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Sample records for 6-hydroxydopamine decreases hippocampal

  1. Decreased response of interneurons in the medial prefrontal cortex to 5-HT₁A receptor activation in the rat 6-hydroxydopamine Parkinson model.

    Zhang, Qiaojun; Wang, Shuang; Zhang, Lina; Zhang, Huan; Qiao, Hongfei; Niu, Xiaolin; Liu, Jian

    2014-08-01

    This study examined the response of interneurons in the medial prefrontal cortex (mPFC) to 5-HT1A receptor agonist 8-OH-DPAT and change in expression of 5-HT1A receptor on glutamate decarboxylase 67 (GAD67)-positive neurons in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc). Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT dose-dependently inhibited the firing rate of the interneurons at all doses tested in sham-operated rats. In 6-OHDA-lesioned rats, 8-OH-DPAT, at the same doses, also inhibited the firing rate of the interneurons, whereas the inhibition was significant only at a high cumulative dose. Furthermore, injection of 8-OH-DPAT into the mPFC inhibited the interneurons in sham-operated rats, while having no effect on firing rate of the interneurons in 6-OHDA-lesioned rats. In contrast to sham-operated rats, SNc lesion reduced the expression of 5-HT1A receptor on GAD67-positive neurons in the prelimbic cortex, a sub-region of the mPFC. Our results indicate that degeneration of the nigrostriatal pathway leads to decreased response of mPFC interneurons to 5-HT1A receptor activation, which attributes to the down-regulation of 5-HT1A receptor expression in these interneurons.

  2. Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents 6-hydroxydopamine induced apoptosis in SH-SY5Y cells.

    Tian, Lin-Lin; Wang, Xue-Jun; Sun, Yu-Ning; Li, Chun-Rong; Xing, Ya-Ling; Zhao, Hai-Bao; Duan, Ming; Zhou, Zhe; Wang, Sheng-Qi

    2008-01-01

    Oxidative stress caused by dopamine may play an important role in the pathogenesis of Parkinson's disease. Salvianolic acid B is an antioxidant derived from the Chinese herb, Salvia miltiorrhiza. In this study, we investigated the neuroprotective effect of salvianolic acid B against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells. Pretreatment of SH-SY5Y cells with salvianolic acid B significantly reduced 6-hydroxydopamine-induced generation of reactive oxygen species, and prevented 6-hydroxydopamine-induced increases in intracellular calcium. Our data demonstrated that 6-hydroxydopamine-induced apoptosis was reversed by salvianolic acid B treatment. Salvianolic acid B reduced the 6-hydroxydopamine-induced increase of caspase-3 activity, and reduced cytochrome C translocation into the cytosol from mitochondria. The 6-hydroxydopamine-induced decrease in the Bcl-x/Bax ratio was prevented by salvianolic acid B. Additionally, salvianolic acid B decreased the activation of extracellular signal-regulated kinase and induced the activation of 6-hydroxydopamine-suppressed protein kinase C. These results indicate that the protective function of salvianolic acid B is dependent upon its antioxidative potential. Our results strongly suggest that salvianolic acid B may be effective in treating neurodegenerative diseases associated with oxidative stress.

  3. Protective effects of Ginkgo biloba extract on 6-hydroxydopamine-induced apoptosis in PC12 cells

    Jie Wang; Yanbo Cheng; Jiale Yin; Qian Lu; Xingshun Xu; Xiaoxing Yin

    2011-01-01

    The present study analyzed the protective effects of Ginkgo biloba extract against 6-hydroxydopamine-induced PC12 cell apoptosis in a model of Parkinson's disease. The results showed that Ginkgo biloba extract had a potent cytoprotective action and inhibited apoptosis of PC12 cells induced by 6-hydroxydopamine. Ginkgo biloba extract decreased the ratio of Bax to Bcl-2 and markedly inhibited the activation of p53 and caspase-3. These experimental findings indicate that Ginkgo biloba extract may significantly reduce the effects of oxidative stress induced by 6-hydroxydopamine in PC12 cells and suppress cell apoptosis. The potential effects of Ginkgo biloba extract might be greater than those of levodopa in the treatment of Parkinson's disease.

  4. Ethanol induces rotational behavior in 6-hydroxydopamine lesioned mice

    Silverman, P.B.

    1987-03-09

    Mice with unilateal striatal lesions created by 6-hydroxydopamine (6HDA) injection were screened for rotational (circling) behavior in response to injection of amphetamine and apomorphine. Those that rotated ipsilaterally in response to amphetamine and contralaterally in response to apomorphine were subsequently challenged with 1 to 3 g/kg (i.p.) ethanol. Surprisingly, ethanol induced dose related contralateral (apomorphine-like) rotation which, despite gross intoxication, was quite marked in most animals. No significant correlation was found between the number of turns made following ethanol and made after apomorphine or amphetamine. 14 references, 2 figures, 1 table.

  5. Elevated striatal Fos immunoreactivity following 6-hydroxydopamine lesioning of the rat is mediated by excitatory amino acid transmission.

    Cooper, A J; Wooller, S; Mitchell, I J

    1995-07-14

    Pharmacological depletion of dopaminergic neurotransmission can result in an elevation in striatal Fos levels. This elevation may occur as a direct result of decreased dopaminergic neurotransmission or indirectly via elevated corticostriatal glutamatergic neurotransmission which occurs secondary to dopamine depletion. To test the hypothesis that elevated N-methyl-D-aspartic acid (NMDA)-mediated corticostriatal transmission may underlie the increase in striatal Fos levels upon dopamine depletion, rats were unilaterally 6-hydroxydopamine lesioned under anaesthesia induced by either barbiturate or the NMDA antagonist, ketamine. Following surgery the animals remained under light anaesthesia for 6 h prior to sacrifice and quantification of striatal Fos immunoreactivity. The results demonstrate that dopamine depletion following 6-hydroxydopamine lesioning can result in elevated striatal Fos levels which can be attenuated by contiguous treatment with an NMDA antagonist. This suggests that the increase in striatal Fos levels observed following dopamine depletion may occur as a result of elevated cytoplasmic calcium levels in the striatal cells.

  6. Clorgyline effect on pineal melatonin biosynthesis in adrenalectomized rats pretreated with 6-hydroxydopamine.

    Reuss, S; Requintina, P J; Riemann, R; Oxenkrug, G F

    1994-01-01

    The response to administration of the specific monoamine oxidase A (MAO-A) blocker clorgyline was investigated in adult male Sprague-Dawley rats which were adrenalectomized four days prior to treatment or were additionally sympathectomized as newborns by injection of 6-hydroxydopamine. In both groups, the contents of pineal indoles melatonin and N-acetylserotonin were augmented, and the contents of 5-hydroxyindoleacetic acid and 5-hydroxyindoletryptophol decreased 90 min following clorgyline injections when compared to rats receiving saline. The observed responses were less pronounced in rats both adrenalectomized and sympathectomized. The results are in line with the hypothesis that preservation from oxidation of both MAO-A substrates, noradrenaline and serotonin, upon clorgyline administration contributes to the observed increase in melatonin biosynthesis thought to be associated with the anti-depressant effects of MAO inhibition.

  7. Dexmedetomidine Regulates 6-hydroxydopamine-Induced Microglial Polarization.

    Zhang, Pei; Li, Yu; Han, Xuechang; Xing, Qunzhi; Zhao, Lei

    2017-02-28

    Microglia have undergone extensive characterization and have been shown to present distinct phenotypes, such as the M1 or M2 phenotypes, depending on their stimuli. As a highly specific neurotoxin, 6-hydroxydopamine (6-OHDA) can be used to further our understanding of the immune response in Parkinson's disease (PD). Dexmedetomidine (DEX), a centrally selective α2-adrenoceptor agonist, performs very well as an anti-anxiety medication, sedative and analgesic. In the present study, we investigated the effects of DEX on 6-OHDA-induced microglial polarization. Our results indicate that treatment with 6-OHDA promotes microglial polarization toward the M1 state in BV2 microglia cells by increasing the release of interleukin (IL)-6, IL-1β, or tumor necrosis factor-α, which can be prevented by pretreatment with DEX. In addition, we found that 6-OHDA blocked IL-4-mediated microglial M2 polarization by suppressing expression of the microglial M2 markers arginase-1 (Arg-1), resistin-like α (Retnla/Fizz1), and chitinase 3-like 3 (Chi3l3/Ym1), which could be ameliorated by pretreatment with DEX. Notably, the inhibitory effects of 6-OHDA on IL-4-mediated induction of the anti-inflammatory marker genes IL-10, IL-13, and transforming growth factor-β2 could be significantly alleviated by pretreatment with DEX in a dose-dependent manner (P < 0.01). Mechanistically, alternations in the activation of signal transducer and activator of transcription 6 were involved in this process. These findings suggest that administration of DEX has the potential to interrupt the process of microgliosis in PD.

  8. Subtle Cardiovascular Dysfunction in the Unilateral 6-Hydroxydopamine-Lesioned Rat

    K. Slack

    2010-01-01

    Full Text Available The present study evaluated whether the unilateral 6-hydroxydopamine (6-OHDA model of Parkinson's disease produces autonomic deficits. Autonomic parameters were assessed by implanting a small radiofrequency telemetry device which measured heart rate variability (HRV, diurnal rhythms of heart rate (HR, core body temperature (cBT and locomotor activity (LA. Rats then received 6-OHDA lesion or sham surgery. 6-OHDA lesioned rats exhibited head and body axis biases, defective sensorimotor function (“disengage” test, and prominent apomorphine rotation (all P<.05 versus controls. Diurnal rhythm of HR was lower for 6-OHDA lesioned rats (n=8 versus controls (n=6; P<.05. Whilst HR decreased similarly in both groups during the day, there was a greater decrease in HR for the 6-OHDA lesioned rats at night (by 38 b.p.m. relative to 17 b.p.m. for controls. LA and cBT did not differ between surgery groups. This study indicates the unilateral 6-OHDA model of PD shows subtle signs of cardiovascular autonomic dysfunction.

  9. Electroacupuncture Alleviates Depressive-Like Symptoms and Modulates BDNF Signaling in 6-Hydroxydopamine Rats

    Sun, Min; Wang, Ke; Yu, Yan; Su, Wen-Ting; Jiang, Xin-Xin

    2016-01-01

    Previous studies have identified the beneficial effects of electroacupuncture (EA) on motor behaviors in Parkinson's disease (PD). However, the role and potential mechanisms of EA in PD-associated depression remain unclear. In the present study, a rat model of PD with unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle was treated using EA for 4 weeks. We found that 100 Hz EA improved several motor phenotypes. In addition, tyrosine hydroxylase (TH) immunohistochemical analysis showed that EA had a minimal impact on the TH-positive profiles of the ipsilateral ventral tegmental area. Compared with the 6-OHDA group, long-term EA stimulation significantly increased sucrose solution consumption and decreased immobility time in the forced swim test. EA treatment did not alter dopamine, norepinephrine, and serotonin levels in the striatum and hippocampus. Noticeably, EA treatment reversed the 6-OHDA-induced abnormal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in the midbrain and hippocampus. These results demonstrate that EA at 100-Hz possesses the ability to improve depressive-like symptoms in PD rats, which is, at least in part, due to the distinct effect of EA on the mesostriatal and mesocorticolimbic dopaminergic pathways. Moreover, BDNF seems to participate in the effect of EA in PD. PMID:27525025

  10. Luteolin modulates 6-hydroxydopamine-induced transcriptional changes of stress response pathways in PC12 cells.

    Ling-Wei Hu

    Full Text Available The neurotoxin 6-hydroxydopamine (6-OHDA, which causes transcriptional changes associated with oxidative and proteotoxic stress, has been widely used to generate an experimental model of Parkinson's disease. The food-derived compound luteolin has multi-target actions including antioxidant, anti-inflammatory and neurotrophic activities. The aim of this study is to investigate how luteolin affects 6-OHDA-mediated stress response pathways. The results showed that when PC12 cells were pre-treated with luteolin (20 µM 30 min prior to 6-OHDA (100 µM exposure, 6-OHDA-induced ROS overproduction, cytotoxicity, caspase-3 activation, and mRNA expression of BIM, TRB3 and GADD34 were significantly attenuated. Moreover, 6-OHDA-mediated cell cycle arrest and transcription of p53 target genes, p21, GADD45α and PUMA, were reduced by luteolin. Luteolin also significantly down-regulated 6-OHDA-mediated unfolded protein response (UPR, leading to decreases in phospho-eIF2α, ATF4, GRP78 and CHOP. In addition, luteolin attenuated 6-OHDA-induced Nrf2-mediated HO-1 and GCLC. Taken together, these results suggest that diminishing intracellular ROS formation and down-regulation of p53, UPR and Nrf2-ARE pathways may be involved in the neuroprotective effect of luteolin.

  11. 6-Hydroxydopamine-induced glutathione alteration occurs via glutathione enzyme system in primary cultured astrocytes

    Ji ZHANG; Jun HU; Jian-hua DING; Hong-hong YAO; Gang HU

    2005-01-01

    Aim: To define the role of enzymes involved in glutathione metabolism in 6-hydroxydopamine (6-OHDA)-induced glutathione alteration in primary cultured astrocytes.Methods: Total glutathione (GSx) levels were determined using the modified enzymatic microtiter plate assay.The mRNA levels ofγ-glutamylcysteine synthetase (γGCS), γ-glutamyltransferase (γGT), glutathione peroxidase (GPx), GR (glutathione reductase), and glutathione transferases (GST) were determined using RT-PCR.γGT activity was determined using γGT assay kits.Results: In primary cultured astrocytes, 6-OHDA induced a significant elevation of cellular GSx levels after treatment for 24 h.However, the GSx levels decreased after 24 h and the values were even lower than the value in the control group without 6-OHDA at 48 h.RT-PCR data showed that the mRNA levels of γGCS, the ratelimiting enzyme of γ-L-glutamyl-L-cysteinylglycine (GSH) synthesis, were increased by 6-OHDA after treatment for 24 h and 48 h; the mRNA levels of GPx, GR, and GST did not alter in 6-OHDA-treated astrocytes after treatment for 24 h and 48 h; and 6-OHDA increased the mRNA levels and the activity of γGT after treatment for 48 h,which induced a decrease in GSx levels, despite the up-regulation of γGCS after exposure to 6-OHDA for 48 h.Conclusion: The change in γGCS correlated with the increase in GSH levels induced by 6-OHDA after treatment for 24 h.GSx levels decreased because of increased γGT mRNA levels and γGT activity induced by 6-OHDA after treatment for 48 h.

  12. Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat.

    Yu, Yong-Peng; Ju, Wei-Ping; Li, Zhen-Guang; Wang, Dao-Zhen; Wang, Yuan-Chen; Xie, An-Mu

    2010-06-08

    Increasing evidence suggests the beneficial effects of acupuncture on Parkinson's disease (PD). Although clinical evidence for the acupuncture anti-Parkinson's disease effect has been demonstrated, the precise mechanism still remains elusive. It has been suggested a relationship between PD and reactive oxygen species (ROS) can result in neurodegeneration. The aim of this study was to evaluate the status of oxidative stress, as well as the antioxidant enzyme response, and the role of acupuncture stimulation at GB34 (Yanglingquan), LR3 (Taichong), ST36 (Zusanli) and SP10 (Xuehai) acupoints on regulating oxidative stress in the nigrostriatal system in the 6-hydroxydopamine (6-OHDA) lesioned rat. Two weeks after unilateral injection of 6-OHDA into the left medial forebrain bundle (MFB), an apomorphine induced rotational behavior test was performed. The levels of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic, viz., reduced glutathione (GSH), and the levels of malondialdehyde (MDA) in the nigrostriatal system were measured to assess the oxidative stress status. Brain MDA levels significantly increased, while GSH levels were decreased in impaired groups with 6-OHDA injection only, accompanied by a marked reduction in the level of SOD and GSH-Px. The levels of oxidative stress related parameters except CAT, as well as the rotational asymmetry, were reversed by acupuncture stimulation. These results showed that acupuncture treatment displayed antioxidative and/or neuroprotective properties in the 6-OHDA lesioned rat and these protective properties might be mediated, at least in part, by involving regulation of the antioxidant defense system.

  13. Hematological disorders in 6-hydroxydopamine-induced rat model of Parkinson’s disease

    Lucian Hritcu

    2008-09-01

    Full Text Available Objective: The present work was undertaken in order to investigate the effects of right-unilateral lesion of substantia nigra neurons by means of 6- hydroxydopamine (6-OHDA, a dopaminergic-selective neurotoxin, on hematological parameters in rats. The primary reason for the using of rat model of Parkinson’s disease was the interest regarding the role of the central dopaminergic system in hematopoiesis regulation because some neurological diseases like Parkinson’s disease are well-correlated with anemia associated with autonomic dysfunction in rats.Material and Methods: Thirty male Wistar rats weighing 200 ± 50 g at the start of the experiment were used. The substantia nigra was right-unilateral lesioned by stereotaxic microinjections of 8 micrograms (free base 6-OHDA, dissolved in 4 µl physiological saline containing 0.1% ascorbic acid, administered through the Hamilton microsyringe over 4.50 minutes. 7 days after neurosurgery, we assessed the total number of white blood cells (WBC, the total number of red blood cells (RBC, hemoglobin level and the erythrocyte indexes (mean cell volume, MCV and mean cell hemoglobin, MCH.Hematological parameters were assayed by a COULTER® Ac◊T 5diff CP-precision instruments for hematology research.Results: 6-OHDA treatment induced a significantly decrease of white blood cells (p<0.03, red blood cells (p<0.01, hemoglobin level (p<0.02 comparative with sham-operated rats. By contrast, in the 6-OHDA-lesioned rats the erythrocyte indexes (mean cell volume, MCV (p<0.04; mean cell hemoglobin, MCH (p<0.01 were significantly enhanced comparative with sham-operated rats.Conclusion: On the whole, the obtained data indicate the important role of the central dopaminergic system in the regulation of erythrocyte dynamics.

  14. 6-Hydroxydopamine inhibits some effects of mescaline centrally administered to rabbits.

    Ferri, S; Reina, R A; Braga, P

    1977-12-19

    The narcotic antagonist naloxone does not antagonize antinociception elicited in the rabbit by 100 microgram/kg of mescaline centrally administered, whereas pretreatment with 6-hydroxydopamine (6-OHDA) inhibits this mescaline effect. Stereotyped behavior of rabbits following central mescaline administration is also prevented by 6-hda pretreatment. Since 6-OHDA in known to produce a degeneration of catecholamine containing nerve terminals, a crucial role of catecholamines is suggested in the complex of effects seen in the rabbit after central administration of the hallucinogen.

  15. Gait analysis in three different 6-hydroxydopamine rat models of Parkinson's disease.

    Zhou, Ming; Zhang, Wangming; Chang, Jingyu; Wang, Jun; Zheng, Weixin; Yang, Yong; Wen, Peng; Li, Min; Xiao, Hu

    2015-01-01

    Gait deficits are important clinical symptoms of Parkinson's disease (PD) but are rarely studied. In this study we made three different rat PD models by administration of 6-hydroxydopamine into caudate putamen (CPU), medial forebrain bundle (MFB) and substantia nigra compact (SNC). We evaluated the gait changes in these models by using a computer-assisted CatWalk system. Correlations of gait parameters with tyrosine hydroxylase protein levels in the CPU and SNC were also investigated. The gait readouts were significantly impaired in both the MFB and SNC groups. However, the MFB group showed a more pronounced impairment than the SNC group. In contrast, only mild and incomplete gait impairment occurred in the CPU group. In addition, some gait parameters demonstrated close correlation with the protein levels of TH. This paper suggests that the 6-hydroxydopamine-induced MFB model is more propitious to study gait dysfunction than the other two models and the CatWalk system can provide reliable and objective criteria to stratify gait changes arising from 6-hydroxydopamine lesioned rats. These findings may hold promise in the study of PD disease progression and new therapeutic methods.

  16. Metabolic-dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson's disease

    Casteels, Cindy [KU Leuven and University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center (MOSAIC), Leuven (Belgium); KU Leuven and University Hospital Gasthuisberg, Division of Nuclear Medicine, Leuven (Belgium); Lauwers, Erwin; Baekelandt, Veerle [KU Leuven, Laboratory for Neurobiology and Gene Therapy, Leuven (Belgium); Bormans, Guy [KU Leuven, Molecular Small Animal Imaging Center (MOSAIC), Leuven (Belgium); KU Leuven, Laboratory for Radiopharmacy, Leuven (Belgium); Laere, Koen van [KU Leuven and University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center (MOSAIC), Leuven (Belgium)

    2008-01-15

    The unilateral 6-hydroxydopamine (6-OHDA) lesion rat model is a well-known acute model for Parkinson's disease (PD). Its validity has been supported by invasive histology, behavioral studies and electrophysiology. Here, we have characterized this model in vivo by multitracer imaging [glucose metabolism and dopamine transporter (DAT)] in relation to behavioral and histological parameters. Eighteen female adult Wistar rats (eight 6-OHDA-lesioned, ten controls) were investigated using multitracer [{sup 18}F]-fluoro-2-deoxy-D-glucose (FDG) and [{sup 18}F]-FECT 2'-[{sup 18}F]-fluoroethyl-(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo(3.2.1)-octane-2-carboxylate small animal positron emission tomography (PET). Relative glucose metabolism and parametric DAT binding images were anatomically standardized to Paxinos space and analyzed on a voxel-basis using SPM2, supplemented by a template-based predefined volumes-of-interest approach. Behavior was characterized by the limb-use asymmetry test; dopaminergic innervation was validated by in vitro tyrosine hydroxylase staining. In the 6-OHDA model, significant glucose hypometabolism is present in the ipsilateral sensory-motor cortex (-6.3%; p = 4 x 10 {sup -6}). DAT binding was severely decreased in the ipsilateral caudate-putamen, nucleus accumbens and substantia nigra (all p < 5 x 10 {sup -9}), as confirmed by the behavioral and histological outcomes. Correlation analysis revealed a positive relationship between the degree of DAT impairment and the change in glucose metabolism in the ipsilateral hippocampus (p = 3 x 10 {sup -5}), while cerebellar glucose metabolism was inversely correlated to the level of DAT impairment (p < 3 x 10 {sup -4}). In vivo cerebral mapping of 6-OHDA-lesioned rats using [ {sup 18}F ]-FDG and [ {sup 18}F ]-FECT small animal PET shows molecular-functional correspondence to the cortico-subcortical network impairments observed in PD patients. This provides a further molecular

  17. Curcumin protects nigral dopaminergic neurons by iron-chelation in the 6-hydroxydopamine rat model of Parkinson's disease

    Xi-Xun Du; Hua-Min Xu; Hong Jiang; Ning Song; Jun Wang; Jun-Xia Xie

    2012-01-01

    [Objective] Curcumin is a plant polyphenolic compound and a major component of spice turmeric (Curcuma longa).It has been reported to possess free radical-scavenging,iron-chelating,and anti-inflammatory properties in different tissues.Our previous study showed that curcumin protects MES23.5 dopaminergic cells from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro.The present study aimed to explore this neuroprotective effect in the 6-OHDAlesioned rat model of Parkinson's disease in vivo.[Methods] Rats were given intragastric curcumin for 24 days.6-OHDA lesioning was conducted on day 4 of curcumin treatment.Dopamine content was assessed by high-performance liquid chromatography with electrochemical detection,tyrosine hydroxylase (TH)-containing neurons by immunohistochemistry,and iron-containing cells by Perls' iron staining.[Results] The dopamine content in the striatum and the number of THimmunoreactive neurons decreased after 6-OHDA treatment.Curcumin pretreatment reversed these changes.Further studies demonstrated that 6-OHDA treatment increased the number of iron-staining cells,which was dramatically decreased by curcumin pretreatment.[Conclusion]The protective effects of curcumin against 6-OHDA may be attributable to the ironchelating activity of curcumin to suppress the iron-induced degeneration of nigral dopaminergic neurons.

  18. Hypericum Perforatum Hydroalcoholic Extract Mitigates Motor Dysfunction and is Neuroprotective in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

    Kiasalari, Zahra; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2016-05-01

    Parkinson's disease is the second most common neurodegenerative disorder with selective and progressive decline of nigral dopaminergic neurons. Hypericum perforatum L. (H. perforatum, St. John's wort) has been traditionally used for management of different disorders, especially mild-to-moderate depression. This study was conducted to evaluate the effect of H. perforatum extract against unilateral striatal 6-hydroxydopamine (6-OHDA) toxicity and to unmask some involved mechanisms. Intrastriatal 6-OHDA-lesioned rats were treated with H. perforatum hydroalcoholic extract at a dose of 200 mg/kg/day started 1 week pre-surgery for 1 week post-surgery. The extract attenuated apomorphine-induced rotational behavior, decreased the latency to initiate and the total time on the narrow beam task, lowered striatal level of malondialdehyde and enhanced striatal catalase activity and reduced glutathione content, normalized striatal expression of glial fibrillary acidic protein, tumor necrosis factor α with no significant effect on mitogen-activated protein kinase, lowered nigral DNA fragmentation, and prevented damage of nigral dopaminergic neurons with a higher striatal tyrosine hydroxylase immunoreactivity. These findings reveal the beneficial effect of H. perforatum via attenuation of DNA fragmentation, astrogliosis, inflammation, and oxidative stress.

  19. Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death.

    Samantha Giordano

    Full Text Available Parkinson's disease is characterized by dopaminergic neurodegeneration and is associated with mitochondrial dysfunction. The bioenergetic susceptibility of dopaminergic neurons to toxins which induce Parkinson's like syndromes in animal models is then of particular interest. For example, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and its active metabolite 1-methyl-4-phenylpyridinium (MPP(+, and 6-hydroxydopamine (6-OHDA, have been shown to induce dopaminergic cell death in vivo and in vitro. Exposure of animals to these compounds induce a range of responses characteristics of Parkinson's disease, including dopaminergic cell death, and Reactive Oxygen Species (ROS production. Here we test the hypothesis that cellular bioenergetic dysfunction caused by these compounds correlates with induction of cell death in differentiated dopaminergic neuroblastoma SH-SY5Y cells. At increasing doses, rotenone induced significant cell death accompanied with caspase 3 activation. At these concentrations, rotenone had an immediate inhibition of mitochondrial basal oxygen consumption rate (OCR concomitant with a decrease of ATP-linked OCR and reserve capacity, as well as a stimulation of glycolysis. MPP(+ exhibited a different behavior with less pronounced cell death at doses that nearly eliminated basal and ATP-linked OCR. Interestingly, MPP(+, unlike rotenone, stimulated bioenergetic reserve capacity. The effects of 6-OHDA on bioenergetic function was markedly less than the effects of rotenone or MPP(+ at cytotoxic doses, suggesting a mechanism largely independent of bioenergetic dysfunction. These studies suggest that these dopaminergic neurotoxins induce cell death through distinct mechanisms and differential effects on cellular bioenergetics.

  20. Local Sympathetic Denervation of Femoral Artery in a Rabbit Model by Using 6-Hydroxydopamine In Situ

    Yufei Jin

    2014-01-01

    Full Text Available Both artery bundle and sympathetic nerve were involved with the metabolism of bone tissues. Whether the enhancing effects of artery bundle result from its accompanying sympathetic nerve or blood supply is still unknown. There is no ideal sympathetic nerve-inhibited method for the in situ denervation of artery bundle. Therefore, we dipped the femoral artery in the 6-hydroxydopamine (6-OHDA locally and observed its effect. Compared with control group, the in situ treatment of 6-OHDA did not damage the normal structure of vascular bundle indicated by hematoxylin-eosin (HE staining. However, the functions of sympathetic nerve was completely inhibited for more than 2 weeks, and only a few function of sympathetic nerve resumed 4 weeks later, evidenced by glyoxylic acid staining and the expression of tyrosine hydroxylase (TH and nerve peptide Y (NPY. Thus, 6-OHDA is promising as an ideal reagent for the local denervation of sympathetic nerve from artery system.

  1. The Flavonoid Hesperetin Alleviates Behavioral Abnormality in 6-Hydroxydopamine Rat Model of Hemi-Parkinsonism

    Tourandokht Baluchnejadmojarad

    2010-11-01

    Full Text Available ABSTRACTParkinson’s disease (PD is a neuropathological and debilitating disorder involving the degeneration of mesencephalic dopaminergic neurons. Neuroprotective effect of hesperetin has already been reported, therefore, this study examined whether the administration of this flavonoid would attenuate behavioral abnormalities in an experimental model of PD in rat. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA, 12.5 μg/5μl of saline-ascorbate-lesioned rats were pretreated i.p. with hesperetin (10 mg/kg. It was found out that hesperetin administration attenuates the rotational behavior in lesioned rats. In summary, hesperetin administration attenuates behavioral abnormality in hemiparkinsonian rats and this may be of benefit, along with other therapies, in neurodegenerative disorders including PD.

  2. Apomorphine-induced biphasic circling behaviour in 6-hydroxydopamine-lesioned rats. A pharmacological kindling phenomenon.

