impairments and the associated detrimental changes in the hippocampus. Two groups of male F344 rats in late middle-age having similar learning and memory abilities were chosen and treated with resveratrol or vehicle for four weeks. Analyses at ~25 months of age uncovered improved learning, memory and mood function in resveratrol-treated animals but impairments in vehicle-treated animals. Resveratrol-treated animals also displayed increased net neurogenesis and microvasculature, and diminished astrocyte hypertrophy and microglial activation in the hippocampus. These results provide novel evidence that resveratrol treatment in late middle age is efficacious for improving memory and mood function in old age. Modulation of the hippocampus plasticity and suppression of chronic low-level inflammation appear to underlie the functional benefits mediated by resveratrol.

  9. Administration of Zinc plus Cyclo-(His-Pro Increases Hippocampal Neurogenesis in Rats during the Early Phase of Streptozotocin-Induced Diabetes

    Directory of Open Access Journals (Sweden)

    Bo Young Choi

    2017-01-01

    Full Text Available The effects of zinc supplementation on hippocampal neurogenesis in diabetes mellitus have not been studied. Herein, we investigated the effects of zinc plus cyclo-(His-Pro (ZC on neurogenesis occurring in the subgranular zone of dentate gyrus after streptozotocin (STZ-induced diabetes. ZC (27 mg/kg was administered by gavage once daily for one or six weeks from the third day after the STZ injection, and histological evaluation was performed at 10 (early phase or 45 (late phase days after STZ injection. We found that the proliferation of progenitor cells in STZ-induced diabetic rats showed an increase in the early phase. Additionally, ZC treatment remarkably increased the number of neural progenitor cells (NPCs and immature neurons in the early phase of STZ-induced diabetic rats. Furthermore, ZC treatment showed increased survival rate of newly generated cells but no difference in the level of neurogenesis in the late phase of STZ-induced diabetic rats. The present study demonstrates that zinc supplementation by ZC increases both NPCs proliferation and neuroblast production at the early phase of diabetes. Thus, this study suggests that zinc supplemented with a histidine/proline complex may have beneficial effects on neurogenesis in patients experiencing the early phase of Type 1 diabetes.

  10. What causes the hippocampal volume decrease in depression? : Are neurogenesis, glial changes and apoptosis implicated?

    NARCIS (Netherlands)

    Czeh, B.; Lucassen, P.J.

    2007-01-01

    Even though in vivo imaging studies document significant reductions of hippocampal volume in depressed patients, the exact underlying cellular mechanisms are unclear. Since stressful life events are associated with an increased risk of developing depression, preclinical studies in which animals are

  11. Absence of the calcium-binding protein calretinin, not of calbindin D-28k, causes a permanent impairment of murine adult hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Kiran eTodkar

    2012-04-01

    Full Text Available Calretinin (CR and calbindin D-28k (CB are cytosolic EF-hand Ca2+-binding proteins and function as Ca2+ buffers affecting the spatiotemporal aspects of Ca2+ transients and possibly also as Ca2+ sensors modulating signaling cascades. In the adult hippocampal circuitry, CR and CB are expressed in specific principal neurons and subsets of interneurons. In addition, CR is transiently expressed within the neurogenic dentate gyrus (DG niche. CR and CB expression during adult neurogenesis mark critical transition stages, onset of differentiation for CR and the switch to adult-like connectivity for CB. Absence of either protein during these stages in null-mutant mice may have functional consequences and contribute to some aspects of the identified phenotypes. We report the impact of CR- and CB-deficiency on the proliferation and differentiation of progenitor cells within the subgranular zone (SGZ neurogenic niche of the DG. Effects were evaluated I 2 and 4 weeks postnatally, during the transition period of the proliferative matrix to the adult state, and II in adult animals (3 months to trace possible permanent changes in adult neurogenesis. The absence of CB from differentiated DG granule cells has no retrograde effect on the proliferative activity of progenitor cells, nor affects survival or migration/differentiation of newborn neurons in the adult DG including the SGZ. On the contrary, lack of CR from immature early postmitotic granule cells causes an early loss in proliferative capacity of the SGZ that is maintained into adult age, when it has a further impact on the migration/survival of newborn granule cells. The transient CR expression at the onset of adult neurogenesis differentiation may thus have two functions: I to serve as a self-maintenance signal for the pool of cells at the same stage of neurogenesis contributing to their survival/differentiation, and II it may contribute to retrograde signaling required for maintenance of the progenitor

  12. Neurogenesis-mediated forgetting minimizes proactive interference.

    Science.gov (United States)

    Epp, Jonathan R; Silva Mera, Rudy; Köhler, Stefan; Josselyn, Sheena A; Frankland, Paul W

    2016-02-26

    Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting.

  13. P2X7 receptor inhibition increases CNTF in the subventricular zone, but not neurogenesis or neuroprotection after stroke in adult mice.

    Science.gov (United States)

    Kang, Seong Su; Keasey, Matthew Phillip; Hagg, Theo

    2013-10-01

    Increasing endogenous ciliary neurotrophic factor (CNTF) expression with a pharmacological agent might be beneficial after stroke as CNTF both promotes neurogenesis and, separately, is neuroprotective. P2X7 purinergic receptor inhibition is neuroprotective in rats and increases CNTF release in rat CMT1A Schwann cells. We, first, investigated the role of P2X7 in regulating CNTF and neurogenesis in adult mouse subventricular zone (SVZ). CNTF expression was increased by daily intravenous injections of the P2X7 antagonist Brilliant Blue G (BBG) in naïve C57BL/6 or Balb/c mice over 3 days. Despite the ∼40-60 % increase or decrease in CNTF with BBG or the agonist BzATP, respectively, the number of proliferated BrdU+SVZ nuclei did not change. BBG failed to increase FGF2, which is involved in CNTF-regulated neurogenesis, but induced IL-6, LIF, and EGF, which are known to reduce SVZ proliferation. Injections of IL-6 next to the SVZ induced CNTF and FGF2, but not proliferation, suggesting that IL-6 counteracts their neurogenesis-inducing effects. Following ischemic injury of the striatum by middle cerebral artery occlusion (MCAO), a 3-day BBG treatment increased CNTF in the medial penumbra containing the SVZ. BBG also induced CNTF and LIF, which are known to be protective following stroke, in the whole striatum after MCAO, but not GDNF or BDNF. However, BBG treatment did not reduce the lesion area or apoptosis in the penumbra. Even so, this study shows that P2X7 can be targeted with systemic drug treatments to differentially regulate neurotrophic factors in the brain following stroke.

  14. A Study on the Effect of Neurogenesis and Regulation of GSK3β/PP2A Expression in Acupuncture Treatment of Neural Functional Damage Caused by Focal Ischemia in MCAO Rats

    Directory of Open Access Journals (Sweden)

    Ding Luo

    2014-01-01

    Full Text Available 170 SD rats were randomly divided to five groups. Rats in model group, no-acupuncture group, and acupuncture group were subjected to MCAO surgery. Acupuncture group received 3 consecutive acupuncture treatments at a parameter that deep in 2 mm towards apex nasi and thrust/lifted at 3 times per second for 1 minute, while model group and no-acupuncture group were no-intervention control groups. Serious neural functional damage and sharp decrease of cerebral blood flow, obvious infarction volume, increased nestin mRNA expression, and immunopositive cells population (nestin+, BrdU+ and nestin/BrdU+ were found in MCAO rats which had not been observed in normal group and sham-operated group. However, the damage was attenuated by rat’s “self-healing” capacity 3 days after MCAO. And the “self-healing” capacity can be strengthen by acupuncture treatment through increasing cerebral blood flow, neurogenesis, and regulation of gene transcription or GSK-3β and PP2A expression. In conclusion, the present study indicates that the underlying mechanism of acupuncture treatment on neural functional damage caused by focal ischemia injury is a multiple interaction which may involve improved cerebral blood supply, neurogenesis, and regulation of gene transcription or GSK-3β and PP2A expression in MCAO rats.

  15. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    Energy Technology Data Exchange (ETDEWEB)

    Khodanovich, M. Yu., E-mail: khodanovich@mail.tsu.ru [Tomsk State University, Research Institute of Biology and Biophysics, Laboratory of Neurobiology (Russian Federation)

    2015-11-17

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  16. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    Science.gov (United States)

    Khodanovich, M. Yu.

    2015-11-01

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  17. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    International Nuclear Information System (INIS)

    Khodanovich, M. Yu.

    2015-01-01

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors

  18. Sex steroids and neurogenesis.

    Science.gov (United States)

    Heberden, Christine

    2017-10-01

    The brain has long been known as a dimorphic organ and as a target of sex steroids. It is also a site for their synthesis. Sex steroids in numerous ways can modify cerebral physiology, and along with many processes adult neurogenesis is also modulated by sex steroids. This review will focus on the effects of the main steroids, estrogens, androgens and progestogens, and unveil some aspects of their partly disclosed mechanisms of actions. Gonadal steroids act on different steps of neurogenesis: cell proliferation seems to be increased by estrogens only, while androgens and progestogens favor neuronal renewal by increasing cell survival; differentiation is a common target. Aging is characterized by a cognitive deficiency, paralleled by a decrease in the rate of neuronal renewal and in the levels of circulating gonadal hormones. Therefore, the effects of gonadal hormones on the aging brain are important to consider. The review will also be expanded to related molecules which are agonists to the nuclear receptors. Sex steroids can modify adult neuronal renewal and the extensive knowledge of their actions on neurogenesis is essential, as it can be a leading pathway to therapeutic perspectives. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress.

    Science.gov (United States)

    Culig, Luka; Surget, Alexandre; Bourdey, Marlene; Khemissi, Wahid; Le Guisquet, Anne-Marie; Vogel, Elise; Sahay, Amar; Hen, René; Belzung, Catherine

    2017-11-01

    Major depression is hypothesized to be associated with dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis. Copyright © 2017 Elsevier Ltd. All rights

  20. Influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats.

    Science.gov (United States)

    Kim, Hong; Lee, Myoung-Hwa; Chang, Hyun-Kyung; Lee, Taeck-Hyun; Lee, Hee-Hyuk; Shin, Min-Chul; Shin, Mal-Soon; Won, Ran; Shin, Hye-Sook; Kim, Chang-Ju

    2006-03-01

    During the prenatal period, the development of individual is influenced by the environmental factors. In the present study, the influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats was investigated. The exposure to the noise during pregnancy caused growth retardation, decreased neurogenesis in the hippocampus, and impaired spatial learning ability in pups. The exposure to music during pregnancy, on the other hand, caused increased neurogenesis in the hippocampus and enhanced spatial learning ability in pups. The present study has shown the importance of the prenatal environmental conditions for the cognition and brain development.

  1. 56Fe particle exposure results in a long-lasting increase in a cellular index of genomic instability and transiently suppresses adult hippocampal neurogenesis in vivo

    Science.gov (United States)

    DeCarolis, Nathan A.; Rivera, Phillip D.; Ahn, Francisca; Amaral, Wellington Z.; LeBlanc, Junie A.; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal R.; Chen, Benjamin P. C.; Eisch, Amelia J.

    2014-07-01

    The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreERT2/R26R:YFP mice, respectively). Mice were subjected to 56Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24 h), intermediate (7 d), and/or long time points (2-3 mo) post-irradiation. 56Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, 56Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. 56Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, 56Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, 56Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support

  2. Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB.

    Science.gov (United States)

    Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Song, Minah; Kim, Hyunjung; Lee, Tae-Kyeong; Lee, Jae Chul; Kim, Young-Myeong; Hwang, In Koo; Kim, Dae Won; Lee, Choong-Hyun; Yan, Bing Chun; Kang, Il Jun; Won, Moo-Ho

    2018-04-25

    Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1 mg/kg and 3 mg/kg rufinamide for 4 weeks. Treatment with 3 mg/kg rufinamide, not 1 mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (p-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and p-CREB. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Forebrain neurogenesis: From embryo to adult.

    Science.gov (United States)

    Dennis, Daniel; Picketts, David; Slack, Ruth S; Schuurmans, Carol

    2016-01-01

    A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16-17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis : From embryo to adult . The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with 'state of the art' techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.

  4. Neurogenesis and The Effect of Antidepressants

    Directory of Open Access Journals (Sweden)

    Philippe Taupin

    2006-01-01

    Full Text Available The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs reside in the adult central nervous system (CNS suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fluoxetine, increase neurogenesis in the dentate gyrus (DG and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.

  5. Neurogenesis and the Effect of Antidepressants

    Directory of Open Access Journals (Sweden)

    Philippe Taupin

    2006-01-01

    Full Text Available The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs reside in the adult central nervous system (CNS suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fluoxetine, increase neurogenesis in the dentate gyrus (DG and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.

  6. Prolonged Running, not Fluoxetine Treatment, Increases Neurogenesis, but does not Alter Neuropathology, in the 3xTg Mouse Model of Alzheimer's Disease.

    NARCIS (Netherlands)

    Marlatt, M.W.; Potter, M.C.; Bayer, T.A.; van Praag, H.; Lucassen, P.J.

    2013-01-01

    Reductions in adult neurogenesis have been documented in the original 3xTg mouse model of Alzheimer's disease (AD), notably occurring at the same age when spatial memory deficits and amyloid plaque pathology appeared. As this suggested reduced neurogenesis was associated with behavioral deficits, we

  7. The combination of ethanol with mephedrone increases the signs of neurotoxicity and impairs neurogenesis and learning in adolescent CD-1 mice

    International Nuclear Information System (INIS)

    Ciudad-Roberts, Andrés; Duart-Castells, Leticia; Camarasa, Jorge; Pubill, David; Escubedo, Elena

    2016-01-01

    A new family of psychostimulants, under the name of cathinones, has broken into the market in the last decade. In light of the fact that around 95% of cathinone consumers have been reported to combine them with alcoholic drinks, we sought to study the consequences of the concomitant administration of ethanol on mephedrone -induced neurotoxicity. Adolescent male Swiss-CD1 mice were administered four times in one day, every 2 h, with saline, mephedrone (25 mg/kg), ethanol (2; 1.5; 1.5; 1 g/kg) and their combination at a room temperature of 26 ± 2 °C. The combination with ethanol impaired mephedrone-induced decreases in dopamine transporter and tyrosine hydroxylase in the frontal cortex; and in serotonin transporter and tryptophan hydroxylase in the hippocampus by approximately 2-fold, 7 days post-treatment. Furthermore, these decreases correlated with a 2-fold increase in lipid peroxidation, measured as concentration of malondialdehyde (MDA), 24 h post-treatment, and were accompanied by changes in oxidative stress-related enzymes. Ethanol also notably potentiated mephedrone-induced negative effects on learning and memory, as well as hippocampal neurogenesis, measured through the Morris water maze (MWM) and 5-bromo-2′-deoxyuridine staining, respectively. These results are of special significance, since alcohol is widely co-abused with amphetamine derivatives such as mephedrone, especially during adolescence, a crucial stage in brain maturation. Given that the hippocampus is greatly involved in learning and memory processes, normal brain development in young adults could be affected with permanent behavioral consequences after this type of drug co-abuse. - Highlights: • Mice were administered a binge regimen of mephedrone plus/minus ethanol. • Ethanol exacerbated mephedrone-induced changes in 5-HT and DA function markers. • Neurochemical alterations were accompanied by an increase in oxidative stress. • Ethanol potentiated mephedrone-induced learning

  8. The combination of ethanol with mephedrone increases the signs of neurotoxicity and impairs neurogenesis and learning in adolescent CD-1 mice

    Energy Technology Data Exchange (ETDEWEB)

    Ciudad-Roberts, Andrés; Duart-Castells, Leticia; Camarasa, Jorge; Pubill, David, E-mail: d.pubill@ub.edu; Escubedo, Elena

    2016-02-15

    A new family of psychostimulants, under the name of cathinones, has broken into the market in the last decade. In light of the fact that around 95% of cathinone consumers have been reported to combine them with alcoholic drinks, we sought to study the consequences of the concomitant administration of ethanol on mephedrone -induced neurotoxicity. Adolescent male Swiss-CD1 mice were administered four times in one day, every 2 h, with saline, mephedrone (25 mg/kg), ethanol (2; 1.5; 1.5; 1 g/kg) and their combination at a room temperature of 26 ± 2 °C. The combination with ethanol impaired mephedrone-induced decreases in dopamine transporter and tyrosine hydroxylase in the frontal cortex; and in serotonin transporter and tryptophan hydroxylase in the hippocampus by approximately 2-fold, 7 days post-treatment. Furthermore, these decreases correlated with a 2-fold increase in lipid peroxidation, measured as concentration of malondialdehyde (MDA), 24 h post-treatment, and were accompanied by changes in oxidative stress-related enzymes. Ethanol also notably potentiated mephedrone-induced negative effects on learning and memory, as well as hippocampal neurogenesis, measured through the Morris water maze (MWM) and 5-bromo-2′-deoxyuridine staining, respectively. These results are of special significance, since alcohol is widely co-abused with amphetamine derivatives such as mephedrone, especially during adolescence, a crucial stage in brain maturation. Given that the hippocampus is greatly involved in learning and memory processes, normal brain development in young adults could be affected with permanent behavioral consequences after this type of drug co-abuse. - Highlights: • Mice were administered a binge regimen of mephedrone plus/minus ethanol. • Ethanol exacerbated mephedrone-induced changes in 5-HT and DA function markers. • Neurochemical alterations were accompanied by an increase in oxidative stress. • Ethanol potentiated mephedrone-induced learning

  9. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus

    Directory of Open Access Journals (Sweden)

    Lorena Varela-Nallar

    2015-01-01

    Full Text Available Andrographolide (ANDRO is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β, a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected.

  10. Detrimental role of prolonged sleep deprivation on adult neurogenesis

    Directory of Open Access Journals (Sweden)

    Carina eFernandes

    2015-04-01

    Full Text Available Adult mammalian brains continuously generate new neurons, a phenomenon called neurogenesis. Both environmental stimuli and endogenous factors are important regulators of neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and neurogenesis in brain function, such as learning, memory and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on neurogenesis.

  11. Detrimental effects of physical inactivity on neurogenesis

    Directory of Open Access Journals (Sweden)

    Trenton Lippert

    2016-01-01

    Full Text Available Patients diagnosed with neurological disorders exhibit a variety of physical and psychiatric symptoms, including muscle atrophy, general immobility, and depression. Patients who participate in physical rehabilitation at times show unexpected clinical improvement, which includes diminished depression and other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for central nervous system (CNS disorders, transplantation of exogenous stem cells, and enhancing the endogenous neurogenesis. The latter therapy utilizes a natural method of re-innervating the injured brain, which may mend neurological impairments. In this study, we examine how inactivity-induced atrophy, using the hindlimb suspension model, alters neurogenesis in rats. The hypothesis is that inactivity inhibits neurogenesis by decreasing circulation growth or trophic factors, such as vascular endothelial growth or neurotrophic factors. The restriction modifies neurogenesis and stem cell differentiation in the CNS, the stem cell microenvironment is examined by the trophic and growth factors, including stress-related proteins. Despite growing evidence revealing the benefits of "increased" exercise on neurogenesis, the opposing theory involving "physical inactivity," which simulates pathological states, continues to be neglected. This novel theory will allow us to explore the effects on neurogenesis by an intransigent stem cell microenvironment likely generated by inactivity. 5-bromo-2-deoxyuridine labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid, and brain levels of trophic factors, growth factors, and stress-related proteins are suggested identifiers of neurogenesis, while evaluation of spontaneous movements will give insight into the psychomotor effects of inactivity. Investigations devised to show how in vivo stimulation, or lack thereof, affects the stem cell microenvironment are necessary to establish

  12. Linking adult olfactory neurogenesis to social behavior

    Directory of Open Access Journals (Sweden)

    Claudia E Feierstein

    2012-11-01

    Full Text Available In the adult brain, new neurons are added to two brain areas: the olfactory bulb and the hippocampus. Newly-generated neurons integrate into the preexisting circuits, bringing a set of unique properties, such as increased plasticity and responsiveness to stimuli. However, the functional implications of the constant addition of these neurons remain unclear, although they are believed to be important for learning and memory. The levels of neurogenesis are regulated by a variety of environmental factors, as well as during learning, suggesting that new neurons could be important for coping with changing environmental demands. Notably, neurogenesis has been shown to be physiologically regulated in relation to reproductive behavior: neurogenesis increases in female mice upon exposure to cues of the mating partners, during pregnancy and lactation, and in male mice upon exposure to their offspring. In this scenario, and because of the key contribution of olfaction to maternal behavior, we sought to investigate the contribution of adult-generated neurons in the olfactory system to maternal behavior and offspring recognition. To do so, we selectively disrupted neurogenesis in the olfactory pathway of female mice using focal irradiation. Disruption of adult neurogenesis in the olfactory bulb did not affect maternal behavior, or the ability of female mice to discriminate familiar from unfamiliar pups. However, reduction of olfactory neurogenesis resulted in abnormal social interaction of female mice, specifically with male conspecifics. Because the olfactory system is crucial for sex recognition, we suggest that the abnormal interaction with males could result from the inability to detect or discriminate male-specific odors and could therefore have implications for the recognition of potential mating partners. Here, I review the results of this and other studies, and discuss their implications for our understanding of the function of adult neurogenesis.

  13. Pharmacovigilance: Tiens Slimming Tea Causes Increased Blood ...

    African Journals Online (AJOL)

    ... possible link between the constituents of the slimming tea and increased blood pressure and also provide evidence of other possible harmful effects that may occur with the use of the slimming tea. Keywords: Pharmacovigilance, hypertension, slimming tea. West African Journal of Pharmacology and Drug Research Vol.

  14. Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death.

    Science.gov (United States)

    Almeida, Ana S; Soares, Nuno L; Vieira, Melissa; Gramsbergen, Jan Bert; Vieira, Helena L A

    2016-01-01

    's increasing number of differentiated neurons in OHSC. In conclusion, CO's increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO's effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies.

  15. Human neural progenitor cell engraftment increases neurogenesis and microglial recruitment in the brain of rats with stroke.

    Directory of Open Access Journals (Sweden)

    Zahra Hassani

    Full Text Available Stem cell transplantation is to date one of the most promising therapies for chronic ischemic stroke. The human conditionally immortalised neural stem cell line, CTX0E03, has demonstrable efficacy in a rodent model of stroke and is currently in clinical trials. Nonetheless, the mechanisms by which it promotes brain repair are not fully characterised. This study investigated the cellular events occurring after CTX0E03 transplantation in the brains of rats that underwent ischemic stroke.We focused on the endogenous proliferative activity of the host brain in response to cell transplantation and determined the identity of the proliferating cells using markers for young neurons (doublecortin, Dcx and microglia (CD11b. So as to determine the chronology of events occurring post-transplantation, we analysed the engrafted brains one week and four weeks post-transplantation.We observed a significantly greater endogenous proliferation in the striatum of ischemic brains receiving a CTX0E03 graft compared to vehicle-treated ischemic brains. A significant proportion of these proliferative cells were found to be Dcx+ striatal neuroblasts. Further, we describe an enhanced immune response after CTX0E03 engraftment, as shown by a significant increase of proliferating CD11b+ microglial cells.Our study demonstrates that few Dcx+ neuroblasts are proliferative in normal conditions, and that this population of proliferative neuroblasts is increased in response to stroke. We further show that CTX0E03 transplantation after stroke leads to the maintenance of this proliferative activity. Interestingly, the preservation of neuronal proliferative activity upon CTX0E03 transplantation is preceded and accompanied by a high rate of proliferating microglia. Our study suggests that microglia might mediate in part the effect of CTX0E03 transplantation on neuronal proliferation in ischemic stroke conditions.

  16. Elevated homocysteine by levodopa is detrimental to neurogenesis in parkinsonian model.

    Directory of Open Access Journals (Sweden)

    Jin Young Shin

    Full Text Available BACKGROUND: Modulation of neurogenesis that acts as an endogenous repair mechanism would have a significant impact on future therapeutic strategies for Parkinson's disease (PD. Several studies demonstrated dopaminergic modulation of neurogenesis in the subventricular zone (SVZ of the adult brain. Levodopa, the gold standard therapy for PD, causes an increase in homocysteine levels that induces neuronal death via N-methyl-D-aspartate (NMDA receptor. The present study investigated whether elevated homocysteine by levodopa treatment in a parkinsonian model would modulate neurogenesis via NMDA receptor signal cascade and compared the effect of levodopa and pramipexol (PPX on neurogenic activity. METHODOLOGY/PRINCIPAL FINDINGS: Neurogenesis was assessed in vitro using neural progenitor cells (NPCs isolated from the SVZ and in vivo with the BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Modulation of homocysteine levels was evaluated using co-cultures of NPCs and astrocytes and PD animals. Immunochemical and Western blot analyses were used to measure neurogenesis and determine the cell death signaling. Levodopa treatment increased release of homocysteine on astrocytes culture media as well as in plasma and brain of PD animals. Increased homocysteine by levodopa led to increased apoptosis of NPCs through the NMDA receptor-dependent the extracellular signal-regulated kinase (ERK signaling pathways. The administration of a NMDA antagonist significantly attenuated apoptotic cell death in levodopa-treated NPCs and markedly increased the number of BrdU-positive cells in the SVZ of levodopa-treated PD animals. Comparative analysis revealed that PPX treatment significantly increased the number of NPCs and BrdU-positive cells in the SVZ of PD animals compared to levodopa treatment. Our present study demonstrated that increased homocysteine by levodopa has a detrimental effect on neurogenesis through NMDA receptor

  17. The male sex pheromone darcin stimulates hippocampal neurogenesis and cell proliferation in the subventricular zone in female mice

    Directory of Open Access Journals (Sweden)

    Emma eHoffman

    2015-04-01

    Full Text Available The integration of newly generated neurons persists throughout life in the mammalian olfactory bulb and hippocampus, regions involved in olfactory and spatial learning. Social cues can be potent stimuli for increasing adult neurogenesis; for example, odors from dominant but not subordinate male mice increase neurogenesis in both brain regions of adult females. However, little is known about the role of neurogenesis in social recognition or the assessment of potential mates. Dominant male mice scent-mark territories using urine that contains a number of pheromones including darcin (MUP20, a male-specific major urinary protein that stimulates rapid learned attraction to the spatial location and individual odor signature of the scent owner. Here we investigate whether exposure to darcin stimulates neurogenesis in the female brain. Hippocampal neurons and cellular proliferation in the lateral ventricles that supply neurons to the olfactory bulbs increased in females exposed for seven days to male urine containing at least 0.5µg/µl darcin. Darcin was effective whether presented alone or in the context of male urine, but other information in male urine appeared to modulate the proliferative response. When exposed to urine from wild male mice, hippocampal proliferation increased only if urine was from the same individual over seven days, suggesting that consistency of individual scent signatures is important. While seven days exposure to male scent initiated the first stages of increased neurogenesis, this caused no immediate increase in female attraction to the scent or in the strength or robustness of spatial learning in short-term conditioned place preference tests. The reliable and consistent stimulation of neurogenesis by a pheromone important in rapid social learning suggests that this may provide an excellent model to explore the relationship between the integration of new neurons and plasticity in spatial and olfactory learning in a socially

  18. Enriched Environment Increases PCNA and PARP1 Levels in Octopus vulgaris Central Nervous System: First Evidence of Adult Neurogenesis in Lophotrochozoa.

    Science.gov (United States)

    Bertapelle, Carla; Polese, Gianluca; Di Cosmo, Anna

    2017-06-01

    Organisms showing a complex and centralized nervous system, such as teleosts, amphibians, reptiles, birds and mammals, and among invertebrates, crustaceans and insects, can adjust their behavior according to the environmental challenges. Proliferation, differentiation, migration, and axonal and dendritic development of newborn neurons take place in brain areas where structural plasticity, involved in learning, memory, and sensory stimuli integration, occurs. Octopus vulgaris has a complex and centralized nervous system, located between the eyes, with a hierarchical organization. It is considered the most "intelligent" invertebrate for its advanced cognitive capabilities, as learning and memory, and its sophisticated behaviors. The experimental data obtained by immunohistochemistry and western blot assay using proliferating cell nuclear antigen and poli (ADP-ribose) polymerase 1 as marker of cell proliferation and synaptogenesis, respectively, reviled cell proliferation in areas of brain involved in learning, memory, and sensory stimuli integration. Furthermore, we showed how enriched environmental conditions affect adult neurogenesis. © 2017 Wiley Periodicals, Inc.

  19. Oppositional effects of serotonin receptors 5-HT1a, 2 and 2c in the regulation of adult hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Friederike Klempin

    2010-07-01

    Full Text Available Serotonin (5-HT appears to play a major role in controlling adult hippocampal neurogenesis and thereby it is relevant for theories linking failing adult neurogenesis to the pathogenesis of major depression and the mechanisms of action of antidepressants. Serotonergic drugs lack acute effects on adult neurogenesis in many studies, which suggests a surprising long latency phase. Here we report that the selective serotonin reuptake inhibitor fluoxetine, which has no acute effect on precursor cell proliferation, causes the well-described increase in net neurogenesis upon prolonged treatment partly by promoting the survival and maturation of new postmitotic neurons. We hypothesized that this result is the cumulative effect of several 5-HT-dependent events in the course of adult neurogenesis. Thus, we used specific agonists and antagonists to 5-HT1a, 2, and 2c receptor subtypes to analyze their impact on different developmental stages. We found that 5-HT exerts acute and opposing effects on proliferation and survival or differentiation of precursor cells by activating the diverse receptor subtypes on different stages within the neuronal lineage in vivo. This was confirmed in vitro by demonstrating that 5-HT1a receptors are involved in self-renewal of precursor cells, whereas 5-HT2 receptors effect both proliferation and promote neuronal differentiation. We propose that under acute conditions 5-HT2 effects counteract the positive proliferative effect of 5-HT1a receptor activation. However, prolonged 5-HT2c receptor activation fosters an increase in late stage progenitor cells and early postmitotic neurons, leading to a net increase in adult neurogenesis. Our data indicate that serotonin does not show effect latency in the adult dentate gyrus. Rather, the delayed response to serotonergic drugs with respect to endpoints downstream of the immediate receptor activity is largely due to the initially antagonistic and un-balanced action of different 5-HT

  20. Enhanced Dentate Neurogenesis after Brain Injury Undermines Long-Term Neurogenic Potential and Promotes Seizure Susceptibility

    Directory of Open Access Journals (Sweden)

    Eric J. Neuberger

    2017-09-01

    Full Text Available Hippocampal dentate gyrus is a focus of enhanced neurogenesis and excitability after traumatic brain injury. Increased neurogenesis has been proposed to aid repair of the injured network. Our data show that an early increase in neurogenesis after fluid percussion concussive brain injury is transient and is followed by a persistent decrease compared with age-matched controls. Post-injury changes in neurogenesis paralleled changes in neural precursor cell proliferation and resulted in a long-term decline in neurogenic capacity. Targeted pharmacology to restore post-injury neurogenesis to control levels reversed the long-term decline in neurogenic capacity. Limiting post-injury neurogenesis reduced early increases in dentate excitability and seizure susceptibility. Our results challenge the assumption that increased neurogenesis after brain injury is beneficial and show that early post-traumatic increases in neurogenesis adversely affect long-term outcomes by exhausting neurogenic potential and enhancing epileptogenesis. Treatments aimed at limiting excessive neurogenesis can potentially restore neuroproliferative capacity and limit epilepsy after brain injury.

  1. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    International Nuclear Information System (INIS)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2015-01-01

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3 + apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB + interneurons, although the number of reelin + interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of cholinergic

  2. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Yoshida, Toshinori [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Shibutani, Makoto, E-mail: mshibuta@cc.tuat.ac.jp [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of

  3. Alternative Splicing in Neurogenesis and Brain Development.

    Science.gov (United States)

    Su, Chun-Hao; D, Dhananjaya; Tarn, Woan-Yuh

    2018-01-01

    Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

  4. Alternative Splicing in Neurogenesis and Brain Development

    Directory of Open Access Journals (Sweden)

    Chun-Hao Su

    2018-02-01

    Full Text Available Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

  5. Enhanced post-ischemic neurogenesis in aging rats

    Directory of Open Access Journals (Sweden)

    Yao-Fang Tan

    2010-08-01

    Full Text Available Hippocampal neurogenesis persists in adult mammals, but its rate declines dramatically with age. Evidence indicates that experimentally-reduced levels of neurogenesis (e.g. by irradiation in young rats has profound influence on cognition as determined by learning and memory tests. In the present study we asked whether in middle-aged, 10-13 months old rats, cell production can be restored towards the level present in young rats. To manipulate neurogenesis we induced bilateral carotid occlusion with hypotension. This procedure is known to increase neurogenesis in young rats, presumably in a compensatory manner, but until now, has never been tested in aging rats. Cell production was measured at 10, 35 and 90 days after ischemia. The results indicate that neuronal proliferation and differentiation can be transiently restored in middle-aged rats. Furthermore, the effects are more pronounced in the dorsal as opposed to ventral hippocampus thus restoring the dorso-ventral gradient seen in younger rats. Our results support previous findings showing that some of the essential features of the age-dependent decline in neurogenesis are reversible. Thus, it may be possible to manipulate neurogenesis and improve learning and memory in old age.

  6. Adult Neurogenesis and Mental Illness

    Science.gov (United States)

    Schoenfeld, Timothy J; Cameron, Heather A

    2015-01-01

    Several lines of evidence suggest that adult neurogenesis, the production of new neurons in adulthood, may play a role in psychiatric disorders, including depression, anxiety, and schizophrenia. Medications and other treatments for mental disorders often promote the proliferation of new neurons; the time course for maturation and integration of new neurons in circuitry parallels the delayed efficacy of psychiatric therapies; adverse and beneficial experiences similarly affect development of mental illness and neurogenesis; and ablation of new neurons in adulthood alters the behavioral impact of drugs in animal models. At present, the links between adult neurogenesis and depression seem stronger than those suggesting a relationship between new neurons and anxiety or schizophrenia. Yet, even in the case of depression there is currently no direct evidence for a causative role. This article reviews the data relating adult neurogenesis to mental illness and discusses where research needs to head in the future. PMID:25178407

  7. Neurotoxic effect of 2,5-hexanedione on neural progenitor cells and hippocampal neurogenesis

    International Nuclear Information System (INIS)

    Kim, Min-Sun; Park, Hee Ra; Park, Mikyung; Kim, So Jung; Kwon, Mugil; Yu, Byung Pal; Chung, Hae Young; Kim, Hyung Sik; Kwack, Seung Jun; Kang, Tae Seok; Kim, Seung Hee; Lee, Jaewon

    2009-01-01

    2,5-Hexanedione (HD), a metabolite of n-hexane, causes central and peripheral neuropathy leading to motor neuron deficits. Although chronic exposure to n-hexane is known to cause gradual sensorimotor neuropathy, there are no reports on the effects of low doses of HD on neurogenesis in the central nervous system. In the current study, we explored HD toxicity in murine neural progenitor cells (NPC), primary neuronal culture and young adult mice. HD (500 nM∼50 μM) dose-dependently suppressed NPC proliferation and cell viability, and also increased the production of reactive oxygen species (ROS). HD (10 or 50 mg/kg for 2 weeks) inhibited hippocampal neuronal and NPC proliferation in 6-week-old male ICR mice, as measured by BrdU incorporation in the dentate gyrus, indicating HD impaired hippocampal neurogenesis. In addition, elevated microglial activation was observed in the hippocampal CA3 region and lateral ventricles of HD-treated mice. Lastly, HD dose-dependently decreased the viability of primary cultured neurons. Based on biochemical and histochemical evidence from both cell culture and HD-treated animals, the neurotoxic mechanisms by which HD inhibits NPC proliferation and hippocampal neurogenesis may relate to its ability to elicit an increased generation of deleterious ROS.

  8. Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin

    Directory of Open Access Journals (Sweden)

    Ryan P. Vetreno

    2018-03-01

    Full Text Available Alcohol abuse and binge drinking are common during adolescence, a developmental period characterized by heightened neuroplasticity. Animal studies reveal that adolescent ethanol exposure decreases hippocampal neurogenesis that persists into adulthood, but the mechanism remains to be fully elucidated. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55, we tested the hypothesis that AIE-induced upregulation of neuroimmune signaling contributes to the loss of hippocampal neurogenesis in adulthood. We found that AIE caused upregulation of multiple proinflammatory Toll-like receptors (TLRs, increased expression of phosphorylated NF-κB p65 (pNF-κB p65 and the cell death marker cleaved caspase 3, and reduced markers of neurogenesis in the adult (P80 hippocampus, which is consistent with persistently increased neuroimmune signaling reducing neurogenesis. We observed a similar increase of pNF-κB p65-immunoreactive cells in the post-mortem human alcoholic hippocampus, an effect that was negatively correlated with age of drinking onset. Voluntary wheel running from P24 to P80 prevented the AIE-induced loss of neurogenesis markers (i.e., nestin and doublecortin in the adult hippocampus that was paralleled by blockade of increased expression of the cell death marker cleaved caspase 3. Wheel running also prevented the AIE-induced increase of hippocampal pNF-κB p65 and induction of neuroimmune NF-κB target genes, including TNFα and IκBα in the adult brain. Administration of the anti-inflammatory drug indomethacin during AIE prevented the loss of neurogenesis markers (i.e., nestin and doublecortin and the concomitant increase of cleaved caspase 3, an effect that was accompanied by blockade of the increase of pNF-κB p65. Similarly, administration of the proinflammatory TLR4 activator lipopolysaccharide resulted in a loss of doublecortin that was paralleled by increased

  9. Exposure to swainsonine impairs adult neurogenesis and spatial learning and memory.

    Science.gov (United States)

    Wang, Jiutao; Song, Lingzhen; Zhang, Qi; Zhang, Wei; An, Lei; Zhang, Yamei; Tong, Dewen; Zhao, Baoyu; Chen, Shulin; Zhao, Shanting

    2015-01-05

    Swainsonine (SW) is an indolizidine triol plant alkaloid isolated from the species Astragalus, colloquially termed locoweed. Ingestion induces severe neurological symptoms of livestock and wildlife, including ataxia, trembling, exaggerated fright reactions. Toxicity to the central and peripheral nervous system is caused by inhibition of lysosomal a-mannosidase (AMA) and accumulation of intracellular oligosaccharide. However, the effects of SW on adult neurogenesis and cognition have remained unclear. Therefore, the present study was conducted to examine the effects of SW on adult neurogenesis and learning as well as memory performance in adult mice. SW (10μg/mL in drinking water) was administered orally to mice for 4 weeks. Our results showed that SW reduced proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of adult mice. In addition, exposure to SW led to down-regulation of doublecortin (DCX) and synaptophysin (SYP) in the hippocampus. However, caspase 3 and glial fibrillary acidic protein (GFAP) levels were significantly increased in SW-treated mice. Finally, SW-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that SW affects adult neurogenesis and cognitive function. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

    Science.gov (United States)

    Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

    2013-12-15

    TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

  11. Carbon monoxide inhalation increases microparticles causing vascular and CNS dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Jiajun; Yang, Ming [Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Kosterin, Paul [Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Salzberg, Brian M. [Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Milovanova, Tatyana N.; Bhopale, Veena M. [Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Thom, Stephen R., E-mail: sthom@smail.umaryland.edu [Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States)

    2013-12-01

    We hypothesized that circulating microparticles (MPs) play a role in pro-inflammatory effects associated with carbon monoxide (CO) inhalation. Mice exposed for 1 h to 100 ppm CO or more exhibit increases in circulating MPs derived from a variety of vascular cells as well as neutrophil activation. Tissue injury was quantified as 2000 kDa dextran leakage from vessels and as neutrophil sequestration in the brain and skeletal muscle; and central nervous system nerve dysfunction was documented as broadening of the neurohypophysial action potential (AP). Indices of injury occurred following exposures to 1000 ppm for 1 h or to 1000 ppm for 40 min followed by 3000 ppm for 20 min. MPs were implicated in causing injuries because infusing the surfactant MP lytic agent, polyethylene glycol telomere B (PEGtB) abrogated elevations in MPs, vascular leak, neutrophil sequestration and AP prolongation. These manifestations of tissue injury also did not occur in mice lacking myeloperoxidase. Vascular leakage and AP prolongation were produced in naïve mice infused with MPs that had been obtained from CO poisoned mice, but this did not occur with MPs obtained from control mice. We conclude that CO poisoning triggers elevations of MPs that activate neutrophils which subsequently cause tissue injuries. - Highlights: • Circulating microparticles (MPs) increase in mice exposed to 100 ppm CO or more. • MPs are lysed by infusing the surfactant polyethylene glycol telomere B. • CO-induced MPs cause neutrophil activation, vascular leak and CNS dysfunction. • Similar tissue injuries do not arise with MPs obtained from air-exposed, control mice.

  12. Goat meat does not cause increased blood pressure.

    Science.gov (United States)

    Sunagawa, Katsunori; Kishi, Tetsuya; Nagai, Ayako; Matsumura, Yuka; Nagamine, Itsuki; Uechi, Shuntoku

    2014-01-01

    While there are persistent rumors that the consumption of goat meat dishes increases blood pressure, there is no scientific evidence to support this. Two experiments were conducted to clarify whether or not blood pressure increases in conjunction with the consumption of goat meat dishes. In experiment 1, 24 Dahl/Iwai rats (15 weeks old, body weight 309.3±11.1 g) were evenly separated into 4 groups. The control group (CP) was fed a diet containing 20% chicken and 0.3% salt on a dry matter basis. The goat meat group (GM) was fed a diet containing 20% goat meat and 0.3% salt. The goat meat/salt group (GS) was fed a diet containing 20% goat meant and 3% to 4% salt. The Okinawan mugwort (Artemisia Princeps Pampan)/salt group (GY) was fed a diet containing 20% goat meat, 3% to 4% salt and 5% of freeze-dried mugwort powder. The experiment 1 ran for a period of 14 weeks during which time the blood pressure of the animals was recorded. The GS, and GY groups consumed significantly more water (pgoat meat does not cause increased blood pressure, rather the large amount of salt used in the preparation of goat meat dishes is responsible for the increase in blood pressure.

  13. Goat Meat Does Not Cause Increased Blood Pressure

    Directory of Open Access Journals (Sweden)

    Katsunori Sunagawa

    2014-01-01

    Full Text Available While there are persistent rumors that the consumption of goat meat dishes increases blood pressure, there is no scientific evidence to support this. Two experiments were conducted to clarify whether or not blood pressure increases in conjunction with the consumption of goat meat dishes. In experiment 1, 24 Dahl/Iwai rats (15 weeks old, body weight 309.3±11.1 g were evenly separated into 4 groups. The control group (CP was fed a diet containing 20% chicken and 0.3% salt on a dry matter basis. The goat meat group (GM was fed a diet containing 20% goat meat and 0.3% salt. The goat meat/salt group (GS was fed a diet containing 20% goat meant and 3% to 4% salt. The Okinawan mugwort (Artemisia Princeps Pampan/salt group (GY was fed a diet containing 20% goat meat, 3% to 4% salt and 5% of freeze-dried mugwort powder. The experiment 1 ran for a period of 14 weeks during which time the blood pressure of the animals was recorded. The GS, and GY groups consumed significantly more water (p<0.01 than the CP and GM groups despite the fact that their diet consumption levels were similar. The body weight of animals in the CP, GM, and GS groups was similar while the animals in the GY group were significantly smaller (p<0.01. The blood pressure in the GM group was virtually the same as the CP group throughout the course of the experiment. In contrast, while the blood pressure of the animals in the GS and GY group from 15 to 19 weeks old was the same as the CP group, their blood pressures were significantly higher (p<0.01 after 20 weeks of age. The GY group tended to have lower blood pressure than the GS group. In experiment 2, in order to clarify whether or not the increase in blood pressure in the GS group and the GY group in experiment 1 was caused by an excessive intake of salt, the effects on blood pressure of a reduction of salt in diet were investigated. When amount of salt in the diet of the GS and GY group was reduced from 4% to 0.3%, the animal

  14. Physical Exercise-Induced Adult Neurogenesis: A Good Strategy to Prevent Cognitive Decline in Neurodegenerative Diseases?

    Directory of Open Access Journals (Sweden)

    Suk-yu Yau

    2014-01-01

    Full Text Available Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain.

  15. Of Mice and Men: Neurogenesis, Cognition and Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Orly eLazarov

    2013-08-01

    Full Text Available Neural stem cells are maintained in the subgranular layer of the dentate gyrus and in the subventricular zone in the adult mammalian brain throughout life. Neurogenesis is continuous, but its extent is tightly regulated by environmental factors, behavior, hormonal state, age and brain health. Increasing evidence supports a role for new neurons in cognitive function in rodents. Recent evidence delineates potential significant differences between adult neurogenesis in rodents and humans. Being context-dependent, neurogenesis in the human brain might be manifested differently than in the rodent brain. Decline in neurogenesis may play a role in cognitive deterioration, leading to the development of progressive learning and memory disorders, such as Alzheimer’s disease. This review discusses the different observations concerning neurogenesis in the rodent and human brain, and their functional implications for the healthy and diseased brain.

  16. Whiplash causes increased laxity of cervical capsular ligament.

    Science.gov (United States)

    Ivancic, Paul C; Ito, Shigeki; Tominaga, Yasuhiro; Rubin, Wolfgang; Coe, Marcus P; Ndu, Anthony B; Carlson, Erik J; Panjabi, Manohar M

    2008-02-01

    Previous clinical studies have identified the cervical facet joint, including the capsular ligaments, as sources of pain in whiplash patients. The goal of this study was to determine whether whiplash caused increased capsular ligament laxity by applying quasi-static loading to whiplash-exposed and control capsular ligaments. A total of 66 capsular ligament specimens (C2/3 to C7/T1) were prepared from 12 cervical spines (6 whiplash-exposed and 6 control). The whiplash-exposed spines had been previously rear impacted at a maximum peak T1 horizontal acceleration of 8 g. Capsular ligaments were elongated at 1mm/s in increments of 0.05 mm until a tensile force of 5 N was achieved and subsequently returned to neutral position. Four pre-conditioning cycles were performed and data from the load phase of the fifth cycle were used for subsequent analyses. Ligament elongation was computed at tensile forces of 0, 0.25, 0.5, 0.75, 1.0, 2.5, and 5.0 N. Two factor, non-repeated measures ANOVA (Pwhiplash-exposed and control groups and between spinal levels. Average elongation of the whiplash-exposed capsular ligaments was significantly greater than that of the control ligaments at tensile forces of 0 and 5 N. No significant differences between spinal levels were observed. Capsular ligament injuries, in the form of increased laxity, may be one component perpetuating chronic pain and clinical instability in whiplash patients.

  17. Transport increase and confinement degradation caused by MARFE

    Science.gov (United States)

    Shi, Peng; Zhuang, Ge; Gao, Li; Zhou, Yinan

    2017-10-01

    Recently, the MARFE phenomenon associated with high density plasmas has been observed on J-TEXT Ohmically heated discharges. The MARFE on J-TEXT is charactered by the poloidally local region at high field side (HFS) edge with high density and strong radiation. At the almost same time of MARFE appearance, the density peaking factor and sawtooth oscillation reach maximum and decrease with density increasing, infers that the plasma confinement is saturated. By analyzing the far-forward scattering signals from polarimeter-interferometer, it is found that the local radial density turbulence at high field edge increases significantly after MARFE onset. It is inferred that the local particle transport at MARFE affected region (HFS edge) is enhanced. The enhancement of radial transport at MARFE affected region is considered as the possible reason for confinement saturation on J-TEXT. Furthermore, the trapped electron mode (TEM) with quasi-coherent characteristics is measured by far-forward scattering. The TEMs are always observed in plasmas with low density, and disappear after the plasma density exceeds a threshold. The density threshold of TEM disappearance is consistent with the density threshold of MARFE onset. The evolution of turbulences affirms that the MARFE may be the cause of energy confinement transition from LOC to SOC.

  18. Spreading depression and focal venous cerebral ischemia enhance cortical neurogenesis

    Directory of Open Access Journals (Sweden)

    Ryo Tamaki

    2017-01-01

    Full Text Available Endogenous neurogenesis can arise from a variety of physiological stimuli including exercise, learning, or “enriched environment” as well as pathological conditions such as ischemia, epilepsy or cortical spreading depression. Whether all these conditions use a common trigger to set off endogenous neurogenesis is yet unclear. We hypothesized that cortical spreading depression (CSD induces neurogenesis in the cerebral cortex and dentate gyrus after cerebral venous ischemia. Forty-two Wistar rats alternatively underwent sham operation (Sham, induction of ten CSDs or venous ischemia provoked via occlusion of two adjacent superficial cortical vein followed by ten induced CSDs (CSD + 2-VO. As an additional control, 15 naïve rats received no intervention except 5-bromo-2′-deoxyuridine (BrdU treatment for 7 days. Sagittal brain slices (40 μm thick were co-stained for BrdU and doublecortin (DCX; new immature neuronal cells on day 9 or NeuN (new mature neuronal cells on day 28. On day 9 after sham operation, cell proliferation and neurogenesis occurred in the cortex in rats. The sole induction of CSD had no effect. But on days 9 and 28, more proliferating cells and newly formed neurons in the ipsilateral cortex were observed in rats subjected to CSD + 2VO than in rats subjected to sham operation. On days 9 and 28, cell proliferation and neurogenesis in the ipsilateral dentate gyrus was increased in sham-operated rats than in naïve rats. Our data supports the hypothesis that induced cortical neurogenesis after CSD + 2-VO is a direct effect of ischemia, rather than of CSD alone.

  19. Whiplash causes increased laxity of cervical capsular ligament

    Science.gov (United States)

    Ivancic, Paul C.; Ito, Shigeki; Tominaga, Yasuhiro; Rubin, Wolfgang; Coe, Marcus P.; Ndu, Anthony B.; Carlson, Erik J.; Panjabi, Manohar M.

    2009-01-01

    Background Previous clinical studies have identified the cervical facet joint, including the capsular ligaments, as sources of pain in whiplash patients. The goal of this study was to determine whether whiplash caused increased capsular ligament laxity by applying quasi-static loading to whiplash-exposed and control capsular ligaments. Methods A total of 66 capsular ligament specimens (C2/3 to C7/T1) were prepared from 12 cervical spines (6 whiplash-exposed and 6 control). The whiplash-exposed spines had been previously rear impacted at a maximum peak T1 horizontal acceleration of 8 g. Capsular ligaments were elongated at 1 mm/s in increments of 0.05 mm until a tensile force of 5 N was achieved and subsequently returned to neutral position. Four pre-conditioning cycles were performed and data from the load phase of the fifth cycle were used for subsequent analyses. Ligament elongation was computed at tensile forces of 0, 0.25, 0.5, 0.75, 1.0, 2.5, and 5.0 N. Two factor, non-repeated measures ANOVA (Pwhiplash-exposed and control groups and between spinal levels. Findings Average elongation of the whiplash-exposed capsular ligaments was significantly greater than that of the control ligaments at tensile forces of 0 and 5 N. No significant differences between spinal levels were observed. Interpretation Capsular ligament injuries, in the form of increased laxity, may be one component perpetuating chronic pain and clinical instability in whiplash patients. PMID:17959284

  20. Heating-insensitive scale increase caused by convective precipitation

    Science.gov (United States)

    Haerter, Jan; Moseley, Christopher; Berg, Peter

    2017-04-01

    The origin of intense convective extremes and their unusual temperature dependence has recently challenged traditional thermodynamic arguments, based on the Clausius-Clapeyron relation. In a sequence of studies (Lenderink and v. Mejgaard, Nat Geosc, 2008; Berg, Haerter, Moseley, Nat Geosc, 2013; and Moseley, Hohenegger, Berg, Haerter, Nat Geosc, 2016) the argument of convective-type precipitation overcoming the 7%/K increase in extremes by dynamical, rather than thermodynamic, processes has been promoted. How can the role of dynamical processes be approached for precipitating convective cloud? One-phase, non-precipitating Rayleigh-Bénard convection is a classical problem in complex systems science. When a fluid between two horizontal plates is sufficiently heated from below, convective rolls spontaneously form. In shallow, non-precipitating atmospheric convection, rolls are also known to form under specific conditions, with horizontal scales roughly proportional to the boundary layer height. Here we explore within idealized large-eddy simulations, how the scale of convection is modified, when precipitation sets in and intensifies in the course of diurnal solar heating. Before onset of precipitation, Bénard cells with relatively constant diameter form, roughly on the scale of the atmospheric boundary layer. We find that the onset of precipitation then signals an approximately linear (in time) increase in horizontal scale. This scale increase progresses at a speed which is rather insensitive to changes in surface temperature or changes in the rate at which boundary conditions change, hinting at spatial characteristics, rather than temperature, as a possible control on spatial scales of convection. When exploring the depth of spatial correlations, we find that precipitation onset causes a sudden disruption of order and a subsequent complete disintegration of organization —until precipitation eventually ceases. Returning to the initial question of convective

  1. Endurance Factors Improve Hippocampal Neurogenesis and Spatial Memory in Mice

    Science.gov (United States)

    Kobilo, Tali; Yuan, Chunyan; van Praag, Henriette

    2011-01-01

    Physical activity improves learning and hippocampal neurogenesis. It is unknown whether compounds that increase endurance in muscle also enhance cognition. We investigated the effects of endurance factors, peroxisome proliferator-activated receptor [delta] agonist GW501516 and AICAR, activator of AMP-activated protein kinase on memory and…

  2. Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy

    Directory of Open Access Journals (Sweden)

    Eleni Paizanis

    2007-01-01

    Full Text Available There is a growing body of evidence that neural stem cells reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone, where it is controlled by several trophic factors and neuroactive molecules. Neurogenesis is involved in processes such as learning and memory and accumulating evidence implicates hippocampal neurogenesis in the physiopathology of depression. We herein review experimental and clinical data demonstrating that stress and antidepressant treatments affect neurogenesis in opposite direction in rodents. In particular, the stimulation of hippocampal neurogenesis by all types of antidepressant drugs supports the view that neuroplastic phenomena are involved in the physiopathology of depression and underlie—at least partly—antidepressant therapy.

  3. Neurogenesis in the aging brain.

    Science.gov (United States)

    Apple, Deana M; Solano-Fonseca, Rene; Kokovay, Erzsebet

    2017-10-01

    Adult neurogenesis is the process of producing new neurons from neural stem cells (NSCs) for integration into the brain circuitry. Neurogenesis occurs throughout life in the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus. However, during aging, NSCs and their progenitors exhibit reduced proliferation and neuron production, which is thought to contribute to age-related cognitive impairment and reduced plasticity that is necessary for some types of brain repair. In this review, we describe NSCs and their niches during tissue homeostasis and how they undergo age-associated remodeling and dysfunction. We also discuss some of the functional ramifications in the brain from NSC aging. Finally, we discuss some recent insights from interventions in NSC aging that could eventually translate into therapies for healthy brain aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Impact of glucocorticoid on neurogenesis

    Directory of Open Access Journals (Sweden)

    Haruki Odaka

    2017-01-01

    Full Text Available Neurogenesis is currently an area of great interest in neuroscience. It is closely linked to brain diseases, including mental disorders and neurodevelopmental disease. Both embryonic and adult neurogeneses are influenced by glucocorticoids secreted from the adrenal glands in response to a variety of stressors. Moreover, proliferation/differentiation of the neural stem/progenitor cells (NSPCs is affected by glucocorticoids through intracellular signaling pathways such as phosphoinositide 3-kinase (PI3K/Akt, hedgehog, and Wnt. Our review presents recent evidence of the impact of glucocorticoids on NSPC behaviors and the underlying molecular mechanisms; this provides important information for understanding the pathological role of glucocorticoids on neurogenesis-associated brain diseases.

  5. Deletion of TLX and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampus.

    Science.gov (United States)

    Kozareva, Danka A; O'Leary, Olivia F; Cryan, John F; Nolan, Yvonne M

    2018-01-01

    Adolescence is a sensitive period of neurodevelopment during which life experiences can have profound effects on the brain. Hippocampal neurogenesis, the neurodevelopmental process of generating functional new neurons from neural stem cells, occurs throughout the lifespan and has been shown to play a role in learning, memory and in mood regulation. In adulthood it is influenced by extrinsic environmental factors such as exercise and stress. Intrinsic factors that regulate hippocampal neurogenesis include the orphan nuclear receptor TLX (Nr2e1) which is primarily expressed in the neurogenic niches of the brain. While mechanisms regulating adult hippocampal neurogenesis have been widely studied, less is known on how hippocampal neurogenesis is affected during adolescence. The aim of this study was to investigate the influence of both TLX and isolation stress on exercise-induced increases in neurogenesis in running and sedentary conditions during adolescence. Single- (isolation stress) wild type and Nr2e1 -/- mice or pair-housed wild type mice were housed in sedentary conditions or allowed free access to running wheels for 3 weeks during adolescence. A reduction of neuronal survival was evident in mice lacking TLX, and exercise did not increase hippocampal neurogenesis in these Nr2e1 -/- mice. This suggests that TLX is necessary for the pro-neurogenic effects of exercise during adolescence. Interestingly, although social isolation during adolescence did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus. Together these data demonstrate the importance of intrinsic and extrinsic factors in promoting an exercise-induced increase in neurogenesis at this key point in life. © 2017 Wiley Periodicals, Inc.

  6. Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration

    Science.gov (United States)

    Suzzi, Stefano; Vargas-Caballero, Mariana; Fransen, Nina L.; Al-Malki, Hussain; Cebrian-Silla, Arantxa; Garcia-Verdugo, Jose Manuel; Riecken, Kristoffer; Fehse, Boris; Perry, V. Hugh

    2014-01-01

    The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour γ-retroviral tracing, transmission electron microscopy and patch-clamp. We found increased neurogenesis during the progression of prion disease, which partially counteracts the effects of chronic neurodegeneration, as evidenced by blocking neurogenesis with cytosine arabinoside, and helps to preserve the hippocampal function. Evidence obtained from human post-mortem samples, of both variant Creutzfeldt-Jakob disease and Alzheimer’s disease patients, also suggests increased neurogenic activity. These results open a new avenue into the exploration of the effects and regulation of neurogenesis during chronic neurodegeneration, and offer a new model to reproduce the changes observed in human neurodegenerative diseases. PMID:24941947

  7. Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model.

    Science.gov (United States)

    Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E; Shi, Yanhong

    2014-06-24

    The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.

  8. Emittance increase caused by core depletion in collisions

    CERN Document Server

    Bruce, R

    2009-01-01

    A new effect is presented, which changes the emittance during colliding-beam operation in circular colliders. If the initial transverse distribution is Gaussian, the collision probability is much higher for particles in the core of the beam than in the tails. When small-amplitude particles are removed, the remaining ones therefore have a larger transverse emittance. This effect, called core depletion, may cause a decrease in luminosity. An approximate analytic model is developed to study the effect and benchmarked against a multiparticle tracking simulation. Finally, the time evolution of the intensity and emittances of a Pb bunch in the Large Hadron Collider (LHC) at CERN is calculated, taking into account also other processes than collisions. The results show that integrated luminosity drops by 3--4% if core depletion is taken into account. It is also found that core depletion causes the transverse emittance to be larger when more experiments are active. This observation could be checked against experimenta...