    Coward, D M

    1983-06-01

    Factors governing the development of apomorphine-induced biphasic circling behaviour in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra were investigated. It was found that a post-lesion time of at least 2--3 weeks and the repeated exposure to apomorphine were essential for its development. Optimal results were obtained when animals received weekly apomorphine, 0.05 mg/kg sc, in post-lesion weeks 6, 7 and 8. Pretreatment with haloperidol, 1.0 and 2.0 mg/kg ip 1 h beforehand in post-lesion week 9, converted the biphasic response into an enhanced, uniphasic one. The findings suggest that the development of the biphasic response to apomorphine is a multi-factorial process representing a pharmacological kindling phenomenon.

  3. Effect of acupuncture on 6-hydroxydopamine-induced nigrostratal dopaminergic neuronal cell death in rats.

    Kim, Yeung-Kee; Lim, Hyung-Ho; Song, Yun-Kyung; Lee, Hee-Hyuk; Lim, Sabina; Han, Seung-Moo; Kim, Chang-Ju

    In this study, we investigated the effect of acupuncture at the Zusanli acupoint (ST36) on the nigrostriatal dopaminergic neuronal cell death in the rats with Parkinson's disease. Two weeks after unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum, an apomorphine-induced rotational behavior test showed significant rotational asymmetry in the rats with Parkinson's disease. Immunostaining for tyrosine hydroxylase demonstrated a dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. Acupuncture at the ST36 for 14 days significantly inhibited rotational asymmetry in the rats with Parkinson's disease, and also protected against 6-OHDA-induced nigrostriatal dopaminergic neuronal loss. These effects of acupuncture were not observed for the non-acupoint (hip) acupuncture. The present study shows that acupuncture at the ST36 acupoint can be used as a useful strategy for the treatment of Parkinson's disease.

  4. Regional brain catecholamine levels and the development of hypertension in the spontaneously hypertensive rat: the effect of 6-hydroxydopamine

    Jong, Wybren de; Buuse, M. van den; Kloet, E.R. de; Versteeg, D.H.G.

    1984-01-01

    To investigate the role of central catecholaminergic pathways in the development of hypertension in the spontaneously hypertensive rat (SHR) the effects of intracerebroventricular (i.c.v.) injections of 6-hydroxydopamine (6-OHDA) were compared with those of local injections near the main ascending n

  5. The role of the subthalamic nucleus in L-DOPA induced dyskinesia in 6-hydroxydopamine lesioned rats.

    Asier Aristieta

    Full Text Available L-DOPA is the most effective treatment for Parkinson's disease (PD, but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration. Our results show that chronic L-DOPA treatment does not modify the abnormal STN activity induced by the 6-hydroxydopamine lesion of the nigrostriatal pathway in this model. Likewise, we observed a loss of STN responsiveness to a single L-DOPA dose both in lesioned and sham animals that received daily L-DOPA treatment. We did not find any correlation between the abnormal involuntary movement (AIM scores and the electrophysiological parameters of STN neurons recorded 24 h or 20-120 min after the last L-DOPA injection, except for the axial subscores. Nonetheless, unilateral chemical ablation of the STN with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia. In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner. Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB, phosphoDARPP-32, dopamine receptor (DR D3 and DRD2/DRD1 ratio. The STN lesion attenuated the striatal molecular changes and normalized the DRD2/DRD1 ratio. Taken together, our results show that the STN plays a role, if modest, in the physiopathology of dyskinesias.

  6. Adipose stromal cells-conditioned medium blocks 6-hydroxydopamine-induced neurotoxicity and reactive oxygen species.

    Gu, Huiying; Wang, Jimmy; Du, Nicole; Tan, Jiangning; Johnstone, Brian; Du, Yansheng

    2013-06-01

    A recent in vivo study suggested that the delivery of adipose stromal cells (ASCs) protected rat brains from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. However, the molecular mechanism that underlies this neuroprotection remains unknown. It was suggested that ASCs-induced neuroprotection possibly resulting from released factors from ASCs. In this study, we investigated whether and how cell-free conditioned media collected from ASCs (ASC-CM) protect neurons against neurotoxicity induced by 6-OHDA in cultured rat rostral mesencephalic neurons (RMN) and cerebellar granule neurons (CGN). We now report that ASC-CM protects both RMN and CGN against 6-OHDA neurotoxicity. Exposure of CGN to 6-OHDA resulted in a significant increases in neuronal ROS and cell death. As expected, pretreatments with ASC-CM dramatically block both 6-OHDA-induced ROS and neurotoxicity. Additionally, ASC-CM also directly attenuated H2O2-induced neuronal death. Our results suggest that ASC-CM could block 6-OHDA-induced neuronal death by inhibiting both 6-OHDA-induced ROS generation and ROS-induced neurotoxicity in neurons. Both antioxidative and neuroprotective effects of ASC-CM may be beneficial in the therapy for Parkinson's disease and other neurodegenerative diseases.

  7. Caffeic acid phenethyl ester protects against the dopaminergic neuronal loss induced by 6-hydroxydopamine in rats.

    Barros Silva, R; Santos, N A G; Martins, N M; Ferreira, D A S; Barbosa, F; Oliveira Souza, V C; Kinoshita, A; Baffa, O; Del-Bel, E; Santos, A C

    2013-03-13

    Caffeic acid phenethyl ester (CAPE) is a botanical compound abundant in honeybees' propolis. It has anti-inflammatory, antiviral, antioxidant, immunomodulatory and antitumor properties. Its beneficial effects against neurodegenerative diseases, including Parkinson's disease, have also been suggested and some mechanisms have been proposed. Mitochondrial damage and oxidative stress are critical events in neurodegeneration. Release of cytochrome c from mitochondria to cytosol and the downstream activation of caspase-3 have been suggested as targets of the protective mechanism of CAPE. Most of the studies addressing the protective effect of CAPE have been performed in cell culture. This is the first study to demonstrate the protective effect of CAPE against the dopaminergic neuronal loss induced by 6-hydroxydopamine (6-OHDA) in rats. It also demonstrates, for the first time, the inhibitory effect of CAPE on mitochondrial permeability transition (MPT), a mediator of neuronal death that triggers cytochrome c release and caspase-3 activation. Scavenging of reactive oxygen species (ROS) and metal chelation was demonstrated in the brain-affected areas of the rats treated with 6-OHDA and CAPE. Additionally, we demonstrated that CAPE does not affect brain mitochondrial function. Based on these findings and on its ability to cross the blood-brain barrier, CAPE is a promising compound to treat Parkinson's and other neurodegenerative diseases.

  8. The flavanoide caffeic acid phenethyl ester blocks 6-hydroxydopamine-induced neurotoxicity.

    Noelker, Carmen; Bacher, Michael; Gocke, Petra; Wei, Xing; Klockgether, Thomas; Du, Yansheng; Dodel, Richard

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons of the substantia nigra pars compacta. 6-Hydroxydopamine (6-OHDA) is specific to dopaminergic neurons in intrastriatal rodent models. It induces neuronal death either via uncoupling mitochondrial oxidative phosphorylation resulting in energy deprivation or alternatively, is associated with its ability to produce hydrogen peroxide, hydroxyl and superoxide radicals. Caffeic acid phenethyl ester (CAPE), an antioxidant flavanoid, has antiviral, anti-inflammatory, antioxidant, and immunomodulatory properties. Recent studies have shown that CAPE has also a neuroprotective effects in ischemia and low potassium-induced neuronal apoptotic models. In cerebellar granule neurons CAPE significantly blocks 6-OHDA mediated cell death (70 microM) in a dose-dependent manner. Furthermore, CAPE was able to modulate the Ca(2+)-induced release of cyctochrome c in isolated liver mitochondria. Caspase-3 activation following 6-OHDA treatment was markedly inhibited in the presence of CAPE. Although the molecular mechanisms associated with CAPE's neuroprotective effects remain to be elucidated in more detail, our results clearly demonstrate a considerable neuroprotective effect of CAPE. Since a mitochondrial insult is a major cause for the degeneration of nigral neurons in PD, we hypothesize that propolis derivatives, in particular CAPE, may have a neuroprotective effect on those cells and may be a promising drug candidate to be taken into in vivo models of PD.

  9. Isoliquiritigenin isolated from licorice Glycyrrhiza uralensis prevents 6-hydroxydopamine-induced apoptosis in dopaminergic neurons.

    Hwang, Cheol Kyu; Chun, Hong Sung

    2012-01-01

    Licorice (Glycyrrhiza uralensis) is a medicinal herb containing various bioactive components implicated in antioxidative, anti-inflammatory, antiviral, and neuroprotective effects, but the effects of licorice against Parkinson's disease (PD)-related dopaminergic cell death have not been studied. In this study, we investigated the protective effects of isoliquiritigenin (ISL) isolated from Glycyrrhiza uralensis on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in a dopaminergic cell line, SN4741. ISL (1 µM) significantly attenuated 6-OHDA (50 µM)-induced reactive oxygen species (ROS) and nitric oxide (NO) generation and apoptotic cell death. ISL pretreatment effectively suppressed 6-OHDA-mediated upregulation of Bax, p-c-Jun N-terminal kinase (JNK), p-p38 mitogen-activated protein (MAP) kinase, cytochrome c release, and caspase 3 activation. In addition, ISL significantly attenuated 6-OHDA-induced Bcl-2, brain-derived neurotrophic factor (BDNF), and mitochondrial membrane potential (MMP) reduction. Pharmacological inhibitors of the phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway reversed ISL-mediated neuroprotection against 6-OHDA toxicity in SN4741 cells. These results provide the first evidence that ISL can protect dopaminergic cells under oxidative stress conditions by regulating the apoptotic process.

  10. Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress.

    Tao, Kai; Wang, Bao; Feng, Dayun; Zhang, Wei; Lu, Fangfang; Lai, Juan; Huang, Lu; Nie, Tiejian; Yang, Qian

    2016-02-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a persistent decline of dopaminergic (DA) neurons in the substantia nigra pars compacta. Despite its frequency, effective therapeutic strategies that halt the neurodegenerative processes are lacking, reinforcing the need to better understand the molecular drivers of this disease. Importantly, increasing evidence suggests that the endoplasmic reticulum (ER) stress-induced unfolded protein response is likely involved in DA neuronal death. Salidroside, a major compound isolated from Rhodiola rosea L., possesses potent anti-oxidative stress properties and protects against DA neuronal death. However, the underlying mechanisms are not well understood. In the present study, we demonstrate that salidroside prevents 6-hydroxydopamine (6-OHDA)-induced cytotoxicity by attenuating ER stress. Furthermore, treatment of a DA neuronal cell line (SN4741) and primary cortical neurons with salidroside significantly reduced neurotoxin-induced increases in cytoplasmic reactive oxygen species and calcium, both of which cause ER stress, and cleaved caspase-12, which is responsible for ER stress-induced cell death. Together, these results suggest that salidroside protects SN4741 cells and primary cortical neurons from 6-OHDA-induced neurotoxicity by attenuating ER stress. This provides a rationale for the investigation of salidroside as a potential therapeutic agent in animal models of PD.

  11. Inhibition by anandamide of 6-hydroxydopamine-induced cell death in PC12 cells.

    Mnich, Katarzyna

    2010-01-01

    6-hydroxydopamine (6-OHDA) is a selective neurotoxin that is widely used to investigate cell death and protective strategies in models of Parkinson\\'s disease. Here, we investigated the effects of the endogenous cannabinoid, anandamide, on 6-OHDA-induced toxicity in rat adrenal phaeochromocytoma PC12 cells. Morphological analysis and caspase-3 activity assay revealed that anandamide inhibited 6-OHDA-induced apoptosis. The protection was not affected by antagonists of either cannabinoid receptors (CB(1) or CB(2)) or the vanilloid receptor TRPV1. Anandamide-dependent protection was reduced by pretreatment with LY294002 (inhibitor of phosphatidylinositol 3-kinase, PI3K) and unaffected by U0126 (inhibitor of extracellularly-regulated kinase). Interestingly, phosphorylation of c-Jun-NH2-terminal kinase (JNK) in cells exposed to 6-OHDA was strongly reduced by anandamide pre-treatment. Furthermore, 6-OHDA induced c-Jun activation and increased Bim expression, both of which were inhibited by anandamide. Together, these data demonstrate antiapoptotic effects of anandamide and also suggest a role for activation of PI3K and inhibition of JNK signalling in anandamide-mediated protection against 6-OHDA.

  12. Neurokinin receptor 3 peptide exacerbates 6-hydroxydopamine-induced dopaminergic degeneration in rats through JNK pathway.

    Chu, John Man Tak; Chan, Ying Shing; Chen, Liang Wei; Yung, Ken Kin Lam

    2012-11-01

    Neurokinin 3 (NK3) receptor is predominantly expressed in striatum and substantia nigra (SN). Evidences have indicated the roles of NK3 receptor in the pathogenesis of Parkinson's disease. By administrating NK3 receptor agonist senktide into 6-hydroxydopamine (6-OHDA)-lesioned rats, exacerbation of dopaminergic degeneration was found in striatum and substantia nigra pars compacta. From apomorphine rotation test, significant increase of contralateral rotation number was detected in 6-OHDA-lesioned rats with senktide injection. Furthermore, tyrosine hydroxylase expression in striatum and substantia nigra pars compacta were examined by immunohistochemistry and Western blotting. Further reduction of tyrosine hydroxylase immunoreactivities was found in 6-OHDA-lesioned rats that received senktide treatment. Also, phosphorylation of N-methyl-D-aspartate receptor 1 subunit was investigated in SN region and significant up-regulation was revealed in senktide-treated 6-OHDA-lesioned rats. Finally, phosphorylation of mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) and c-Jun were examined in nigral region. Up-regulation of phosphorylated JNK molecules was shown in SN region after senktide injection. In line with this evidence, phosphorylation of c-Jun at Ser 63 and Ser 73 was also up-regulated by senktide treatment, thus presenting new aspects that NK3 peptide could exacerbate 6-OHDA toxicity in in vivo models and the possible mechanism may be contributed by the modulation of N-methyl-D-aspartate receptor 1 subunit and JNK pathway activities.

  13. 6-Hydroxydopamine and radiofrequency lesions of the lateral entorhinal cortex facilitate an operant appetitive conditioning task in mice.

    Gauthier, M; Soumireu-Mourat, B

    1981-07-02

    The entorhinal cortex seems heterogeneous as dopaminergic terminals are present only in the anterior part of the lateral entorhinal cortex. In order to clarify the interaction of this cortex with the hippocampus in memory processes, the effects of either 6-hydroxydopamine or radiofrequency bilateral lesions were compared. Both lesions enhance the retention of a Skinner task with continuous reinforcement schedule. Involvement of dopamine in memory processes is discussed.

  14. Distinct Effects of Rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on Cellular Bioenergetics and Cell Death

    Samantha Giordano; Jisun Lee; Victor M. Darley-Usmar; Jianhua Zhang

    2012-01-01

    Parkinson's disease is characterized by dopaminergic neurodegeneration and is associated with mitochondrial dysfunction. The bioenergetic susceptibility of dopaminergic neurons to toxins which induce Parkinson's like syndromes in animal models is then of particular interest. For example, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP(+)), and 6-hydroxydopamine (6-OHDA), have been shown to induce dopaminergic cell death ...

  15. Effects of 6-hydroxydopamine exposure on motor activity and biochemical expression in zebrafish (Danio rerio) larvae.

    Feng, Chien-Wei; Wen, Zhi-Hong; Huang, Shi-Ying; Hung, Han-Chun; Chen, Chun-Hong; Yang, San-Nan; Chen, Nan-Fu; Wang, Hui-Min; Hsiao, Chung-Der; Chen, Wu-Fu

    2014-06-01

    Parkinson's disease (PD) is a neurodegenerative disease that is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, current treatments for PD are mainly palliative. Recently, researchers discovered that neurotoxins can induce Parkinsonian-like symptoms in zebrafish. No study to date has investigated the characteristics of PD, such as neuroinflammation factors, oxidative stress, or ubiquitin dysfunction, in this model. Therefore, the current study was aimed at utilizing commonly used clinical drugs, minocycline, vitamin E, and Sinemet, to test the usefulness of this model. Previous studies had indicated that DA cell loss was greater with 6-hydroxydopamine (6-OHDA) than with other neurotoxins. Thus, we first challenged zebrafish with 6-OHDA immersion and found a significant reduction in zebrafish locomotor activity; we then reversed the locomotor disruptions by treatment with vitamin E, Sinemet, or minocycline. The present study also analyzed the mRNA expression of parkin, pink1, and cd-11b, because the expression of these molecular targets has been shown to result in attenuation in mammalian models of PD. Vitamin E, Sinemet, and minocycline significantly reversed 6-OHDA-induced changes of parkin, pink1, and cd-11b mRNA expression in zebrafish. Moreover, we assessed tyrosine hydroxylase (TH) expression to confirm the therapeutic effects of vitamin E tested on this PD model and established that vitamin E reversed the 6-OHDA-induced damage on TH expression. Our results provide some support for the validity of this in vivo Parkinson's model, and we hope that this model will be more widely used in the future.

  16. Calcitriol promotes augmented dopamine release in the lesioned striatum of 6-hydroxydopamine treated rats

    Cass, Wayne A.; Peters, Laura E.; Fletcher, Anita M.; Yurek, David M.

    2014-01-01

    Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These effects include upregulating trophic factor levels, and reducing the severity of some central nervous system lesions. While previous studies have shown that calcitriol can be neuroprotective in 6-hydroxydopamine (6-OHDA) rodent models of PD, the present experiments were designed to examine the ability of calcitriol to promote restoration of extracellular DA levels and tissue content of DA in animals previously lesioned with 6-OHDA. Male Fischer-344 rats were given a single injection of 12 µg 6-OHDA into the right striatum. Four weeks later the animals were administered vehicle or calcitriol (0.3 or 1.0 µg/kg, s.c.) once a day for eight consecutive days. Three weeks after the calcitriol treatments in vivo microdialysis experiments were conducted to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in both potassium and amphetamine evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. In animals treated with 6-OHDA followed by calcitriol there was significantly greater potassium and amphetamine evoked overflow of DA from the lesioned striatum compared to that from the control animals. The calcitriol treatments also led to increases in postmortem tissue levels of DA in the striatum and substantia nigra. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons. PMID:24858239

  17. 5-HT1A Receptor Activation Improves Anti-Cataleptic Effects of Levodopa in 6-Hydroxydopamine-Lesioned Rats

    S. Reyhani-Rad

    2011-12-01

    Full Text Available Background and the purpose of the study: In Parkinsons disease (PD prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID. In this investigation the effect of 8-OHDAPT, as a 5-HT1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA lesioned male Wistar rats was investigated. Methods: Catalepsy was induced by unilateral injection of 6-OHDA (8 μg/2μl/rat into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p. L-DOPA (15 mg/kg twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20. Results and major conclusion: The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p. and L-DOPA (15 mg/kg, ip. 8-Hydroxy-2-(di-n-propylamino tetralin (8-OHDAPT improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip was abolished by 1-(2-methyoxyphenyl-4-[4-(2-phthalamido butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p. as a 5-HT1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT1A and dopaminergic neurons.

  18. Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity

    Palmiter Richard D

    2005-12-01

    Full Text Available Abstract Background Autosomal recessive juvenile parkinsonism (AR-JP is caused by mutations in the parkin gene which encodes an E3 ubiquitin-protein ligase. Parkin is thought to be critical for protecting dopaminergic neurons from toxic insults by targeting misfolded or oxidatively damaged proteins for proteasomal degradation. Surprisingly, mice with targeted deletions of parkin do not recapitulate robust behavioral or pathological signs of parkinsonism. Since Parkin is thought to protect against neurotoxic insults, we hypothesized that the reason Parkin-deficient mice do not develop parkinsonism is because they are not exposed to appropriate environmental triggers. To test this possibility, we challenged Parkin-deficient mice with neurotoxic regimens of either methamphetamine (METH or 6-hydroxydopamine (6-OHDA. Because Parkin function has been linked to many of the pathways involved in METH and 6-OHDA toxicity, we predicted that Parkin-deficient mice would be more sensitive to the neurotoxic effects of these agents. Results We found no signs consistent with oxidative stress, ubiquitin dysfunction, or degeneration of striatal dopamine neuron terminals in aged Parkin-deficient mice. Moreover, results from behavioral, neurochemical, and immunoblot analyses indicate that Parkin-deficient mice are not more sensitive to dopaminergic neurotoxicity following treatment with METH or 6-OHDA. Conclusion Our results suggest that the absence of a robust parkinsonian phenotype in Parkin-deficient mice is not due to the lack of exposure to environmental triggers with mechanisms of action similar to METH or 6-OHDA. Nevertheless, Parkin-deficient mice could be more sensitive to other neurotoxins, such as rotenone or MPTP, which have different mechanisms of action; therefore, identifying conditions that precipitate parkinsonism specifically in Parkin-deficient mice would increase the utility of this model and could provide insight into the mechanism of AR

  19. Immunohistochemical changes of nigrostriatal tyrosine hydroxylase and dopamine transporter in the golden hamster after a single intrastriatal injection of 6-hydroxydopamine.

    Rodríguez, Sebastián; Uchida, Kazuyuki; Nakayama, Hiroyuki

    2013-05-01

    One of the most important models for analyzing the pathomorphological aspects of Parkinson's disease (PD) is the 6-hydroxydopamine (6-OHDA) model where lesions of the nigrostriatal axis are observed when 6-OHDA is intrastriatally injected. Despite the widespread use in rats, only few studies about the toxicity of 6-OHDA have been carried out in other species. In the present study, we evaluated for the first time the effects of a single intrastriatal injection of 6-OHDA (20 μg dissolved in 2 μl of vehicle) in the young-adult golden hamster (GH). Significant decreases in tyrosine hydroxylase (TH)-positive area and dopamine transporter (DAT)-positive area were found in the ipsilateral striatum 3 days after the injection. These decreases in immunoreactivity continued for 7 days and a recovery trend was found at days 15 and 21 post injection. On the other hand, no effect of injection was found on the contralateral side. In the substantia nigra pars compacta (SNpc), a significant decrease in the number of TH-positive cells appeared one week after the injection with the peak in the loss of TH-positive immunoreactivity being recorded two weeks post-injection. On the basis of the results herein reported, we believe that the GH is a suitable model for studying the patterns of spontaneous recovery of striatal axons following the 6-OHDA intrastriatal injection.

  20. Phytic Acid Protects against 6-Hydroxydopamine-Induced Dopaminergic Neuron Apoptosis in Normal and Iron Excess Conditions in a Cell Culture Model

    Qi Xu

    2011-01-01

    Full Text Available Iron may play an important role in Parkinson's disease (PD since it can induce oxidative stress-dependent neurodegeneration. The objective of this study was to determine whether the iron chelator, phytic acid (IP6 can protect against 6-hydroxydopamine- (6-OHDA- induced apoptosis in immortalized rat mesencephalic dopaminergic cells under normal and iron-excess conditions. Caspase-3 activity was increased about 6-fold after 6-OHDA treatment (compared to control; <.001 and 30 μmol/L IP6 pretreatment decreased it by 38% (<.05. Similarly, a 63% protection (<.001 against 6-OHDA induced DNA fragmentation was observed with IP6 pretreatment. Under iron-excess condition, a 6-fold increase in caspase-3 activity (<.001 and a 42% increase in DNA fragmentation (<.05 with 6-OHDA treatment were decreased by 41% (<.01 and 27% (<.05, respectively, with 30 μmol/L IP6. Together, our data suggest that IP6 protects against 6-OHDA-induced cell apoptosis in both normal and iron-excess conditions, and IP6 may offer neuroprotection in PD.

  1. Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats

    Seigers, Riejanne; Schagen, Sanne B.; Coppens, Caroline M.; van der Most, Peter J.; van Dam, Frits S. A. M.; Koolhaas, Jaap M.; Buwalda, Bauke

    2009-01-01

    Methotrexate (MTX) is a cytostatic agent used in adjuvant chemotherapy for treatment of breast cancer and is associated with cognitive impairment in a subgroup of patients. The aim of this paper is to test whether MTX can rapidly affect various brain structures resulting in decreased hippocampal cel

  2. Activation of GSK-3β and Caspase-3 Occurs in Nigral Dopamine Neurons during the Development of Apoptosis Activated by a Striatal Injection of 6-Hydroxydopamine

    Hernandez-Baltazar, Daniel; Mendoza-Garrido, Maria E.; Martinez-Fong, Daniel

    2013-01-01

    The 6-Hydroxydopamine (6-OHDA) rat model of Parkinson's disease is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising therapeutic interventions. This work evaluated whether a single striatal injection of 6-OHDA causes progressive apoptosis of dopamine (DA) neurons and activation of glycogen synthase kinase 3β (GSK-3β) and caspase-3 in the substantia nigra compacta (SNc). The loss of DA neurons was shown by three neuron markers; tyrosine hydroxylase (TH), NeuN, and β-III tubulin. Apoptosis activation was determined using Apostain and immunostaining against cleaved caspase-3 and GSK-3β pY216. We also explored the possibility that cleaved caspase-3 is produced by microglia and astrocytes. Our results showed that the 6-OHDA caused loss of nigral TH(+) cells, progressing mainly in rostrocaudal and lateromedial directions. In the neostriatum, a severe loss of TH(+) terminals occurred from day 3 after lesion. The disappearance of TH(+) cells was associated with a decrease in NeuN and β-III tubulin immunoreactivity and an increase in Apostain, cleaved caspase-3, and GSK-3β pY216 in the SNc. Apostain immunoreactivity was observed from days 3 to 21 postlesion. Increased levels of caspase-3 immunoreactivity in TH(+) cells were detected from days 1 to 15, and the levels then decreased to day 30 postlesion. The cleaved caspase-3 also collocated with microglia and astrocytes indicating its participation in glial activation. Our results suggest that caspase-3 and GSK-3β pY216 activation might participate in the DA cell death and that the active caspase-3 might also participate in the neuroinflammation caused by the striatal 6-OHDA injection. PMID:23940672

  3. In vivo visualization and monitoring of viable neural stem cells using noninvasive bioluminescence imaging in the 6-hydroxydopamine-induced mouse model of Parkinson disease.

    Im, Hyung-Jun; Hwang, Do Won; Lee, Han Kyu; Jang, Jaeho; Lee, Song; Youn, Hyewon; Jin, Yeona; Kim, Seung U; Kim, E Edmund; Kim, Yong Sik; Lee, Dong Soo

    2013-06-01

    Transplantation of neural stem cells (NSCs) has been proposed as a treatment for Parkinson disease (PD). The aim of this study was to monitor the viability of transplanted NSCs expressing the enhanced luciferase gene in a mouse model of PD in vivo. The PD animal model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA). The behavioral test using apomorphine-induced rotation and positron emission tomography with [18F]N-(3-fluoropropyl)-2'-carbomethoxy-3'-(4-iodophenyl)nortropane ([18F]FP-CIT) were conducted. HB1.F3 cells transduced with an enhanced firefly luciferase retroviral vector (F3-effLuc cells) were transplanted into the right striatum. In vivo bioluminescence imaging was repeated for 2 weeks. Four weeks after transplantation, [18F]FP-CIT PET and the rotation test were repeated. All 6-OHDA-injected mice showed markedly decreased [18F]FP-CIT uptake in the right striatum. Transplanted F3-effLuc cells were visualized on the right side of the brain in all mice by bioluminescence imaging. The bioluminescence intensity of the transplanted F3-effLuc cells gradually decreased until it was undetectable by 10 days. The behavioral test showed that stem cell transplantation attenuated the motor symptoms of PD. No significant change was found in [18F]FP-CIT imaging after cell transplantation. We successfully established an in vivo bioluminescence imaging system for the detection of transplanted NSCs in a mouse model of PD. NSC transplantation induced behavioral improvement in PD model mice.

  4. Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP⁺-induced apoptosis but not rotenone or 6-hydroxydopamine toxicity.

    Garcia-Garcia, Aracely; Anandhan, Annandurai; Burns, Michaela; Chen, Han; Zhou, You; Franco, Rodrigo

    2013-11-01

    Controversial reports on the role of autophagy as a survival or cell death mechanism in dopaminergic cell death induced by parkinsonian toxins exist. We investigated the alterations in autophagic flux and the role of autophagy protein 5 (Atg5)-dependent autophagy in dopaminergic cell death induced by parkinsonian toxins. Dopaminergic cell death induced by the mitochondrial complex I inhibitors 1-methyl-4-phenylpyridinium (MPP⁺) and rotenone, the pesticide paraquat, and the dopamine analog 6-hydroxydopamine (6-OHDA) was paralleled by increased autophagosome accumulation. However, when compared with basal autophagy levels using chloroquine, autophagosome accumulation was a result of impaired autophagic flux. Only 6-OHDA induced an increase in autophagosome formation. Overexpression of a dominant negative form of Atg5 increased paraquat- and MPP⁺-induced cell death. Stimulation of mammalian target of rapamycin (mTOR)-dependent signaling protected against cell death induced by paraquat, whereas MPP⁺-induced toxicity was enhanced by wortmannin, a phosphoinositide 3-kinase class III inhibitor, rapamycin, and trehalose, an mTOR-independent autophagy activator. Modulation of autophagy by either pharmacological or genetic approaches had no effect on rotenone or 6-OHDA toxicity. Cell death induced by parkinsonian neurotoxins was inhibited by the pan caspase inhibitor (Z-VAD), but only caspase-3 inhibition was able to decrease MPP⁺-induced cell death. Finally, inhibition of the lysosomal hydrolases, cathepsins, increased the toxicity by paraquat and MPP⁺, supporting a protective role of Atg5-dependent autophagy and lysosomes degradation pathways on dopaminegic cell death. These results demonstrate that in dopaminergic cells, Atg5-dependent autophagy acts as a protective mechanism during apoptotic cell death induced by paraquat and MPP⁺ but not during rotenone or 6-OHDA toxicity.

  5. Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons.

    Janssen, Megan J; Leiva-Salcedo, Elias; Buonanno, Andres

    2012-10-03

    The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term potentiation at CA1 pyramidal neuron synapses in slices are mediated indirectly by dopamine. Here we studied whether NRG/ErbB signaling directly regulates interneuron intrinsic excitability by pharmacologically isolating ErbB4-expressing neurons in rat dissociated hippocampal cultures, which lack dopaminergic innervation. We found that NRG1 acutely attenuates ErbB4-expressing interneuron excitability by depolarizing the firing threshold; neurons treated with the pan-ErbB inhibitor PD158780 or negative for ErbB4 were unaffected. These effects of NRG1 are primarily attributable to decreased voltage-gated sodium channel activity, as current density was attenuated by ∼60%. In stark contrast, NRG1 had minor effects on whole-cell potassium currents. Our data reveal the direct actions of NRG1 signaling in ErbB4-expressing interneurons, and offer novel insight into how NRG1/ErbB4 signaling can impact hippocampal activity.

  6. Buyuan Congnao decoction decreases hippocampal beta-amyloid expression in a rat model of Alzheimer's disease

    Min Chen; Jing Wang; Cairong Ming

    2012-01-01

    A mixture of ibotenic acid and β-amyloid 1-42 was injected into the hippocampus of a rat model of Alzheimer's disease, followed by intragastric administration of a traditional Chinese medicine Buyuan Congnao decoction (main components included radix astragali, radix polygoni multiflori preparata, rhizoma acori talarinowii, radix polygalae, fructus alpiniae oxyphyllae, and radix glycyrrhizae preparata) and a piracetam suspension.Following treatment with traditional Chinese medicine or western medicine, β-amyloid expression decreased and neuronal morphology was normal in the rat hippocampal CA1 region, in addition to significantly shortened average latency in the Morris water navigation task.These findings suggested that compound prescription of Buyuan Congnao decoction, similar to the curative effects of piracetam, decreased hippocampal β-amyloid expression in a rat model of Alzheimer's disease, as well as improved learning and memory.

  7. Role of reactive oxygen species in extracellular signal-regulated protein kinase phosphorylation and 6-hydroxydopamine cytotoxicity

    Scott M Kulich; Charleen T Chu

    2003-02-01

    A number of reports indicate the potential for redox signalling via extracellular signal-regulated protein kinases (ERK) during neuronal injury. We have previously found that sustained ERK activation contributes to toxicity elicited by 6-hydroxydopamine (6-OHDA) in the B65 neuronal cell line. To determine whether reactive oxygen species (ROS) play a role in mediating ERK activation and 6-OHDA toxicity, we examined the effects of catalase, superoxide dismutase (SOD1), and metalloporphyrin antioxidants (‘SOD mimetics’) on 6-OHDA-treated cells. We found that catalase and metalloporphyrin antioxidants not only conferred protection against 6-OHDA but also inhibited development of sustained ERK phosphorylation in both differentiated and undifferentiated B65 cells. However, exogenously added SOD1 and heat-inactivated catalase had no effect on either toxicity or sustained ERK phosphorylation. This correlation between antioxidant protection and inhibition of 6-OHDA-induced sustained ERK phosphorylation suggests that redox regulation of ERK signalling cascades may contribute to neuronal toxicity.

  8. Sesamin imparts neuroprotection against intrastriatal 6-hydroxydopamine toxicity by inhibition of astroglial activation, apoptosis, and oxidative stress.

    Baluchnejadmojarad, Tourandokht; Mansouri, Monireh; Ghalami, Jamileh; Mokhtari, Zahra; Roghani, Mehrdad

    2017-04-01

    Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders in elders. Sesamin is a lignan compound and the active constituent of sesame oil with antioxidant and anti-inflammatory properties. This study was carried out to explore the mechanisms underlying sesamin effect against unilateral striatal 6-hydroxydopamine (6-OHDA) model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with sesamin at doses of 10 or 20mg/kg/day for one week. Sesamin at a dose of 20mg/kg attenuated motor imbalance in narrow beam test, lowered striatal level of malondialdehyde (MDA) and reactive oxygen species (ROS), improved superoxide dismutase (SOD) activity, lowered striatal caspase 3 activity and α-synuclein expression, attenuated glial fibrillary acidic protein (GFAP) immunoreactivity, depressed nigral neuronal apoptosis, and prevented damage of dopaminergic neurons using tyrosine hydroxylase (TH) immunohistochemistry. These findings reveal the reversal effect of sesamin in 6-OHDA model of PD via attenuation of apoptosis, astrogliosis, oxidative stress, and down-regulation of α-synuclein.

  9. The 6-hydroxydopamine-induced nigrostriatal neurodegeneration produces microglia-like NG2 glial cells in the rat substantia nigra.

    Kitamura, Yoshihisa; Inden, Masatoshi; Minamino, Hideaki; Abe, Mari; Takata, Kazuyuki; Taniguchi, Takashi

    2010-11-01

    Neuron/glial 2 (NG2)-expressing cells are often referred to as oligodendrocyte precursor cells. NG2-expressing cells have also been identified as multipotent progenitor cells. However, microglia-like NG2 glial cells have not been fully examined in neurodegenerative disorders such as Parkinson's disease (PD). In the present study, we chose two rat models of PD, i.e., intranigral or intrastriatal injection of 6-hydroxydopamine (6-OHDA), since the cell bodies of dopamine (DA) neurons, which form a nigrostriatal pathway, are in the substantia nigra pars compacta (SNpc) while their nerve terminals are in the striatum. In the nigral 6-OHDA-injected model, activated NG2-positive cells were detected in the SNpc but not in the striatum. In contrast, in the striatal 6-OHDA-injected model, these cells were detected in both the SNpc and the striatum. In both models, activated NG2-positive cells were located close to surviving tyrosine hydroxylase (TH)-positive neurons in the SNpc. In addition, activated NG2-positive cells in the SNpc coexpressed ionized calcium-binding adaptor molecule 1 (Iba1), a microglia/macrophage marker. Interestingly, these double-positive glial cells coexpressed glial cell line-derived neurotrophic factor (GDNF). These results suggest that microglia-like NG2 glial cells may help protect DA neurons and may lead to new therapeutic targets in PD.

  10. BIOCHEMICAL ESTIMATIONS IN 6-HYDROXYDOPAMINE-INDUCED RAT MODEL OF PARKINSON’S DISEASE

    Alin Ciobica

    2007-12-01

    OHDA (8µg/4µl was right-unilateral injected in substantia nigra (SN and ventral tegmental area (VTA, and 20 days after neurosurgery the activity of superoxid dismutase (SOD and glutathione peroxidase (GPX from the temporal lobe homogenate was assessed. A significant decrease in both markers was found in the temporal lobe 20 days after neurotoxin administration. These results support that an early event in the course of dopamine depletion following 6-OHDA administration is the generation of oxidative stress.

  11. Cardiac Dysregulation and Myocardial Injury in a 6-Hydroxydopamine-Induced Rat Model of Sympathetic Denervation.

    Yue-Hua Jiang

    Full Text Available Cardiac sympathetic denervation is found in various cardiac pathologies; however, its relationship with myocardial injury has not been thoroughly investigated.Twenty-four rats were assigned to the normal control group (NC, sympathectomy control group (SC, and a sympathectomy plus mecobalamin group (SM. Sympathectomy was induced by injection of 6-OHDA, after which, the destruction and distribution of sympathetic and vagal nerve in the left ventricle (LV myocardial tissue were determined by immunofluorescence and ELISA. Heart rate variability (HRV, ECG and echocardiography, and assays for myocardial enzymes in serum before and after sympathectomy were examined. Morphologic changes in the LV by HE staining and transmission electron microscope were used to estimate levels of myocardial injury and concentrations of inflammatory cytokines were used to reflect the inflammatory reaction.Injection of 6-OHDA decreased NE (933.1 ± 179 ng/L for SC vs. 3418.1± 443.6 ng/L for NC, P < 0.01 and increased NGF (479.4± 56.5 ng/mL for SC vs. 315.85 ± 28.6 ng/mL for NC, P < 0.01 concentrations. TH expression was reduced, while ChAT expression showed no change. Sympathectomy caused decreased HRV and abnormal ECG and echocardiography results, and histopathologic examinations showed myocardial injury and increased collagen deposition as well as inflammatory cell infiltration in the cardiac tissue of rats in the SC and SM groups. However, all pathologic changes in the SM group were less severe compared to those in the SC group.Chemical sympathectomy with administration of 6-OHDA caused dysregulation of the cardiac autonomic nervous system and myocardial injuries. Mecobalamin alleviated inflammatory and myocardial damage by protecting myocardial sympathetic nerves.

  12. Mitochondrial Dynamics and Mitophagy in the 6-Hydroxydopamine Preclinical Model of Parkinson's Disease

    Galindo, Maria F.; Solesio, Maria E.; Atienzar-Aroca, Sandra; Zamora, Maria J.; Jordán Bueso, Joaquín

    2012-01-01

    We discuss the participation of mitochondrial dynamics and autophagy in the 6-hydroxidopamine-induced Parkinson's disease model. The regulation of dynamic mitochondrial processes such as fusion, fission, and mitophagy has been shown to be an important mechanism controlling cellular fate. An imbalance in mitochondrial dynamics may contribute to both familial and sporadic neurodegenerative diseases including Parkinson's disease. With special attention we address the role of second messengers as the role of reactive oxygen species and the mitochondria as the headquarters of cell death. The role of molecular signaling pathways, for instance, the participation of Dynamin-related protein 1(Drp1), will also be addressed. Furthermore evidence demonstrates the therapeutic potential of small-molecule inhibitors of mitochondrial division in Parkinson's disease. For instance, pharmacological inhibition of Drp1, through treatment with the mitochondrial division inhibitor-1, results in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. Deciphering the signaling cascades that underlie mitophagy triggered by 6-OHDA, as well as the mechanisms that determine the selectivity of this response, will help to better understand this process and may have impact on human treatment strategies of Parkinson's disease. PMID:22966477

  13. Mitochondrial dynamics and mitophagy in the 6-hydroxydopamine preclinical model of Parkinson's disease.

    Galindo, Maria F; Solesio, Maria E; Atienzar-Aroca, Sandra; Zamora, Maria J; Jordán Bueso, Joaquín

    2012-01-01

    We discuss the participation of mitochondrial dynamics and autophagy in the 6-hydroxidopamine-induced Parkinson's disease model. The regulation of dynamic mitochondrial processes such as fusion, fission, and mitophagy has been shown to be an important mechanism controlling cellular fate. An imbalance in mitochondrial dynamics may contribute to both familial and sporadic neurodegenerative diseases including Parkinson's disease. With special attention we address the role of second messengers as the role of reactive oxygen species and the mitochondria as the headquarters of cell death. The role of molecular signaling pathways, for instance, the participation of Dynamin-related protein 1(Drp1), will also be addressed. Furthermore evidence demonstrates the therapeutic potential of small-molecule inhibitors of mitochondrial division in Parkinson's disease. For instance, pharmacological inhibition of Drp1, through treatment with the mitochondrial division inhibitor-1, results in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. Deciphering the signaling cascades that underlie mitophagy triggered by 6-OHDA, as well as the mechanisms that determine the selectivity of this response, will help to better understand this process and may have impact on human treatment strategies of Parkinson's disease.

  14. Regional distributions of manganese, iron, copper, and zinc in the brains of 6-hydroxydopamine-induced parkinsonian rats.

    Tarohda, Tohru; Ishida, Yasushi; Kawai, Keiichi; Yamamoto, Masayoshi; Amano, Ryohei

    2005-09-01

    Time courses of changes in manganese, iron, copper, and zinc concentrations were examined in regions of the brain of a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease using inductively coupled plasma mass spectrometry (ICP-MS). The concentrations were simultaneously determined in brain section at the level of the substantia nigra 1, 3, 7, 10, 14, and 21 days after the 6-OHDA treatment and compared with those of control rats. The distributions of these elements were obtained for 18 regions of the sagittal section (1-mm thick). The ICP-MS results indicated that Mn, Fe, Cu, and Zn levels of the 6-OHDA-induced parkinsonian brain were observed to increase in all regions that lay along the dopaminergic pathway. In the substantia nigra, the increase in Mn level occurred rapidly from 3 to 7 days and preceded those in the other elements, reaching a plateau in the 6-OHDA brain. Iron and Zn levels increased gradually until 7 days and then increased rapidly from 7 to 10 days. The increase in the copper level was slightly delayed. In other regions, such as the globus pallidus, putamen, and amygdala, the levels of Mn, Fe, Cu, and Zn increased with time after 6-OHDA treatment, although the time courses of their changes were region-specific. These findings contribute to our understanding of the roles of Mn and Fe in the induction of neurological symptoms and progressive loss of dopaminergic neurons in the development of Parkinson's disease. Manganese may hold the key to disturbing cellular Fe homeostasis and accelerating Fe levels, which play the most important role in the development of Parkinson's disease.

  15. Inhibition of Mitochondrial Clearance and Cu/Zn-SOD Activity Enhance 6-Hydroxydopamine-Induced Neuronal Apoptosis.

    In, Sua; Hong, Chang-Won; Choi, Boyoung; Jang, Bong-Geum; Kim, Min-Ju

    2016-01-01

    Parkinson's disease (PD) is a common movement disorder among neurodegenerative diseases, involving neuronal cell death in the substantia nigra of the midbrain. Although mechanisms of cell death in PD have been studied, the exact molecular pathogenesis is still unclear. Here, we explore the relationship between two types of cell death, autophagy and apoptosis, which have been studied separately in parkinsonian mimetic model of 6-hydroxydopamine (6-OHDA). 6-OHDA induced autophagy firstly and then later inhibition of autophagy flux occurred with apoptosis. The apoptosis was prevented by treatment of pan-caspase inhibitor, zVAD-fmk (benzyloxycarbonyl-VAD-fluoromethylketone (zVAD)), or early phase inhibitor of autophagy, 3-methyladenine (3-MA), indicating that autophagic induction was followed by the apoptosis. Interestingly, late step inhibitor of autophagy, bafilomycin A1 (BafA), aggravated 6-OHDA-induced apoptosis. This was associated with mitochondrial abnormality such as the inhibition of damaged mitochondrial clearance and aberrant increase of extracellular oxygen consumption. Furthermore, treatment of BafA did not inhibit 6-OHDA-mediated superoxide formation but strongly reduced the hydrogen peroxide production to below basal levels, indicating failure from superoxide to hydrogen peroxide. These results were accompanied by a lowered expression and activity of copper/zinc superoxide dismutase (Cu/Zn-SOD) but not of manganese SOD (MnSOD) and catalase. Thus, the present study suggests that crosstalk among apoptosis, autophagy, and oxidative stress is a causative factor of 6-OHDA-induced neuronal death and provides a mechanistic understanding of PD pathogenesis.

  16. Synergistic Antiparkinsonian Effect of Flunarizine, Glibenclamide and B Vitamins in a Rat 6-Hydroxydopamine Model; The Role of Malondialdehyde

    Sarookhani

    2016-08-01

    Full Text Available Background The current study evaluated the effects of a combination of flunarizine (flu a calcium channel blocker, glibenclamide (Glib, a KATP channels blocker and B vitamins (B com on the behavioral symptoms of 6-hydroxydopamine (6-OHDA-induced model of Parkinson disease to examine the synergistic antiparkinsonian effects of the drugs and supplements. Also the level of malondialdehyde (MDA was measured in blood and brain suspensions to find probable neuroprotective mechanism of these materials. Methods 6-OHDA was injected into striatum of rats by stereotaxic surgery. Pretreatment with flu, Glib and B com was started before the surgery and continued to three weeks after the surgery. Development and severity of Parkinson disease were evaluated by the conventional behavioral tests. MDA values were measured spectrophotometrically, using thiobarbituric acid test and the MDA standard curve. Results Pretreatment with a combination of flu, Glib and B com ameliorated the behavioral symptoms of Parkinson disease. The effect of the combination was significantly more potent than those of flu, Glib or B com, solely. Pretreatment with the combination or using only Glib or B com separately, reduced the level of MDA in blood and brain, significantly. However, the effect of the combination was significantly more potent than those of Glib or B com, solely. Conclusions Since the severity of the behavioral symptoms in the 6-OHDA-induced model of Parkinson disease reflects the degree of the lesion in substantia nigra (SN dopaminergic neurons, it is suggested that using the combination had neuroprotective effects. The obtained data suggest a synergistic neuroprotective and antiparkinsonian effect for flu, Glib and B com. At least, a part of this effect was mediated through inhibition of oxidative stress.

  17. Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats.

    Ma, Delin; Shuler, Jeffrey M; Raider, Kayla D; Rogers, Robert S; Wheatley, Joshua L; Geiger, Paige C; Stanford, John A

    2015-07-10

    Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson's disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats' nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist.

  18. Human albumin prevents 6-hydroxydopamine-induced loss of tyrosine hydroxylase in in vitro and in vivo.

    Li-Juan Zhang

    Full Text Available Human albumin has recently been demonstrated to protect brain neurons from injury in rat ischemic brain. However, there is no information available about whether human albumin can prevent loss of tyrosine hydroxylase (TH expression of dopaminergic (DA neurons induced by 6-hydroxydopamine (6-OHDA toxicity that is most commonly used to create a rat model of Parkinson's disease (PD. In the present study, two microliters of 1.25% human albumin were stereotaxically injected into the right striatum of rats one day before or 7 days after the 6-OHDA lesion in the same side. D-Amphetamine-induced rotational asymmetry was measured 7 days, 3 and 10 weeks after 6-OHDA lesion. We observed that intrastriatal administration of human albumin significantly reduced the degree of rotational asymmetry. The number of TH-immunoreactive neurons present in the substantia nigra was greater in 6-OHDA lesioned rats following human albumin-treatment than non-human albumin treatment. TH-immunoreactivity in the 6-OHDA-lesioned striatum was also significantly increased in the human albumin-treated rats. To examine the mechanisms underlying the effects of human albumin, we challenged PC12 cells with 6-OHDA as an in vitro model of PD. Incubation with human albumin prevented 6-OHDA-induced reduction of cell viability in PC12 cell cultures, as measured by MTT assay. Furthermore, human albumin reduced 6-OHDA-induced formation of reactive oxygen species (ROS and apoptosis in cultured PC12 cells, as assessed by flow cytometry. Western blot analysis showed that human albumin inhibited 6-OHDA-induced activation of JNK, c-Jun, ERK, and p38 mitogen-activated protein kinases (MAPK signaling in PC12 cultures challenged with 6-OHDA. Human albumin may protect against 6-OHDA toxicity by influencing MAPK pathway followed by anti-ROS formation and anti-apoptosis.

  19. Acupuncture prevents 6-hydroxydopamine-induced neuronal death in the nigrostriatal dopaminergic system in the rat Parkinson's disease model.

    Park, Hi-Joon; Lim, Sabina; Joo, Wan-Seok; Yin, Chang-Shik; Lee, Hyang-Sook; Lee, Hye-Jung; Seo, Jung Chul; Leem, Kanghyun; Son, Yang-Sun; Kim, Youn-Jung; Kim, Chang-Ju; Kim, Yong-Sik; Chung, Joo-Ho

    2003-03-01

    Parkinson's disease (PD) is a chronic neurodegenerative disorder, and it has been suggested that treatments promoting survival and functional recovery of affected dopaminergic neurons could have a significant and long-term therapeutic value. In the present study, we investigated the neuroprotective effects of acupuncture on the nigrostriatal system in rat unilaterally lesioned with 6-hydroxydopamine (6-OHDA, 4 microg/microl, intrastriatal injection) using tyrosine hydroxylase (TH) and receptor for brain-derived neurotrophic factor, trkB, immunohistochemistries. Two weeks after the lesions were made, rats presented with asymmetry in rotational behavior (118.3 +/- 17.5 turns/h) following injection with apomorphine, a dopamine receptor agonist (0.5 mg/kg, sc). In contrast, acupunctural treatment at acupoints GB34 and LI3 was shown to significantly reduce this motor deficit (14.6 +/- 13.4 turns/h). Analysis via TH immunohistochemistry revealed a substantial loss of cell bodies in the substantia nigra (SN) (45.7% loss) and their terminals in the dorsolateral striatum ipsilateral to the 6-OHDA-induced lesion. However, acupunctural treatment resulted in the enhanced survival of dopaminergic neurons in the SN (21.4% loss) and their terminals in the dorsolateral striatum. Acupuncture also increased the expression of trkB significantly (35.6% increase) in the ipsilateral SN. In conclusion, we observed that only acupuncturing without the use of any drug has the neuroprotective effects against neuronal death in the rat PD model and these protective properties of acupuncture could be mediated by trkB.

  20. Dietary and Intraperitoneal Administration of Selenium Provide Comparable Protection in the 6-Hydroxydopamine Lesion Rat Model of Parkinson's Disease

    Cecilia M. Fox

    2007-01-01

    Full Text Available Significant research implicates the involvement of free radicals in the manifestation of Parkinson's disease. The antioxidant, selenium is a vital dietary component for mammals. It is present in the active center of glutathione peroxidase, an antioxidant enzyme that scavenges peroxides and protects membrane lipids and macromolecules from oxidative insult. The purpose of this research was to determine an effective means of delivering selenium as well as an appropriate time frame for antioxidant administration that would elicit a protective response in rats challenged with an intranigral 6-hydroxydopamine (6-OHDA lesion. In the first part of this study, Fischer 344 rats were placed into one of four groups: selenium enhanced diet, control diet, intraperitoneal injection of selenium as Na2SeO3 or intraperitoneal injection of distilled water. All treatments were delivered prior to an intranigral 6-OHDA lesion. Animals were euthanized two weeks post lesion and their brains processed for tyrosine hydroxylase (TH immunocytochemistry. Average dopamine neuron survival in the substantia nigra of control animals was less than 22%; whereas nigral dopamine neuron survival in the selenium fed group was 49.7% and 56.0% in the selenium injected group. Based on these results, a subsequent study was designed utilizing the selenium enhanced diet method of antioxidant administration. To examine the neuroprotective effect of long-term selenium treatment, pregnant Fischer 344 rats were exposed to either selenium enhanced or control rat chow. Their pups were treated with the same diet as their mothers and lesioned with 6-OHDA at two months of age. Animals were euthanized and their brains were processed for TH immunocytochemistry. Nigral dopamine neuron survival for the selenium treated animals was significantly protective (59% when compared to the control chow fed animals (29.6%. However, when compared to the short-term exposure of selenium rat chow in the previous

  1. Cell viability and dopamine secretion of 6-hydroxydopamine-treated PC12 cells co-cultured with bone marrow-derived mesenchymal stem cells

    Yue Tang; Yongchun Cui; Fuliang Luo; Xiaopeng Liu; Xiaojuan Wang; Aili Wu; Junwei Zhao; Zhong Tian; Like Wu

    2012-01-01

    In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesenchymal stem cells against 6-hydroxydopamine-induced neurotoxicity and to verify whether the mechanism of action relates to abnormal α-synuclein accumulation in cells. Results showed that co-culture with bone marrow-derived mesenchymal stem cells enhanced PC12 cell viability and dopamine secretion in a cell dose-dependent manner. MitoLight staining was used to confirm that PC12 cells co-cultured with bone marrow-derived mesenchymal stem cells demonstrate reduced levels of cell apoptosis. Immunocytochemistry and western blot analysis found the quantity of α-synuclein accumulation was significantly reduced in PC12 cell and bone marrow-derived mesenchymal stem cell co-cultures. These results indicate that bone marrow-derived mesenchymal stem cells can attenuate 6-hydroxydopamine-induced cytotoxicity by reducing abnormal α-synuclein accumulation in PC12 cells.

  2. CB1 receptor deficiency decreases wheel-running activity: consequences on emotional behaviours and hippocampal neurogenesis.

    Dubreucq, Sarah; Koehl, Muriel; Abrous, Djoher N; Marsicano, Giovanni; Chaouloff, Francis

    2010-07-01

    Chronic voluntary wheel-running activity has been reported to hypersensitise central CB1 receptors in mice. On the other hand, pharmacological findings suggest that the CB1 receptor could be involved in wheel-running behaviour and in running-induced neurogenesis in the hippocampus. We analysed wheel-running behaviour for 6 weeks and measured its consequences on hippocampal neurogenesis in CB1 knockout (CB1(-/-)) animals, compared to wild-type (CB1(+/+)) littermates. Because wheel running has been shown to affect locomotor reactivity in novel environments, memory for aversive events and depression-like behaviours, we also assessed these behaviours in control and running CB1(+/+) and CB1(-/-) mice. When compared with running CB1(+/+) mice, the distance covered weekly by CB1(-/-) mice was decreased by 30-40%, an observation accounted for by decreased time spent and maximal velocity on the wheels. Analyses of running distances with respect to the light/dark cycle revealed that mutant covered less distance throughout both the inactive and the active phases of that cycle. Locomotion in an activity cage, exploration in an open field, and immobility time in the forced swim test proved insensitive to chronic wheel running in either genotype. Wheel running, per se, did not influence the expression and extinction of cued fear memory but counteracted in a time-dependent manner the deficiency of extinction measured in CB1(-/-) mice. Hippocampal neurogenesis, assessed by doublecortin labelling of immature neurons in the dentate gyrus, was lowered by 40% in control CB1(-/-) mice, compared to control CB1(+/+) mice. Although CB1(-/-) mice ran less than their wild-type littermates, the 6-week running protocol increased neurogenesis to similar extents (37-39%) in both genotypes. This study suggests that mouse CB1 receptors control wheel running but not its neurogenic consequences in the hippocampus.

  3. Environmental enrichment and working memory tasks decrease hippocampal cell proliferation after wheel running--A role for the prefrontal cortex in hippocampal plasticity?

    Schaefers, Andrea T U

    2015-10-22

    Despite an increasing amount of evidence about the regulation of adult hippocampal neurogenesis on the local level, less attention has been paid to its systemic embedding in wider brain circuits. The aim of the present study was to obtain evidence for a potential role of the prefrontal cortex in the regulation of adult hippocampal neurogenesis. We hypothesised that activation of the prefrontal cortex by environmental enrichment or a working-memory task would decrease previously enhanced cell proliferation rates. Wheel running was applied as a common stimulator of cell proliferation in CD1 mice reared under deprivation of natural environmental stimulation. Next, the animals were assigned to four groups for different treatments in the following three days: housing under continued deprivation, environmental enrichment, a spatial-delayed alternation task in an automated T-maze that activates the prefrontal cortex by working-memory requirements or a control task in the automated T-maze differing only in the single parameter working-memory-associated delay. Both the environmental enrichment and spatial-delayed alternation tasks decreased cell proliferation rates in the dentate gyrus compared to deprived housing and the control task in the T-maze. As the control animals underwent the same procedures and stressors and differed only in the single parameter working-memory-associated delay, the working-memory requirement seems to be the crucial factor for decreasing cell proliferation rates. Taken together, these results suggest that the prefrontal cortex may play a role in the regulation of hippocampal cell proliferation.

  4. Neuregulin Directly Decreases Voltage-Gated Sodium Current in Hippocampal ErbB4-Expressing Interneurons

    Janssen, Megan J.; Leiva-Salcedo, Elias; Buonanno, Andres

    2012-01-01

    The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term poten...

  5. Depletion of cortical norepinephrine in rats by 6-hydroxydopamine does not impair performance of a delayed-nonmatching-to-sample task.

    Koger, S M; Mair, R G

    1992-08-01

    Rats were trained on a spatial delayed-nonmatching-to-sample (DNMTS) task, matched for performance, and randomly assigned to treatment with dorsal noradrenergic bundle injections of either 6-hydroxydopamine, to deplete cortical norepinephrine (NE), or vehicle, to control for the effects of surgery. After recovery, there were no significant differences between the groups when retrained on the DNMTS task at retention intervals (RI) from 0.1 to 15.0 s. Furthermore, no differences were observed when rats were trained at a 6.0-s RI filled with distracting stimuli or when dummy information runs were added to increase proactive interference. These results demonstrate that depletion of cortical NE cannot account for the DNMTS performance deficits observed in rats recovered from pyrithiamine-induced thiamine deficiency (Knoth & Mair, 1991; Robinson & Mair, 1992).