  9. Nuclear deterrents: Intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis.

    Science.gov (United States)

    O'Léime, Ciarán S; Cryan, John F; Nolan, Yvonne M

    2017-11-01

    Hippocampal neurogenesis, the process by which new neurons are born and develop into the host circuitry, begins during embryonic development and persists throughout adulthood. Over the last decade considerable insights have been made into the role of hippocampal neurogenesis in cognitive function and the cellular mechanisms behind this process. Additionally, an increasing amount of evidence exists on the impact of environmental factors, such as stress and neuroinflammation on hippocampal neurogenesis and subsequent impairments in cognition. Elevated expression of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus is established as a significant contributor to the neuronal demise evident in many neurological and psychiatric disorders and is now known to negatively regulate hippocampal neurogenesis. In order to prevent the deleterious effects of IL-1β on neurogenesis it is necessary to identify signalling pathways and regulators of neurogenesis within neural progenitor cells that can interact with IL-1β. Nuclear receptors are ligand regulated transcription factors that are involved in modulating a large number of cellular processes including neurogenesis. In this review we focus on the signalling mechanisms of specific nuclear receptors involved in regulating neurogenesis (glucocorticoid receptors, peroxisome proliferator activated receptors, estrogen receptors, and nuclear receptor subfamily 2 group E member 1 (NR2E1 or TLX)). We propose that these nuclear receptors could be targeted to inhibit neuroinflammatory signalling pathways associated with IL-1β. We discuss their potential to be therapeutic targets for neuroinflammatory disorders affecting hippocampal neurogenesis and associated cognitive function. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal

    Science.gov (United States)

    Hanson, Nicola D; Owens, Michael J; Nemeroff, Charles B

    2011-01-01

    The neurogenesis hypothesis of depression posits (1) that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and (2) that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment. PMID:21937982

  11. Inhibition of Neurogenesis by Zika virus Infection.

    Science.gov (United States)

    Ahmad, Fahim; Siddiqui, Amna; Kamal, Mohammad A; Sohrab, Sayed S

    2018-02-01

    The association between Zika virus infection and neurological disorder has raised urgent global alarm. The ongoing epidemic has triggered quick responses in the scientific community. The first case of Zika virus was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of travel-associated Zika virus infection have also been reported in the United States. Zika virus is primarily transmitted by mosquito belongs to the genus Aedes that are widely distributed throughout the world including the Southern United States. Additionally, the virus can also be transmitted from males to females by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and development of microcephaly in their unborn babies. This finding is a cause for grave concern since microcephaly is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicate that Zika virus infection affects the growth of fetal neural progenitor cells and cerebral neurons that results in malformation of cerebral cortex leading to microcephaly. Recently, it has been reported that Zika virus infection deregulates the signaling pathway of neuronal cell and inhibit the neurogenesis resulting into dementia. In this review we have discussed about the information about cellular and molecular mechanisms in neurodegeneration of human neuronal cells and inhibit the neurogenesis. Additionally, this information will be very helpful further not only in neuro-scientific research but also designing and development of management strategies for microcephaly and other mosquito borne disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Interleukin-1β: A New Regulator of the Kynurenine Pathway Affecting Human Hippocampal Neurogenesis

    Science.gov (United States)

    Zunszain, Patricia A; Anacker, Christoph; Cattaneo, Annamaria; Choudhury, Shanas; Musaelyan, Ksenia; Myint, Aye Mu; Thuret, Sandrine; Price, Jack; Pariante, Carmine M

    2012-01-01

    Increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. Here, we show for the first time how IL-1β, a pro-inflammatory cytokine shown to be increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. IL-1β was detrimental to neurogenesis, as shown by a decrease in the number of doublecortin-positive neuroblasts (−28%), and mature, microtubule-associated protein-2-positive neurons (−36%). Analysis of the enzymes that regulate the kynurenine pathway showed that IL-1β induced an upregulation of transcripts for indolamine-2,3-dioxygenase (IDO), kynurenine 3-monooxygenase (KMO), and kynureninase (42-, 12- and 30-fold increase, respectively, under differentiating conditions), the enzymes involved in the neurotoxic arm of the kynurenine pathway. Moreover, treatment with IL-1β resulted in an increase in kynurenine, the catabolic product of IDO-induced tryptophan metabolism. Interestingly, co-treatment with the KMO inhibitor Ro 61-8048 reversed the detrimental effects of IL-1β on neurogenesis. These observations indicate that IL-1β has a critical role in regulating neurogenesis whereas affecting the availability of tryptophan and the production of enzymes conducive to toxic metabolites. Our results suggest that inhibition of the kynurenine pathway may provide a new therapy to revert inflammatory-induced reduction in neurogenesis. PMID:22071871

  13. Histone deacetylases control neurogenesis in embryonic brain by inhibition of BMP2/4 signaling.

    Directory of Open Access Journals (Sweden)

    Maya Shakèd

    Full Text Available BACKGROUND: Histone-modifying enzymes are essential for a wide variety of cellular processes dependent upon changes in gene expression. Histone deacetylases (HDACs lead to the compaction of chromatin and subsequent silencing of gene transcription, and they have recently been implicated in a diversity of functions and dysfunctions in the postnatal and adult brain including ocular dominance plasticity, memory consolidation, drug addiction, and depression. Here we investigate the role of HDACs in the generation of neurons and astrocytes in the embryonic brain. PRINCIPAL FINDINGS: As a variety of HDACs are expressed in differentiating neural progenitor cells, we have taken a pharmacological approach to inhibit multiple family members. Inhibition of class I and II HDACs in developing mouse embryos with trichostatin A resulted in a dramatic reduction in neurogenesis in the ganglionic eminences and a modest increase in neurogenesis in the cortex. An identical effect was observed upon pharmacological inhibition of HDACs in in vitro-differentiating neural precursors derived from the same brain regions. A reduction in neurogenesis in ganglionic eminence-derived neural precursors was accompanied by an increase in the production of immature astrocytes. We show that HDACs control neurogenesis by inhibition of the bone morphogenetic protein BMP2/4 signaling pathway in radial glial cells. HDACs function at the transcriptional level by inhibiting and promoting, respectively, the expression of Bmp2 and Smad7, an intracellular inhibitor of BMP signaling. Inhibition of the BMP2/4 signaling pathway restored normal levels of neurogenesis and astrogliogenesis to both ganglionic eminence- and cortex-derived cultures in which HDACs were inhibited. CONCLUSIONS: Our results demonstrate a transcriptionally-based regulation of BMP2/4 signaling by HDACs both in vivo and in vitro that is critical for neurogenesis in the ganglionic eminences and that modulates cortical

  14. Neurogenesis dan Faktor-Faktor yang Berpengaruh

    Directory of Open Access Journals (Sweden)

    Ria Puspitawati

    2015-09-01

    Full Text Available Development of nerve tissue is known as neurogenesis. Vertebrate neve system has various functional capabilities from sensory perception, motor coordination, to the ability in producing motivation, spatial abilities, learning and memorizing due to various cell types that accurately connected and interact to each other. The connections between various nerve cells are continuously developed from the embryonic time until the early period of life. Recent studies have showed that neurogenesis in certain regions of nerve tissue can still be found in adults. This article reviews the cellular mechanism of neurogenesis and conditions that have role in the process.

  15. BMP signaling mediates effects of exercise on hippocampal neurogenesis and cognition in mice.

    Directory of Open Access Journals (Sweden)

    Kevin T Gobeske

    2009-10-01

    Full Text Available Exposure to exercise or to environmental enrichment increases the generation of new neurons in the adult hippocampus and promotes certain kinds of learning and memory. While the precise role of neurogenesis in cognition has been debated intensely, comparatively few studies have addressed the mechanisms linking environmental exposures to cellular and behavioral outcomes. Here we show that bone morphogenetic protein (BMP signaling mediates the effects of exercise on neurogenesis and cognition in the adult hippocampus. Elective exercise reduces levels of hippocampal BMP signaling before and during its promotion of neurogenesis and learning. Transgenic mice with decreased BMP signaling or wild type mice infused with a BMP inhibitor both exhibit remarkable gains in hippocampal cognitive performance and neurogenesis, mirroring the effects of exercise. Conversely, transgenic mice with increased BMP signaling have diminished hippocampal neurogenesis and impaired cognition. Exercise exposure does not rescue these deficits, suggesting that reduced BMP signaling is required for environmental effects on neurogenesis and learning. Together, these observations show that BMP signaling is a fundamental mechanism linking environmental exposure with changes in cognitive function and cellular properties in the hippocampus.

  16. From network structure to network reorganization: implications for adult neurogenesis

    International Nuclear Information System (INIS)

    Schneider-Mizell, Casey M; Zochowski, Michal R; Sander, Leonard M; Parent, Jack M; Ben-Jacob, Eshel

    2010-01-01

    Networks can be dynamical systems that undergo functional and structural reorganization. One example of such a process is adult hippocampal neurogenesis, in which new cells are continuously born and incorporate into the existing network of the dentate gyrus region of the hippocampus. Many of these introduced cells mature and become indistinguishable from established neurons, joining the existing network. Activity in the network environment is known to promote birth, survival and incorporation of new cells. However, after epileptogenic injury, changes to the connectivity structure around the neurogenic niche are known to correlate with aberrant neurogenesis. The possible role of network-level changes in the development of epilepsy is not well understood. In this paper, we use a computational model to investigate how the structural and functional outcomes of network reorganization, driven by addition of new cells during neurogenesis, depend on the original network structure. We find that there is a stable network topology that allows the network to incorporate new neurons in a manner that enhances activity of the persistently active region, but maintains global network properties. In networks having other connectivity structures, new cells can greatly alter the distribution of firing activity and destroy the initial activity patterns. We thus find that new cells are able to provide focused enhancement of network only for small-world networks with sufficient inhibition. Network-level deviations from this topology, such as those caused by epileptogenic injury, can set the network down a path that develops toward pathological dynamics and aberrant structural integration of new cells

  17. Distemper virus encephalitis exerts detrimental effects on hippocampal neurogenesis.

    Science.gov (United States)

    von Rüden, E-L; Avemary, J; Zellinger, C; Algermissen, D; Bock, P; Beineke, A; Baumgärtner, W; Stein, V M; Tipold, A; Potschka, H

    2012-08-01

    Despite knowledge about the impact of brain inflammation on hippocampal neurogenesis, data on the influence of virus encephalitis on dentate granule cell neurogenesis are so far limited. Canine distemper is considered an interesting model of virus encephalitis, which can be associated with a chronic progressing disease course and can cause symptomatic seizures. To determine the impact of canine distemper virus (CDV) infection on hippocampal neurogenesis, we compared post-mortem tissue from dogs with infection with and without seizures, from epileptic dogs with non-viral aetiology and from dogs without central nervous system diseases. The majority of animals with infection and with epilepsy of non-viral aetiology exhibited neuronal progenitor numbers below the age average in controls. Virus infection with and without seizures significantly decreased the mean number of neuronal progenitor cells by 43% and 76% as compared to age-matched controls. Ki-67 labelling demonstrated that hippocampal cell proliferation was neither affected by infection nor by epilepsy of non-viral aetiology. Analysis of CDV infection in cells expressing caspase-3, doublecortin or Ki-67 indicated that infection of neuronal progenitor cells is extremely rare and suggests that infection might damage non-differentiated progenitor cells, hamper neuronal differentiation and promote glial differentiation. A high inter-individual variance in the number of lectin-reactive microglial cells was evident in dogs with distemper infection. Statistical analyses did not reveal a correlation between the number of lectin-reactive microglia cells and neuronal progenitor cells. Our data demonstrate that virus encephalitis with and without seizures can exert detrimental effects on hippocampal neurogenesis, which might contribute to long-term consequences of the disease. The lack of a significant impact of distemper virus on Ki-67-labelled cells indicates that the infection affected neuronal differentiation and

  18. Sonic hedgehog signaling regulates amygdalar neurogenesis and extinction of fear memory.

    Science.gov (United States)

    Hung, Hui-Chi; Hsiao, Ya-Hsin; Gean, Po-Wu

    2015-10-01

    It is now recognized that neurogenesis occurs throughout life predominantly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. In the present study, we investigated the relationship between neurogenesis in the amygdala and extinction of fear memory. Mice received 15 tone-footshock pairings. Twenty-four hours after training, the mice were given 15 tone-alone trials (extinction training) once per day for 7 days. Two hours before extinction training, the mice were injected intraperitoneally with 5-bromo-3-deoxyuridine (BrdU). BrdU-positive and NeuN-positive cells were analyzed 52 days after the training. A group of mice that received tone-footshock pairings but no extinction training served as controls (FC+No-Ext). The number of BrdU(+)/NeuN(+) cells was significantly higher in the extinction (FC+Ext) than in the FC+No-Ext mice. Proliferation inhibitor methylazoxymethanol acetate (MAM) or DNA synthesis inhibitor cytosine arabinoside (Ara-C) reduced neurogenesis and retarded extinction. Silencing Sonic hedgehog (Shh) gene with short hairpin interfering RNA (shRNA) by means of a retrovirus expression system to knockdown Shh specifically in the mitotic neurons reduced neurogenesis and retarded extinction. By contrast, over-expression of Shh increased neurogenesis and facilitated extinction. These results suggest that amygdala neurogenesis and Shh signaling are involved in the extinction of fear memory. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  19. Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

    Science.gov (United States)

    Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

    2014-09-01

    The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. L-carnitine contributes to enhancement of neurogenesis from mesenchymal stem cells through Wnt/β-catenin and PKA pathway.

    Science.gov (United States)

    Fathi, Ezzatollah; Farahzadi, Raheleh; Charoudeh, Hojjatollah Nozad

    2017-03-01

    The identification of factors capable of enhancing neurogenesis has great potential for cellular therapies in neurodegenerative diseases. Multiple studies have shown the neuroprotective effects of L-carnitine (LC). This study determined whether neuronal differentiation of rat adipose tissue-derived mesenchymal stem cells (ADSCs) can be activated by LC. In this study, protein kinase A (PKA) and Wnt/β-catenin pathways were detected to show if this activation was due to these pathways. The expression of LC-induced neurogenesis markers in ADSCs was characterized using real-time PCR. ELISA was conducted to assess the expression of cyclic adenosine monophosphate (cAMP) and PKA. The expression of β-catenin, reduced dickkopf1 (DKK1), low-density lipoprotein receptor-related protein 5 (LRP5), Wnt1, and Wnt3a genes as Wnt/β-catenin signaling members were used to detect the Wnt/β-catenin pathway. It was observed that LC could promote neurogenesis in ADSCs as well as expression of some neurogenic markers. Moreover, LC causes to increase the cAMP levels and PKA activity. Treatment of ADSCs with H-89 (dihydrochloride hydrate) as PKA inhibitor significantly inhibited the promotion of neurogenic markers, indicating that the PKA signaling pathway could be involved in neurogenesis induction. Analyses of real-time PCR data showed that the mRNA expressions of β-catenin, DKK1, LRP5c-myc, Wnt1, and Wnt3a were increased in the presence of LC. Therefore, the present study showed that LC promotes ADSCs neurogenesis and the LC-induced neurogenic markers could be due to both the PKA and Wnt/β-catenin signaling pathway. Impact statement Neural tissue has long been believed as incapable of regeneration and the identification of cell types and factors capable of neuronal differentiation has generated intense interest. Mesenchymal stem cells (MSCs) are considered as potential targets for stem cell-based therapy. L-carnitin (LC) as an antioxidant may have neuroprotective effects in

  1. Endogenous neurogenesis in the human brain following cerebral infarction.

    Science.gov (United States)

    Minger, Stephen L; Ekonomou, Antigoni; Carta, Eloisa M; Chinoy, Amish; Perry, Robert H; Ballard, Clive G

    2007-01-01

    Increased endogenous neurogenesis has a significant regenerative role in many experimental models of cerebrovascular diseases, but there have been very few studies in humans. We therefore examined whether there was evidence of altered endogenous neurogenesis in an 84-year-old patient who suffered a cerebrovascular accident 1 week prior to death. Using antibodies that specifically label neural stem/neural progenitor cells, we examined the presence of immunopositive cells around and distant from the infarcted area, and compared this with a control, age-matched individual. Interestingly, a large number of neural stem cells, vascular endothelial growth factor-immunopositive cells and new blood vessels were observed only around the region of infarction, and none in the corresponding brain areas of the healthy control. In addition, an increased number of neural stem cells was observed in the neurogenic region of the lateral ventricle wall. Our results suggest increased endogenous neurogenesis associated with neovascularization and migration of newly-formed cells towards a region of cerebrovascular damage in the adult human brain and highlight possible mechanisms underlying this process.

  2. Nitric Oxide Regulates Neurogenesis in the Hippocampus following Seizures

    Directory of Open Access Journals (Sweden)

    Bruno P. Carreira

    2015-01-01

    Full Text Available Hippocampal neurogenesis is changed by brain injury. When neuroinflammation accompanies injury, activation of resident microglial cells promotes the release of inflammatory cytokines and reactive oxygen/nitrogen species like nitric oxide (NO. In these conditions, NO promotes proliferation of neural stem cells (NSC in the hippocampus. However, little is known about the role of NO in the survival and differentiation of newborn cells in the injured dentate gyrus. Here we investigated the role of NO following seizures in the regulation of proliferation, migration, differentiation, and survival of NSC in the hippocampus using the kainic acid (KA induced seizure mouse model. We show that NO increased the proliferation of NSC and the number of neuroblasts following seizures but was detrimental to the survival of newborn neurons. NO was also required for the maintenance of long-term neuroinflammation. Taken together, our data show that NO positively contributes to the initial stages of neurogenesis following seizures but compromises survival of newborn neurons.

  3. Magnetic resonance beacon to detect intracellular microRNA during neurogenesis.

    Science.gov (United States)

    Lee, Jonghwan; Jin, Yeon A; Ko, Hae Young; Lee, Yong Seung; Heo, Hyejung; Cho, Sujeong; Kim, Soonhag

    2015-02-01

    Magnetic resonance imaging (MRI) offers great spatial resolution for viewing deep tissues and anatomy. We developed a self-assembling signal-on magnetic fluorescence nanoparticle to visualize intracellular microRNAs (miRNAs or miRs) during neurogenesis using MRI. The self-assembling nanoparticle (miR124a MR beacon) was aggregated by the incubation of three different oligonucleotides: a 3' adaptor, a 5' adaptor, and a linker containing miR124a-binding sequences. The T2-weighted magnetic resonance (MR) signal of the self-assembled nanoparticle was quenched when miR124a was absent from test tubes or was minimally expressed in cells and tissues. When miR124a was present in test tubes or highly expressed in vitro and in vivo during P19 cell neurogenesis, it hybridized with the miR124a MR beacon, causing the linker to detach, resulting in increased signal-on MRI intensity. This MR beacon can be used as a new imaging probe to monitor the miRNA-mediated regulation of cellular processes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice

    Directory of Open Access Journals (Sweden)

    Klaus Fabel

    2009-11-01

    Full Text Available Voluntary physical exercise (wheel running, RUN and environmental enrichment (ENR both stimulate adult hippocampal neurogenesis but do so by different mechanisms. RUN induces precursor cell proliferation, whereas ENR exerts a survival-promoting effect on newborn cells. In addition, continued RUN prevented the physiologically occurring age-related decline in precursor cell in the dentate gyrus but did not lead to a corresponding increase in net neurogenesis. We hypothesized that in the absence of appropriate cognitive stimuli the potential for neurogenesis could not be realized but that an increased potential by proliferating precursor cells due to RUN could actually lead to more adult neurogenesis if an appropriate survival-promoting stimulus follows the exercise. We thus asked whether a sequential combination of RUN and ENR (RUNENR would show additive effects that are distinct from the application of either paradigm alone. We found that the effects of 10 days of RUN followed by 35 days of ENR were additive in that the combined stimulation yielded an approximately 30% greater increase in new neurons than either stimulus alone, which also increased neurogenesis. Surprisingly, this result indicates that although overall the amount of proliferating cells in the dentate gyrus is poorly predictive of net adult neurogenesis, an increased neurogenic potential nevertheless provides the basis for a greater efficiency of the same survival-promoting stimulus. We thus propose that physical activity can “prime” the neurogenic region of the dentate gyrus for increased neurogenesis in the case the animal is exposed to an additional cognitive stimulus, here represented by the enrichment paradigm.

  5. Deletion of running-induced hippocampal neurogenesis by irradiation prevents development of an anxious phenotype in mice.

    Directory of Open Access Journals (Sweden)

    Johannes Fuss

    2010-09-01

    Full Text Available Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxiety.

  6. Neuronal Rac1 Is Required for Learning-Evoked Neurogenesis

    Science.gov (United States)

    Anderson, Matthew P.; Freewoman, Julia; Cord, Branden; Babu, Harish; Brakebusch, Cord

    2013-01-01

    Hippocampus-dependent learning and memory relies on synaptic plasticity as well as network adaptations provided by the addition of adult-born neurons. We have previously shown that activity-induced intracellular signaling through the Rho family small GTPase Rac1 is necessary in forebrain projection neurons for normal synaptic plasticity in vivo, and here we show that selective loss of neuronal Rac1 also impairs the learning-evoked increase in neurogenesis in the adult mouse hippocampus. Earlier work has indicated that experience elevates the abundance of adult-born neurons in the hippocampus primarily by enhancing the survival of neurons produced just before the learning event. Loss of Rac1 in mature projection neurons did reduce learning-evoked neurogenesis but, contrary to our expectations, these effects were not mediated by altering the survival of young neurons in the hippocampus. Instead, loss of neuronal Rac1 activation selectively impaired a learning-evoked increase in the proliferation and accumulation of neural precursors generated during the learning event itself. This indicates that experience-induced alterations in neurogenesis can be mechanistically resolved into two effects: (1) the well documented but Rac1-independent signaling cascade that enhances the survival of young postmitotic neurons; and (2) a previously unrecognized Rac1-dependent signaling cascade that stimulates the proliferative production and retention of new neurons generated during learning itself. PMID:23884931

  7. Amyloid β Is Not the Major Factor Accounting for Impaired Adult Hippocampal Neurogenesis in Mice Overexpressing Amyloid Precursor Protein

    Directory of Open Access Journals (Sweden)

    Hongyu Pan

    2016-10-01

    Full Text Available Adult hippocampal neurogenesis was impaired in several Alzheimer's disease models overexpressing mutant human amyloid precursor protein (hAPP. However, the effects of wild-type hAPP on adult neurogenesis and whether the impaired adult hippocampal neurogenesis was caused by amyloid β (Aβ or APP remained unclear. Here, we found that neurogenesis was impaired in the dentate gyrus (DG of adult mice overexpressing wild-type hAPP (hAPP-I5 compared with controls. However, the adult hippocampal neurogenesis was more severely impaired in hAPP-I5 than that in hAPP-J20 mice, which express similar levels of hAPP mRNA but much higher levels of Aβ. Furthermore, reducing Aβ levels did not affect the number of doublecortin-positive cells in the DG of hAPP-J20 mice. Our results suggested that hAPP was more likely an important factor inhibiting adult neurogenesis, and Aβ was not the major factor affecting neurogenesis in the adult hippocampus of hAPP mice.

  8. Age-dependent kinetics of dentate gyrus neurogenesis in the absence of cyclin D2

    Directory of Open Access Journals (Sweden)

    Ansorg Anne

    2012-05-01

    Full Text Available Abstract Background Adult neurogenesis continuously adds new neurons to the dentate gyrus and the olfactory bulb. It involves the proliferation and subsequent differentiation of neuronal progenitors, and is thus closely linked to the cell cycle machinery. Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins. Among them, D-type cyclins control the exit from the G1 phase of the cell cycle. Cyclin D2 (cD2 has been shown to be required for the generation of new neurons in the neurogenic niches of the adult brain. It is differentially expressed during hippocampal development, and adult cD2 knock out (cD2KO mice virtually lack neurogenesis in the dentate gyrus and olfactory bulb. In the present study we examined the dynamics of postnatal and adult neurogenesis in the dentate gyrus (DG of cD2KO mice. Animals were injected with bromodeoxyuridine at seven time points during the first 10 months of life and brains were immunohistochemically analyzed for their potential to generate new neurons. Results Compared to their WT litters, cD2KO mice had considerably reduced numbers of newly born granule cells during the postnatal period, with neurogenesis becoming virtually absent around postnatal day 28. This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death. CD2KO mice did not show any of the age-related changes in neurogenesis and granule cell numbers that were seen in WT litters. Conclusions The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development. In cD2KO mice, hippocampal neurogenesis ceases at a time point at which the tertiary germinative matrix stops proliferating, indicating that cD2 becomes an essential requirement for ongoing neurogenesis with the transition from developmental to adult neurogenesis. Our data further support the notion that

  9. Progranulin regulates neurogenesis in the developing vertebrate retina.

    Science.gov (United States)

    Walsh, Caroline E; Hitchcock, Peter F

    2017-09-01

    We evaluated the expression and function of the microglia-specific growth factor, Progranulin-a (Pgrn-a) during developmental neurogenesis in the embryonic retina of zebrafish. At 24 hpf pgrn-a is expressed throughout the forebrain, but by 48 hpf pgrn-a is exclusively expressed by microglia and/or microglial precursors within the brain and retina. Knockdown of Pgrn-a does not alter the onset of neurogenic programs or increase cell death, however, in its absence, neurogenesis is significantly delayed-retinal progenitors fail to exit the cell cycle at the appropriate developmental time and postmitotic cells do not acquire markers of terminal differentiation, and microglial precursors do not colonize the retina. Given the link between Progranulin and cell cycle regulation in peripheral tissues and transformed cells, we analyzed cell cycle kinetics among retinal progenitors following Pgrn-a knockdown. Depleting Pgrn-a results in a significant lengthening of the cell cycle. These data suggest that Pgrn-a plays a dual role during nervous system development by governing the rate at which progenitors progress through the cell cycle and attracting microglial progenitors into the embryonic brain and retina. Collectively, these data show that Pgrn-a governs neurogenesis by regulating cell cycle kinetics and the transition from proliferation to cell cycle exit and differentiation. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 77: 1114-1129, 2017. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc.

  10. Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

    International Nuclear Information System (INIS)

    Ji, Jian-feng; Ji, Sheng-jun; Sun, Rui; Li, Kun; Zhang, Yuan; Zhang, Li-yuan; Tian, Ye

    2014-01-01

    Highlights: •Forced exercise can ameliorate WBI induced cognitive impairment in our rat model. •Mature BDNF plays an important role in the effects of forced exercise. •Exercise may be a possible treatment of the radiation-induced cognitive impairment. -- Abstract: Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non

  11. Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ji, Jian-feng; Ji, Sheng-jun; Sun, Rui; Li, Kun; Zhang, Yuan; Zhang, Li-yuan; Tian, Ye, E-mail: dryetian@hotmail.com

    2014-01-10

    Highlights: •Forced exercise can ameliorate WBI induced cognitive impairment in our rat model. •Mature BDNF plays an important role in the effects of forced exercise. •Exercise may be a possible treatment of the radiation-induced cognitive impairment. -- Abstract: Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non

  12. Inducible Activation of ERK5 MAP Kinase Enhances Adult Neurogenesis in the Olfactory Bulb and Improves Olfactory Function

    Science.gov (United States)

    Wang, Wenbin; Lu, Song; Li, Tan; Pan, Yung-Wei; Zou, Junhui; Abel, Glen M.; Xu, Lihong; Storm, Daniel R.

    2015-01-01

    Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury. PMID:25995470

  13. APC/C-Cdh1 coordinates neurogenesis and cortical size during development

    Science.gov (United States)

    Delgado-Esteban, Maria; García-Higuera, Irene; Maestre, Carolina; Moreno, Sergio; Almeida, Angeles

    2013-12-01

    The morphology of the adult brain is the result of a delicate balance between neural progenitor proliferation and the initiation of neurogenesis in the embryonic period. Here we assessed whether the anaphase-promoting complex/cyclosome (APC/C) cofactor, Cdh1—which regulates mitosis exit and G1-phase length in dividing cells—regulates neurogenesis in vivo. We use an embryo-restricted Cdh1 knockout mouse model and show that functional APC/C-Cdh1 ubiquitin ligase activity is required for both terminal differentiation of cortical neurons in vitro and neurogenesis in vivo. Further, genetic ablation of Cdh1 impairs the ability of APC/C to promote neurogenesis by delaying the exit of the progenitor cells from the cell cycle. This causes replicative stress and p53-mediated apoptotic death resulting in decreased number of cortical neurons and cortex size. These results demonstrate that APC/C-Cdh1 coordinates cortical neurogenesis and size, thus posing Cdh1 in the molecular pathogenesis of congenital neurodevelopmental disorders, such as microcephaly.

  14. Deficient plasticity in the hippocampus and the spiral of addiction: focus on adult neurogenesis.

    Science.gov (United States)

    Canales, Juan J

    2013-01-01

    Addiction is a complex neuropsychiatric disorder which causes disruption at multiple levels, including cognitive, emotional, and behavioral domains. Traditional biological theories of addiction have focused on the mesolimbic dopamine pathway and the nucleus accumbens as anatomical substrates mediating addictive-like behaviors. More recently, we have begun to recognize the engagement and dynamic influence of a much broader circuitry which encompasses the frontal cortex, the amygdala, and the hippocampus. In particular, neurogenesis in the adult hippocampus has become a major focus of attention due to its ability to influence memory, motivation, and affect, all of which are disrupted in addiction. First, I summarize toxicological data that reveal strongly suppressive effects of drug exposure on adult hippocampal neurogenesis. Then, I discuss the impact of deficient neurogenesis on learning and memory function, stress responsiveness and affective behavior, as they relate to addiction. Finally, I examine recent behavioral observations that implicate neurogenesis in the adult hippocampus in the emergence and maintenance of addictive behavior. The evidence reviewed here suggests that deficient neurogenesis is associated with several components of the downward spiraling loop that characterizes addiction, including elevated sensitivity to drug-induced reward and reinforcement, enhanced neurohormonal responsiveness, emergence of a negative affective state, memory impairment, and inflexible behavior.

  15. EVA1A/TMEM166 Regulates Embryonic Neurogenesis by Autophagy

    Directory of Open Access Journals (Sweden)

    Mengtao Li

    2016-03-01

    Full Text Available Self-renewal and differentiation of neural stem cells is essential for embryonic neurogenesis, which is associated with cell autophagy. However, the mechanism by which autophagy regulates neurogenesis remains undefined. Here, we show that Eva1a/Tmem166, an autophagy-related gene, regulates neural stem cell self-renewal and differentiation. Eva1a depletion impaired the generation of newborn neurons, both in vivo and in vitro. Conversely, overexpression of EVA1A enhanced newborn neuron generation and maturation. Moreover, Eva1a depletion activated the PIK3CA-AKT axis, leading to the activation of the mammalian target of rapamycin and the subsequent inhibition of autophagy. Furthermore, addition of methylpyruvate to the culture during neural stem cell differentiation rescued the defective embryonic neurogenesis induced by Eva1a depletion, suggesting that energy availability is a significant factor in embryonic neurogenesis. Collectively, these data demonstrated that EVA1A regulates embryonic neurogenesis by modulating autophagy. Our results have potential implications for understanding the pathogenesis of neurodevelopmental disorders caused by autophagy dysregulation.

  16. Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice.

    Directory of Open Access Journals (Sweden)

    Anna Fiorentini

    Full Text Available BACKGROUND: Alzheimer's disease (AD is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular β-amyloid (Aβ plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. METHODOLOGY/PRINCIPAL FINDINGS: The double transgenic (Tg CRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. The differentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3β and subsequent activation of Wnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium's ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines as brain Aβ deposition and pathology increases. CONCLUSIONS: Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.

  17. Is forebrain neurogenesis a potential repair mechanism after stroke?

    OpenAIRE

    Inta, Dragos; Gass, Peter

    2015-01-01

    The use of adult subventricular zone (SVZ) neurogenesis as brain repair strategy after stroke represents a hot topic in neurologic research. Recent radiocarbon-14 dating has revealed a lack of poststroke neurogenesis in the adult human neocortex; however, adult neurogenesis has been shown to occur, even under physiologic conditions, in the human striatum. Here, these results are contrasted with experimental poststroke neurogenesis in the murine brain. Both in humans and in rodents, the SVZ ge...

  18. Discovery of efficient stimulators for adult hippocampal neurogenesis based on scaffolds in dragon's blood.

    Science.gov (United States)

    Liang, Jian-Hua; Yang, Liang; Wu, Si; Liu, Si-Si; Cushman, Mark; Tian, Jing; Li, Nuo-Min; Yang, Qing-Hu; Zhang, He-Ao; Qiu, Yun-Jie; Xiang, Lin; Ma, Cong-Xuan; Li, Xue-Meng; Qing, Hong

    2017-08-18

    Reduction of hippocampal neurogenesis caused by aging and neurological disorders would impair neural circuits and result in memory loss. A new lead compound (N-trans-3',4'-methylenedioxystilben-4-yl acetamide 27) has been discovered to efficiently stimulate adult rats' neurogenesis. In-depth structure-activity relationship studies proved the necessity of a stilbene scaffold that is absent in highly cytotoxic analogs such as chalcones and heteroaryl rings and inactive analogs such as diphenyl acetylene and diphenyl ethane, and validated the importance of an NH in the carboxamide and a methylenedioxy substituent on the benzene ring. Immunohistochemical staining and biochemical analysis indicate, in contrast to previously reported neuroprotective chemicals, N-stilbenyl carboxamides have extra capacity for neuroproliferation-type neurogenesis, thereby providing a foundation for improving the plasticity of the adult mammalian brain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Impaired neurogenesis of the dentate gyrus is associated with pattern separation deficits: A computational study.

    Science.gov (United States)

    Faghihi, Faramarz; Moustafa, Ahmed A

    2016-09-01

    The separation of input patterns received from the entorhinal cortex (EC) by the dentate gyrus (DG) is a well-known critical step of information processing in the hippocampus. Although the role of interneurons in separation pattern efficiency of the DG has been theoretically known, the balance of neurogenesis of excitatory neurons and interneurons as well as its potential role in information processing in the DG is not fully understood. In this work, we study separation efficiency of the DG for different rates of neurogenesis of interneurons and excitatory neurons using a novel computational model in which we assume an increase in the synaptic efficacy between excitatory neurons and interneurons and then its decay over time. Information processing in the EC and DG was simulated as information flow in a two layer feed-forward neural network. The neurogenesis rate was modeled as the percentage of new born neurons added to the neuronal population in each time bin. The results show an important role of an optimal neurogenesis rate of interneurons and excitatory neurons in the DG in efficient separation of inputs from the EC in pattern separation tasks. The model predicts that any deviation of the optimal values of neurogenesis rates leads to different decreased levels of the separation deficits of the DG which influences its function to encode memory.

  20. Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior.

    Science.gov (United States)

    Sun, Dong; Sun, Xiang-Dong; Zhao, Lu; Lee, Dae-Hoon; Hu, Jin-Xia; Tang, Fu-Lei; Pan, Jin-Xiu; Mei, Lin; Zhu, Xiao-Juan; Xiong, Wen-Cheng

    2018-01-08

    Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

  1. Cadmium inhibits neurogenesis in zebrafish embryonic brain development

    Energy Technology Data Exchange (ETDEWEB)

    Chow, Elly Suk Hen [Division of Biology, California Institute of Technology, 1200 California Boulevard, Pasadena, CA 91125 (United States); Hui, Michelle Nga Yu; Lin Chunchi [Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong (China); Cheng Shukhan [Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong (China)], E-mail: bhcheng@cityu.edu.hk

    2008-05-01

    Cadmium is a non-essential heavy metal found abundantly in the environment. Children of women exposed to cadmium during pregnancy display lower motor and perceptual abilities. High cadmium body burden in children is also related to impaired intelligence and lowered school achievement. However, little is known about the molecular and cellular basis of developmental neurotoxicity in the sensitive early life stages of animals. In this study, we explore neurological deficits caused by cadmium during early embryonic stages in zebrafish by examining regionalization of the neural tube, pattern formation and cell fate determination, commitment of proneural genes and induction of neurogenesis. We show that cadmium-treated embryos developed a smaller head with unclear boundaries between the brain subdivisions, particularly in the mid-hindbrain region. Embryos display normal anterior to posterior regionalization; however, the commitment of neural progenitor cells was affected by cadmium. We observe prominent reductions in the expression of several proneuronal genes including ngn1 in cell clusters, zash1a in the developing optic tectum, and zash1b in the telencephalon and tectum. Cadmium-treated embryos also have fewer differentiated neurons and glia in the facial sensory ganglia as indicated by decreased zn-12 expression. Also, a lower transcription level of neurogenic genes, ngn1 and neuroD, is observed in neurons. Our data suggest that cadmium-induced neurotoxicity can be caused by impaired neurogenesis, resulting in markedly reduced neuronal differentiation and axonogenesis.

  2. Cadmium inhibits neurogenesis in zebrafish embryonic brain development

    International Nuclear Information System (INIS)

    Chow, Elly Suk Hen; Hui, Michelle Nga Yu; Lin Chunchi; Cheng Shukhan

    2008-01-01

    Cadmium is a non-essential heavy metal found abundantly in the environment. Children of women exposed to cadmium during pregnancy display lower motor and perceptual abilities. High cadmium body burden in children is also related to impaired intelligence and lowered school achievement. However, little is known about the molecular and cellular basis of developmental neurotoxicity in the sensitive early life stages of animals. In this study, we explore neurological deficits caused by cadmium during early embryonic stages in zebrafish by examining regionalization of the neural tube, pattern formation and cell fate determination, commitment of proneural genes and induction of neurogenesis. We show that cadmium-treated embryos developed a smaller head with unclear boundaries between the brain subdivisions, particularly in the mid-hindbrain region. Embryos display normal anterior to posterior regionalization; however, the commitment of neural progenitor cells was affected by cadmium. We observe prominent reductions in the expression of several proneuronal genes including ngn1 in cell clusters, zash1a in the developing optic tectum, and zash1b in the telencephalon and tectum. Cadmium-treated embryos also have fewer differentiated neurons and glia in the facial sensory ganglia as indicated by decreased zn-12 expression. Also, a lower transcription level of neurogenic genes, ngn1 and neuroD, is observed in neurons. Our data suggest that cadmium-induced neurotoxicity can be caused by impaired neurogenesis, resulting in markedly reduced neuronal differentiation and axonogenesis

  3. Correlations between Hippocampal Neurogenesis and Metabolic Indices in Adult Nonhuman Primates

    Directory of Open Access Journals (Sweden)

    Tarique D. Perera

    2011-01-01

    Full Text Available Increased neurogenesis in feeding centers of the murine hypothalamus is associated with weight loss in diet-induced obese rodents (Kokoeva et al., 2005 and Matrisciano et al., 2010, but this relationship has not been examined in other species. Postmortem hippocampal neurogenesis rates and premortem metabolic parameters were statistically analyzed in 8 chow-fed colony-reared adult bonnet macaques. Dentate gyrus neurogenesis, reflected by the immature neuronal marker, doublecortin (DCX, and expression of the antiapoptotic gene factor, B-cell lymphoma 2 (BCL-2, but not the precursor proliferation mitotic marker, Ki67, was inversely correlated with body weight and crown-rump length. DCX and BCL-2 each correlated positively with blood glucose level and lipid ratio (total cholesterol/high-density lipoprotein. This study demonstrates that markers of dentate gyrus neuroplasticity correlate with metabolic parameters in primates.

  4. Neurodegenerative diseases: exercising towards neurogenesis and neuroregeneration

    Directory of Open Access Journals (Sweden)

    Eng-Tat Ang

    2010-07-01

    Full Text Available Currently, there is still no effective therapy for neurodegenerative diseases (NDD such as Alzheimer’s disease (AD and Parkinson’s disease (PD despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician’s and the scientist’s needs, and to highlight current research investigating exercise as a therapeutic or preventive measure.

  5. Adult neurogenesis modifies excitability of the dentate gyrus

    Directory of Open Access Journals (Sweden)

    Taruna eIkrar

    2013-12-01

    Full Text Available Adult-born dentate granule neurons contribute to memory encoding functions of the dentate gyrus (DG such as pattern separation. However, local circuit-mechanisms by which adult-born neurons partake in this process are poorly understood. Computational, neuroanatomical and electrophysiological studies suggest that sparseness of activation in the granule cell layer (GCL is conducive for pattern separation. A sparse coding scheme is thought to facilitate the distribution of similar entorhinal inputs across the GCL to decorrelate overlapping representations and minimize interference. Here we used fast voltage-sensitive dye (VSD imaging combined with laser photostimulation and electrical stimulation to examine how selectively increasing adult DG neurogenesis influences local circuit activity and excitability. We show that DG of mice with more adult-born neurons exhibits decreased strength of neuronal activation and more restricted excitation spread in GCL while maintaining effective output to CA3c. Conversely, blockade of adult hippocampal neurogenesis changed excitability of the DG in the opposite direction. Analysis of GABAergic inhibition onto mature dentate granule neurons in the DG of mice with more adult-born neurons shows a modest readjustment of perisomatic inhibitory synaptic gain without changes in overall inhibitory tone, presynaptic properties or GABAergic innervation pattern. Retroviral labeling of connectivity in mice with more adult-born neurons showed increased number of excitatory synaptic contacts of adult-born neurons onto hilar interneurons. Together, these studies demonstrate that adult hippocampal neurogenesis modifies excitability of mature dentate granule neurons and that this non-cell autonomous effect may be mediated by local circuit mechanisms such as excitatory drive onto hilar interneurons. Modulation of DG excitability by adult-born dentate granule neurons may enhance sparse coding in the GCL to influence pattern

  6. NeuroD modulates opioid agonist-selective regulation of adult neurogenesis and contextual memory extinction.

    Science.gov (United States)

    Zheng, Hui; Zhang, Yue; Li, Wen; Loh, Horace H; Law, Ping-Yee

    2013-04-01

    Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of neurogenic differentiation 1 (NeuroD) activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate or magnitude. Fentanyl-induced CPP required much longer time for extinction than morphine-induced CPP. We observed a parallel decrease in NeuroD activities and neurogenesis after morphine-induced CPP, but not after fentanyl-induced CPP. Increasing NeuroD activities with NeuroD-lentivirus (nd-vir) injection at the dentate gyrus before CPP training reversed morphine-induced decreases in NeuroD activities and neurogenesis, and prolonged the time required for extinction of morphine-induced CPP. On the other hand, decreasing NeuroD activities via injection of miRNA-190-virus (190-vir) reversed the fentanyl effect on NeuroD and neurogenesis and shortened the time required for extinction of fentanyl-induced CPP. Another contextual memory task, the Morris Water Maze (MWM), was affected similarly by alteration of NeuroD activities. The reduction in NeuroD activities either by morphine treatment or 190-vir injection decreased MWM task retention, while the increase in NeuroD activities by nd-vir prolonged MWM task retention. Thus, by controlling NeuroD activities, opioid agonists differentially regulate adult neurogenesis and subsequent contextual memory retention. Such drug-related memory regulation could have implications in eventual context-associated relapse.

  7. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Directory of Open Access Journals (Sweden)

    Sanberg Paul R

    2008-02-01

    Full Text Available Abstract Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

  8. Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer's disease

    International Nuclear Information System (INIS)

    Zheng, Rui; Zhang, Zhong-Hao; Chen, Chen; Chen, Yao; Jia, Shi-Zheng; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li

    2017-01-01

    The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce β-amyloid peptide (Aβ) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1–10 μM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 μM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3β activity, which would further activated the β-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 μg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3β-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective

  9. Is the increase in allergic respiratory disease caused by a cohort effect?

    DEFF Research Database (Denmark)

    Linneberg, A; Nielsen, N H; Madsen, F

    2002-01-01

    -sectional studies have shown that the prevalence of allergic sensitization decreases with increasing age. This could reflect the natural course of allergic sensitization. Alternatively, this could reflect that the increase in sensitization is caused by a cohort effect, i.e. an increase among subjects born during...... by a cohort effect. Thus, changes in lifestyle or environmental factors that occurred around or after 1960 may have contributed to this increase....

  10. Nootropic agents stimulate neurogenesis. Brain Cells, Inc.: WO2007104035.

    Science.gov (United States)

    Taupin, Philippe

    2009-05-01

    The application is in the field of adult neurogenesis, neural stem cells and cellular therapy. It aims to characterize the activity of nootropic agents on adult neurogenesis in vitro. Nootropic agents are substances improving cognitive and mental abilities. AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and nootropic agents were assessed for the potential to differentiate human neural progenitor and stem cells into neuronal cells in vitro. They were also tested for their behavioural activity on the novel object recognition task. AMPA, piracetam, FK-960 and SGS-111 induce and stimulate neuronal differentiation of human-derived neural progenitor and stem cells. SGS-111 increases the number of visits to the novel object. The neurogenic activity of piracetam and SGS-111 is mediated through AMPA receptor. The neurogenic activity of SGS-111 may contribute and play a role in its nootropic activity. These results suggest that nootropic agents may elicit some of their effects through their neurogenic activity. The application claims the use of nootropic agents for their neurogenic activity and for the treatment of neurological diseases, disorders and injuries, by stimulating or increasing the generation of neuronal cells in the adult brain.

  11. Factors That Modulate Neurogenesis: A Top-Down Approach.

    Science.gov (United States)

    LaDage, Lara D

    2016-08-24

    Although hippocampal neurogenesis in the adult brain has been conserved across the vertebrate lineage, laboratory studies have primarily examined this phenomenon in rodent models. This approach has been successful in elucidating important factors and mechanisms that can modulate rates of hippocampal neurogenesis, including hormones, environmental complexity, learning and memory, motor stimulation, and stress. However, recent studies have found that neurobiological research on neurogenesis in rodents may not easily translate to, or explain, neurogenesis patterns in nonrodent systems, particularly in species examined in the field. This review examines some of the evolutionary and ecological variables that may also modulate neurogenesis patterns. This 'top-down' and more naturalistic approach, which incorporates ecology and natural history, particularly of nonmodel species, may allow for a more comprehensive understanding of the functional significance of neurogenesis. © 2016 S. Karger AG, Basel.

  12. Increasing RpoS expression causes cell death in Borrelia burgdorferi.

    Directory of Open Access Journals (Sweden)

    Linxu Chen

    Full Text Available RpoS, one of the two alternative σ factors in Borrelia burgdorferi, is tightly controlled by multiple regulators and, in turn, determines expression of many critical virulence factors. Here we show that increasing RpoS expression causes cell death. The immediate effect of increasing RpoS expression was to promote bacterial division and as a consequence result in a rapid increase in cell number before causing bacterial death. No DNA fragmentation or degradation was observed during this induced cell death. Cryo-electron microscopy showed induced cells first formed blebs, which were eventually released from dying cells. Apparently blebbing initiated cell disintegration leading to cell death. These findings led us to hypothesize that increasing RpoS expression triggers intracellular programs and/or pathways that cause spirochete death. The potential biological significance of induced cell death may help B. burgdorferi regulate its population to maintain its life cycle in nature.

  13. Tau protein and adult hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Almudena eFuster-Matanzo

    2012-07-01

    Full Text Available Tau protein is a microtubule associated protein found in the axonal compartment that stabilizes neuronal microtubules under normal physiological conditions. Tau metabolism has attracted much attention because of its role in neurodegenerative disorders called tauopathies, mainly Alzheimer disease. Here, we review recent findings suggesting that axonal outgrowth in subgranular zone during adult hippocampal neurogenesis requires a dynamic microtubule network and tau protein facilitates to maintain that dynamic cytoskeleton. Those functions are carried out in part by tau isoform with only three microtubule-binding domains (without exon 10 and by presence of hypherphosphorylated tau forms. Thus, tau is a good marker and a valuable tool to study new axons in adult neurogenesis.

  14. Spatial relational memory requires hippocampal adult neurogenesis.

    Directory of Open Access Journals (Sweden)

    David Dupret

    Full Text Available The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.

  15. Contribution of constitutively proliferating precursor cell subtypes to dentate neurogenesis after cortical infarcts

    Directory of Open Access Journals (Sweden)

    Oberland Julia

    2010-11-01

    Full Text Available Abstract Background It is well known that focal ischemia increases neurogenesis in the adult dentate gyrus of the hippocampal formation but the cellular mechanisms underlying this proliferative response are only poorly understood. We here investigated whether precursor cells which constitutively proliferate before the ischemic infarct contribute to post-ischemic neurogenesis. To this purpose, transgenic mice expressing green fluorescent protein (GFP under the control of the nestin promoter received repetitive injections of the proliferation marker bromodeoxyuridine (BrdU prior to induction of cortical infarcts. We then immunocytochemically analyzed the fate of these BrdU-positive precursor cell subtypes from day 4 to day 28 after the lesion. Results Quantification of BrdU-expressing precursor cell populations revealed no alteration in number of radial glia-like type 1 cells but a sequential increase of later precursor cell subtypes in lesioned animals (type 2a cells at day 7, type 3 cells/immature neurons at day 14. These alterations result in an enhanced survival of mature neurons 4 weeks postinfarct. Conclusions Focal cortical infarcts recruit dentate precursor cells generated already before the infarct and significantly contribute to an enhanced neurogenesis. Our findings thereby increase our understanding of the complex cellular mechanisms of postlesional neurogenesis.

  16. Omega-3 fatty acids upregulate adult neurogenesis

    OpenAIRE

    Beltz, Barbara S.; Tlusty, Michael F.; Benton, Jeannie L.; Sandeman, David C.

    2007-01-01

    Omega-3 fatty acids play crucial roles in the development and function of the central nervous system. These components, which must be obtained from dietary sources, have been implicated in a variety of neurodevelopmental and psychiatric disorders. Furthermore, the presence of omega-6 fatty acids may interfere with omega-3 fatty acid metabolism. The present study investigated whether changes in dietary ratios of omega-3:omega-6 fatty acids influence neurogenesis in the lobster (Homarus america...

  17. Adult Neurogenesis Supports Short-Term Olfactory Memory

    OpenAIRE

    Arenkiel, Benjamin R.

    2010-01-01

    Adult neurogenesis has captivated neuroscientists for decades, with hopes that understanding the programs underlying this phenomenon may provide unique insight toward avenues for brain repair. Interestingly, however, despite intense molecular and cellular investigation, the evolutionary roles and biological functions for ongoing neurogenesis have remained elusive. Here I review recent work published in the Journal of Neuroscience that reveals a functional role for continued neurogenesis towar...

  18. Adult neurogenesis supports short-term olfactory memory.

    Science.gov (United States)

    Arenkiel, Benjamin R

    2010-06-01

    Adult neurogenesis has captivated neuroscientists for decades, with hopes that understanding the programs underlying this phenomenon may provide unique insight toward avenues for brain repair. Interestingly, however, despite intense molecular and cellular investigation, the evolutionary roles and biological functions for ongoing neurogenesis have remained elusive. Here I review recent work published in the Journal of Neuroscience that reveals a functional role for continued neurogenesis toward forming short-term olfactory memories.

  19. Testing and diagnosis of the cause of increased vibration of the fan plant's support structure

    Directory of Open Access Journals (Sweden)

    Varju Đerđ

    2015-01-01

    Full Text Available This paper presents a procedure of determining the causes of increased vibration of a fan plant and its support structure in the PUC 'Subotička toplana'. Excessive vibrations were observed following the installation of the frequency converter, thus a methodological approach of testing-analysis-diagnosis has been applied. Based on the definition of the causes of this problem, the paper also suggests possible repair procedures.

  20. Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice.

    Science.gov (United States)

    Kuzumaki, Naoko; Ikegami, Daigo; Imai, Satoshi; Narita, Michiko; Tamura, Rie; Yajima, Marie; Suzuki, Atsuo; Miyashita, Kazuhiko; Niikura, Keiichi; Takeshima, Hideyuki; Ando, Takayuki; Ushijima, Toshikazu; Suzuki, Tsutomu; Narita, Minoru

    2010-09-01

    A variety of mechanisms that contribute to the accumulation of age-related damage and the resulting brain dysfunction have been identified. Recently, decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. However, the molecular mechanism of decreased neurogenesis with aging is still unclear. In the present study, we investigated whether aging decreases neurogenesis accompanied by the activation of microglia and astrocytes, which increases the expression of IL-1beta in the hippocampus, and whether in vitro treatment with IL-1beta in neural stem cells directly impairs neurogenesis. Ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were increased in the dentate gyrus of the hippocampus of 28-month-old mice. Furthermore, the mRNA level of IL-1beta was significantly increased without related histone modifications. Moreover, a significant increase in lysine 9 on histone H3 (H3K9) trimethylation at the promoter of NeuroD (a neural progenitor cell marker) was observed in the hippocampus of aged mice. In vitro treatment with IL-1beta in neural stem cells prepared from whole brain of E14.5 mice significantly increased H3K9 trimethylation at the NeuroD promoter. These findings suggest that aging may decrease hippocampal neurogenesis via epigenetic modifications accompanied by the activation of microglia and astrocytes with the increased expression of IL-1beta in the hippocampus.

  1. Perlecan controls neurogenesis in the developing telencephalon

    Directory of Open Access Journals (Sweden)

    Fairén Alfonso

    2007-04-01

    Full Text Available Abstract Background Perlecan is a proteoglycan expressed in the basal lamina of the neuroepithelium during development. Perlecan absence does not impair basal lamina assembly, although in the 55% of the mutants early disruptions of this lamina conducts to exencephaly, impairing brain development. The rest of perlecan-null brains complete its prenatal development, maintain basal lamina continuity interrupted by some isolated ectopias, and are microcephalic. Microcephaly consists of thinner cerebral walls and underdeveloped ganglionic eminences. We have studied the mechanisms that generate brain atrophy in telencephalic areas where basal lamina is intact. Results Brain atrophy in the absence of perlecan started in the ventral forebrain and extended to lateral and dorsal parts of the cortex in the following stages. First, the subpallial forebrain developed poorly in early perlecan-null embryos, because of a reduced cell proliferation: the number of cells in mitosis decreased since the early stages of development. This reduction resulted in a decreased tangential migration of interneurons to the cerebral cortex. Concomitant with the early hypoplasia observed in the medial ganglionic eminences, Sonic Hedgehog signal decreased in the perlecan-null floor plate basal lamina at E12.5. Second, neurogenesis in the pallial neuroepithelium was affected in perlecan deficient embryos. We found reductions of nearly 50% in the number of cells exiting the cell cycle at E12–E13. The labeling index, which was normal at this age, significantly decreased with advancing corticogenesis. Moreover, nestin+ or PCNA+ progenitors increased since E14.5, reaching up to about 150% of the proportion of PCNA+ cells in the wild-type at E17.5. Thus, labeling index reduction together with increased progenitor population, suggests that atrophy is the result of altered cell cycle progression in the cortical progenitors. Accordingly, less neurons populated the cortical plate and

  2. The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment.

    Science.gov (United States)

    Donega, Vanessa; van Velthoven, Cindy T J; Nijboer, Cora H; Kavelaars, Annemieke; Heijnen, Cobi J

    2013-05-01

    Neurogenesis continues throughout adulthood. The neurogenic capacity of the brain increases after injury by, e.g., hypoxia-ischemia. However, it is well known that in many cases brain damage does not resolve spontaneously, indicating that the endogenous regenerative capacity of the brain is insufficient. Neonatal encephalopathy leads to high mortality rates and long-term neurologic deficits in babies worldwide. Therefore, there is an urgent need to develop more efficient therapeutic strategies. The latest findings indicate that stem cells represent a novel therapeutic possibility to improve outcome in models of neonatal encephalopathy. Transplanted stem cells secrete factors that stimulate and maintain neurogenesis, thereby increasing cell proliferation, neuronal differentiation, and functional integration. Understanding the molecular and cellular mechanisms underlying neurogenesis after an insult is crucial for developing tools to enhance the neurogenic capacity of the brain. The aim of this review is to discuss the endogenous capacity of the neonatal brain to regenerate after a cerebral ischemic insult. We present an overview of the molecular and cellular mechanisms underlying endogenous regenerative processes during development as well as after a cerebral ischemic insult. Furthermore, we will consider the potential to use stem cell transplantation as a means to boost endogenous neurogenesis and restore brain function.

  3. PMC-12, a traditional herbal medicine, enhances learning memory and hippocampal neurogenesis in mice.

    Science.gov (United States)

    Park, Hee Ra; Kim, Ju Yeon; Lee, Yujeong; Chun, Hye Jeong; Choi, Young Whan; Shin, Hwa Kyoung; Choi, Byung Tae; Kim, Cheol Min; Lee, Jaewon

    2016-03-23

    The beneficial effects of traditional Korean medicine are recognized during the treatment of neurodegenerative conditions, such as, Alzheimer's disease and neurocognitive dysfunction, and recently, hippocampal neurogenesis has been reported to be associated with memory function. In this study, the authors investigated the beneficial effects of polygonum multiflorum Thunberg complex composition-12 (PMC-12), which is a mixture of four medicinal herbs, that is, Polygonum multiflorum, Polygala tenuifolia, Rehmannia glutinosa, and Acorus gramineus, on hippocampal neurogenesis, learning, and memory in mice. PMC-12 was orally administered to male C57BL/6 mice (5 weeks old) at 100 or 500 mg/kg daily for 2 weeks. PMC-12 administration significantly was found to increase the proliferation of neural progenitor cells and the survival of newly-generated cells in the dentate gyrus. In the Morris water maze test, the latency times of PMC-12 treated mice (100 or 500 mg/kg) were shorter than those of vehicle-control mice. In addition, PMC-12 increased the levels of BDNF, p-CREB, and synaptophysin, which are known to be associated with neural plasticity and hippocampal neurogenesis. These findings suggest PMC-12 enhances hippocampal neurogenesis and neurocognitive function and imply that PMC-12 ameliorates memory impairment and cognitive deficits. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Doc Title: Adult Hippocampal Neurogenesis is Impaired by Transient Developmental Thyroid Hormone Disruption

    Data.gov (United States)

    U.S. Environmental Protection Agency — Severe thyroid hormone (TH) deprivation during development impairs neurogenesis throughout the brain. The hippocampus also maintains a capacity for neurogenesis...

  5. Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Müller Anke

    2010-06-01

    Full Text Available Abstract Background Adult neurogenesis is a particular example of brain plasticity that is partially modulated by the endocannabinoid system. Whereas the impact of synthetic cannabinoids on the neuronal progenitor cells has been described, there has been lack of information about the action of plant-derived extracts on neurogenesis. Therefore we here focused on the effects of Δ9-tetrahydrocannabinol (THC and Cannabidiol (CBD fed to female C57Bl/6 and Nestin-GFP-reporter mice on proliferation and maturation of neuronal progenitor cells and spatial learning performance. In addition we used cannabinoid receptor 1 (CB1 deficient mice and treatment with CB1 antagonist AM251 in Nestin-GFP-reporter mice to investigate the role of the CB1 receptor in adult neurogenesis in detail. Results THC and CBD differed in their effects on spatial learning and adult neurogenesis. CBD did not impair learning but increased adult neurogenesis, whereas THC reduced learning without affecting adult neurogenesis. We found the neurogenic effect of CBD to be dependent on the CB1 receptor, which is expressed over the whole dentate gyrus. Similarly, the neurogenic effect of environmental enrichment and voluntary wheel running depends on the presence of the CB1 receptor. We found that in the absence of CB1 receptors, cell proliferation was increased and neuronal differentiation reduced, which could be related to CB1 receptor mediated signaling in Doublecortin (DCX-expressing intermediate progenitor cells. Conclusion CB1 affected the stages of adult neurogenesis that involve intermediate highly proliferative progenitor cells and the survival and maturation of new neurons. The pro-neurogenic effects of CBD might explain some of the positive therapeutic features of CBD-based compounds.

  6. Cervical HSV-2 infection causes cervical remodeling and increases risk for ascending infection and preterm birth

    Science.gov (United States)

    McGee, Devin; Poncil, Sharra; Patterson, Amanda

    2017-01-01

    Preterm birth (PTB), or birth before 37 weeks gestation, is the leading cause of neonatal mortality worldwide. Cervical viral infections have been established as risk factors for PTB in women, although the mechanism leading to increased risk is unknown. Using a mouse model of pregnancy, we determined that intra-vaginal HSV2 infection caused increased rates of preterm birth following an intra-vaginal bacterial infection. HSV2 infection resulted in histological changes in the cervix mimicking cervical ripening, including significant collagen remodeling and increased hyaluronic acid synthesis. Viral infection also caused aberrant expression of estrogen and progesterone receptor in the cervical epithelium. Further analysis using human ectocervical cells demonstrated a role for Src kinase in virus-mediated changes in estrogen receptor and hyaluronic acid expression. In conclusion, HSV2 affects proteins involved in tissue hormone responsiveness, causes significant changes reminiscent of premature cervical ripening, and increases risk of preterm birth. Studies such as this improve our chances of identifying clinical interventions in the future. PMID:29190738

  7. Acupuncture for neurogenesis in experimental ischemic stroke: a systematic review and meta-analysis.

    Science.gov (United States)

    Lu, Lin; Zhang, Xiao-guang; Zhong, Linda L D; Chen, Zi-xian; Li, Yan; Zheng, Guo-qing; Bian, Zhao-xiang

    2016-01-20

    Acupuncture has been used for patients with stroke and post-stroke rehabilitation for thousands of years. Previous studies reported that acupuncture enhanced stroke recovery through neurogenesis. Hence, we conducted a systematic review and meta-analysis for preclinical studies to assess the current evidence for acupuncture effect on neurogenesis in treating ischaemic stroke. Studies were obtained from six databases, including PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, VIP information database, and Chinese Biomedical Literature Database, Ultimately, 34 studies containing 1617 animals were identified. Neurogenesis markers of Brdu, Nestin, PSA-NCAM, NeuN and GFAP were selected as major outcomes. The pooled results of 15 studies marked with Brdu showed significant effects of acupuncture for improving proliferation when compared with control groups (P acupuncture for increasing proliferation when compared with control groups (P acupuncture for enhancing migration when compared with control groups (P acupuncture for stimulating differentiation when compared with control groups (P acupuncture is a prospective therapy targeting neurogenesis for ischemic stroke.

  8. Central proliferation and neurogenesis is impaired in type 2 diabetes and prediabetes animal models.

    Directory of Open Access Journals (Sweden)

    Juan Jose Ramos-Rodriguez

    Full Text Available Type 2 diabetes (T2D is an important risk factor to suffer dementia, including Alzheimer's disease (AD, and some neuropathological features observed in dementia could be mediated by T2D metabolic alterations. Since brain atrophy and impaired neurogenesis have been observed both T2D and AD we analyzed central nervous system (CNS morphological alterations in the db/db mice (leptin receptor KO mice, as a model of long-term insulin resistance and T2D, and in C57Bl6 mice fed with high fat diet (HFD, as a model of diet induced insulin resistance and prediabetes. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. We also detected increased neurogenesis and cell proliferation rates in young db/db mice when compared with control littermates. Our study shows that metabolic parameters serve as predictors of both atrophy and altered proliferation and neurogenesis in the CNS. Moreover in the cortex, atrophy, cell proliferation and neurogenesis were significantly correlated. Our data suggest that T2D may underline some of the pathological features observed in the dementia process. They also support that blood glucose control in elderly patients could help to slow down dementia evolution and maybe, improve its prognosis.

  9. Regulation of neurogenesis: factors affecting of new neurons formation in adult mammals brain

    Directory of Open Access Journals (Sweden)

    Michalina Respondek

    2015-12-01

    Full Text Available Neurogenesis is a complex and multi-step process of generating completely functional neurons. This process in adult brain is based on pluripotentional neuronal stem cells (NSC, which are able to proliferation and differentiation into mature neurons or glial cells. NSC are located in subgranular zone inside hippocampus and in subventricular zone. The new neurons formation depends on many endo- and exogenous factors which modulate each step of neurogenesis. This article describes the most important regulators of adult neurogenesis, mainly: neurotrophins, growth factors, hormones, neurotransmitters and microenvironment of NSC. Some drugs, especially antipsychotics, antidepressants and normothymics may affect the neurogenic properties of adult brain. Moreover pathological processes such as neuroinflammation, stroke or epilepsy are able to induce proliferation of NSC. The proneurogenic effects of psychotropic drugs and pathological processes are associated with their ability to increase some hormones and neurotrophins level, as well as with rising the expression of antiapoptotic Bcl-2 protein and metalloproteinase MMP-2. Additionaly, some drugs, for example haloperidol, are able to block prolactin and dopaminergic neuroblasts receptors. Down-regulation of adult neurogenesis is associated with alcohol abuse and high stress level. Negative effect of many drugs, such as cytostatics, COX-2 inhibitors and opioides was also observed. The proneurogenic effect of described factors suggest their broad therapeutic potential and gives a new perspective on an effective and modern treatment of many neuropsychiatric disorders. This effect can also help to clarify the pathogenesis of disorders associated with proliferation and degeneration of adult brain cells.

  10. Role of adult hippocampal neurogenesis in stress resilience

    Directory of Open Access Journals (Sweden)

    Brunno R. Levone

    2015-01-01

    Full Text Available There is a growing appreciation that adult hippocampal neurogenesis plays a role in emotional and cognitive processes related to psychiatric disorders. Although many studies have investigated the effects of stress on adult hippocampal neurogenesis, most have not focused on whether stress-induced changes in neurogenesis occur specifically in animals that are more resilient or more susceptible to the behavioural and neuroendocrine effects of stress. Thus, in the present review we explore whether there is a clear relationship between stress-induced changes in adult hippocampal neurogenesis, stress resilience and antidepressant-induced recovery from stress-induced changes in behaviour. Exposure to different stressors is known to reduce adult hippocampal neurogenesis, but some stressors have also been shown to exert opposite effects. Ablation of neurogenesis does not lead to a depressive phenotype, but it can enhance responsiveness to stress and affect stress susceptibility. Monoaminergic-targeted antidepressants, environmental enrichment and adrenalectomy are beneficial for reversing stress-induced changes in behaviour and have been shown to do so in a neurogenesis-dependant manner. In addition, stress and antidepressants can affect hippocampal neurogenesis, preferentially in the ventral hippocampus. Together, these data show that adult hippocampal neurogenesis may play a role in the neuroendocrine and behavioural responses to stress, although it is not yet fully clear under which circumstances neurogenesis promotes resilience or susceptibility to stress. It will be important that future studies carefully examine how adult hippocampal neurogenesis can contribute to stress resilience/susceptibility so that it may be appropriately exploited for the development of new and more effective treatments for stress-related psychiatric disorders.

  11. Galectin-1 is expressed in early-type neural progenitor cells and down-regulates neurogenesis in the adult hippocampus

    Directory of Open Access Journals (Sweden)

    Imaizumi Yoichi

    2011-01-01

    Full Text Available Abstract Background In the adult mammalian brain, neural stem cells (NSCs proliferate in the dentate gyrus (DG of the hippocampus and generate new neurons throughout life. A multimodal protein, Galectin-1, is expressed in neural progenitor cells (NPCs and implicated in the proliferation of the NPCs in the DG. However, little is known about its detailed expression profile in the NPCs and functions in adult neurogenesis in the DG. Results Our immunohistochemical and morphological analysis showed that Galectin-1 was expressed in the type 1 and 2a cells, which are putative NSCs, in the subgranular zone (SGZ of the adult mouse DG. To study Galectin-1's function in adult hippocampal neurogenesis, we made galectin-1 knock-out mice on the C57BL6 background and characterized the effects on neurogenesis. In the SGZ of the galectin-1 knock-out mice, increased numbers of type 1 cells, DCX-positive immature progenitors, and NeuN-positive newborn neurons were observed. Using triple-labeling immunohistochemistry and morphological analyses, we found that the proliferation of the type-1 cells was increased in the SGZ of the galectin-1 knock-out mice, and we propose that this proliferation is the mechanism for the net increase in the adult neurogenesis in these knock-out mice DG. Conclusions Galectin-1 is expressed in the neural stem cells and down-regulates neurogenesis in the adult hippocampus.

  12. Inducible activation of ERK5 MAP kinase enhances adult neurogenesis in the olfactory bulb and improves olfactory function.

    Science.gov (United States)

    Wang, Wenbin; Lu, Song; Li, Tan; Pan, Yung-Wei; Zou, Junhui; Abel, Glen M; Xu, Lihong; Storm, Daniel R; Xia, Zhengui

    2015-05-20

    Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury. Copyright © 2015 the authors 0270-6474/15/357833-17$15.00/0.

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

    Directory of Open Access Journals (Sweden)

    Kuan Zhang

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

  14. Untangling the Influences of Voluntary Running, Environmental Complexity, Social Housing and Stress on Adult Hippocampal Neurogenesis

    Science.gov (United States)

    Grégoire, Catherine-Alexandra; Bonenfant, David; Le Nguyen, Adalie; Aumont, Anne; Fernandes, Karl J. L.

    2014-01-01

    Environmental enrichment (EE) exerts powerful effects on brain physiology, and is widely used as an experimental and therapeutic tool. Typical EE paradigms are multifactorial, incorporating elements of physical exercise, environmental complexity, social interactions and stress, however the specific contributions of these variables have not been separable using conventional housing paradigms. Here, we evaluated the impacts of these individual variables on adult hippocampal neurogenesis by using a novel “Alternating EE” paradigm. For 4 weeks, adult male CD1 mice were alternated daily between two enriched environments; by comparing groups that differed in one of their two environments, the individual and combinatorial effects of EE variables could be resolved. The Alternating EE paradigm revealed that (1) voluntary running for 3 days/week was sufficient to increase both mitotic and post-mitotic stages of hippocampal neurogenesis, confirming the central importance of exercise; (2) a complex environment (comprised of both social interactions and rotated inanimate objects) had no effect on neurogenesis itself, but enhanced depolarization-induced c-Fos expression (attributable to social interactions) and buffered stress-induced plasma corticosterone levels (attributable to inanimate objects); and (3) neither social isolation, group housing, nor chronically increased levels of plasma corticosterone had a prolonged impact on neurogenesis. Mouse strain, handling and type of running apparatus were tested and excluded as potential confounding factors. These findings provide valuable insights into the relative effects of key EE variables on adult neurogenesis, and this “Alternating EE” paradigm represents a useful tool for exploring the contributions of individual EE variables to mechanisms of neural plasticity. PMID:24465980

  15. Untangling the influences of voluntary running, environmental complexity, social housing and stress on adult hippocampal neurogenesis.

    Directory of Open Access Journals (Sweden)

    Catherine-Alexandra Grégoire

    Full Text Available Environmental enrichment (EE exerts powerful effects on brain physiology, and is widely used as an experimental and therapeutic tool. Typical EE paradigms are multifactorial, incorporating elements of physical exercise, environmental complexity, social interactions and stress, however the specific contributions of these variables have not been separable using conventional housing paradigms. Here, we evaluated the impacts of these individual variables on adult hippocampal neurogenesis by using a novel "Alternating EE" paradigm. For 4 weeks, adult male CD1 mice were alternated daily between two enriched environments; by comparing groups that differed in one of their two environments, the individual and combinatorial effects of EE variables could be resolved. The Alternating EE paradigm revealed that (1 voluntary running for 3 days/week was sufficient to increase both mitotic and post-mitotic stages of hippocampal neurogenesis, confirming the central importance of exercise; (2 a complex environment (comprised of both social interactions and rotated inanimate objects had no effect on neurogenesis itself, but enhanced depolarization-induced c-Fos expression (attributable to social interactions and buffered stress-induced plasma corticosterone levels (attributable to inanimate objects; and (3 neither social isolation, group housing, nor chronically increased levels of plasma corticosterone had a prolonged impact on neurogenesis. Mouse strain, handling and type of running apparatus were tested and excluded as potential confounding factors. These findings provide valuable insights into the relative effects of key EE variables on adult neurogenesis, and this "Alternating EE" paradigm represents a useful tool for exploring the contributions of individual EE variables to mechanisms of neural plasticity.

  16. Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization.

    Science.gov (United States)

    Bulin, Sarah E; Mendoza, Matthew L; Richardson, Devon R; Song, Kwang H; Solberg, Timothy D; Yun, Sanghee; Eisch, Amelia J

    2018-03-01

    Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. © 2017 Society for the Study of Addiction.

  17. Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications.

    Science.gov (United States)

    Galea, L A M; Wainwright, S R; Roes, M M; Duarte-Guterman, P; Chow, C; Hamson, D K

    2013-11-01

    The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurones in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex- and experience-dependent way. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely unexpected because the physiology of males and females is different, with the most notable difference being that females gestate and nurse the offspring. Furthermore, reproductive experience (i.e. pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression, and the present review provides early evidence of the functional links between the hormonal modulation of neurogenesis that may contribute to the regulation of cognition and stress. © 2013 British Society for Neuroendocrinology.

  18. Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function

    Science.gov (United States)

    Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plas...

  19. Neurogenesis and brain injury: managing a renewable resource for repair

    OpenAIRE

    Hallbergson, Anna F.; Gnatenco, Carmen; Peterson, Daniel A.

    2003-01-01

    The brain shows limited ability to repair itself, but neurogenesis in certain areas of the adult brain suggests that neural stem cells may be used for structural brain repair. It will be necessary to understand how neurogenesis in the adult brain is regulated to develop strategies that harness neural stem cells for therapeutic use.

  20. Impact of trichostatin A and sodium valproate treatment on post-stroke neurogenesis and behavioral outcomes in immature mice

    Directory of Open Access Journals (Sweden)

    Shanu eGeorge

    2013-08-01

    Full Text Available Stroke in the neonatal brain frequently results in neurologic impairments including cognitive disability. We investigated the effect of long-term sodium valproate (valproate and Trichostatin A (TSA treatment upon post-stroke neurogenesis in the dentate gyrus (DG of stroke-injured immature mice. Decreased or abnormal integration of newborn DG neurons into hippocampal circuits can result in impaired visual-spatial function, abnormal modulation of mood-related behaviors, and the development of post-stroke epilepsy. Unilateral carotid ligation of P12 CD1 mice was followed by treatment with valproate, TSA, or vehicle for 2 weeks, BrdU administration for measurement of neurogenesis, and perfusion at P42 or P60. Behavior testing was conducted from P38-42. No detrimental effects on behavior testing were noted with TSA treatment, but mildly impaired cognitive function was noted with valproate-treated injured animals compared to normal animals. Significant increases in DG neurogenesis with both TSA and valproate treatment were noted with later administration of BrdU. Increased mortality and impaired weight gain was noted in the valproate-treated ligated animals, but not in the TSA-treated animals. In summary, the impact of HDAC inhibition upon post-stroke SGZ neurogenesis is likely to depend on the age of the animal at the time point when neurogenesis is assessed, duration of HDAC inhibition before BrdU labeling, and/or the stage in the evolution of the injury.

  1. Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy.

    Science.gov (United States)

    Haricharan, Svasti; Dong, Jie; Hein, Sarah; Reddy, Jay P; Du, Zhijun; Toneff, Michael; Holloway, Kimberly; Hilsenbeck, Susan G; Huang, Shixia; Atkinson, Rachel; Woodward, Wendy; Jindal, Sonali; Borges, Virginia F; Gutierrez, Carolina; Zhang, Hong; Schedin, Pepper J; Osborne, C Kent; Tweardy, David J; Li, Yi

    2013-12-31

    While a first pregnancy before age 22 lowers breast cancer risk, a pregnancy after age 35 significantly increases life-long breast cancer risk. Pregnancy causes several changes to the normal breast that raise barriers to transformation, but how pregnancy can also increase cancer risk remains unclear. We show in mice that pregnancy has different effects on the few early lesions that have already developed in the otherwise normal breast-it causes apoptosis evasion and accelerated progression to cancer. The apoptosis evasion is due to the normally tightly controlled STAT5 signaling going astray-these precancerous cells activate STAT5 in response to pregnancy/lactation hormones and maintain STAT5 activation even during involution, thus preventing the apoptosis normally initiated by oncoprotein and involution. Short-term anti-STAT5 treatment of lactation-completed mice bearing early lesions eliminates the increased risk after a pregnancy. This chemoprevention strategy has important implications for preventing increased human breast cancer risk caused by pregnancy. DOI: http://dx.doi.org/10.7554/eLife.00996.001.

  2. The satiating hormone amylin enhances neurogenesis in the area postrema of adult rats

    Directory of Open Access Journals (Sweden)

    Claudia G. Liberini

    2016-10-01

    Full Text Available Objective: Adult neurogenesis in the subgranular zone and subventricular zone is generally accepted, but its existence in other brain areas is still controversial. Circumventricular organs, such as the area postrema (AP have recently been described as potential neurogenic niches in the adult brain. The AP is the major site of action of the satiating hormone amylin. Amylin has been shown to promote the formation of neuronal projections originating from the AP in neonatal rodents but the role of amylin in adult neurogenesis remains unknown. Methods: To test this, we first performed an RNA-sequencing of the AP of adult rats acutely injected with either amylin (20 μg/kg, amylin plus the amylin receptor antagonist AC187 (500 μg/kg or vehicle. Second, animals were subcutaneously equipped with minipumps releasing either amylin (50 μg/kg/day or vehicle for 3 weeks to assess cell proliferation and differentiation with the 5′-bromo-2-deoxyuridine (BrdU technique. Results: Acute amylin injections affected genes involved in pathways and processes that control adult neurogenesis. Amylin consistently upregulated NeuroD1 transcript and protein in the adult AP, and this effect was blocked by the co-administration of AC187. Further, chronic amylin treatment increased the number of newly proliferated AP-cells and significantly promoted their differentiation into neurons rather than astrocytes. Conclusion: Our findings revealed a novel role of the satiating hormone amylin in promoting neurogenesis in the AP of adult rats. Keywords: Amylin, Adult neurogenesis, Area postrema, BrdU, Circumventricular organs

  3. Adult hippocampal neurogenesis and cognitive aging

    Directory of Open Access Journals (Sweden)

    Román Darío Moreno Fernández

    2013-12-01

    Full Text Available Aging is a normal developmental process associated with neurobiological changes leading to cognitive alterations with preserved, impaired, and enhanced functions. Evidence from animal and human studies is reviewed to explore the potential role of hippocampal plasticity on age-related cognitive changes with special attention to adult hippocampal neurogenesis. Results from lesion and stimulation strategies, as well as correlation data, support either a direct or modulatory role for adult newborn neurons in cognition at advanced ages. Further research on this topic may help to develop new treatments and to improve the quality of life of older people.

  4. Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

    Science.gov (United States)

    Tilot, Amanda K; Gaugler, Mary K; Yu, Qi; Romigh, Todd; Yu, Wanfeng; Miller, Robert H; Frazier, Thomas W; Eng, Charis

    2014-06-15

    PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Aging causes collateral rarefaction and increased severity of ischemic injury in multiple tissues

    Science.gov (United States)

    Faber, James E.; Zhang, Hua; Lassance-Soares, Roberta M.; Prabhakar, Pranay; Najafi, Amir H.; Burnett, Mary Susan; Epstein, Stephen E.

    2011-01-01

    Objective Aging is a major risk factor for increased ischemic tissue injury. Whether collateral rarefaction and impaired remodeling contribute to this is unknown. We quantified the number and diameter of native collaterals, and their remodeling in 3-, 16-, 24-, and 31-months-old mice. Methods and Results Aging caused an “age-dose-dependent” greater drop in perfusion immediately after femoral artery ligation, followed by a diminished recovery of flow and increase in tissue injury. These effects were associated with a decline in collateral number, diameter and remodeling. Angiogenesis was also impaired. Mechanistically, these changes were not accompanied by reduced recruitment of T-cells or macrophages to remodeling collaterals. However, eNOS signaling was dysfunctional, as indicated by increased protein nitrosylation and less phosphorylated eNOS and VASP in collateral wall cells. The cerebral circulation exhibited a similar age-dose-dependent loss of collateral number and diameter and increased tortuosity, resulting in an increase in collateral resistance and infarct volume (e.g., 6- and 3-fold, respectively, in 24-months-old mice) after artery occlusion. This was not associated with rarefaction of similarly-sized arterioles. Collateral remodeling was also reduced. Conclusions Our findings demonstrate that aging causes rarefaction and insufficiency of the collateral circulation in multiple tissues, resulting in more severe ischemic tissue injury. PMID:21617137

  6. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults.

    Science.gov (United States)

    Tseng, Fen-Yu; Lin, Wen-Yuan; Lin, Cheng-Chieh; Lee, Long-Teng; Li, Tsai-Chung; Sung, Pei-Kun; Huang, Kuo-Chin

    2012-08-21

    This study sought to evaluate the relationship between subclinical hypothyroidism (SCH) and all-cause and cardiovascular disease (CVD) mortality. SCH may increase the risks of hypercholesterolemia and atherosclerosis. The associations between SCH and all-cause or CVD mortality are uncertain, on the basis of the results of previous studies. A baseline cohort of 115,746 participants without a history of thyroid disease, ≥20 years of age, was recruited in Taiwan. SCH was defined as a serum thyroid-stimulating hormone (TSH) level of 5.0 to 19.96 mIU/l with normal total thyroxine concentrations. Euthyroidism was defined as a serum TSH level of 0.47 to 4.9 mIU/l. Cox proportional hazards regression analysis was used to estimate the relative risks (RRs) of death from all-cause and CVD for adults with SCH during a 10-year follow-up period. There were 3,669 deaths during the follow-up period; 680 deaths were due to CVD. Compared with subjects with euthyroidism, after adjustment for age, sex, body mass index, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, betel nut chewing, physical activity, income, and education level, the RRs (95% confidence interval) of deaths from all-cause and CVD among subjects with SCH were 1.30 (1.02 to 1.66), and 1.68 (1.02 to 2.76), respectively. Adult Taiwanese with SCH had an increased risk for all-cause mortality and CVD death. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  7. Role of adult neurogenesis in hippocampal-cortical memory consolidation

    Science.gov (United States)

    2014-01-01

    Acquired memory is initially dependent on the hippocampus (HPC) for permanent memory formation. This hippocampal dependency of memory recall progressively decays with time, a process that is associated with a gradual increase in dependency upon cortical structures. This process is commonly referred to as systems consolidation theory. In this paper, we first review how memory becomes hippocampal dependent to cortical dependent with an emphasis on the interactions that occur between the HPC and cortex during systems consolidation. We also review the mechanisms underlying the gradual decay of HPC dependency during systems consolidation from the perspective of memory erasures by adult hippocampal neurogenesis. Finally, we discuss the relationship between systems consolidation and memory precision. PMID:24552281

  8. Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats.

    Science.gov (United States)

    Chen, Chong; Shen, Feng-Yan; Zhao, Xuan; Zhou, Tao; Xu, Dao-Jie; Wang, Zhi-Ru; Wang, Ying-Wei

    2015-01-01

    Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. © The Author(s) 2015.

  9. Low-Dose Sevoflurane Promotes Hippocampal Neurogenesis and Facilitates the Development of Dentate Gyrus-Dependent Learning in Neonatal Rats

    Directory of Open Access Journals (Sweden)

    Chong Chen

    2015-04-01

    Full Text Available Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8% sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4–6 were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks.

  10. Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate-induced injury is lost by middle age

    OpenAIRE

    Hattiangady, Bharathi; Rao, Muddanna S.; Shetty, Ashok K.

    2008-01-01

    A remarkable up-regulation of neurogenesis through increased proliferation of neural stem/progenitor cells (NSCs) is a well-known plasticity displayed by the young dentate gyrus (DG) following brain injury. To ascertain whether this plasticity is preserved during aging, we quantified DG neurogenesis in the young adult, middle-aged and aged F344 rats after kainic acid induced hippocampal injury. Measurement of new cells that are added to the dentate granule cell layer (GCL) between post-injury...

  11. Electrically evoked local muscle contractions cause an increase in hippocampal BDNF.

    Science.gov (United States)

    Maekawa, Takahiro; Ogasawara, Riki; Tsutaki, Arata; Lee, Kihyuk; Nakada, Satoshi; Nakazato, Koichi; Ishii, Naokata

    2018-05-01

    High-intensity exercise has recently been shown to cause an increase in brain-derived neurotropic factor (BDNF) in the hippocampus. Some studies have suggested that myokines secreted from contracting skeletal muscle, such as irisin (one of the truncated form of fibronectin type III domain-containing protein 5 (FNDC5)), play important roles in this process. Thus, we hypothesized that locally evoked muscle contractions may cause an increase of BDNF in the hippocampus through some afferent mechanisms. Under anesthesia, Sprague-Dawley rats were fixed on a custom-made dynamometer and their triceps surae muscles were made to maximally contract via delivery of electric stimulations of the sciatic nerve (100 Hz with 1-ms pulse and 3-s duration). Following 50 repeated maximal isometric contractions, the protein expressions of BDNF and activation of its receptor in the hippocampus significantly increased compared with the sham-operated control rats. However, the expression of both BDNF and FNDC5 within stimulated muscles did not significantly increase, nor did their serum concentrations change. These results indicate that local muscular contractions under unconsciousness can induce BDNF expression in the hippocampus. This effect may be mediated by peripheral reception of muscle contraction, but not by systemic factors.

  12. Progress to extinction: increased specialisation causes the demise of animal clades.

    Science.gov (United States)

    Raia, P; Carotenuto, F; Mondanaro, A; Castiglione, S; Passaro, F; Saggese, F; Melchionna, M; Serio, C; Alessio, L; Silvestro, D; Fortelius, M

    2016-08-10

    Animal clades tend to follow a predictable path of waxing and waning during their existence, regardless of their total species richness or geographic coverage. Clades begin small and undifferentiated, then expand to a peak in diversity and range, only to shift into a rarely broken decline towards extinction. While this trajectory is now well documented and broadly recognised, the reasons underlying it remain obscure. In particular, it is unknown why clade extinction is universal and occurs with such surprising regularity. Current explanations for paleontological extinctions call on the growing costs of biological interactions, geological accidents, evolutionary traps, and mass extinctions. While these are effective causes of extinction, they mainly apply to species, not clades. Although mass extinctions is the undeniable cause for the demise of a sizeable number of major taxa, we show here that clades escaping them go extinct because of the widespread tendency of evolution to produce increasingly specialised, sympatric, and geographically restricted species over time.

  13. Progress to extinction: increased specialisation causes the demise of animal clades

    Science.gov (United States)

    Raia, P.; Carotenuto, F.; Mondanaro, A.; Castiglione, S.; Passaro, F.; Saggese, F.; Melchionna, M.; Serio, C.; Alessio, L.; Silvestro, D.; Fortelius, M.

    2016-08-01

    Animal clades tend to follow a predictable path of waxing and waning during their existence, regardless of their total species richness or geographic coverage. Clades begin small and undifferentiated, then expand to a peak in diversity and range, only to shift into a rarely broken decline towards extinction. While this trajectory is now well documented and broadly recognised, the reasons underlying it remain obscure. In particular, it is unknown why clade extinction is universal and occurs with such surprising regularity. Current explanations for paleontological extinctions call on the growing costs of biological interactions, geological accidents, evolutionary traps, and mass extinctions. While these are effective causes of extinction, they mainly apply to species, not clades. Although mass extinctions is the undeniable cause for the demise of a sizeable number of major taxa, we show here that clades escaping them go extinct because of the widespread tendency of evolution to produce increasingly specialised, sympatric, and geographically restricted species over time.

  14. Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease

    International Nuclear Information System (INIS)

    Tang, Jun; Song, Min; Wang, Yanyan; Fan, Xiaotang; Xu, Haiwei; Bai, Yun

    2009-01-01

    In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP swe /PS1 ΔE9 mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP swe /PS1 ΔE9 transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

  15. Impairments in neurogenesis are not tightly linked to depressive behavior in a transgenic mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Daniel M Iascone

    Full Text Available Alzheimer's disease (AD, the most common cause of dementia, is also associated with depression. Although the precise mechanisms that lead to depression in AD are unknown, the impairments in adult hippocampal neurogenesis observed in AD may play a role. Adult-born neurons play a critical role in regulating both cognition and mood, and reduced hippocampal neurogenesis is associated with depression in other neurological disorders. To assess the relationship between Alzheimer's disease, neurogenesis, and depression, we studied human amyloid precursor protein (hAPP transgenic mice, a well-characterized model of AD. We report that reductions in hippocampal neurogenesis are evident early in disease progression in hAPP mice, but a mild depressive phenotype manifests only in later stages of disease. We found that hAPP mice exhibited a reduction in BrdU-positive cells in the subgranular zone of the dentate gyrus in the hippocampus, as well as a reduction in doublecortin-expressing cells, relative to nontransgenic controls at 5-7 months of age. These alterations in neurogenesis appeared to worsen with age, as the magnitude of reduction in doublecortin-expressing cells was greater in hAPP mice at 13-15 months of age. Only 13-15 month old hAPP mice exhibited depressive behavior in the tail suspension test. However, mice at both age groups exhibited deficits in spatial memory, which was observed in the Morris water maze test for hippocampus-dependent memory. These findings indicate that neurogenesis impairments are accompanied by cognitive deficits, but are not tightly linked to depressive behavior in hAPP mice.

  16. Glehnia littoralis Extract Promotes Neurogenesis in the Hippocampal Dentate Gyrus of the Adult Mouse through Increasing Expressions of Brain-Derived Neurotrophic Factor and Tropomyosin-Related Kinase B

    Directory of Open Access Journals (Sweden)

    Joon Ha Park

    2018-01-01

    Conclusion: G. littoralis extract promots cell proliferation, neuroblast differentiation, and neuronal maturation in the hippocampal DG, and neurogenic effects might be closely related to increases of BDNF and TrkB proteins by G. littoralis extract treatment.

  17. Inhibition of phosphatidylinositol-3-kinase causes increased sensitivity to radiation through a PKB-dependent mechanism

    International Nuclear Information System (INIS)

    Gottschalk, Alexander R.; Doan, Albert; Nakamura, Jean L.; Stokoe, David; Haas-Kogan, Daphne A.

    2005-01-01

    Purpose: To identify whether inhibition of phosphatidylinositol-3-kinase (PI3K) causes increased radiosensitivity through inhibition of protein kinase B (PKB), implicating PKB as an important therapeutic target in prostate cancer. Methods and Materials: The prostate cancer cell line LNCaP was treated with the PI3K inhibitor LY294002, radiation, and combinations of the two therapies. Apoptosis and survival were measured by cell cycle analysis, Western blot analysis for cleaved poly (ADP-ribose) polymerase, and clonogenic survival. To test the hypothesis that inhibition of PKB is responsible for LY294002-induced radiosensitivity, LNCaP cells expressing a constitutively active form of PKB were used. Results: The combination of PI3K inhibition and radiation caused an increase in apoptosis and a decrease in clonogenic survival when compared to either modality alone. The expression of constitutively activated PKB blocked apoptosis induced by combination of PI3K inhibition and radiation and prevented radiosensitization by LY294002. Conclusion: These data indicate that PI3K inhibition increases sensitivity of prostate cancer cell lines to ionizing radiation through inactivation of PKB. Therefore, PTEN mutations, which lead to PKB activation, may play an important role in the resistance of prostate cancer to radiation therapy. Targeted therapy against PKB could be beneficial in the management of prostate cancer patients

  18. Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function.

    Science.gov (United States)

    Poulose, Shibu M; Miller, Marshall G; Scott, Tammy; Shukitt-Hale, Barbara

    2017-11-01

    Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plasticity, brain homeostasis, and maintenance in the central nervous system and is a crucial factor in preserving the cognitive function and repair of damaged brain cells affected by aging and brain disorders. Intrinsic factors such as aging, neuroinflammation, oxidative stress, and brain injury, as well as lifestyle factors such as high-fat and high-sugar diets and alcohol and opioid addiction, negatively affect adult neurogenesis. Conversely, many dietary components such as curcumin, resveratrol, blueberry polyphenols, sulforaphane, salvionic acid, polyunsaturated fatty acids (PUFAs), and diets enriched with polyphenols and PUFAs, as well as caloric restriction, physical exercise, and learning, have been shown to induce neurogenesis in adult brains. Although many of the underlying mechanisms by which nutrients and dietary factors affect adult neurogenesis have yet to be determined, nutritional approaches provide promising prospects to stimulate adult neurogenesis and combat neurodegenerative diseases and cognitive decline. In this review, we summarize the evidence supporting the role of nutritional factors in modifying adult neurogenesis and their potential to preserve cognitive function during aging. © 2017 American Society for Nutrition.

  19. Adult hippocampal neurogenesis in natural populations of mammals.

    Science.gov (United States)

    Amrein, Irmgard

    2015-05-01

    This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  20. Molecular Beacon-Based MicroRNA Imaging During Neurogenesis.

    Science.gov (United States)

    Lee, Jonghwan; Kim, Soonhag

    2016-01-01

    The fluorescence monitoring system for examining endogenous microRNA (miRNA) activity in cellular level provides crucial information on not only understanding a critical role of miRNA involving a variety of biological processes, but also evaluating miRNA expression patterns in a noninvasive manner. In this protocol, we report the details of a new procedure for a molecular beacon-based miRNA monitoring system, which includes the illustration scheme for miRNA detection strategy, exogenous miRNA detection, and measurement of endogenous miRNA expression level during neurogenesis. The fluorescence signal of miR-124a beacon quenched by BHQ2 was gradually recovered as increasing concentration of the miR-124a in tube. The functional work of miR-124a beacon was examined in intracellular environment, allowing for the internalization of the miR-124a beacon by lipofectamine, which resulted in activated fluorescent signals of the miR-124a beacon in the HeLa cells after the addition of synthetic miR-124a. The endogenous miR-124a expression level was detected by miR-124a beacon system during neurogenesis, showing brighter fluorescence intensity in cytoplasmic area of P19 cells after induction of neuronal differentiation by retinoic acid. The molecular beacon based-miRNA detection technique could be applicable to the simultaneous visualization of a variety of miRNA expression patterns using different fluorescence dyes. For the study of examining endogenous miRNA expression level using miRNA-beacon system, if cellular differentiation step is already prepared, transfection step of miR-124a beacon into P19 cells, and acquisition of activated fluorescence signal measured by confocal microscope can be conducted approximately within 6 h.

  1. The helix-loop-helix protein id1 controls stem cell proliferation during regenerative neurogenesis in the adult zebrafish telencephalon.

    Science.gov (United States)

    Rodriguez Viales, Rebecca; Diotel, Nicolas; Ferg, Marco; Armant, Olivier; Eich, Julia; Alunni, Alessandro; März, Martin; Bally-Cuif, Laure; Rastegar, Sepand; Strähle, Uwe

    2015-03-01

    The teleost brain has the remarkable ability to generate new neurons and to repair injuries during adult life stages. Maintaining life-long neurogenesis requires careful management of neural stem cell pools. In a genome-wide expression screen for transcription regulators, the id1 gene, encoding a negative regulator of E-proteins, was found to be upregulated in response to injury. id1 expression was mapped to quiescent type I neural stem cells in the adult telencephalic stem cell niche. Gain and loss of id1 function in vivo demonstrated that Id1 promotes stem cell quiescence. The increased id1 expression observed in neural stem cells in response to injury appeared independent of inflammatory signals, suggesting multiple antagonistic pathways in the regulation of reactive neurogenesis. Together, we propose that Id1 acts to maintain the neural stem cell pool by counteracting neurogenesis-promoting signals. © 2014 AlphaMed Press.

  2. Curcumin enhances neurogenesis and cognition in aged rats: implications for transcriptional interactions related to growth and synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Suzhen Dong

    Full Text Available BACKGROUND: Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. METHODOLOGY: We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. CONCLUSIONS: The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity.

  3. Curcumin Enhances Neurogenesis and Cognition in Aged Rats: Implications for Transcriptional Interactions Related to Growth and Synaptic Plasticity

    Science.gov (United States)

    Mitchell, E. Siobhan; Xiu, Jin; Tiwari, Jyoti K.; Hu, Yinghe; Cao, Xiaohua; Zhao, Zheng

    2012-01-01

    Background Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. Methodology We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. Conclusions The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity. PMID:22359574

  4. Do pulmonary artery catheters cause or increase tricuspid or pulmonic valvular regurgitation?

    Science.gov (United States)

    Sherman, S V; Wall, M H; Kennedy, D J; Brooker, R F; Butterworth, J

    2001-05-01

    There are few quantitative data on the extent or mechanism of pulmonary artery catheter (PAC)-induced valvular dysfunction. We hypothesized that PACs cause or worsen tricuspid and pulmonic valvular regurgitation, and tested this hypothesis by using transesophageal echocardiography. In 54 anesthetized adult patients, we measured color Doppler jet areas of tricuspid regurgitation (TR) in two planes (midesophageal [ME] 4-chamber and right ventricular inflow-outflow views) and pulmonic insufficiency (PI) in one plane (ME aortic valve long-axis view), both before and after we advanced a PAC into the pulmonary artery. Regurgitant jet areas and hemodynamic measurements were compared by using paired t-test. There were no significant changes in blood pressure or heart rate after passage of the PAC. After PAC placement, the mean PI jet area was not significantly increased. The mean TR jet area increased significantly in the right ventricular inflow-outflow view (+0.37 +/- 0.11 cm(2)) (P = 0.0014), but did not increase at the ME 4-chamber view. Seventeen percent of patients had an increase in TR jet area > or =1 cm(2); 8% of patients had an increase in PI jet area >/=1 cm(2). In patients without pulmonic or tricuspid valvular pathology, placement of a pulmonary artery catheter (PAC) worsened tricuspid regurgitation, which is consistently visualized in the right ventricular inflow-outflow view, and often not seen in the midesophageal 4-chamber view. This is consistent with malcoaptation of the anterior and posterior leaflets. PAC-induced pulmonic insufficiency was rarely detected in the midesophageal aortic valve long-axis view. We conclude that a PAC is very unlikely to be the sole cause of severe tricuspid regurgitation or pulmonic insufficiency.

  5. Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Zheng, Rui; Zhang, Zhong-Hao; Chen, Chen; Chen, Yao; Jia, Shi-Zheng; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li

    2017-03-25

    The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce β-amyloid peptide (Aβ) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1-10 μM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 μM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3β activity, which would further activated the β-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 μg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3β-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective in

  6. Malnutrition is associated with increased mortality in older adults regardless of the cause of death.

    Science.gov (United States)

    Söderström, Lisa; Rosenblad, Andreas; Thors Adolfsson, Eva; Bergkvist, Leif

    2017-02-01

    Malnutrition predicts preterm death, but whether this is valid irrespective of the cause of death is unknown. The aim of the present study was to determine whether malnutrition is associated with cause-specific mortality in older adults. This cohort study was conducted in Sweden and included 1767 individuals aged ≥65 years admitted to hospital in 2008-2009. On the basis of the Mini Nutritional Assessment instrument, nutritional risk was assessed as well nourished (score 24-30), at risk of malnutrition (score 17-23·5) or malnourished (score malnutrition, and 9·4 % of the participants were malnourished. During a median follow-up of 5·1 years, 839 participants (47·5 %) died. The multiple Cox regression model identified significant associations (hazard ratio (HR)) between malnutrition and risk of malnutrition, respectively, and death due to neoplasms (HR 2·43 and 1·32); mental or behavioural disorders (HR 5·73 and 5·44); diseases of the nervous (HR 4·39 and 2·08), circulatory (HR 1·95 and 1·57) or respiratory system (HR 2·19 and 1·49); and symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified (HR 2·23 and 1·43). Malnutrition and risk of malnutrition are associated with increased mortality regardless of the cause of death, which emphasises the need for nutritional screening to identify older adults who may require nutritional support in order to avoid preterm death.

  7. Evidence of increasing drought severity caused by temperature rise in southern Europe

    International Nuclear Information System (INIS)

    Vicente-Serrano, Sergio M; Lopez-Moreno, Juan-I; Lorenzo-Lacruz, Jorge; García-Ruiz, José M; Azorin-Molina, Cesar; Morán-Tejeda, Enrique; Revuelto, Jesús; Beguería, Santiago; Sanchez-Lorenzo, Arturo; Trigo, Ricardo; Coelho, Fatima; Espejo, Francisco

    2014-01-01

    We use high quality climate data from ground meteorological stations in the Iberian Peninsula (IP) and robust drought indices to confirm that drought severity has increased in the past five decades, as a consequence of greater atmospheric evaporative demand resulting from temperature rise. Increased drought severity is independent of the model used to quantify the reference evapotranspiration. We have also focused on drought impacts to drought-sensitive systems, such as river discharge, by analyzing streamflow data for 287 rivers in the IP, and found that hydrological drought frequency and severity have also increased in the past five decades in natural, regulated and highly regulated basins. Recent positive trend in the atmospheric water demand has had a direct influence on the temporal evolution of streamflows, clearly identified during the warm season, in which higher evapotranspiration rates are recorded. This pattern of increase in evaporative demand and greater drought severity is probably applicable to other semiarid regions of the world, including other Mediterranean areas, the Sahel, southern Australia and South Africa, and can be expected to increasingly compromise water supplies and cause political, social and economic tensions among regions in the near future. (paper)

  8. Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

    Directory of Open Access Journals (Sweden)

    Deepti Chugh

    Full Text Available Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age and tonic-clonic (3.5-4 months phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread.

  9. Increased all-cause mortality with psychotropic medication in Parkinson's disease and controls

    DEFF Research Database (Denmark)

    Frandsen, Rune; Baandrup, Lone; Kjellberg, Jakob

    2014-01-01

    AIM: Use of medication and polypharmacy is common as the population ages and its disease burden increases. We evaluated the association of antidepressants, benzodiazepines, antipsychotics and combinations of psychotropic drugs with all-cause mortality in patients with Parkinson's disease (PD...... of psychotropic medication in PD patients and controls. Hazard ratios were as follows for the medication types: selective serotonin reuptake inhibitors or serotonin-noradrenalin reuptake inhibitors, PD HR = 1.19, 95% CI = 1.04-1.36; Control HR = 1.77, 95% CI = 1.64-1.91; benzodiazepines, PD HR = 1.17, 95% CI = 0.......20-1.76; Control HR = 2.00, 95% CI 1.66-2.43; and combinations of these drugs compared with non-medicated PD patients and controls. Discontinuation of medication was associated with decreased mortality in both groups. CONCLUSIONS: The use of psychotropic medication in the elderly is associated with increased...

  10. Particulate matter air pollution causes oxidant-mediated increase in gut permeability in mice

    Directory of Open Access Journals (Sweden)

    Keshavarzian Ali

    2011-06-01

    Full Text Available Abstract Background Exposure to particulate matter (PM air pollution may be an important environmental factor leading to exacerbations of inflammatory illnesses in the GI tract. PM can gain access to the gastrointestinal (GI tract via swallowing of air or secretions from the upper airways or mucociliary clearance of inhaled particles. Methods We measured PM-induced cell death and mitochondrial ROS generation in Caco-2 cells stably expressing oxidant sensitive GFP localized to mitochondria in the absence or presence of an antioxidant. C57BL/6 mice were exposed to a very high dose of urban PM from Washington, DC (200 μg/mouse or saline via gastric gavage and small bowel and colonic tissue were harvested for histologic evaluation, and RNA isolation up to 48 hours. Permeability to 4kD dextran was measured at 48 hours. Results PM induced mitochondrial ROS generation and cell death in Caco-2 cells. PM also caused oxidant-dependent NF-κB activation, disruption of tight junctions and increased permeability of Caco-2 monolayers. Mice exposed to PM had increased intestinal permeability compared with PBS treated mice. In the small bowel, colocalization of the tight junction protein, ZO-1 was lower in the PM treated animals. In the small bowel and colon, PM exposed mice had higher levels of IL-6 mRNA and reduced levels of ZO-1 mRNA. Increased apoptosis was observed in the colon of PM exposed mice. Conclusions Exposure to high doses of urban PM causes oxidant dependent GI epithelial cell death, disruption of tight junction proteins, inflammation and increased permeability in the gut in vitro and in vivo. These PM-induced changes may contribute to exacerbations of inflammatory disorders of the gut.

  11. Fluoxetine Regulates Neurogenesis In Vitro Through Modulation of GSK-3β/β-Catenin Signaling

    Science.gov (United States)

    Hui, Jiaojie; Zhang, Jianping; Kim, Hoon; Tong, Chang; Ying, Qilong; Li, Zaiwang; Mao, Xuqiang; Shi, Guofeng; Yan, Jie; Zhang, Zhijun

    2015-01-01

    Background: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. Methods: The aim of this study was to determine whether GSK-3β/β-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine’s regulation of GSK-3β/β-catenin signaling pathway were also examined. Results: Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. Conclusions: The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation. PMID:25522429

  12. Hippocampal Neurogenesis and the Brain Repair Response to Brief Stereotaxic Insertion of a Microneedle

    Directory of Open Access Journals (Sweden)

    Shijie Song

    2013-01-01

    Full Text Available We tested the hypothesis that transient microinjury to the brain elicits cellular and humoral responses that stimulate hippocampal neurogenesis. Brief stereotaxic insertion and removal of a microneedle into the right hippocampus resulted in (a significantly increased expression of granulocyte-colony stimulating factor (G-CSF, the chemokine MIP-1a, and the proinflammatory cytokine IL12p40; (b pronounced activation of microglia and astrocytes; and (c increase in hippocampal neurogenesis. This study describes immediate and early humoral and cellular mechanisms of the brain’s response to microinjury that will be useful for the investigation of potential neuroprotective and deleterious effects of deep brain stimulation in various neuropsychiatric disorders.

  13. Increased thermohaline stratification as a possible cause for an ocean anoxic event in the Cretaceous period.

    Science.gov (United States)

    Erbacher, J; Huber, B T; Norris, R D; Markey, M

    2001-01-18

    Ocean anoxic events were periods of high carbon burial that led to drawdown of atmospheric carbon dioxide, lowering of bottom-water oxygen concentrations and, in many cases, significant biological extinction. Most ocean anoxic events are thought to be caused by high productivity and export of carbon from surface waters which is then preserved in organic-rich sediments, known as black shales. But the factors that triggered some of these events remain uncertain. Here we present stable isotope data from a mid-Cretaceous ocean anoxic event that occurred 112 Myr ago, and that point to increased thermohaline stratification as the probable cause. Ocean anoxic event 1b is associated with an increase in surface-water temperatures and runoff that led to decreased bottom-water formation and elevated carbon burial in the restricted basins of the western Tethys and North Atlantic. This event is in many ways similar to that which led to the more recent Plio-Pleistocene Mediterranean sapropels, but the greater geographical extent and longer duration (approximately 46 kyr) of ocean anoxic event 1b suggest that processes leading to such ocean anoxic events in the North Atlantic and western Tethys were able to act over a much larger region, and sequester far more carbon, than any of the Quaternary sapropels.

  14. Neurogenesis in the olfactory bulb induced by paced mating in the female rat is opioid dependent.

    Directory of Open Access Journals (Sweden)

    Marianela Santoyo-Zedillo

    Full Text Available The possibility to control the rate of sexual stimulation that the female rat receives during a mating encounter (pacing increases the number of newborn neurons that reach the granular layer of the accessory olfactory bulb (AOB. If females mate repeatedly, the increase in the number of neurons is observed in other regions of the AOB and in the main olfactory bulb (MOB. It has also been shown that paced mating induces a reward state mediated by opioids. There is also evidence that opioids modulate neurogenesis. In the present study, we evaluated whether the opioid receptor antagonist naloxone (NX could reduce the increase in neurogenesis in the AOB induced by paced mating. Ovariectomized female rats were randomly divided in 5 different groups: 1 Control (not mated treated with saline, 2 control (not mated treated with naloxone, 3 females that mated without controlling the sexual interaction (no-pacing, 4 females injected with saline before pacing the sexual interaction and 5 females injected with NX before a paced mating session. We found, as previously described, that paced mating induced a higher number of new cells in the granular layer of the AOB. The administration of NX before paced mating, blocked the increase in the number of newborn cells and prevented these cells from differentiating into neurons. These data suggest that opioid peptides play a fundamental role in the neurogenesis induced by paced mating in female rats.

  15. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats

    OpenAIRE

    Klomp, A.; Václavů, L.; Meerhoff, G.F.; Reneman, L.; Lucassen, P.J.

    2014-01-01

    The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal developm...

  16. The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment

    OpenAIRE

    Donega, Vanessa; van Velthoven, Cindy TJ; Nijboer, Cora H; Kavelaars, Annemieke; Heijnen, Cobi J

    2013-01-01

    Neurogenesis continues throughout adulthood. The neurogenic capacity of the brain increases after injury by, e.g., hypoxia–ischemia. However, it is well known that in many cases brain damage does not resolve spontaneously, indicating that the endogenous regenerative capacity of the brain is insufficient. Neonatal encephalopathy leads to high mortality rates and long-term neurologic deficits in babies worldwide. Therefore, there is an urgent need to develop more efficient therapeutic strategie...

  17. Cortical neurogenesis in the absence of centrioles.

    Science.gov (United States)

    Insolera, Ryan; Bazzi, Hisham; Shao, Wei; Anderson, Kathryn V; Shi, Song-Hai

    2014-11-01

    Neuronal production in the mammalian cortex depends on extensive mitoses of radial glial progenitors (RGPs) residing in the ventricular zone (VZ). We examined the function of centrioles in RGPs during cortical neurogenesis in mice by conditional removal of SAS-4, a protein that is required for centriole biogenesis. SAS-4 deletion led to a progressive loss of centrioles, accompanied by RGP detachment from the VZ. Delocalized RGPs did not become outer subventricular zone RGPs (oRGs). Although they remained proliferative, ectopic RGPs, as well as those in the VZ, with a centrosomal deficit exhibited prolonged mitosis, p53 upregulation and apoptosis, resulting in neuronal loss and microcephaly. Simultaneous removal of p53 fully rescued RGP death and microcephaly, but not RGP delocalization and randomized mitotic spindle orientation. Our findings define the functions of centrioles in anchoring RGPs in the VZ and ensuring their efficient mitoses, and reveal the robust adaptability of RGPs in the developing cortex.

  18. Glehnia littoralis Extract Promotes Neurogenesis in the Hippocampal Dentate Gyrus of the Adult Mouse through Increasing Expressions of Brain-Derived Neurotrophic Factor and Tropomyosin-Related Kinase B.

    Science.gov (United States)

    Park, Joon Ha; Shin, Bich Na; Ahn, Ji Hyeon; Cho, Jeong Hwi; Lee, Tae-Kyeong; Lee, Jae-Chul; Jeon, Yong Hwan; Kang, Il Jun; Yoo, Ki-Yeon; Hwang, In Koo; Lee, Choong Hyun; Noh, Yoo Hun; Kim, Sung-Su; Won, Moo-Ho; Kim, Jong Dai

    2018-03-20

    Glehnia littoralis has been used for traditional Asian medicine, which has diverse therapeutic activities. However, studies regarding neurogenic effects of G. littoralis have not yet been considered. Therefore, in this study, we examined effects of G. littoralis extract on cell proliferation, neuroblast differentiation, and the maturation of newborn neurons in the hippocampus of adult mice. A total of 39 male ICR mice (12 weeks old) were randomly assigned to vehicle-treated and 100 and 200 mg/kg G. littoralis extract-treated groups (n = 13 in each group). Vehicle and G. littoralis extract were orally administrated for 28 days. To examine neurogenic effects of G. littoralis extract, we performed immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU, an indicator for cell proliferation) and doublecortin (DCX, an immature neuronal marker) and double immunofluorescence staining for BrdU and neuronal nuclear antigen (NeuN, a mature neuronal marker). In addition, we examined expressional changes of brain-derived neurotrophic factor (BDNF) and its major receptor tropomyosin-related kinase B (TrkB) using Western blotting analysis. Treatment with 200 mg/kg, not 100 mg/kg, significantly increased number of BrdU-immunoreactive ( + ) and DCX + cells (48.0 ± 3.1 and 72.0 ± 3.8 cells/section, respectively) in the subgranular zone (SGZ) of the dentate gyrus (DG) and BrdU + /NeuN + cells (17.0 ± 1.5 cells/section) in the granule cell layer as well as in the SGZ. In addition, protein levels of BDNF and TrkB (about 232% and 244% of the vehicle-treated group, respectively) were significantly increased in the DG of the mice treated with 200 mg/kg of G. littoralis extract. G. littoralis extract promots cell proliferation, neuroblast differentiation, and neuronal maturation in the hippocampal DG, and neurogenic effects might be closely related to increases of BDNF and TrkB proteins by G. littoralis extract treatment.

  19. Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats

    Directory of Open Access Journals (Sweden)

    Cesar A. Acevedo-Triana

    2017-05-01

    Full Text Available Background Exercise can change cellular structure and connectivity (neurogenesis or synaptogenesis, causing alterations in both behavior and working memory. The aim of this study was to evaluate the effect of exercise on working memory and hippocampal neurogenesis in adult male Wistar rats using a T-maze test. Methods An experimental design with two groups was developed: the experimental group (n = 12 was subject to a forced exercise program for five days, whereas the control group (n = 9 stayed in the home cage. Six to eight weeks after training, the rats’ working memory was evaluated in a T-maze test and four choice days were analyzed, taking into account alternation as a working memory indicator. Hippocampal neurogenesis was evaluated by means of immunohistochemistry of BrdU positive cells. Results No differences between groups were found in the behavioral variables (alternation, preference index, time of response, time of trial or feeding, or in the levels of BrdU positive cells. Discussion Results suggest that although exercise may have effects on brain structure, a construct such as working memory may require more complex changes in networks or connections to demonstrate a change at behavioral level.

  20. Understanding adult neurogenesis beyond its role in learning and memory formation

    Directory of Open Access Journals (Sweden)

    Ab Latif Wani

    2017-04-01

    Full Text Available There has been a shift in the understanding of brain, neurons, and their functional role over the last two decades. Earlier it was believed that the brain was a static organ and was not subject to any change throughout life. An understanding was developed later that brain reorganizes its structure by a specific property called neuroplasticity. Recent research shows that the brain generates new neurons even in the adult stage, and this process is called adult neurogenesis. Although researchers still not have all the answers about the newborn neurons, and why and how they are generated, and what is their role, some have highlighted the importance of these in learning and memory formation, and even in memories of fear and spatial navigation. A wide range of environmental experience influences the generation of newborn neurons and their functional variability. There are questions about how different environmental experiences cause the differences in the generation of new neurons. Recently the field of optogenetics attempted to answer the questions on adult neurogenesis. However there are still questions about adult neurogenesis which needs a more naturalistic approach, for their better understanding.

  1. LRRK2: an éminence grise of Wnt-mediated neurogenesis?

    Directory of Open Access Journals (Sweden)

    Daniel C Berwick

    2013-05-01

    Full Text Available The importance of Leucine-Rich Repeat Kinase 2 (LRRK2 to mature neurons is well-established, since mutations in PARK8, the gene encoding LRRK2, are the most common known cause of Parkinson’s disease. Nonetheless, despite the LRRK2 knockout mouse having no overt neurodevelopmental defect, numerous lines of in vitro data point towards a central role for this protein in neurogenesis. Roles for LRRK2 have been described in many key processes, including neurite outgrowth and the regulation of microtubule dynamics. Moreover, LRRK2 has been implicated in cell cycle control, suggesting additional roles in neurogenesis that precede terminal differentiation. However, we contend that the suggested function of LRRK2 as a scaffolding protein at the heart of numerous Wnt signaling cascades provides the most tantalizing link to neurogenesis in the developing brain. Numerous lines of evidence show a critical requirement for multiple Wnt pathways in the development of certain brain regions, not least the dopaminergic neurons of the ventral mid-brain. In conclusion, these observations indicate a function of LRRK2 as a subtle yet critical mediator of the action of Wnt ligands on developing neurons. We suggest that LRRK2 loss- or gain-of-function are likely modifiers of developmental phenotypes seen in animal models of Wnt signaling deregulation, a hypothesis that can be tested by cross-breeding relevant genetically modified experimental strains.

  2. Cause marketing for tissue and organ donation to increase public awareness

    International Nuclear Information System (INIS)

    Strong, M.; Neely, D.; Warnack, K.; Willits, M.; Yriondo, L.

    1999-01-01

    Today the science of marketing is being applied more and more to increase the rate of tissue and organ donation in the United States. To benefit from the proven tools and techniques of successful marketing in the for-profit world transplantation agencies across the country are turning to integrated marketing communications strategies and strategic partnerships to help achieve their goals.The methods used in cause marketing include: Establishing clear and measurable outcomes and goals; building a marketing plan and timeline to achieve the goals; gathering resources (funding, personnel, organizations, partnerships) to execute the plan, implementation, and measurement of outcomes. This session will review the Tissue and Organ Donation campaign implemented in the Northwest and will touch on the national awareness program developed by United Network for Organ Sharing (UNOS) in the United States. Segments of the Northwest's integrated campaign will include market segmentation strategies and targeted marketing, campaign development, public service advertising and public education campaigns. Media utilized include print, bus signs and billboards, broadcast (radio and TV), video and the internet. Strategies include public service advertising, paid advertising through sponsorships, direct mail, workshops and public speaking. The success of traditional product marketing can be achieved in cause marketing with a long-term, focused public education campaign. The potential benefit to the international community warrants exploration of similar strategies to overcome cultural resistance to life saving transplantation

  3. Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice.