  6. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille;

    2016-01-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss...... model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD....... weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect...

  7. Neuroprotective effects of dimerumic acid and deferricoprogen from Monascus purpureus NTU 568-fermented rice against 6-hydroxydopamine-induced oxidative stress and apoptosis in differentiated pheochromocytoma PC-12 cells.

    Tseng, Wei-Ting; Hsu, Ya-Wen; Pan, Tzu-Ming

    2016-08-01

    Context Oxidative stress plays a key role in neurodegenerative disorders, including Parkinson's disease (PD). Rice fermented with Monascus purpureus Went (Monascaceae) NTU 568 (red mould rice) was found to contain antioxidants, including dimerumic acid (DMA) and deferricoprogen (DFC). Objective The effects of DMA and DFC on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity and potential protective mechanisms in differentiated PC-12 pheochromocytoma cells were investigated. Materials and methods DMA (0-60 μM) or DFC (0-10 μM) was co-treated with 6-OHDA (200 μM, 24 h exposure) in differentiated PC-12 cells. Cell viability and intercellular reactive oxygen species (ROS) were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 2',7'-dichlorofluorescein-diacetate (DCFH-DA) assays, respectively. Cell apoptosis was determined by DNA fragmentation analysis and propidium iodide staining by flow cytometry. Western blot analysis was used to measure the levels of cell protein expression. Results DMA and DFC significantly increased cell viability to 72% and 81% in 6-OHDA-induced differentiated PC-12 cell cultures, respectively. Furthermore, DMA and DFC reduced 6-OHDA-induced formation of extracellular and intercellular ROS by 25% and 20%, respectively, and decreased NADPH oxidase-2 expression in differentiated PC-12 cells. DMA and DFC inhibited 6-OHDA-induced apoptosis and decreased activation of caspase-3 via regulation of Bcl-2-associated X protein (Bax) and Bcl-2 protein expression in differentiated PC-12 cells. Conclusion DMA and DFC may protect against 6-OHDA toxicity by inhibiting ROS formation and apoptosis. These results showed that the metabolites from M. purpureus NTU 568 fermentation were potential therapeutic agents for PD induced by oxidative damage and should be encouraged for further research.

  8. Ischemic preconditioning decreases intracellular zinc accumulation induced by oxygen-glucose deprivation in gerbil hippocampal CA1 neurons.

    Miyawaki, Takahiro; Yokota, Hidenori; Oguro, Keiji; Kato, Kengo; Shimazaki, Kuniko

    2004-05-27

    In normal gerbils, intracellular zinc ions ([Zn2+]i) and calcium ions ([Ca2+]i) accumulate in hippocampal CA1 neurons after global ischemia. We examined whether ischemic preconditioning modifies these changes in gerbil hippocampal slices. In normal slices, large increases in [Zn2+]i and [Ca2+]i were observed in the stratum radiatum of the CA1 area after oxygen-glucose deprivation. In preconditioned slices, there were significantly decreased peak levels of [Zn2+]i and [Ca2+]i in CA1. However, there were no differences in the peak levels of these ions in CA3 and dentate gyrus. These results suggest that modified [Zn2+]i and [Ca2+]i accumulation after an ischemic insult might be important for the mechanisms of ischemic tolerance induced by preconditioning.

  9. Resveratrol increases antioxidant defenses and decreases proinflammatory cytokines in hippocampal astrocyte cultures from newborn, adult and aged Wistar rats.

    Bellaver, Bruna; Souza, Débora Guerini; Souza, Diogo Onofre; Quincozes-Santos, André

    2014-06-01

    Astrocytes are responsible for modulating neurotransmitter systems and synaptic information processing, ionic homeostasis, energy metabolism, maintenance of the blood-brain barrier, and antioxidant and inflammatory responses. Our group recently published a culture model of cortical astrocytes obtained from adult Wistar rats. In this study, we established an in vitro model for hippocampal astrocyte cultures from adult (90 days old) and aged (180 days old) Wistar rats. Resveratrol, a polyphenol found in grapes and red wine, exhibits antioxidant, anti-inflammatory, anti-aging and neuroprotective effects that modulate glial functions. Here, we evaluated the effects of resveratrol on GSH content, GS activity, TNF-α and IL-1β levels in hippocampal astrocytes from newborn, adult and aged Wistar rats. We observed a decrease in antioxidant defenses and an increase in the inflammatory response in hippocampal astrocytes from adult and aged rats compared to classical astrocyte cultures from newborn rats. Resveratrol prevented these effects. These findings reinforce the neuroprotective effects of resveratrol, which are mainly associated with antioxidant and anti-inflammatory activities.

  10. Increased efficacy of the 6-hydroxydopamine lesion of the median forebrain bundle in small rats, by modification of the stereotaxic coordinates.

    Torres, E M; Lane, E L; Heuer, A; Smith, G A; Murphy, E; Dunnett, S B

    2011-08-30

    The 6-hydroxydopamine (6-OHDA) lesion is the most widely used rat model of Parkinson's disease. A single unilateral injection of 6-OHDA into the median forebrain bundle (MFB) selectively destroys dopamine neurons in the ipsilateral substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), removing more than 95% of the dopamine innervation from target areas. The stereotaxic coordinates used to deliver 6-OHDA to the MFB have been used in our laboratory successfully for more than 25 years. However, in recent years we have observed a decline in the success rate of this lesion. Previously regular success rates of >80% of rats lesioned, have become progressively more variable, with rates as low as 20% recorded in some experiments. Having excluded variability of the neurotoxin and operator errors, we hypothesized that the change seen might be due to the use of smaller rats at the time of first surgery. An attempt to proportionally adjust the lesion coordinates base on head size did not increase lesion efficacy. However, in support of the small rat hypothesis it was observed that, using the standard coordinates, rat's heads had a "nose-up" position in the stereotaxic fame. Adjustment of the nose bar to obtain a flat head position during surgery improved lesion success, and subsequent adjustments of the lesion coordinates to account for smaller head size led to a greatly increased lesion efficacy (>90%) as assessed by amphetamine induced rotation.

  11. [Effects of hypothalamic microinjections of 6-hydroxydopamine (6-OHDA) on estral cycle and morphology of the genital tract in the female rat (author's transl)].

    Sala, M A; Oteui, J T; Benedetti, W I

    1975-01-01

    To determine whether central catecholaminergic pathways are involved in the neural contral of gonadotrophin secretion, they were interrupted at the hypothalamic level by microinjections of 6-hydroxydopamine (6-OHDA). The effects on ovulation, estral cycle and ovarian and uterine histology were studied. Microinjections of 50 mug of 6-OHDA hydrobromyde were made bilaterally into the anterolateral hypothalamus in a group of rats. Another group was injected with 25 mug of 6-OHDA, while a control group recieved an equivalent volume (5 mul) of saline with ascorbic acid. Animals injected with 50 mug of 6-OHDA showed blockade of ovulation, vaginal cytology characteristics of persistent estrous, polyfollicular ovaries and enlarged uteri with hypertrophic endometrial glands. In the group injected with 25 mug, similiar effects were demonstrated, but the number of affected animals was smaller than that in the 50 mug group. Control animals dit not show modifications, either in estral cycle or in ovarian and uterine histology. These results suggest that 6-OHDA injected into the anterolateral hypothalmus interferes with catecholaminergic pathways that participate in the neural control of ovulation.

  12. Neuroprotective Effects of Sulphated Agaran from Marine Alga Gracilaria cornea in Rat 6-Hydroxydopamine Parkinson's Disease Model: Behavioural, Neurochemical and Transcriptional Alterations.

    Souza, Ricardo Basto; Frota, Annyta Fernandes; Sousa, Rayane Siqueira; Cezario, Nayara Araújo; Santos, Tarcizio Brito; Souza, Luziana Mara Frota; Coura, Chistiane Oliveira; Monteiro, Valdécio Silvano; Cristino Filho, Gerardo; Vasconcelos, Silvânia Maria Mendes; da Cunha, Rodrigo Maranguape Silva; Aguiar, Lissiana Magna Vasconcelos; Benevides, Norma Maria Barros

    2017-02-01

    Parkinson's disease (PD) is a multifactorial disease associated with the degeneration of dopaminergic neurons and behavioural alterations. Natural bioactive compounds may provide new therapeutic alternatives for neurodegenerative disorders, such as PD. The sulphated polysaccharides isolated from marine algae are heterogenic molecules that show different biological activities. The red marine alga Gracilaria cornea has a sulphated polysaccharide (SA-Gc) with structure and anti-inflammatory and antinociceptive activities reported in the literature. Therefore, this study aimed to evaluate the neuroprotective effects of SA-Gc in rat model PD induced by 6-hydroxydopamine (6-OHDA). Firstly, we established the PD model in rats, induced by an intrastriatal injection (int.) of 6-OHDA, followed by a single administration of SA-Gc (15, 30 or 60 μg; int.). On the 14th day, behavioural tests were performed. After killing, brain areas were dissected and used for neurochemical and/or transcriptional analyses. The results showed that SA-Gc (60 μg, int.) promoted neuroprotective effects in vivo through reducing the oxidative/nitroactive stress and through alterations in the monoamine contents induced by 6-OHDA. Furthermore, SA-Gc modulated the transcription of neuroprotective and inflammatory genes, as well as returning behavioural activities and weight gain to normal conditions. Thus, this study reports the neuroprotective effects of SA-Gc against 6-OHDA in rats.

  13. Early expression of the receptor for advanced glycation end products in a toxic model produced by 6-hydroxydopamine in the rat striatum.

    Serratos, Iris N; Castellanos, Pilar; Pastor, Nina; Millán-Pacheco, César; Colín-González, Ana Laura; Rembao, Daniel; Pérez-Montfort, Ruy; Cabrera, Nallely; Sánchez-García, Aurora; Gómez, Isabel; Rangel-López, Edgar; Santamaria, Abel

    2016-04-05

    The receptor for advanced glycation end products (RAGE) is commonly involved in different neurodegenerative and inflammatory disorders. The cellular signaling associated to RAGE activation may occur upon binding to different ligands. In this study we investigated whether the toxic model produced by 6-hydroxydopamine (6-OHDA) in rats comprises early noxious responses related to RAGE-mediated signaling cascades. In order to explore a possible interaction between 6-OHDA and RAGE, affinity parameters of RAGE with 6-OHDA were estimated by different means. The possible binding sites of 6-OHDA with the VC1 homodimer for both rat and human RAGE were also modeled. Our results show that the striatal infusion of 6-OHDA recruits RAGE upregulation, as evidenced by an early expression of the receptor. 6-OHDA was also found to bind the VC1 homodimer, although its affinity was moderate when compared to other ligands. This work contributes to the understanding of the role of RAGE activation for 6-OHDA-induced neurotoxicity.

  14. Dietary-induced obesity disrupts trace fear conditioning and decreases hippocampal reelin expression.

    Reichelt, Amy C; Maniam, Jayanthi; Westbrook, R Frederick; Morris, Margaret J

    2015-01-01

    Both obesity and over-consumption of palatable high fat/high sugar "cafeteria" diets in rats has been shown to induce cognitive deficits in executive function, attention and spatial memory. Adult male Sprague-Dawley rats were fed a diet that supplemented standard lab chow with a range of palatable foods eaten by people for 8 weeks, or regular lab chow. Memory was assessed using a trace fear conditioning procedure, whereby a conditioned stimulus (CS) is presented for 10s and then 30s after its termination a foot shock (US) is delivered. We assessed freezing to the CS (flashing light) in a neutral context, and freezing in the context associated with footshock. A dissociation was observed between levels of freezing in the context and to the CS associated with footshock. Cafeteria diet fed rats froze less than control chow fed rats in the context associated with footshock (P<0.01), indicating that encoding of a hippocampus-dependent context representation was impaired in these rats. Conversely, cafeteria diet fed rats froze more (P<0.05) to the CS than chow fed rats, suggesting that when hippocampal function was compromised the cue was the best predictor of footshock, as contextual information was not encoded. Dorsal hippocampal mRNA expression of inflammatory and neuroplasticity markers was analysed at the end of the experiment, 10 weeks of diet. Of these, mRNA expression of reelin, which is known to be important in long term potentiation and neuronal plasticity, was significantly reduced in cafeteria diet fed rats (P=0.003). This implicates reductions in hippocampal plasticity in the contextual fear memory deficits seen in the cafeteria diet fed rats.

  15. Eriocaulon buergerianum extract protects PC12 cells and neurons in zebrafish against 6-hydroxydopamine-induced damage

    Lin Zhixiu

    2011-04-01

    Full Text Available Abstract Background Ericaulon buergerianum (Gujingcao is an ophthalmic, anti-inflammatory and antimicrobial Chinese medicinal herb. This study aims to investigate the neuroprotective effects of Ericaulon buergerianum ethanol extract (EBE and to elucidate its underlying action mechanism. Methods The viability of dopaminergic (DA neuron in zebrafish was examined by anti-tyrosine hydroxylase (TH immunostaining. The locomotor activity of zebrafish was assessed with a digital video tracking system. The viability and cellular damage of the PC12 cells were determined by MTT and LDH assays respectively. The nuclear morphological changes in apoptotic cells were evaluated with DNA staining by Hoechst 33342 dye. Intracellular nitric oxide (NO was quantified by DAF-FM diacetate staining. The expression of inducible nitric oxide synthase (iNOS was determined by Western blot. Results EBE inhibited the 6-OHDA-induced decrease in total distance of movement in zebrafish. Pretreatments of EBE (25, 50, 100 and 200 μg/ml increased the viability of 6-OHDA-damaged PC12 cells in a dose dependent manner. Protection against 6-OHDA-induced nuclear fragmentation and accumulation of apoptotic bodies was also observed in EBE pretreated cells. Anti-oxidative (inhibition of NO production and iNOS expression in PC12 cells in vitro activities of EBE are related to its neuroprotective effects in 6-OHDA-induced DA neuron damage. Conclusion EBE exhibited significant neuroprotective activities in zebrafish, including recovery of dopaminergic neuron loss caused by 6-OHDA in a dose-dependent manner in vivo, inhibition of 6-OHDA-induced decrease of total distance in movement in zebrafish. The iNOS-NO pathway may be involved.

  16. Antioxidant Activity of Oral Administration of Rosmarinus Officinalis Leaves Extract on Rat's Hippocampus which Exposed to 6-Hydroxydopamine

    Arashpour Rasoul

    2016-01-01

    Full Text Available Carnosic acid, a diterpene of Rosemarinus officinalis leaves extract (RE, has potent antioxidant activity in vitro. The dopaminergic connection of substantia nigra pars compacta to the hippocampus might be affected by oxidative stress which caused cognitive impairment observed in the early phase of Parkinson's disease (PD. Adult male Wistar rats were lesioned bilaterally by intra-nigral injection of 6-OHDA, and divided into six groups: four groups that orally given RE containing 40% of carnosic acid, at doses of 25, 50 and 100 mg/kg (treated rats and distilled water (H2O, once daily for a period of 14 days before and after the injury. There were also two another groups as control rats which injected by normal saline and untreated lesion group. The injured animals were evaluated for their spatial memory performance by Morris Water Maze test. Lesioned rats showed significant increase in escape latency, as compared with control group. Two weeks after injury, tissue samples were collected from the hippocampus. Levels of catalase (CAT, glutathione peroxidase (GPX and superoxide dismutase (SOD, malondialdehyde (MDA and reactive oxygen species (ROS were determined. There were significant increase of SOD, GPX and CAT enzymes activities in RE50 treated group as compared to lesioned rats. We found a significant decrease of ROS in RE50 treated group as compared to Lesioned rats. These findings provide evidence that 50 mg/kg of RE decreased oxidative damage of the hippocampus induced by 6-OHDA and serve as potential candidate for the treatment of PD.

  17. The phosphodiesterase type 2 inhibitor BAY 60-7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity.

    Soares, Ligia Mendes; Meyer, Erika; Milani, Humberto; Steinbusch, Harry W M; Prickaerts, Jos; de Oliveira, Rúbia M Weffort

    2017-02-01

    Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60-7550, a selective phosphodiesterase type 2 inhibitor (PDE2-I), presents memory-enhancing and anxiolytic-like properties. The behavioral effects of BAY 60-7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2-I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion (BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze (EZM), object location task (OLT) and forced swim test (FST). The effects of BAY 60-7550 were evaluated on neuronal nuclei (NeuN), caspase-9, cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus-dependent cognitive function and induced despair-like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase-9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with BAY 60-7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, BAY 60-7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity.

  18. Persistent hyperdopaminergia decreases the peak frequency of hippocampal theta oscillations during quiet waking and REM sleep.

    Kafui Dzirasa

    Full Text Available Long-term changes in dopaminergic signaling are thought to underlie the pathophysiology of a number of psychiatric disorders. Several conditions are associated with cognitive deficits such as disturbances in attention processes and learning and memory, suggesting that persistent changes in dopaminergic signaling may alter neural mechanisms underlying these processes. Dopamine transporter knockout (DAT-KO mice exhibit a persistent five-fold increase in extracellular dopamine levels. Here, we demonstrate that DAT-KO mice display lower hippocampal theta oscillation frequencies during baseline periods of waking and rapid-eye movement sleep. These altered theta oscillations are not reversed via treatment with the antidopaminergic agent haloperidol. Thus, we propose that persistent hyperdopaminergia, together with secondary alterations in other neuromodulatory systems, results in lower frequency activity in neural systems responsible for various cognitive processes.

  19. Pharmacognostical Analysis and Protective Effect of Standardized Extract and Rizonic Acid from Erythrina velutina against 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

    Silva, Aline H.; Fonseca, Francisco Noé; Pimenta, Antônia T. A.; Lima, MaryAnne S.; Silveira, Edilberto Rocha; Viana, Glauce S. B.; Vasconcelos, Silvânia M. M.; Leal, Luzia Kalyne A. M.

    2016-01-01

    Background: Erythrina velutina is a tree common in the northeast of Brazil extensively used by traditional medicine for the treatment of central nervous system disorders. Objective: To develop a standardized ethanol extract of E. velutina (EEEV) and to investigate the neuroprotective potential of the extract and rizonic acid (RA) from E. velutina on neuronal cells. Materials and methods: The plant drug of E. velutina previously characterized was used for the production of EEEV. Three methods were evaluated in order to obtain an extract with higher content of phenols. The neuroprotective effect of standardized EEEV (HPLC-PDA) and RA was investigated on SH-SY5Y cell exposure to the neurotoxin 6-hydroxydopamine (6-OHDA). Results: The powder of the plant drug was classified as moderately coarse and several quality control parameters were determined. EEEV produced by percolation gave the highest phenol content when related to others extractive methods, and its HPLC-PDA analysis allowed to identify four flavonoids and RA, some reported for the first time for the species. EEEV and RA reduced significantly the neurotoxicity induced by 6-OHDA in SH-SY5Y cells determined by the MTT assay and the nitrite concentration. EEEV also showed a free radical scavenging activity. Conclusion: This is the first pharmacological study about E. velutina which used a controlled standardized extract since the preparation of the herbal drug. This extract and RA, acting as an antioxidant, presents a neuroprotective effect suggesting that they have potential for future development as a therapeutic agent in neurodegenerative disease as Parkinson. SUMMARY The powder of Erythrina velutina was classified as moderately coarse and several quality-control parameters were determined.Ethanolic extract from E. velutina (EEEV) produced by percolation gave the highest phenol content when related to others extractive methods and its HPLC–PDA analysis of EEEV allowed to identify four flavonoids and rizonic

  20. Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine: implications for reparative therapy in Parkinson's disease.

    Cova, Lidia; Bossolasco, Patrizia; Armentero, Marie-Therese; Diana, Valentina; Zennaro, Eleonora; Mellone, Manuela; Calzarossa, Cinzia; Cerri, Silvia; Deliliers, Giorgio Lambertenghi; Polli, Elio; Blandini, Fabio; Silani, Vincenzo

    2012-03-01

    Stem cell (SC) transplantation represents a promising tool to treat neurodegenerative disorders, such as Parkinson's disease (PD), but positive therapeutic outcomes require elucidation of the biological mechanisms involved. Therefore, we investigated human Mesenchymal SCs (hMSCs) ability to protect murine differentiated Neural SCs (mdNSCs) against the cytotoxic effects of 6-hydroxydopamine (6-OHDA) in a co-culture model mimicking the in vivo neurovascular niche. The internalization of 6-OHDA mainly relies on its uptake by the dopamine active transporter (DAT), but its toxicity could also involve other pathways. We demonstrated that mdNSCs consistently expressed DAT along the differentiative process. Exposure to 6-OHDA did not affect hMSCs, but induced DAT-independent apoptosis in mdNSCs with generation of reactive oxygen species and caspases 3/7 activation. The potential neuroprotective action of hMSCs on mdNSCs exposed to 6-OHDA was tested in different co-culture conditions, in which hMSCs were added to mdNSCs prior to, simultaneously, or after 6-OHDA treatment. In the presence of the neurotoxin, the majority of mdNSCs acquired an apoptotic phenotype, while co-cultures with hMSCs significantly increased their survival (up to 70%) in all conditions. Multiplex human angiogenic array analysis on the conditioned media demonstrated that cytokine release by hMSCs was finely modulated. Moreover, sole growth factor addition yielded a similar neuroprotective effect on mdNSCs. In conclusion, our findings demonstrate that hMSCs protect mdNSCs against 6-OHDA neurotoxicity, and rescue cells from ongoing neurodegeneration likely through the release of multiple cytokines. Our findings provide novel insights for the development of therapeutic strategies designed to counteract the neurodegenerative processes of PD.

  1. Striatal adenosine A{sub 2A} receptor-mediated positron emission tomographic imaging in 6-hydroxydopamine-lesioned rats using [{sup 18}F]-MRS5425

    Bhattacharjee, Abesh Kumar; Lang Lixin; Jacobson, Orit [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Shinkre, Bidhan [Chemical Biology Unit, Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Ma Ying [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Niu Gang [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Department of Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892 (United States); Trenkle, William C. [Chemical Biology Unit, Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Jacobson, Kenneth A. [Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Chen Xiaoyuan [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Kiesewetter, Dale O., E-mail: dk7k@nih.gov [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States)

    2011-08-15

    Introduction: A{sub 2A} receptors are expressed in the basal ganglia, specifically in striatopallidal GABAergic neurons in the striatum (caudate-putamen). This brain region undergoes degeneration of presynaptic dopamine projections and depletion of dopamine in Parkinson's disease. We developed an {sup 18}F-labeled A{sub 2A} analog radiotracer ([{sup 18}F]-MRS5425) for A{sub 2A} receptor imaging using positron emission tomography (PET). We hypothesized that this tracer could image A{sub 2A} receptor changes in the rat model for Parkinson's disease, which is created following unilateral injection of the monoaminergic toxin 6-hydroxydopamine (6-OHDA) into the substantia nigra. Methods: [{sup 18}F]-MRS5425 was injected intravenously in anesthetized rats, and PET imaging data were collected. Image-derived percentage injected doses per gram (%ID/g) in regions of interest was measured in the striatum of normal rats and in rats unilaterally lesioned with 6-OHDA after intravenous administration of saline (baseline), D{sub 2} agonist quinpirole (1.0 mg/kg) or D{sub 2} antagonist raclopride (6.0 mg/kg). Results: Baseline %ID/g reached a maximum at 90 s and maintained plateau for 3.5 min, and then declined slowly thereafter. In 6-OHDA-lesioned rats, %ID/g was significantly higher in the lesioned side compared to the intact side, and the baseline total %ID/g (data from both hemispheres were combined) was significantly higher compared to quinpirole stimulation starting from 4.5 min until the end of acquisition at 30 min. Raclopride did not produce any change in uptake compared to baseline or between the hemispheres. Conclusion: Thus, increase of A{sub 2A} receptor-mediated uptake of radioactive MRS5425 could be a superior molecular target for Parkinson's imaging.

  2. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD.

  3. Effects of (-)-sesamin on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and dopaminergic neuronal cells of Parkinson's disease rat models.

    Park, Hyun Jin; Zhao, Ting Ting; Lee, Kyung Sook; Lee, Seung Ho; Shin, Keon Sung; Park, Keun Hong; Choi, Hyun Sook; Lee, Myung Koo

    2015-01-01

    The present study investigated the effects of (-)-sesamin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity using PC12 cells and dopaminergic neuronal cells of 6-OHDA-lesioned rat model of Parkinson's disease (PD). In PC12 cells, treatment with (-)-sesamin (25 µM) reduced 6-OHDA (100 µM)-induced cell death and induced transient extracellular signal-regulated kinase (ERK1/2) phosphorylation and Bad phosphorylation at Ser112 (BadSer112). In contrast, sustained ERK1/2 phosphorylation, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK1/2) phosphorylation, and cleaved-caspase-3 activity, all of which were induced by 6-OHDA (100 µM), were inhibited by treatment with (-)-sesamin (25 µM). Furthermore, co-treatment with (-)-sesamin (30 mg/kg, p.o.) once a day for 28 days significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the substantia nigra-striatum of 6-OHDA-lesioned rat model of PD with or without L-DOPA treatment. These results suggest that (-)-sesamin protects 6-OHDA-induced cytotoxicity via the activation of transient ERK1/2-BadSer112 system and the inhibition of sustained ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells. (-)-Sesamin also shows protective effects on long-term L-DOPA therapy in dopaminergic neuronal cells of PD rat models. (-)-Sesamin may serve as adjuvant therapeutics in PD.

  4. An in vivo microdialysis study of FLZ penetration through the blood-brain barrier in normal and 6-hydroxydopamine induced Parkinson's disease model rats.

    Hou, Jinfeng; Liu, Qian; Li, Yingfei; Sun, Hua; Zhang, Jinlan

    2014-01-01

    FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson's disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances.

  5. Amygdala kindling increases fear responses and decreases glucocorticoid receptor mRNA expression in hippocampal regions.

    Kalynchuk, Lisa E; Meaney, Michael J

    2003-12-01

    Amygdala kindling dramatically increases fearful behavior in rats. Because kindling-induced fear increases in magnitude as rats receive more stimulations, kindling provides an excellent model for studying the nature and neural mechanisms of fear sensitization. In the present experiment, we studied whether the development of kindling-induced fear is related to changes in glucocorticoid receptor (GR) mRNA expression in various brain regions. Rats received 20, 60 or 100 amygdala kindling stimulations or 100 sham stimulations. One day after the final stimulation, their fearful behavior was assessed in an unfamiliar open field. Then, the rats were sacrificed and their brains were processed for in situ hybridization of GR mRNA expression. We found that compared with the sham-stimulated rats, the rats that received 60 or 100 kindling stimulations were significantly more fearful in the open field and also had significantly less GR mRNA expression in the dentate gyrus and CA1 subfield of the hippocampus. Importantly, the changes in fearful behavior were significantly correlated with the changes in GR mRNA expression. These results suggest that alterations in GR mRNA expression in hippocampal regions may play a role in the development of kindling-induced fear.

  6. Chronic zinc exposure decreases the surface expression of NR2A-containing NMDA receptors in cultured hippocampal neurons.

    Jia Zhu

    Full Text Available BACKGROUND: Zinc distributes widely in the central nervous system, especially in the hippocampus, amygdala and cortex. The dynamic balance of zinc is critical for neuronal functions. Zinc modulates the activity of N-methyl-D-aspartate receptors (NMDARs through the direct inhibition and various intracellular signaling pathways. Abnormal NMDAR activities have been implicated in the aetiology of many brain diseases. Sustained zinc accumulation in the extracellular fluid is known to link to pathological conditions. However, the mechanism linking this chronic zinc exposure and NMDAR dysfunction is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We reported that chronic zinc exposure reduced the numbers of NR1 and NR2A clusters in cultured hippocampal pyramidal neurons. Whole-cell and synaptic NR2A-mediated currents also decreased. By contrast, zinc did not affect NR2B, suggesting that chronic zinc exposure specifically influences NR2A-containg NMDARs. Surface biotinylation indicated that zinc exposure attenuated the membrane expression of NR1 and NR2A, which might arise from to the dissociation of the NR2A-PSD-95-Src complex. CONCLUSIONS: Chronic zinc exposure perturbs the interaction of NR2A to PSD-95 and causes the disorder of NMDARs in hippocampal neurons, suggesting a novel action of zinc distinct from its acute effects on NMDAR activity.

  7. Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery.