    Science.gov (United States)

    Moon, Minho; Jeong, Hyun Uk; Choi, Jin Gyu; Jeon, Seong Gak; Song, Eun Ji; Hong, Seon-Pyo; Oh, Myung Sook

    2016-09-15

    It is generally accepted that functional and structural changes within the hippocampus are involved in learning and memory and that adult neurogenesis in this region may modulate cognition. The extract of Cuscuta japonica Choisy (CJ) is a well-known traditional Chinese herbal medicine that has been used since ancient times as a rejuvenation remedy. The systemic effects of this herb are widely known and can be applied for the treatment of a number of physiological diseases, but there is a lack of evidence describing its effects on brain function. Thus, the present study investigated whether CJ would enhance memory function and/or increase hippocampal neurogenesis using mice orally administered with CJ water extract or vehicle for 21days. Performance on the novel object recognition and passive avoidance tests revealed that treatment with CJ dose-dependently improved the cognitive function of mice. Additionally, CJ increased the Ki-67-positive proliferating cells and the number of doublecortin-stained neuroblasts in the dentate gyrus (DG) of the hippocampus, and double labeling with 5-bromo-2-deoxyuridine and neuronal specific nuclear protein showed that CJ increased the number of mature neurons in the DG. Finally, CJ resulted in the upregulated expression of neurogenic differentiation factor, which is essential for the maturation and differentiation of granule cells in the hippocampus. Taken together, the present findings indicate that CJ stimulated neuronal cell proliferation, differentiation, and maturation, which are all processes associated with neurogenesis. Additionally, these findings suggest that CJ may improve learning and memory via the enhancement of adult hippocampal neurogenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Hydrodynamic behaviour of crusted soils in the Sahel: a possible cause for runoff increase?

    Science.gov (United States)

    Malam Abdou, M.; Vandervaere, J.-P.; Bouzou Moussa, I.; Descroix, L.

    2012-04-01

    Crusted soils are in extension in the Sahel. As rainfall has decreased over the past decades (it is now increasing again in the central Sahel) and no significant change was observed in rainfall intensity and in its time and space distribution, it is supposed that land use management is the main cause for crusts cover increase. Fallow shortening, lack of manure, and land overexploitation (wood harvesting, overgrazing) are frequently cited as main factors of soil degradation. Based on field measurements in some small catchments of Western Niger, the hydrodynamics behaviour of the newly crusted soils of this area is described, mostly constituted by erosion crusts. A strong fall in soil saturated conductivity and in the active porosity as well as a rise in bulk density all lead to a quick onset of runoff production. Results are shown from field experiments in sedimentary and basement areas leading to similar conclusions. In both contexts, runoff plot production was measured at the rain event scale from 10-m2 parcels as well as at the catchment outlet. Soil saturated conductivity was reduced by one order of magnitude when crusting occurs, leading to a sharp runoff coefficient increase, from 4% in a weeded millet field and 10% in an old fallow to more than 60% in a erosion-crusted topsoil at the plot scale. At the experimental catchment scale, runoff coefficient has doubled in less than 20 years. In pure Sahelian basins, this resulted in endorheism breaching, and in a widespread river discharge increase. For some right bank tributaries of the Niger River, discharge is three times higher now than before the drought years, in spite of the remaining rainfall deficit. On the other hand, a general increase in flooding hazard frequency is observed in the whole Sahelian stripe. The role of surface crusts in the Sahel is discussed leading to the implementation of new experiments in the future.

  5. Aminopropyl carbazole analogues as potent enhancers of neurogenesis.

    Science.gov (United States)

    Yoon, Hye Jin; Kong, Sun-Young; Park, Min-Hye; Cho, Yongsung; Kim, Sung-Eun; Shin, Jae-Yeon; Jung, Sunghye; Lee, Jiyoun; Farhanullah; Kim, Hyun-Jung; Lee, Jeewoo

    2013-11-15

    Neural stem cells are multipotent and self-renewing cells that can differentiate into new neurons and hold great promise for treating various neurological disorders including multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Small molecules that can trigger neurogenesis and neuroprotection are particularly useful not only because of their therapeutic implications but also because they can provide an invaluable tool to study the mechanisms of neurogenesis. In this report, we have developed and screened 25 aminopropyl carbazole derivatives that can enhance neurogenesis of cultured neural stem cells. Among these analogues, compound 9 demonstrated an excellent proneurogenic and neuroprotective activity with no apparent toxicity. We believe that compound 9 can serve as an excellent lead to develop various analogues and to study the underlying mechanisms of neurogenesis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. THE SOCIAL ENVIRONMENT AND NEUROGENESIS IN THE ADULT MAMMALIAN BRAIN

    Directory of Open Access Journals (Sweden)

    Claudia eLieberwirth

    2012-05-01

    Full Text Available Adult neurogenesis—the formation of new neurons in adulthood—has been shown to be modulated by a variety of endogenous (e.g., trophic factors, neurotransmitters, and hormones as well as exogenous (e.g., physical activity and environmental complexity factors. Research on exogenous regulators of adult neurogenesis has focused primarily on the non-social environment. Most recently, however, evidence has emerged suggesting that the social environment can also affect adult neurogenesis. The present review details the effects of adult-adult (e.g., mating, conspecific, and chemosensory signal exposure and adult-offspring (e.g., gestation, parenthood, and exposure to offspring interactions on adult neurogenesis. In addition, the effects of a stressful social environment (e.g., lack of social support and dominant-subordinate interactions on adult neurogenesis are reviewed. The underlying hormonal mechanisms and potential functional significance of adult-generated neurons in mediating social behaviors are also discussed.

  7. Divergent Roles of Central Serotonin in Adult Hippocampal Neurogenesis

    Directory of Open Access Journals (Sweden)

    Ning-Ning Song

    2017-06-01

    Full Text Available The central serotonin (5-HT system is the main target of selective serotonin reuptake inhibitors (SSRIs, the first-line antidepressants widely used in current general practice. One of the prominent features of chronic SSRI treatment in rodents is the enhanced adult neurogenesis in the hippocampus, which has been proposed to contribute to antidepressant effects. Therefore, tremendous effort has been made to decipher how central 5-HT regulates adult hippocampal neurogenesis. In this paper, we review how changes in the central serotonergic system alter adult hippocampal neurogenesis. We focus on data obtained from three categories of genetically engineered mouse models: (1 mice with altered central 5-HT levels from embryonic stages, (2 mice with deletion of 5-HT receptors from embryonic stages, and (3 mice with altered central 5-HT system exclusively in adulthood. These recent findings provide unique insights to interpret the multifaceted roles of central 5-HT on adult hippocampal neurogenesis and its associated effects on depression.

  8. Wasps are the cause of an increasing mastitis problem in dairy cattle in Israel.

    Science.gov (United States)

    Yeruham, I; Braverman, Y; Schwimmer, A

    1998-07-01

    The German wasp Vespula germanica (Fabr.) (Hymenoptera: Vespidae) has been observed to injure dairy cows teats, causing lesions which can lead to mastitis. The number of dairy herds in Israel reported to be affected in this way has increased from five prior to 1989 to 32 from 1989 to 1993. Likewise, the geographical distribution of the colonies of these wasps has expanded from the Galilee to the northern Negev. Most cases of mastitis appeared during August and September when the wasps were most active; the predominant organism isolated was Streptococcus dysgalactiae. Apparently the wasps served as a vector in spreading S. dysgalactiae infection in the herds. More adult cows than first-calving cows were affected. The teats of the front quarters were more affected than those of the hind quarters.

  9. InSAR detects increase in surface subsidence caused by an Arctic tundra fire

    Science.gov (United States)

    Liu, Lin; Jafarov, Elchin E.; Schaefer, Kevin M.; Jones, Benjamin M.; Zebker, Howard A.; Williams, Christopher A.; Rogan, John; Zhang, Tingjun

    2014-01-01

    Wildfire is a major disturbance in the Arctic tundra and boreal forests, having a significant impact on soil hydrology, carbon cycling, and permafrost dynamics. This study explores the use of the microwave Interferometric Synthetic Aperture Radar (InSAR) technique to map and quantify ground surface subsidence caused by the Anaktuvuk River fire on the North Slope of Alaska. We detected an increase of up to 8 cm of thaw-season ground subsidence after the fire, which is due to a combination of thickened active layer and permafrost thaw subsidence. Our results illustrate the effectiveness and potential of using InSAR to quantify fire impacts on the Arctic tundra, especially in regions underlain by ice-rich permafrost. Our study also suggests that surface subsidence is a more comprehensive indicator of fire impacts on ice-rich permafrost terrain than changes in active layer thickness alone.

  10. Extreme Wildlife Declines and Concurrent Increase in Livestock Numbers in Kenya: What Are the Causes?

    Directory of Open Access Journals (Sweden)

    Joseph O Ogutu

    Full Text Available There is growing evidence of escalating wildlife losses worldwide. Extreme wildlife losses have recently been documented for large parts of Africa, including western, Central and Eastern Africa. Here, we report extreme declines in wildlife and contemporaneous increase in livestock numbers in Kenya rangelands between 1977 and 2016. Our analysis uses systematic aerial monitoring survey data collected in rangelands that collectively cover 88% of Kenya's land surface. Our results show that wildlife numbers declined on average by 68% between 1977 and 2016. The magnitude of decline varied among species but was most extreme (72-88% and now severely threatens the population viability and persistence of warthog, lesser kudu, Thomson's gazelle, eland, oryx, topi, hartebeest, impala, Grevy's zebra and waterbuck in Kenya's rangelands. The declines were widespread and occurred in most of the 21 rangeland counties. Likewise to wildlife, cattle numbers decreased (25.2% but numbers of sheep and goats (76.3%, camels (13.1% and donkeys (6.7% evidently increased in the same period. As a result, livestock biomass was 8.1 times greater than that of wildlife in 2011-2013 compared to 3.5 times in 1977-1980. Most of Kenya's wildlife (ca. 30% occurred in Narok County alone. The proportion of the total "national" wildlife population found in each county increased between 1977 and 2016 substantially only in Taita Taveta and Laikipia but marginally in Garissa and Wajir counties, largely reflecting greater wildlife losses elsewhere. The declines raise very grave concerns about the future of wildlife, the effectiveness of wildlife conservation policies, strategies and practices in Kenya. Causes of the wildlife declines include exponential human population growth, increasing livestock numbers, declining rainfall and a striking rise in temperatures but the fundamental cause seems to be policy, institutional and market failures. Accordingly, we thoroughly evaluate wildlife

  11. Extreme Wildlife Declines and Concurrent Increase in Livestock Numbers in Kenya: What Are the Causes?

    Science.gov (United States)

    Ogutu, Joseph O.; Piepho, Hans-Peter; Said, Mohamed Y.; Ojwang, Gordon O.; Njino, Lucy W.; Kifugo, Shem C.; Wargute, Patrick W.

    2016-01-01

    There is growing evidence of escalating wildlife losses worldwide. Extreme wildlife losses have recently been documented for large parts of Africa, including western, Central and Eastern Africa. Here, we report extreme declines in wildlife and contemporaneous increase in livestock numbers in Kenya rangelands between 1977 and 2016. Our analysis uses systematic aerial monitoring survey data collected in rangelands that collectively cover 88% of Kenya’s land surface. Our results show that wildlife numbers declined on average by 68% between 1977 and 2016. The magnitude of decline varied among species but was most extreme (72–88%) and now severely threatens the population viability and persistence of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, topi, hartebeest, impala, Grevy’s zebra and waterbuck in Kenya’s rangelands. The declines were widespread and occurred in most of the 21 rangeland counties. Likewise to wildlife, cattle numbers decreased (25.2%) but numbers of sheep and goats (76.3%), camels (13.1%) and donkeys (6.7%) evidently increased in the same period. As a result, livestock biomass was 8.1 times greater than that of wildlife in 2011–2013 compared to 3.5 times in 1977–1980. Most of Kenya’s wildlife (ca. 30%) occurred in Narok County alone. The proportion of the total “national” wildlife population found in each county increased between 1977 and 2016 substantially only in Taita Taveta and Laikipia but marginally in Garissa and Wajir counties, largely reflecting greater wildlife losses elsewhere. The declines raise very grave concerns about the future of wildlife, the effectiveness of wildlife conservation policies, strategies and practices in Kenya. Causes of the wildlife declines include exponential human population growth, increasing livestock numbers, declining rainfall and a striking rise in temperatures but the fundamental cause seems to be policy, institutional and market failures. Accordingly, we thoroughly evaluate

  12. Dentate Gyrus Neurogenesis, Integration, and microRNAs

    OpenAIRE

    Luikart, Bryan W; Perederiy, Julia V; Westbrook, Gary L

    2011-01-01

    Neurons are born and become a functional part of the synaptic circuitry in adult brains. The proliferative phase of neurogenesis has been extensively reviewed. We therefore focus this review on a few topics addressing the functional role of adult-generated newborn neurons in the dentate gyrus. We discuss the evidence for a link between neurogenesis and behavior. We then describe the steps in the integration of newborn neurons into a functioning mature synaptic circuit. Given the profound effe...

  13. Linking adult hippocampal neurogenesis with human physiology and disease.

    Science.gov (United States)

    Bowers, Megan; Jessberger, Sebastian

    2016-07-01

    We here review the existing evidence linking adult hippocampal neurogenesis and human brain function in physiology and disease. Furthermore, we aim to point out where evidence is missing, highlight current promising avenues of investigation, and suggest future tools and approaches to foster the link between life-long neurogenesis and human brain function. Developmental Dynamics 245:702-709, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. Conservation threats due to human-caused increases in fire frequency in Mediterranean-climate ecosystems.

    Science.gov (United States)

    Syphard, Alexandra D; Radeloff, Volker C; Hawbaker, Todd J; Stewart, Susan I

    2009-06-01

    Periodic wildfire is an important natural process in Mediterranean-climate ecosystems, but increasing fire recurrence threatens the fragile ecology of these regions. Because most fires are human-caused, we investigated how human population patterns affect fire frequency. Prior research in California suggests the relationship between population density and fire frequency is not linear. There are few human ignitions in areas with low population density, so fire frequency is low. As population density increases, human ignitions and fire frequency also increase, but beyond a density threshold, the relationship becomes negative as fuels become sparser and fire suppression resources are concentrated. We tested whether this hypothesis also applies to the other Mediterranean-climate ecosystems of the world. We used global satellite databases of population, fire activity, and land cover to evaluate the spatial relationship between humans and fire in the world's five Mediterranean-climate ecosystems. Both the mean and median population densities were consistently and substantially higher in areas with than without fire, but fire again peaked at intermediate population densities, which suggests that the spatial relationship is complex and nonlinear. Some land-cover types burned more frequently than expected, but no systematic differences were observed across the five regions. The consistent association between higher population densities and fire suggests that regardless of differences between land-cover types, natural fire regimes, or overall population, the presence of people in Mediterranean-climate regions strongly affects the frequency of fires; thus, population growth in areas now sparsely settled presents a conservation concern. Considering the sensitivity of plant species to repeated burning and the global conservation significance of Mediterranean-climate ecosystems, conservation planning needs to consider the human influence on fire frequency. Fine-scale spatial

  15. Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain.

    Science.gov (United States)

    Strahan, J Alex; Walker, William H; Montgomery, Taylor R; Forger, Nancy G

    2017-06-01

    Minocycline, an antibiotic of the tetracycline family, inhibits microglia in many paradigms and is among the most commonly used tools for examining the role of microglia in physiological processes. Microglia may play an active role in triggering developmental neuronal cell death, although findings have been contradictory. To determine whether microglia influence developmental cell death, we treated perinatal mice with minocycline (45 mg/kg) and quantified effects on dying cells and microglial labeling using immunohistochemistry for activated caspase-3 (AC3) and ionized calcium-binding adapter molecule 1 (Iba1), respectively. Contrary to our expectations, minocycline treatment from embryonic day 18 to postnatal day (P)1 caused a > tenfold increase in cell death 8 h after the last injection in all brain regions examined, including the primary sensory cortex, septum, hippocampus and hypothalamus. Iba1 labeling was also increased in most regions. Similar effects, although of smaller magnitude, were seen when treatment was delayed to P3-P5. Minocycline treatment from P3 to P5 also decreased overall cell number in the septum at weaning, suggesting lasting effects of the neonatal exposure. When administered at lower doses (4.5 or 22.5 mg/kg), or at the same dose 1 week later (P10-P12), minocycline no longer increased microglial markers or cell death. Taken together, the most commonly used microglial "inhibitor" increases cell death and Iba1 labeling in the neonatal mouse brain. Minocycline is used clinically in infant and pediatric populations; caution is warrented when using minocycline in developing animals, or extrapolating the effects of this drug across ages. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 753-766, 2017. © 2016 Wiley Periodicals, Inc.

  16. Physical Exercise Leads to Rapid Adaptations in Hippocampal Vasculature : Temporal Dynamics and Relationship to Cell Proliferation and Neurogenesis

    NARCIS (Netherlands)

    Van der Borght, Karin; Kobor-Nyakas, Dora E.; Klauke, Karin; Eggen, Bart J. L.; Nyakas, Csaba; Van der Zee, Eddy A.; Meerlo, Peter

    2009-01-01

    Increased levels of angiogenesis and neurogenesis possibly mediate the beneficial effects of physical activity on hippocampal plasticity. This study was designed to investigate the temporal dynamics of exercise-induced changes in hippocampal angiogenesis and cell proliferation. Mice were housed with

  17. Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis

    Science.gov (United States)

    Opendak, Maya; Offit, Lily; Monari, Patrick; Schoenfeld, Timothy J.; Sonti, Anup N.; Cameron, Heather A.

    2016-01-01

    Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP–thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus. SIGNIFICANCE STATEMENT To investigate cellular processes underlying adaptation to social instability, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Unexpectedly, these changes were accompanied by changes in social strategies without evidence of impairments in cognition or anxiety regulation. Restoring adult neurogenesis in disrupted rats using oxytocin and conditionally suppressing the production of new neurons in socially naive GFAP–thymidine kinase rats showed that loss of 6-week-old neurons may be responsible for adaptive changes in social behavior. PMID:27358459

  18. BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells

    Directory of Open Access Journals (Sweden)

    Jingjun Li

    2016-09-01

    Full Text Available Neural stem cells and progenitor cells (NPCs are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases.

  19. Smoking Prevalence Among Mugla School of Health Sciences Students and Causes of Leading Increase in Smoking

    Directory of Open Access Journals (Sweden)

    Metin Picakciefe

    2007-08-01

    Full Text Available The purpose of this study was to determine the smoking prevalence among Mugla School of Health Sciences students, to determine the effects the increasing causes of smoking and their education about adverse health outcome of smoking. A cross-sectional study was performed among Mugla School of Health Sciences students in Mugla University. All students (417 in Mugla School of Health Sciences included in the study. The participation rates was 85.1%. Data were obtained by the self-administered questionnaire without teachers in classes. SPSS 11.0 was used for data analysis, and the differentiation was assessed by Chi-square analysis. P < 0.05 was accepted statistically significant. The prevalence of current smokers was 25.3% among students in Mugla School of Health Sciences. The students stated that the most important factor of smoking initiation was stress (59.2%. The univariable analysis showed that the friends’ smoking (p: 0.000 , having knowledge about smoking habits of teachers (p: 0.020 , alcohol consumption (p: 0.000, and other smokers out of parent in the home (p: 0.000 was significantly associated with increasing rate of smoking prevalence. The smoking prevalence was quite high (25.3% among Mugla School of Health Sciences students in Mugla University. It is needed to decreasing smoking prevalence among students that antismoking education should be reevaluated, that antismoking campaign should be administered in schools. [TAF Prev Med Bull 2007; 6(4.000: 267-272

  20. Increased pulmonary vascular permeability as a cause of re-expansion edema in rabbits

    International Nuclear Information System (INIS)

    Pavlin, D.J.; Nessly, M.L.; Cheney, F.W.

    1981-01-01

    In order to study the mechanism(s) underlying re-expansion edema, we measured the concentration of labeled albumin (RISA) in the extravascular, extracellular water (EVECW) of the lung as a measure of pulmonary vascular permeability. Re-expansion edema was first induced by rapid re-expansion of rabbit lungs that had been collapsed for 1 wk by pneumothorax. The RISA in EVECW was expressed as a fraction of its plasma concentration: (RISA)L/(RISA)PL. The volume of EVECW (ml/gm dry lung) was measured using a 24 Na indicator. Results in re-expansion edema were compared with normal control lungs and with oleic acid edema as a model of permeability edema. In re-expanded lungs, EVECW (3.41 +/- SD 1.24 ml/g) and (RISA)L/(RISA)PL 0.84 +/- SD 0.15) were significantly increased when compared with normal control lungs (2.25 +/- 0.41 ml/g and 0.51 +/- 0.20, respectively). Results in oleic acid edema (5.66 +/- 2.23 ml/g and 0.84 +/- 0.23) were similar to re-expansion edema. This suggested that re-expansion edema is due to increased pulmonary vascular permeability caused by mechanical stresses applied to the lung during re-expansion

  1. The public's belief in climate change and its human cause are increasing over time.

    Science.gov (United States)

    Milfont, Taciano L; Wilson, Marc S; Sibley, Chris G

    2017-01-01

    Polls examining public opinion on the subject of climate change are now commonplace, and one-off public opinion polls provide a snapshot of citizen's opinions that can inform policy and communication strategies. However, cross-sectional polls do not track opinions over time, thus making it impossible to ascertain whether key climate change beliefs held by the same group of individuals are changing or not. Here we examine the extent to which individual's level of agreement with two key beliefs ("climate change is real" and "climate change is caused by humans") remain stable or increase/decrease over a six-year period in New Zealand using latent growth curve modelling (n = 10,436). Data were drawn from the New Zealand Attitudes and Values Study, a probabilistic national panel study, and indicated that levels of agreement to both beliefs have steadily increased over the 2009-2015 period. Given that climate change beliefs and concerns are key predictors of climate change action, our findings suggest that a combination of targeted endeavors, as well as serendipitous events, may successfully convey the emergency of the issue.

  2. Pacemaker lead fracture without an increase in lead impedance caused by cardiac fibroma

    Directory of Open Access Journals (Sweden)

    Daisuke Sato

    2013-12-01

    Full Text Available We report the case of a 64-year-old man who had a permanent pacemaker with a unipolar silicone electrode positioned in the right ventricle in 1989 for sinus node dysfunction. On a routine checkup in June 2011, a 28-mm-diameter mass was discovered, which appeared to adhere to the tricuspid valve and the ventricular lead. The size of the mass did not change for the next 6 months, and the lead impedance was maintained at around 500–600 Ω. Because pacing failure was observed in January 2012, he underwent an urgent pacemaker check; however, the lead impedance was found not to have increased greatly (689 Ω. Nevertheless, the pacemaker lead was noted to be fractured at the tricuspid level. His echocardiogram showed new severe tricuspid regurgitation and a floating mass around the lead. We extracted the fractured lead, enucleated the tumor, replaced the tricuspid valve, and placed an epicardial lead. Macroscopic examination revealed that the tumor surrounded the fractured lead and covered the stump. Pathological examination revealed that the tumor was composed of fibrous connective tissue. We presumed that electric current continued to flow through the stump of the fractured unipolar lead to the generator, and this might have caused the limited increase in lead impedance.

  3. Effects of Sun ginseng on memory enhancement and hippocampal neurogenesis.

    Science.gov (United States)

    Lee, Chang Hwan; Kim, Jong Min; Kim, Dong Hyun; Park, Se Jin; Liu, Xiaotong; Cai, Mudan; Hong, Jin Gyu; Park, Jeong Hill; Ryu, Jong Hoon

    2013-09-01

    Panax ginseng C.A. Meyer has been used in traditional herb prescriptions for thousands of years. A heat-processing method has been used to increase the efficacy of ginseng, yielding what is known as red ginseng. In addition, recently, a slightly modified heat-processing method was applied to ginseng, to obtain a new type of processed ginseng with increased biological activity; this new form of ginseng is referred to as Sun ginseng (SG). The aim of this study was to investigate the effect of SG on memory enhancement and neurogenesis in the hippocampal dentate gyrus (DG) region. The subchronic administration of SG (for 14 days) significantly increased the latency time in the passive avoidance task relative to the administration of the vehicle control (P memory-enhancing activities and that these effects are mediated, in part, by the increase in the levels of pERK and pAkt and by the increases in cell proliferation and cell survival. Copyright © 2012 John Wiley & Sons, Ltd.

  4. Beliefs of people taking antidepressants about causes of depression and reasons for increased prescribing rates.

    Science.gov (United States)

    Read, John; Cartwright, Claire; Gibson, Kerry; Shiels, Christopher; Haslam, Nicholas

    2014-10-01

    Public beliefs about the causes of mental health problems are related to desire for distance and pessimism about recovery, and are therefore frequently studied. The beliefs of people receiving treatment are researched less often. An online survey on causal beliefs about depression and experiences with antidepressants was completed by 1829 New Zealand adults prescribed anti-depressants in the preceding five years, 97.4% of whom proceeded to take antidepressants. The most frequently endorsed of 17 causal beliefs were family stress, relationship problems, loss of loved one, financial problems, isolation, and abuse or neglect in childhood. Factor analysis produced three factors: 'bio-genetic', 'adulthood stress' and 'childhood adversity'. The most strongly endorsed explanations for increases in antidepressant prescribing invoked improved identification, reduced stigma and drug company marketing. The least strongly endorsed was 'Anti-depressants are the best treatment'. Regression analyses revealed that self-reported efficacy of the antidepressants was positively associated with bio-genetic causal beliefs, negatively associated with childhood adversity beliefs and unrelated to adulthood stress beliefs. The belief that 'People cannot׳ get better by themselves even if they try' was positively associated with bio-genetic beliefs. The convenience sample may have been biased towards a favourable view of bio-genetic explanations, since 83% reported that the medication reduced their depression. Clinicians׳ should consider exploring patients׳ causal beliefs. The public, even when taking antidepressants, continues to hold a multi-factorial causal model of depression with a primary emphasis on psycho-social causes. A three factor model of those beliefs may lead to more sophisticated understandings of relationships with stigma variables. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Juvenile social defeat stress exposure persistently impairs social behaviors and neurogenesis.

    Science.gov (United States)

    Mouri, Akihiro; Ukai, Mayu; Uchida, Mizuki; Hasegawa, Sho; Taniguchi, Masayuki; Ito, Takahiro; Hida, Hirotake; Yoshimi, Akira; Yamada, Kiyofumi; Kunimoto, Shohko; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

    2018-05-01

    Adverse juvenile experiences, including physical abuse, often have negative health consequences later in life. We investigated the influence of social defeat stress exposure as juveniles on neuropsychological behaviors, and the causal role of glucocorticoids in abnormal behaviors and impairment of neurogenesis in mice exposed to the stress. The juvenile (24-day-old) and adult (70-day-old) male C57BL/6J mice were exposed to social defeat stress induced by an aggressive ICR mouse. Social defeat stress exposure as juveniles, even for 1 day, induced persistent social avoidance to the unfamiliar ICR mouse in the social interaction test, but that was not observed in mice exposed to the stress as adults. Social avoidance by the stress exposure as juveniles for 10 consecutive days was observed, when the target mouse was not only unfamiliar ICR but also another C57BL/J mouse, but not an absent or an anesthetized ICR mouse. The stress exposure did not induce anxiety- and depression-like behaviors in spontaneous locomotor activity, elevated plus-maze test, marble-burying test, forced swimming test, or sucrose preference test. Serum corticosterone levels increased immediately after the stress exposure. The hippocampal neurogenesis was suppressed 1 day and 4 weeks after the stress exposure. Administration of mifepristone, a glucocorticoid receptor antagonist, prior to each stress exposure, blocked the persistent social avoidance and suppression of neurogenesis. In conclusion, social avoidance induced by social defeat stress exposure as juveniles are more persistent than that as adults. These social avoidances are associated with suppression of hippocampal neurogenesis via glucocorticoid receptors. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning.

    Science.gov (United States)

    Catlow, Briony J; Song, Shijie; Paredes, Daniel A; Kirstein, Cheryl L; Sanchez-Ramos, Juan

    2013-08-01

    Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

  7. Increased reactive oxygen species levels cause ER stress and cytotoxicity in andrographolide treated colon cancer cells.

    Science.gov (United States)

    Banerjee, Aditi; Banerjee, Vivekjyoti; Czinn, Steven; Blanchard, Thomas

    2017-04-18

    Chemotherapy continues to play an essential role in the management of many cancers including colon cancer, the third leading cause of death due to cancer in the United States. Many naturally occurring plant compounds have been demonstrated to possess anti-cancer cell activity and have the potential to supplement existing chemotherapy strategies. The plant metabolite andrographolide induces cell death in cancer cells and apoptosis is dependent upon the induction of endoplasmic reticulum stress (ER stress) leading to the unfolded protein response (UPR). The goal of the present study was to determine the mechanism by which andrographolide induces ER stress and to further evaluate its role in promoting cell death pathways. The T84 and COLO 205 cancer cell lines were used to demonstrate that andrographolide induces increased ROS levels, corresponding anti-oxidant response molecules, and reduced mitochondrial membrane potential. No increases in ROS levels were detected in control colon fibroblast cells. Andrographolide-induced cell death, UPR signaling, and CHOP, Bax, and caspase 3 apoptosis elements were all inhibited in the presence of the ROS scavenger NAC. Additionally, andrographolide-induced suppression of cyclins B1 and D1 were also reversed in the presence of NAC. Finally, Akt phosphorylation and phospho-mTOR levels that are normally suppressed by andrographolide were also expressed at normal levels in the absence of ROS. These data demonstrate that andrographolide induces ER stress leading to apoptosis through the induction of ROS and that elevated ROS also play an important role in down-regulating cell cycle progression and cell survival pathways as well.

  8. Tight Skin 2 Mice Exhibit Delayed Wound Healing Caused by Increased Elastic Fibers in Fibrotic Skin.

    Science.gov (United States)

    Long, Kristen B; Burgwin, Chelsea M; Huneke, Richard; Artlett, Carol M; Blankenhorn, Elizabeth P

    2014-09-01

    Rationale: The Tight Skin 2 (Tsk2) mouse model of systemic sclerosis (SSc) has many features of human disease, including tight skin, excessive collagen deposition, alterations in the extracellular matrix (ECM), increased elastic fibers, and occurrence of antinuclear antibodies with age. A tight skin phenotype is observed by 2 weeks of age, but measurable skin fibrosis is only apparent at 10 weeks. We completed a series of wound healing experiments to determine how fibrosis affects wound healing in Tsk2/+ mice compared with their wild-type (WT) littermates. Method: We performed these experiments by introducing four 4 mm biopsy punched wounds on the back of each mouse, ventral of the midline, and observed wound healing over 10 days. Tsk2/+ mice showed significantly delayed wound healing and increased wound size compared with the WT littermates at both 5 and 10 weeks of age. We explored the potential sources of this response by wounding Tsk2/+ mice that were genetically deficient either for the NLRP3 inflammasome (a known fibrosis mediator), or for elastic fibers in the skin, using a fibulin-5 knockout. Conclusion: We found that the loss of elastic fibers restores normal wound healing in the Tsk2/+ mouse and that the loss of the NLRP3 inflammasome had no effect. We conclude that elastic fiber dysregulation is the primary cause of delayed wound healing in the Tsk2/+ mouse and therapies that promote collagen deposition in the tissue matrix in the absence of elastin deposition might be beneficial in promoting wound healing in SSc and other diseases.

  9. Anorectal stimulation causes increased colonic motor activity in subjects with spinal cord injury.

    Science.gov (United States)

    Korsten, Mark A; Singal, Ashwani K; Monga, Amit; Chaparala, Geeta; Khan, Amir M; Palmon, Ron; Mendoza, John Reagan D; Lirio, Juan P; Rosman, Alan S; Spungen, Ann; Bauman, William A

    2007-01-01

    Difficulty with evacuation (DWE) is a major problem after spinal cord injury (SCI). Stimulation of the anal canal and lower rectum, accomplished using a gloved finger (so-called digital rectal stimulation or DRS) is often used as an adjunct to laxatives and enemas to facilitate bowel evacuation. However, the basis for the efficacy of DRS is not known. This study assessed the effect of DRS on colonic motility. Six subjects with SCI were studied several hours after a bowel care session. Colonic motility was assessed using a manometric catheter (affixed endoscopically to the splenic flexure) at baseline, during DRS, and after DRS. In addition, evacuation of barium oatmeal paste (with the consistency of stool and introduced into the rectum and descending colon) was assessed simultaneously using fluoroscopic techniques. The mean number (+/- SEM) of peristaltic waves per minute increased from 0 at baseline to 1.9 (+/- 0.5/min) during DRS and 1.5 (+/- 0.3/min) during the period immediately after cessation of DRS (P < 0.05). The mean amplitude (+/- SEM) of the peristaltic contractions was 43.4 (+/- 2.2) mmHg. The frequency of contractions, as well as amplitude of contractions, during or immediately after DRS was not significantly different. These manometric changes in response to DRS were accompanied by expulsion of barium oatmeal paste in every subject by the fifth DRS. DRS causes left-sided colonic activity in subjects with SCI. At least in part, an anorectal colonic reflex that results in enhanced contractions of the descending colon and rectum may contribute to bowel evacuation in individuals with SCI.

  10. Constrained parameterisation of photosynthetic capacity causes significant increase of modelled tropical vegetation surface temperature

    Science.gov (United States)

    Kattge, J.; Knorr, W.; Raddatz, T.; Wirth, C.

    2009-04-01

    Photosynthetic capacity is one of the most sensitive parameters of terrestrial biosphere models whose representation in global scale simulations has been severely hampered by a lack of systematic analyses using a sufficiently broad database. Due to its coupling to stomatal conductance changes in the parameterisation of photosynthetic capacity may potentially influence transpiration rates and vegetation surface temperature. Here, we provide a constrained parameterisation of photosynthetic capacity for different plant functional types in the context of the photosynthesis model proposed by Farquhar et al. (1980), based on a comprehensive compilation of leaf photosynthesis rates and leaf nitrogen content. Mean values of photosynthetic capacity were implemented into the coupled climate-vegetation model ECHAM5/JSBACH and modelled gross primary production (GPP) is compared to a compilation of independent observations on stand scale. Compared to the current standard parameterisation the root-mean-squared difference between modelled and observed GPP is substantially reduced for almost all PFTs by the new parameterisation of photosynthetic capacity. We find a systematic depression of NUE (photosynthetic capacity divided by leaf nitrogen content) on certain tropical soils that are known to be deficient in phosphorus. Photosynthetic capacity of tropical trees derived by this study is substantially lower than standard estimates currently used in terrestrial biosphere models. This causes a decrease of modelled GPP while it significantly increases modelled tropical vegetation surface temperatures, up to 0.8°C. These results emphasise the importance of a constrained parameterisation of photosynthetic capacity not only for the carbon cycle, but also for the climate system.

  11. A possible cause of epistaxis: increased masked hypertension prevalence in patients with epistaxis.

    Science.gov (United States)

    Acar, Baran; Yavuz, Bunyamin; Yıldız, Erdem; Ozkan, Selcuk; Ayturk, Mehmet; Sen, Omer; Deveci, Onur Sinan

    Epistaxis and hypertension are frequent conditions in the adult population. Masked hypertension is defined as a clinical condition in which a patient's office blood pressure level is epistaxis. The prevalence of this condition in patients with epistaxis is not well defined. This study aimed to evaluate the prevalence of masked hypertension using the results of office blood pressure measurement compared with the results of ambulatory blood pressure monitoring. Sixty patients with epistaxis and 60 control subjects were enrolled in the study. All patients with epistaxis and controls without history of hypertension underwent physical examination, including office blood pressure measurement, ambulatory or home blood pressure, and measurement of anthropometric parameters. Mean age was similar between the epistaxis group and the controls - 21-68 years (mean 42.9) for the epistaxis group and 18-71 years (mean 42.2) for the control group. A total of 20 patients (33.3%) in the epistaxis group and 7 patients (11.7%) in the control group (p=0.004) had masked hypertension. Night-time systolic blood pressure was significantly higher in patients with epistaxis than in the control group (pepistaxis (p=0.517). This study demonstrates increased masked hypertension prevalence in patients with epistaxis. We suggest that all patients with epistaxis should undergo ambulatory or home blood pressure to detect masked hypertension, which could be a possible cause of epistaxis. Copyright © 2016 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  12. Stage-dependent alterations of progenitor cell proliferation and neurogenesis in an animal model of Wernicke-Korsakoff syndrome.

    Science.gov (United States)

    Vetreno, Ryan P; Klintsova, Anna; Savage, Lisa M

    2011-05-19

    Alcohol-induced Wernicke-Korsakoff syndrome (WKS) culminates in bilateral diencephalic lesion and severe amnesia. Using the pyrithiamine-induced thiamine deficiency (PTD) animal paradigm of WKS, our laboratory has demonstrated hippocampal dysfunction in the absence of gross anatomical pathology. Extensive literature has revealed reduced hippocampal neurogenesis following a neuropathological insult, which might contribute to hippocampus-based learning and memory impairments. Thus, the current investigation was conducted to determine whether PTD treatment altered hippocampal neurogenesis in a stage-dependent fashion. Male Sprague-Dawley rats were assigned to one of 4 stages of thiamine deficiency based on behavioral symptoms: pre-symptomatic stage, ataxic stage, early post-opisthotonus stage, or the late post-opisthotonus stage. The S-phase mitotic marker 5'-bromo-2'-deoxyuridine (BrdU) was administered at the conclusion of each stage following thiamine restoration and subjects were perfused 24 hours or 28 days after BrdU to assess cellular proliferation or neurogenesis and survival, respectively. Dorsal hippocampal sections were immunostained for BrdU (proliferating cell marker), NeuN (neurons), GFAP (astrocytes), Iba-1 (microglia), and O4 (oligodendrocytes). The PTD treatment increased progenitor cell proliferation and survival during the early post-opisthotonus stage. However, levels of neurogenesis were reduced during this stage as well as the late post-opisthotonus stage where there was also an increase in astrocytogenesis. The diminished numbers of newly generated neurons (BrdU/NeuN co-localization) was paralleled by increased BrdU cells that did not co-localize with any of the phenotypic markers during these later stages. These data demonstrate that long-term alterations in neurogenesis and gliogenesis might contribute to the observed hippocampal dysfunction in the PTD model and human WKS. Published by Elsevier B.V.

  13. MicroRNA-9 Couples Brain Neurogenesis and Angiogenesis

    Directory of Open Access Journals (Sweden)

    Romain Madelaine

    2017-08-01

    Full Text Available In the developing brain, neurons expressing VEGF-A and blood vessels grow in close apposition, but many of the molecular pathways regulating neuronal VEGF-A and neurovascular system development remain to be deciphered. Here, we show that miR-9 links neurogenesis and angiogenesis through the formation of neurons expressing VEGF-A. We found that miR-9 directly targets the transcription factors TLX and ONECUTs to regulate VEGF-A expression. miR-9 inhibition leads to increased TLX and ONECUT expression, resulting in VEGF-A overexpression. This untimely increase of neuronal VEGF-A signal leads to the thickening of blood vessels at the expense of the normal formation of the neurovascular network in the brain and retina. Thus, this conserved transcriptional cascade is critical for proper brain development in vertebrates. Because of this dual role on neural stem cell proliferation and angiogenesis, miR-9 and its downstream targets are promising factors for cellular regenerative therapy following stroke and for brain tumor treatment.

  14. The interplay between the hippocampus and the amygdala in regulating aberrant hippocampal neurogenesis during protracted abstinence from alcohol dependence

    Directory of Open Access Journals (Sweden)

    Chitra D Mandyam

    2013-06-01

    Full Text Available The development of alcohol dependence involves elevated anxiety, low mood, and increased sensitivity to stress, collectively labeled negative affect. Particularly interesting is the recent accumulating evidence that sensitized extrahypothalamic stress systems (e.g., hyperglutamatergic activity, blunted hypothalamic-pituitary-adrenal [HPA] hormonal levels, altered corticotropin-releasing factor signaling, and altered glucocorticoid receptor signaling in the extended amygdala are evident in withdrawn dependent rats, supporting the hypothesis that pathological neuroadaptations in the extended amygdala contribute to the negative affective state. Notably, hippocampal neurotoxicity observed as aberrant dentate gyrus (DG neurogenesis (neurogenesis is a process where neural stem cells in the adult hippocampal subgranular zone generate DG granule cell neurons and DG neurodegeneration are observed in withdrawn dependent rats. These correlations between withdrawal and aberrant neurogenesis in dependent rats suggest that alterations in the DG could be hypothesized to be due to compromised HPA axis activity and associated hyperglutamatergic activity originating from the basolateral amygdala in withdrawn dependent rats. This review discusses a possible link between the neuroadaptations in the extended amygdala stress systems and the resulting pathological plasticity that could facilitate recruitment of new emotional memory circuits in the hippocampus as a function of aberrant DG neurogenesis.

  15. CXCR4 antagonist AMD3100 reverses the neurogenesis and behavioral recovery promoted by forced limb-use in stroke rats.

    Science.gov (United States)

    Zhao, Shanshan; Qu, Huiling; Zhao, Yi; Xiao, Ting; Zhao, Mei; Li, Yong; Jolkkonen, Jukka; Cao, Yunpeng; Zhao, Chuansheng

    2015-01-01

    Forced limb-use can enhance neurogenesis and behavioral recovery as well as increasing the level of stromal cell-derived factor-1 (SDF-1) in stroke rats. We examined whether the SDF-1/CXCR4 pathway is involved in the enhanced neurogenesis and promoted behavioral recovery induced by forced limb-use in the chronic phase of stroke. The CXCR4 antagonist, AMD3100, was used to block the SDF-1/CXCR4 pathway in the ischemic rats. Brain ischemia was induced by endothelin-1. One week after ischemia, the unimpaired forelimb of rats was immobilized for 3 weeks. The proliferation, migration, and survival of DCX-positive cells in the subventricular zone (SVZ), and the dendritic complexity of DCX-positive cells in the dentate gyrus (DG), as well as the inflammatory response in the infarcted striatum were analyzed by immunohistochemistry. Functional recovery was assessed in beam-walking and water maze tests. Forced limb-use enhanced the proliferation, migration, dendritic complexity and the survival of newborn neurons. Furthermore, forced limb-use suppressed the inflammatory response and improved both motor and cognitive functions after stroke. AMD3100 significantly abrogated the enhanced neurogenesis and behavioral recovery induced by forced limb-use without influencing the inflammatory response. SDF-1/CXCR4 pathway seems to be involved in the enhancement of neurogenesis and behavioral recovery induced by post-stroke forced limb-use.

  16. p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex

    Directory of Open Access Journals (Sweden)

    Camille Belzil

    2014-05-01

    Full Text Available Apical neural progenitors (aNPs drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600 in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.

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

    Science.gov (United States)

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

  18. Neurotransmitter regulation of adult neurogenesis: putative therapeutic targets.

    Science.gov (United States)

    Vaidya, V A; Vadodaria, K C; Jha, S

    2007-10-01

    The evidence that new neuron addition takes place in the mammalian brain throughout adult life has dramatically altered our perspective of the potential for plasticity in the adult CNS. Although several recent reports suggest a latent neurogenic capacity in multiple brain regions, the two major neurogenic niches that retain the ability to generate substantial numbers of new neurons in adult life are the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) in the hippocampal formation. The discovery of adult neurogenesis has also unveiled a novel therapeutic target for the repair of damaged neuronal circuits. In this regard, understanding the endogenous mechanisms that regulate adult neurogenesis holds promise both for a deeper understanding of this form of structural plasticity, as well as the identification of pathways that can serve as therapeutic targets to manipulate adult neurogenesis. The purpose of the present review is to discuss the regulation of adult neurogenesis by neurotransmitters and to highlight the relevance of these endogenous regulators as targets to modulate adult neurogenesis in a clinical context.

  19. Effects of amphetamine administration on neurogenesis in adult rats

    Directory of Open Access Journals (Sweden)

    Tomasz Stępień

    2017-12-01

    Full Text Available In our study expression of phospho-(Ser-10-histone H3 (pH3S10, a marker for the early stage of neurogenesis, and cellular early response genes were investigated using c-Fos protein as an example of a transcription factor in the neurogenic process in rats. Neurogenesis in the adult brain is regulated by endo- and exogenous factors, which influence the proliferation potential of progenitor cells and accelerate the dendritic development of newborn neurons. D-amphetamine, a psychoactive substance, is one of the exogenous factors able to influence the process of neurogenesis. The rats were injected with D-amphetamine at a dose of 1.5 mg/kg/body weight (b.w. under one administration scheme. Analysis of the pH3S10 and c-Fos expression levels in the group of D-amphetamine administered rats provided evidence of enhanced expression of these proteins in the regions of neurogenesis occurrence in rats. However, conclusions concerning stimulant effects of amphetamine on neurogenesis should be formulated with great caution, taking into account amphetamine dosage and the administration scheme. It should also be remembered that doses of psychoactive substances used in animal models can be lethal to humans.

  20. Neurogenesis and growth factors expression after complete spinal cord transection in Pleurodeles waltlii

    Directory of Open Access Journals (Sweden)

    Amira Z Zaky

    2015-01-01

    Full Text Available Following spinal lesion, connections between the supra-spinal centers and spinal neuronal networks can be disturbed, which causes the deterioration or even the complete absence of sublesional locomotor activity. In Mammals, possibilities of locomotion restoration are much reduced since descending tracts either have very poor regenerative ability or do not regenerate at all. However, in lower Vertebrates, there is spontaneous locomotion recuperation after complete spinal cord transection at the mid-trunk level. This phenomenon depends on a translesional descending axon re-growth originating from the brainstem. On the other hand, cellular and molecular mechanisms underlying spinal cord regeneration and in parallel, locomotion restoration of the animal, are not well known. FGF-2 plays an important role in different processes such as neural induction, neuronal progenitor proliferation and their differentiation. Studies had shown an over expression of this growth factor after tail amputation. Nestin, a protein specific for intermediate filaments, is considered as an early marker for neuronal precursors. It has been recently shown that its expression increases after tail transection in Urodeles. Using this marker and western blots, our results show that the increase in the number of FGF-2 and FGFR2 mRNAs is correlated with an increase in neurogenesis especially in the central canal lining cells immediately after lesion. This study also confirms that spinal cord re-growth through the lesion site initially follows a rostrocaudal direction. In addition to its role known in neuronal differentiation, FGF-2 could be implicated in the differentiation of ependymal cells into neuronal progenitors.

  1. Olfactory memory is enhanced in mice exposed to extremely low-frequency electromagnetic fields via Wnt/β-catenin dependent modulation of subventricular zone neurogenesis.

    Science.gov (United States)

    Mastrodonato, Alessia; Barbati, Saviana Antonella; Leone, Lucia; Colussi, Claudia; Gironi, Katia; Rinaudo, Marco; Piacentini, Roberto; Denny, Christine A; Grassi, Claudio

    2018-01-10

    Exposure to extremely low-frequency electromagnetic fields (ELFEF) influences the expression of key target genes controlling adult neurogenesis and modulates hippocampus-dependent memory. Here, we assayed whether ELFEF stimulation affects olfactory memory by modulating neurogenesis in the subventricular zone (SVZ) of the lateral ventricle, and investigated the underlying molecular mechanisms. We found that 30 days after the completion of an ELFEF stimulation protocol (1 mT; 50 Hz; 3.5 h/day for 12 days), mice showed enhanced olfactory memory and increased SVZ neurogenesis. These effects were associated with upregulated expression of mRNAs encoding for key regulators of adult neurogenesis and were mainly dependent on the activation of the Wnt pathway. Indeed, ELFEF stimulation increased Wnt3 mRNA expression and nuclear localization of its downstream target β-catenin. Conversely, inhibition of Wnt3 by Dkk-1 prevented ELFEF-induced upregulation of neurogenic genes and abolished ELFEF's effects on olfactory memory. Collectively, our findings suggest that ELFEF stimulation increases olfactory memory via enhanced Wnt/β-catenin signaling in the SVZ and point to ELFEF as a promising tool for enhancing SVZ neurogenesis and olfactory function.

  2. Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells.

    Science.gov (United States)

    Farioli-Vecchioli, Stefano; Mattera, Andrea; Micheli, Laura; Ceccarelli, Manuela; Leonardi, Luca; Saraulli, Daniele; Costanzi, Marco; Cestari, Vincenzo; Rouault, Jean-Pierre; Tirone, Felice

    2014-07-01

    Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here, we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral ventricle, observed in mice lacking the antiproliferative gene Btg1. We also evaluated for the first time how running influences the cell cycle kinetics of stem and precursor subpopulations of wild-type and Btg1-null mice, using a new method to determine the cell cycle length. Our data show that in wild-type mice running leads to a cell cycle shortening only of NeuroD1-positive progenitor cells. In contrast, in Btg1-null mice, physical exercise fully reactivates the defective hippocampal neurogenesis, by shortening the S-phase length and the overall cell cycle duration of both neural stem (glial fibrillary acidic protein(+) and Sox2(+)) and progenitor (NeuroD1(+)) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null early-postnatal mice and to expand the pool of adult neural stem and progenitor cells. Such a sustained increase of cell proliferation in Btg1-null mice after running provides a long-lasting increment of proliferation, differentiation, and production of newborn neurons, which rescues the impaired pattern separation previously identified in Btg1-null mice. This study shows that running positively affects the cell cycle kinetics of specific subpopulations of newly generated neurons and suggests that the plasticity of neural stem cells without cell cycle inhibitory control is reactivated by running, with implications for the long-term modulation of neurogenesis. © 2014 AlphaMed Press.

  3. Toll-like receptor 2 promotes neurogenesis from the dentate gyrus after photothrombotic cerebral ischemia in mice.

    Science.gov (United States)

    Seong, Kyung-Joo; Kim, Hyeong-Jun; Cai, Bangrong; Kook, Min-Suk; Jung, Ji-Yeon; Kim, Won-Jae

    2018-03-01

    The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury, the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdU-positive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved-caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double-positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain.

  4. Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases

    Directory of Open Access Journals (Sweden)

    He Liu

    2016-01-01

    Full Text Available Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain tumors.

  5. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

    Directory of Open Access Journals (Sweden)

    Astha Malik

    Full Text Available Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ. Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte

  6. Mouse embryonic retina delivers information controlling cortical neurogenesis.

    Directory of Open Access Journals (Sweden)

    Ciro Bonetti

    2010-12-01

    Full Text Available The relative contribution of extrinsic and intrinsic mechanisms to cortical development is an intensely debated issue and an outstanding question in neurobiology. Currently, the emerging view is that interplay between intrinsic genetic mechanisms and extrinsic information shape different stages of cortical development. Yet, whereas the intrinsic program of early neocortical developmental events has been at least in part decoded, the exact nature and impact of extrinsic signaling are still elusive and controversial. We found that in the mouse developing visual system, acute pharmacological inhibition of spontaneous retinal activity (retinal waves-RWs during embryonic stages increase the rate of corticogenesis (cell cycle withdrawal. Furthermore, early perturbation of retinal spontaneous activity leads to changes of cortical layer structure at a later time point. These data suggest that mouse embryonic retina delivers long-distance information capable of modulating cell genesis in the developing visual cortex and that spontaneous activity is the candidate long-distance acting extrinsic cue mediating this process. In addition, these data may support spontaneous activity to be a general signal coordinating neurogenesis in other developing sensory pathways or areas of the central nervous system.

  7. Aging, neurogenesis, and caloric restriction in different model organisms.

    Science.gov (United States)

    Arslan-Ergul, Ayca; Ozdemir, A Tugrul; Adams, Michelle M

    2013-08-01

    Brain aging is a multifactorial process that is occurring across multiple cognitive domains. A significant complaint that occurs in the elderly is a decrement in learning and memory ability. Both rodents and zebrafish exhibit a similar problem with memory during aging. The neurobiological changes that underlie this cognitive decline are complex and undoubtedly influenced by many factors. Alterations in the birth of new neurons and neuron turnover may contribute to age-related cognitive problems. Caloric restriction is the only non-genetic intervention that reliably increases life span and healthspan across multiple organisms although the molecular mechanisms are not well-understood. Recently the zebrafish has become a popular model organism for understanding the neurobiological consequences but to date very little work has been performed. Similarly, few studies have examined the effects of dietary restriction in zebrafish. Here we review the literature related to memory decline, neurogenesis, and caloric restriction across model organisms and suggest that zebrafish has the potential to be an important animal model for understanding the complex interactions between age, neurobiological changes in the brain, and dietary regimens or their mimetics as interventions.

  8. Analysis of accident caused by temperature increase at the RA reactor in Vinca

    International Nuclear Information System (INIS)

    Afgan, N; Kulundzic, P.

    1964-06-01

    The objective of this work was to determine the maximum time interval without accident due to mechanical failures. The following accidents caused by mechanical failures are taken into account: loss of moderator flow, moderator leaking with or without circulation, and accidents caused by removal of fuel channels from the reactor vessel. Obtained numerical and experimental results are presented. Experimental device installed at the reactor was used for verification of calculation results. The analysis was done for the most damaging conditions and thus the obtained results represent the lowest boundary values [sr

  9. Increased cytotoxicity and streptolysin O activity in group G streptococcal strains causing invasive tissue infections

    DEFF Research Database (Denmark)

    Siemens, Nikolai; Kittang, Bård R; Chakrakodi, Bhavya

    2015-01-01

    Streptococcus dysgalactiae subsp. equisimilis (SDSE) has emerged as an important cause of severe skin and soft tissue infections, but little is known of the pathogenic mechanisms underlying tissue pathology. Patient samples and a collection of invasive and non-invasive group G SDSE strains (n = 6...

  10. Germline heterozygous variants in genes associated with familial hemophagocytic lymphohistiocytosis as a cause of increased bleeding

    DEFF Research Database (Denmark)

    Fager Ferrari, Marcus; Leinoe, Eva; Rossing, Maria

    2018-01-01

    Familial hemophagocytic lymphohistiocytosis (FHL) is caused by biallelic variants in genes regulating granule secretion in cytotoxic lymphocytes. In FHL3-5, the affected genes UNC13D, STX11 and STXBP2 have further been shown to regulate the secretion of platelet granules, giving rise to compromised...

  11. Violent video games cause an increase in aggression long after the game has been turned off

    NARCIS (Netherlands)

    Bushman, B.J.; Gibson, B

    2011-01-01

    Experimental studies show that violent video games cause people to behave more aggressively, but how long does the effect last? In most experiments, aggression is measured immediately after gameplay. The present experiment is the first to test the long-term causal effects of violent video games on

  12. Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development

    NARCIS (Netherlands)

    K.E. Slegtenhorst-Eegdeman; D.G. de Rooij; M. Verhoef-Post (Miriam); H.J.G. van de Kant (Henk); C.E. Bakker (Cathy); B.A. Oostra (Ben); J.A. Grootegoed (Anton); A.P.N. Themmen (Axel)

    1998-01-01

    textabstractThe fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5'-untranslated region of the gene involved, the fragile

  13. Unlocking mechanisms in interleukin-1β-induced changes in hippocampal neurogenesis--a role for GSK-3β and TLX.

    Science.gov (United States)

    Green, H F; Nolan, Y M

    2012-11-20

    Glycogen synthase kinase-3β (GSK-3β) and the orphan nuclear receptor tailless homolog (TLX) are key regulators of hippocampal neurogenesis, which has been reported to be dysregulated in both neurodegenerative and psychiatric disorders. Inflammation is also implicated in the neuropathology of these disorders because of increased levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the brain. At elevated levels, IL-1β signaling through the IL-1 receptor type 1 has been shown to be detrimental to hippocampal neurogenesis. TLX is required to maintain neural stem/progenitor cells (NSPCs) in an undifferentiated state and is involved in NSPC fate determination, while GSK-3β negatively regulates Wnt signaling, a vital pathway promoting neurogenesis. This study shows that GSK-3β inhibition using a small-molecule inhibitor and the mood stabilizer lithium restores the IL-1β-induced decrease in NSPC proliferation and neuronal differentiation of embryonic rat hippocampal NSPCs to control levels. The IL-1β-induced effect on NSPCs is paralleled by a decrease in TLX expression that can be prevented by GSK-3β inhibition. The present results suggest that GSK-3β ameliorates the anti-proliferative and pro-gliogenic effects of IL-1β, and that TLX is vulnerable to inflammatory insult. Strategies to reduce GSK-3β activity or to increase TLX expression may facilitate the restoration of hippocampal neurogenesis in neuroinflammatory conditions where neurogenesis is impaired.

  14. Effects of increased alcohol availability during adolescence on the risk of all-cause and cause-specific disability pension: a natural experiment.

    Science.gov (United States)

    Thern, Emelie; de Munter, Jeroen; Hemmingsson, Tomas; Davey Smith, George; Ramstedt, Mats; Tynelius, Per; Rasmussen, Finn

    2017-06-01

    To test if being exposed to increased alcohol availability during adolescence is associated with an increased risk of receiving disability pension due to all-cause, alcohol use disorders and mental disorders. Register-based population-based study using a natural experiment setting, the alcohol policy change in Sweden (1967-68), with increased access to strong beer in a narrow time window and geographical area. The individuals exposed to the policy change were compared with non-exposed individuals living in the rest of Sweden, excluding a border area. Sweden. A total of 518 810 individuals (70 761 in the intervention group; 448 049 in the control group) born 1948-1953, aged 14-20 years during the policy change. Date and diagnosis of the outcome variable of disability pension due to all-cause, alcohol use disorders and mental disorders were obtained from the Swedish National Social Insurance Agency database from 1971 to 2013. Individual and family level socio-demographic and health-related covariates, as well as a regional level covariate, were included. Compared with the control group, adolescents exposed to the alcohol policy change were at an increased risk of receiving disability pension due to all-causes [hazard ratio (HR) = 1.09, 95% confidence interval (CI) = 1.07-1.11], alcohol use disorders (HR = 1.17, 95% CI = 1.05-1.30) and mental disorders (HR = 1.19, 95% CI = 1.15-1.23). In Sweden, a natural experiment with a 43-year follow-up suggests that exposure to increased alcohol availability during adolescence is associated with an increased risk of receiving a disability pension due to all-cause, alcohol use disorder and mental disorder diagnoses. © 2017 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

  15. Adult Neurogenesis and Neurodegenerative Diseases: A Systems Biology Perspective

    Science.gov (United States)

    Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.

    2016-01-01

    New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. PMID:26879907

  16. Inhibitory effects of caffeine on hippocampal neurogenesis and function.

    Science.gov (United States)

    Han, Myoung-Eun; Park, Kyu-Hyun; Baek, Sun-Yong; Kim, Bong-Seon; Kim, Jae-Bong; Kim, Hak-Jin; Oh, Sae-Ock

    2007-05-18

    Caffeine is one of the most extensively consumed psychostimulants in the world. However, compared to short-term effects of caffeine, the long-term effects of caffeine consumption on learning and memory are poorly characterized. The present study found that long-term consumption of low dose caffeine (0.3 g/L) slowed hippocampus-dependent learning and impaired long-term memory. Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls. From these results, we concluded that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.

  17. Total and cause-specific mortality by moderately and markedly increased ferritin concentrations

    DEFF Research Database (Denmark)

    Ellervik, Christina; Marott, Jacob Louis; Tybjærg-Hansen, Anne

    2014-01-01

    . Stepwise increasing concentrations of ferritin were associated with a stepwise increased risk of premature death overall (log rank, P = 2 × 10(-22)), with median survival of 55 years at ferritin concentrations ≥600 μg/L, 72 years at 400-599 μg/L, 76 years at 200-399 μg/L, and 79 years at ferritin

  18. Will a game cause increased fruit/vegetable intake and physical activity in elementary school children?

    OpenAIRE

    Trimble, Derek

    2017-01-01

    Background Incentives increase healthy lifestyle choices. Schools don’t have financial resources for an incentive program. Research Question Is there a way to increase fruit and vegetable intake and physical activity in elementary school children at little or no cost to the school?

  19. High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS Improves Functional Recovery by Enhancing Neurogenesis and Activating BDNF/TrkB Signaling in Ischemic Rats

    Directory of Open Access Journals (Sweden)

    Jing Luo

    2017-02-01

    Full Text Available Repetitive transcranial magnetic stimulation (rTMS has rapidly become an attractive therapeutic approach for stroke. However, the mechanisms underlying this remain elusive. This study aimed to investigate whether high-frequency rTMS improves functional recovery mediated by enhanced neurogenesis and activation of brain-derived neurotrophic factor (BDNF/tropomyosin-related kinase B (TrkB pathway and to compare the effect of conventional 20 Hz rTMS and intermittent theta burst stimulation (iTBS on ischemic rats. Rats after rTMS were sacrificed seven and 14 days after middle cerebral artery occlusion (MCAO, following evaluation of neurological function. Neurogenesis was measured using specific markers: Ki67, Nestin, doublecortin (DCX, NeuN and glial fibrillary acidic protein (GFAP, and the expression levels of BDNF were visualized by Western blotting and RT-PCR analysis. Both high-frequency rTMS methods significantly improved neurological function and reduced infarct volume. Moreover, 20 Hz rTMS and iTBS significantly promoted neurogenesis, shown by an increase of Ki67/DCX, Ki67/Nestin, and Ki67/NeuN-positive cells in the peri-infarct striatum. These beneficial effects were accompanied by elevated protein levels of BDNF and phosphorylated-TrkB. In conclusion, high-frequency rTMS improves functional recovery possibly by enhancing neurogenesis and activating BDNF/TrkB signaling pathway and conventional 20 Hz rTMS is better than iTBS at enhancing neurogenesis in ischemic rats.

  20. Meta-analysis : High-dosage vitamin E supplementation may increase all-cause mortality

    NARCIS (Netherlands)

    Miller, ER; Pastor-Barriuso, R; Dalal, D; Riemersma, RA; Appel, LJ; Guallar, E

    2005-01-01

    Background: Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non-statistically significant increases in total mortality. Purpose: To perform a

  1. Transient increase in Zn2+ in hippocampal CA1 pyramidal neurons causes reversible memory deficit.

    Directory of Open Access Journals (Sweden)

    Atsushi Takeda

    Full Text Available The translocation of synaptic Zn(2+ to the cytosolic compartment has been studied to understand Zn(2+ neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn(2+ in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn(2+ in the hippocampus was induced with clioquinol (CQ, a zinc ionophore. Zn(2+ delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn(2+ levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl(2 into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn(2+ in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn(2+ and/or the preferential vulnerability to Zn(2+ in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn(2+ in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn(2+. The present study indicates that the transient increase in cytosolic Zn(2+ in CA1 pyramidal neurons reversibly impairs object recognition memory.

  2. Transient increase in Zn2+ in hippocampal CA1 pyramidal neurons causes reversible memory deficit.

    Science.gov (United States)

    Takeda, Atsushi; Takada, Shunsuke; Nakamura, Masatoshi; Suzuki, Miki; Tamano, Haruna; Ando, Masaki; Oku, Naoto

    2011-01-01

    The translocation of synaptic Zn(2+) to the cytosolic compartment has been studied to understand Zn(2+) neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn(2+) in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn(2+) in the hippocampus was induced with clioquinol (CQ), a zinc ionophore. Zn(2+) delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP) in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn(2+) levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl(2) into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn(2+) in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn(2+) and/or the preferential vulnerability to Zn(2+) in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn(2+) in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn(2+). The present study indicates that the transient increase in cytosolic Zn(2+) in CA1 pyramidal neurons reversibly impairs object recognition memory.

  3. Increasing Reliability by Means of Root Cause Aware HARQ and Interference Coordination

    DEFF Research Database (Denmark)

    Soret, Beatriz; Gerardino, Guillermo Andrés Pocovi; Pedersen, Klaus I.

    2015-01-01

    The arrival of mission critical applications in the context of vehicular, medical and industrial wireless communications calls for reliability constraints never seen before in cellular systems. Enhanced Inter-Cell Interference Coordination (eICIC) has been widely investigated in the context of LTE......-A Heterogeneous Networks, but always with load balancing and resource partitioning purposes. Given the broad range of new use cases targeting ultra high reliability, we propose the use of on-demand eICIC for reducing the BLER of the retransmissions of critical users while minimizing the impact to the rest...... of the network. Combined with a ROot Cause Aware HARQ (ROCA-HARQ), which provides additional information when a transmission fails, the joint mechanism is relevant for any LTE/LTE-A deployment and can be easily implemented in a real network. System-level simulations show attractive BLER reductions up to 80...

  4. Temperature increase can cause hyperecdysonism in American lobsters (Homarus americanus) injected with ecdysterone

    Energy Technology Data Exchange (ETDEWEB)

    Aiken, D E; Waddy, S L

    1975-10-01

    In the lobster Homarus americanus the threshold dose for premolt acceleration by ecdysterone can be altered by changes in temperature. Two dose levels of ecdysterone (0.5 and 1.0 ..mu..g/g body weight) were compared at three different temperatures (10, 17, 21/sup 0/C); all three doses remained subthreshold at 10/sup 0/C but at 17/sup 0/C the 1.0-..mu..g dose caused hyperecdysonism--rapid but abnormal completion of premolt terminating in death at ecdysis. In contrast, the 0.5-..mu..g dose remained subthreshold even at 21/sup 0/C. These results demonstrate a dose-temperature relation for response to injected ecdysterone.

  5. [Increasing incidence of community-acquired pneumonia caused by atypical microorganisms].

    Science.gov (United States)

    Tazón-Varela, M A; Alonso-Valle, H; Muñoz-Cacho, P; Gallo-Terán, J; Piris-García, X; Pérez-Mier, L A

    2017-09-01

    Knowing the most common microorganisms in our environment can help us to make proper empirical treatment decisions. The aim is to identify those microorganisms causing community-acquired pneumonia. An observational, descriptive and prospective study was conducted, including patients over 14 years with a clinical and radiographic diagnosis of community-acquired pneumonia during a 383 consecutive day period. A record was made of sociodemographic variables, personal history, prognostic severity scales, progress, and pathogenic agents. The aetiological diagnosis was made using blood cultures, detection of Streptococcus pneumoniae and Legionella pneumophila urinary antigens, sputum culture, influenza virus and Streptococcus pyogenes detection. Categorical variables are presented as absolute values and percentages, and continuous variables as their means and standard deviations. Of the 287 patients included in the study (42% women, mean age 66±22 years), 10.45% died and 70% required hospital admission. An aetiological diagnosis was achieved in 43 patients (14.98%), with 16 microorganisms found in 59 positive samples. The most frequently isolated pathogen was Streptococcus pneumonia (24/59, 41%), followed by gram-negative enteric bacilli, Klebsiella pneumonia, Escherichia coli, Serratia marcescens and Enterobacter cloacae isolated in 20% of the samples (12/59), influenza virus (5/59, 9%), methicillin-resistant Staphylococcus aureus (3/59, 5%), Pseudomonas aeruginosa (2/59, 3%), Moraxella catarrhalis (2/59, 3%), Legionella pneumophila (2/59, 3%), and Haemophilus influenza (2/59, 3%). Polymicrobial infections accounted for 14% (8/59). A high percentage of atypical microorganisms causing community-acquired pneumonia were found. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  6. Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP{sub swe}/PS1{sub {Delta}E9} transgenic mouse model of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Jun [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China); Department of Physiology, Third Military Medical University, Chongqing 400038 (China); Song, Min; Wang, Yanyan [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China); Fan, Xiaotang [Department of Histology and Embryology, Third Military Medical University, Chongqing 400038 (China); Xu, Haiwei, E-mail: haiweixu2001@yahoo.com.cn [Department of Physiology, Third Military Medical University, Chongqing 400038 (China); Bai, Yun, E-mail: baiyungene@gmail.com [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China)

    2009-07-31

    In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP{sub swe}/PS1{sub {Delta}E9} mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP{sub swe}/PS1{sub {Delta}E9} transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

  7. Causes for the recent increase in sea surface salinity in the north ...

    African Journals Online (AJOL)

    When comparing the period 2002–2009 with the period 1993–2001, significant changes in the salt budget were identified. The increase in SSS in the more recent period appeared to be driven by changes in the atmospheric freshwater flux, mainly attributed to a regional decrease in precipitation. Horizontal advection partly ...

  8. Is Global Warming Likely to Cause an Increased Incidence of Malaria?

    African Journals Online (AJOL)

    The rise in the average temperature of earth has been described as global warming which is mainly attributed to the increasing phenomenon of the greenhouse effect. It is believed that global warming can have several harmful effects on human health, both directly and indirectly. Since malaria is greatly influenced by ...

  9. Motion in images is essential to cause motion sickness symptoms, but not to increase postural sway

    NARCIS (Netherlands)

    Lubeck, A.J.A.; Bos, J.E.; Stins, J.F.

    2015-01-01

    Abstract Objective It is generally assumed that motion in motion images is responsible for increased postural sway as well as for visually induced motion sickness (VIMS). However, this has not yet been tested. To that end, we studied postural sway and VIMS induced by motion and still images. Method

  10. Does football cause an increase in degenerative disease of the lumbar spine?

    Science.gov (United States)

    Gerbino, Peter G; d'Hemecourt, Pierre A

    2002-02-01

    Degenerative disease of the lumbar spine is exceedingly common. Whether any specific activity increases the likelihood of developing degenerative disc disease (DDD) or facet degeneration (FD) has enormous implications. Within the field of occupational medicine there are specific activities, occupations, and morphologic characteristics that have been related to low back pain. Several specific risk factors have been conclusively linked to low back pain, and in particular DDD and FD. Within the sport of American football, there has long been the feeling that many athletes have or will develop low back pain, DDD, and FD. Proving that certain risk factors present in football will predictably lead to an increase in LBP, DDD, and FD is more difficult. At this time, it can be said that football players, in general, increase their risk of developing low back pain, DDD, and FD as their years of involvement with their sport increase. Because specific spine injuries like fracture, disc herniation, and spondylolysis are more frequent in football players, the resulting DDD and FD are greater than that of the general population. The weightlifting and violent hyperextension that are part of American football are independent risk factors for degenerative spine disease.

  11. Is Global Warming likely to cause an increased incidence of Malaria?

    Science.gov (United States)

    Nabi, SA; Qader, SS

    2009-01-01

    The rise in the average temperature of earth has been described as global warming which is mainly attributed to the increasing phenomenon of the greenhouse effect. It is believed that global warming can have several harmful effects on human health, both directly and indirectly. Since malaria is greatly influenced by climatic conditions because of its direct relationship with the mosquito population, it is widely assumed that its incidence is likely to increase in a future warmer world. This review article discusses the two contradictory views regarding the association of global warming with an increased incidence of malaria. On one hand, there are many who believe that there is a strong association between the recent increase in malaria incidence and global warming. They predict that as global warming continues, malaria is set to spread in locations where previously it was limited, due to cooler climate. On the other hand, several theories have been put forward which are quite contrary to this prediction. There are multiple other factors which are accountable for the recent upsurge of malaria: for example drug resistance, mosquito control programs, public health facilities, and living standards. PMID:21483497

  12. Probable causes of increasing brucellosis in free-ranging elk of the Greater Yellowstone Ecosystem

    Science.gov (United States)

    Cross, P.C.; Cole, E.K.; Dobson, A.P.; Edwards, W.H.; Hamlin, K.L.; Luikart, G.; Middleton, A.D.; Scurlock, B.M.; White, P.J.

    2010-01-01

    While many wildlife species are threatened, some populations have recovered from previous overexploitation, and data linking these population increases with disease dynamics are limited. We present data suggesting that free-ranging elk (Cervus elaphus) are a maintenance host for Brucella abortus in new areas of the Greater Yellowstone Ecosystem (GYE). Brucellosis seroprevalence in free-ranging elk increased from 0-7% in 1991-1992 to 8-20% in 2006-2007 in four of six herd units around the GYE. These levels of brucellosis are comparable to some herd units where elk are artificially aggregated on supplemental feeding grounds. There are several possible mechanisms for this increase that we evaluated using statistical and population modeling approaches. Simulations of an age-structured population model suggest that the observed levels of seroprevalence are unlikely to be sustained by dispersal from supplemental feeding areas with relatively high seroprevalence or an older age structure. Increases in brucellosis seroprevalence and the total elk population size in areas with feeding grounds have not been statistically detectable. Meanwhile, the rate of seroprevalence increase outside the feeding grounds was related to the population size and density of each herd unit. Therefore, the data suggest that enhanced elk-to-elk transmission in free-ranging populations may be occurring due to larger winter elk aggregations. Elk populations inside and outside of the GYE that traditionally did not maintain brucellosis may now be at risk due to recent population increases. In particular, some neighboring populations of Montana elk were 5-9 times larger in 2007 than in the 1970s, with some aggregations comparable to the Wyoming feeding-ground populations. Addressing the unintended consequences of these increasing populations is complicated by limited hunter access to private lands, which places many ungulate populations out of administrative control. Agency-landowner hunting access

  13. Cancer causes increased mortality and is associated with altered apoptosis in murine sepsis.

    Science.gov (United States)

    Fox, Amy C; Robertson, Charles M; Belt, Brian; Clark, Andrew T; Chang, Katherine C; Leathersich, Ann M; Dominguez, Jessica A; Perrone, Erin E; Dunne, W Michael; Hotchkiss, Richard S; Buchman, Timothy G; Linehan, David C; Coopersmith, Craig M

    2010-03-01

    Whereas most septic patients have an underlying comorbidity, most animal models of sepsis use mice that were healthy before the onset of infection. Malignancy is the most common comorbidity associated with sepsis. The purpose of this study was to determine whether mice with cancer have a different response to sepsis than healthy animals. Prospective, randomized controlled study. Animal laboratory in a university medical center. C57Bl/6 mice. Animals received a subcutaneous injection of either 250,000 cells of the transplantable pancreatic adenocarcinoma cell line Pan02 (cancer) or phosphate-buffered saline (healthy). Three weeks later, mice given Pan02 cells had reproducible, nonmetastatic tumors. Both groups of mice then underwent intratracheal injection of either Pseudomonas aeruginosa (septic) or 0.9% NaCl (sham). Animals were killed 24 hrs postoperatively or followed-up 7 days for survival. Mice with cancer and healthy mice appeared similar when subjected to sham operation, although cancer animals had lower levels of T- and B-lymphocyte apoptosis. Septic mice with cancer had increased mortality compared to previously healthy septic mice subjected to the identical injury (52% vs. 28%; p = .04). This was associated with increased bacteremia but no difference in local pulmonary infection. Septic mice with cancer also had increased intestinal epithelial apoptosis. Although sepsis induced an increase in T- and B-lymphocyte apoptosis in all animals, septic mice with cancer had decreased T- and B-lymphocyte apoptosis compared to previously healthy septic mice. Serum and pulmonary cytokines, lung histology, complete blood counts, and intestinal proliferation were similar between septic mice with cancer and previously healthy septic mice. When subjected to the same septic insult, mice with cancer have increased mortality compared to previously healthy animals. Decreased systemic bacterial clearance and alterations in intestinal epithelial and lymphocyte apoptosis may

  14. Microglia and their CX3CR1 signaling are involved in hippocampal- but not olfactory bulb-related memory and neurogenesis.

    Science.gov (United States)

    Reshef, Ronen; Kreisel, Tirzah; Beroukhim Kay, Dorsa; Yirmiya, Raz

    2014-10-01

    Recent studies demonstrate that microglia play an important role in cognitive and neuroplasticity processes, at least partly via microglial CX3C receptor 1 (CX3CR1) signaling. Furthermore, microglia are responsive to environmental enrichment (EE), which modulates learning, memory and neurogenesis. In the present study we examined the role of microglial CX3CR1 signaling in hippocampal- and olfactory-bulb (OB)-related memory and neurogenesis in homozygous mice with microglia-specific transgenic expression of GFP under the CX3CR1 promoter (CX3CR1(-/-) mice), in which the CX3CR1 gene is functionally deleted, as well as heterozygous CX3CR1(+/-) and WT controls. We report that the CX3CR1-deficient mice displayed better hippocampal-dependent memory functioning and olfactory recognition, along with increased number and soma size of hippocampal microglia, suggestive of mild activation status, but no changes in OB microglia. A similar increase in hippocampal-dependent memory functioning and microglia number was also induced by pharmacological inhibition of CX3CR1 signaling, using chronic (2weeks) i.c.v. administration of CX3CR1 blocking antibody. In control mice, EE improved hippocampal-dependent memory and neurogenesis, and increased hippocampal microglia number and soma size, whereas odor enrichment (OE) improved olfactory recognition and OB neurogenesis without changing OB microglia status. In CX3CR1-deficient mice, EE and OE did not produce any further improvement in memory functioning or neurogenesis and had no effect on microglial status. These results support the notion that in the hippocampus microglia and their interactions with neurons via the CX3CR1 play an important role in memory functioning and neurogenesis, whereas in the OB microglia do not seem to be involved in these processes. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention.

    Science.gov (United States)

    Kim, Ah Hyun; Chun, Hye Jeong; Lee, Seulah; Kim, Hyung Sik; Lee, Jaewon

    2017-08-01

    Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is commonly used in commercial and household products, such as, computers, televisions, mobile phones, and electronic boards. TBBPA can accumulate in human body fluids, and it has been reported that TBBPA possesses endocrine disruptive activity. However, the neurotoxic effect of TBBPA on hippocampal neurogenesis has not yet been investigated. Accordingly, the present study was undertaken to evaluate the effect of TBBPA on adult hippocampal neurogenesis and cognitive function. Male C57BL/6 mice were orally administrated vehicle or TBBPA (20 mg/kg, 100 mg/kg, or 500 mg/kg daily) for two weeks. TBBPA was observed to significantly and dose-dependently reduce the survival of newly generated cells in the hippocampus but not to affect the proliferation of newly generated cells. Numbers of hippocampal BrdU and NeuN positive cells were dose-dependently reduced by TBBPA, indicating impaired neurogenesis in the hippocampus. Interestingly, glial activation without neuronal death was observed in hippocampi exposed to TBBPA. Furthermore, memory retention was found to be adversely affected by TBBPA exposure by a mechanism involving suppression of the BDNF-CREB signaling pathway. The study suggests high dose TBBPA disrupts hippocampal neurogenesis and induces associated memory deficits. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Does developmental hypothyroidism produce lasting effects on adult neurogenesis?

    Science.gov (United States)

    The subgranular zone of the dentate gyrus (DO) of the adult hippocampus generates new neurons throughout life. Thyroid hormones (TH) are essential for brain development, but impaired neurogenesis with adult hypothyroidism has also been reported. We investigated the role of milder...

  17. Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function

    Directory of Open Access Journals (Sweden)

    Myung-Hoon Han

    2016-12-01

    Full Text Available Neurological diseases such as Alzheimer, Parkinson, and ischemic stroke have increased in occurrence and become important health issues throughout the world. There is currently no effective therapeutic strategy for addressing neurological deficits after the development of these major neurological disorders. In recent years, it has become accepted that adult neural stem cells located in the subventricular and subgranular zones have the ability to proliferate and differentiate in order to replace lost or damaged neural cells. There have been many limitations in the clinical application of both endogenous and exogenous neurogenesis for neurological disorders. However, many studies have investigated novel mechanisms in neurogenesis and have shown that these limitations can potentially be overcome with appropriate stimulation and various approaches. We will review concepts related to possible therapeutic strategies focused on the perspective of neurogenesis for the treatment of patients diagnosed with Alzheimer disease, Parkinson disease, and ischemic stroke based on current reports.

  18. Carotenoid crystal formation in Arabidopsis and carrot roots caused by increased phytoene synthase protein levels.

    Directory of Open Access Journals (Sweden)

    Dirk Maass

    Full Text Available BACKGROUND: As the first pathway-specific enzyme in carotenoid biosynthesis, phytoene synthase (PSY is a prime regulatory target. This includes a number of biotechnological approaches that have successfully increased the carotenoid content in agronomically relevant non-green plant tissues through tissue-specific PSY overexpression. We investigated the differential effects of constitutive AtPSY overexpression in green and non-green cells of transgenic Arabidopsis lines. This revealed striking similarities to the situation found in orange carrot roots with respect to carotenoid amounts and sequestration mechanism. METHODOLOGY/PRINCIPAL FINDINGS: In Arabidopsis seedlings, carotenoid content remained unaffected by increased AtPSY levels although the protein was almost quantitatively imported into plastids, as shown by western blot analyses. In contrast, non-photosynthetic calli and roots overexpressing AtPSY accumulated carotenoids 10 and 100-fold above the corresponding wild-type tissues and contained 1800 and 500 microg carotenoids per g dry weight, respectively. This increase coincided with a change of the pattern of accumulated carotenoids, as xanthophylls decreased relative to beta-carotene and carotene intermediates accumulated. As shown by polarization microscopy, carotenoids were found deposited in crystals, similar to crystalline-type chromoplasts of non-green tissues present in several other taxa. In fact, orange-colored carrots showed a similar situation with increased PSY protein as well as carotenoid levels and accumulation patterns whereas wild white-rooted carrots were similar to Arabidopsis wild type roots in this respect. Initiation of carotenoid crystal formation by increased PSY protein amounts was further confirmed by overexpressing crtB, a bacterial PSY gene, in white carrots, resulting in increased carotenoid amounts deposited in crystals. CONCLUSIONS: The sequestration of carotenoids into crystals can be driven by the

  19. Ocean Acidification Causes Increased Calcium Carbonate Turnover during Larval Shell Formation

    Science.gov (United States)

    Frieder, C.; Pan, F.; Applebaum, S.; Manahan, D. T.

    2016-02-01

    Mollusca is a major taxon for studies of the evolution and mechanisms of calcification. Under current and future ocean change scenarios, decreases in shell size have been observed in many molluscan species during early development. The mechanistic basis for these decreases are of significant interest. In this study, Pacific oyster larvae (Crassostrea gigas) reared at aragonite undersaturation (Ω > 1). Coupling radioisotope tracer assays with mineral mass measurements allowed calculation of calcification budgets for first shell formation in veliger stage larvae. Three primary mechanisms (in order of increasing effect) contributed to the change in shell mass at undersaturation: delayed onset of calcification, increased dissolution rates, and decreased net calcification rates. The observation of dissolution indicates turnover of the newly formed shell, and physicochemical constraints of undersaturation provide a mechanistic basis for decreased calcification.

  20. [Light pollution increases morbidity and mortality rate from different causes in male rats].

    Science.gov (United States)

    Bukalev, A V; Vinogradova, I A; Zabezhinskiĭ, M A; Semenchenko, A V; Anisimov, V N

    2012-01-01

    The influence of different light regimes (constant light--LL; constant darkness--DD; standard light regime--LD, 12 hours light 12 hours darkness; natural lightening of the North-West of Russia--NL) on the dynamics of life's morbidity rate, spontaneous tumorigenesis and frequency of some kinds of non-tumor pathology revealed at the post-mortem examination of male rats was studied. It was found out that the maintenance of animals at LL and NL conditions led to the increase of the number of infectious diseases, substantially faster development of spontaneous tumors and the increase of non-tumor diseases in comparison with the animals kept at LD (standard light) regime. Light deprivation (DD) led to substantial reduction of development of new growth, of non-tumor and infectious diseases in comparison with the similar parameters in standard light regime.

  1. Collapse of a historic oyster fishery: diagnosing causes and identifying paths toward increased resilience

    Directory of Open Access Journals (Sweden)

    Edward V. Camp

    2015-09-01

    Full Text Available Diagnosing causal factors of change at the ecosystem level is challenging because multiple drivers often interact at various spatial and temporal scales. We employ an integrated natural and social science approach to assess potential mechanisms leading to the collapse of an estuarine social-ecological system, and recommend future paths to increased system resilience. Our case study is the collapse of the eastern oyster (Crassostrea virginica fishery in Apalachicola Bay, Florida, USA, and the associated impacts on local resource dependent communities. The oyster fishery collapse is the most recent in a series of environmental stressors to this region, which have included hurricanes and tropical storms, drought, and the Deepwater Horizon oil spill. We found it likely that the oyster collapse was not related to contamination from the recent oil spill, but rather to factors affecting oyster recruitment and survival, which may have been mediated by both human, e.g., fishing-related habitat alteration, and environmental, e.g., increased natural mortality from predators and disease, factors. The relative impact of each of these factors is likely to increase in the future because of changing climate and increased demand for fishery, water, and petroleum resources. Successful restoration and persistence of a viable oyster fishery will depend on: (1 implementation of some minimal best management practices, e.g., extensive habitat restoration via shell addition, and some spatial closures to harvest, (2 improving environmental knowledge and promoting episodic learning through enhanced monitoring and experimental management, and (3 continued community engagement necessary to produce adaptable governance suitable to responding to future unexpected challenges.

  2. Working the night shift causes increased vascular stress and delayed recovery in young women.

    Science.gov (United States)

    Lo, Shih-Hsiang; Lin, Lian-Yu; Hwang, Jing-Shiang; Chang, Yu-Yin; Liau, Chiau-Suong; Wang, Jung-Der

    2010-08-01

    Shiftwork has been associated with elevated blood pressure (BP) and decreased heart-rate variability (HRV), factors that may increase the long-term risk of cardiovascular-related mortality and morbidity. This study explored the effect of shiftwork on dynamic changes in autonomic control of HRV (cardiac stress), systolic BP and diastolic BP, i.e., SBP and DBP (vascular stress), and recovery in the same subjects working different shifts. By studying the same subjects, the authors could reduce the effect of possible contribution of between-subject variation from genetic predisposition and environmental factors. The authors recruited 16 young female nurses working rotating shifts--day (08:00-16:00 h), evening (16:00-00:00 h), and night (00:00-08:00 h)--and 6 others working the regular day shift. Each nurse received simultaneous and repeated 48-h ambulatory electrocardiography and BP monitoring during their work day and the following off-duty day. Using a linear mixed-effect model to adjust for day shift, the results of the repeated-measurements and self-comparisons found significant shift differences in vascular stress. While working the night shift, the nurses showed significant increases in vascular stress, with increased SBP of 9.7 mm Hg. The changes of SBP and DBP seemed to peak during waking time at the same time on the day off as they did on the working day. Whereas HRV profiles usually returned to baseline level after each shift, the SBP and DBP of night-shift workers did not completely return to baseline levels the following off-duty day (p night shift, they do not completely recover from increases in vascular stress on that day.

  3. Increase of Carrier-to-Noise Ratio in GPS Receivers Caused by Continuous-Wave Interference

    Directory of Open Access Journals (Sweden)

    J. Li

    2016-09-01

    Full Text Available The increased use of personal private devices (PPDs is drawing greater attention to the effects of continuous-wave interference (CWI on the performance of global positioning system (GPS receivers. The effective carrier-to-noise density ratio (C/N0, an essential index of GNSS receiver performance, is studied in this paper. Receiver tracking performance deteriorates in the presence of interference. Hence, the effective C/N0, which measures tracking performance, decreases. However, simulations and bench tests have shown that the effective C/N0 may increase in the presence of CWI. The reason is that a sinusoidal signal is induced by the CWI in the correlator and may be tracked by the carrier tracking loop. Thus, the effective carrier power depends on the power of the signal induced by the CWI, and the effective C/N0 increases with the power of the CWI. The filtering of the CWI in the carrier tracking loop correlator and its effect on the phase locked loop (PLL tracking performance are analyzed. A mathematical model of the effect of the CWI on the effective C/N0 is derived. Simulation results show that the proposed model is more accurate than existing models, especially when the jam-to-signal ratio (JSR is greater than 30 dBc.

  4. S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms

    Directory of Open Access Journals (Sweden)

    Indira Mendez-David

    2017-07-01

    Full Text Available Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor’s (AMPAR activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM possessing procognitive, neurotrophic properties and enhancing synaptic plasticity. Here, we investigated the antidepressant/anxiolytic-like effects of S 47445 in a mouse model of anxiety/depression based on chronic corticosterone administration (CORT and in the Chronic Mild Stress (CMS model in rats. Four doses of S 47445 (0.3 to 10 mg/kg, oral route, 4 and 5 weeks, respectively were assessed in both models. In mouse, behavioral effects were tested in various anxiety-and depression-related behaviors : the elevated plus maze (EPM, open field (OF, splash test (ST, forced swim test (FST, tail suspension test (TST, fur coat state and novelty suppressed feeding (NSF as well as on hippocampal neurogenesis and dendritic arborization in comparison to chronic fluoxetine treatment (18 mg/kg, p.o.. In rats, behavioral effects of S 47445 were monitored using sucrose consumption and compared to those of imipramine or venlafaxine (10 mg/kg, i.p. during the whole treatment period and after withdrawal of treatments. In a mouse model of genetic ablation of hippocampal neurogenesis (GFAP-Tk model, neurogenesis dependent/independent effects of chronic S 47445 treatment were tested, as well as BDNF hippocampal expression. S 47445 reversed CORT-induced depressive-like state by increasing grooming duration and reversing coat state’s deterioration. S 47445 also decreased the immobility duration in TST and FST. The highest doses (3 and 10 mg/kg seem the most effective for antidepressant-like activity in CORT mice. Furthermore, S 47445 significantly reversed the anxiety phenotype observed in OF (at 1 mg/kg and EPM (from 1 mg/kg. In the CMS

  5. Effects of Maternal Behavior Induction and Pup Exposure on Neurogenesis in Adult, Virgin Female Rats

    Science.gov (United States)

    Furuta, Miyako; Bridges, Robert S.

    2009-01-01

    The states of pregnancy and lactation bring about a range of physiological and behavioral changes in the adult mammal that prepare the mother to care for her young. Cell proliferation increases in the subventricular zone (SVZ) of the female rodent brain during both pregnancy and lactation when compared to that in cycling, diestrous females. In the present study, the effects of maternal behavior induction and pup exposure on neurogenesis in nulliparous rats were examined in order to determine whether maternal behavior itself, independent of pregnancy and lactation, might affect neurogenesis. Adult, nulliparous, Sprague-Dawley, female rats were exposed daily to foster young in order to induce maternal behavior. Following the induction of maternal behavior each maternal subject plus females that were exposed to pups for a comparable number of test days, but did not display maternal behavior, and subjects that had received no pup exposure were injected with bromodeoxyuridine (BrdU, 90 mg/kg, i.v.). Brain sections were double-labeled for BrdU and the neural marker, NeuN, to examine the proliferating cell population. Increases in the number of double-labeled cells were found in the maternal virgin brain when compared with the number of double-labeled cells present in non-maternal, pup-exposed nulliparous rats and in females not exposed to young. No changes were evident in the dentate gyrus of the hippocampus as a function of maternal behavior. These data indicate that in nulliparous female rats maternal behavior itself is associated with the stimulation of neurogenesis in the SVZ. PMID:19712726

  6. Sources of Increased Spring and Streamflow Caused by the 2014 South Napa Earthquake

    Science.gov (United States)

    Rytuba, J. J.; Holzer, T. L.

    2014-12-01

    Seasonally dry springs and creeks began flowing over a broad region in the hills around Napa following the M6.0 South Napa earthquake on August 24, 2014. Flows in hillside creek beds, which were dry before the earthquake, were reported from 19 km west, to 6 km east, and 18 km north of Napa and the epicenter, an area that shook at MMI≥VI. The exact timing of the increased flow is unknown because the earthquake occurred at 3:20 AM PDT. A gaging station on the Napa River, which is downstream from several tributaries that began flowing after the earthquake, showed a sudden increase of flow rate within 45 minutes following the earthquake. The sudden increase at the gaging station suggests flows initiated either contemporaneously with or very soon after the strong shaking. This timing is consistent with eyewitness accounts of other streams and springs at daylight, a few hours after the earthquake. One of the largest increases of streamflow was in Green Valley, where a streamflow rate of about 100 cubic hectometers per day was measured in Wild Horse Creek. Two types of waters are being discharged in the Wild Horse Creek drainage: 1) water with low iron concentration that has exchanged with rhyolitic flows and tuffs in the upper part of the drainage; and 2) high iron concentration water that has exchanged with basaltic andesite in the middle part of drainage (vertical interval of about 75 meters). The high iron waters are depositing FeOOH other iron phases. Mixing of the two water types results in water with pH 6.9 and conductivity of 0.197 mS. This water is used by the Vallejo Water District for domestic purposes after it is mixed with recent surface water runoff stored in Lake Frey reservoir in order to improve its quality. Other drainages that have increased flow since the earthquake have water chemistry consistent with exchange with rhyolitic flows and tuffs that are the dominant rock type in these drainages.

  7. Hyperthyroidism causes mechanical insufficiency of myocardium with possibly increased SR Ca2+-ATPase activity.

    Science.gov (United States)

    Takeuchi, Koh; Minakawa, M; Otaki, M; Odagiri, S; Itoh, K; Murakami, A; Yaku, H; Kitamura, N

    2003-12-01

    Hyperthyroidism is known to affect multiple organ functions, and thyroid hormone has been known to improve myocardial function in a failing heart. The purpose of this study is to elucidate the functional and metabolic effects of thyroid hormone on myocardium in a rat model exposed to long-term excess thyroid hormone, particularly focusing on the SR Ca(2+)-ATPase (SERCA2) function. 3,5,3'-Triiodo-L-thyronine (T3), or the vehicle, was subcutaneously given for 4 weeks (T3 and control [C] group). Bolus I.V. Thapsigargin (TG) was used to test the SERCA2 function (C-TG and T3-TG) in Langendorff perfused heart. Myocardial functions such as LV-developed pressure (LVDP; mmHg), +/- dP/dt (mmHg/s), tau (ms), and oxygen consumption (MVO(2); ml/min/g wt) were measured. SERCA2 and GLUT4 protein level were also evaluated by Western immunoblotting. Left ventricle to body weight (LV/BW) ratio was significantly higher in the T3 group. Both negative dP/dt and tau were significantly decreased by TG. It is interesting that the decrement of negative dP/dt and tau attained by TG was significantly larger in the hyperthyroid group (T3-TG) than in a normal heart (C-TG). SERCA2 and GLUT4 protein levels were not significantly different between control and the T3 group. We conclude that prolonged exposure to thyroid hormone causes hypertrophy of the myocardium and an augmentation of the SR Ca(2+) ATPase activity. Care must be taken in hyperthyroid heart during the ischemia-reperfusion process where the SRECA2 function is inhibited.

  8. Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine.

    Science.gov (United States)

    Cellini, Miriam; Santaguida, Maria Giulia; Gatto, Ilenia; Virili, Camilla; Del Duca, Susanna Carlotta; Brusca, Nunzia; Capriello, Silvia; Gargano, Lucilla; Centanni, Marco

    2014-08-01

    An increased need for T4 has been described in patients with different gastrointestinal disorders. However, there is a lack of systematic studies assessing the need for T4 in hypothyroid patients with lactose intolerance, a widespread and often occult disorder. The objective of the study was to assess the replacement T4 dose required in hypothyroid patients with lactose intolerance. This was a cohort study. The study was conducted at an outpatient endocrinology unit in a University Hospital. The replacement T4 dose has been analyzed, from 2009 to 2012, in 34 hypothyroid patients due to Hashimoto's thyroiditis and lactose intolerance and being noncompliant with a lactose-free diet. An individually tailored T4 dose was measured. In all patients with isolated Hashimoto's thyroiditis, target TSH (median TSH 1.02 mU/L) was obtained at a median T4 dose of 1.31 μg/kg/d. In patients with lactose intolerance, only five of 34 patients reached the desired TSH (median TSH 0.83 mU/L) with a similar T4 dose (1.29 μg/kg/d). In the remaining 29 patients, the T4 dose was progressively increased and the target TSH (median TSH 1.21 mU/L) was attained at a median T4 dose of 1.81 μg/kg/d (+38%, P lactose intolerance, a median T4 dose of 1.72 μg/kg/d (+31% P lactose intolerance significantly increased the need for oral T4 in hypothyroid patients.

  9. Hepatic radiofrequency ablation causes an increase of circulating histones in patients with hepatocellular carcinoma.

    Science.gov (United States)

    Gu, Tao; Ge, Yang; Song, Yuezhang; Fu, Zhanzhao; Zhang, Yunjie; Wang, Guangxia; Shao, Shasha; Wen, Tao

    2015-11-01

    Radiofrequency ablation (RFA) has been increasingly accepted for the treatment of hepatocellular carcinoma (HCC). However, RFA has been associated with an obvious systemic inflammatory response, but little is known about the underlying mechanisms. Circulating histones are recently identified as pivotal inflammatory mediators. Hence, we investigated whether circulating histones are involved in RFA-related inflammation. Serial blood samples were collected from 42 HCC patients undergoing RFA at 3 time points: pre-RFA, post-RFA (within 24 h), and in 4-week follow up after RFA. Plasma histones, myeloperoxidase (MPO), inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α), liver damage parameters (ALT, AST), and creatinine were measured. Compared to pre-RFA (0.837 μg/ml), there was a significant increase in the levels of circulating histones within 24 h post-RFA (4.576 μg/ml, p histones decreased to pre-RFA levels in 4-week follow up after RFA. Meanwhile, MPO, IL-6, and IL-10 were elevated remarkably within 24 h post-RFA, indicative of an occurrence of the inflammatory response. Notably, histone levels correlated well with MPO (r = 0.5678), IL-6 (r = 0.4851), and IL-10 (r = 0.3574), respectively. In addition, there was a significant damage of liver function in patients within 24 h post-RFA, evidenced by the increased levels of ALT and AST. No changes in creatinine levels were observed. These data demonstrate that circulating histones are excessively released in HCC patients treated with RFA, which may lead to systemic inflammation by stimulating neutrophil activation and promoting cytokine production. Circulating histones may act as a novel marker to indicate the extent of inflammation related to RFA.

  10. Steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics

    OpenAIRE

    Povlsen, Bo; Povlsen, Sebastian D

    2014-01-01

    Shoulder pain is very common in diabetic patients and often treated with steroid injections, with subsequent increases in blood glucose levels or the need for additional insulin being questioned. We report a case of significant and prolonged elevation of blood glucose levels and resultant insulin requirement in a type 1 diabetic man after a single 40 mg injection of triamcinolone for shoulder pain. Within 48 h, the shoulder pain as assessed by a visual analogue scale (0–10) was reduced to zer...

  11. Modern Electronic Devices: An Increasingly Common Cause of Skin Disorders in Consumers.

    Science.gov (United States)

    Corazza, Monica; Minghetti, Sara; Bertoldi, Alberto Maria; Martina, Emanuela; Virgili, Annarosa; Borghi, Alessandro

    2016-01-01

    : The modern conveniences and enjoyment brought about by electronic devices bring with them some health concerns. In particular, personal electronic devices are responsible for rising cases of several skin disorders, including pressure, friction, contact dermatitis, and other physical dermatitis. The universal use of such devices, either for work or recreational purposes, will probably increase the occurrence of polymorphous skin manifestations over time. It is important for clinicians to consider electronics as potential sources of dermatological ailments, for proper patient management. We performed a literature review on skin disorders associated with the personal use of modern technology, including personal computers and laptops, personal computer accessories, mobile phones, tablets, video games, and consoles.

  12. Saikosaponin D relieves unpredictable chronic mild stress induced depressive-like behavior in rats: involvement of HPA axis and hippocampal neurogenesis.

    Science.gov (United States)

    Li, Hong-Yan; Zhao, Ying-Hua; Zeng, Min-Jie; Fang, Fang; Li, Min; Qin, Ting-Ting; Ye, Lu-Yu; Li, Hong-Wei; Qu, Rong; Ma, Shi-Ping

    2017-11-01

    Saikosaponin D (SSD), a major bioactive component isolated from Radix Bupleuri, has been reported to exert neuroprotective properties. The present study was designed to investigate the anti-depressant-like effects and the potential mechanisms of SSD. Behavioural tests including sucrose preference test (SPT), open field test (OFT) and forced swim test (FST) were performed to study the antidepressant-like effects of SSD. In addition, we examined corticosterone and glucocorticoid receptor (GR) levels to evaluate hypothalamic-pituitary-adrenal (HPA) axis function. Furthermore, hippocampal neurogenesis was assessed by testing doublecortin (DCX) levels, and neurotrophic molecule levels were also investigated in the hippocampus of rats. We found that unpredictable chronic mild stress (UCMS) rats displayed lost body weight, decreased sucrose consumption in SPT, reduced locomotive activity in OFT, and increased immobility time in FST. Chronic treatment with SSD (0.75, 1.50 mg/kg) remarkably ameliorated the behavioral deficiency induced by UCMS procedure. SSD administration downregulated elevated serum corticosterone levels, as well as alleviated the suppression of GR expression and nuclear translocation caused by UCMS, suggesting that SSD is able to remit the dysfunction of HPA axis. In addition, Western blot and immunohistochemistry analysis showed that SSD treatment significantly increased the generation of neurons in the hippocampus of UCMS rats indicated by elevated DCX levels. Moreover, hippocampal neurotrophic molecule levels of UCMS rats such as phosphorylated cAMP response element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were raised after SSD treatment. Together, Our results suggest that SSD opposed UCMS-induced depressive behaviors in rats, which was mediated, partially, by the enhancement of HPA axis function and consolidation of hippocampal neurogenesis.

  13. RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders.

    Directory of Open Access Journals (Sweden)

    Mingyan Lin

    Full Text Available Genome-wide expression analysis using next generation sequencing (RNA-Seq provides an opportunity for in-depth molecular profiling of fundamental biological processes, such as cellular differentiation and malignant transformation. Differentiating human neurons derived from induced pluripotent stem cells (iPSCs provide an ideal system for RNA-Seq since defective neurogenesis caused by abnormalities in transcription factors, DNA methylation, and chromatin modifiers lie at the heart of some neuropsychiatric disorders. As a preliminary step towards applying next generation sequencing using neurons derived from patient-specific iPSCs, we have carried out an RNA-Seq analysis on control human neurons. Dramatic changes in the expression of coding genes, long non-coding RNAs (lncRNAs, pseudogenes, and splice isoforms were seen during the transition from pluripotent stem cells to early differentiating neurons. A number of genes that undergo radical changes in expression during this transition include candidates for schizophrenia (SZ, bipolar disorder (BD and autism spectrum disorders (ASD that function as transcription factors and chromatin modifiers, such as POU3F2 and ZNF804A, and genes coding for cell adhesion proteins implicated in these conditions including NRXN1 and NLGN1. In addition, a number of novel lncRNAs were found to undergo dramatic changes in expression, one of which is HOTAIRM1, a regulator of several HOXA genes during myelopoiesis. The increase we observed in differentiating neurons suggests a role in neurogenesis as well. Finally, several lncRNAs that map near SNPs associated with SZ in genome wide association studies also increase during neuronal differentiation, suggesting that these novel transcripts may be abnormally regulated in a subgroup of patients.

  14. The Internet and Video Games: Causes of Increased Aggressiveness Among Young People

    Directory of Open Access Journals (Sweden)

    Nataša Ružić

    2011-12-01

    Full Text Available The increase in youth violence is among the most serious problems facing modern society. Many experts adhere to the opinion that responsibility for this phenomenon is borne by families, schools, and the media. The so-called digital generation spends much of its free time on the Internet and accepts the values imposed by the media. The modern criterion of success is to reach glory by any means necessary. As such, it is understandable that young people, eager for publicity, look for creative ways to attract attention. One of the most expedient ways to achieve fame and prove their ‘originality’ is by posting videos of violent behavior on websites like YouTube. The Internet has brought limitless freedom in the exposure of inappropriate content and has thus contributed to an increase in violence among the young, primarily through the video games industry. Based on all the above, we argue that the Internet has spurred and intensified the development of cyberbullying.

  15. Increased norepinephrine release from dog pulmonary artery caused by nitrous oxide

    International Nuclear Information System (INIS)

    Rorie, D.K.; Tyce, G.M.; Sill, J.C.

    1986-01-01

    The effects of nitrous oxide on the release and metabolism of norepinephrine (NE) at neuroeffector junctions in dog pulmonary artery were examined. Helical strips of artery were incubated in Krebs-Ringer solution containing L-( 3 H)NE and mounted for superfusion. The arterial strips were studied in the presence of 95% oxygen-5% carbon dioxide, 70% nitrogen-30% oxygen, or 70% nitrous oxide-30% oxygen. During the 60 min of each experiment, five samples of superfusion fluid were collected for analysis and the effluxes of ( 3 H)NE and its radiolabeled metabolites were measured before and during electrical stimulation and during recovery from stimulation. ( 3 H)Norepinephrine was separated from its metabolites in the superfusate and in extracts of artery by column chromatography and quantitated by liquid scintillation spectrometry. Nitrous oxide significantly increased the fractional loss of total radioactivity and the amount of NE in the superfusate both during resting conditions and during stimulation. Nitrous oxide had no effect on the proportions of radioactivity among metabolites of NE in the superfusate or on the profile of NE metabolites remaining in the tissue after experimentation. These findings are consistent with increased NE release as a direct effect of nitrous oxide on nerve endings

  16. Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

    International Nuclear Information System (INIS)

    Eberhart, Charles G; Chaudhry, Aneeka; Daniel, Richard W; Khaki, Leila; Shah, Keerti V; Gravitt, Patti E

    2005-01-01

    p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT), and 8 supratentorial primitive neuroectodermal tumors (sPNET) using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3) was readily detected. Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein

  17. Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

    Directory of Open Access Journals (Sweden)

    Shah Keerti V

    2005-02-01

    Full Text Available Abstract Background p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. Methods p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT, and 8 supratentorial primitive neuroectodermal tumors (sPNET using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. Results p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3 was readily detected. Conclusion Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein.

  18. Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

    Science.gov (United States)

    Eberhart, Charles G; Chaudhry, Aneeka; Daniel, Richard W; Khaki, Leila; Shah, Keerti V; Gravitt, Patti E

    2005-01-01

    Background p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. Methods p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT), and 8 supratentorial primitive neuroectodermal tumors (sPNET) using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. Results p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3) was readily detected. Conclusion Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein. PMID:15717928

  19. Increasing temperature causes flowering onset time changes of alpine ginger Roscoea in the Central Himalayas

    Directory of Open Access Journals (Sweden)

    Dharmalingam Mohandass

    2015-09-01

    Full Text Available Recent herbarium-based phenology assessments of many plant species have found significant responses to global climate change over the previous century. In this study, we investigate how the flowering phenology of three alpine ginger Roscoea species responses to climate change over the century from 1913 to 2011, by comparing between herbarium-based phenology records and direct flowering observations. According to the observations, flowering onset of the three alpine ginger species occurred either 22 days earlier or was delayed by 8–30 days when comparing the mean peak flowering date between herbarium-based phenology records and direct flowering observations. It is likely that this significant change in flowering onset is due to increased annual minimum and maximum temperatures and mean annual temperature by about 0.053°C per year. Our results also show that flowering time changes occurred due to an increasing winter–spring minimum temperature and monsoon minimum temperature, suggesting that these Roscoea species respond greatly to climate warming resulting in changes on flowering times.

  20. Steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics.

    Science.gov (United States)

    Povlsen, Bo; Povlsen, Sebastian D

    2014-09-08

    Shoulder pain is very common in diabetic patients and often treated with steroid injections, with subsequent increases in blood glucose levels or the need for additional insulin being questioned. We report a case of significant and prolonged elevation of blood glucose levels and resultant insulin requirement in a type 1 diabetic man after a single 40 mg injection of triamcinolone for shoulder pain. Within 48 h, the shoulder pain as assessed by a visual analogue scale (0-10) was reduced to zero, but the elevated insulin requirements continued for 4 weeks after the injection. This finding suggests that steroid injections for shoulder pain in diabetics may not always be as safe as previously thought. We propose that medical practitioners advise their patients to monitor their glucose levels more carefully after such injections and that caution is exercised when considering administrating these injections to those who have poorly controlled blood glucose levels preinjection to avoid ketoacidosis. 2014 BMJ Publishing Group Ltd.

  1. Increased alcohol consumption as a cause of alcoholism, without similar evidence for depression

    DEFF Research Database (Denmark)

    Wium-Andersen, Marie Kim; Orsted, David Dynnes; Tolstrup, Janne Schurmann

    2015-01-01

    BACKGROUND: Increased alcohol consumption has been associated with depression and alcoholism, but whether these associations are causal remains unclear. We tested whether alcohol consumption is causally associated with depression and alcoholism. METHODS: We included 78 154 men and women aged 20...... randomization design with antidepressant medication use and hospitalization/death, with depression and alcoholism as outcomes. RESULTS: In prospective analyses, the multifactorially adjusted hazard ratio for participants reporting >6 drinks/day vs participants reporting 0.1-1 drinks/day was 1.28 (95% confidence...... interval, 1.00-1.65) for prescription antidepressant use, with a corresponding hazard ratio of 0.80 (0.45-1.45) for hospitalization/death with depression and of 11.7 (8.77-15.6) for hospitalization/death with alcoholism. For hospitalization/death with alcoholism, instrumental variable analysis yielded...

  2. Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility

    DEFF Research Database (Denmark)

    Fedulov, Alexey V; Leme, Adriana; Yang, Zhiping

    2008-01-01

    Maternal immune responses can promote allergy development in offspring, as shown in a model of increased susceptibility to asthma in babies of ovalbumin (OVA)-sensitized and -challenged mother mice. We investigated whether inflammatory responses to air pollution particles (diesel exhaust particles...... inflammatory responses were evaluated 48 hours after exposure. Offspring of particle- or buffer-treated mothers were sensitized and aerosolized with OVA, followed by assays of airway hyperresponsiveness (AHR) and allergic inflammation (AI). Nonpregnant females had the expected minimal response to "inert" TiO(2......). In contrast, pregnant mice showed robust and persistent acute inflammation after both TiO(2) and DEP. Genomic profiling identified genes differentially expressed in pregnant lungs exposed to TiO(2). Neonates of mothers exposed to TiO(2) (and DEP, but not PBS) developed AHR and AI, indicating that pregnancy...

  3. Macrosegregation and Grain Formation Caused by Convection Associated with Directional Solidification Through Cross-Section Increase

    Science.gov (United States)

    Ghods, Masoud; Lauer, Mark; Tewari, Surendra; Poirier, David; Grugel, Richard

    2016-01-01

    Cylindrical Al-7 wt% Silicon, Al-19 wt% Copper and Lead-6 wt% Antimony alloy samples were directionally solidified (DS) with liquid above, solid below, and gravity pointing down, in graphite crucibles having an abrupt cross-sectional increase. These alloys have similar solidification shrinkage but are expected to have different degrees of thermosolutal convection during solidification. Microstructures in the DS samples in the vicinity of the section change have been studied in order to examine the effect of convection associated with the combined influence of thermosolutal effects and solidification shrinkage. Extensive radial and axial macrosegregation associated with cross-section change is observed. It also appears that steepling and local primary alpha-phase remelting resulting from convection are responsible for stray grain formation at the reentrant corners. Preliminary results from a numerical model, which includes solidification shrinkage and thermosolutal convection in the mushy zone, indicate that these regions are prone to solutal remelting of dendrites.

  4. Pd-nanoparticles cause increased toxicity to kiwifruit pollen compared to soluble Pd(II)

    International Nuclear Information System (INIS)

    Speranza, Anna; Leopold, Kerstin; Maier, Marina; Taddei, Anna Rita; Scoccianti, Valeria

    2010-01-01

    In the present study, endpoints including in vitro pollen performance (i.e., germination and tube growth) and lethality were used as assessments of nanotoxicity. Pollen was treated with 5-10 nm-sized Pd particles, similar to those released into the environment by catalytic car exhaust converters. Results showed Pd-nanoparticles altered kiwifruit pollen morphology and entered the grains more rapidly and to a greater extent than soluble Pd(II). At particulate Pd concentrations well below those of soluble Pd(II), pollen grains experienced rapid losses in endogenous calcium and pollen plasma membrane damage was induced. This resulted in severe inhibition and subsequent cessation of pollen tube emergence and elongation at particulate Pd concentrations as low as 0.4 mg L -1 . Particulate Pd emissions related to automobile traffic have been increasing and are accumulating in the environment. This could seriously jeopardize in vivo pollen function, with impacts at an ecosystem level. - Nanoparticulate Pd - which resembles emissions from automobile catalysts - affects pollen to a higher extent than soluble Pd.

  5. Pd-nanoparticles cause increased toxicity to kiwifruit pollen compared to soluble Pd(II)

    Energy Technology Data Exchange (ETDEWEB)

    Speranza, Anna, E-mail: anna.speranza@unibo.i [Dipartimento di Biologia, Universita di Bologna, via Irnerio 42, 40126 Bologna (Italy); Leopold, Kerstin, E-mail: kerstin.leopold@lrz.tu-muenchen.d [Arbeitsgruppe fuer Analytische Chemie, Technische Universitaet Muenchen, Garching (Germany); Maier, Marina, E-mail: marina.maier@ch.tum.d [Arbeitsgruppe fuer Analytische Chemie, Technische Universitaet Muenchen, Garching (Germany); Taddei, Anna Rita, E-mail: artaddei@unitus.i [CIME, Universita della Tuscia, Viterbo (Italy); Scoccianti, Valeria, E-mail: valeria.scoccianti@uniurb.i [Dipartimento di Scienze dell' Uomo, dell' Ambiente e della Natura, Universita di Urbino ' Carlo Bo' , Urbino (Italy)

    2010-03-15

    In the present study, endpoints including in vitro pollen performance (i.e., germination and tube growth) and lethality were used as assessments of nanotoxicity. Pollen was treated with 5-10 nm-sized Pd particles, similar to those released into the environment by catalytic car exhaust converters. Results showed Pd-nanoparticles altered kiwifruit pollen morphology and entered the grains more rapidly and to a greater extent than soluble Pd(II). At particulate Pd concentrations well below those of soluble Pd(II), pollen grains experienced rapid losses in endogenous calcium and pollen plasma membrane damage was induced. This resulted in severe inhibition and subsequent cessation of pollen tube emergence and elongation at particulate Pd concentrations as low as 0.4 mg L{sup -1}. Particulate Pd emissions related to automobile traffic have been increasing and are accumulating in the environment. This could seriously jeopardize in vivo pollen function, with impacts at an ecosystem level. - Nanoparticulate Pd - which resembles emissions from automobile catalysts - affects pollen to a higher extent than soluble Pd.

  6. Oxidized fish oil in rat pregnancy causes high newborn mortality and increases maternal insulin resistance.

    Science.gov (United States)

    Albert, Benjamin B; Vickers, Mark H; Gray, Clint; Reynolds, Clare M; Segovia, Stephanie A; Derraik, José G B; Lewandowski, Paul A; Garg, Manohar L; Cameron-Smith, David; Hofman, Paul L; Cutfield, Wayne S

    2016-09-01

    Fish oil is commonly taken by pregnant women, and supplements sold at retail are often oxidized. Using a rat model, we aimed to assess the effects of supplementation with oxidized fish oil during pregnancy in mothers and offspring, focusing on newborn viability and maternal insulin sensitivity. Female rats were allocated to a control or high-fat diet and then mated. These rats were subsequently randomized to receive a daily gavage treatment of 1 ml of unoxidized fish oil, a highly oxidized fish oil, or control (water) throughout pregnancy. At birth, the gavage treatment was stopped, but the same maternal diets were fed ad libitum throughout lactation. Supplementation with oxidized fish oil during pregnancy had a marked adverse effect on newborn survival at day 2, leading to much greater odds of mortality than in the control (odds ratio 8.26) and unoxidized fish oil (odds ratio 13.70) groups. In addition, maternal intake of oxidized fish oil during pregnancy led to increased insulin resistance at the time of weaning (3 wks after exposure) compared with control dams (HOMA-IR 2.64 vs. 1.42; P = 0.044). These data show that the consumption of oxidized fish oil is harmful in rat pregnancy, with deleterious effects in both mothers and offspring. Copyright © 2016 the American Physiological Society.

  7. Mutations at Several Loci Cause Increased Expression of Ribonucleotide Reductase in Escherichia coli

    Science.gov (United States)

    Feeney, Morgan Anne; Ke, Na

    2012-01-01

    Production of deoxyribonucleotides for DNA synthesis is an essential and tightly regulated process. The class Ia ribonucleotide reductase (RNR), the product of the nrdAB genes, is required for aerobic growth of Escherichia coli. In catalyzing the reduction of ribonucleotides, two of the cysteines of RNR become oxidized, forming a disulfide bond. To regenerate active RNR, the cell uses thioredoxins and glutaredoxins to reduce the disulfide bond. Strains that lack thioredoxins 1 and 2 and glutaredoxin 1 do not grow because RNR remains in its oxidized, inactive form. However, suppressor mutations that lead to RNR overproduction allow glutaredoxin 3 to reduce sufficient RNR for growth of these mutant strains. We previously described suppressor mutations in the dnaA and dnaN genes that had such effects. Here we report the isolation of new mutations that lead to increased levels of RNR. These include mutations that were not known to influence production of RNR previously, such as a mutation in the hda gene and insertions in the nrdAB promoter region of insertion elements IS1 and IS5. Bioinformatic analysis raises the possibility that IS element insertion in this region represents an adaptive mechanism in nrdAB regulation in E. coli and closely related species. We also characterize mutations altering different amino acids in DnaA and DnaN from those isolated before. PMID:22247510

  8. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

    Science.gov (United States)

    Klomp, Anne; Václavů, Lena; Meerhoff, Gideon F; Reneman, Liesbeth; Lucassen, Paul J

    2014-01-01

    The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

  9. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

    Directory of Open Access Journals (Sweden)

    Anne Klomp

    Full Text Available The antidepressant drug fluoxetine (Prozac has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b effects on tryptophan hydroxylase (TPH expression, a measure of serotonin synthesis; c whether treatment effects during adolescence differed from treatment at an adult age, and d whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+ cells and of the number of young migratory neurons (doublecortin+, revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

  10. Effects of rapamycin treatment after controlled cortical impact injury on neurogenesis and synaptic reorganization in the mouse dentate gyrus

    Directory of Open Access Journals (Sweden)

    Corwin R Butler

    2015-11-01

    Full Text Available Post-traumatic epilepsy (PTE is one consequence of traumatic brain injury (TBI. A prominent cell signaling pathway activated in animal models of both TBI and epilepsy is the mammalian target of rapamycin (mTOR. Inhibition of mTOR with rapamycin has shown promise as a potential modulator of epileptogenesis in several animal models of epilepsy, but cellular mechanisms linking mTOR expression and epileptogenesis are unclear. In this study, the role of mTOR in modifying functional hippocampal circuit reorganization after focal TBI induced by controlled cortical impact was investigated. Rapamycin (3 or 10 mg/kg, an inhibitor of mTOR signaling, was administered by intraperitoneal injection beginning on the day of injury and continued daily until tissue collection. Relative to controls, rapamycin treatment reduced dentate granule cell area in the hemisphere ipsilateral to the injury two weeks post-injury. Brain injury resulted in a significant increase in doublecortin immunolabeling in the dentate gyrus ipsilateral to the injury, indicating increased neurogenesis shortly after TBI. Rapamycin treatment prevented the increase in doublecortin labeling, with no overall effect on Fluoro-Jade B staining in the ipsilateral hemisphere, suggesting that rapamycin treatment reduced posttraumatic neurogenesis but did not prevent cell loss after injury. At later times post-injury (8-13 weeks, evidence of mossy fiber sprouting and increased recurrent excitation of dentate granule cells was detected, which were attenuated by rapamycin treatment. Rapamycin treatment also diminished seizure prevalence relative to vehicle-treated controls after TBI. Collectively, these results support a role for adult neurogenesis in PTE development and suggest that suppression of epileptogenesis by mTOR inhibition includes effects on post-injury neurogenesis.