    Lapchak, P A; Miller, P J; Collins, F; Jiao, S

    1997-05-01

    The effects of intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor were tested on low dose (0.05 mg/kg) apomorphine-induced rotations and tyrosine hydroxylase activity in the substantia nigra and striatum of stable 6-hydroxydopamine-lesioned rats. In addition, we determined if 6-hydroxydopamine lesions in the absence or presence of treatment affected neuropeptide (substance P, met-enkephalin, dynorphin) content in the striatum. Glial cell line-derived neurotrophic factor, when administered intranigrally, prevented apomorphine-induced rotational behaviour for 11 weeks following a single injection. In comparison, intraventricularly-administered glial cell line-derived neurotrophic factor produced a transient reduction in rotational behaviour that lasted for two to three weeks following a single injection. We also show that rotational behaviour is reduced following each subsequent intraventricular injection of glial cell line-derived neurotrophic factor given every six weeks, a time-point when baseline rotation deficits were re-established. Intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor significantly reduced weight gain in all 6-hydroxydopamine-lesioned rats in this study. Following behavioural analysis where a confirmed improvement of behaviour was established, tissues were dissected for neurochemical analysis. In lesioned rats with intranigral injections of administered glial cell line-derived neurotrophic factor, significant increases of nigral, but not striatal tyrosine hydroxylase activity were measured. Additionally, 6-hydroxydopamine lesions significantly increased striatal dynorphin (61-139%) and met-enkephalin (81-139%), but not substance P levels. In these rats, intranigrally-administered glial cell line-derived neurotrophic factor injections reversed lesion-induced increases in nigral dynorphin A levels and increased nigral dopamine levels, but did not alter nigral met

  8. Hippocampal interneurons expressing glutamic acid decarboxylase and calcium-binding proteins decrease with aging in Fischer 344 rats.

    Shetty, A K; Turner, D A

    1998-05-04

    Aging leads to alterations in the function and plasticity of hippocampal circuitry in addition to behavioral changes. To identify critical alterations in the substrate for inhibitory circuitry as a function of aging, we evaluated the numbers of hippocampal interneurons that were positive for glutamic acid decarboxylase and those that expressed calcium-binding proteins (parvalbumin, calbindin, and calretinin) in young adult (4-5 months old) and aged (23-25 months old) male Fischer 344 rats. Both the overall interneuron population and specific subpopulations of interneurons demonstrated a commensurate decline in numbers throughout the hippocampus with aging. Interneurons positive for glutamic acid decarboxylase were significantly depleted in the stratum radiatum of CA1, the strata oriens, radiatum and pyramidale of CA3, the dentate molecular layer, and the dentate hilus. Parvalbumin interneurons showed significant reductions in the strata oriens and pyramidale of CA1, the stratum pyramidale of CA3, and the dentate hilus. The reductions in calbindin interneurons were more pronounced than other calcium-binding protein-positive interneurons and were highly significant in the strata oriens and radiatum of both CA1 and CA3 subfields and in the dentate hilus. Calretinin interneurons were decreased significantly in the strata oriens and radiatum of CA3, in the dentate granule cell and molecular layers, and in the dentate hilus. However, the relative ratio of parvalbumin-, calbindin-, and calretinin-positive interneurons compared with glutamic acid decarboxylase-positive interneurons remained constant with aging, suggesting actual loss of interneurons expressing calcium-binding proteins with age. This loss contrasts with the reported preservation of pyramidal neurons with aging in the hippocampus. Functional decreases in inhibitory drive throughout the hippocampus may occur due to this loss, particularly alterations in the processing of feed-forward information through the

  9. Tonic GABAA conductance decreases membrane time constant and increases EPSP-spike precision in hippocampal pyramidal neurons

    Agnieszka I Wlodarczyk

    2013-12-01

    Full Text Available Because of a complex dendritic structure, pyramidal neurons have a large membrane surface relative to other cells and so a large electrical capacitance and a large membrane time constant (τm. This results in slow depolarizations in response to excitatory synaptic inputs, and consequently increased and variable action potential latencies, which may be computationally undesirable. Tonic activation of GABAA receptors increases membrane conductance and thus regulates neuronal excitability by shunting inhibition. In addition, tonic increases in membrane conductance decrease the membrane time constant (τm, and improve the temporal fidelity of neuronal firing. Here we performed whole-cell current clamp recordings from hippocampal CA1 pyramidal neurons and found that bath application of 10 µM GABA indeed decreases τm in these cells. GABA also decreased first spike latency and jitter (standard deviation of the latency produced by current injection of 2 rheobases (500 ms. However, when larger current injections (3-6 rheobases were used, GABA produced no significant effect on spike jitter, which was low. Using mathematical modelling we demonstrate that the tonic GABAA conductance decreases rise time, decay time and half-width of EPSPs in pyramidal neurons. A similar effect was observed on EPSP/IPSP pairs produced by stimulation of Schaffer collaterals: the EPSP part of the response became shorter after application of GABA. Consistent with the current injection data, a significant decrease in spike latency and jitter was obtained in cell attached recordings only at near-threshold stimulation (50% success rate, S50. When stimulation was increased to 2- or 3- times S50, GABA significantly affected neither spike latency nor spike jitter. Our results suggest that a decrease in τm associated with elevations in ambient GABA can improve EPSP-spike precision at near-threshold synaptic inputs.

  10. Tonic GABAA conductance decreases membrane time constant and increases EPSP-spike precision in hippocampal pyramidal neurons.

    Wlodarczyk, Agnieszka I; Xu, Chun; Song, Inseon; Doronin, Maxim; Wu, Yu-Wei; Walker, Matthew C; Semyanov, Alexey

    2013-01-01

    Because of a complex dendritic structure, pyramidal neurons have a large membrane surface relative to other cells and so a large electrical capacitance and a large membrane time constant (τm). This results in slow depolarizations in response to excitatory synaptic inputs, and consequently increased and variable action potential latencies, which may be computationally undesirable. Tonic activation of GABAA receptors increases membrane conductance and thus regulates neuronal excitability by shunting inhibition. In addition, tonic increases in membrane conductance decrease the membrane time constant (τm), and improve the temporal fidelity of neuronal firing. Here we performed whole-cell current clamp recordings from hippocampal CA1 pyramidal neurons and found that bath application of 10μM GABA indeed decreases τm in these cells. GABA also decreased first spike latency and jitter (standard deviation of the latency) produced by current injection of 2 rheobases (500 ms). However, when larger current injections (3-6 rheobases) were used, GABA produced no significant effect on spike jitter, which was low. Using mathematical modeling we demonstrate that the tonic GABAA conductance decreases rise time, decay time and half-width of EPSPs in pyramidal neurons. A similar effect was observed on EPSP/IPSP pairs produced by stimulation of Schaffer collaterals: the EPSP part of the response became shorter after application of GABA. Consistent with the current injection data, a significant decrease in spike latency and jitter was obtained in cell attached recordings only at near-threshold stimulation (50% success rate, S50). When stimulation was increased to 2- or 3- times S50, GABA significantly affected neither spike latency nor spike jitter. Our results suggest that a decrease in τm associated with elevations in ambient GABA can improve EPSP-spike precision at near-threshold synaptic inputs.

  11. Re-imagining the future: repetition decreases hippocampal involvement in future simulation.

    Valerie van Mulukom

    Full Text Available Imagining or simulating future events has been shown to activate the anterior right hippocampus (RHC more than remembering past events does. One fundamental difference between simulation and memory is that imagining future scenarios requires a more extensive constructive process than remembering past experiences does. Indeed, studies in which this constructive element is reduced or eliminated by "pre-imagining" events in a prior session do not report differential RHC activity during simulation. In this fMRI study, we examined the effects of repeatedly simulating an event on neural activity. During scanning, participants imagined 60 future events; each event was simulated three times. Activation in the RHC showed a significant linear decrease across repetitions, as did other neural regions typically associated with simulation. Importantly, such decreases in activation could not be explained by non-specific linear time-dependent effects, with no reductions in activity evident for the control task across similar time intervals. Moreover, the anterior RHC exhibited significant functional connectivity with the whole-brain network during the first, but not second and third simulations of future events. There was also evidence of a linear increase in activity across repetitions in right ventral precuneus, right posterior cingulate and left anterior prefrontal cortex, which may reflect source recognition and retrieval of internally generated contextual details. Overall, our findings demonstrate that repeatedly imagining future events has a decremental effect on activation of the hippocampus and many other regions engaged by the initial construction of the simulation, possibly reflecting the decreasing novelty of simulations across repetitions, and therefore is an important consideration in the design of future studies examining simulation.

  12. Decreased Myelinated Fibers in the Hippocampal Dentate Gyrus of the Tg2576 Mouse Model of Alzheimer’s Disease

    Lu, Wei; Yang, Shu; Zhang, Lei; Chen, Lin; Chao, Feng-Lei; Luo, Yan-min; Xiao, Qian; Gu, Heng-Wei; Jiang, Rong; Tang, Yong

    2016-01-01

    Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by deficits in cognition and memory. Although amyloid-β (Aβ) accumulation is known to be the earliest pathological event that triggers subsequent neurodegeneration, how Aβ accumulation causes behavioral deficits remains incompletely understood. In this study, using the Morris water maze test, ELISA and stereological methods, we examined spatial learning and memory performance, the soluble Aβ concentration and the myelination of fibers in the hippocampus of 4-, 6-, 8- and 10-month-old Tg2576 AD model mice. Our results showed that spatial learning and memory performance was significantly impaired in the Tg2576 mice compared to the wild type (WT) controls and that the myelinated fiber length in the hippocampal dentate gyrus (DG) was markedly decreased from 0.33 ± 0.03 km in the WT controls to 0.17 ± 0.02 km in the Tg2576 mice at 10 months of age. However, the concentrations of soluble Aβ40 and Aβ42 were significantly increased as early as 4-6 months of age. The decreased myelinated fiber length in the DG may contribute to the spatial learning and memory deficits of Tg2576 mice. Therefore, we suggest that the significant accumulation of soluble Aβ may serve as a preclinical biomarker for AD diagnosis and that protecting myelinated fibers may represent a novel strategy for delaying the progression of early-stage AD. PMID:26971933

  13. Decreased expression of hippocampal Na⁺/Ca²⁺ exchanger isoform-1 by pentylenetetrazole kindling in mice.

    Kawanai, Takuya; Taruta, Atsuki; Inoue, Aya; Watanabe, Ryo; Ago, Yukio; Hashimoto, Hitoshi; Hasebe, Shigeru; Ooi, Yasuhiro; Takuma, Kazuhiro; Matsuda, Toshio

    2015-09-01

    Previous studies have shown that inhibitors of the Na(+)/Ca(2+) exchanger (NCX) attenuate seizure activity in drug-induced epilepsy models, but the role of NCX in epilepsy is not fully understood. The present study examined the effects of pentylenetetrazole (PTZ)-induced kindling on the mRNA expression of NCX isoforms (NCX1, NCX2 and NCX3) in mouse brain. Chronic administration of PTZ at 40mg/kg resulted in kindling seizure development. It caused decreases in the mRNA levels of NCX1 and NCX2, but not NCX3, in the hippocampus. Changes in NCX isoform expression levels were not observed in the prefrontal cortex or striatum. Acute PTZ at 40mg/kg, which caused little seizure activity, also decreased NCX2, but not NCX1 mRNA levels in the hippocampus. These results suggest that down-regulation of hippocampal NCX1 expression is associated with PTZ-induced kindling seizure development.

  14. CEPO对6-OHDA诱导PC12细胞损伤的保护作用%Experimental exploration on the protective effect of CEPO on 6-hydroxydopamine-induced injury of PC12 cells

    贾钰; 雷万龙; 欧阳丽斯; 马宇昕; 陈嘉昌; 阳桂香; 李幽兰; 刘冰冰; 穆淑花; 陈思

    2013-01-01

    Objective To investigate the effect and possible mechanisms of carbamylated erythropoietin (CEPO) in inhibiting the injury of PC12 cells induced by 6-hydroxydopamine (6-OHDA). Methods PC12 cells were divided into the three groups: control group, 6-OHDA group and 6-OHDA + CEPO group. The PC12 cells viability was measured by CCK8 assay. Flow cytometry (FCM) was used to determine apoptosis rate of PC12 cells. The expression of cleaved caspase-3 was detected by western-blotting. The expression of Bcl-2 and Bax mRNA in PC12 cells were measured by Reverse transcriptase polymerase chain reaction (RT-PCR). Results CCK8 assay showed that the cell viability of PC12 cells treated with 200μmol 6-OHDA decreased to 56.70±7.86%, while 40U CEPO treatment increased the cell viability to (87.9±5.3)% (P<0.05). Flow cytometry demonstrated that CEPO treatment significantly inhibited the apoptosis of PC12 cells induced by 6-OHDA (P<0.05). RT-PCR results showed that the expression of Bcl-2 and Bax mRNA in PC12 cells were significantly upregulated and downregulated by CEPO as compared with 6-OHDA treated group (P< 0.05 ). Western-blotting showed CEPO treatment markedly induced the downregulation of cleaved caspase-3 expression compared to 6-OHDA treatment alone (P<0.05). Conclusion CEPO protects PC12 cells from injury and apoptosis induced by 6-OHDA. The protective effect of CEPO might be executed by upregulation of Bcl-2 and downregulation of Bax and Caspase-3 expression in PC12 cells.%目的 探讨氨甲酰化促红细胞生成素(CEPO)对6-羟基多巴胺(6-hydroxydopamine,6-OHDA)诱导PC12细胞损伤及凋亡的保护作用及其可能机制.方法 借助CCK8、流式细胞(Flow cytometry,FCM)、Western-blotting和逆转录PCR(RT-PCR)技术检测PC12模型细胞相关指标的变化,实验数据以SPSS15软件统计分析.结果 CCK8结果显示6-OHDA处理能够显著降低PC12模型细胞的存活率,而CEPO处理对其变化显示抑制作用;FCM技术探察结果显示,6

  15. MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.

    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Shubha

    2017-03-15

    Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

  16. Feasibility of establishing model of Parkinson disease by injecting 6-hydroxydopamine at different parts of the nigrostriatal pathway in the brain of rats

    Yuefei Shen; Xuean Mo; Guifang Long

    2006-01-01

    BACKGROUND: Previous researches found that animal models with Parkinson disease (PD) could be established by injecting 6-hydroxydopamine (6-OHDA) into medial forebrain bundle (MFB), substantia nigra compacta (SNC) and caudate-putamen complex (CPU) of the nigrostriatal pathway.OBJECTIVE: To compare behavioral, biochemical and histological properties of these rats undergoing the 6-OHDA injections in the areas of MFB, SNC and CPU respectively.DESIGN: Controlled observational study.SETTING: Department of Neurology, First Affiliated Hospital of Guangxi Medical University.MATERIALS: A total of 64 adult female SD rats weighing 180-230 g were provided by the Animal Experimental Center of Guangxi Medical University. 6-OHDA (Sigma Company, USA); Brain solid positioner (Standard model 51600, Stoelting Co., IL, USA); rotational monitoring of little animal (type QL-1, USA);high liquid chromatography (HLC, Waters Company).METHODS: The experiment was carried out in the Medical Experimental Center of Guangxi Medical University from February to December 2005. ① According to digital table, 64 SD rats were divided into MFB group, SNC group, CPU group and control group with 16 in each group. On the basis of the brain atlas of Paxinos, rats in the first three groups were injected with 5 μL 6-OHDA into right MFB (0 mm of line of incisor tooth, A/P 4.4 mm, L/R 1.2 mm, O/V -7.8 mm), SNC (line of incisor tooth just equal to horizon,A/P -4.8 mm, L/R 1.6 mm, O/V -7.8 mm) and CPU (0 mm of line of incisor tooth, A/P 1.2 mm, L/R 2.7 mm,O/V -5.4 mm), respectively. The rats in control group were injected with 5 μL ascorbic acid solution (2 g/L). One week after operation, 0.1 g/L apomorphine (Apo, 0.05 mg/kg) was subcutaneously injected into neck and then rotational behavior induced by Apo was recorded once a week for 8 weeks. The PD models were considered successful only when rotational times more than or equal to 7 times per minute.② Eight weeks after operation, micro-perfusion was used to

  17. Enhanced glutamate, IP3 and cAMP activity in the cerebral cortex of Unilateral 6-hydroxydopamine induced Parkinson's rats: Effect of 5-HT, GABA and bone marrow cell supplementation

    Romeo Chinthu

    2011-01-01

    Full Text Available Abstract Parkinson's disease is characterized by progressive cell death in the substantia nigra pars compacta, which leads to dopamine depletion in the striatum and indirectly to cortical dysfunction. Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease and glutamate receptor mediated excitotoxicity has been suggested to be one of the possible causes of the neuronal degeneration. In the present study, the effects of serotonin, gamma-aminobutyric acid and bone marrow cells infused intranigrally to substantia nigra individually and in combination on unilateral 6-hydroxydopamine induced Parkinson's rat model was analyzed. Scatchard analysis of total glutamate and NMDA receptor binding parameters showed a significant increase in Bmax (P

  18. Loss of forebrain MTCH2 decreases mitochondria motility and calcium handling and impairs hippocampal-dependent cognitive functions

    Ruggiero, Antonella; Aloni, Etay; Korkotian, Eduard; Zaltsman, Yehudit; Oni-Biton, Efrat; Kuperman, Yael; Tsoory, Michael; Shachnai, Liat; Levin-Zaidman, Smadar; Brenner, Ori; Segal, Menahem; Gross, Atan

    2017-01-01

    Mitochondrial Carrier Homolog 2 (MTCH2) is a novel regulator of mitochondria metabolism, which was recently associated with Alzheimer’s disease. Here we demonstrate that deletion of forebrain MTCH2 increases mitochondria and whole-body energy metabolism, increases locomotor activity, but impairs motor coordination and balance. Importantly, mice deficient in forebrain MTCH2 display a deficit in hippocampus-dependent cognitive functions, including spatial memory, long term potentiation (LTP) and rates of spontaneous excitatory synaptic currents. Moreover, MTCH2-deficient hippocampal neurons display a deficit in mitochondria motility and calcium handling. Thus, MTCH2 is a critical player in neuronal cell biology, controlling mitochondria metabolism, motility and calcium buffering to regulate hippocampal-dependent cognitive functions. PMID:28276496

  19. Melatonin protects against oxygen and glucose deprivation by decreasing extracellular glutamate and Nox-derived ROS in rat hippocampal slices.

    Patiño, Paloma; Parada, Esther; Farré-Alins, Victor; Molz, Simone; Cacabelos, Ramón; Marco-Contelles, José; López, Manuela G; Tasca, Carla I; Ramos, Eva; Romero, Alejandro; Egea, Javier

    2016-12-01

    Therapeutic interventions on pathological processes involved in the ischemic cascade, such as oxidative stress, neuroinflammation, excitotoxicity and/or apoptosis, are of urgent need for stroke treatment. Melatonin regulates a large number of physiological actions and its beneficial properties have been reported. The aim of this study was to investigate whether melatonin mediates neuroprotection in rat hippocampal slices subjected to oxygen-glucose-deprivation (OGD) and glutamate excitotoxicity. Thus, we describe here that melatonin significantly reduced the amount of lactate dehydrogenase released in the OGD-treated slices, reverted neuronal injury caused by OGD-reoxygenation in CA1 and CA3 hippocampal regions, restored the reduction of GSH content of the hippocampal slices induced by OGD, and diminished the oxidative stress produced in the reoxygenation period. Furthermore, melatonin afforded maximum protection against glutamate-induced toxicity and reversed the glutamate released almost basal levels, at 10 and 30μM concentration, respectively. Consequently, we propose that melatonin might strongly and positively influence the outcome of brain ischemia/reperfusion.

  20. Fermented soybeans, Chungkookjang, prevent hippocampal cell death and β-cell apoptosis by decreasing pro-inflammatory cytokines in gerbils with transient artery occlusion.

    Park, Sunmin; Kim, Da Sol; Kang, Sunna; Moon, Bo Reum

    2016-02-01

    Since Chungkookjang, a short-term fermented soybean, is known to improve glucose metabolism and antioxidant activity, it may prevent the neurological symptoms and glucose disturbance induced by artery occlusion. We investigated the protective effects and mechanisms of traditional (TFC) and standardized Chungkookjang fermented with Bacillus licheniformis (BLFC) against ischemia/reperfusion damage in the hippocampal CA1 region and against hyperglycemia after transient cerebral ischemia in gerbils. Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 min to render them ischemic or a sham operation. Ischemic gerbils were fed either a 40% fat diet containing 10% of either cooked soybean (CSB), TFC, or BLFC for 28 days. Neuronal cell death and cytokine expression in the hippocampus, neurological deficit, serum cytokine levels, and glucose metabolism were measured. TFC and BLFC contained more isoflavonoid aglycones than CSB. Artery occlusion increased the expressions of IL-1β and TNF-α as well as cell death in the hippocampal CA1 region and induced severe neurological symptoms. CSB, TFC, and BLFC prevented the neuronal cell death and the symptoms such as dropped eyelid, bristling hair, reduced muscle tone and flexor reflex, and abnormal posture and walking patterns, and suppressed cytokine expressions. CSB was less effective than TFC and BLFC. Artery occlusion induced glucose intolerance due to decreased insulin secretion and β-cell mass. TFC and BLFC prevented the impairment of glucose metabolism by artery occlusion. Especially TFC and BLFC increased β-cell proliferation and suppressed the β-cell apoptosis by suppressing TNF-α and IL-1β which in turn decreased cleaved caspase-3 that caused apoptosis. In conclusion, TFC and BLFC may prevent and alleviate neuronal cell death in the hippocampal CA1 region and neurological symptoms and poststroke hyperglycemia in gerbils with artery occlusion. This might be associated with

  1. Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer's disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis.

    Cui, YuanBo; Ma, ShanShan; Zhang, ChunYan; Cao, Wei; Liu, Min; Li, DongPeng; Lv, PengJu; Xing, Qu; Qu, RuiNa; Yao, Ning; Yang, Bo; Guan, FangXia

    2017-03-01

    Stem cell transplantation represents a promising therapy for central nervous system injuries, but its application to Alzheimer's disease (AD) is still limited and the potential mechanism for cognition improvement remains to be elucidated. In the present study, we used Tg2576 mice which express AD-like pathological forms of amyloid precursor protein (APP) to investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) intravenous transplantation on AD mice. Interestingly, hUC-MSCs transplantation significantly ameliorated cognitive function of AD mice without altering Aβ levels in hippocampus. Remarkably, hUC-MSCs transplantation reduced oxidative stress in hippocampus of AD mice by decreasing the level of malondialdehyde (MDA), increasing the level of nitric oxide (NO), enhancing the activity of superoxide dismutase (SOD) and neuronal nitric oxide synthase (nNOS). The mechanisms underlying the improved cognitive function may be linked to hippocampal neurogenesis and an up-regulation of neuronal synaptic plasticity related proteins levels including silent information regulator 1 (Sirt1), brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN). Taken together, our findings suggest that hUC-MSCs can improve cognition of AD mice by decreasing oxidative stress and promoting hippocampal neurogenesis. These results suggest that modulating hUC-MSCs to generate excess neuroprotective factors could provide a viable therapy to treat AD.

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

    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. Nanomolar concentrations of inorganic lead increase Ca2+ efflux and decrease intracellular free Ca2+ ion concentrations in cultured rat hippocampal neurons by a calmodulin-dependent mechanism.

    Ferguson, C; Kern, M; Audesirk, G

    2000-06-01

    Inorganic lead (Pb2+) activates calmodulin, which in turn may stimulate many other cellular processes. The plasma membrane Ca2+ ATPase is a calmodulin-stimulated enzyme that plays the major role in regulating the "resting" intracellular free Ca2+ ion concentration, [Ca2+]i. We hypothesized that exposing neurons to low levels of Pb2+ would cause Pb2+ to enter the cytoplasm, and that intracellular Pb2+, by activating calmodulin, would stimulate plasma membrane Ca2+ ATPase activity, thereby increasing Ca2+ extrusion and reducing [Ca2+]i. We used the ratiometric Ca2+ indicator fura-2 to estimate changes in [Ca2+]i. In vitro calibrations of fura-2 with solutions of defined free Ca2+ and free Pb2+ concentrations showed that, at free Ca2+ concentrations from 10 nM to 1000 nM, adding Pb2+ caused either no significant change in the F340/F380 ratio (free Pb2+ concentrations from 100 fM to 1 pM) or increased the F340/F380 ratio (free Pb2+ concentrations from 5 to 50 pM). Therefore, fura-2 should be suitable for estimating Pb2+-induced decreases in [Ca2+]i, but not increases in [Ca2+]i. We exposed cultured embryonic rat hippocampal neurons to 100 nM Pb2+ for periods from 1 hour to 2 days and measured the F340/F380 ratio; the ratio decreased significantly by 9 to 16% at all time points, indicating that Pb2+ exposure decreased [Ca2+]i. In neurons loaded with 45Ca, Pb2+ exposure increased Ca2+ efflux for at least two hours; by 24 hours, Ca2+ efflux returned to control levels. Influx of 45Ca was not altered by Pb2+ exposure. Low concentrations (250 nM) of the calmodulin inhibitor calmidazolium had no effect on either 45Ca efflux or on the F340/F380 ratio in fura-loaded control neurons, but completely eliminated the increase in 45Ca efflux and decrease in F340/F380 ratio in Pb2+-exposed neurons. Zaldoride, another calmodulin inhibitor, also eliminated the decrease in F340/F380 ratio in Pb2+-exposed neurons. We conclude that Pb2+ exposure decreases [Ca2+]i and increases Ca2+ efflux

  4. Upregulation of glutathione peroxidase-1 expression and activity by glial cell line-derived neurotrophic factor promotes high-level protection of PC12 cells against 6-hydroxydopamine and hydrogen peroxide toxicities.

    Gharib, Ehsan; Gardaneh, Mossa; Shojaei, Sahar

    2013-06-01

    We examined the impact of strong co-presence and function of glutathione peroxidase-1 (GPX-1) and glial cell line-derived neurotrophic factor (GDNF) on protecting the rat dopaminergic pheochromocytoma cell line PC12 against 6-hydroxydopamine (6-OHDA) and hydrogen peroxide (H₂O₂) toxicities. Primarily, GPX-1 over-expression by PC12 cells infected with pLV-GPX1 lentivirus vectors significantly increased cell survival against 6-OHDA toxicity (pcells with astro-CM of GDNF-over-secreting astrocytes (Test astro-CM) significantly induced GPX-1 expression, peroxidase enzymatic activity, and intra-cellular glutathione (GSH) levels. These changes paralleled with protection of 90% of GDNF⁺/GPX1⁺ PC12 cells against toxicity, a rate that was 37% up from their un-infected un-treated (GDNF⁻/GPX1⁻) controls (pcells that received only Control astro-CM (GPX⁺/GDNF⁻) (pcell groups, increased cell survival against either compound was further confirmed by increased live cell counts measured by double staining. Following depletion of intra-cellular GSH, only 46% of pLV-GPX1 cells survived 6-OHDA toxicity, whereas over 70% of them were saved upon GDNF treatment (pcells and maximized by addition of GDNF. Comparison analyses established correlations between GPX-1-GDNF co-presence and both enhanced cell protection and diminished levels of activated caspase-3. Our data collectively indicate that GDNF is capable of inducing anti-oxidant activities of intra-cellular GPX-1 and that growth-promoting potential of GDNF and anti-oxidant properties of GPX-1 can, in concert, maximize survival of dopaminergic neurons.

  5. Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model.

    Calió, Michele Longoni; Marinho, Darci Sousa; Ko, Gui Mi; Ribeiro, Renata Rodrigues; Carbonel, Adriana Ferraz; Oyama, Lila Missae; Ormanji, Milene; Guirao, Tatiana Pinoti; Calió, Pedro Luiz; Reis, Luciana Aparecida; Simões, Manuel de Jesus; Lisbôa-Nascimento, Telma; Ferreira, Alice Teixeira; Bertoncini, Clélia Rejane Antônio

    2014-05-01

    Stroke is the most common cause of motor disabilities and is a major cause of mortality worldwide. Adult stem cells have been shown to be effective against neuronal degeneration through mechanisms that include both the recovery of neurotransmitter activity and a decrease in apoptosis and oxidative stress. We chose the lineage stroke-prone spontaneously hypertensive rat (SHRSP) as a model for stem cell therapy. SHRSP rats can develop such severe hypertension that they generally suffer a stroke at approximately 1 year of age. The aim of this study was to evaluate whether mesenchymal stem cells (MSCs) decrease apoptotic death and oxidative stress in existing SHRSP brain tissue. The results of qRT-PCR assays showed higher levels of the antiapoptotic Bcl-2 gene in the MSC-treated animals, compared with untreated. Our study also showed that superoxide, apoptotic cells, and by-products of lipid peroxidation decreased in MSC-treated SHRSP to levels similar those found in the animal controls, Wistar Kyoto rats. In addition, we saw a repair of morphological damage at the hippocampal region after MSC transplantation. These data suggest that MSCs have neuroprotective and antioxidant potential in stroke-prone spontaneously hypertensive rats.