  11. Spaceflight Causes Increased Virulence of Serratia Marcescens on a Drosophila Melanogaster Host

    Science.gov (United States)

    Bhattacharya, Sharmila; Wade, William; Clemens-Grisham, Rachel; Hosamani, Ravikumar; Bhardwaj, Shilpa R.; Lera, Matthew P.; Gresser, Amy L.

    2015-01-01

    Drosophila melanogaster, or the fruit fly, has long been an important organism for Earth-based research, and is now increasingly utilized as a model system to understand the biological effects of spaceflight. Studies in Drosophila melanogaster have shown altered immune responses in 3rd instar larvae and adult males following spaceflight, changes similar to those observed in astronauts. In addition, spaceflight has also been shown to affect bacterial physiology, as evidenced by studies describing altered virulence of Salmonella typhimurium following spaceflight and variation in biofilm growth patterns for the opportunistic pathogen Pseudomonas aeruginosa during flight. We recently sent Serratia marcescens Db11, a Drosophila pathogen and an opportunistic human pathogen, to the ISS on SpaceX-5 (Fruit Fly Lab-01). S. marcescens samples were stored at 4degC for 24 days on-orbit and then allowed to grow for 120 hours at ambient station temperature before being returned to Earth. Upon return, bacteria were isolated and preserved in 50% glycerol or RNAlater. Storage, growth, and isolation for ground control samples were performed using the same procedures. Spaceflight and ground samples stored in 50% glycerol were diluted and injected into 5-7-day-old ground-born adult D. melanogaster. Lethality was significantly greater in flies injected with the spaceflight samples compared to those injected with ground bacterial samples. These results indicate a shift in the virulence profile of the spaceflight S. marcescens Db11 and will be further assessed with molecular biological analyses. Our findings strengthen the conclusion that spaceflight impacts the virulence of bacterial pathogens on model host organisms such as the fruit fly. This research was supported by NASA's ISS Program Office (ISSPO) and Space Life and Physical Sciences Research and Applications (SLPSRA).

  12. Splenectomy Causes 10-Fold Increased Risk of Portal Venous System Thrombosis in Liver Cirrhosis Patients.

    Science.gov (United States)

    Qi, Xingshun; Han, Guohong; Ye, Chun; Zhang, Yongguo; Dai, Junna; Peng, Ying; Deng, Han; Li, Jing; Hou, Feifei; Ning, Zheng; Zhao, Jiancheng; Zhang, Xintong; Wang, Ran; Guo, Xiaozhong

    2016-07-19

    BACKGROUND Portal venous system thrombosis (PVST) is a life-threatening complication of liver cirrhosis. We conducted a retrospective study to comprehensively analyze the prevalence and risk factors of PVST in liver cirrhosis. MATERIAL AND METHODS All cirrhotic patients without malignancy admitted between June 2012 and December 2013 were eligible if they underwent contrast-enhanced CT or MRI scans. Independent predictors of PVST in liver cirrhosis were calculated in multivariate analyses. Subgroup analyses were performed according to the severity of PVST (any PVST, main portal vein [MPV] thrombosis >50%, and clinically significant PVST) and splenectomy. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. RESULTS Overall, 113 cirrhotic patients were enrolled. The prevalence of PVST was 16.8% (19/113). Splenectomy (any PVST: OR=11.494, 95%CI=2.152-61.395; MPV thrombosis >50%: OR=29.987, 95%CI=3.247-276.949; clinically significant PVST: OR=40.415, 95%CI=3.895-419.295) and higher hemoglobin (any PVST: OR=0.974, 95%CI=0.953-0.996; MPV thrombosis >50%: OR=0.936, 95%CI=0.895-0.980; clinically significant PVST: OR=0.935, 95%CI=0.891-0.982) were the independent predictors of PVST. The prevalence of PVST was 13.3% (14/105) after excluding splenectomy. Higher hemoglobin was the only independent predictor of MPV thrombosis >50% (OR=0.952, 95%CI=0.909-0.997). No independent predictors of any PVST or clinically significant PVST were identified in multivariate analyses. Additionally, PVST patients who underwent splenectomy had a significantly higher proportion of clinically significant PVST but lower MELD score than those who did not undergo splenectomy. In all analyses, the in-hospital mortality was not significantly different between cirrhotic patient with and without PVST. CONCLUSIONS Splenectomy may increase by at least 10-fold the risk of PVST in liver cirrhosis independent of severity of liver dysfunction.

  13. Evaluation of a C57BL/6J × 129S1/SvImJ Hybrid Nestin-Thymidine Kinase Transgenic Mouse Model for Studying the Functional Significance of Exercise-Induced Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Hamilton, G F; Majdak, P; Miller, D S; Bucko, P J; Merritt, J R; Krebs, C P; Rhodes, J S

    2015-01-01

    New neurons are continuously generated in the adult hippocampus but their function remains a mystery. The nestin thymidine kinase (nestin-TK) transgenic method has been used for selective and conditional reduction of neurogenesis for the purpose of testing the functional significance of new neurons in learning, memory and motor performance. Here we explored the nestin-TK model on a hybrid genetic background (to increase heterozygosity, and "hybrid vigor"). Transgenic C57BL/6J (B6) were crossed with 129S1/SvImJ (129) producing hybrid offspring (F1) with the B6 half of the genome carrying a herpes simplex virus thymidine kinase (TK) transgene regulated by a modified nestin promoter. In the presence of exogenously administered valganciclovir, new neurons expressing TK undergo apoptosis. Female B6 nestin-TK mice ( n = 80) were evaluated for neurogenesis reduction as a positive control. Male and female F1 nestin-TK mice ( n = 223) were used to determine the impact of neurogenesis reduction on the Morris water maze (MWM) and rotarod. All mice received BrdU injections to label dividing cells and either valganciclovir or control chow, with or without a running wheel for 30 days. Both the F1 and B6 background displayed approximately 50% reduction in neurogenesis, a difference that did not impair learning and memory on the MWM or rotarod performance. Running enhanced neurogenesis and performance on the rotarod but not MWM suggesting the F1 background may not be suitable for studying pro-cognitive effects of exercise on MWM. Greater reduction of neurogenesis may be required to observe behavioral impacts. Alternatively, new neurons may not play a critical role in learning, or compensatory mechanisms in pre-existing neurons could have masked the deficits. Further work using these and other models for selectively reducing neurogenesis are needed to establish the functional significance of adult hippocampal neurogenesis in behavior.

  14. SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory.

    Science.gov (United States)

    Chen, Qian; Kogan, Jeffrey H; Gross, Adam K; Zhou, Yuan; Walton, Noah M; Shin, Rick; Heusner, Carrie L; Miyake, Shinichi; Tajinda, Katsunori; Tamura, Kouichi; Matsumoto, Mitsuyuki

    2012-09-01

    SREB2/GPR85, a member of the super-conserved receptor expressed in brain (SREB) family, is the most conserved G-protein-coupled receptor in vertebrate evolution. Previous human and mouse genetic studies have indicated a possible link between SREB2 and schizophrenia. SREB2 is robustly expressed in the hippocampal formation, especially in the dentate gyrus, a structure with an established involvement in psychiatric disorders and cognition. However, the function of SREB2 in the hippocampus remains elusive. Here we show that SREB2 regulates hippocampal adult neurogenesis, which impacts on cognitive function. Bromodeoxyuridine incorporation and immunohistochemistry were conducted in SREB2 transgenic (Tg, over-expression) and knockout (KO, null-mutant) mice to quantitatively assay adult neurogenesis and newborn neuron dendritic morphology. Cognitive responses associated with adult neurogenesis alteration were evaluated in SREB2 mutant mice. In SREB2 Tg mice, both new cell proliferation and new neuron survival were decreased in the dentate gyrus, whereas an enhancement of new neuron survival occurred in SREB2 KO mouse dentate gyrus. Doublecortin staining revealed dendritic morphology deficits of newly generated neurons in SREB2 Tg mice. In a spatial pattern separation task, SREB2 Tg mice displayed a decreased ability to discriminate spatial relationships, whereas SREB2 KO mice had enhanced abilities in this task. Additionally, SREB2 Tg and KO mice had reciprocal phenotypes in a Y-maze working memory task. Our results indicate that SREB2 is a negative regulator of adult neurogenesis and consequential cognitive functions. Inhibition of SREB2 function may be a novel approach to enhance hippocampal adult neurogenesis and cognitive abilities to ameliorate core symptoms of psychiatric patients. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  15. Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress.

    Science.gov (United States)

    Bonilha, Vera L; Bell, Brent A; Rayborn, Mary E; Samuels, Ivy S; King, Anna; Hollyfield, Joe G; Xie, Chengsong; Cai, Huaibin

    2017-03-01

    Oxidative stress alters physiological function in most biological tissues and can lead to cell death. In the retina, oxidative stress initiates a cascade of events leading to focal loss of RPE and photoreceptors, which is thought to be a major contributing factor to geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative stress under normal and pathological conditions remains largely unknown. A better understanding of the mechanisms involved in regulating RPE and photoreceptors oxidative stress response is greatly needed. To this end we evaluated photoreceptor and RPE changes in mice deficient in DJ-1, a protein that is thought to be important in protecting cells from oxidative stress. Young (3 months) and aged (18 months) DJ-1 knockout (DJ-1 KO) and age-matched wild-type mice were examined. In both group of aged mice, scanning laser ophthalmoscopy (SLO) showed the presence of a few autofluorescent foci. The 18 month-old DJ-1 KO retinas were also characterized by a noticeable increase in RPE fluorescence to wild-type. Optical coherence tomography (OCT) imaging demonstrated that all retinal layers were present in the eyes of both DJ-1 KO groups. ERG comparisons showed that older DJ-1 KO mice had reduced sensitivity under dark- and light-adapted conditions compared to age-matched control. Histologically, the RPE contained prominent vacuoles in young DJ-1 KO group with the appearance of enlarged irregularly shaped RPE cells in the older group. These were also evident in OCT and in whole mount RPE/choroid preparations labeled with phalloidin. Photoreceptors in the older DJ-1 KO mice displayed decreased immunoreactivity to rhodopsin and localized reduction in cone markers compared to the wild-type control group. Lower levels of activated Nrf2 were evident in retina/RPE lysates in both young and old DJ-1 KO mouse groups compared to wild-type control levels. Conversely, higher levels of protein carbonyl derivatives and i

  16. Hypertension impairs hippocampus-related adult neurogenesis, CA1 neuron dendritic arborization and long-term memory.

    Science.gov (United States)

    Shih, Y-H; Tsai, S-F; Huang, S-H; Chiang, Y-T; Hughes, M W; Wu, S-Y; Lee, C-W; Yang, T-T; Kuo, Y-M

    2016-05-13

    Hypertension is associated with neurodegenerative diseases and cognitive impairment. Several studies using spontaneous hypertensive rats to study the effect of hypertension on memory performance and adult hippocampal neurogenesis have reached inconsistent conclusions. The contradictory findings may be related to the genetic variability of spontaneous hypertensive rats due to the conventional breeding practices. The objective of this study is to examine the effect of hypertension on hippocampal structure and function in isogenic mice. Hypertension was induced by the '2 kidneys, 1 clip' method (2K1C) which constricted one of the two renal arteries. The blood pressures of 2K1C mice were higher than the sham group on post-operation day 7 and remained high up to day 28. Mice with 2K1C-induced hypertension had impaired long-term, but not short-term, memory. Dendritic complexity of CA1 neurons and hippocampal neurogenesis were reduced by 2K1C-induced hypertension on post-operation day 28. Furthermore, 2K1C decreased the levels of hippocampal brain-derived neurotrophic factor, while blood vessel density and activation status of astrocytes and microglia were not affected. In conclusion, hypertension impairs hippocampus-associated long-term memory, dendritic arborization and neurogenesis, which may be caused by down-regulation of brain-derived neurotrophic factor signaling pathways. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis.

    Directory of Open Access Journals (Sweden)

    Stephen N Sansom

    2009-06-01

    Full Text Available Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells

  18. Oligodendrogenesis and neurogenesis in remyelination in the cuprizone model of multiple sclerosis: correlation with the degree of lesion

    Science.gov (United States)

    Pishchelko, A.; Khodanovich, M.; Pan, E.; Glazacheva, V.; Akulov, A.; Yarnykh, V.

    2017-08-01

    In this research, a cuprizone model of multiple sclerosis (MS) was used to study oligodendrogenesis and neurogenesis in remyelination. It has been shown that, with the administration of cuprizone, the amount of myelin in a number of structures of white and gray matter and the level of neurogenesis decrease, while the level of oligodendrogenesis increases. The withdrawal of cuprizone leads to the restoration of myelin content, the reduction of the excessive production of oligodendrocytes and to the restoration of the number of neurons to control values. The negative correlation between the number of oligodendrocyte precursors (OPCs) and the degree of demyelination of the corpus callosum indicates migration of OLG precursors from the subventricular zone (SVZ) to the structure during demyelination.

  19. Amitriptyline-mediated cognitive enhancement in aged 3×Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity.

    Directory of Open Access Journals (Sweden)

    Wayne Chadwick

    Full Text Available Approximately 35 million people worldwide suffer from Alzheimer's disease (AD. Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD. After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB. These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.

  20. Social isolation disrupts hippocampal neurogenesis in young non-human primates

    Directory of Open Access Journals (Sweden)

    Simone M Cinini

    2014-03-01

    Full Text Available Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for one or three weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming - an indicative of attenuation of tension - was reduced among isolated marmosets. These results were consistent with increased cortisol levels after one and three weeks of isolation. After social isolation (one or three weeks, reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling. Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions.

  1. The role of genes involved in neuroplasticity and neurogenesis in the observation of a gene-environment interaction (GxE) in schizophrenia.

    Science.gov (United States)

    Le Strat, Yann; Ramoz, Nicolas; Gorwood, Philip

    2009-05-01

    Schizophrenia is a multifactorial disease characterized by a high heritability. Several candidate genes have been suggested, with the strongest evidences for genes encoding dystrobrevin binding protein 1 (DTNBP1), neuregulin 1 (NRG1), neuregulin 1 receptor (ERBB4) and disrupted in schizophrenia 1 (DISC1), as well as several neurotrophic factors. These genes are involved in neuronal plasticity and play also a role in adult neurogenesis. Therefore, the genetic basis of schizophrenia could involve different factors more or less specifically required for neuroplasticity, including the synapse maturation, potentiation and plasticity as well as neurogenesis. Following the model of Knudson in tumors, we propose a two-hit hypothesis of schizophrenia. In this model of gene-environment interaction, a variant in a gene related to neurogenesis is transmitted to the descent (first hit), and, secondarily, an environmental factor occurs during the development of the central nervous system (second hit). Both of these vulnerability and trigger factors are probably necessary to generate a deficit in neurogenesis and therefore to cause schizophrenia. The literature supporting this gene x environment hypothesis is reviewed, with emphasis on some molecular pathways, raising the possibility to propose more specific molecular medicine.

  2. Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate

    Directory of Open Access Journals (Sweden)

    Timothy J. Petros

    2015-11-01

    Full Text Available Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination.

  3. NMDA and kainate receptor expression, long-term potentiation, and neurogenesis in the hippocampus of long-lived Ames dwarf mice.

    Science.gov (United States)

    Sharma, Sunita; Darland, Diane; Lei, Saobo; Rakoczy, Sharlene; Brown-Borg, Holly M

    2012-06-01

    In the current study, we investigated changes in N-methyl D-aspartate (NMDA) and kainate receptor expression, long-term potentiation (LTP), and neurogenesis in response to neurotoxic stress in long-living Ames dwarf mice. We hypothesized that Ames dwarf mice have enhanced neurogenesis that enables retention of spatial learning and memory with age and promotes neurogenesis in response to injury. Levels of the NMDA receptors (NR)1, NR2A, NR2B, and the kainate receptor (KAR)2 were increased in Ames dwarf mice, relative to wild-type littermates. Quantitative assessment of the excitatory postsynaptic potential in Schaffer collaterals in hippocampal slices from Ames dwarf mice showed an increased response in high-frequency induced LTP over time compared with wild type. Kainic acid (KA) injection was used to promote neurotoxic stress-induced neurogenesis. KA mildly increased the number of doublecortin-positive neurons in wild-type mice, but the response was significantly enhanced in the Ames dwarf mice. Collectively, these data support our hypothesis that the enhanced learning and memory associated with the Ames dwarf mouse may be due to elevated levels of NMDA and KA receptors in hippocampus and their ability to continue producing new neurons in response to neuronal damage.

  4. Erythrocyte membrane-encapsulated celecoxib improves the cognitive decline of Alzheimer's disease by concurrently inducing neurogenesis and reducing apoptosis in APP/PS1 transgenic mice.

    Science.gov (United States)

    Guo, Jing-Wen; Guan, Pei-Pei; Ding, Wei-Yan; Wang, Si-Ling; Huang, Xue-Shi; Wang, Zhan-You; Wang, Pu

    2017-11-01

    Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB-RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated β-amyloid proteins (Aβ) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE 2 ) and PGD 2 , PGE 2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-3ζ, and PGD 2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Food restriction reduces neurogenesis in the avian hippocampal formation.

    Directory of Open Access Journals (Sweden)

    Barbara-Anne Robertson

    Full Text Available The mammalian hippocampus is particularly vulnerable to chronic stress. Adult neurogenesis in the dentate gyrus is suppressed by chronic stress and by administration of glucocorticoid hormones. Post-natal and adult neurogenesis are present in the avian hippocampal formation as well, but much less is known about its sensitivity to chronic stressors. In this study, we investigate this question in a commercial bird model: the broiler breeder chicken. Commercial broiler breeders are food restricted during development to manipulate their growth curve and to avoid negative health outcomes, including obesity and poor reproductive performance. Beyond knowing that these chickens are healthier than fully-fed birds and that they have a high motivation to eat, little is known about how food restriction impacts the animals' physiology. Chickens were kept on a commercial food-restricted diet during the first 12 weeks of life, or released from this restriction by feeding them ad libitum from weeks 7-12 of life. To test the hypothesis that chronic food restriction decreases the production of new neurons (neurogenesis in the hippocampal formation, the cell proliferation marker bromodeoxyuridine was injected one week prior to tissue collection. Corticosterone levels in blood plasma were elevated during food restriction, even though molecular markers of hypothalamic-pituitary-adrenal axis activation did not differ between the treatments. The density of new hippocampal neurons was significantly reduced in the food-restricted condition, as compared to chickens fed ad libitum, similar to findings in rats at a similar developmental stage. Food restriction did not affect hippocampal volume or the total number of neurons. These findings indicate that in birds, like in mammals, reduction in hippocampal neurogenesis is associated with chronically elevated corticosterone levels, and therefore potentially with chronic stress in general. This finding is consistent with the

  6. A weak magnetic field inhibits hippocampal neurogenesis in SD rats

    Science.gov (United States)

    Zhang, B.; Tian, L.; Cai, Y.; Pan, Y.

    2017-12-01

    Geomagnetic field is an important barrier that protects life forms on Earth from solar wind and radiation. Paleomagnetic data have well demonstrated that the strength of ancient geomagnetic field was dramatically weakened during a polarity transition. Accumulating evidence has shown that weak magnetic field exposures has serious adverse effects on the metabolism and behaviors in organisms. Hippocampal neurogenesis occurs throughout life in mammals' brains which plays a key role in brain function, and can be influenced by animals' age as well as environmental factors, but few studies have examined the response of hippocampal neurogenesis to it. In the present study, we have investigated the weak magnetic field effects on hippocampal neurogenesis of adult Sprague Dawley (SD) rats. Two types of magnetic fields were used, a weak magnetic field (≤1.3 μT) and the geomagnetic fields (51 μT).The latter is treated as a control condition. SD rats were exposure to the weak magnetic field up to 6 weeks. We measured the changes of newborn nerve cells' proliferation and survival, immature neurons, neurons and apoptosis in the dentate gyrus (DG) of hippocampus in SD rats. Results showed that, the weak magnetic field (≤1.3 μT) inhibited their neural stem cells proliferation and significantly reduced the survival of newborn nerve cells, immature neurons and neurons after 2 or 4 weeks continuous treatment (i.e. exposure to weak magnetic field). Moreover, apoptosis tests indicated the weak magnetic field can promote apoptosis of nerve cells in the hippocampus after 4 weeks treatment. Together, our new data indicate that weak magnetic field decrease adult hippocampal neurogenesis through inhibiting neural stem cells proliferation and promoting apoptosis, which provides useful experimental constraints on better understanding the mechanism of linkage between life and geomagnetic field.

  7. Dynamic learning and memory, synaptic plasticity and neurogenesis: an update

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš

    2014-01-01

    Roč. 8, APR 1 (2014), s. 106 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GA14-03627S Grant - others:Rada Programu interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111204 Institutional support: RVO:67985823 Keywords : learning * memory * synaptic plasticity * neurogenesis Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

  8. Juvenile neurogenesis makes essential contributions to adult brain structure and plays a sex-dependent role in fear memories

    Directory of Open Access Journals (Sweden)

    Jesse Daniel Cushman

    2012-02-01

    Full Text Available Postnatal-neurogenesis (PNN contributes neurons to olfactory bulb (OB and dentate gyrus (DG throughout juvenile development, but the quantitative amount, temporal dynamics and functional roles of this contribution have not been defined. By using transgenic mouse models for cell lineage tracing and conditional cell ablation, we found that juvenile neurogenesis gradually increased the total number of granule neurons by approximately 40% in OB, and by 25% in DG, between two weeks and two months of age, and that total numbers remained stable thereafter. These findings indicate that the overwhelming majority of net postnatal neuronal addition in these regions occurs during the juvenile period and that adult neurogenesis contributes primarily to replacement of granule cells in both regions. Behavioral analysis in our conditional cell ablation mouse model showed that complete loss of PNN throughout both the juvenile and adult period produced a specific set of sex-dependent cognitive changes. We observed normal hippocampus-independent delay fear conditioning, but excessive generalization of fear to a novel auditory stimulus, which is consistent with a role for PNN in psychopathology. Standard contextual fear conditioning was intact, however, pre-exposure dependent contextual fear was impaired suggesting a specific role for PNN in incidental contextual learning. Contextual discrimination between two highly similar contexts was enhanced; suggesting either enhanced contextual pattern separation or impaired temporal integration. We also observed a reduced reliance on olfactory cues, consistent with a role for OB PNN in the efficient processing of olfactory information. Thus, juvenile neurogenesis adds substantively to the total numbers of granule neurons in OB and DG during periods of critical juvenile behavioral development, including weaning, early social interactions and sexual maturation, and plays a sex-dependent role in fear memories.

  9. The aPKC-CBP Pathway Regulates Adult Hippocampal Neurogenesis in an Age-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Ayden Gouveia

    2016-10-01

    Full Text Available While epigenetic modifications have emerged as attractive substrates to integrate environmental changes into the determination of cell identity and function, specific signals that directly activate these epigenetic modifications remain unknown. Here, we examine the role of atypical protein kinase C (aPKC-mediated Ser436 phosphorylation of CBP, a histone acetyltransferase, in adult hippocampal neurogenesis and memory. Using a knockin mouse strain (CbpS436A in which the aPKC-CBP pathway is deficient, we observe impaired hippocampal neuronal differentiation, maturation, and memory and diminished binding of CBP to CREB in 6-month-old CbpS436A mice, but not at 3 months of age. Importantly, elevation of CREB activity rescues these deficits, and CREB activity is reduced whereas aPKC activity is increased in the murine hippocampus as they age from 3 to 6 months regardless of genotype. Thus, the aPKC-CBP pathway is a homeostatic compensatory mechanism that modulates hippocampal neurogenesis and memory in an age-dependent manner in response to reduced CREB activity.

  10. UV irradiation to mouse skin decreases hippocampal neurogenesis and synaptic protein expression via HPA axis activation.

    Science.gov (United States)

    Han, Mira; Ban, Jae-Jun; Bae, Jung-Soo; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

    2017-11-14

    The skin senses external environment, including ultraviolet light (UV). Hippocampus is a brain region that is responsible for memory and emotion. However, changes in hippocampus by UV irradiation to the skin have not been studied. In this study, after 2 weeks of UV irradiation to the mouse skin, we examined molecular changes related to cognitive functions in the hippocampus and activation of the hypothalamic-pituitary-adrenal (HPA) axis. UV exposure to the skin decreased doublecortin-positive immature neurons and synaptic proteins, including N-methyl-D-aspartate receptor 2 A and postsynaptic density protein-95, in the hippocampus. Moreover, we observed that UV irradiation to the skin down-regulated brain-derived neurotrophic factor expression and ERK signaling in the hippocampus, which are known to modulate neurogenesis and synaptic plasticity. The cutaneous and central HPA axes were activated by UV, which resulted in significant increases in serum levels of corticosterone. Subsequently, UV irradiation to the skin activated the glucocorticoid-signaling pathway in the hippocampal dentate gyrus. Interestingly, after 6 weeks of UV irradiation, mice showed depression-like behavior in the tail suspension test. Taken together, our data suggest that repeated UV exposure through the skin may negatively affect hippocampal neurogenesis and synaptic plasticity along with HPA axis activation.

  11. Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis

    Directory of Open Access Journals (Sweden)

    Alexandre A.S.F. Raposo

    2015-03-01

    Full Text Available The proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program.

  12. Impaired Sleep, Circadian Rhythms and Neurogenesis in Diet-Induced Premature Aging

    Directory of Open Access Journals (Sweden)

    Alexander J. Stankiewicz

    2017-10-01

    Full Text Available Chronic high caloric intake (HCI is a risk factor for multiple major human disorders, from diabetes to neurodegeneration. Mounting evidence suggests a significant contribution of circadian misalignment and sleep alterations to this phenomenon. An inverse temporal relationship between sleep, activity, food intake, and clock mechanisms in nocturnal and diurnal animals suggests that a search for effective therapeutic approaches can benefit from the use of diurnal animal models. Here, we show that, similar to normal aging, HCI leads to the reduction in daily amplitude of expression for core clock genes, a decline in sleep duration, an increase in scoliosis, and anxiety-like behavior. A remarkable decline in adult neurogenesis in 1-year old HCI animals, amounting to only 21% of that in age-matched Control, exceeds age-dependent decline observed in normal 3-year old zebrafish. This is associated with misalignment or reduced amplitude of daily patterns for principal cell cycle regulators, cyclins A and B, and p20, in brain tissue. Together, these data establish HCI in zebrafish as a model for metabolically induced premature aging of sleep, circadian functions, and adult neurogenesis, allowing for a high throughput approach to mechanistic studies and drug trials in a diurnal vertebrate.

  13. Paracrine control of vascularization and neurogenesis by neurotrophins.

    Science.gov (United States)

    Emanueli, Costanza; Schratzberger, Peter; Kirchmair, Rudolf; Madeddu, Paolo

    2003-10-01

    The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies.

  14. Is improved lane keeping during cognitive load caused by increased physical arousal or gaze concentration toward the road center?

    Science.gov (United States)

    Li, Penghui; Markkula, Gustav; Li, Yibing; Merat, Natasha

    2018-08-01

    Driver distraction is one of the main causes of motor-vehicle accidents. However, the impact on traffic safety of tasks that impose cognitive (non-visual) distraction remains debated. One particularly intriguing finding is that cognitive load seems to improve lane keeping performance, most often quantified as reduced standard deviation of lateral position (SDLP). The main competing hypotheses, supported by current empirical evidence, suggest that cognitive load improves lane keeping via either increased physical arousal, or higher gaze concentration toward the road center, but views are mixed regarding if, and how, these possible mediators influence lane keeping performance. Hence, a simulator study was conducted, with participants driving on a straight city road section whilst completing a cognitive task at different levels of difficulty. In line with previous studies, cognitive load led to increased physical arousal, higher gaze concentration toward the road center, and higher levels of micro-steering activity, accompanied by improved lane keeping performance. More importantly, during the high cognitive task, both physical arousal and gaze concentration changed earlier in time than micro-steering activity, which in turn changed earlier than lane keeping performance. In addition, our results did not show a significant correlation between gaze concentration and physical arousal on the level of individual task recordings. Based on these findings, various multilevel models for micro-steering activity and lane keeping performance were conducted and compared, and the results suggest that all of the mechanisms proposed by existing hypotheses could be simultaneously involved. In other words, it is suggested that cognitive load leads to: (i) an increase in arousal, causing increased micro-steering activity, which in turn improves lane keeping performance, and (ii) an increase in gaze concentration, causing lane keeping improvement through both (a) further increased micro

  15. Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair.

    Science.gov (United States)

    Li, Xing; Zhao, Yannan; Cheng, Shixiang; Han, Sufang; Shu, Muya; Chen, Bing; Chen, Xuyi; Tang, Fengwu; Wang, Nuo; Tu, Yue; Wang, Bin; Xiao, Zhifeng; Zhang, Sai; Dai, Jianwu

    2017-08-01

    Studies have shown that endogenous neural stem cells (NSCs) activated by spinal cord injury (SCI) primarily generate astrocytes to form glial scar. The NSCs do not differentiate into neurons because of the adverse microenvironment. In this study, we defined the activation timeline of endogenous NSCs in rats with severe SCI. These injury-activated NSCs then migrated into the lesion site. Cetuximab, an EGFR signaling antagonist, significantly increased neurogenesis in the lesion site. Meanwhile, implanting cetuximab modified linear ordered collagen scaffolds (LOCS) into SCI lesion sites in dogs resulted in neuronal regeneration, including neuronal differentiation, maturation, myelination, and synapse formation. The neuronal regeneration eventually led to a significant locomotion recovery. Furthermore, LOCS implantation could also greatly decrease chondroitin sulfate proteoglycan (CSPG) deposition at the lesion site. These findings suggest that endogenous neurogenesis following acute complete SCI is achievable in species ranging from rodents to large animals via functional scaffold implantation. LOCS-based Cetuximab delivery system has a promising therapeutic effect on activating endogenous neurogenesis, reducing CSPGs deposition and improving motor function recovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Photoperiod mediated changes in olfactory bulb neurogenesis and olfactory behavior in male white-footed mice (Peromyscus leucopus.

    Directory of Open Access Journals (Sweden)

    James C Walton

    Full Text Available Brain plasticity, in relation to new adult mammalian neurons generated in the subgranular zone of the hippocampus, has been well described. However, the functional outcome of new adult olfactory neurons born in the subventricular zone of the lateral ventricles is not clearly defined, as manipulating neurogenesis through various methods has given inconsistent and conflicting results in lab mice. Several small rodent species, including Peromyscus leucopus, display seasonal (photoperiodic brain plasticity in brain volume, hippocampal function, and hippocampus-dependent behaviors; plasticity in the olfactory system of photoperiodic rodents remains largely uninvestigated. We exposed adult male P. leucopus to long day lengths (LD and short day lengths (SD for 10 to 15 weeks and then examined olfactory bulb cell proliferation and survival using the thymidine analog BrdU, olfactory bulb granule cell morphology using Golgi-Cox staining, and behavioral investigation of same-sex conspecific urine. SD mice did not differ from LD counterparts in granular cell morphology of the dendrites or in dendritic spine density. Although there were no differences due to photoperiod in habituation to water odor, SD mice rapidly habituated to male urine, whereas LD mice did not. In addition, short day induced changes in olfactory behavior were associated with increased neurogenesis in the caudal plexiform and granule cell layers of the olfactory bulb, an area known to preferentially respond to water-soluble odorants. Taken together, these data demonstrate that photoperiod, without altering olfactory bulb neuronal morphology, alters olfactory bulb neurogenesis and olfactory behavior in Peromyscus leucopus.

  17. Exposure to Music and Noise During Pregnancy Influences Neurogenesis and Thickness in Motor and Somatosensory Cortex of Rat Pups

    Directory of Open Access Journals (Sweden)

    Chang-Hee Kim

    2013-09-01

    Full Text Available Purpose Prenatal environmental conditions affect the development of the fetus. In the present study, we investigated the effects of exposure to music and noise during pregnancy on neurogenesis and thickness in the motor and somatosensory cortex of rat pups. Methods The pregnant rats in the music-applied group were exposed to 65 dB of comfortable music for 1 hour, once per day, from the 15th day of pregnancy until delivery. The pregnant rats in the noise-applied group were exposed to 95 dB of sound from a supersonic sound machine for 1 hour, once per day, from the 15th day of pregnancy until delivery. After birth, the offspring were left undisturbed together with their mother. The rat pups were sacrificed at 21 days after birth. Results Exposure to music during pregnancy increased neurogenesis in the motor and somatosensory cortex of rat pups. In contrast, rat pups exposed to noise during pregnancy showed decreased neurogenesis and thickness in the motor and somatosensory cortex. Conclusions Our study suggests that music and noise during the developmental period are important factors influencing brain development and urogenital disorders.

  18. Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer's disease.

    Science.gov (United States)

    Biscaro, Barbara; Lindvall, Olle; Tesco, Giuseppina; Ekdahl, Christine T; Nitsch, Roger M

    2012-01-01

    Activated microglia with macrophage-like functions invade and surround β-amyloid (Aβ) plaques in Alzheimer's disease (AD), possibly contributing to the turnover of Aβ, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis. To determine the role of microglia on neurogenesis in brains with Aβ pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1). Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of Aβ and Aβ-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice. These results suggest a role for microglia in Aβ-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of Aβ pathology. Copyright © 2012 S. Karger AG, Basel.

  19. Physical exercise improves functional recovery through mitigation of autophagy, attenuation of apoptosis and enhancement of neurogenesis after MCAO in rats.

    Science.gov (United States)

    Zhang, Liying; Hu, Xiquan; Luo, Jing; Li, Lili; Chen, Xingyong; Huang, Ruxun; Pei, Zhong

    2013-04-08

    Physical exercise improves functional recovery after stroke through a complex mechanism that is not fully understood. Transient focal cerebral ischemia induces autophagy, apoptosis and neurogenesis in the peri-infarct region. This study is aimed to examine the effects of physical exercise on autophagy, apoptosis and neurogenesis in the peri-infarct region in a rat model of transient middle cerebral artery occlusion (MCAO). We found that autophagosomes, as labeled by microtubule-associated protein 1A light chain 3-II (LC3-II), were evident in the peri-infarct region at 3 days after 90-minute MCAO. Moreover, 44.6% of LC3-positive cells were also stained with TUNEL. The number of LC3 positive cells was significantly lower in physical exercise group than in control group at 14 and 21 days after MCAO. Suppression of autophagosomes by physical exercise was positively associated with improvement of neurological function. In addition, physical exercise significantly decreased the number of TUNEL-positive cells and increased the numbers of Ki67-positive, a proliferative marker, and insulin-like growth factor-1 (IGF-1) positive cells at 7, 14, and 21 days after MCAO. The present results demonstrate that physical exercise enhances neurological function possibly by reduction of autophagosome accumulation, attenuation of apoptosis and enhancement of neurogenesis in the peri-infarct region after transient MCAO in rats.

  20. Botulinum toxin injection causes hyper-reflexia and increased muscle stiffness of the triceps surae muscle in the rat.

    Science.gov (United States)

    Pingel, Jessica; Wienecke, Jacob; Lorentzen, Jakob; Nielsen, Jens Bo

    2016-12-01

    Botulinum toxin is used with the intention of diminishing spasticity and reducing the risk of development of contractures. Here, we investigated changes in muscle stiffness caused by reflex activity or elastic muscle properties following botulinum toxin injection in the triceps surae muscle in rats. Forty-four rats received injection of botulinum toxin in the left triceps surae muscle. Control measurements were performed on the noninjected contralateral side in all rats. Acute experiments were performed, 1, 2, 4, and 8 wk following injection. The triceps surae muscle was dissected free, and the Achilles tendon was cut and attached to a muscle puller. The resistance of the muscle to stretches of different amplitudes and velocities was systematically investigated. Reflex-mediated torque was normalized to the maximal muscle force evoked by supramaximal stimulation of the tibial nerve. Botulinum toxin injection caused severe atrophy of the triceps surae muscle at all time points. The force generated by stretch reflex activity was also strongly diminished but not to the same extent as the maximal muscle force at 2 and 4 wk, signifying a relative reflex hyperexcitability. Passive muscle stiffness was unaltered at 1 wk but increased at 2, 4, and 8 wk (P botulinum toxin causes a relative increase in reflex stiffness, which is likely caused by compensatory neuroplastic changes. The stiffness of elastic elements in the muscles also increased. The data are not consistent with the ideas that botulinum toxin is an efficient antispastic medication or that it may prevent development of contractures. Copyright © 2016 the American Physiological Society.

  1. The mammalian adult neurogenesis gene ontology (MANGO provides a structural framework for published information on genes regulating adult hippocampal neurogenesis.

    Directory of Open Access Journals (Sweden)

    Rupert W Overall

    Full Text Available BACKGROUND: Adult hippocampal neurogenesis is not a single phenotype, but consists of a number of sub-processes, each of which is under complex genetic control. Interpretation of gene expression studies using existing resources often does not lead to results that address the interrelatedness of these processes. Formal structure, such as provided by ontologies, is essential in any field for comprehensive interpretation of existing knowledge but, until now, such a structure has been lacking for adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We have created a resource with three components 1. A structured ontology describing the key stages in the development of adult hippocampal neural stem cells into functional granule cell neurons. 2. A comprehensive survey of the literature to annotate the results of all published reports on gene function in adult hippocampal neurogenesis (257 manuscripts covering 228 genes to the appropriate terms in our ontology. 3. An easy-to-use searchable interface to the resulting database made freely available online. The manuscript presents an overview of the database highlighting global trends such as the current bias towards research on early proliferative stages, and an example gene set enrichment analysis. A limitation of the resource is the current scope of the literature which, however, is growing by around 100 publications per year. With the ontology and database in place, new findings can be rapidly annotated and regular updates of the database will be made publicly available. CONCLUSIONS/SIGNIFICANCE: The resource we present allows relevant interpretation of gene expression screens in terms of defined stages of postnatal neuronal development. Annotation of genes by hand from the adult neurogenesis literature ensures the data are directly applicable to the system under study. We believe this approach could also serve as an example to other fields in a 'bottom-up' community effort complementing the already

  2. Analysis of Potentials to Increase Iranian life Expectancy with Removing the Leading Causes of Mortality in 2010

    Directory of Open Access Journals (Sweden)

    Mohammad Sasanipour

    2016-08-01

    Full Text Available Introduction: Recent studies on Iranian mortality clearly underscore the role of cardiovascular diseases, unintentional injuries, and cancers as three leading causes of reduced life expectancy during the last three decades. The purpose of current study is to measure the effect of these causes on 2010 life table for Iran. Materials & Method:The number of registered death by age and sex and death distribution by cause for Iran in 2010 are obtained from death registration system operated by the Ministry of Health and to know more about the population at risk population forecast information of the Statistical Centre of Iran (SCI is used. The obtained data are analyzed using Multiple Decrement Life Table and Kitagava analysis method. Results: The results show that three leading causes of death are account for 13 years potential lost life of Iranian men and women. More detailed results indicate that cardiovascular diseases, cancers, and unintentional injuries play larger roles in this regard while men are more likely to die by unintentional injuries than women. Life expectancy of middle aged men are more affected by unintentional injuries while old aged women are more affected by cardiovascular diseases. Conclusion: Particular consideration of risk factors of cardiovascular diseases of both sexes and males death by unintentional injuries is of utmost importance in reducing mortality rate and increasing life expectancy as a result.

  3. Statin treatment prevents increased cardiovascular and all-cause mortality associated with clarithromycin in patients with stable coronary heart disease

    DEFF Research Database (Denmark)

    Jensen, Gorm B; Hilden, Jørgen; Als-Nielsen, Bodil

    2010-01-01

    In the CLARICOR trial, significantly increased cardiovascular (CV) and all-cause mortality in stable patients with coronary heart disease were observed after a short course of clarithromycin. We report on the impact of statin treatment at entry on the CV and all-cause mortality. The multicenter...... CLARICOR trial randomized patients to oral clarithromycin (500 mg daily; n = 2172) versus matching placebo (daily; n = 2201) for 2 weeks. Patients were followed through public databases. In the 41% patients on statin treatment at entry, no significant effect of clarithromycin was observed on CV (hazard...... ratio [HR], 0.68, 95% confidence interval [CI], 0.38-1.22; P = 0.20) or all-cause mortality (HR, 1.08; 95% CI, 0.71-1.65; P = 0.72) at 2.6-year follow up. In the patients not on statin treatment at entry, clarithromycin was associated with a significant increase in CV (HR, 1.90; 95% CI, 1.34-2.67; P = 0...

  4. Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.

    Science.gov (United States)

    Pihlstrøm, Hege; Dahle, Dag Olav; Mjøen, Geir; Pilz, Stefan; März, Winfried; Abedini, Sadollah; Holme, Ingar; Fellström, Bengt; Jardine, Alan G; Holdaas, Hallvard

    2015-02-01

    Hyperparathyroidism is reported in 10% to 66% of renal transplant recipients (RTR). The influence of persisting hyperparathyroidism on long-term clinical outcomes in RTR has not been examined in a large prospective study. We investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality by Cox Proportional Hazard survival analyses in 1840 stable RTR derived from the Assessment of LEscol in Renal Transplantation trial. Patients were recruited in a mean of 5.1 years after transplantation, and follow-up time was 6 to 7 years. Significant associations between PTH and all 3 outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 units; P=0.004), and with graft loss (6% increased risk per 10 units; PHyperparathyroidism is an independent, potentially remediable, risk factor for renal graft loss and all-cause mortality in RTR.

  5. Intranasal Delivery of Plasma and Platelet Growth Factors Using PRGF-Endoret System Enhances Neurogenesis in a Mouse Model of Alzheimer’s Disease

    Science.gov (United States)

    Anitua, Eduardo; Pascual, Consuelo; Pérez-Gonzalez, Rocio; Antequera, Desiree; Padilla, Sabino; Orive, Gorka; Carro, Eva

    2013-01-01

    Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer’s disease (AD) induced by a combination of toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret), an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1) mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU), doublecortin (DCX), and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD. PMID:24069173

  6. Intranasal delivery of plasma and platelet growth factors using PRGF-Endoret system enhances neurogenesis in a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Eduardo Anitua

    Full Text Available Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD induced by a combination of toxic amyloid-β peptide (Aβ and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret, an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1 mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU, doublecortin (DCX, and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD.

  7. Intranasal delivery of plasma and platelet growth factors using PRGF-Endoret system enhances neurogenesis in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Anitua, Eduardo; Pascual, Consuelo; Pérez-Gonzalez, Rocio; Antequera, Desiree; Padilla, Sabino; Orive, Gorka; Carro, Eva

    2013-01-01

    Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret), an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1) mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU), doublecortin (DCX), and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD.

  8. Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths.

    Science.gov (United States)

    Yende, Sachin; D'Angelo, Gina; Mayr, Florian; Kellum, John A; Weissfeld, Lisa; Kaynar, A Murat; Young, Tammy; Irani, Kaikobad; Angus, Derek C

    2011-01-01

    Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease.

  9. Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths.

    Directory of Open Access Journals (Sweden)

    Sachin Yende

    Full Text Available Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP, but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes.In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality.Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses.Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease.

  10. Combination of aging and dimethylhydrazine treatment causes an increase in cancer-stem cell population of rat colonic crypts.

    Science.gov (United States)

    Levi, Edi; Misra, Sandhya; Du, Jianhua; Patel, Bhaumik B; Majumdar, Adhip P N

    2009-07-31

    Aging is associated with increased incidence of colon cancers. It is also becoming evident that cancer stem cells (CSC) play a vital role in the pathogenesis and prognosis of colon cancer. Recently, we reported the presence of colon cancer stem-like cells in macroscopically normal mucosa in patients with adenomatous polyps and that they increase with aging, suggesting that aging may predispose the colon to carcinogenesis. In the current study we have examined the combined effects of aging and carcinogen exposure on the status of colon CSCs in an experimental model. We used young (4-6 months) and aged (22-24 months) rats and exposed them to the carcinogen, dimethylhydroxide (DMH). We investigated the expression of colon cancer stem cell markers, CD44, CD166, EpCam, and ALDH1 as well as EGFR expression in normal colonic crypt epithelium following carcinogen treatment. Our results demonstrate that aging per se or carcinogen treatment alone causes an increase in the number of colon cancer stems cells, as evidenced by increased immunoreactive-CSC-markers positive cells in the colonic mucosa. In aged rats, carcinogen exposure results in a more pronounced increase in colon cancer stem cells. Our study shows that in aging colon the effects of carcinogens are more pronounced, and an increase in colon CSCs is one of the earliest changes preceding tumor development. Moreover, the current investigation of the use of a panel of immunohistochemical markers of colon CSC can potentially serve as a prognostic marker during screening for colon cancer.

  11. All-cause mortality increased by environmental cadmium exposure in the Japanese general population in cadmium non-polluted areas.

    Science.gov (United States)

    Suwazono, Yasushi; Nogawa, Kazuhiro; Morikawa, Yuko; Nishijo, Muneko; Kobayashi, Etsuko; Kido, Teruhiko; Nakagawa, Hideaki; Nogawa, Koji

    2015-07-01

    The aim of the present study was to evaluate the effect of environmental cadmium (Cd) exposure indicated by urinary Cd on all-cause mortality in the Japanese general population. A 19-year cohort study was conducted in 1067 men and 1590 women aged 50 years or older who lived in three cadmium non-polluted areas in Japan. The subjects were divided into four quartiles based on creatinine adjusted U-Cd (µg g(-1) cre). The hazard ratio (HR) and 95% confidence interval (CI) for continuous U-Cd or the quartiles of U-Cd were estimated for all-cause mortality using a proportional hazards regression.The all-cause mortality rates per 1000 person years were 31.2 and 15.1 in men and women, respectively. Continuous U-Cd (+1 µg g(-1) cre) was significantly related to the all-cause mortality in men (HR 1.05, 95% CI: 1.02-1.09) and women (HR 1.04, 95% CI: 1.01-1.07). Furthermore in men, the third (1.96-3.22 µg g(-1) cre) and fourth quartile (≥3.23 µg g(-1) cre) of U-Cd showed a significant, positive HR (third: HR 1.35, 95% CI: 1.03-1.77, fourth: HR 1.64, 95% CI: 1.26-2.14) for all-cause mortality compared with the first quartile (women, the fourth quartile of U-Cd (≥4.66 µg g(-1) cre) also showed a significant HR (1.49, 95% CI 1.11-2.00) for all-cause mortality compared with the first quartile (<1.46 µg g(-1) cre).In the present study, U-Cd was significantly associated with increased mortality in the Japanese general population, indicating that environmental Cd exposure adversely affects the life prognosis in Cd non-polluted areas in Japan. Copyright © 2014 John Wiley & Sons, Ltd.

  12. A mutation in the centriole-associated protein centrin causes genomic instability via increased chromosome loss in Chlamydomonas reinhardtii

    Directory of Open Access Journals (Sweden)

    Marshall Wallace F

    2005-05-01

    Full Text Available Abstract Background The role of centrioles in mitotic spindle function remains unclear. One approach to investigate mitotic centriole function is to ask whether mutation of centriole-associated proteins can cause genomic instability. Results We addressed the role of the centriole-associated EF-hand protein centrin in genomic stability using a Chlamydomonas reinhardtii centrin mutant that forms acentriolar bipolar spindles and lacks the centrin-based rhizoplast structures that join centrioles to the nucleus. Using a genetic assay for loss of heterozygosity, we found that this centrin mutant showed increased genomic instability compared to wild-type cells, and we determined that the increase in genomic instability was due to a 100-fold increase in chromosome loss rates compared to wild type. Live cell imaging reveals an increased rate in cell death during G1 in haploid cells that is consistent with an elevated rate of chromosome loss, and analysis of cell death versus centriole copy number argues against a role for multipolar spindles in this process. Conclusion The increased chromosome loss rates observed in a centrin mutant that forms acentriolar spindles suggests a role for centrin protein, and possibly centrioles, in mitotic fidelity.

  13. Increased heart rate caused by atrial pacing with the closed-loop stimulation function prevented micturition syncope

    Directory of Open Access Journals (Sweden)

    Tatsuo Haraki, MD,PhD

    2013-10-01

    Full Text Available A 70-year-old man had been experiencing syncope several times a year. We implanted a DDD pacemaker with closed-loop stimulation (CLS function. When he urinated early in the morning, his increased atrial pacing rates elevated his heart rate (HR during and after micturition. After implantation of the DDD-CLS mode, he did not experience symptoms. In contrast, in the DDD-R mode, his intrinsic HR changed to atrial pacing after micturition but decreased to the basal rate within 2 min, and he experienced a sense of cold perspiration and presyncope. Increased HRs caused by atrial pacing with the CLS function were useful in the prevention of micturition syncope.

  14. Hybrid and electric low-noise cars cause an increase in traffic accidents involving vulnerable road users in urban areas.

    Science.gov (United States)

    Brand, Stephan; Petri, Maximilian; Haas, Philipp; Krettek, Christian; Haasper, Carl

    2013-01-01

    Due to resource scarcity, the number of low-noise and electric cars is expected to increase rapidly. The frequent use of these cars will lead to a significant reduction of traffic related noise and pollution. On the other hand, due to the adaption and conditioning of vulnerable road users the number of traffic accidents involving pedestrians and bicyclists is postulated to increase as well. Children, older people with reduced eyesight and the blind are especially reliant on a combination of acoustic and visual warning signals with approaching or accelerating vehicles. This is even more evident in urban areas where the engine sound is the dominating sound up to 30 kph (kilometres per hour). Above this, tyre-road interaction is the main cause of traffic noise. With the missing typical engine sound a new sound design is necessary to prevent traffic accidents in urban areas. Drivers should not be able to switch the sound generator off.

  15. Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain.

    Science.gov (United States)

    Tang, Jason J; Podratz, Jewel L; Lange, Miranda; Scrable, Heidi J; Jang, Mi-Hyeon; Windebank, Anthony J

    2017-07-07

    Mechano growth factor (MGF) is a splice variant of IGF-1 first described in skeletal muscle. MGF induces muscle cell proliferation in response to muscle stress and injury. In control mice we found endogenous expression of MGF in neurogenic areas of the brain and these levels declined with age. To better understand the role of MGF in the brain, we used transgenic mice that constitutively overexpressed MGF from birth. MGF overexpression significantly increased the number of BrdU+ proliferative cells in the dentate gyrus (DG) of the hippocampus and subventricular zone (SVG). Although MGF overexpression increased the overall rate of adult hippocampal neurogenesis at the proliferation stage it did not alter the distribution of neurons at post-mitotic maturation stages. We then used the lac-operon system to conditionally overexpress MGF in the mouse brain beginning at 1, 3 and 12 months with histological and behavioral observation at 24 months of age. With conditional overexpression there was an increase of BrdU+ proliferating cells and BrdU+ differentiated mature neurons in the olfactory bulbs at 24 months when overexpression was induced from 1 and 3 months of age but not when started at 12 months. This was associated with preserved olfactory function. In vitro, MGF increased the size and number of neurospheres harvested from SVZ-derived neural stem cells (NSCs). These findings indicate that MGF overexpression increases the number of neural progenitor cells and promotes neurogenesis but does not alter the distribution of adult newborn neurons at post-mitotic stages. Maintaining youthful levels of MGF may be important in reversing age-related neuronal loss and brain dysfunction.

  16. Traumatic brain injury causes long-term behavioral changes related to region-specific increases of cerebral blood flow.

    Science.gov (United States)

    Pöttker, Bruno; Stöber, Franziska; Hummel, Regina; Angenstein, Frank; Radyushkin, Konstantin; Goldschmidt, Jürgen; Schäfer, Michael K E

    2017-12-01

    Traumatic brain injury (TBI) is a leading cause of disability and death and survivors often suffer from long-lasting motor impairment, cognitive deficits, anxiety disorders and epilepsy. Few experimental studies have investigated long-term sequelae after TBI and relations between behavioral changes and neural activity patterns remain elusive. We examined these issues in a murine model of TBI combining histology, behavioral analyses and single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (CBF) as a proxy for neural activity. Adult C57Bl/6N mice were subjected to unilateral cortical impact injury and investigated at early (15-57 days after lesion, dal) and late (184-225 dal) post-traumatic time points. TBI caused pronounced tissue loss of the parietal cortex and subcortical structures and enduring neurological deficits. Marked perilesional astro- and microgliosis was found at 57 dal and declined at 225 dal. Motor and gait pattern deficits occurred at early time points after TBI and improved over the time. In contrast, impaired performance in the Morris water maze test and decreased anxiety-like behavior persisted together with an increased susceptibility to pentylenetetrazole-induced seizures suggesting alterations in neural activity patterns. Accordingly, SPECT imaging of CBF indicated asymmetric hemispheric baseline neural activity patterns. In the ipsilateral hemisphere, increased baseline neural activity was found in the amygdala. In the contralateral hemisphere, homotopic to the structural brain damage, the hippocampus and distinct cortex regions displayed increased baseline neural activity. Thus, regionally elevated CBF along with behavioral alterations indicate that increased neural activity is critically involved in the long-lasting consequences of TBI.

  17. Increased Expression of FoxM1 Transcription Factor in Respiratory Epithelium Inhibits Lung Sacculation and Causes Clara Cell Hyperplasia

    Science.gov (United States)

    Wang, I-Ching; Zhang, Yufang; Snyder, Jonathan; Sutherland, Mardi J.; Burhans, Michael S.; Shannon, John M.; Park, Hyun Jung; Whitsett, Jeffrey A.; Kalinichenko, Vladimir V.

    2010-01-01

    Foxm1 is a member of the Forkhead Box (Fox) family of transcription factors. Foxm1 (previously called Foxm1b, HFH-11B, Trident, Win, or MPP2) is expressed in multiple cell types and plays important roles in cellular proliferation, differentiation and tumorigenesis. Genetic deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibits lung maturation and causes respiratory failure after birth. However, the role of Foxm1 during postnatal lung morphogenesis remains unknown. In the present study, Foxm1 expression was detected in epithelial cells of conducting and peripheral airways and changing dynamically with lung maturation. To discern the biological role of Foxm1 in the prenatal and postnatal lung, a novel transgenic mouse line that expresses a constitutively active form of FoxM1 (FoxM1 N-terminal deletion mutant or FoxM1-ΔN) under the control of lung epithelial-specific SPC promoter was produced. Expression of the FoxM1-ΔN transgene during embryogenesis caused epithelial hyperplasia, inhibited lung sacculation and expression of the type II epithelial marker, pro-SPC. Expression of FoxM1-ΔN mutant during the postnatal period did not influence alveologenesis but caused focal airway hyperplasia and increased proliferation of Clara cells. Likewise, expression of FoxM1-ΔN mutant in conducting airways with Scgb1a1 promoter was sufficient to induce Clara cell hyperplasia. Furthermore, FoxM1-ΔN cooperated with activated K-Ras to induce lung tumor growth in vivo. Increased activity of Foxm1 altered lung sacculation, induced proliferation in the respiratory epithelium and accelerated lung tumor growth, indicating that precise regulation of Foxm1 is critical for normal lung morphogenesis and development of lung cancer. PMID:20816795

  18. EPO Receptor Gain-of-Function Causes Hereditary Polycythemia, Alters CD34+ Cell Differentiation and Increases Circulating Endothelial Precursors

    Science.gov (United States)

    Perrotta, Silverio; Cucciolla, Valeria; Ferraro, Marcella; Ronzoni, Luisa; Tramontano, Annunziata; Rossi, Francesca; Scudieri, Anna Chiara; Borriello, Adriana; Roberti, Domenico; Nobili, Bruno; Cappellini, Maria Domenica; Oliva, Adriana; Amendola, Giovanni; Migliaccio, Anna Rita; Mancuso, Patrizia; Martin-Padura, Ines; Bertolini, Francesco; Yoon, Donghoon; Prchal, Josef T.; Della Ragione, Fulvio

    2010-01-01

    Background Gain-of-function of erythropoietin receptor (EPOR) mutations represent the major cause of primary hereditary polycythemia. EPOR is also found in non-erythroid tissues, although its physiological role is still undefined. Methodology/Principal Findings We describe a family with polycythemia due to a heterozygous mutation of the EPOR gene that causes a G→T change at nucleotide 1251 of exon 8. The novel EPOR G1251T mutation results in the replacement of a glutamate residue by a stop codon at amino acid 393. Differently from polycythemia vera, EPOR G1251T CD34+ cells proliferate and differentiate towards the erythroid phenotype in the presence of minimal amounts of EPO. Moreover, the affected individuals show a 20-fold increase of circulating endothelial precursors. The analysis of erythroid precursor membranes demonstrates a heretofore undescribed accumulation of the truncated EPOR, probably due to the absence of residues involved in the EPO-dependent receptor internalization and degradation. Mutated receptor expression in EPOR-negative cells results in EPOR and Stat5 phosphorylation. Moreover, patient erythroid precursors present an increased activation of EPOR and its effectors, including Stat5 and Erk1/2 pathway. Conclusions/Significance Our data provide an unanticipated mechanism for autosomal dominant inherited polycythemia due to a heterozygous EPOR mutation and suggest a regulatory role of EPO/EPOR pathway in human circulating endothelial precursors homeostasis. PMID:20700488

  19. Early life stress- and sex-dependent effects on hippocampal neurogenesis

    NARCIS (Netherlands)

    Lucassen, P.J.; Korosi, A.; Krugers, H.J.; Oomen, C.A.; Fink, G.

    2017-01-01

    Neurogenesis refers to the birth of new neurons in an adult brain, a form of structural plasticity that has been implicated in cognition, mood, and anxiety, and is well regulated by environmental and hormonal factors. Exposure to stress (hormones) generally inhibits neurogenesis. Here, we discuss

  20. Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.A.; Naninck, E.F.G.; Fitzsimons, C.P.; van Dam, A.M.; Czeh, B.; Korosi, A.