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

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

    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 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3(+) apoptotic cells. At ≥120mg/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 ≥120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥120mg/kg decreased phosphorylated TRKB(+) interneurons, although the number of reelin(+) interneurons was unchanged. At 600mg/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.

  7. Diphenytoin, riluzole and lidocaine: three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity.

    Diao, Lihong; Hellier, Jennifer L; Uskert-Newsom, Jessica; Williams, Philip A; Staley, Kevin J; Yee, Audrey S

    2013-10-01

    Epilepsy is a condition affecting 1-2% of the population, characterized by the presence of spontaneous, recurrent seizures. The most common type of acquired epilepsy is temporal lobe epilepsy (TLE). Up to 30% of patients with TLE are refractory to currently available compounds, and there is an urgent need to identify novel targets for therapy. Here, we utilized the in-vitro CA3 burst preparation to examine alterations in network excitability, characterized by changes in interburst interval. Specifically, we show that bath application of three different sodium channel blockers-diphenytoin, riluzole, and lidocaine-slow spontaneous CA3 bursts. This in turn, decreased the epileptiform activity. These compounds work at different sites on voltage-gated sodium channels, but produce a similar network phenotype of decreased excitability. In the case of diphenytoin and riluzole, the change in network activity (i.e., increased interburst intervals) was persistent following drug washout. Lidocaine application, however, only increased the CA3 interburst interval when it was in the bath solution. Thus, its action was not permanent and resulted in returning CA3 bursting to baseline levels. These data demonstrate that the CA3 burst preparation provides a relatively easy and quick platform for identifying compounds that can decrease network excitability, providing the initial screen for further and more complex in-vivo, freely-behaving animal studies.

  8. Effect of Passive Smoking on the Rotational Behavior and Striatal Dopamine Content of 6-hydroxydopamine-induced Rat Model of Parkinson Disease%被动吸烟对帕金森病大鼠旋转行为和纹状体多巴胺含量的影响

    董宁; 孙圣刚; 陈吉相; 王涛

    2001-01-01

    目的 观察被动吸烟对帕金森病(PD)大鼠的影响,以验证流行病学研究的结论,为PD研究提供一条新的线索。方法 用6-羟基多巴胺(6-OHDA)立体定向注入大鼠一侧黑质致密部和中脑被盖腹侧区建立偏侧PD模型,观察术前4周开始给予的被动吸烟(持续6周)和术后2周对成功模型给予的被动吸烟(持续2周)对阿朴吗啡诱发的旋转行为及纹状体DA含量的影响。结果 术前4周开始被动吸烟的大鼠旋转行为有减少趋势,受损侧纹状体DA含量较对照组升高。术后2周,成功模型给予的被动吸烟对PD大鼠的旋转行为及纹状体DA含量均无影响。结论 被动吸烟可减轻6-OHDA对黑质DA能神经元的损伤。%Objective To observe the effect of passive smoking on therotational behavior and striatal dopamine content of the rat Parkinson disease (PD) model. Methods Creating the PD rat model by unilaterally injecting 6-hydroxydopamine(6-OHDA) into the substantia nigra pars compacta(SNpc) and the ventral tegmental area(VTA), the effects of passive smoking on the apomorphine-induced rotation behavior and the dopamine content of striatum beginning four weeks before the operation(lasting six weeks) or two weeks after the operation(lasting two weeks) in the successful models were observed. Results Rats received passive smoking beginning four weeks before the operation had a tendency to decrease the apomorphine-induced rotation behavior. The dopamine content of the striatum was elevated as compared to the control group. Passive smoking beginning two weeks after the operation in the successful models did not alter either the rotation behavior or the DA content of striatum. Conclusions Passive smoking can partially protect DA neurons of substantia nigra from the damage of 6-OHDA.

  9. Increased entorhinal-prefrontal theta synchronization parallels decreased entorhinal-hippocampal theta synchronization during learning and consolidation of associative memory.

    Kaori eTakehara-Nishiuchi

    2012-01-01

    Full Text Available Memories are thought to be encoded as a distributed representation in the neocortex. The medial prefrontal cortex (mPFC has been shown to support the expression of memories that initially depend on the hippocampus (HPC, yet the mechanisms by which the HPC and mPFC access the distributed representations in the neocortex are unknown. By measuring phase synchronization of local field potential (LFP oscillations, we found that learning initiated changes in neuronal communication of the HPC and mPFC with the lateral entorhinal cortex (LEC, an area that is connected with many other neocortical regions. LFPs were recorded simultaneously from the three brain regions while rats formed an association between an auditory stimulus (CS and eyelid stimulation (US in a trace eyeblink conditioning paradigm, as well as during retention one month following learning. Over the course of learning, theta oscillations in the LEC and mPFC became strongly synchronized following the presentation of the CS on trials in which rats exhibited a conditioned response (CR, and this strengthened synchronization was also observed during retention one month after learning. In contrast, CS-evoked theta synchronization between the LEC and HPC decreased with learning. Our results suggest that the communication between the LEC and mPFC is strengthened with learning whereas the communication between the LEC and HPC is concomitantly weakened, suggesting that enhanced LEC-mPFC communication may be a key process for theoretically-proposed neocortical reorganization accompanying encoding and consolidation of a memory.

  10. Blockade of Ca2+-permeable AMPA/kainate channels decreases oxygen-glucose deprivation-induced Zn2+ accumulation and neuronal loss in hippocampal pyramidal neurons.

    Yin, Hong Z; Sensi, Stefano L; Ogoshi, Fumio; Weiss, John H

    2002-02-15

    Synaptic release of Zn2+ and its translocation into postsynaptic neurons probably contribute to neuronal injury after ischemia or epilepsy. Studies in cultured neurons have revealed that of the three major routes of divalent cation entry, NMDA channels, voltage-sensitive Ca2+ channels (VSCCs), and Ca2+-permeable AMPA/kainate (Ca-A/K) channels, Ca-A/K channels exhibit the highest permeability to exogenously applied Zn2+. However, routes through which synaptically released Zn2+ gains entry to postsynaptic neurons have not been characterized in vivo. To model ischemia-induced Zn2+ movement in a system approximating the in vivo situation, we subjected mouse hippocampal slice preparations to controlled periods of oxygen and glucose deprivation (OGD). Timm's staining revealed little reactive Zn2+ in CA1 and CA3 pyramidal neurons of slices exposed in the presence of O2 and glucose. However, 15 min of OGD resulted in marked labeling in both regions. Whereas strong Zn2+ labeling persisted if both the NMDA antagonist MK-801 and the VSCC blocker Gd3+ were present during OGD, the presence of either the Ca-A/K channel blocker 1-naphthyl acetyl spermine (NAS) or the extracellular Zn2+ chelator Ca2+ EDTA substantially decreased Zn2+ accumulation in pyramidal neurons of both subregions. In parallel experiments, slices were subjected to 5 min OGD exposures as described above, followed 4 hr later by staining with the cell-death marker propidium iodide. As in the Timm's staining experiments, substantial CA1 or CA3 pyramidal neuronal damage occurred despite the presence of MK-801 and Gd3+, whereas injury was decreased by NAS or by Ca2+ EDTA (in CA1).

  11. Decreased hippocampal homoarginine and increased nitric oxide and nitric oxide synthase levels in rats parallel training in a radial arm maze.

    Sase, Ajinkya; Nawaratna, Gayan; Hu, Shengdi; Wu, Guoyao; Lubec, Gert

    2016-09-01

    L-homoarginine (hArg) is derived from enzymatic guanidination of lysine. It was demonstrated that hArg is a substrate for nitric oxide (NO) synthesis, blocks lysine transport and inhibits the uptake of arginine into synaptosomes and modulates GABA responses ex vivo. As there is limited information on its physiological roles in the brain, the aim of the study was to show whether hippocampal or frontal lobe (FL) hArg is paralleling training in the radial arm maze (RAM) or NO formation. Hippocampi and FL of male Sprague-Dawley rats were taken from trained or yoked in a RAM. Then hArg and metabolites, NO and NO synthase (NOS) were determined by standard methods. The animals learned the task in the RAM showing significant reduction of working memory errors. hArg showed decreased levels in both brain regions of trained animals as compared to yoked animals. Nitrate plus nitrite (NOx) concentrations and NOS activity were significantly increased in hippocampi, F(1,36) = 170.5; P ≤ 0.0001 and FL, F(1,36) = 74.67; P ≤ 0.0001 of trained animals as compared to yoked animals. Levels of hArg were negatively correlated with NOx in hippocampus (r = -0.6355; P = 0.0483) but not in FL and with lysine in the FL (r = -0.6650; P = 0.0358). NOx levels were positively correlated with NOS in both the hippocampus (r = 0.7474; P = 0.0129) and FL (r = 0.9563; P ≤  0.0001). These novel findings indicate that hArg is linked to NO formation in hippocampus but not in FL and is paralleling spatial memory in the RAM.

  12. Reynosin protects against neuronal toxicity in dopamine-induced SH-SY5Y cells and 6-hydroxydopamine-lesioned rats as models of Parkinson's disease: Reciprocal up-regulation of E6-AP and down-regulation of α-synuclein.

    Ham, Ahrom; Kim, Dong-Woo; Kim, Kyeong Ho; Lee, Sung-Jin; Oh, Ki-Bong; Shin, Jongheon; Mar, Woongchon

    2013-08-01

    Aggregation of α-synuclein (ASYN) is considered a major determinant of neuronal loss in Parkinson's disease (PD). E6-associated protein (E6-AP), an E3 ubiquitin protein ligase, has been known to promote the degradation of α-synuclein. The aim of this study was to assess the effects of the sesquiterpene lactone reynosin on dopamine (DA)-induced neuronal toxicity and regulation of E6-associated protein and α-synuclein proteins in both in vitro and in vivo models of Parkinson's disease. Usi"ng flow cytometry and western blot analysis, we determined that reynosin significantly protected both against cell death from dopamine-induced toxicity in human neuroblastoma SH-SY5Y cells and against the loss of tyrosine hydroxylase (TH)-positive cells in 6-hydroxydopamine (6-OHDA)-lesioned rats (a rodent Parkinson's disease model system). In addition, reynosin made up-regulation of E6-associated protein expression and down-regulation of the over-expression of α-synuclein protein in both dopamine-treated SH-SY5Y cells and 6-hydroxydopamine-lesioned rats. These results suggest that the protective effect of reynosin against dopamine-induced neuronal cell death may be due to the reciprocal up-regulation of E6-associated protein and down-regulation of α-synuclein protein expression.

  13. 偏侧帕金森大鼠模型各个发病时期多巴胺能系统的动态监测%The unilateral 6-hydroxydopamine lesion rats' dynamic supervision about the nigrostriatal dopaminergic system in various stages of its pathogenesis

    曹非; 陈涵; 张潇潇; 孙圣刚

    2012-01-01

    Objective To dynamically supervise the changes of the nigrostriatal dopaminergic system of rats with unilateral 6-hydroxydopamine(6-OHDA) lesion in various stages of its pathogenesis and to find out the rules of the changes ,and to build up a model of treatment for the further research. Methods The unilateral lesioned rat models of Parkinsons Disease with 6-0HDA were treated with levodopa for 14 days after the successful models were made. Each 7 days during the course, we measure the behavioral rotations, count the numbers of the tyrosine hydroxylase(TH)positive cells ,the dopamine(DA) contents, and make the Nissle stain. Results At the first and the second time points, the concentration of DA collapsed by 16.7% and 80% , the numbers of TH positive cells decreased by 47. 97% and 93. 28% , besides the Nissl's bodies were cut by 31. 4% and 46. 4% . After the treatment with low dose of levodopa, the rotational behaviour and the number of the TH positive cells and the Nissl's bodies didn t change obviously. Only the concentration of DA increased to 58. 3% of that of the control group . Conclusion These items all positively related to each other during the pathogenesis. The low-dose administration of levodopa for a short time only had some effect on the ascending of the concentration of dopamine for in advanced Parkinsons disease.%目的 动态监测帕金森大鼠不同发病阶段多巴胺能系统的改变,掌握其变化规律和各指标间的量化关系,为进一步实验提供动物治疗模型.方法 偏侧两点注射法制作帕金森病大鼠模型,模型成功两周后给予小剂量左旋多巴治疗一周.每周检测纹状体多巴胺(DA)含量,黑质酪氨酸羟化酶(TH)染色和尼氏染色,观察行为学改变.结果 一周后即发病的代偿期,行为学开始出现向健侧的旋转;两周后即失代偿期,旋转次数加重至最高峰.前两周多巴胺含量分别较正常对照侧减少16.7%和80%,TH阳性细胞分别下降47.97

  14. Icariin reverses corticosterone-induced depression-like behavior, decrease in hippocampal brain-derived neurotrophic factor (BDNF) and metabolic network disturbances revealed by NMR-based metabonomics in rats.

    Gong, Meng-Juan; Han, Bin; Wang, Shu-mei; Liang, Sheng-wang; Zou, Zhong-jie

    2016-05-10

    Previously published reports have revealed the antidepressant-like effects of icariin in a chronic mild stress model of depression and in a social defeat stress model in mice. However, the therapeutic effect of icariin in an animal model of glucocorticoid-induced depression remains unclear. This study aimed to investigate antidepressant-like effect and the possible mechanisms of icariin in a rat model of corticosterone (CORT)-induced depression by using a combination of behavioral and biochemical assessments and NMR-based metabonomics. The depression model was established by subcutaneous injections of CORT for 21 consecutive days in rats, as evidenced by reduced sucrose intake and hippocampal brain-derived neurotrophic factor (BDNF) levels, together with an increase in immobility time in a forced swim test (FST). Icariin significantly increased sucrose intake and hippocampal BDNF level and decreased the immobility time in FST in CORT-induced depressive rats, suggesting its potent antidepressant activity. Moreover, metabonomic analysis identified eight, five and three potential biomarkers associated with depression in serum, urine and brain tissue extract, respectively. These biomarkers are primarily involved in energy metabolism, lipid metabolism, amino acid metabolism and gut microbe metabolism. Icariin reversed the pathological process of CORT-induced depression, partially via regulation of the disturbed metabolic pathways. These results provide important mechanistic insights into the protective effects of icariin against CORT-induced depression and metabolic dysfunction.

  15. Repeated electroconvulsive stimuli have long-lasting effects on hippocampal BDNF and decrease immobility time in the rat forced swim test.

    Li, Bingjin; Suemaru, Katsuya; Cui, Ranji; Araki, Hiroaki

    2007-03-27

    Electroconvulsive therapy is considered an effective treatment for severe depression. However, the mechanisms for its long-lasting antidepressant efficacy are poorly understood. In the present study, we investigated changes of the immobility time in the forced swim test and brain-derived neurotrophic factor (BDNF) protein after withdrawal from 14-day repeated electroconvulsive stimuli (ECS, 50 mA, 0.2 s) in rats. Immobility time in the forced swim test was markedly decreased 6 h after withdrawal following 14-day ECS treatment. Thereafter, prolongation of the withdrawal period gradually diminished the decreasing effect of immobility time, but significant effects persisted for up to 3 days after the withdrawal. Locomotor activity in the open-field test increased 6 h after withdrawal from the ECS treatment, and the enhanced effect persisted for at least 7 days. The BDNF protein level in the hippocampus was markedly increased 6 h after the withdrawal, and remained high for at least 7 days. These findings provide further evidence that repeated ECS has long-lasting effect on increase in BDNF and locomotor activity and decrease in immobility time in the forced swim test.

  16. Hippocampal formation

    Cappaert, N.L.M.; van Strien, N.M.; Witter, M.P.; Paxinos, G.

    2015-01-01

    The hippocampal formation and parahippocampal region are prominent components of the rat nervous system and play a crucial role in learning, memory, and spatial navigation. Many new details regarding the entorhinal cortex have been discovered since the previous edition, and the growing interest in t

  17. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    Berghauzen-Maciejewska, Klemencja; Wardas, Jadwiga; Kosmowska, Barbara; Głowacka, Urszula; Kuter, Katarzyna; Ossowska, Krystyna

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  18. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    Klemencja Berghauzen-Maciejewska

    Full Text Available Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day and imipramine (10 mg/kg ip once a day were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG] and amygdala (basolateral/lateral as well as the BDNF mRNA content in the habenula (medial/lateral. The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core and ventral tegmental area (VTA. Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  19. Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain.

    Kalm, Marie; Karlsson, Niklas; Nilsson, Marie K L; Blomgren, Klas

    2013-09-01

    Radiotherapy is a major cause of long-term complications in survivors of pediatric brain tumors. These complications include intellectual and memory impairments as well as perturbed growth and puberty. We investigated the long-term effects of a single 8 Gy irradiation dose to the brains of 14-day-old mice. Behavior was assessed one year after irradiation using IntelliCage and open field, followed by immunohistochemical investigation of proliferation and neurogenesis in the dentate gyrus of the hippocampus. We found a 61% reduction in proliferation and survival (BrdU incorporation 4 weeks prior to sacrifice), 99% decrease in neurogenesis (number of doublecortin-positive cells) and gliosis (12% higher astrocyte density) one year following irradiation. Irradiated animals displayed increased activity in a novel environment but decreased activity in their home cage. Place learning in the IntelliCage was unaffected by irradiation but reversal learning was impaired. Irradiated animals persevered in visiting previously correct corners to a higher extent compared to control animals. Hence, despite the virtual absence of neurogenesis in these old mice, spatial learning could take place. Reversal learning however, where a previous memory was replaced with a new one, was partly impaired. This model is useful to study the so called late effects of radiotherapy to the young brain and to evaluate possible interventions.

  20. The effect of amygdala kindling on hippocampal neurogenesis coincides with decreased reelin and DISC1 expression in the adult dentate gyrus.

    Fournier, N M; Andersen, D R; Botterill, J J; Sterner, E Y; Lussier, A L; Caruncho, H J; Kalynchuk, L E

    2010-05-01

    Temporal lobe seizures can induce the proliferation and abnormal migration of newly generated dentate granule cells, but little is known about the molecular mechanisms that govern these pathological events. Reelin and DISC1 (disrupted-in-schizophrenia 1) are proteins that play a regulatory role in the maturation and integration of new neurons in the developing and adult brain. In this study, we examined whether amygdala kindling results in aberrant neurogenesis and altered expression of reelin and DISC1 in the adult dentate gyrus. Using doublecortin immunohistochemistry, we found that short-term kindling (i.e., 30 electrical stimulations) significantly increased the number of immature neurons in the dentate subgranular zone (SGZ), whereas long-term kindling (i.e., 99 electrical stimulations) did not. However, doublecortin-labeled neurons in long-term kindled rats showed greater dendritic complexity than they did in short-term kindled or control rats. We also found that long-term kindling decreased the number of reelin-positive cells and decreased DISC1 expression in the dentate granule cell layer and subgranular zone. Interestingly, kindling-induced changes in reelin and DISC1 expression coincided with the appearance of ectopically located Prox1-labeled granule cells in the hilus. These effects occurred independently of alterations in granule cell layer length, dentate volume, or the number of hilar neurons. Taken together, these findings suggest a novel role for DISC1 in the pathophysiology of temporal lobe epilepsy and further suggest that changes in reelin and DISC1 expression may contribute to aberrant neurogenesis in the kindling model.

  1. Chronic Spinal Cord Electrical Stimulation Protects Against 6-hydroxydopamine Lesions

    Yadav, Amol P.; Fuentes, Romulo; Zhang, Hao; Vinholo, Thais; Wang, Chi-Han; Freire, Marco Aurelio M.; Nicolelis, Miguel A. L.

    2014-01-01

    Although L-dopa continues to be the gold standard for treating motor symptoms of Parkinson's disease (PD), it presents long-term complications. Deep brain stimulation is effective, but only a small percentage of idiopathic PD patients are eligible. Based on results in animal models and a handful of patients, dorsal column stimulation (DCS) has been proposed as a potential therapy for PD. To date, the long-term effects of DCS in animal models have not been quantified. Here, we report that DCS applied twice a week in rats treated with bilateral 6-OHDA striatal infusions led to a significant improvement in symptoms. DCS-treated rats exhibited a higher density of dopaminergic innervation in the striatum and higher neuronal cell count in the substantia nigra pars compacta compared to a control group. These results suggest that DCS has a chronic therapeutical and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients.

  2. [Hippocampal stroke].

    Rollnik, J D; Traitel, B; Dietrich, B; Lenz, O

    2015-02-01

    Unilateral cerebral ischemia of the hippocampus is very rare. This paper reviews the literature and presents the case of a 59-year-old woman with an amnestic syndrome due to a left hippocampal stroke. The patient suffered from retrograde amnesia which was most severe over the 2 days prior to presenting and a slight anterograde amnesia. In addition, a verbal memory disorder was confirmed 1 week after admission by neurological tests. As risk factors, arterial hypertension and a relative hyper-beta lipoproteinemia were found. This case shows that unilateral amnestic stroke, e.g. in the hippocampus region, may be the cause of an amnestic syndrome and should be included in the differential diagnostics.

  3. Neonatal administration of phencyclidine decreases the number of putative inhibitory interneurons and increases neural excitability to auditory paired clicks in the hippocampal CA3 region of freely moving adult mice.

    Okamoto, M; Katayama, T; Suzuki, Y; Hoshino, K-Y; Yamada, H; Matsuoka, N; Jodo, E

    2012-11-08

    Animals exposed to phencyclidine (PCP) during the neonatal period have fewer GABAergic interneurons in the corticolimbic area, including the hippocampus, and exhibit abnormal behaviors after attaining maturation that correspond with schizophrenic symptoms. Since a lack of inhibitory interneurons in the hippocampus has also been reported in postmortem studies of patients with schizophrenia, the deficit may induce abnormal activity of hippocampal neurons that underlies pathological states in schizophrenia. However, it remains unclear how PCP treatment during the neonatal period affects the discharge activity of hippocampal neurons in adulthood. In the current study, single unit responses of hippocampal CA3 neurons to paired auditory clicks were recorded in freely moving mice repeatedly injected with PCP or saline during the neonatal period. The recorded neurons were classified into two subpopulations, narrow-spike neurons and broad-spike neurons, based on the spike width. The spontaneous discharge rate was higher in the narrow-spike neurons than in the broad-spike neurons, indicating that the narrow-spike neurons correspond with hippocampal inhibitory neurons. The proportion of narrow-spike neurons was significantly smaller in neonatally PCP-treated mice than in saline-treated mice. The broad-spike neurons that exhibited a response magnitude to the second click as large as that to the first click (E/E-type response) showed longer response duration to the paired clicks in PCP-treated mice than in the saline-treated mice. Further, the number of neurons with E/E-type response was higher in the PCP-treated mice than in the saline-treated mice. Finally, the attenuation of an auditory-evoked potential component, N40, to the second click (sensory gating) was blunted in the PCP-treated mice when compared with that in the saline-treated mice. These results suggest that the neonatal administration of PCP induced a deficit of inhibitory interneurons and altered discharge

  4. Novel genetic loci associated with hippocampal volume

    Hibar, Derrek P.; Adams, Hieab H. H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L.; Hofer, Edith; Renteria, Miguel E.; Bis, Joshua C.; Arias-Vasquez, Alejandro; Ikram, M. Kamran; Desrivières, Sylvane; Vernooij, Meike W.; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S.; Armstrong, Nicola J.; Athanasiu, Lavinia; Axelsson, Tomas; Beecham, Ashley H.; Beiser, Alexa; Bernard, Manon; Blanton, Susan H.; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brickman, Adam M.; Carmichael, Owen; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Chouraki, Vincent; Cuellar-Partida, Gabriel; Crivello, Fabrice; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Giddaluru, Sudheer; Goldman, Aaron L.; Gottesman, Rebecca F.; Grimm, Oliver; Griswold, Michael E.; Guadalupe, Tulio; Gutman, Boris A.; Hass, Johanna; Haukvik, Unn K.; Hoehn, David; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Jørgensen, Kjetil N.; Karbalai, Nazanin; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Liewald, David C. M.; Lopez, Lorna M.; Luciano, Michelle; Macare, Christine; Marquand, Andre F.; Matarin, Mar; Mather, Karen A.; Mattheisen, Manuel; McKay, David R.; Milaneschi, Yuri; Muñoz Maniega, Susana; Nho, Kwangsik; Nugent, Allison C.; Nyquist, Paul; Loohuis, Loes M. Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pirpamer, Lukas; Pütz, Benno; Ramasamy, Adaikalavan; Richards, Jennifer S.; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rommelse, Nanda; Ropele, Stefan; Rose, Emma J.; Royle, Natalie A.; Rundek, Tatjana; Sämann, Philipp G.; Saremi, Arvin; Satizabal, Claudia L.; Schmaal, Lianne; Schork, Andrew J.; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V.; Sprooten, Emma; Strike, Lachlan T.; Teumer, Alexander; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Trompet, Stella; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Lee, Sven J.; Van der Meer, Dennis; Van Donkelaar, Marjolein M. J.; Van Eijk, Kristel R.; Van Erp, Theo G. M.; Van Rooij, Daan; Walton, Esther; Westlye, Lars T.; Whelan, Christopher D.; Windham, Beverly G.; Winkler, Anderson M.; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Yanek, Lisa R.; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P.; Agartz, Ingrid; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A.; Arepalli, Sampath; Assareh, Amelia A.; Barral, Sandra; Bastin, Mark E.; Becker, Diane M.; Becker, James T.; Bennett, David A.; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I.; Brodaty, Henry; Brouwer, Rachel M.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Bulayeva, Kazima B.; Cahn, Wiepke; Calhoun, Vince D.; Cannon, Dara M.; Cavalleri, Gianpiero L.; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R.; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E.; Czisch, Michael; Dale, Anders M.; Davies, Gareth E.; De Craen, Anton J. M.; De Geus, Eco J. C.; De Jager, Philip L.; De Zubicaray, Greig I.; Deary, Ian J.; Debette, Stéphanie; DeCarli, Charles; Delanty, Norman; Depondt, Chantal; DeStefano, Anita; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C.; Duggirala, Ravi; Dyer, Thomas D.; Enzinger, Christian; Erk, Susanne; Espeseth, Thomas; Fedko, Iryna O.; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E.; Fleischman, Debra A.; Ford, Ian; Fornage, Myriam; Foroud, Tatiana M.; Fox, Peter T.; Francks, Clyde; Fukunaga, Masaki; Gibbs, J. Raphael; Glahn, David C.; Gollub, Randy L.; Göring, Harald H. H.; Green, Robert C.; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Håberg, Asta K.; Hansell, Narelle K.; Hardy, John; Hartman, Catharina A.; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G.; Heslenfeld, Dirk J.; Ho, Beng-Choon; Hoekstra, Pieter J.; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Huentelman, Matthew; Pol, Hilleke E. Hulshoff; Ikeda, Masashi; Jack Jr, Clifford R.; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G.; Jukema, J. Wouter; Kahn, René S.; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L.; Lopez, Oscar L.; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S.; McDonald, Colm; McIntosh, Andrew M.; McMahon, Francis J.; McMahon, Katie L.; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W.; Morris, Derek W.; Mosley, Thomas H.; Mühleisen, Thomas W.; Müller-Myhsok, Bertram; Nalls, Michael A.; Nauck, Matthias; Nichols, Thomas E.; Niessen, Wiro J.; Nöthen, Markus M.; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L.; Ophoff, Roel A.; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W. J. H.; Pike, G. Bruce; Potkin, Steven G.; Psaty, Bruce M.; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L.; Romanczuk-Seiferth, Nina; Rotter, Jerome I.; Ryten, Mina; Sacco, Ralph L.; Sachdev, Perminder S.; Saykin, Andrew J.; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter R.; Sigursson, Sigurdur; Simmons, Andrew; Singleton, Andrew; Sisodiya, Sanjay M.; Smith, Colin; Smoller, Jordan W.; Soininen, Hilkka; Steen, Vidar M.; Stott, David J.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Tsolaki, Magda; Tzourio, Christophe; Uitterlinden, Andre G.; Hernández, Maria C. Valdés; Van der Brug, Marcel; van der Lugt, Aad; van der Wee, Nic J. A.; Van Haren, Neeltje E. M.; van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N.; Vellas, Bruno; Veltman, Dick J.; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M.; Wassink, Thomas H.; Weale, Michael E.; Weinberger, Daniel R.; Weiner, Michael W.; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y.; Wright, Clinton B.; Zielke, Ronald H.; Zonderman, Alan B.; Martin, Nicholas G.; Van Duijn, Cornelia M.; Wright, Margaret J.; Longstreth, W. T.; Schumann, Gunter; Grabe, Hans J.; Franke, Barbara; Launer, Lenore J.; Medland, Sarah E.; Seshadri, Sudha; Thompson, Paul M.; Ikram, M. Arfan

    2017-01-01

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. PMID:28098162

  5. Hippocampal subfield volumes in mood disorders.

    Cao, B; Passos, I C; Mwangi, B; Amaral-Silva, H; Tannous, J; Wu, M-J; Zunta-Soares, G B; Soares, J C

    2017-01-24

    Volume reduction and shape abnormality of the hippocampus have been associated with mood disorders. However, the hippocampus is not a uniform structure and consists of several subfields, such as the cornu ammonis (CA) subfields CA1-4, the dentate gyrus (DG) including a granule cell layer (GCL) and a molecular layer (ML) that continuously crosses adjacent subiculum (Sub) and CA fields. It is known that cellular and molecular mechanisms associated with mood disorders may be localized to specific hippocampal subfields. Thus, it is necessary to investigate the link between the in vivo hippocampal subfield volumes and specific mood disorders, such as bipolar disorder (BD) and major depressive disorder (MDD). In the present study, we used a state-of-the-art hippocampal segmentation approach, and we found that patients with BD had reduced volumes of hippocampal subfields, specifically in the left CA4, GCL, ML and both sides of the hippocampal tail, compared with healthy subjects and patients with MDD. The volume reduction was especially severe in patients with bipolar I disorder (BD-I). We also demonstrated that hippocampal subfield volume reduction was associated with the progression of the illness. For patients with BD-I, the volumes of the right CA1, ML and Sub decreased as the illness duration increased, and the volumes of both sides of the CA2/3, CA4 and hippocampal tail had negative correlations with the number of manic episodes. These results indicated that among the mood disorders the hippocampal subfields were more affected in BD-I compared with BD-II and MDD, and manic episodes had focused progressive effect on the CA2/3 and CA4 and hippocampal tail.Molecular Psychiatry advance online publication, 24 January 2017; doi:10.1038/mp.2016.262.

  6. Grafts of fetal locus coeruleus neurons in rat amygdala-piriform cortex suppress seizure development in hippocampal kindling.

    Barry, D I; Wanscher, B; Kragh, J; Bolwig, T G; Kokaia, M; Brundin, P; Björklund, A; Lindvall, O

    1989-11-01

    Hippocampal kindling was investigated in rats with a 6-hydroxydopamine-induced lesion of the forebrain catecholamine system after implantation of neural tissue from the fetal locus coeruleus region either bilaterally into the amygdala-piriform cortex (i.e., distant to the kindling site) or unilaterally into the hippocampus (close to the kindling site). Lesioned animals with either sham grafts or control grafts consisting of fetal striatal tissue showed a kindling rate much faster than that of normal controls. In contrast, in rats with bilateral locus coeruleus grafts in the amygdala-piriform cortex (implanted at three sites) the development of seizures was similar to that of controls and significantly slower than that in lesioned animals with sham grafts. All these animals had bilateral surviving grafts with a mean of 125 noradrenergic cells per implantation site. In the animals with locus coeruleus grafts in the stimulated hippocampus the kindling rate did not differ from that in the lesioned animals with control grafts. Most of these animals had large surviving grafts and showed a dense noradrenergic reinnervation of the implanted hippocampus. The present findings indicate that grafting of fetal pontine tissue (rich in noradrenergic neurons) to a site distant to the stimulation focus, but important for the generalization and spread of seizures, can retard the development of seizures in hippocampal kindling. Together with the data of our previous report this study also indicates that noradrenergic reinnervation of both hippocampi is important for the seizure-suppressant action in hippocampal kindling of locus coeruleus grafts implanted in the hippocampus.

  7. Hippocampal Neurogenesis and Ageing

    Couillard-Després, Sébastien

    2012-01-01

    Although significant inconsistencies remain to be clarified, a role for neurogenesis in hippocampal functions, such as cognition, has been suggested by several reports. Yet, investigation in various species of mammals, including humans, revealed that rates of hippocampal neurogenesis are steadily declining with age. The very low levels of hippocampal neurogenesis persisting in the aged brain have been suspected to underlie the cognitive deficits observed in elderly. However, current evidence ...

  8. Osthole Improves Spatial Memory Deficits in Rats via Hippocampal α1-Adrenergic and D1/D2 Receptors

    Li-Wei Lin

    2013-01-01

    Full Text Available The present study evaluated the effect of osthole, an active ingredient isolated from Cnidium monnieri L. Cusson, on spatial memory deficits caused by central neurotoxins using the Morris water maze in rats. The involvement of catecholaminergic receptors on the memory-enhancing effect of osthole in rat hippocampus was further investigated by intrahippocampal injection of catecholaminergic receptor antagonists. Intracisternal injection of osthole (10 μg/brain improved the spatial performance and working memory impairments caused by the catecholaminergic neurotoxin 6-hydroxydopamine. No significant differences in swimming speeds were observed among sham, neurotoxin-induced, and osthole-treated groups. Intracisternal osthole injection also attenuated the spatial performance and working memory impairments caused by the α1 receptor antagonist phenoxybenzamine, the D1 receptor antagonist SCH 23390, and the D2 receptor antagonist sulpiride. Therefore, we demonstrated that the effect of osthole on improving spatial memory deficits may be related to the activation of hippocampal α1 and D1/D2 receptors.

  9. Hippocampal neuroplasticity in major depressive disorder.

    Malykhin, N V; Coupland, N J

    2015-11-19

    One of the most replicated findings has been that hippocampus volume is decreased in patients with major depressive disorder (MDD). Recent volumetric magnetic resonance imaging (MRI) studies suggest that localized differences in hippocampal volume may be more prominent than global differences. Preclinical and post-mortem studies in MDD indicated that different subfields of the hippocampus may respond differently to stress and may also have differential levels of plasticity in response to antidepressant treatment. Advances in high-field MRI allowed researchers to visualize and measure hippocampal subfield volumes in MDD patients in vivo. The results of these studies provide the first in vivo evidence that hippocampal volume reductions in MDD are specific to the cornu ammonis and dentate gyrus hippocampal subfields, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. In this review we discuss how recent advances in neuroimaging allow researchers to further understand hippocampal neuroplasticity in MDD and how it is related to antidepressant treatment, memory function, and disease progression.

  10. Local denervation of sympathetic nerve from the femoral artery using 6-hydroxydopamine in a rabbit model%6-羟多巴胺去除股动脉交感神经的动物模型建立及相关研究

    靳宇飞; 李富航; 毕龙; 裴国献

    2014-01-01

    目的 探讨6-羟多巴胺(6-OHDA)在体内去除兔股动脉交感神经的可行性,以期为研究单纯血管本身在组织工程骨中有无神经化作用提供理想的动物实验模型. 方法 分离16只新西兰兔右侧股动脉,采用不同药物处理:实验组采用含0.1 mg/mL 6-OHDA和质量百分比为0.1%抗坏血酸Krebs缓冲液处理,为确定药物干预后交感神经的恢复时间,将实验组再分为7d、14d和28 d取材组(n=4);对照组(n=4)采用仅含0.1%抗坏血酸Krebs缓冲液处理.分别用苏木精-伊红(HE)染色、乙醛酸激发单胺荧光染色检测股动脉组织变化、交感神经分布情况,并通过Western blot检测酪酸羟化酶(TH)和神经肽Y(NPY)蛋白表达水平的差异. 结果 HE染色结果显示:与对照组相比,3个取材组股动脉组织血管壁结构完整,无明显形态学改变.乙醛酸激发单胺荧光染色结果显示:对照组股动脉可见大量交感神经呈网状和放射状分布;7d和14 d取材组几乎不可见交感神经,28 d取材组有少量交感神经.Western blot检测结果表明:对照组、7d取材组、14d取材组及28 d取材组TH/β-actin比值平均分别为0.70±0.08、0.19±0.08、0.20±0.06、0.33 ±0.06; NPY/β-actin比值平均分别为0.68±0.14、0.14±0.02、0.17±0.02、0.53±0.10,各取材组的TH和NPY蛋白表达量较对照组均显著减少,而28 d取材组的TH和NPY蛋白表达量较7d、14d取材组明显增多,差异均有统计学意义(P<0.05). 结论 体内局部应用6-OHDA可有效去除股动脉交感神经纤维,是一种可行的血管壁去交感神经方法.本研究建立了一种理想的化学去股动脉交感神经的动物模型.%Objective To explore an effective method to remove sympathetic nerve from the femoral artery in a rabbit model.Methods Femoral arteries from 16 New Zealand rabbits were separated and treated with different drugs.The femoral arteries were processed with Krebs buffer containing 0.1 mg/mL 6

  11. Hippocampal kindling: corticosterone modulation of induced seizures

    Kloet, E.R. de; Cottrell, G.A.; Nyakas, C.; Bohus, B.

    1984-01-01

    The effect of adrenalectomy (ADX) and corticosterone replacement was studied on seizures induced by hippocampal kindling. A complex series of changes occurred in after-discharge (AD) and behavioural depression (BD) during the immediate hours after ADX, culminating at day 1 in markedly decreased AD a

  12. Taurine increases hippocampal neurogenesis in aging mice

    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.

  13. Empathy in hippocampal amnesia.

    Beadle, J N; Tranel, D; Cohen, N J; Duff, M C

    2013-01-01

    Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. The scientific investigation of empathy has focused on characterizing its cognitive and neural substrates, and has pointed to the importance of a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate). While the hippocampus has rarely been the focus of empathy research, the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity) make it well-suited to meet some of the crucial demands of empathy, and a careful investigation of this possibility could make a significant contribution to the neuroscientific understanding of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female) with focal, bilateral hippocampal (HC) damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. Unlike healthy comparison participants, in response to the empathy inductions hippocampal patients reported no increase in empathy ratings or prosocial behavior. The results provide preliminary evidence for a role for hippocampal declarative memory in empathy.

  14. Neuropeptides and hippocampal neurogenesis.

    Zaben, M J; Gray, W P

    2013-12-01

    Hippocampal neurogenesis is important for modulating the behavioural responses to stress and for certain forms of learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation-neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Neuropeptides such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and galanin have emerged as important mediators for signalling local and extrinsic interneuronal activity to subgranular zone precursors. Here we review the distribution of these neuropeptides and their receptors in the neurogenic area of the hippocampus and their precise effects on hippocampal neurogenesis. We also discuss neuropeptides' potential involvement in functional aspects of hippocampal neurogenesis particularly their involvement in the modulation of learning and memory and behavior responses.

  15. Empathy in hippocampal amnesia

    Janelle N Beadle

    2013-03-01

    Full Text Available The scientific investigation of empathy has become a cornerstone in the field of social cognition. Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. Scientific investigations of empathy have focused on characterizing its cognitive and neural substrates, pointing to a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate. While the hippocampus has rarely been the focus of empathy research, we propose that there are compelling reasons to inquire about the contribution of the hippocampus to social cognition. We propose that the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity make it well-suited to meet the demands of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female with focal, bilateral hippocampal (HC damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. In response to the empathy inductions, unlike healthy comparison participants, hippocampal patients reported no increase in empathy ratings or prosocial behavior from the control condition. Taken together, these results provide preliminary evidence for a role of hippocampal declarative memory in empathy.

  16. Preservation of hippocampal neuron numbers and hippocampal subfield volumes in behaviorally characterized aged tree shrews

    Keuker, J.I.H.; de Biurrun, G.; Luiten, P.G.M.; Fuchs, E.

    2004-01-01

    Aging is associated with a decreased ability to store and retrieve information. The hippocampal formation plays a critical role in such memory processes, and its integrity is affected during normal aging. We used tree shrews (Tupaia belangeri) as an animal model of aging, because in many characteris

  17. Culturing rat hippocampal neurons.

    Audesirk, G; Audesirk, T; Ferguson, C

    2001-01-01

    Cultured neurons are widely used to investigate the mechanisms of neurotoxicity. Embryonic rat hippocampal neurons may be grown as described under a wide variety of conditions to suit differing experimental procedures, including electrophysiology, morphological analysis of neurite development, and various biochemical and molecular analyses.

  18. Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice

    Yun-feng LI; Hong-xia CHEN; Ying LIU; You-zhi ZHANG; Yan-qin LIU; Jin LI

    2006-01-01

    Aim:To explore the mechanism of agmatine's antidepressant action.Methods: Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period.The open-field behaviors of the mice were displayed and recorded using a Videomex-V image analytic system automatically.For bromodeoxyuridine (BrdU;thymidine analog as a marker for dividing cells) labeling,the mice were injected with BrdU (100 mg/kg,ip,twice per d for 2 d),and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry.The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and 3H-thymidine incorporation assay.Results:After the onset of chronic stress,the locomotor activity of the mice in the open field significantly decreased,while coadministration of agmatine 10 mg/kg (po) blocked it.Furthermore,the number of BrdU-labeled cells in the hippocampal dentate gyrus significantly decreased in chronically stressed mice, which was also blocked by chronic coadministration with agmatine 10 mg/kg (po). Four weeks after the BrdU injection, some of the new born cells matured and became neurons, as determined by double labeling for BrdU and neuron specific enolase (NSE), a marker for mature neurons.In vitro treatment with agmatine 0.1-10 μmo1/L for 3 d significantly increased the proliferation of the cultured hippocampal progenitor cells in a dose-dependent manner.Conclusion:We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice.This may be one of the important mechanisms involved in agmatine's antidepressant action.

  19. Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia

    Ebdrup, Bjørn Hylsebeck; Glenthøj, Birte; Rasmussen, Hans;

    2010-01-01

    that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared...

  20. Preservation of hippocampal neuron numbers and hippocampal subfield volumes in behaviorally characterized aged tree shrews.

    Keuker, Jeanine I H; de Biurrun, Gabriel; Luiten, Paul G M; Fuchs, Eberhard

    2004-01-19

    Aging is associated with a decreased ability to store and retrieve information. The hippocampal formation plays a critical role in such memory processes, and its integrity is affected during normal aging. We used tree shrews (Tupaia belangeri) as an animal model of aging, because in many characteristics, tree shrews are closer to primates than they are to rodents. Young and aged male tree shrews performed a holeboard spatial memory task, which permits assessment of reference and working memory. Upon completion of the behavioral measurements, we carried out modified stereological analyses of neuronal numbers in various subdivisions of the hippocampus and used the Cavalieri method to calculate the volumes of these subfields. Results showed that the working memory of aged tree shrews was significantly impaired compared with that of young animals, whereas the hippocampus-dependent reference memory remained unchanged by aging. Estimation of the number of neurons revealed preserved neuron numbers in the subiculum, in the subregions CA1, CA2, CA3, and in the hilus of the dentate gyrus. Volume measurements showed no aging-related changes in the volume of any of these hippocampal subregions, or in the molecular and granule cell layers of the dentate gyrus of tree shrews. We conclude that the observed changes in memory performance in aging tree shrews are not accompanied by observable reductions of hippocampal neuron numbers or hippocampal volume, rather, the changes in memory performance are more likely the result of modified subcellular mechanisms that are affected by the aging process.

  1. Active sulforhodamine 101 uptake into hippocampal astrocytes.

    Christian Schnell

    Full Text Available Sulforhodamine 101 (SR101 is widely used as a marker of astrocytes. In this study we investigated labeling of astrocytes by SR101 in acute slices from the ventrolateral medulla and the hippocampus of transgenic mice expressing EGFP under the control of the astrocyte-specific human GFAP promoter. While SR101 efficiently and specifically labeled EGFP-expressing astrocytes in hippocampus, we found that the same staining procedure failed to label astrocytes efficiently in the ventrolateral medulla. Although carbenoxolone is able to decrease the SR101-labeling of astrocytes in the hippocampus, it is unlikely that SR101 is taken up via gap-junction hemichannels because mefloquine, a blocker for pannexin and connexin hemichannels, was unable to prevent SR101-labeling of hippocampal astrocytes. However, SR101-labeling of the hippocampal astrocytes was significantly reduced by substrates of organic anion transport polypeptides, including estron-3-sulfate and dehydroepiandrosterone sulfate, suggesting that SR101 is actively transported into hippocampal astrocytes.

  2. Disappearance and recovery of catecholamine innervation in brain regions of adult goldfish following 6-hydroxydopamine treatment.

    Contestabile, A; Friz, T; Caravaggio, M V

    1979-10-01

    The effect of 6-OHDA treatment on catecholamine innervation was studied in the cerebellum, optic tectum and lobus vagi of the goldfish. Catecholamine terminals completely disappeared in less than two weeks after intraventricular injection of 10 microgram 6-OHDA. In periods comprised between 40 days and 4 months after drug injection, catecholamine terminals reappeared to a different degree. The cerebellum showed the highest recovery and, as far as the valvula cerebelli was concerned, also over-innervation. The remarkable power to restore catecholamine innervation led to a distribution of reappearing terminals similar to that of normal animals in the different layers of the three structures examined.

  3. Moxibustion upregulates hippocampal progranulin expression

    Tao Yi; Li Qi; Ji Li; Jing-jing Le; Lei Shao; Xin Du; Jing-cheng Dong

    2016-01-01

    In China, moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome, but its mechanisms are largely un-known. More recently, the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome, and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis. In the present study, we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms. Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome. The acupointsGuanyuan (CV4) and Zusanli (ST36, bilateral) were simultaneously administered moxibustion. Untreated chronic fatigue syndrome rats and normal rats were used as controls. Results from the forced swimming test, open ifeld test, tail suspension test, real-time PCR, enzyme-linked immunosor-bent assay, and western blot assay showed that moxibustion treatment decreased mRNA expression of corticotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone and corticosterone levels in plasma, and markedly increased progranulin mRNA and protein expression in the hippocampus. These ifndings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome, at least in part, by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.

  4. Moxibustion upregulates hippocampal progranulin expression

    Tao Yi

    2016-01-01

    Full Text Available In China, moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome, but its mechanisms are largely unknown. More recently, the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome, and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis. In the present study, we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms. Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome. The acupoints Guanyuan (CV4 and Zusanli (ST36, bilateral were simultaneously administered moxibustion. Untreated chronic fatigue syndrome rats and normal rats were used as controls. Results from the forced swimming test, open field test, tail suspension test, real-time PCR, enzyme-linked immunosorbent assay, and western blot assay showed that moxibustion treatment decreased mRNA expression of corticotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone and corticosterone levels in plasma, and markedly increased progranulin mRNA and protein expression in the hippocampus. These findings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome, at least in part, by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.

  5. Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique

    Brodin, N. Patrik; af Rosenschold, Per Munck; Blomstrand, Malin;

    2014-01-01

    BackgroundWe investigated how varying the treatment margin and applying hippocampal sparing and proton therapy impact the risk of neurocognitive impairment in pediatric medulloblastoma patients compared with current standard 3D conformal radiotherapy.MethodsWe included 17 pediatric medulloblastoma...... boost. Neurocognitive impairment risk was estimated based on dose-response models from pediatric CNS malignancy survivors and compared among different margins and treatment techniques.ResultsMean hippocampal dose and corresponding risk of cognitive impairment were decreased with decreasing treatment...

  6. Hippocampal activity during the transverse patterning task declines with cognitive competence but not with age

    Leirer Vera M

    2010-09-01

    Full Text Available Abstract Background The hippocampus is a brain region that is particularly affected by age-related morphological changes. It is generally assumed that a loss in hippocampal volume results in functional deficits that contribute to age-related cognitive decline. In a combined cross-sectional behavioural and magnetoencephalography (MEG study we investigated whether hippocampal-associated neural current flow during a transverse patterning task - which requires learning relational associations between stimuli - correlates with age and whether it is modulated by cognitive competence. Results Better performance in several tests of verbal memory, verbal fluency and executive function was indeed associated with higher hippocampal neural activity. Age, however, was not related to the strength of hippocampal neural activity: elderly participants responded slower than younger individuals but on average produced the same neural mass activity. Conclusions Our results suggest that in non-pathological aging, hippocampal neural activity does not decrease with age but is rather related to cognitive competence.

  7. Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory.

    Parihar, V K; Hattiangady, B; Kuruba, R; Shuai, B; Shetty, A K

    2011-02-01

    Maintenance of neurogenesis in adult hippocampus is important for functions such as mood and memory. As exposure to unpredictable chronic stress (UCS) results in decreased hippocampal neurogenesis, enhanced depressive- and anxiety-like behaviors, and memory dysfunction, it is believed that declined hippocampal neurogenesis mainly underlies the behavioral and cognitive abnormalities after UCS. However, the effects of predictable chronic mild stress (PCMS) such as the routine stress experienced in day-to-day life on functions such as mood, memory and hippocampal neurogenesis are unknown. Using FST and EPM tests on a prototype of adult rats, we demonstrate that PCMS (comprising 5 min of daily restraint stress for 28 days) decreases depressive- and anxiety-like behaviors for prolonged periods. Moreover, we illustrate that decreased depression and anxiety scores after PCMS are associated with ~1.8-fold increase in the production and growth of new neurons in the hippocampus. Additionally, we found that PCMS leads to enhanced memory function in WMT as well as NORT. Collectively, these findings reveal that PCMS is beneficial to adult brain function, which is exemplified by increased hippocampal neurogenesis and improved mood and cognitive function.

  8. Relation between hippocampal gamma waves and behavioral disturbances induced by phencyclidine and methamphetamine.

    Ma, J; Leung, L S

    2000-06-15

    The relationship between hippocampal electrical activity and behavioral hyperactivity induced by either phencyclidine (PCP) or methamphetamine (MAP) was examined in freely behaving rats. The EEGs at the hippocampal CA1 region were simultaneously recorded with the animal's behavior for 2 h after administration of either PCP or MAP. PCP (10 mg/kg, intraperitoneal (i.p.)) significantly increased locomotor activity including rearing, walking, head-weaving and circling. Spectral analysis of the EEG showed that hippocampal gamma waves (30-70 Hz), but not other frequency bands, were significantly increased from 5 to 120 min after systemic injection of PCP. Inactivation of the medial septum with muscimol, a gamma-aminobutyric acid receptor A agonist, 15 min prior to injection of PCP, suppressed both hippocampal gamma waves and locomotor activity. MAP (1.5 mg/kg, i.p.) also increased locomotor activity for longer than 2 h. During the behavioral hyperactivity induced by MAP, hippocampal EEG showed θ and gamma rhythms that were not significantly different from those during walking before MAP. However, MAP-induced behavioral activity was suppressed by pre-injection of muscimol in the medial septum, which also decreased hippocampal gamma activity. It is suggested that the medial septum plays a role in mediating behavioral disturbances induced by both PCP and MAP through control of the hippocampal electrical activity, and that hippocampal gamma waves may play a permissible role in the expression of behaviors.

  9. Low dose of corticosterone treatment with exercise increases hippocampal cell proliferation, and improves cognition

    Suk-Yu Yau; Jada Chia-Di Lee; Benson Wui-Man Lau; Tatia M.C. Lee; Yick-Pang Ching; Siu-Wa Tang; Kwok-Fai So

    2011-01-01

    Intermediate level of stress is beneficial for brain functions, whereas extreme low level or high level of stress is deleterious. We have previously shown that chronic exposure to high doses of corticosterone (CORT) suppressed hippocampal plasticity and physical exercise in terms of running counteracted the detrimental effects of CORT treatment. We aimed to study whether a mild stress, that mimicked by a treatment with low CORT dose, improved hippocampal plasticity in terms of hippocampal cell proliferation and dendritic remodeling, and to examine whether running with CORT treatment showed an additive effect on improving hippocampal plasticity. The rats were treated with 20 mg/kg CORT for 14 days with or without running, followed by Morris water maze test or forced swim test. The hippocampal proliferating cells was labeled by intraperitoneal injection of 5-bromo-2'-deoxyuridine. The dendritic morphology was analyzed using Golgi staining method. Treatment with 20 mg/kg CORT alone yielded a higher number of hippocampal cell proliferation and significantly increased dendritic branching compared to vehicle-treated non-runners, but had no behavioral effects. In contrast, CORT treatment with running showed an additive increase in hippocampal cell proliferation and dendritic remodeling that was associated with improved spatial learning and decreased depression-like behavior; however, there was no additive improvement in behavior compared to vehicle-treated runners. These findings suggest that mild stress does not always cause detrimental effect on the brain, and combining mild stress with running could promote hippocampal plasticity via inducing cell proliferation and dendritic remodeling.