    2015-01-01

    Exposure to stress is one of the best-known negative regulators of adult neurogenesis (AN). We discuss changes in neurogenesis in relation to exposure to stress, glucocorticoid hormones, and inflammation, with a particular focus on early development and on lasting effects of stress. Although the

  1. Decreased miR-128 and increased miR-21 synergistically cause podocyte injury in sepsis.

    Science.gov (United States)

    Wang, Shanshan; Wang, Jun; Zhang, Zengdi; Miao, Hongjun

    2017-08-01

    Glomerular podocytes are injured in sepsis. We studied, in a sepsis patient, whether microRNAs (miRNAs) play a role in the podocyte injury. Podocytes were cultured and treated with lipopolysaccharide (LPS). Filtration barrier function of podocyte was analyzed with albumin influx assay. Nephrin level was analyzed with reverse transcription polymerase chain reaction (RT-PCR) and western blot. MiRNAs were detected using miRNAs PCR Array and in situ hybridization. MiRNA target sites were evaluated with luciferase reporter assays. LPS impaired the filtration barrier function of podocytes. MiR-128 level was decreased and miR-21 level was increased in podocytes in vitro and in the sepsis patient. The decrease in miR-128 was sufficient to induce the loss of nephrin and the impairment of filtration barrier function, while the increase of miR-21 exacerbated the process. Snail and phosphatase and tensin homolog (PTEN) were identified as the targets of miR-128 and miR-21. Decreased miR-128 induced Snail expression, and the increased miR-21 stabilized Snail by regulating the PTEN/Akt/GSK3β pathway. Supplementation of miR-128 and inhibition of miR-21 suppressed Snail expression and prevented the podocyte injury induced by LPS. Our study suggests that decreased miR-128 and increased miR-21 synergistically cause podocyte injury and are the potential therapeutic targets in sepsis.

  2. [Effects and consequence of recurrent seizures of neonatal rat on the hippocampal neurogenesis].

    Science.gov (United States)

    Shi, Xiu-yu; Wang, Ji-wen; Sun, Ruo-peng

    2006-04-01

    U-labeled cells increased significantly in the seizure group compared with the matched controls at P52 (P < 0.01). Most BrdU-labeled cells in granular cell layer (GCL) of both seizure group and control group coexpressed NF200. Recurrent seizures during neonatal period lead to decreased neurogenesis at the early stage after the third seizure, and at later time points increase of neurogenesis. Most of newly generated cells can differentiate into neurons.

  3. TV viewing time is associated with increased all-cause mortality in Brazilian adults independent of physical activity.

    Science.gov (United States)

    Turi, B C; Monteiro, H L; Lemes, Í R; Codogno, J S; Lynch, K R; Asahi Mesquita, C A; Fernandes, R A

    2018-02-01

    The purpose of this study was to investigate the association between television (TV) viewing and all-cause mortality among Brazilian adults after 6 years of follow-up. This longitudinal study started in 2010 in the city of Bauru, SP, Brazil, and involved 970 adults aged ≥50 years. Mortality was reported by relatives and confirmed in medical records of the Brazilian National Health System. Physical activity (PA) and TV viewing were assessed by the Baecke questionnaire. Health status, sociodemographic and behavioral covariates were considered as potential confounders. After 6 years of follow-up, 89 deaths were registered (9.2% [95% CI=7.4%-11%]). Type 2 diabetes mellitus was associated with higher risk of mortality (P-value=.012). Deaths correlated significantly with age (ρ=.188; P-value=.001), overall PA score (ρ=-.128; P-value=.001) and TV viewing (ρ=.086; P-value=.007). Lower percentage of participants reported TV viewing time as often (16%) and very often (5.7%), but there was an association between higher TV viewing time ("often" and "very often" grouped together) and increased mortality after 6 years of follow-up (P-value=.006). The higher TV viewing time was associated with a 44.7% increase in all-cause mortality (HR=1.447 [1.019-2.055]), independently of other potential confounders. In conclusion, the findings from this cohort study identified increased risk of mortality among adults with higher TV viewing time, independently of PA and other variables. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Transient impairment of hippocampus-dependent learning and memory in relatively low-dose of acute radiation syndrome is associated with inhibition of hippocampal neurogenesis

    International Nuclear Information System (INIS)

    Kim, Joong-Sun; Lee, Hae-June; Kim, Jong-Choon

    2008-01-01

    Neurogenesis in the adult hippocampus, which occurs constitutively, is vulnerable to ionizing radiation. In the relatively low-dose exposure of acute radiation syndrome (ARS), the change in the adult hippocampal function is poorly understood. This study analyzed the changes in apoptotic cell death and neurogenesis in the DGs of hippocampi from adult ICR mice with single whole-body gamma-irradiation using the TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method and immunohistochemical markers of neurogenesis, Ki-67 and doublecortin (DCX). In addition, the hippocampus-dependent learning and memory tasks after single whole-body gamma-irradiation were examined in order to evaluate the hippocampus-related behavioral dysfunction in the relatively low-dose exposure of ARS. The number of TUNEL-positive apoptotic nuclei in the dentate gyrus (DG) was increased 6-12 h after acute gamma-irradiation (a single dose of 0.5 to 4 Gy). In contrast, the number of Ki-67- and DCX-positive cells began to decrease significantly 6 h postirradiation, reaching its lowest level 24 h after irradiation. The level of Ki-67 and DCX immunoreactivity decreased in a dose-dependent manner within the range of irradiation applied (0-4 Gy). In passive avoidance and object recognition memory test, the mice trained 1 day after acute irradiation (2 Gy) showed significant memory deficits, compared with the sham controls. In conclusion, the pattern of the hippocampus-dependent memory dysfunction is consistent with the change in neurogenesis after acute irradiation. It is suggested that a relatively low dose of ARS in adult ICR mice is sufficiently detrimental to interrupt the functioning of the hippocampus, including learning and memory, possibly through the inhibition of neurogenesis. (author)

  5. Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later

    Science.gov (United States)

    Bond, Allison M.; Ming, Guo-li; Song, Hongjun

    2015-01-01

    Summary Adult somatic stem cells in various organs maintain homeostatic tissue regeneration and enhance plasticity. Since its initial discovery five decades ago, investigations of adult neurogenesis and neural stem cells have led to an established and expanding field that has significantly influenced many facets of neuroscience, developmental biology and regenerative medicine. Here we review recent progress and focus on questions related to adult mammalian neural stem cells that also apply to other somatic stem cells. We further discuss emerging topics that are guiding the field toward better understanding adult neural stem cells and ultimately applying these principles to improve human health. PMID:26431181

  6. Air quality models and unusually large ozone increases: Identifying model failures, understanding environmental causes, and improving modeled chemistry

    Science.gov (United States)

    Couzo, Evan A.

    Several factors combine to make ozone (O3) pollution in Houston, Texas, unique when compared to other metropolitan areas. These include complex meteorology, intense clustering of industrial activity, and significant precursor emissions from the heavily urbanized eight-county area. Decades of air pollution research have borne out two different causes, or conceptual models, of O 3 formation. One conceptual model describes a gradual region-wide increase in O3 concentrations "typical" of many large U.S. cities. The other conceptual model links episodic emissions of volatile organic compounds to spatially limited plumes of high O3, which lead to large hourly increases that have exceeded 100 parts per billion (ppb) per hour. These large hourly increases are known to lead to violations of the federal O 3 standard and impact Houston's status as a non-attainment area. There is a need to further understand and characterize the causes of peak O 3 levels in Houston and simulate them correctly so that environmental regulators can find the most cost-effective pollution controls. This work provides a detailed understanding of unusually large O 3 increases in the natural and modeled environments. First, we probe regulatory model simulations and assess their ability to reproduce the observed phenomenon. As configured for the purpose of demonstrating future attainment of the O3 standard, the model fails to predict the spatially limited O3 plumes observed in Houston. Second, we combine ambient meteorological and pollutant measurement data to identify the most likely geographic origins and preconditions of the concentrated O3 plumes. We find evidence that the O3 plumes are the result of photochemical activity accelerated by industrial emissions. And, third, we implement changes to the modeled chemistry to add missing formation mechanisms of nitrous acid, which is an important radical precursor. Radicals control the chemical reactivity of atmospheric systems, and perturbations to

  7. Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles.

    Science.gov (United States)

    Santos, Tiago; Ferreira, Raquel; Quartin, Emanuel; Boto, Carlos; Saraiva, Cláudia; Bragança, José; Peça, João; Rodrigues, Cecília; Ferreira, Lino; Bernardino, Liliana

    2017-09-01

    Neurogenic niches constitute a powerful endogenous source of new neurons that can be used for brain repair strategies. Neuronal differentiation of these cells can be regulated by molecules such as retinoic acid (RA) or by mild levels of reactive oxygen species (ROS) that are also known to upregulate RA receptor alpha (RARα) levels. Data showed that neural stem cells from the subventricular zone (SVZ) exposed to blue light (405nm laser) transiently induced NADPH oxidase-dependent ROS, resulting in β-catenin activation and neuronal differentiation, and increased RARα levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis both in vitro and in vivo, while offering a temporal and spatial control of RA release. In conclusion, this combinatory treatment offers great advantages to potentiate neuronal differentiation, and provides an innovative and efficient application for brain regenerative therapies. Controlling the differentiation of stem cells would support the development of promising brain regenerative therapies. Blue light transiently increased reactive oxygen species, resulting in neuronal differentiation and increased retinoic acid receptor (RARα) levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis, while offering a temporal and spatial control of RA release. In this sense, our approach relying on the modulation of endogenous stem cells for the generation of new neurons may support the development of novel clinical therapies. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  8. Progranulin causes adipose insulin resistance via increased autophagy resulting from activated oxidative stress and endoplasmic reticulum stress.

    Science.gov (United States)

    Guo, Qinyue; Xu, Lin; Li, Huixia; Sun, Hongzhi; Liu, Jiali; Wu, Shufang; Zhou, Bo

    2017-01-31

    Progranulin (PGRN) has recently emerged as an important regulator for insulin resistance. However, the direct effect of progranulin in adipose insulin resistance associated with the autophagy mechanism is not fully understood. In the present study, progranulin was administered to 3T3-L1 adipocytes and C57BL/6 J mice with/without specific inhibitors of oxidative stress and endoplasmic reticulum stress, and metabolic parameters, oxidative stress, endoplasmic reticulum stress and autophagy markers were assessed. Progranulin treatment increased iNOS expression, NO synthesis and ROS generation, and elevated protein expressions of CHOP, GRP78 and the phosphorylation of PERK, and caused a significant increase in Atg7 and LC3-II protein expression and a decreased p62 expression, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake, demonstrating that progranulin activated oxidative stress and ER stress, elevated autophagy and induced insulin insensitivity in adipocytes and adipose tissue of mice. Interestingly, inhibition of iNOS and ER stress both reversed progranulin-induced stress response and increased autophagy, protecting against insulin resistance in adipocytes. Furthermore, the administration of the ER stress inhibitor 4-phenyl butyric acid reversed the negative effect of progranulin in vivo. Our findings showed the clinical potential of the novel adipokine progranulin in the regulation of insulin resistance, suggesting that progranulin might mediate adipose insulin resistance, at least in part, by inducing autophagy via activated oxidative stress and ER stress.

  9. Possible causes of the recent rapid increase in the radial increment of silver fir in the Western Carpathians

    International Nuclear Information System (INIS)

    Bošeľa, Michal; Petráš, Rudolf; Sitková, Zuzana; Priwitzer, Tibor; Pajtík, Jozef; Hlavatá, Helena; Sedmák, Róbert; Tobin, Brian

    2014-01-01

    Silver fir is one of the most productive and ecologically valuable native European tree species, however, it has been experiencing decline which has periodically occurred over its natural range. This paper aims to investigate the recent climate–growth relationships of silver fir (Abies alba Mill.) and its temporal change along the course of its life. Long-term tree-ring databases, as well as records on climate, atmospheric SO 2 , NO 3 and acid concentrations from four different regions in the Western Carpathians were used. The results provide clear evidence of significant increase of silver fir's radial increment over the entire Western Carpathian area since 1970–1980. The results indicated that the most probable factors behind the rapid recovery of tree radial increment were reductions in emissions of NO 3 and SO 2 , alongside a significant increase in mean June, July and April temperatures. Highlights: • Silver fir radial growth was mostly related to mean month late winter temperatures. • Silver fir growth also responded to summer, especially July temperatures. • Strength of the climate–growth response has gradually increased since 1960–1980. • SO 2 , NO 3 , and recent climate change as major factor of the rapid radial growth recovery. -- Reductions of SO 2 and NO 3 emission along with climate change are the major causes of the recent recovery of Silver fir radial growth

  10. Declines in Malaria Burden and All-Cause Child Mortality following Increases in Control Interventions in Senegal, 2005-2010.

    Science.gov (United States)

    Thwing, Julie; Eckert, Erin; Dione, Demba Anta; Tine, Roger; Faye, Adama; Yé, Yazoume; Ndiop, Medoune; Cisse, Moustapha; Ndione, Jacques Andre; Diouf, Mame Birame; Ba, Mady

    2017-09-01

    Malaria is endemic in Senegal. The national malaria control strategy focuses on achieving universal coverage for major interventions, with a goal of reaching preelimination status by 2018. Senegal began distribution of insecticide-treated nets (ITNs) and introduced artemisinin-based combination therapy in 2006, then introduced rapid diagnostic tests in 2007. We evaluated the impact of these efforts using a plausibility design based on malaria's contribution to all-cause under-five mortality (ACCM) and considering other contextual factors which may influence ACCM. Between 2005 and 2010, household ownership of ITNs increased from 20% to 63%, and the proportion of people sleeping under an ITN the night prior to the survey increased from 6% to 29%. Malaria parasite prevalence declined from 6% to 3% from 2008 to 2010 among children under five. Some nonmalaria indicators of child health improved, for example, increase of complete vaccination coverage from 58% to 64%; however, nutritional indicators deteriorated, with an increase in stunting from 16% to 26%. Although economic indicators improved, environmental conditions favored an increase in malaria transmission. ACCM decreased 40% between 2005 and 2010, from 121 (95% confidence interval [CI] 113-129) to 72 (95% CI 66-77) per 1,000, and declines were greater among age groups, epidemiologic zones, and wealth quintiles most at risk for malaria. After considering coverage of malaria interventions, trends in malaria morbidity, effects of contextual factors, and trends in ACCM, it is plausible that malaria control interventions contributed to a reduction in malaria mortality and to the impressive gains in child survival in Senegal.

  11. Associations between short-term exposure to ambient sulfur dioxide and increased cause-specific mortality in 272 Chinese cities.

    Science.gov (United States)

    Wang, Lijun; Liu, Cong; Meng, Xia; Niu, Yue; Lin, Zhijing; Liu, Yunning; Liu, Jiangmei; Qi, Jinlei; You, Jinling; Tse, Lap Ah; Chen, Jianmin; Zhou, Maigeng; Chen, Renjie; Yin, Peng; Kan, Haidong

    2018-04-28

    Ambient sulfur dioxide (SO 2 ) remains a major air pollutant in developing countries, but epidemiological evidence about its health effects was not abundant and inconsistent. To evaluate the associations between short-term exposure to SO 2 and cause-specific mortality in China. We conducted a nationwide time-series analysis in 272 major Chinese cities (2013-2015). We used the over-dispersed generalized linear model together with the Bayesian hierarchical model to analyze the data. Two-pollutant models were fitted to test the robustness of the associations. We conducted stratification analyses to examine potential effect modifications by age, sex and educational level. On average, the annual-mean SO 2 concentrations was 29.8 μg/m 3 in 272 cities. We observed positive and associations of SO 2 with total and cardiorespiratory mortality. A 10 μg/m 3 increase in two-day average concentrations of SO 2 was associated with increments of 0.59% in mortality from total non-accidental causes, 0.70% from total cardiovascular diseases, 0.55% from total respiratory diseases, 0.64% from hypertension disease, 0.65% from coronary heart disease, 0.58% from stroke, and 0.69% from chronic obstructive pulmonary disease. In two-pollutant models, there were no significant differences between single-pollutant model and two-pollutant model estimates with fine particulate matter, carbon monoxide and ozone, but the estimates decreased substantially after adjusting for nitrogen dioxide, especially in South China. The associations were stronger in warmer cities, in older people and in less-educated subgroups. This nationwide study demonstrated associations of daily SO 2 concentrations with increased total and cardiorespiratory mortality, but the associations might not be independent from NO 2 . Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. Sodium bicarbonate causes dose-dependent increases in cerebral blood flow in infants and children with single ventricle physiology

    Science.gov (United States)

    Buckley, Erin M.; Naim, Maryam Y.; Lynch, Jennifer M.; Goff, Donna A.; Schwab, Peter J.; Diaz, Laura K.; Nicolson, Susan C.; Montenegro, Lisa M.; Lavin, Natasha A.; Durduran, Turgut; Spray, Thomas L.; Gaynor, J. William; Putt, Mary E.; Yodh, A.G.; Fogel, Mark A.; Licht, Daniel J.

    2013-01-01

    Background Sodium bicarbonate (NaHCO3) is a common treatment for metabolic acidemia, however little definitive information exists regarding its treatment efficacy and cerebral hemodynamic effects. This pilot observational study quantifies relative changes in cerebral blood flow (rCBF) and oxy and deoxy-hemoglobin concentrations (ΔHbO2 and ΔHb) due to bolus administration of NaHCO3 in patients with mild base deficits. Methods Infants and children with hypoplastic left heart syndrome (HLHS) were recruited prior to cardiac surgery. NaHCO3 was given as needed for treatment of base deficit. Diffuse optical spectroscopies were employed for 15 minutes post-injection to non-invasively monitor ΔHb, ΔHbO2 and rCBF relative to baseline prior to NaHCO3 administration. Results Twenty-two anesthetized and mechanically ventilated HLHS patients (1 day to 4 years old) received a median (interquartile range) dose of 1.1 (0.8, 1.8) mEq/kg NaHCO3 administered intravenously over 10–20 seconds to treat a base deficit of −4 (−6, −3) mEq/l. NaHCO3 caused significant dose-dependent increases in rCBF, however population averaged ΔHb or Δ4HbO2 compared to controls were not significant. Conclusions Dose-dependent increases in cerebral blood flow (CBF) caused by bolus NaHCO3 are an important consideration in vulnerable populations wherein risk of rapid CBF fluctuations does not outweigh the benefit of treating a base deficit. PMID:23403802

  13. Hippocampal neurogenesis and cortical cellular plasticity in Wahlberg's epauletted fruit bat: a qualitative and quantitative study.

    Science.gov (United States)

    Gatome, Catherine W; Mwangi, Deter K; Lipp, Hans-Peter; Amrein, Irmgard

    2010-01-01

    Species-specific characteristics of neuronal plasticity emerging from comparative studies can address the functional relevance of hippocampal or cortical plasticity in the light of ecological adaptation and evolutionary history of a given species. Here, we present a quantitative and qualitative analysis of neurogenesis in young and adult free-living Wahlberg's epauletted fruit bats. Using the markers for proliferating cell nuclear antigen (PCNA), bromodeoxyuridine (BrdU), doublecortin (DCX) and polysialic acid neural cell adhesion molecule (PSA-NCAM), our findings in the hippocampus, olfactory bulb and cortical regions are described and compared to reports in other mammals. Expressed as a percentage of the total number of granule cells, PCNA- and BrdU-positive cells accounted for 0.04 in young to 0.01% in adult animals; DCX-positive cells for 0.05 (young) to 0.01% (adult); PSA-NCAM-positive cells for 0.1 (young) to 0.02% (adult), and pyknotic cells for 0.007 (young) to 0.005% (adult). The numbers were comparable to other long-lived, late-maturing mammals such as primates. A significant increase in the total granule cell number from young to adult animals demonstrated the successful formation and integration of new cells. In adulthood, granule cell number appeared stable and was surprisingly low in comparison to other species. Observations in the olfactory bulb and rostral migratory stream were qualitatively similar to descriptions in other species. In the ventral horn of the lateral ventricle, we noted prominent expression of DCX and PSA-NCAM forming a temporal migratory stream targeting the piriform cortex, possibly reflecting the importance of olfaction to these species. Low, but persistent hippocampal neurogenesis in non-echolocating fruit bats contrasted the findings in echolocating microbats, in which hippocampal neurogenesis was largely absent. Together with the observed intense cortical plasticity in the olfactory system of fruit bats we suggest a

  14. Prenatal neurogenesis in autism spectrum disorders

    Science.gov (United States)

    Kaushik, Gaurav; Zarbalis, Konstantinos

    2016-03-01

    An ever-increasing body of literature describes compelling evidence that a subset of young children on the autism spectrum show abnormal cerebral growth trajectories. In these cases, normal cerebral size at birth is followed by a period of abnormal growth and starting in late childhood often by regression compared to unaffected controls. Recent work has demonstrated an abnormal increase in the number of neurons of the prefrontal cortex suggesting that cerebral size increase in autism is driven by excess neuronal production. In addition, some affected children display patches of abnormal laminar positioning of cortical projection neurons. As both cortical projection neuron numbers and their correct layering within the developing cortex requires the undisturbed proliferation of neural progenitors, it appears that neural progenitors lie in the center of the autism pathology associated with early brain overgrowth. Consequently, autism spectrum disorders associated with cerebral enlargement should be viewed as birth defects of an early embryonic origin with profound implications for their early diagnosis, preventive strategies, and therapeutic intervention.

  15. Maintaining appearances-The role of p53 in adult neurogenesis

    International Nuclear Information System (INIS)

    Medrano, Silvia; Scrable, Heidi

    2005-01-01

    In the adult mammalian brain, neuronal turnover continues to replenish cells in existing neuronal circuits, such as those involved either in odor discrimination or in learning and memory, throughout life. With age, however, the capacity for neurogenesis diminishes and these functions become impaired. Neuronal turnover is a two-step process, which first generates excess neuronal progenitors and then eliminates all but the few that differentiate into fully functional neurons. This process requires a fine balance between cell proliferation and cell death. Altered activity of the tumor suppressor p53 can upset this balance by affecting the rate of cell proliferation, but not the rate of cell death, in neurogenic regions of the adult brain. Genetically engineered mice in which p53 activity is increased demonstrate that premature loss of neurogenic capacity is linked to accelerated organismal aging

  16. Increased Mortality in Schizophrenia Due to Cardiovascular Disease – A Non-Systematic Review of Epidemiology, Possible Causes, and Interventions

    Science.gov (United States)

    Ringen, Petter Andreas; Engh, John A.; Birkenaes, Astrid B.; Dieset, Ingrid; Andreassen, Ole A.

    2014-01-01

    Background: Schizophrenia is among the major causes of disability worldwide and the mortality from cardiovascular disease (CVD) is significantly elevated. There is a growing concern that this health challenge is not fully understood and efficiently addressed. Methods: Non-systematic review using searches in PubMed on relevant topics as well as selection of references based on the authors’ experience from clinical work and research in the field. Results: In most countries, the standardized mortality rate in schizophrenia is about 2.5, leading to a reduction in life expectancy between 15 and 20 years. A major contributor of the increased mortality is due to CVD, with CVD mortality ranging from 40 to 50% in most studies. Important causal factors are related to lifestyle, including poor diet, lack of physical activity, smoking, and substance abuse. Recent findings suggest that there are overlapping pathophysiology and genetics between schizophrenia and CVD-risk factors, further increasing the liability to CVD in schizophrenia. Many pharmacological agents used for treating psychotic disorders have side effects augmenting CVD risk. Although several CVD-risk factors can be effectively prevented and treated, the provision of somatic health services to people with schizophrenia seems inadequate. Further, there is a sparseness of studies investigating the effects of lifestyle interventions in schizophrenia, and there is little knowledge about effective programs targeting physical health in this population. Discussion: The risk for CVD and CVD-related deaths in people with schizophrenia is increased, but the underlying mechanisms are not fully known. Coordinated interventions in different health care settings could probably reduce the risk. There is an urgent need to develop and implement effective programs to increase life expectancy in schizophrenia, and we argue that mental health workers should be more involved in this important task. PMID:25309466

  17. Increased mortality in schizophrenia due to cardiovascular disease – a non-systematic review of epidemiology, possible causes and interventions

    Directory of Open Access Journals (Sweden)

    Petter Andreas eRingen

    2014-09-01

    Full Text Available Background: Schizophrenia is among the major causes of disability worldwide and the mortality from cardiovascular disease (CVD is significantly elevated. There is a growing concern that this health challenge is not fully understood and efficiently addressed.Methods: Non-systematic review using searches in PubMed on relevant topics as well as selection of references based on the authors experience from clinical work and research in the field.Results: In most countries, the standardized mortality rate (SMR in schizophrenia is about 2.5, leading to a reduction in life expectancy between 15 and 20 years. A major contributor of the increased mortality is due to CVD, with CVD mortality ranging from 40-50% in most studies. Important causal factors are related to lifestyle, including poor diet, lack of physical activity, smoking and substance abuse. Recent findings suggest that there are overlapping pathophysiology and genetics between schizophrenia and CVD risk factors, further increasing the liability to CVD in schizophrenia. Many pharmacological agents used for treating psychotic disorders have side effects augmenting CVD risk. Although several CVD risk factors can be effectively prevented and treated, the provision of somatic health services to people with schizophrenia seems inadequate. Further, there is a sparseness of studies investigating the effects of life-style interventions in schizophrenia, and there is little knowledge about effective programs targeting physical health in this population. Discussion: The risk for CVD and CVD-related deaths in people with schizophrenia is increased, but the underlying mechanisms are not fully known. Coordinated interventions in different health care settings could probably reduce the risk. There is an urgent need to develop and implement effective programs to increase life expectancy in schizophrenia, and we argue that mental health workers should be more involved in this important task.

  18. Increased mortality in schizophrenia due to cardiovascular disease - a non-systematic review of epidemiology, possible causes, and interventions.

    Science.gov (United States)

    Ringen, Petter Andreas; Engh, John A; Birkenaes, Astrid B; Dieset, Ingrid; Andreassen, Ole A

    2014-01-01

    Schizophrenia is among the major causes of disability worldwide and the mortality from cardiovascular disease (CVD) is significantly elevated. There is a growing concern that this health challenge is not fully understood and efficiently addressed. Non-systematic review using searches in PubMed on relevant topics as well as selection of references based on the authors' experience from clinical work and research in the field. In most countries, the standardized mortality rate in schizophrenia is about 2.5, leading to a reduction in life expectancy between 15 and 20 years. A major contributor of the increased mortality is due to CVD, with CVD mortality ranging from 40 to 50% in most studies. Important causal factors are related to lifestyle, including poor diet, lack of physical activity, smoking, and substance abuse. Recent findings suggest that there are overlapping pathophysiology and genetics between schizophrenia and CVD-risk factors, further increasing the liability to CVD in schizophrenia. Many pharmacological agents used for treating psychotic disorders have side effects augmenting CVD risk. Although several CVD-risk factors can be effectively prevented and treated, the provision of somatic health services to people with schizophrenia seems inadequate. Further, there is a sparseness of studies investigating the effects of lifestyle interventions in schizophrenia, and there is little knowledge about effective programs targeting physical health in this population. The risk for CVD and CVD-related deaths in people with schizophrenia is increased, but the underlying mechanisms are not fully known. Coordinated interventions in different health care settings could probably reduce the risk. There is an urgent need to develop and implement effective programs to increase life expectancy in schizophrenia, and we argue that mental health workers should be more involved in this important task.

  19. Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion.

    Directory of Open Access Journals (Sweden)

    Oumei Cheng

    Full Text Available Sleep deprivation (SD plays a complex role in central nervous system (CNS diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR.One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU and neuron-specific enolase (NSE, respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.

  20. Neurogenesis in Aplysia californica resembles nervous system formation in vertebrates

    International Nuclear Information System (INIS)

    Jacob, M.H.

    1984-01-01

    The pattern of neurogenesis of the central nervous system of Aplysia californica was investigated by [ 3 H]thymidine autoradiography. Large numbers of animals at a series of early developmental stages were labeled with [ 3 H]thymidine for 24 or 48 hr and were subsequently sampled at specific intervals throughout the life cycle. I found that proliferative zones, consisting of columnar and placodal ectodermal cells, are established in regions of the body wall adjacent to underlying mesodermal cells. Mitosis in the proliferative zones generates a population of cells which leave the surface and migrate inward to join the nearby forming ganglia. Tracing specific [ 3 H]thymidine-labeled cells from the body wall to a particular ganglion and within the ganglion over time suggests that the final genomic replication of the neuronal precursors occurs before the cells join the ganglion while glial cell precursors and differentiating glial cells continue to divide within the ganglion for some time. Ultrastructural examination of the morphological features of the few mitosing cells observed within the Aplysia central nervous system supports this interpretation. The pattern of neurogenesis in the Aplysia central nervous system resembles the proliferation of cells in the neural tube and the migration of neural crest and ectodermal placode cells in the vertebrate nervous system but differs from the pattern described for other invertebrates

  1. Increasing incidence of penicillin- and cefotaxime-resistant Streptococcus pneumoniae causing meningitis in India: Time for revision of treatment guidelines?

    Science.gov (United States)

    Verghese, Valsan Philip; Veeraraghavan, Balaji; Jayaraman, Ranjith; Varghese, Rosemol; Neeravi, Ayyanraj; Jayaraman, Yuvaraj; Thomas, Kurien; Mehendale, Sanjay M

    2017-01-01

    Pneumococcal meningitis is a life-threatening infection, requiring prompt diagnosis and effective treatment. Penicillin resistance in pneumococcal infections is a concern. Here, we present the antibiotic susceptibility profile of pneumococcal meningeal isolates from January 2008 to August 2016 to elucidate treatment guidelines for pneumococcal meningitis. Invasive pneumococcal isolates from all age groups, were included in this study. Minimum inhibitory concentrations for the isolates were identified by agar dilution technique and VITEK System 2. Serotyping of isolates was done by co-agglutination technique. Out of 830 invasive pneumococcal isolates, 167 (20.1%) isolates were from meningeal infections. Cumulative penicillin resistance in pneumococcal meningitis was 43.7% and cefotaxime non-susceptibility was 14.9%. Penicillin resistance amongst meningeal isolates in those younger than 5 years, 5-16 years of age and those aged 16 years and older was 59.7%, 50% and 27.3%, respectively, with non-susceptibility to cefotaxime in the same age groups being 18%, 22.2% and 10.4%. Penicillin resistance amongst pneumococcal meningeal isolates increased from 9.5% in 2008 to 42.8% in 2016, whereas cefotaxime non-susceptibility increased from 4.7% in 2008 to 28.5% in 2016. Serotypes 14, 19F, 6B, 6A, 23F, 9V and 5 were the most common serotypes causing meningitis, with the first five accounting for over 75% of resistant isolates. The present study reports increasing penicillin resistance and cefotaxime non-susceptibility to pneumococcal meningitis in our setting. This highlights the need for empiric therapy with third-generation cephalosporins and vancomycin for all patients with meningitis while awaiting results of culture and susceptibility testing.

  2. Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

    Directory of Open Access Journals (Sweden)

    Abhilash P. Appu

    2017-06-01

    Full Text Available Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA, a deacetylase that catabolizes N-acetylaspartate (NAA. The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation, expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2-like 2 (NRF-2 in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms.

  3. Glucagon-Like Peptide-1 as Predictor of Body Mass Index and Dentate Gyrus Neurogenesis: Neuroplasticity and the Metabolic Milieu

    Directory of Open Access Journals (Sweden)

    Jeremy D. Coplan

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1, and body mass index (BMI in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

  4. Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

    Science.gov (United States)

    Besnard, Antoine; Sahay, Amar

    2016-01-01

    The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)–CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal–cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD. PMID:26068726

  5. Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels.

    Science.gov (United States)

    Vignisse, Julie; Sambon, Margaux; Gorlova, Anna; Pavlov, Dmitrii; Caron, Nicolas; Malgrange, Brigitte; Shevtsova, Elena; Svistunov, Andrey; Anthony, Daniel C; Markova, Natalyia; Bazhenova, Natalyia; Coumans, Bernard; Lakaye, Bernard; Wins, Pierre; Strekalova, Tatyana; Bettendorff, Lucien

    2017-07-01

    Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200mg/kg/day in drinking water for 20days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3β (GSK-3β) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent

  6. Adult hippocampal neurogenesis: an important target associated with antidepressant effects of exercise.

    Science.gov (United States)

    Sun, Lina; Sun, Qingshan; Qi, Jinshun

    2017-10-26

    Depression is a prevalent devastating mental disorder that affects the normal life of patients and brings a heavy burden to whole society. Although many efforts have been made to attenuate depressive/anxiety symptoms, the current clinic antidepressants have limited effects. Scientists have long been making attempts to find some new strategies that can be applied as the alternative antidepressant therapy. Exercise, a widely recognized healthy lifestyle, has been suggested as a therapy that can relieve psychiatric stress. However, how exercise improves the brain functions and reaches the antidepressant target needs systematic summarization due to the complexity and heterogeneous feature of depression. Brain plasticity, especially adult neurogenesis in the hippocampus, is an important neurophysiology to facilitate animals for neurogenesis can occur in not only humans. Many studies indicated that an appropriate level of exercise can promote neurogenesis in the adult brains. In this article, we provide information about the antidepressant effects of exercise and its implications in adult neurogenesis. From the neurogenesis perspective, we summarize evidence about the effects of exercise in enhancing neurogenesis in the hippocampus through regulating growth factors, neurotrophins, neurotransmitters and metabolism as well as inflammations. Taken together, a large number of published works indicate the multiple benefits of exercise in the brain functions of animals, particularly brain plasticity like neurogenesis and synaptogenesis. Therefore, a new treatment method for depression therapy can be developed by regulating the exercise activity.

  7. Trading new neurons for status: Adult hippocampal neurogenesis in eusocial Damaraland mole-rats.

    Science.gov (United States)

    Oosthuizen, M K; Amrein, I

    2016-06-02

    Diversity in social structures, from solitary to eusocial, is a prominent feature of subterranean African mole-rat species. Damaraland mole-rats are eusocial, they live in colonies that are characterized by a reproductive division of labor and a subdivision into castes based on physiology and behavior. Damaraland mole-rats are exceptionally long lived and reproductive animals show delayed aging compared to non-reproductive animals. In the present study, we described the hippocampal architecture and the rate of hippocampal neurogenesis of wild-derived, adult Damaraland mole-rats in relation to sex, relative age and social status or caste. Overall, Damaraland mole-rats were found to have a small hippocampus and low rates of neurogenesis. We found no correlation between neurogenesis and sex or relative age. Social status or caste was the most prominent modulator of neurogenesis. An inverse relationship between neurogenesis and social status was apparent, with queens displaying the lowest neurogenesis while the worker mole-rats had the most. As there is no natural progression from one caste to another, social status within a colony was relatively stable and is reflected in the level of neurogenesis. Our results correspond to those found in the naked mole-rat, and may reflect an evolutionary and environmentally conserved trait within social mole-rat species. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. IFN-{gamma} enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Baron, Rona; Nemirovsky, Anna; Harpaz, Idan

    2008-01-01

    the spatial learning and memory performance of the animals. In older mice, the effect of IFN-gamma is more pronounced in both wild-type mice and mice with Alzheimer's-like disease and is associated with neuroprotection. In addition, IFN-gamma reverses the increase in oligodendrogenesis observed in a mouse...... mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin-6 and tumor necrosis factor-alpha, the adaptive immunity cytokine IFN-gamma enhances neurogenesis in the dentate gyrus of adult mice and improves...

  9. Graves' disease and toxic nodular goiter are both associated with increased mortality but differ with respect to the cause of death

    DEFF Research Database (Denmark)

    Brandt, Frans; Thvilum, Marianne; Pedersen, Dorthe Almind

    2013-01-01

    Background: Hyperthyroidism has been associated with increased all-cause mortality. Whether the underlying cause of hyperthyroidism influences this association is unclear. Our objectives were to explore whether mortality risk and cause of death differ between Graves' disease (GD) and toxic nodular...

  10. Protective effect of Lycium Barbarum polysaccharides on dextromethorphan-induced mood impairment and neurogenesis suppression.

    Science.gov (United States)

    Po, Kevin Kai-Ting; Leung, Joseph Wai-Hin; Chan, Jackie Ngai-Man; Fung, Timothy Kai-Hang; Sánchez-Vidaña, Dalinda Isabel; Sin, Emily Lok-Lam; So, Kwok-Fai; Lau, Benson Wui-Man; Siu, Andrew Man-Hong

    2017-09-01

    Dextromethorphan (DXM) is one of the common drugs abused by adolescents. It is the active ingredient found in cough medicine which is used for suppressing cough. High dosage of DXM can induce euphoria, dissociative effects and even hallucinations. Chronic use of DXM may also lead to depressive-related symptoms. Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of ageing-related neurodegenerative diseases. A recent study has shown the potential beneficial effect of Lycium barbarum to reduce depression-like behavior. In the present study, we investigated the role of Lycium barbarum polysaccharide (LBP) to alleviate DXM-induced emotional distress. Sprague Dawley rats were divided into 4 groups (n=6 per group), including the normal control (vehicles only), DXM-treated group (40 mg/kg DXM), LBP-treated group (1 mg/kg LBP) and DXM+ LBP-treated group (40 mg/kg DXM and 1 mg/kg LBP). After two-week treatment, the DXM-treated group showed increased depression-like and social anxiety-like behaviors in the forced swim test and social interaction test respectively. On the other hand, the adverse behavioral effects induced by DXM were reduced by LBP treatment. Histological results showed that LBP treatment alone did not promote hippocampal neurogenesis when compared to the normal control, but LBP could lessen the suppression of hippocampal neurogenesis induced by DXM. The findings provide insights for the potential use of wolfberry as an adjunct treatment option for alleviating mood disturbances during rehabilitation of cough syrup abusers. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Effects of Scopolamine and Melatonin Cotreatment on Cognition, Neuronal Damage, and Neurogenesis in the Mouse Dentate Gyrus.

    Science.gov (United States)

    Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Choi, Soo Young; Lee, Yun Lyul; Kang, Il Jun; Hwang, In Koo; Lee, Tae-Kyeong; Shin, Bich-Na; Lee, Jae-Chul; Hong, Seongkweon; Jeon, Yong Hwan; Shin, Myoung Cheol; Cho, Jun Hwi; Won, Moo-Ho; Lee, Young Joo

    2018-03-01

    It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double-labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment.

  12. Increasing Rates of Brain Tumours in the Swedish National Inpatient Register and the Causes of Death Register

    Directory of Open Access Journals (Sweden)

    Lennart Hardell

    2015-04-01

    Full Text Available Radiofrequency emissions in the frequency range 30 kHz–300 GHz were evaluated to be Group 2B, i.e., “possibly”, carcinogenic to humans by the International Agency for Research on Cancer (IARC at WHO in May 2011. The Swedish Cancer Register has not shown increasing incidence of brain tumours in recent years and has been used to dismiss epidemiological evidence on a risk. In this study we used the Swedish National Inpatient Register (IPR and Causes of Death Register (CDR to further study the incidence comparing with the Cancer Register data for the time period 1998–2013 using joinpoint regression analysis. In the IPR we found a joinpoint in 2007 with Annual Percentage Change (APC +4.25%, 95% CI +1.98, +6.57% during 2007–2013 for tumours of unknown type in the brain or CNS. In the CDR joinpoint regression found one joinpoint in 2008 with APC during 2008–2013 +22.60%, 95% CI +9.68, +37.03%. These tumour diagnoses would be based on clinical examination, mainly CT and/or MRI, but without histopathology or cytology. No statistically significant increasing incidence was found in the Swedish Cancer Register during these years. We postulate that a large part of brain tumours of unknown type are never reported to the Cancer Register. Furthermore, the frequency of diagnosis based on autopsy has declined substantially due to a general decline of autopsies in Sweden adding further to missing cases. We conclude that the Swedish Cancer Register is not reliable to be used to dismiss results in epidemiological studies on the use of wireless phones and brain tumour risk.

  13. Learning an operant conditioning task differentially induces gliogenesis in the medial prefrontal cortex and neurogenesis in the hippocampus.

    Directory of Open Access Journals (Sweden)

    Maximiliano Rapanelli

    Full Text Available Circuit modification associated with learning and memory involves multiple events, including the addition and remotion of newborn cells trough adulthood. Adult neurogenesis and gliogenesis were mainly described in models of voluntary exercise, enriched environments, spatial learning and memory task; nevertheless, it is unknown whether it is a common mechanism among different learning paradigms, like reward dependent tasks. Therefore, we evaluated cell proliferation, neurogenesis, astrogliogenesis, survival and neuronal maturation in the medial prefrontal cortex (mPFC and the hippocampus (HIPP during learning an operant conditioning task. This was performed by using endogenous markers of cell proliferation, and a bromodeoxiuridine (BrdU injection schedule in two different phases of learning. Learning an operant conditioning is divided in two phases: a first phase when animals were considered incompletely trained (IT, animals that were learning the task when they performed between 50% and 65% of the responses, and a second phase when animals were considered trained (Tr, animals that completely learned the task when they reached 100% of the responses with a latency time lower than 5 seconds. We found that learning an operant conditioning task promoted cell proliferation in both phases of learning in the mPFC and HIPP. Additionally, the results presented showed that astrogliogenesis was induced in the medial prefrontal cortex (mPFC in both phases, however, the first phase promoted survival of these new born astrocytes. On the other hand, an increased number of new born immature neurons was observed in the HIPP only in the first phase of learning, whereas, decreased values were observed in the second phase. Finally, we found that neuronal maturation was induced only during the first phase. This study shows for the first time that learning a reward-dependent task, like the operant conditioning, promotes neurogenesis, astrogliogenesis, survival and

  14. Effect of calcitonin gene-related peptide on the neurogenesis of rat adipose-derived stem cells in vitro.

    Directory of Open Access Journals (Sweden)

    Qin Yang

    Full Text Available Calcitonin gene-related peptide (CGRP promotes neuron recruitment and neurogenic activity. However, no evidence suggests that CGRP affects the ability of stem cells to differentiate toward neurogenesis. In this study, we genetically modified rat adipose-derived stem cells (ADSCs with the CGRP gene (CGRP-ADSCs and subsequently cultured in complete neural-induced medium. The formation of neurospheres, cellular morphology, and proliferative capacity of ADSCs were observed. In addition, the expression of the anti-apoptotic protein Bcl-2 and special markers of neural cells, such as Nestin, MAP2, RIP and GFAP, were evaluated using Western blot and immunocytochemistry analysis. The CGRP-ADSCs displayed a greater proliferation than un-transduced (ADSCs and Vector-transduced (Vector-ADSCs ADSCs (p<0.05, and lower rates of apoptosis, associated with the incremental expression of Bcl-2, were also observed for CGRP-ADSCs. Moreover, upon neural induction, CGRP-ADSCs formed markedly more and larger neurospheres and showed round cell bodies with more branching extensions contacted with neighboring cells widely. Furthermore, the expression levels of Nestin, MAP2, and RIP in CGRP-ADSCs were markedly increased, resulting in higher levels than the other groups (p<0.05; however, GFAP was distinctly undetectable until day 7, when slight GFAP expression was detected among all groups. Wnt signals, primarily Wnt 3a, Wnt 5a and β-catenin, regulate the neural differentiation of ADSCs, and CGRP gene expression apparently depends on canonical Wnt signals to promote the neurogenesis of ADSCs. Consequently, ADSCs genetically modified with CGRP exhibit stronger potential for differentiation and neurogenesis in vitro, potentially reflecting the usefulness of ADSCs as seed cells in therapeutic strategies for spinal cord injury.

  15. Cat odor causes long-lasting contextual fear conditioning and increased pituitary-adrenal activation, without modifying anxiety.

    Science.gov (United States)

    Muñoz-Abellán, Cristina; Daviu, Nuria; Rabasa, Cristina; Nadal, Roser; Armario, Antonio

    2009-10-01

    A single exposure to a cat or cat odors has been reported by some groups to induce contextual and auditory fear conditioning and long-lasting changes in anxiety-like behaviour, but there is no evidence for parallel changes in biological stress markers. In the present study we demonstrated in male rats that exposure to a novel environment containing a cloth impregnated with cat fur odor resulted in avoidance of the odor, lower levels of activity and higher pituitary-adrenal (PA) response as compared to those exposed to the novel environment containing a clean cloth, suggesting increased levels of stress in the former animals. When re-exposed 9 days later to the same environment with a clean cloth, previously cat fur exposed rats again showed avoidance of the cloth area and lower levels of activity, suggesting development of contextual fear conditioning, which again was associated with a higher PA activation. In contrast, unaltered both anxiety-like behaviour and PA responsiveness to an elevated plus-maze were found 7 days after cat odor exposure. It is concluded that: (i) PA activation is able to reflect both the stressful properties of cat fur odor and odor-induced contextual fear conditioning; (ii) development of cat odor-induced contextual fear conditioning is independent of the induction of long-lasting changes in anxiety-like behaviour; and (iii) greater PA activation during exposure to the odor context is not explained by non-specific sensitization of the PA axis caused by previous exposure to cat fur odor.

  16. Ghrelin-induced hippocampal neurogenesis and enhancement of cognitive function are mediated independently of GH/IGF-1 axis: lessons from the spontaneous dwarf rats.

    Science.gov (United States)

    Li, Endan; Kim, Yumi; Kim, Sehee; Park, Seungjoon

    2013-01-01

    We recently have reported that ghrelin modulates adult hippocampal neurogenesis. However, there is a possibility that the action of ghrelin on hippocampal neurogenesis could be, in part, due to the ability of ghrelin to stimulate the GH/insulin-like growth factor (IGF)-1 axis, where both GH and IGF-1 infusions are known to increase hippocampal neurogenesis. To explore this possibility, we assessed the impact of ghrelin on progenitor cell proliferation and differentiation in the dentate gyrus (DG) of spontaneous dwarf rats (SDRs), a dwarf strain with a mutation of the GH gene resulting in total loss of GH. Double immunohistochemical staining revealed that Ki-67-positive progenitor cells and doublecortin (DCX)-positive neuroblasts in the DG of the SDRs expressed ghrelin receptors. We found that ghrelin treatment in the SDRs significantly increased the number of proliferating cell nuclear antigen- and BrdU-labeled cells in the DG. The number of DCX-labeled cells in the DG of ghrelin-treated SDRs was also significantly increased compared with the vehicle-treated controls. To test whether ghrelin has a direct effect on cognitive performance independently of somatotropic axis, hippocampus-dependent learning and memory were assessed using the Y-maze and novel object recognition (NOR) test in the SDRs. Ghrelin treatment for 4 weeks by subcutaneous osmotic pump significantly increased alternation rates in the Y-maze and exploration time for novel object in the NOR test compared to vehicle-treated controls. Our results indicate that ghrelin-induced adult hippocampal neurogenesis and enhancement of cognitive function are mediated independently of somatotropic axis.

  17. Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with GH-treated GH deficiency? A systematic literature analysis

    DEFF Research Database (Denmark)

    Klefter, O.; Feldt-Rasmussen, U.

    2009-01-01

    to a muscle modulating effect, and if treatment with GH would primarily increase muscle mass and strength with a secondary increase in BMD/BMC, thus supporting the present physiological concept that mass and strength of bones are mainly determined by dynamic loads from the skeletal muscles. METHOD: We...... performed a systematic literature analysis, including 51 clinical trials published between 1996 and 2008, which had studied the development in muscle mass, muscle strength, BMD, and/or BMC in GH-treated adult GHD patients. RESULTS: GH therapy had an anabolic effect on skeletal muscle. The largest increase...... in muscle mass occurred during the first 12 months of therapy. Most trials measuring BMD/BMC reported significant increases from baseline values. The significant increases in BMD/BMC occurred after 12-18 months of treatment, i.e. usually later than the increases in muscle parameters. Only seven trials...

  18. Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with GH-treated GH deficiency?

    DEFF Research Database (Denmark)

    Klefter, Oliver; Feldt-Rasmussen, Ulla

    2009-01-01

    to a muscle modulating effect, and if treatment with GH would primarily increase muscle mass and strength with a secondary increase in BMD/BMC, thus supporting the present physiological concept that mass and strength of bones are mainly determined by dynamic loads from the skeletal muscles. METHOD: We...... performed a systematic literature analysis, including 51 clinical trials published between 1996 and 2008, which had studied the development in muscle mass, muscle strength, BMD, and/or BMC in GH-treated adult GHD patients. RESULTS: GH therapy had an anabolic effect on skeletal muscle. The largest increase...... in muscle mass occurred during the first 12 months of therapy. Most trials measuring BMD/BMC reported significant increases from baseline values. The significant increases in BMD/BMC occurred after 12-18 months of treatment, i.e. usually later than the increases in muscle parameters. Only seven trials...

  19. Intermittent hypoxia causes histological kidney damage and increases growth factor expression in a mouse model of obstructive sleep apnea.

    Directory of Open Access Journals (Sweden)

    Bisher Abuyassin

    have an increased glomerular area (by 1.13 fold, p< 0.001 and expansion of mesangial matrix (by 1.8 fold, p< 0.01. Moreover, the glomerular expressions of TGF-β1, CTGF and VEGF-A proteins were 2.7, 2.2 and 3.8-fold higher in mice exposed to IH (p< 0.05 for all. Furthermore, western blotting protein analysis demonstrates that IH-exposed mice express higher levels of TGF-β1, CTGF and VEGF-A proteins by 1.9, 4.0 and 1.6-fold (p< 0.05 for all respectively. Renal cellular apoptosis was greater in the IH group as shown by an increased cortical Bax/Bcl-2 protein ratio (p< 0.01 and higher fluorometric TUNEL staining (p< 0.001. Finally, 24-hr urinary albumin levels were higher in mice exposed to IH (43.4 μg vs 9.7 μg, p< 0.01, while there were no differences in serum creatinine levels between the two groups. We conclude that IH causes kidney injury that is accompanied by glomerular hypertrophy, mesangial matrix expansion, increased expression of glomerular growth factors and an increased cellular apoptosis.

  20. Intermittent hypoxia causes histological kidney damage and increases growth factor expression in a mouse model of obstructive sleep apnea.

    Science.gov (United States)

    Abuyassin, Bisher; Badran, Mohammad; Ayas, Najib T; Laher, Ismail

    2018-01-01

    increased glomerular area (by 1.13 fold, p< 0.001) and expansion of mesangial matrix (by 1.8 fold, p< 0.01). Moreover, the glomerular expressions of TGF-β1, CTGF and VEGF-A proteins were 2.7, 2.2 and 3.8-fold higher in mice exposed to IH (p< 0.05 for all). Furthermore, western blotting protein analysis demonstrates that IH-exposed mice express higher levels of TGF-β1, CTGF and VEGF-A proteins by 1.9, 4.0 and 1.6-fold (p< 0.05 for all) respectively. Renal cellular apoptosis was greater in the IH group as shown by an increased cortical Bax/Bcl-2 protein ratio (p< 0.01) and higher fluorometric TUNEL staining (p< 0.001). Finally, 24-hr urinary albumin levels were higher in mice exposed to IH (43.4 μg vs 9.7 μg, p< 0.01), while there were no differences in serum creatinine levels between the two groups. We conclude that IH causes kidney injury that is accompanied by glomerular hypertrophy, mesangial matrix expansion, increased expression of glomerular growth factors and an increased cellular apoptosis.

  1. Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats

    International Nuclear Information System (INIS)

    Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Sugita-Konishi, Yoshiko; Yoshida, Toshinori; Shibutani, Makoto

    2015-01-01

    Highlights: • Maternal AFB 1 exposure effect on hippocampal neurogenesis was examined in rats. • AFB 1 reversibly reduced cell proliferation and type-3 progenitor cells in the SGZ. • Suppressed cholinergic signals to GABAergic interneurons may reduce type-3 cells. • Suppressed BDNF–TRKB signaling may contribute to aberration of neurogenesis. • The NOAEL for offspring was determined to be 0.1 ppm (7.1–13.6 μg/kg BW/day). - Abstract: To elucidate the maternal exposure effects of aflatoxin B 1 (AFB 1 ) and its metabolite aflatoxin M 1 , which is transferred into milk, on postnatal hippocampal neurogenesis, pregnant Sprague-Dawley rats were provided a diet containing AFB 1 at 0, 0.1, 0.3, or 1.0 ppm from gestational day 6 to day 21 after delivery on weaning. Offspring were maintained through postnatal day (PND) 77 without AFB 1 exposure. Following exposure to 1.0 ppm AFB 1 , offspring showed no apparent systemic toxicity at weaning, whereas dams showed increased liver weight and DNA repair gene upregulation in the liver. In the hippocampal dentate gyrus of male PND 21 offspring, the number of doublecortin + progenitor cells were decreased, which was associated with decreased proliferative cell population in the subgranular zone at ≥0.3 ppm, although T-box brain 2 + cells, tubulin beta III + cells, gamma-H2A histone family, member X + cells, and cyclin-dependent kinase inhibitor 1A + cells did not fluctuate in number. AFB 1 exposure examined at 1.0 ppm also resulted in transcript downregulation of the cholinergic receptor subunit Chrna7 and dopaminergic receptor Drd2 in the dentate gyrus, although there was no change in transcript levels of DNA repair genes. In the hippocampal dentate hilus, interneurons expressing CHRNA7 or phosphorylated tropomyosin receptor kinase B (TRKB) decreased at ≥0.3 ppm. On PND 77, there were no changes in neurogenesis-related parameters. These results suggested that maternal AFB 1 exposure reversibly affects hippocampal

  2. Third harmonic generation imaging of intact human cerebral organoids to assess key components of early neurogenesis in Rett Syndrome (Conference Presentation)

    Science.gov (United States)

    Yildirim, Murat; Feldman, Danielle; Wang, Tianyu; Ouzounov, Dimitre G.; Chou, Stephanie; Swaney, Justin; Chung, Kwanghun; Xu, Chris; So, Peter T. C.; Sur, Mriganka

    2017-02-01

    Rett Syndrome (RTT) is a pervasive, X-linked neurodevelopmental disorder that predominantly affects girls. It is mostly caused by a sporadic mutation in the gene encoding methyl CpG-binding protein 2 (MeCP2).The clinical features of RTT are most commonly reported to emerge between the ages of 6-18 months and implicating RTT as a disorder of postnatal development. However, a variety of recent evidence from our lab and others demonstrates that RTT phenotypes are present at the earliest stages of brain development including neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. We have used RTT patient-derived induced pluripotent stem cells to generate 3D human cerebral organoids that can serve as a model for human neurogenesis in vitro. We aim to expand on our existing findings in order to determine aberrancies at individual stages of neurogenesis by performing structural and immunocytochemical staining in isogenic control and MeCP2-deficient organoids. In addition, we aim to use Third Harmonic Generation (THG) microscopy as a label-free, nondestructive 3D tissue visualization method in order to gain a complete understanding of the structural complexity that underlies human neurogenesis. As a proof of concept, we have performed THG imaging in healthy intact human cerebral organoids cleared with SWITCH. We acquired an intrinsic THG signal with the following laser configurations: 400 kHz repetition rate, 65 fs pulse width laser at 1350 nm wavelength. In these THG images, nuclei are clearly delineated and cross sections demonstrate the depth penetration capacity (< 1mm) that extends throughout the organoid. Imaging control and MeCP2-deficient human cerebral organoids in 2D sections reveals structural and protein expression-based alterations that we expect will be clearly elucidated via both THG and three-photon fluorescence microscopy.

  3. MicroRNA-124 slows down the progression of Huntington′s disease by promoting neurogenesis in the striatum

    Directory of Open Access Journals (Sweden)

    Tian Liu

    2015-01-01

    Full Text Available MicroRNA-124 contributes to neurogenesis through regulating its targets, but its expression both in the brain of Huntington′s disease mouse models and patients is decreased. However, the effects of microRNA-124 on the progression of Huntington′s disease have not been reported. Results from this study showed that microRNA-124 increased the latency to fall for each R6/2 Huntington′s disease transgenic mouse in the rotarod test. 5-Bromo-2′-deoxyuridine (BrdU staining of the striatum shows an increase in neurogenesis. In addition, brain-derived neurotrophic factor and peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein levels in the striatum were increased and SRY-related HMG box transcription factor 9 protein level was decreased. These findings suggest that microRNA-124 slows down the progression of Huntington′s disease possibly through its important role in neuronal differentiation and survival.

  4. Effects of curcumin on short-term spatial and recognition memory, adult neurogenesis and neuroinflammation in a streptozotocin-induced rat model of dementia of Alzheimer's type.

    Science.gov (United States)

    Bassani, Taysa B; Turnes, Joelle M; Moura, Eric L R; Bonato, Jéssica M; Cóppola-Segovia, Valentín; Zanata, Silvio M; Oliveira, Rúbia M M W; Vital, Maria A B F

    2017-09-29

    Curcumin is a natural polyphenol with evidence of antioxidant, anti-inflammatory and neuroprotective properties. Recent evidence also suggests that curcumin increases cognitive performance in animal models of dementia, and this effect would be related to its capacity to enhance adult neurogenesis. The aim of this study was to test the hypothesis that curcumin treatment would be able to preserve cognition by increasing neurogenesis and decreasing neuroinflammation in the model of dementia of Alzheimer's type induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) in Wistar rats. The animals were injected with ICV-STZ or vehicle and curcumin treatments (25, 50 and 100mg/kg, gavage) were performed for 30days. Four weeks after surgery, STZ-lesioned animals exhibited impairments in short-term spatial memory (Object Location Test (OLT) and Y maze) and short-term recognition memory (Object Recognition Test - ORT), decreased cell proliferation and immature neurons (Ki-67- and doublecortin-positive cells, respectively) in the subventricular zone (SVZ) and dentate gyrus (DG) of hippocampus, and increased immunoreactivity for the glial markers GFAP and Iba-1 (neuroinflammation). Curcumin treatment in the doses of 50 and 100mg/kg prevented the deficits in recognition memory in the ORT, but not in spatial memory in the OLT and Y maze. Curcumin treatment exerted only slight improvements in neuroinflammation, resulting in no improvements in hippocampal and subventricular neurogenesis. These results suggest a positive effect of curcumin in object recognition memory which was not related to hippocampal neurogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Absence of the neurogenesis-dependent nuclear receptor TLX induces inflammation in the hippocampus.

    Science.gov (United States)

    Kozareva, Danka A; Hueston, Cara M; Ó'Léime, Ciarán S; Crotty, Suzanne; Dockery, Peter; Cryan, John F; Nolan, Yvonne M

    2017-08-20

    The orphan nuclear receptor TLX (Nr2e1) is a key regulator of hippocampal neurogenesis. Impaired adult hippocampal neurogenesis has been reported in neurodegenerative and psychiatric conditions including dementia and stress-related depression. Neuroinflammation is also implicated in the neuropathology of these disorders, and has been shown to negatively affect hippocampal neurogenesis. To investigate a role for TLX in hippocampal neuroinflammation, we assessed microglial activation in the hippocampus of mice with a spontaneous deletion of TLX. Results from our study suggest that a lack of TLX is implicated in deregulation of microglial phenotype and that consequently, the survival and function of newborn cells in the hippocampus is impaired. TLX may be an important target in understanding inflammatory-associated impairments in neurogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions

    Science.gov (United States)

    Ming, Guo-li; Song, Hongjun

    2011-01-01

    Summary Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade. PMID:21609825

  7. Regulation of hippocampal neurogenesis by systemic factors including stress, glucocorticoids, sleep, and inflammation

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.; van Dam, A.-M.; Czéh, B.; Gage, F.H.; Kempermann, G.; Song, H.

    2008-01-01

    This review summarizes and discusses the regulation of adult neurogenesis and hippocampal cellular plasticity by systemic factors. We focus on the role of stress, glucocorticoids, and related factors such as sleep deprivation and inflammation.

  8. Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action

    International Nuclear Information System (INIS)

    Scherzberg, Maria-Christina; Kiehl, Andreas; Zivkovic, Aleksandra; Stark, Holger; Stein, Jürgen; Fürst, Robert; Steinhilber, Dieter; Ulrich-Rückert, Sandra

    2015-01-01

    (Z)-3,5,4′-Trimethoxystilbene (Z-TMS) is a resveratrol analog with increased antiproliferative activity towards a number of cancer cell lines compared to resveratrol, which has been shown to inhibit tubulin polymerization in vitro. The purpose of this study was to investigate if Z-TMS still shows potential for the prevention of metabolic diseases as known for resveratrol. Cell growth inhibition was determined with IC 50 values for Z-TMS between 0.115 μM and 0.473 μM (resveratrol: 110.7 μM to 190.2 μM). Flow cytometric analysis revealed a G 2 /M arrest after Z-TMS treatment, whereas resveratrol caused S phase arrest. Furthermore, Z-TMS was shown to impair microtubule polymerization. Beneficial effects on lipid accumulation were observed for resveratrol, but not for Z-TMS in an in vitro steatosis model. (E)-Resveratrol was confirmed to elevate cAMP levels, and knockdown of AMPK attenuated the antiproliferative activity, while Z-TMS did not show significant effects in these experiments. SIRT1 and AMPK activities were further measured indirectly via induction of the target gene small heterodimer partner (SHP). Thereby, (E)-resveratrol, but not Z-TMS, showed potent induction of SHP mRNA levels in an AMPK- and SIRT1-dependent manner, as confirmed by knockdown experiments. We provide evidence that Z-TMS does not show beneficial metabolic effects, probably due to loss of activity towards resveratrol target genes. Moreover, our data support previous findings that Z-TMS acts as an inhibitor of tubulin polymerization. These findings confirm that the methylation of resveratrol leads to profound changes in the mode of action, which should be taken into consideration when conducting lead structure optimization approaches. - Highlights: • Methylation of resveratrol leads to profound changes in biologic activity. • Z-TMS does not prevent hepatic steatosis, but inhibits tubulin polymerization. • Resveratrol analog Z-TMS does not influence known targets like PDEs, SIRT1

  9. Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action

    Energy Technology Data Exchange (ETDEWEB)

    Scherzberg, Maria-Christina; Kiehl, Andreas; Zivkovic, Aleksandra; Stark, Holger [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Stein, Jürgen [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Department of Internal Medicine, Sachsenhausen Hospital, Frankfurt am Main (Germany); Fürst, Robert [Institute of Pharmaceutical Biology, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Steinhilber, Dieter [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Ulrich-Rückert, Sandra, E-mail: sandra.ulrich@em.uni-frankfurt.de [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany)

    2015-08-15

    (Z)-3,5,4′-Trimethoxystilbene (Z-TMS) is a resveratrol analog with increased antiproliferative activity towards a number of cancer cell lines compared to resveratrol, which has been shown to inhibit tubulin polymerization in vitro. The purpose of this study was to investigate if Z-TMS still shows potential for the prevention of metabolic diseases as known for resveratrol. Cell growth inhibition was determined with IC{sub 50} values for Z-TMS between 0.115 μM and 0.473 μM (resveratrol: 110.7 μM to 190.2 μM). Flow cytometric analysis revealed a G{sub 2}/M arrest after Z-TMS treatment, whereas resveratrol caused S phase arrest. Furthermore, Z-TMS was shown to impair microtubule polymerization. Beneficial effects on lipid accumulation were observed for resveratrol, but not for Z-TMS in an in vitro steatosis model. (E)-Resveratrol was confirmed to elevate cAMP levels, and knockdown of AMPK attenuated the antiproliferative activity, while Z-TMS did not show significant effects in these experiments. SIRT1 and AMPK activities were further measured indirectly via induction of the target gene small heterodimer partner (SHP). Thereby, (E)-resveratrol, but not Z-TMS, showed potent induction of SHP mRNA levels in an AMPK- and SIRT1-dependent manner, as confirmed by knockdown experiments. We provide evidence that Z-TMS does not show beneficial metabolic effects, probably due to loss of activity towards resveratrol target genes. Moreover, our data support previous findings that Z-TMS acts as an inhibitor of tubulin polymerization. These findings confirm that the methylation of resveratrol leads to profound changes in the mode of action, which should be taken into consideration when conducting lead structure optimization approaches. - Highlights: • Methylation of resveratrol leads to profound changes in biologic activity. • Z-TMS does not prevent hepatic steatosis, but inhibits tubulin polymerization. • Resveratrol analog Z-TMS does not influence known targets like

  10. Wnt/β-catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid-induced epilepsy.

    Science.gov (United States)

    Qu, Zhengyi; Su, Fang; Qi, Xueting; Sun, Jianbo; Wang, Hongcai; Qiao, Zhenkui; Zhao, Hong; Zhu, Yulan

    2017-10-01

    Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis with massive neuronal loss and severe gliosis. Aberrant neurogenesis has been shown in the epileptogenesis process of temporal lobe epilepsy. However, the molecular mechanisms underlying aberrant neurogenesis remain unclear. The roles of Wnt signalling cascade have been well established in neurogenesis during multiple aspects. Here, we used kainic acid-induced rat epilepsy model to investigate whether Wnt/β-catenin signalling pathway is involved in the aberrant neurogenesis in temporal lobe epilepsy. Immunostaining and western blotting results showed that the expression levels of β-catenin, Wnt3a, and cyclin D1, the key regulators in Wnt signalling pathway, were up-regulated during acute epilepsy induced by the injection of kainic acids, indicating that Wnt signalling pathway was activated in kainic acid-induced temporal lobe epilepsy. Moreover, BrdU labelling results showed that blockade of the Wnt signalling by knocking down β-catenin attenuated aberrant neurogenesis induced by kainic acids injection. Altogether, Wnt/β-catenin signalling pathway mediated hippocampal neurogenesis during epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis. Aberrant neurogenesis has been shown to involve in the epileptogenesis process of temporal lobe epilepsy. In the present study, we discovered that Wnt3a/β-catenin signalling pathway serves as a link between aberrant neurogenesis and underlying remodelling in the hippocampus, leading to temporal lobe epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Interaction Effect of Social Isolation and High Dose Corticosteroid on Neurogenesis and Emotional Behavior

    OpenAIRE

    Chan, Jackie N.-M.; Lee, Jada C.-D.; Lee, Sylvia S. P.; Hui, Katy K. Y.; Chan, Alan H. L.; Fung, Timothy K.-H.; S?nchez-Vida?a, Dalinda I.; Lau, Benson W.-M.; Ngai, Shirley P.-C.

    2017-01-01

    Hypercortisolemia is one of the clinical features found in depressed patients. This clinical feature has been mimicked in animal studies via application of exogenous corticosterone (CORT). Previous studies suggested that CORT can induce behavioral disturbance in anxious-depressive like behavior, which is associated with suppressed neurogenesis. Hippocampal neurogenesis plays an important role in adult cognitive and behavioral regulation. Its suppression may thus lead to neuropsychiatric disor...

  12. NeuroD Modulates Opioid Agonist-Selective Regulation of Adult Neurogenesis and Contextual Memory Extinction

    OpenAIRE

    Zheng, Hui; Zhang, Yue; Li, Wen; Loh, Horace H; Law, Ping-Yee

    2013-01-01

    Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of neurogenic differentiation 1 (NeuroD) activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate o...

  13. Tooth loss early in life suppresses neurogenesis and synaptophysin expression in the hippocampus and impairs learning in mice.

    Science.gov (United States)

    Kubo, Kin-Ya; Murabayashi, Chika; Kotachi, Mika; Suzuki, Ayumi; Mori, Daisuke; Sato, Yuichi; Onozuka, Minoru; Azuma, Kagaku; Iinuma, Mitsuo

    2017-02-01

    Tooth loss induced neurological alterations through activation of a stress hormone, corticosterone. Age-related hippocampal morphological and functional changes were accelerated by early tooth loss in senescence-accelerated mouse prone 8 (SAMP8). In order to explore the mechanism underlying the impaired hippocampal function resulting from early masticatory dysfunction due to tooth loss, we investigated the effects of early tooth loss on plasma corticosterone levels, learning ability, neurogenesis, and synaptophysin expression in the hippocampus later in life of SAMP8 mice. We examined the effects of tooth loss soon after tooth eruption (1 month of age) on plasma corticosterone levels, learning ability in the Morris water maze, newborn cell proliferation, survival and differentiation in the hippocampal dentate gyrus, and synaptophysin expression in the hippocampus of aged (8 months of age) SAMP8 mice. Aged mice with early tooth loss exhibited increased plasma corticosterone levels, hippocampus-dependent learning deficits in the Morris water maze, decreased cell proliferation, and cell survival in the dentate gyrus, and suppressed synaptophysin expression in the hippocampus. Newborn cell differentiation in the hippocampal dentate gyrus, however, was not affected by early tooth loss. These findings suggest that learning deficits in aged SAMP8 mice with tooth loss soon after tooth eruption are associated with suppressed neurogenesis and decreased synaptophysin expression resulting from increased plasma corticosterone levels, and that long-term tooth loss leads to impaired cognitive function in older age. Copyright © 2016. Published by Elsevier Ltd.

  14. Evidence for Increased Aggressiveness in a Recent Widespread Strain of Puccinia striiformis f. sp. tritici Causing Stripe Rust of Wheat

    DEFF Research Database (Denmark)

    Milus, Eugene A; Kristensen, Kristian; Hovmøller, Mogens S

    2009-01-01

    Stripe rust (yellow rust) of wheat, caused by Puccinia striiformis f. sp. tritici, has become more severe in eastern United States, Australia, and elsewhere since 2000. Recent research has shown that this coincided with a global spread of two closely related strains that were similar based on vir...... that wheat rust fungi can adapt to warmer temperatures and cause severe disease in previously unfavorable environments......Stripe rust (yellow rust) of wheat, caused by Puccinia striiformis f. sp. tritici, has become more severe in eastern United States, Australia, and elsewhere since 2000. Recent research has shown that this coincided with a global spread of two closely related strains that were similar based...... regimes for latent period, lesion length, lesion width, lesion area, and spore production on adult plants of a susceptible wheat cultivar with no known genes for resistance to stripe rust. "New" isolates (since 2000) were significantly more aggressive than "old" isolates (before 2000) for all variables...

  15. Adult Neurogenesis in Sheep: Characterization and Contribution to Reproduction and Behavior

    Science.gov (United States)

    Lévy, Frederic; Batailler, Martine; Meurisse, Maryse; Migaud, Martine

    2017-01-01

    Sheep have many advantages to study neurogenesis in comparison to the well-known rodent models. Their development and life expectancy are relatively long and they possess a gyrencephalic brain. Sheep are also seasonal breeders, a characteristic that allows studying the involvement of hypothalamic neurogenesis in the control of seasonal reproduction. Sheep are also able to individually recognize their conspecifics and develop selective and lasting bonds. Adult olfactory neurogenesis could be adapted to social behavior by supporting recognition of conspecifics. The present review reveals the distinctive features of the hippocampal, olfactory, and hypothalamic neurogenesis in sheep. In particular, the organization of the subventricular zone and the dynamic of neuronal maturation differs from that of rodents. In addition, we show that various physiological conditions, such as seasonal reproduction, gestation, and lactation differently modulate these three neurogenic niches. Last, we discuss recent evidence indicating that hypothalamic neurogenesis acts as an important regulator of the seasonal control of reproduction and that olfactory neurogenesis could be involved in odor processing in the context of maternal behavior. PMID:29109674

  16. Prion diseases and adult neurogenesis: how do prions counteract the brain's endogenous repair machinery?

    Science.gov (United States)

    Relaño-Ginés, Aroa; Lehmann, Sylvain; Crozet, Carole

    2014-01-01

    Scientific advances in stem cell biology and adult neurogenesis have raised the hope that neurodegenerative disorders could benefit from stem cell-based therapy. Adult neurogenesis might be part of the physiological regenerative process, however it might become impaired by the disease's mechanism and therefore contribute to neurodegeneration. In prion disorders this endogenous repair system has rarely been studied. Whether adult neurogenesis plays a role or not in brain repair or in the propagation of prion pathology remains unclear. We have recently investigated the status of adult neural stem cells isolated from prion-infected mice. We were able to show that neural stem cells accumulate and replicate prions thus resulting in an alteration of their neuronal destiny. We also reproduced these results in adult neural stem cells, which were infected in vitro. The fact that endogenous adult neurogenesis could be altered by the accumulation of misfolded prion protein represents another great challenge. Inhibiting prion propagation in these cells would thus help the endogenous neurogenesis to compensate for the injured neuronal system. Moreover, understanding the endogenous modulation of the neurogenesis system would help develop effective neural stem cell-based therapies.

  17. Neurogenesis in the brain auditory pathway of a marsupial, the northern native cat (Dasyurus hallucatus)

    International Nuclear Information System (INIS)

    Aitkin, L.; Nelson, J.; Farrington, M.; Swann, S.

    1991-01-01

    Neurogenesis in the auditory pathway of the marsupial Dasyurus hallucatus was studied. Intraperitoneal injections of tritiated thymidine (20-40 microCi) were made into pouch-young varying from 1 to 56 days pouch-life. Animals were killed as adults and brain sections were prepared for autoradiography and counterstained with a Nissl stain. Neurons in the ventral cochlear nucleus were generated prior to 3 days pouch-life, in the superior olive at 5-7 days, and in the dorsal cochlear nucleus over a prolonged period. Inferior collicular neurogenesis lagged behind that in the medial geniculate, the latter taking place between days 3 and 9 and the former between days 7 and 22. Neurogenesis began in the auditory cortex on day 9 and was completed by about day 42. Thus neurogenesis was complete in the medullary auditory nuclei before that in the midbrain commenced, and in the medial geniculate before that in the auditory cortex commenced. The time course of neurogenesis in the auditory pathway of the native cat was very similar to that in another marsupial, the brushtail possum. For both, neurogenesis occurred earlier than in eutherian mammals of a similar size but was more protracted

  18. ALTERED HIPPOCAMPAL NEUROGENESIS AND AMYGDALAR NEURONAL ACTIVITY IN ADULT MICE WITH REPEATED EXPERIENCE OF AGGRESSION

    Directory of Open Access Journals (Sweden)

    Dmitriy eSmagin

    2015-12-01

    Full Text Available The repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos positive cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights.

  19. Thermal-hydraulic causes of increase of dynamic stresses and cracks in the covers of vessel reactors

    International Nuclear Information System (INIS)

    Proskuryakov, K.N.

    2006-01-01

    Paper presents data of measurements and of analysis of the WWER-1000 reactor NPP equipment process noises manifesting occurrence of the latent dynamic processes. The NPP is shown to have unused abilities to prolong the equipment service life and to reduce possibility of the equipment thermally and hydraulically caused unexpected malfunctions [ru

  20. Increased orosomucoid in urine is an independent predictor of cardiovascular and all-cause mortality in patients with type 2 diabetes at 10 years of follow-up

    DEFF Research Database (Denmark)

    Svendstrup, Mathilde; Christiansen, Merete Skovdal; Magid, Erik

    2013-01-01

    To evaluate whether increased urinary orosomucoid excretion rate (UOER) is an independent predictor of cardiovascular and all-cause mortality in type 2 diabetes (T2DM) and type 1 diabetes (T1DM) at 10years of follow-up.......To evaluate whether increased urinary orosomucoid excretion rate (UOER) is an independent predictor of cardiovascular and all-cause mortality in type 2 diabetes (T2DM) and type 1 diabetes (T1DM) at 10years of follow-up....

  1. Botulinum toxin injection causes hyper-reflexia and increased muscle stiffness of the triceps surae muscle in the rat

    DEFF Research Database (Denmark)

    Pingel, Jessica; Wienecke, Jacob; Lorentzen, Jakob

    2016-01-01

    Botulinum toxin is used to diminish spasticity and reduce the risk of development of contractures. Here, we investigated changes in muscle stiffness caused by reflex activity or elastic muscle properties following botulinum toxin injection in the triceps surae muscle in rats. Forty-four rats...... received injection of botulinum toxin in the left triceps surae muscle. Control measurements were performed on the non-injected contralateral side in all rats. Acute experiments were performed 1, 2, 4 and 8 weeks following injection. The triceps surae muscle was dissected free, the Achilles tendon was cut...... and attached to a muscle puller. The resistance of the muscle to stretches of different amplitudes and velocities was systematically investigated. Reflex mediated torque was normalized to the maximal muscle force (Mmax) evoked by supramaximal stimulation of the tibial nerve. Botulinum toxin injection caused...

  2. Increased Mortality in Schizophrenia Due to Cardiovascular Disease – A Non-Systematic Review of Epidemiology, Possible Causes, and Interventions

    OpenAIRE

    Ringen, Petter Andreas; Engh, John A.; Birkenaes, Astrid B.; Dieset, Ingrid; Andreassen, Ole A.

    2014-01-01

    Background: Schizophrenia is among the major causes of disability worldwide and the mortality from cardiovascular disease (CVD) is significantly elevated. There is a growing concern that this health challenge is not fully understood and efficiently addressed. Methods: Non-systematic review using searches in PubMed on relevant topics as well as selection of references based on the authors’ experience from clinical work and research in the field. Results: In most countries, the standardiz...

  3. Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

    Directory of Open Access Journals (Sweden)

    Clara Penas

    2015-04-01

    Full Text Available Although casein kinase 1δ (CK1δ is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/CCdh1 ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CCdh1 controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.

  4. Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway.

    Science.gov (United States)

    Chaker, Zayna; George, Caroline; Petrovska, Marija; Caron, Jean-Baptiste; Lacube, Philippe; Caillé, Isabelle; Holzenberger, Martin

    2016-05-01

    Hypothalamic tanycytes are specialized glial cells lining the third ventricle. They are recently identified as adult stem and/or progenitor cells, able to self-renew and give rise to new neurons postnatally. However, the long-term neurogenic potential of tanycytes and the pathways regulating lifelong cell replacement in the adult hypothalamus are largely unexplored. Using inducible nestin-CreER(T2) for conditional mutagenesis, we performed lineage tracing of adult hypothalamic stem and/or progenitor cells (HySC) and demonstrated that new neurons continue to be born throughout adult life. This neurogenesis was targeted to numerous hypothalamic nuclei and produced different types of neurons in the dorsal periventricular regions. Some adult-born neurons integrated the median eminence and arcuate nucleus during aging and produced growth hormone releasing hormone. We showed that adult hypothalamic neurogenesis was tightly controlled by insulin-like growth factors (IGF). Knockout of IGF-1 receptor from hypothalamic stem and/or progenitor cells increased neuronal production and enhanced α-tanycyte self-renewal, preserving this stem cell-like population from age-related attrition. Our data indicate that adult hypothalamus retains the capacity of cell renewal, and thus, a substantial degree of structural plasticity throughout lifespan. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Putative Adult Neurogenesis in Old World Parrots: The Congo African Grey Parrot (Psittacus erithacus) and Timneh Grey Parrot (Psittacus timneh).

    Science.gov (United States)

    Mazengenya, Pedzisai; Bhagwandin, Adhil; Manger, Paul R; Ihunwo, Amadi O

    2018-01-01

    In the current study, we examined for the first time, the potential for adult neurogenesis throughout the brain of the Congo African grey parrot ( Psittacus erithacus ) and Timneh grey parrot ( Psittacus timneh ) using immunohistochemistry for the endogenous markers proliferating cell nuclear antigen (PCNA), which labels proliferating cells, and doublecortin (DCX), which stains immature and migrating neurons. A similar distribution of PCNA and DCX immunoreactivity was found throughout the brain of the Congo African grey and Timneh grey parrots, but minor differences were also observed. In both species of parrots, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, subventricular zone of the lateral wall of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and the rhombencephalon. The olfactory bulb and telencephalic subdivisions exhibited a higher density of both PCNA and DCX immunoreactive cells than any other brain region. DCX immunoreactive staining was stronger in the telencephalon than in the subtelencephalic structures. There was evidence of proliferative hot spots in the dorsal and ventral poles of the lateral ventricle in the Congo African grey parrots at rostral levels, whereas only the dorsal accumulation of proliferating cells was observed in the Timneh grey parrot. In most pallial regions the density of PCNA and DCX stained cells increased from rostral to caudal levels with the densest staining in the nidopallium caudolaterale (NCL). The widespread distribution of PCNA and DCX in the brains of both parrot species suggest the importance of adult neurogenesis and neuronal plasticity during learning and adaptation to external environmental variations.

  6. Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

    NARCIS (Netherlands)

    Rosendahl, Alva; Niemann, Gianina; Lange, Sascha; Ahadzadeh, Erfan; Krebs, Christian; Contrepas, Aurelie; van Goor, Harry; Wiech, Thorsten; Bader, Michael; Schwake, Michael; Peters, Judith; Stahl, Rolf; Nguyen, Genevieve; Wenzel, Ulrich

    Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is

  7. Protein-Energy Malnutrition (PEM is Believed to Lead to an Increased Susceptibility to Infection, or cause Impaired Immunity

    Directory of Open Access Journals (Sweden)

    Mellova Amir Masrizal

    2003-08-01

    Full Text Available Infection, occurring with malnutrition, is a major cause of morbidity in all age groups and is responsible for two-thirds of all death under 5 yr of age in developing countries. Many cells of the immune system are known to depend for their function on metabolic pathways that employ various nutrients as critical factors. The most consistent changes in immune competence in PEM are in cell-mediated immunity, the bactericidal function of neutrophils, the complement system, the secretory immunoglobin A, and antibody response.

  8. Temporal Discontiguity Is neither Necessary nor Sufficient for Learning-Induced Effects on Adult Neurogenesis

    Science.gov (United States)

    Leuner, Benedetta; Waddell, Jaylyn; Gould, Elizabeth; Shors, Tracey J.

    2012-01-01

    Some, but not all, types of learning and memory can influence neurogenesis in the adult hippocampus. Trace eyeblink conditioning has been shown to enhance the survival of new neurons, whereas delay eyeblink conditioning has no such effect. The key difference between the two training procedures is that the conditioning stimuli are separated in time during trace but not delay conditioning. These findings raise the question of whether temporal discontiguity is necessary for enhancing the survival of new neurons. Here we used two approaches to test this hypothesis. First, we examined the influence of a delay conditioning task in which the duration of the conditioned stimulus (CS) was increased nearly twofold, a procedure that critically engages the hippocampus. Although the CS and unconditioned stimulus are contiguous, this very long delay conditioning procedure increased the number of new neurons that survived. Second, we examined the influence of learning the trace conditioned response (CR) after having acquired the CR during delay conditioning, a procedure that renders trace conditioning hippocampal-independent. In this case, trace conditioning did not enhance the survival of new neurons. Together, these results demonstrate that associative learning increases the survival of new neurons in the adult hippocampus, regardless of temporal contiguity. PMID:17192426

  9. Co-exposure to ultrafine particulate matter and ozone causes electrocardiogram changes indicative of increased arrhythmia risk in mice

    Science.gov (United States)

    Numerous studies have shown a relationship between acute air pollution exposure and increased risk for cardiovascular morbidity and mortality. Due to the inherent complexity of air pollution, recent studies have focused on co-exposures to better understand potential interactions....

  10. BIRDS AS A MODEL TO STUDY ADULT NEUROGENESIS: BRIDGING EVOLUTIONARY, COMPARATIVE AND NEUROETHOLOGICAL APPROCHES

    Science.gov (United States)

    BARNEA, ANAT; PRAVOSUDOV, VLADIMIR

    2011-01-01

    During the last few decades evidence has demonstrated that adult neurogenesis is a well-preserved feature throughout the animal kingdom. In birds, ongoing neuronal addition occurs rather broadly, to a number of brain regions. This review describes adult avian neurogenesis and neuronal recruitment, discusses factors that regulate these processes, and touches upon the question of their genetic control. Several attributes make birds an extremely advantageous model to study neurogenesis. First, song learning exhibits seasonal variation that is associated with seasonal variation in neuronal turnover in some song control brain nuclei, which seems to be regulated via adult neurogenesis. Second, food-caching birds naturally use memory-dependent behavior in learning locations of thousands of food caches scattered over their home ranges. In comparison with other birds, food-caching species have relatively enlarged hippocampi with more neurons and intense neurogenesis, which appears to be related to spatial learning. Finally, migratory behavior and naturally occurring social systems in birds also provide opportunities to investigate neurogenesis. Such diversity of naturally-occurring memory-based behaviors, combined with the fact that birds can be studied both in the wild and in the laboratory, make them ideal for investigation of neural processes underlying learning. This can be done by using various approaches, from evolutionary and comparative to neuroethological and molecular. Finally, we connect the avian arena to a broader view by providing a brief comparative and evolutionary overview of adult neurogenesis and by discussing the possible functional role of the new neurons. We conclude by indicating future directions and possible medical applications. PMID:21929623

  11. Combination Of Aging And Dimethylhydrazine Treatment Causes An Increase In The Stem Cell Population Of Rat Colonic Crypts

    OpenAIRE

    Levi, Edi; Misra, Sandhya; Du, Jianhua; Patel, Bhaumik B.; Majumdar, Adhip P. N.

    2009-01-01

    Aging is associated with increased incidence of colon cancers. It is also becoming evident that cancer stem cells (CSC) play a vital role in the pathogenesis and prognosis of colon cancer. Recently, we reported the presence of colon cancer stem-like cells in macroscopically normal mucosa in patients with adenomatous polyps and that they increase with aging, suggesting that aging may predispose the colon to carcinogenesis. In the current study we have examined the combined effects of aging and...

  12. Protracted postnatal neurogenesis and radiosensitivity in the rabbit's dentate gyrus

    International Nuclear Information System (INIS)

    Gueneau, G.; Baille, V.; Dubos, M.; Court, L.

    1986-01-01

    In the hippocampal formation of a 3-month-old rabbit submitted to a 4.5 Gy gamma irradiation a cytologic study with light and electron microscopy allowed us to make clear the dentate gyrus particular radiosensitivity as soon as the first hours after irradiation. The pycnosis lesion observed in the subgranular zone has drawn our attention in particular. We apply ourselves to describe and precise the lesion and its evolution; thanks to an autoradiographic study, we have shown its link with late postnatal neurogenesis which goes on in this zone and at last we have used the subgranular cells 'radiosensitivity as a biological test allowing to compare the various rays' effects (gamma and neutron rays). In the brain of a one-month-old monkey submitted to a 4 Gy total irradiation the same pycnotic lesion is observed: 1) in the dentate gyrus's subgranular zone and 2) in the cerebellum's outer granular layer. These two postnatal proliferative zones remain particularly sensitive to ionizing radiations. (orig.)

  13. Neuronal Subtype Generation During Postnatal Olfactory Bulb Neurogenesis.

    Science.gov (United States)

    Angelova, Alexandra; Tiveron, Marie-Catherine; Cremer, Harold; Beclin, Christophe

    2018-01-01

    In the perinatal and adult forebrain, regionalized neural stem cells lining the ventricular walls produce different types of olfactory bulb interneurons. Although these postnatal stem cells are lineage related to their embryonic counterparts that produce, for example, cortical, septal, and striatal neurons, their output at the level of neuronal phenotype changes dramatically. Tiveron et al. investigated the molecular determinants underlying stem cell regionalization and the gene expression changes inducing the shift from embryonic to adult neuron production. High-resolution gene expression analyses of different lineages revealed that the zinc finger proteins, Zic1 and Zic2, are postnatally induced in the dorsal olfactory bulb neuron lineage. Functional studies demonstrated that these factors confer a GABAergic and calretinin-positive phenotype to neural stem cells while repressing dopaminergic fate. Based on these findings, we discuss the molecular mechanisms that allow acquisition of new traits during the transition from embryonic to adult neurogenesis. We focus on the involvement of epigenetic marks and emphasize why the identification of master transcription factors, that instruct the fate of postnatally generated neurons, can help in deciphering the mechanisms driving fate transition from embryonic to adult neuron production.

  14. Neuronal Subtype Generation During Postnatal Olfactory Bulb Neurogenesis

    Directory of Open Access Journals (Sweden)

    Alexandra Angelova

    2018-02-01

    Full Text Available In the perinatal and adult forebrain, regionalized neural stem cells lining the ventricular walls produce different types of olfactory bulb interneurons. Although these postnatal stem cells are lineage related to their embryonic counterparts that produce, for example, cortical, septal, and striatal neurons, their output at the level of neuronal phenotype changes dramatically. Tiveron et al. investigated the molecular determinants underlying stem cell regionalization and the gene expression changes inducing the shift from embryonic to adult neuron production. High-resolution gene expression analyses of different lineages revealed that the zinc finger proteins, Zic1 and Zic2, are postnatally induced in the dorsal olfactory bulb neuron lineage. Functional studies demonstrated that these factors confer a GABAergic and calretinin-positive phenotype to neural stem cells while repressing dopaminergic fate. Based on these findings, we discuss the molecular mechanisms that allow acquisition of new traits during the transition from embryonic to adult neurogenesis. We focus on the involvement of epigenetic marks and emphasize why the identification of master transcription factors, that instruct the fate of postnatally generated neurons, can help in deciphering the mechanisms driving fate transition from embryonic to adult neuron production.

  15. Effects of Aging on Hippocampal Neurogenesis After Irradiation

    International Nuclear Information System (INIS)

    Cheng, Zoey; Li, Yu-Qing; Wong, C. Shun

    2016-01-01

    Purpose: To assess the influence of aging on hippocampal neuronal development after irradiation (IR). Methods and Materials: Male mice, 2, 4, 6, 12, and 18 months of age, were given a single dose of 0 or 5 Gy of IR. A bromodeoxyuridine (BrdU) incorporation study was used to label newborn cells. Neural progenitors, newborn neurons, and microglia in dentate gyrus (DG) were identified by phenotypic markers, and their numbers were quantified by nonbiased stereology 9 weeks after IR. Results: BrdU-positive or newborn cells in DG decreased with aging and after IR. The number of neuroblasts and newborn neurons decreased with aging, and a further significant reduction was observed after IR. Total type 1 cells (the putative neural stem cells), and newborn type 1 cells decreased with aging, and further reduction in total type 1 cells was observed after IR. Aging-associated activation of microglia in hippocampus was enhanced after IR. Conclusions: The aging-associated decline in hippocampal neurogenesis was further inhibited after IR. Ablation of neural progenitors and activation of microglia may contribute to the inhibition of neuronal development after IR across all ages.

  16. Neurogenesis in spinal cord of mouse: an autoradiographic analysis

    International Nuclear Information System (INIS)

    Nornes, H.O.; Carry, M.

    1978-01-01

    An autoradiographic analysis of the time and sites of origin, and the migration and setting patterns of neurons was made in the spinal cord of the mouse. The neurons originated on days 10-15 of gestation with temporal gradients along the ventrodorsal and rostrocaudal axes. The motor neurons originated on days 10-11 of gestation; the neurons in the intermediate gray region originated on days 11-14 of gestation; the neurons of the head of the dorsal horn originated on days 12-14 of gestation. The neurons that originated on days 10 and 11 originated and migrated primarily from the basal plate, and they settled in the adjacent regions of the intermediate zone; those neurons formed on days 12-14 originated and migrated primarily from the alar plate, and it was concluded that these neuroblasts similarly settled in the adjacent regions of the intermediate zone. Extraventricular proliferation, which presumably signaled the initial stages of gliogenesis, was first observed on day 12 of gestation. This study supports the classical idea of the mosaic pattern of neurogenesis in the embryonic spinal cord. (Auth.)

  17. Effects of Aging on Hippocampal Neurogenesis After Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Zoey [Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Institute of Medical Science, University of Toronto, Toronto, Ontario (Canada); Li, Yu-Qing [Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Wong, C. Shun, E-mail: shun.wong@sunnybrook.ca [Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Institute of Medical Science, University of Toronto, Toronto, Ontario (Canada); Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario (Canada)

    2016-04-01

    Purpose: To assess the influence of aging on hippocampal neuronal development after irradiation (IR). Methods and Materials: Male mice, 2, 4, 6, 12, and 18 months of age, were given a single dose of 0 or 5 Gy of IR. A bromodeoxyuridine (BrdU) incorporation study was used to label newborn cells. Neural progenitors, newborn neurons, and microglia in dentate gyrus (DG) were identified by phenotypic markers, and their numbers were quantified by nonbiased stereology 9 weeks after IR. Results: BrdU-positive or newborn cells in DG decreased with aging and after IR. The number of neuroblasts and newborn neurons decreased with aging, and a further significant reduction was observed after IR. Total type 1 cells (the putative neural stem cells), and newborn type 1 cells decreased with aging, and further reduction in total type 1 cells was observed after IR. Aging-associated activation of microglia in hippocampus was enhanced after IR. Conclusions: The aging-associated decline in hippocampal neurogenesis was further inhibited after IR. Ablation of neural progenitors and activation of microglia may contribute to the inhibition of neuronal development after IR across all ages.

  18. Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis.

    Science.gov (United States)

    Coradazzi, Marino; Gulino, Rosario; Fieramosca, Francesco; Falzacappa, Lucia Verga; Riggi, Margherita; Leanza, Giampiero

    2016-12-01

    Noradrenergic neurons in the locus coeruleus play a role in learning and memory, and their loss is an early event in Alzheimer's disease pathogenesis. Moreover, noradrenaline may sustain hippocampal neurogenesis; however, whether are these events related is still unknown. Four to five weeks following the selective immunotoxic ablation of locus coeruleus neurons, young adult rats underwent reference and working memory tests, followed by postmortem quantitative morphological analyses to assess the extent of the lesion, as well as the effects on proliferation and/or survival of neural progenitors in the hippocampus. When tested in the Water Maze task, lesioned animals exhibited no reference memory deficit, whereas working memory abilities were seen significantly impaired, as compared with intact or sham-lesioned controls. Stereological analyses confirmed a dramatic noradrenergic neuron loss associated to reduced proliferation, but not survival or differentiation, of 5-bromo-2'deoxyuridine-positive progenitors in the dentate gyrus. Thus, ascending noradrenergic afferents may be involved in more complex aspects of cognitive performance (i.e., working memory) possibly via newly generated progenitors in the hippocampus. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain.

    Directory of Open Access Journals (Sweden)

    Manohar B Mutnal

    2011-01-01

    Full Text Available Congenital cytomegalovirus (CMV brain infection causes serious neuro-developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. But, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV and the pattern of injury to the developing brain.We used our MCMV infection model and a multi-color flow cytometry approach to quantify the effect of viral infection on the developing brain, identifying specific target cells and the consequent effect on neurogenesis. In this study, we show that neural stem cells (NSCs and neuronal precursor cells are the principal target cells for MCMV in the developing brain. In addition, viral infection was demonstrated to cause a loss of NSCs expressing CD133 and nestin. We also showed that infection of neonates leads to subsequent abnormal brain development as indicated by loss of CD24(hi cells that incorporated BrdU. This neonatal brain infection was also associated with altered expression of Oct4, a multipotency marker; as well as down regulation of the neurotrophins BDNF and NT3, which are essential to regulate the birth and differentiation of neurons during normal brain development. Finally, we report decreased expression of doublecortin, a marker to identify young neurons, following viral brain infection.MCMV brain infection of newborn mice causes significant loss of NSCs, decreased proliferation of neuronal precursor cells, and marked loss of young neurons.

  20. Conditional Deletion of PDK1 in the Forebrain Causes Neuron Loss and Increased Apoptosis during Cortical Development

    Directory of Open Access Journals (Sweden)

    Congyu Xu

    2017-10-01

    Full Text Available Decreased expression but increased activity of PDK1 has been observed in neurodegenerative disease. To study in vivo function of PDK1 in neuron survival during cortical development, we generate forebrain-specific PDK1 conditional knockout (cKO mice. We demonstrate that PDK1 cKO mice display striking neuron loss and increased apoptosis. We report that PDK1 cKO mice exhibit deficits on several behavioral tasks. Moreover, PDK1 cKO mice show decreased activities for Akt and mTOR. These results highlight an essential role of endogenous PDK1 in the maintenance of neuronal survival during cortical development.

  1. Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage

    DEFF Research Database (Denmark)

    Syljuåsen, Randi G; Sørensen, Claus Storgaard; Hansen, Lasse Tengbjerg

    2005-01-01

    by increased amounts of nonextractable RPA protein, formation of single-stranded DNA, and induction of DNA strand breaks. Moreover, these responses were prevented by siRNA-mediated downregulation of Cdk2 or the replication initiation protein Cdc45, or by addition of the CDK inhibitor roscovitine. We propose...

  2. Increasing severity of damage caused by floods in the Spanish Mediterranean coast (1960-2014), climate change or vulnerability?

    Science.gov (United States)

    Perez, Alfredo; Gil, Salvador; Lopez, Francisco; Barriendos, Mariano

    2016-04-01

    In recent decades, there has been an increase in physical and economic losses (WMO, CRED and UCL, 2014) that raises serious concerns in society. Climate change projections may explain the rise in flood losses; however, these shouldn't be considered yet (Bouwer, 2011). According to IPCC (2014), there is low confidence in anthropogenic climate change affecting the frequency and magnitude of fluvial floods on a global scale. In other words, this increase in flood events is not completely related to the higher frequency of heavy rainfall. To illustrate the aforementioned, a spatial example can be seen in the study area. In the Spanish Mediterranean coast, we see an increase in economic losses within the last 50 years due to flood events (Gil et al., 2014). It seems that the socio-economic growth and the rise of housing construction (Gaja, 2008) have led to an increase in vulnerability and exposure which are mainly responsible for those losses and the increase in severity of flood events (Pérez et al., 2015). Furthermore, this situation will probably become more precarious if some climate forecasts are met [IPCC, 2014; AEMET, 2015], and if the economic model fails to adopt efficient adaptive measures. Therefore, it is interesting to focus attention on social factors either within the present or future scenario in order to minimise the potential consequences and improve the adaptation. The main objective of this work focuses on the study of the evolution of the severity of the floods in the Spanish Mediterranean coast for the period (1960-2015). To do that, a statistical analysis of the data base [Gil et al., 2014; extended to the entire Spanish Mediterranean coast (MEDIFLOOD)] and a multiscale mapping (local, provincial and regional level) of the frequency of these events will take place in order to make comparisons and show spatiotemporal patterns according to the severity events evolution. Preliminary results show some interesting statistically significant

  3. Increased Remnant Cholesterol Explains Part of Residual Risk of All-Cause Mortality in 5414 Patients with Ischemic Heart Disease

    DEFF Research Database (Denmark)

    Jepsen, Anne-Marie K; Langsted, Anne; Varbo, Anette

    2016-01-01

    measured remnant cholesterol; importantly, however, measured remnant cholesterol made up only 9% of calculated remnant cholesterol at nonfasting triglyceride concentrations 1 mmol/L (89 mg/dL) and only 43% at triglycerides >5 mmol/L (443 mg/dL). Multivariable-adjusted hazard ratios for all-cause mortality...... compared with patients with calculated remnant cholesterol concentrations in the 0 to 60th percentiles were 1.2 (95% CI, 1.1-1.4) for patients in the 61st to 80th percentiles, 1.3 (1.1-1.5) for the 81st to 90th percentiles, 1.5 (1.1-1.8) for the 91st to 95th percentiles, and 1.6 (1.2-2.0) for patients...... in the 96th to 100th percentiles (trend, P 1.0 (0.8-1.1), 1.2 (1.0-1.4), 1.1 (0.9-1.5), and 1.3 (1.1-1.7) (trend, P = 0.006), and for measured LDL cholesterol 1.0 (0.9-1.1), 1.0 (0.8-1.2), 1.0 (0.8-1.3), and 1.1 (0.8-1.4) (trend, P = 0...

  4. Using genetics to explore whether the cholesterol-lowering drug ezetimibe may cause an increased risk of cancer

    DEFF Research Database (Denmark)

    Kobberø Lauridsen, Bo; Stender, Stefan; Frikke-Schmidt, Ruth

    2017-01-01

    Background: Results from randomized controlled trials (RCTs) have raised concern that the cholesterol-lowering drug ezetimibe might increase the risk of cancer. We tested the hypothesis that genetic variation in NPC1L1, mimicking treatment with ezetimibe, was associated with an increased risk...... of cancer. Methods: We included 67 257 individuals from the general population. Of these, 8333 developed cancer and 2057 died of cancer from 1968 to 2011. To mimic the effect of ezetimibe, we calculated weighted allele scores based on the low-density lipoprotein (LDL) cholesterol-lowering(= NPC1L1......-inhibitory) effect of each variant. We tested the associations of the NPC1L1 allele scores with LDL cholesterol and with risk of any cancer, death from any cancer and 27 site-specific cancers. As a positive control, we tested the association of the NPC1L1 allele scores with risk of ischaemic vascular disease...

  5. Lack of chemokine signaling through CXCR5 causes increased mortality, ventricular dilatation and deranged matrix during cardiac pressure overload.

    Directory of Open Access Journals (Sweden)

    Anne Waehre

    Full Text Available RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF, but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/- displayed increased mortality during a follow-up of 80 days after aortic banding (AB. Following three weeks of AB, CXCR5(-/- developed significant left ventricular (LV dilatation compared to wild type (WT mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs were significantly reduced in AB CXCR5(-/- compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/- mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly.

  6. Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia.

    Science.gov (United States)

    DeBoer, Mark D; Zhu, Xin Xia; Levasseur, Peter; Meguid, Michael M; Suzuki, Susumu; Inui, Akio; Taylor, John E; Halem, Heather A; Dong, Jesse Z; Datta, Rakesh; Culler, Michael D; Marks, Daniel L

    2007-06-01

    Cancer cachexia is a debilitating syndrome of anorexia and loss of lean body mass that accompanies many malignancies. Ghrelin is an orexigenic hormone with a short half-life that has been shown to improve food intake and weight gain in human and animal subjects with cancer cachexia. We used a rat model of cancer cachexia and administered human ghrelin and a synthetic ghrelin analog BIM-28131 via continuous infusion using sc osmotic minipumps. Tumor-implanted rats receiving human ghrelin or BIM-28131 exhibited a significant increase in food consumption and weight gain vs. saline-treated animals. We used dual-energy x-ray absorptiometry scans to show that the increased weight was due to maintenance of lean mass vs. a loss of lean mass in saline-treated animals. Also, BIM-28131 significantly limited the loss of fat mass normally observed in tumor-implanted rats. We further performed real-time PCR analysis of the hypothalami and brainstems and found that ghrelin-treated animals exhibited a significant increase in expression of orexigenic peptides agouti-related peptide and neuropeptide Y in the hypothalamus and a significant decrease in the expression of IL-1 receptor-I transcript in the hypothalamus and brainstem. We conclude that ghrelin and a synthetic ghrelin receptor agonist improve weight gain and lean body mass retention via effects involving orexigenic neuropeptides and antiinflammatory changes.

  7. Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy.

    Science.gov (United States)

    Paradisi, M; Fernández, M; Del Vecchio, G; Lizzo, G; Marucci, G; Giulioni, M; Pozzati, E; Antonelli, T; Lanzoni, G; Bagnara, G P; Giardino, L; Calzà, L

    2010-10-01

    Neurogenesis in adult humans occurs in at least two areas of the brain, the subventricular zone of the telencephalon and the subgranular layer of the dentate gyrus in the hippocampal formation. We studied dentate gyrus subgranular layer neurogenesis in patients subjected to tailored antero-mesial temporal resection including amygdalohippocampectomy due to pharmacoresistant temporal lobe epilepsy (TLE) using the in vitro neurosphere assay. Sixteen patients were enrolled in the study; mesial temporal sclerosis (MTS) was present in eight patients. Neurogenesis was investigated by ex vivo neurosphere expansion in the presence of mitogens (epidermal growth factor + basic fibroblast growth factor) and spontaneous differentiation after mitogen withdrawal. Growth factor synthesis was investigated by qRT-PCR in neurospheres. We demonstrate that in vitro proliferation of cells derived from dentate gyrus of TLE patients is dependent on disease duration. Moreover, the presence of MTS impairs proliferation. As long as in vitro proliferation occurs, neurogenesis is maintained, and cells expressing a mature neurone phenotype (TuJ1, MAP2, GAD) are spontaneously formed after mitogen withdrawal. Finally, formed neurospheres express mRNAs encoding for growth (vascular endothelial growth factor) as well as neurotrophic factors (brain-derived neurotrophic factor, ciliary neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor). We demonstrated that residual neurogenesis in the subgranular layer of the dentate gyrus in TLE is dependent on diseases duration and absent in MTS. © 2010 The Authors. Neuropathology and Applied Neurobiology © 2010 British Neuropathological Society.

  8. Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia.

    Science.gov (United States)

    Kim, Ju Young; Liu, Cindy Y; Zhang, Fengyu; Duan, Xin; Wen, Zhexing; Song, Juan; Feighery, Emer; Lu, Bai; Rujescu, Dan; St Clair, David; Christian, Kimberly; Callicott, Joseph H; Weinberger, Daniel R; Song, Hongjun; Ming, Guo-li

    2012-03-02

    How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Increasing obesity in treated female HIV patients from Sub-Saharan Africa: Potential causes and possible targets for intervention

    Directory of Open Access Journals (Sweden)

    Claire eMcCormick

    2014-11-01

    Full Text Available Objectives To investigate changing nutritional demographics of treated HIV-1-infected patients and explore causes of obesity, particularly in women of African origin.Methods We prospectively reviewed nutritional demographics of clinic attenders at an urban European HIV clinic during four one-month periods at 3-yearly intervals (2001, 2004, 2007, and 2010 and in two consecutive whole-year reviews (2010-11 and 2011-12. Risk-factors for obesity were assessed by multiple linear regression. A sub-study of 50 HIV-positive African female patients investigated body-size/shape perception using numerical, verbal and pictorial cues. Results We found a dramatic rise in the prevalence of obesity (BMI >30 kg/m2, from 8.5% (2001 to 28% (2011-12 for all clinic attenders, of whom 86% were on antiretroviral treatment. Women of African origin were most affected, 49% being obese, with a further 32% overweight (BMI 25-30 kg/m2, in 2012. Clinical factors strongly associated with obesity included female gender, black African ethnicity, non-smoking, age and CD4 count (all P<0.001; greater duration of cART did not predict obesity. Individual weight-time trends mostly showed slow long-term progressive weight gain. Investigating body weight perception, we found that weight and adiposity were underestimated by obese subjects, who showed a greater disparity between perceived and actual adiposity (P<0.001. Obese subjects targeted more obese target ideal body shapes (P<0.01, but were less satisfied with their body shape overall (P=0.02. Conclusions Seropositive African women on antiretroviral treatment are at heightened risk of obesity. Although multifactorial, bodyweight perception represents a potential target for intervention.

  10. Increased alcohol consumption as a cause of alcoholism, without similar evidence for depression: a Mendelian randomization study.

    Science.gov (United States)

    Wium-Andersen, Marie Kim; Ørsted, David Dynnes; Tolstrup, Janne Schurmann; Nordestgaard, Børge Grønne

    2015-04-01

    Increased alcohol consumption has been associated with depression and alcoholism, but whether these associations are causal remains unclear. We tested whether alcohol consumption is causally associated with depression and alcoholism. We included 78,154 men and women aged 20-100 years randomly selected in 1991-2010 from the general population of Copenhagen, Denmark, and genotyped 68,486 participants for two genetic variants in two alcohol dehydrogenase (ADH) genes, ADH-1B (rs1229984) and ADH-1C (rs698). We performed observational and causal analyses using a Mendelian randomization design with antidepressant medication use and hospitalization/death, with depression and alcoholism as outcomes. In prospective analyses, the multifactorially adjusted hazard ratio for participants reporting >6 drinks/day vs participants reporting 0.1-1 drinks/day was 1.28 (95% confidence interval, 1.00-1.65) for prescription antidepressant use, with a corresponding hazard ratio of 0.80 (0.45-1.45) for hospitalization/death with depression and of 11.7 (8.77-15.6) for hospitalization/death with alcoholism. For hospitalization/death with alcoholism, instrumental variable analysis yielded a causal odds ratio of 28.6 (95 % confidence interval 6.47-126) for an increase of 1 drink/day estimated from the combined genotype combination, whereas the corresponding multifactorially adjusted observational odds ratio was 1.28 (1.25-1.31). Corresponding odds ratios were 1.11 (0.67-1.83) causal and 1.04 (1.03-1.06) observational for prescription antidepressant use, and 4.52 (0.99-20.5) causal and 0.98 (0.94-1.03) observational for hospitalization/death with depression. These data indicate that the association between increased alcohol consumption and alcoholism is causal, without similar strong evidence for depression. © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

  11. Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice.

    Directory of Open Access Journals (Sweden)

    Shigeki Moriguchi

    Full Text Available Dehydroepiandrosterone (DHEA is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII, protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG and improves depressive-like behaviors observed in OBX mice. Chronic treatment with DHEA at 30 or 60 mg/kg p.o. for 14 days significantly improved hippocampal LTP impaired in OBX mice concomitant with increased CaMKII autophosphorylation and GluR1 (Ser-831 phosphorylation in the DG. Chronic DHEA treatment also ameliorated depressive-like behaviors in OBX mice, as assessed by tail suspension and forced swim tests, while a single DHEA treatment had no affect. DHEA treatment also significantly increased the number of BrdU-positive neurons in the subgranular zone of the DG of OBX mice, an increase inhibited by treatment with NE-100, a sigma-1 receptor antagonist. DHEA treatment also significantly increased phosphorylation of Akt (Ser-473, Akt (Ser-308 and ERK in the DG. Furthermore, GSK-3β (Ser-9 phosphorylation increased in the DG of OBX mice possibly accounting for increased neurogenesis through Akt activation. Finally, we confirmed that DHEA treatment of OBX mice increases the number of BrdU-positive neurons co-expressing β-catenin, a downstream GSK-3βtarget. Overall, we conclude that sigma-1 receptor stimulation by DHEA ameliorates OBX-induced depressive-like behaviors by increasing neurogenesis in the DG through activation of the Akt/GSK-3β/β-catenin pathway.

  12. Children with low birth weight and low gestational age in Oslo, Norway: immigration is not the cause of increasing proportions.

    OpenAIRE

    Stoltenberg, C; Magnus, P

    1995-01-01

    STUDY OBJECTIVE--To determine the influence of children born to immigrant mothers on the total proportions of low birth weight and preterm deliveries in Oslo and to explain the increases in the proportions of children with low birth weight and low gestational age since 1980-1982. DESIGN--This was a cross sectional study based on Norwegian Medical Birth Registry data and information on mothers' country of birth from the Central Bureau of Statistics. SETTING--Oslo, Norway 1968-91. POPULATION--A...

  13. Repeated exposure of the developing rat brain to magnetic resonance imaging did not affect neurogenesis, cell death or memory function

    International Nuclear Information System (INIS)

    Zhu, Changlian; Gao, Jianfeng; Li, Qian; Huang, Zhiheng; Zhang, Yu; Li, Hongfu; Kuhn, Hans-Georg; Blomgren, Klas

    2011-01-01

    Research highlights: → The effect of MRI on the developing brain is a matter of debate. → Repeated exposure to MRI did not affect neurogenesis. → Memory function was not affected by repeated MRI during development. → Neither late gestation nor young postnatal brains were affected by MRI. → Repeated MRI did not cause cell death in the neurogenic region of the hippocampus. -- Abstract: The effect of magnetic fields on the brain is a matter of debate. The objective of this study was to investigate whether repeated exposure to strong magnetic fields, such as during magnetic resonance imaging (MRI), could elicit changes in the developing rat brain. Embryonic day 15 (E15) and postnatal day 14 (P14) rats were exposed to MRI using a 7.05 T MR system. The animals were anesthetized and exposed for 35 min per day for 4 successive days. Control animals were anesthetized but no MRI was performed. Body temperature was maintained at 37 o C. BrdU was injected after each session (50 mg/kg). One month later, cell proliferation, neurogenesis and astrogenesis in the dentate gyrus were evaluated, revealing no effects of MRI, neither in the E15, nor in the P14 group. DNA damage in the dentate gyrus in the P14 group was evaluated on P18, 1 day after the last session, using TUNEL staining. There was no difference in the number of TUNEL-positive cells after MRI compared with controls, neither in mature neurons, nor in newborn progenitors (BrdU/TUNEL double-labeled cells). Novel object recognition was performed to assess memory function 1 month after MRI. There was no difference in the recognition index observed after MRI compared with the control rats, neither for the E15, nor for the P14 group. In conclusion, repeated exposure to MRI did not appear to affect neurogenesis, cell death or memory function in rats, neither in late gestation (E15-E18) nor in young postnatal (P14-P17) rats.

  14. Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

    Science.gov (United States)

    López-Hidalgo, Rosa; Ballestín, Raul; Vega, Jessica; Blasco-Ibáñez, José M.; Crespo, Carlos; Gilabert-Juan, Javier; Nácher, Juan; Varea, Emilio

    2016-01-01

    Down syndrome (DS) is caused by the presence of an extra copy of the chromosome 21 and it is the most common aneuploidy producing intellectual disability. Neural mechanisms underlying this alteration may include defects in the formation of neuronal networks, information processing and brain plasticity. The murine model for DS, Ts65Dn, presents reduced adult neurogenesis. This reduction has been suggested to underlie the hypocellularity of the hippocampus as well as the deficit in olfactory learning in the Ts65Dn mice. Similar alterations have also been observed in individuals with DS. To determine whether the impairment in adult neurogenesis is, in fact, responsible for the hypocellularity in the hippocampus and physiology of the olfactory bulb, we have analyzed cell proliferation and neuronal maturation in the two major adult neurogenic niches in the Ts656Dn mice: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Additionally, we carried out a study to determine the survival rate and phenotypic fate of newly generated cells in both regions, injecting 5′BrdU and sacrificing the mice 21 days later, and analyzing the number and phenotype of the remaining 5′BrdU-positive cells. We observed a reduction in the number of proliferating (Ki67 positive) cells and immature (doublecortin positive) neurons in the subgranular and SVZ of Ts65Dn mice, but we did not observe changes in the number of surviving cells or in their phenotype. These data correlated with a lower number of apoptotic cells (cleaved caspase 3 positive) in Ts65Dn. We conclude that although adult Ts65Dn mice have a lower number of proliferating cells, it is compensated by a lower level of cell death. This higher survival rate in Ts65Dn produces a final number of mature cells similar to controls. Therefore, the reduction of adult neurogenesis cannot be held responsible for the neuronal hypocellularity in the hippocampus or for the olfactory learning deficit of Ts65Dn mice

  15. Long-term increased carnitine palmitoyltransferase 1A expression in ventromedial hypotalamus causes hyperphagia and alters the hypothalamic lipidomic profile.

    Directory of Open Access Journals (Sweden)

    Paula Mera

    Full Text Available Lipid metabolism in the ventromedial hypothalamus (VMH has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. Carnitine palmitoyltransferase (CPT 1A is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation and it has been proposed as a crucial mediator of fasting and ghrelin orexigenic signalling. However, the relationship between changes in CPT1A activity and the intracellular downstream effectors in the VMH that contribute to appetite modulation is not fully understood. To this end, we examined the effect of long-term expression of a permanently activated CPT1A isoform by using an adeno-associated viral vector injected into the VMH of rats. Peripherally, this procedure provoked hyperghrelinemia and hyperphagia, which led to overweight, hyperglycemia and insulin resistance. In the mediobasal hypothalamus (MBH, long-term CPT1AM expression in the VMH did not modify acyl-CoA or malonyl-CoA levels. However, it altered the MBH lipidomic profile since ceramides and sphingolipids increased and phospholipids decreased. Furthermore, we detected increased vesicular γ-aminobutyric acid transporter (VGAT and reduced vesicular glutamate transporter 2 (VGLUT2 expressions, both transporters involved in this orexigenic signal. Taken together, these observations indicate that CPT1A contributes to the regulation of feeding by modulating the expression of neurotransmitter transporters and lipid components that influence the orexigenic pathways in VMH.

  16. Enhanced Biofilm Formation and Increased Resistance to Antimicrobial Agents and Bacterial Invasion Are Caused by Synergistic Interactions in Multispecies Biofilms

    DEFF Research Database (Denmark)

    Burmølle, Mette; Webb, J.S.; Rao, D.

    2006-01-01

    from the surface of the marine alga Ulva australis, were screened for synergistic interactions within biofilms when present together in different combinations. Four isolates, Microbacterium phyllosphaerae, Shewanella japonica, Dokdonia donghaensis, and Acinetobacter lwoffii, were found to interact......Most biofilms in their natural environments are likely to consist of consortia of species that influence each other in synergistic and antagonistic manners. However, few reports specifically address interactions within multispecies biofilms. In this study, 17 epiphytic bacterial strains, isolated...... synergistically in biofilms formed in 96-well microtiter plates: biofilm biomass was observed to increase by >167% in biofilms formed by the four strains compared to biofilms composed of single strains. When exposed to the antibacterial agent hydrogen peroxide or tetracycline, the relative activity (exposed...

  17. Mutation of the key residue for extraribosomal function of ribosomal protein S19 cause increased grooming behaviors in mice.

    Science.gov (United States)

    Chen, Jun; Kaitsuka, Taku; Fujino, Rika; Araki, Kimi; Tomizawa, Kazuhito; Yamamoto, Tetsuro

    2016-08-26

    Ribosomal protein S19 (RP S19) possesses ribosomal function as RP S19 monomer and extraribosomal function as cross-linked RP S19 oligomers which function as a ligand of the complement 5a (C5a) receptor (CD88). We have generated a Gln137Glu-RP S19 knock-in (KI) mouse, which is shown to possess the weakened extraribosomal function of RP S19. Because whether the extraribosomal function of RP S19 has a role in brain function had been unclear, we performed behavioral analysis on these mice and demonstrated that KI mice displayed an increased grooming behavior during open-field test and elevated plus maze test and an enhanced freezing behavior in contextual fear conditioning test. These results suggest an involvement of RP S19 oligomers in some anxiety-like behavior, especially grooming behavior. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability

    Directory of Open Access Journals (Sweden)

    Chen Leilei

    2011-05-01

    Full Text Available Abstract Background Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model. Methods An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF were isolated to further investigate molecular mechanism of eIF-5A2 in aging. Results Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p Conclusion These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instabili