  10. Novel genetic loci associated with hippocampal volume

    D.P. Hibar (Derrek); H.H.H. Adams (Hieab); N. Jahanshad (Neda); G. Chauhan (Ganesh); J.L. Stein; E. Hofer (Edith); M.E. Rentería (Miguel); J.C. Bis (Joshua); A. Arias-Vásquez (Alejandro); Ikram, M.K. (M. Kamran); S. Desrivières (Sylvane); M.W. Vernooij (Meike); L. Abramovic; S. Alhusaini (Saud); N. Amin (Najaf); M. Andersson (Micael); K. Arfanakis (Konstantinos); B. Aribisala (Benjamin); N.J. Armstrong (Nicola J.); L. Athanasiu (Lavinia); T. Axelsson (Tomas); A.H. Beecham (Ashley); A. Beiser (Alexa); M. Bernard (Manon); S.H. Blanton (Susan H.); M.M. Bohlken (Marc M.); M.P.M. Boks (Marco); L.B.C. Bralten (Linda); A.M. Brickman (Adam M.); Carmichael, O. (Owen); M.M. Chakravarty (M. Mallar); Q. Chen (Qiang); C.R.K. Ching (Christopher); V. Chouraki (Vincent); G. Cuellar-Partida (Gabriel); F. Crivello (Fabrice); A. den Braber (Anouk); Doan, N.T. (Nhat Trung); S.M. Ehrlich (Stefan); S. Giddaluru (Sudheer); A.L. Goldman (Aaron L.); R.F. Gottesman (Rebecca); O. Grimm (Oliver); M.D. Griswold (Michael); T. Guadalupe (Tulio); Gutman, B.A. (Boris A.); J. Hass (Johanna); U.K. Haukvik (Unn); D. Hoehn (David); A.J. Holmes (Avram); M. Hoogman (Martine); D. Janowitz (Deborah); T. Jia (Tianye); Jørgensen, K.N. (Kjetil N.); N. Karbalai (Nazanin); D. Kasperaviciute (Dalia); S. Kim (Shinseog); M. Klein (Marieke); B. Kraemer (Bernd); P.H. Lee (Phil); D.C. Liewald (David C.); L.M. Lopez (Lorna); M. Luciano (Michelle); C. MacAre (Christine); Marquand, A.F. (Andre F.); M. Matarin (Mar); R. Mather; M. Mattheisen (Manuel); McKay, D.R. (David R.); Milaneschi, Y. (Yuri); S. Muñoz Maniega (Susana); K. Nho (Kwangsik); A.C. Nugent (Allison); P. Nyquist (Paul); Loohuis, L.M.O. (Loes M. Olde); J. Oosterlaan (Jaap); M. Papmeyer (Martina); Pirpamer, L. (Lukas); B. Pütz (Benno); A. Ramasamy (Adaikalavan); Richards, J.S. (Jennifer S.); S.L. Risacher (Shannon); R. Roiz-Santiañez (Roberto); N. Rommelse (Nanda); S. Ropele (Stefan); E.J. Rose (Emma); N.A. Royle (Natalie); T. Rundek (Tatjana); P.G. Sämann (Philipp); Saremi, A. (Arvin); C.L. Satizabal (Claudia L.); L. Schmaal (Lianne); N.J. Schork (Nicholas); Shen, L. (Li); J. Shin (Jean); Shumskaya, E. (Elena); A.V. Smith (Albert Vernon); R. Sprooten (Roy); V.M. Strike (Vanessa); A. Teumer (Alexander); D. Tordesillas-Gutierrez (Diana); R. Toro (Roberto); D. Trabzuni (Danyah); S. Trompet (Stella); D. Vaidya (Dhananjay); J. van der Grond (Jeroen); S. van der Lee (Sven); Van Der Meer, D. (Dennis); M.M.J. Van Donkelaar (Marjolein M. J.); K.R. van Eijk (Kristel); T.G.M. van Erp (Theo G.); Van Rooij, D. (Daan); E. Walton (Esther); L.T. Westlye (Lars); C.D. Whelan (Christopher); B.G. Windham (B Gwen); A.M. Winkler (Anderson); K. Wittfeld (Katharina); G. Woldehawariat (Girma); A. Björnsson (Asgeir); Wolfers, T. (Thomas); L.R. Yanek (Lisa); Yang, J. (Jingyun); A.P. Zijdenbos; M.P. Zwiers (Marcel); I. Agartz (Ingrid); L. Almasy (Laura); D. Ames (David); Amouyel, P. (Philippe); O.A. Andreassen (Ole A.); S. Arepalli (Sampath); A.A. Assareh; S. Barral (Sandra); M.E. Bastin (Mark); Becker, D.M. (Diane M.); J.T. Becker; D.A. Bennett (David A.); J. Blangero (John); H. van Bokhoven (Hans); D.I. Boomsma (Dorret); H. Brodaty (Henry); R.M. Brouwer (Rachel); H.G. Brunner; M. Buckner; J.K. Buitelaar (Jan); K. Bulayeva (Kazima); W. Cahn (Wiepke); V.D. Calhoun Vince D. (V.); D.M. Cannon (Dara); G. Cavalleri (Gianpiero); Cheng, C.-Y. (Ching-Yu); S. Cichon (Sven); M.R. Cookson (Mark); A. Corvin (Aiden); B. Crespo-Facorro (Benedicto); J.E. Curran (Joanne); M. Czisch (Michael); A.M. Dale (Anders); G.E. Davies (Gareth); A.J. de Craen (Anton); E.J.C. de Geus (Eco); P.L. de Jager (Philip); G.I. de Zubicaray (Greig); I.J. Deary (Ian J.); S. Debette (Stéphanie); C. DeCarli (Charles); N. Delanty; C. Depondt (Chantal); A.L. DeStefano (Anita); A. Dillman (Allissa); S. Djurovic (Srdjan); D.J. Donohoe (Dennis); D.A. Drevets (Douglas); Duggirala, R. (Ravi); M.D. Dyer (Matthew); C. Enzinger (Christian); S. Erk; T. Espeseth (Thomas); Fedko, I.O. (Iryna O.); Fernández, G. (Guillén); L. Ferrucci (Luigi); S.E. Fisher (Simon); D. Fleischman (Debra); I. Ford (Ian); M. Fornage (Myriam); T. Foroud (Tatiana); P.T. Fox (Peter); C. Francks (Clyde); Fukunaga, M. (Masaki); Gibbs, J.R. (J. Raphael); D.C. Glahn (David); R.L. Gollub (Randy); H.H.H. Göring (Harald H.); R.C. Green (Robert C.); O. Gruber (Oliver); V. Gudnason (Vilmundur); S. Guelfi (Sebastian); Håberg, A.K. (Asta K.); N.K. Hansell (Narelle); J. Hardy (John); C.A. Hartman (C.); Hashimoto, R. (Ryota); K. Hegenscheid (Katrin); J. Heinz (Judith); S. Le Hellard (Stephanie); D.G. Hernandez (Dena); D.J. Heslenfeld (Dirk); Ho, B.-C. (Beng-Choon); P.J. Hoekstra (Pieter); W. Hoffmann (Wolfgang); A. Hofman (Albert); F. Holsboer (Florian); G. Homuth (Georg); N. Hosten (Norbert); J.J. Hottenga (Jouke Jan); M.J. Huentelman (Matthew); H.H. Pol; Ikeda, M. (Masashi); Jack, C.R. (Clifford R.); S. Jenkinson (Sarah); R. Johnson (Robert); Jönsson, E.G. (Erik G.); J.W. Jukema; R. Kahn; Kanai, R. (Ryota); I. Kloszewska (Iwona); Knopman, D.S. (David S.); P. Kochunov (Peter); Kwok, J.B. (John B.); S. Lawrie (Stephen); H. Lemaître (Herve); X. Liu (Xinmin); D.L. Longo (Dan L.); O.L. Lopez (Oscar L.); S. Lovestone (Simon); Martinez, O. (Oliver); J.-L. Martinot (Jean-Luc); V.S. Mattay (Venkata S.); McDonald, C. (Colm); A.M. McIntosh (Andrew); McMahon, F.J. (Francis J.); McMahon, K.L. (Katie L.); P. Mecocci (Patrizia); I. Melle (Ingrid); Meyer-Lindenberg, A. (Andreas); S. Mohnke (Sebastian); Montgomery, G.W. (Grant W.); D.W. Morris (Derek W); T.H. Mosley (Thomas H.); T.W. Mühleisen (Thomas); B. Müller-Myhsok (B.); M.A. Nalls (Michael); M. Nauck (Matthias); T.E. Nichols (Thomas); W.J. Niessen (Wiro); M.M. Nöthen (Markus); L. Nyberg (Lars); Ohi, K. (Kazutaka); R.L. Olvera (Rene); R.A. Ophoff (Roel); M. Pandolfo (Massimo); T. Paus (Tomas); Z. Pausova (Zdenka); B.W.J.H. Penninx (Brenda); Pike, G.B. (G. Bruce); S.G. Potkin (Steven); B.M. Psaty (Bruce); S. Reppermund; M. Rietschel (M.); J.L. Roffman (Joshua); N. Seiferth (Nina); J.I. Rotter (Jerome I.); M. Ryten (Mina); Sacco, R.L. (Ralph L.); P.S. Sachdev (Perminder); A.J. Saykin (Andrew); R. Schmidt (Reinhold); Schmidt, H. (Helena); C.J. Schofield (Christopher); Sigursson, S. (Sigurdur); Simmons, A. (Andrew); A. Singleton (Andrew); S.M. Sisodiya (Sanjay); Smith, C. (Colin); J.W. Smoller; H. Soininen (H.); V.M. Steen (Vidar); D.J. Stott (David J.); J. Sussmann (Jessika); A. Thalamuthu (Anbupalam); A.W. Toga (Arthur W.); B. Traynor (Bryan); J.C. Troncoso (Juan); M. Tsolaki (Magda); C. Tzourio (Christophe); A.G. Uitterlinden (André); Hernández, M.C.V. (Maria C. Valdés); M.P. van der Brug (Marcel); A. van der Lugt (Aad); N.J. van der Wee (Nic); N.E.M. van Haren (Neeltje E.); D. van 't Ent (Dennis); M.J.D. van Tol (Marie-José); B.N. Vardarajan (Badri); B. Vellas (Bruno); D.J. Veltman (Dick); H. Völzke (Henry); H.J. Walter (Henrik); J. Wardlaw (Joanna); A.M.J. Wassink (Annemarie); M.E. Weale (Michael); Weinberger, D.R. (Daniel R.); Weiner, M.W. (Michael W.); Wen, W. (Wei); E. Westman (Eric); T.J.H. White (Tonya); Wong, T.Y. (Tien Y.); Wright, C.B. (Clinton B.); R.H. Zielke (Ronald H.); A.B. Zonderman; N.G. Martin (Nicholas); C.M. van Duijn (Cock); M.J. Wright (Margaret); W.T. Longstreth Jr; G. Schumann (Gunter); H.J. Grabe (Hans Jörgen); B. Franke (Barbara); L.J. Launer (Lenore); S.E. Medland (Sarah Elizabeth); S. Seshadri (Sudha); P.M. Thompson (Paul); M.K. Ikram (Kamran)

    2017-01-01

    textabstractThe hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpi

  11. A comparative proteome analysis of hippocampal tissue from schizophrenic and Alzheimer's disease individuals.

    Edgar, P F; Schonberger, S J; Dean, B; Faull, R L; Kydd, R; Cooper, G J

    1999-03-01

    The proteins expressed by a genome have been termed the proteome. Comparative proteome analysis of brain tissue offers a novel means to identify biologically significant gene products that underlie psychopathology. In this study we collected post mortem hippocampal tissue from the brains of seven schizophrenic, seven Alzheimer's disease (AD) and seven control individuals. Hippocampal proteomes were visualised by two-dimensional gel electrophoresis of homogenised tissue. A mean of 549 (s.d. 35) proteins were successfully matched between each disease group and the control group. In comparison with the control hippocampal proteome, eight proteins in the schizophrenic hippocampal proteome were found to be decreased and eight increased in concentration, whereas, in the AD hippocampal proteome, 35 proteins were decreased and 73 were increased in concentration (Pdiazepam binding inhibitor (DBI) by N-terminal sequence analysis. DBI can regulate the action of the GABA(A) receptor. Protein changes involved 6% of the assessed AD hippocampal proteome, whereas, in schizophrenia protein changes involved less than 1% of the assessed hippocampal proteome. We conclude that schizophrenia has a subtle neuropathological presentation and comparative proteome analysis is a viable means by which to investigate diseases of the brain at the molecular level.

  12. Modeling Impaired Hippocampal Neurogenesis after Radiation Exposure.

    Cacao, Eliedonna; Cucinotta, Francis A

    2016-03-01

    Radiation impairment of neurogenesis in the hippocampal dentate gyrus is one of several factors associated with cognitive detriments after treatment of brain cancers in children and adults with radiation therapy. Mouse models have been used to study radiation-induced changes in neurogenesis, however the models are limited in the number of doses, dose fractions, age and time after exposure conditions that have been studied. The purpose of this study is to develop a novel predictive mathematical model of radiation-induced changes to neurogenesis using a system of nonlinear ordinary differential equations (ODEs) to represent the time, age and dose-dependent changes to several cell populations participating in neurogenesis as reported in mouse experiments exposed to low-LET radiation. We considered four compartments to model hippocampal neurogenesis and, consequently, the effects of radiation treatment in altering neurogenesis: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN) and (4) glioblasts (GB). Because neurogenesis is decreasing with increasing mouse age, a description of the age-related dynamics of hippocampal neurogenesis is considered in the model, which is shown to be an important factor in comparisons to experimental data. A key feature of the model is the description of negative feedback regulation on early and late neuronal proliferation after radiation exposure. The model is augmented with parametric descriptions of the dose and time after irradiation dependences of activation of microglial cells and a possible shift of NSC proliferation from neurogenesis to gliogenesis reported at higher doses (∼10 Gy). Predictions for dose-fractionation regimes and for different mouse ages, and prospects for future work are then discussed.

  13. Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance

    Cisternas, Pedro; Salazar, Paulina; Serrano, Felipe G.; Montecinos-Oliva, Carla; Arredondo, Sebastián B.; Varela-Nallar, Lorena; Barja, Salesa; Vio, Carlos P.; Gomez-Pinilla, Fernando; Inestrosa, Nibaldo C.

    2017-01-01

    Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7 weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders. PMID:26300486

  14. Fluoxetine inhibits dendrite atrophy of hippocampal neurons by decreasing nitric oxide synthase expression in rat depression model%氟西汀通过降低一氧化氮合酶的表达而抑制抑郁症模型大鼠海马神经元树突萎缩

    罗兰; 谭仁祥

    2001-01-01

    AIM: To study the effect of fluoxetine on dendrite atrophy of hippocampal neurons in rat depression model.METHODS: CMS ( chronic mild stress ), mimicking human depression, was used as the animal depression model. The neurons shape and numbers of nitric oxide synthase positive cells in the hippocampal subfields were measured by Nissl staining and histochemical staining of NADPH (nicotinamide adenine dinucleotide phosphate)diaphorase respectively. RESULTS: CMS deforms neurons in the hippocampal formation, and fluoxetine can renormalize the deformed neurons by inhibiting the nitric oxide synthase catalyzing the over-production of NO,which lead subsequently to the morphological abnormality in the circumscribed area of brain. CONCLUSION:Fluoxetine, an antidepressant, renormalizes dendrite atrophy of hippocampal neurons by inhibiting nitric oxide synthase overexpression in rat chronic mild stress model.%目的:研究氟西汀对抑郁症大鼠模型的海马神经元树突萎缩的作用.方法:用慢性温和性应激模型作为抑郁症模型,采用尼氏染色观察海马各亚区神经元形态,用NADPH-d组化染色方法测定了海马中一氧化氮合酶阳性神经元的数量.结果:慢性温和性应激对海马神经元有一定的损伤,主要表现在神经元树突的萎缩,而氟西汀可使这些受损神经元恢复正常,这种作用与氟西汀抑制海马区的一氧化氮合酶阳性神经元的数量减少相关.结论:氟西汀可通过抑制海马区一氧化氮合酶的过度表达而阻止或扭转抑郁症模型大鼠海马神经元树突的萎缩.

  15. Lactation-induced reduction in hippocampal neurogenesis is reversed by repeated stress exposure

    Hillerer, K.M.; Neumann, I. D.; Couillard-Despres, S.; Aigner, L.; Slattery, D.A.

    2014-01-01

    The peripartum period is a time of high susceptibility for mood and anxiety disorders, some of which have recently been associated with alterations in hippocampal neurogenesis. Several factors including stress, aging, and, perhaps unexpectedly, lactation have been shown to decrease hippocampal neurogenesis. Intriguingly, lactation is also a time of reduced stress responsivity suggesting that the effect of stress on neurogenic processes may differ during this period. Therefore, the aim of the ...

  16. Hippocampal neurogenesis dysfunction linked to depressive-like behaviors in a neuroinflammation induced model of depression.

    Tang, Ming-Ming; Lin, Wen-Juan; Pan, Yu-Qin; Guan, Xi-Ting; Li, Ying-Cong

    2016-07-01

    Our previous work found that triple central lipopolysaccharide (LPS) administration could induce depressive-like behaviors and increased central pro-inflammatory cytokines mRNA, hippocampal cytokine mRNA in particular. Since several neuroinflammation-associated conditions have been reported to impair neurogenesis, in this study, we further investigated whether the neuroinflammation induced depression would be associated with hippocampal neurogenesis dysfunction. An animal model of depression induced by triple central lipopolysaccharide (LPS) administration was used. In the hippocampus, the neuroinflammatory state evoked by LPS was marked by an increased production of pro-inflammatory cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor-α. It was found that rats in the neuroinflammatory state exhibited depressive-like behaviors, including reduced saccharin preference and locomotor activity as well as increased immobility time in the tail suspension test and latency to feed in the novelty suppressed feeding test. Adult hippocampal neurogenesis was concomitantly inhibited, including decreased cell proliferation and newborn cell survival. We also demonstrated that the decreased hippocampal neurogenesis in cell proliferation was significantly correlated with the depressive-like phenotypes of decreased saccharine preference and distance travelled, the core and characteristic symptoms of depression, under neuro inflammation state. These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of biological mechanisms underlying depression induced by neruoinflammation.

  17. Hippocampal Abnormalities and Seizure Recurrence

    J Gordon Millichap

    2006-08-01

    Full Text Available Hippocampal volumetry and T2 relaxometry were performed on 84 consecutive patients (adolescents and adults with partial epilepsy submitted to antiepileptic drug (AED withdrawal after at least 2 years of seizure control, in a study at State University of Campinas-UNICAMP, Brazil.

  18. Postnatal morphine administration alters hippocampal development in rats.

    Traudt, Christopher M; Tkac, Ivan; Ennis, Kathleen M; Sutton, Leah M; Mammel, Daniel M; Rao, Raghavendra

    2012-01-01

    Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have an altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo (1)H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine, and myo-insotol were decreased, whereas concentrations of glutathione, phosphoethanolamine, and choline-containing compounds were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure.

  19. Hippocampal ER stress and learning deficits following repeated pyrethroid exposure.

    Hossain, Muhammad M; DiCicco-Bloom, Emanuel; Richardson, Jason R

    2015-01-01

    Endoplasmic reticulum (ER) stress is implicated as a significant contributor to neurodegeneration and cognitive dysfunction. Previously, we reported that the widely used pyrethroid pesticide deltamethrin causes ER stress-mediated apoptosis in SK-N-AS neuroblastoma cells. Whether or not this occurs in vivo remains unknown. Here, we demonstrate that repeated deltamethrin exposure (3 mg/kg every 3 days for 60 days) causes hippocampal ER stress and learning deficits in adult mice. Repeated exposure to deltamethrin caused ER stress in the hippocampus as indicated by increased levels of C/EBP-homologous protein (131%) and glucose-regulated protein 78 (96%). This was accompanied by increased levels of caspase-12 (110%) and activated caspase-3 (50%). To determine whether these effects resulted in learning deficits, hippocampal-dependent learning was evaluated using the Morris water maze. Deltamethrin-treated animals exhibited profound deficits in the acquisition of learning. We also found that deltamethrin exposure resulted in decreased BrdU-positive cells (37%) in the dentate gyrus of the hippocampus, suggesting potential impairment of hippocampal neurogenesis. Collectively, these results demonstrate that repeated deltamethrin exposure leads to ER stress, apoptotic cell death in the hippocampus, and deficits in hippocampal precursor proliferation, which is associated with learning deficits.

  20. The effect of estrogen synthesis inhibition on hippocampal memory.

    Bayer, Janine; Rune, Gabriele; Schultz, Heidrun; Tobia, Michael J; Mebes, Imke; Katzler, Olaf; Sommer, Tobias

    2015-06-01

    17-Beta-estradiol (E2) facilitates long term-potentiation (LTP) and increases spine synapse density in hippocampal neurons of ovariectomized rodents. Consistent with these beneficial effects on the cellular level, E2 improves hippocampus-dependent memory. A prominent approach to study E2 effects in rodents is the inhibition of its synthesis by letrozole, which reduces LTPs and spine synapse density. In the current longitudinal functional magnetic resonance imaging (fMRI) study, we translated this approach to humans and compared the impact of E2 synthesis inhibition on memory performance and hippocampal activity in post-menopausal women taking letrozole (n = 21) to controls (n = 24). In particular, we employed various behavioral memory paradigms that allow the disentanglement of hippocampus-dependent and -independent memory. Consistent with the literature on rodents, E2 synthesis inhibition specifically impaired hippocampus-dependent memory, however, this did not apply to the same degree to all of the employed paradigms. On the neuronal level, E2 depletion tended to decrease hippocampal activity during encoding, whereas it increased activity in the anterior cingulate and the dorsolateral prefrontal cortex. We thus infer that the inhibition of E2 synthesis specifically impairs hippocampal functioning in humans, whereas the increased prefrontal activity presumably reflects a compensatory mechanism, which is already known from studies on cognitive aging and Alzheimer's disease.

  1. Role of adult hippocampal neurogenesis in persistent pain.

    Apkarian, A Vania; Mutso, Amelia A; Centeno, Maria V; Kan, Lixin; Wu, Melody; Levinstein, Marjorie; Banisadr, Ghazal; Gobeske, Kevin T; Miller, Richard J; Radulovic, Jelena; Hen, René; Kessler, John A

    2016-02-01

    The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain.

  2. Impairment of cognitive function and reduced hippocampal cholinergic activity in a rat model of chronic intermittent hypoxia

    Chunling Zhao; Yan Chen; Chunlai Zhang; Linya Lü; Qian Xu

    2011-01-01

    The present study established a rat model of chronic intermittent hypoxia (CIH) to simulate obstructive sleep apnea syndrome. CIH rats were evaluated for cognitive function using the Morris water maze, and neuronal pathology in the hippocampus was observed using hematoxylin-eosin staining. In addition, hippocampal choline acetyl transferase (ChAT) and nicotinic acetylcholine receptor (nAChR) expression was determined by immunohistochemistry. Our results revealed necrotic hippocampal neurons, decreased ChAT and nAChR expression, as well as cognitive impairment in CIH rats. These results suggest that hippocampal neuronal necrosis and decreased cholinergic activity may be involved in CIH-induced cognitive impairment in rats.

  3. Sericin can reduce hippocampal neuronal apoptosis by activating the Akt signal transduction pathway in a rat model of diabetes mellitus

    Zhihong Chen; Yaqiang He; Chengjun Song; Zhijun Dong; Zhejun Su; Jingfeng Xue

    2012-01-01

    In the present study, a rat model of type 2 diabetes mellitus was established by continuous peritoneal injection of streptozotocin. Following intragastric perfusion of sericin for 35 days, blood glucose levels significantly reduced, neuronal apoptosis in the hippocampal CA1 region decreased, hippocampal phosphorylated Akt and nuclear factor kappa B expression were enhanced, but Bcl-xL/Bcl-2 associated death promoter expression decreased. Results demonstrated that sericin can reduce hippocampal neuronal apoptosis in a rat model of diabetes mellitus by regulating abnormal changes in the Akt signal transduction pathway.

  4. Clinical and Cognitive Correlates of Structural Hippocampal Change in "At-Risk" Older Adults.

    Elcombe, Emma L; Lagopoulos, Jim; Mowszowski, Loren; Diamond, Keri; Paradise, Matthew; Hickie, Ian B; Lewis, Simon J G; Naismith, Sharon L

    2014-06-01

    With estimates of dementia expected to rise over the coming decades, there is interest in understanding the factors associated with promoting neuroprotection and limiting neurodegeneration. In this study, we examined the change in the volume of the hippocampus over a 2-month period in 34 older people "at risk" of cognitive decline (mean age = 66.8 years, 38% male). Factors that were examined included cognitive reserve, neuropsychological functioning, depression as well as a lifestyle (cognitive training) intervention. The results showed that over a 2-month period, increases in hippocampal size were associated with having higher premorbid intellect, greater occupational attainment, superior memory, and higher levels of functioning. Conversely, depression and disability were associated with decreases in hippocampal volume. Cognitive training was not associated with changes in hippocampal volume. These findings suggest that factors associated with cognitive reserve, cognition and depression may play an integral pathophysiological role in determining hippocampal volumes in "at-risk" older adults.

  5. Hippocampal deep brain stimulation reverses physiological and behavioural deficits in a rodent model of schizophrenia.

    Perez, Stephanie M; Shah, Amiksha; Asher, Amber; Lodge, Daniel J

    2013-07-01

    Subcortical dopamine system dysregulation has been suggested to underlie the positive symptoms of schizophrenia. Recent preclinical investigations and human imaging studies have proposed that the augmented dopamine system function observed in schizophrenia patients may be secondary to aberrant hippocampal activity. Thus, we posit that the hippocampus represents a novel therapeutic target for the treatment of schizophrenia. Here we provide evidence of the effectiveness of a unique approach aimed at decreasing hippocampal function in a rodent model of schizophrenia. Specifically, in a rodent model of schizophrenia, we demonstrate that ventral hippocampal (vHipp) deep brain stimulation (DBS) can normalize aberrant dopamine neuron activity and behaviours associated with positive symptoms. In addition, we provide evidence that this approach may also be effective in restoring deficits in cognitive function, often left unaltered by conventional antipsychotic medications. Therefore, we have provided initial preclinical evidence demonstrating the feasibility of hippocampal DBS as a potential novel approach for the treatment of schizophrenia.

  6. Arachidonic acid incorporation and turnover is decreased in sympathetically denervated rat heart.

    Patrick, Casey B; McHowat, Jane; Rosenberger, Thad A; Rapoport, Stanley I; Murphy, Eric J

    2005-06-01

    Heart sympathetic denervation can accompany Parkinson's disease, but the effect of this denervation on cardiac lipid-mediated signaling is unknown. To address this issue, rats were sympathetically denervated with 6-hydroxydopamine (6-OHDA, 50 mg/kg ip) and infused with 170 muCi/kg of either [1-(14)C]palmitic acid ([1-(14)C]16:0) or [1-(14)C]arachidonic acid ([1-(14)C]20:4 n-6), and kinetic parameters were assessed using a steady-state radiotracer model. Heart norepinephrine and epinephrine levels were decreased 82 and 85%, respectively, in denervated rats, and this correlated with a 34% reduction in weight gain in treated rats. Fatty acid tracer uptake was not significantly different between groups for either tracer, although the dilution coefficient lambda was increased in [1-(14)C]20:4 n-6-infused rats, which indicates that less 20:4 n-6 was recycled in denervated rats. In [1-(14)C]16:0-infused rats, incorporation rate and turnover values of 16:0 in stable lipid compartments were unchanged, which is indicative of preservation of beta-oxidation. In [1-(14)C]20:4 n-6-infused rats, there were dramatic reductions in incorporation rate (60-84%) and turnover value (56-85%) in denervated rats that were dependent upon the lipid compartment. In addition, phospholipase A(2) activity was reduced 40% in treated rats, which is consistent with the reduction observed in 20:4 n-6 turnover. These results demonstrate marked reductions in 20:4 n-6 incorporation rate and turnover in sympathetic denervated rats and thereby suggest an effect on lipid-mediated signal transduction mediated by a reduction in phospholipase A(2) activity.

  7. Correlation between volume and morphological changes in the hippocampal formation in Alzheimer's disease: rounding of the outline of the hippocampal body on coronal MR images

    Adachi, Michito; Sato, Takamichi [Ohshima Clinic, Department of Radiology, Yamagata (Japan); Kawakatsu, Shinobu [Yamagata University School of Medicine, Department of Psychiatry, Yamagata (Japan); Ohshima, Fumi [Ohshima Clinic, Department of Neurology, Yamagata (Japan)

    2012-10-15

    The aim of this study was to investigate whether the outline of the hippocampal body becomes rounded on coronal magnetic resonance imaging (MRI) as the volume of the hippocampal formation decreases in Alzheimer's disease (AD). Institutional review board approval of the study protocol was obtained, and all subjects provided informed consent for the mini-mental state examination (MMSE) and MRI. The MRI and MMSE were prospectively performed in all 103 subjects (27 men and 76 women; mean age {+-} standard deviation, 77.7 {+-} 7.8 years) who had AD or were concerned about having of dementia and who consulted our institute over 1 year. The subjects included 14 non-dementia cases (MMSE score {>=} 28) and 89 AD cases (MMSE score {<=} 27). The total volume of the bilateral hippocampal formation (VHF) was assessed with a tracing method, and the ratio of the VHF to the intracranial volume (RVHF) and the rounding ratio (RR) of the hippocampal body (mean ratio of its short dimension to the long dimension in the bilateral hippocampal body) were calculated. Using Spearman's correlation coefficient, the correlations between RR and VHF and between RR and RVHF were assessed. Correlation coefficients between RR and VHF and between RR and RVHF were -0.419 (p < 0.01) and -0.418 (p < 0.01), respectively. There was a significant negative correlation between RR and the volume of the hippocampal formation. The outline of the body of the hippocampal formation becomes rounded on coronal images as its volume decreases in AD. (orig.)

  8. Hippocampal GABA transporter distribution in patients with temporal lobe epilepsy and hippocampal sclerosis

    Schijns, O.; Karaca, U.; Andrade, P.; Nijs, L. de; Kusters, B.; Peeters, A.; Dings, J.; Pannek, H.; Ebner, A.; Rijkers, K.; Hoogland, G.

    2015-01-01

    PURPOSE: To determine hippocampal expression of neuronal GABA-transporter (GAT-1) and glial GABA-transporter (GAT-3) in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). METHODS: Hippocampal sections were immunohistochemically stained for GABA-transporter 1 and GABA-transpor

  9. A grading system for hippocampal sclerosis based on the degree of hippocampal mossy fiber sprouting

    Gispen, W.H.; Proper, E.A.; Jansen, G.H.; Veelen, C.W. van; Rijen, P.C. van; Graan, P.N.E. de

    2001-01-01

    Abstract. In patients suffering from temporal lobe epilepsy (TLE) a highly variable degree of hippocampal sclerosis (HS) can be observed. For standard neuropathological evaluation after hippocampal resection, neuronal cell loss in the hippocampal subareas is assessed (Wyler score 0-4) [Wyler et al.

  10. Hippocampal amnesia disrupts creative thinking.

    Duff, Melissa C; Kurczek, Jake; Rubin, Rachael; Cohen, Neal J; Tranel, Daniel

    2013-12-01

    Creativity requires the rapid combination and recombination of existing mental representations to create novel ideas and ways of thinking. The hippocampal system, through its interaction with neocortical storage sites, provides a relational database necessary for the creation, updating, maintenance, and juxtaposition of mental representations used in service of declarative memory. Given this functionality, we hypothesized that hippocampus would play a critical role in creative thinking. We examined creative thinking, as measured by verbal and figural forms of the torrance tests of creative thinking (TTCT), in a group of participants with hippocampal damage and severe declarative memory impairment as well as in a group of demographically matched healthy comparison participants. The patients with bilateral hippocampal damage performed significantly worse than comparison participants on both the verbal and figural portions of the TTCT. These findings suggest that hippocampus plays a role critical in creative thinking, adding to a growing body of work pointing to the diverse ways the hallmark processing features of hippocampus serve a variety of behaviors that require flexible cognition.

  11. Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons

    Pham Serena

    2011-08-01

    Full Text Available Abstract Background Oxidative stress plays an important role in neuronal dysfunction and neuron loss in Alzheimer's brain. Previous studies have reported downregulation of CREB-mediated transcription by oxidative stress and Aβ. The promoter for CREB itself contains cyclic AMP response elements. Therefore, we examined the expression of CREB in the hippocampal neurons of Tg2576 mice, AD post-mortem brain and in cultured rat hippocampal neurons exposed to Aβ aggregates. Results Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS-extracted Aβ and CREB protein levels in Alzheimer's post-mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to Aβ fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in Aβ-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against Aβ-induced neuronal apoptosis. Conclusions Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression.

  12. Damage of hippocampal neurons in rats with chronic alcoholism

    Ailin Du; Hongbo Jiang; Lei Xu; Na An; Hui Liu; Yinsheng Li; Ruiling Zhang

    2014-01-01

    Chronic alcoholism can damage the cytoskeleton and aggravate neurological deifcits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6%alcohol for 42 days. Endog-enous hydrogen sulifde content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were signiifcantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear mem-brane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin.

  13. Neuroprotective effect of piperine on primarily cultured hippocampal neurons.

    Fu, Min; Sun, Zhao-Hui; Zuo, Huan-Cong

    2010-01-01

    It was previously reported that piperine (PIP) significantly blocks convulsions induced by intracerebroventricular injection of threshold doses of kainate, but had no or only slight effects on convulsions induced by L-glutamate, N-methyl-D-aspartate and guanidinosuccinate. In traditional Chinese medicine, black pepper has been used for epileptic treatment; however, the exact mechanism is still unclear. We reported here in that appropriate concentration of PIP effectively inhibites the synchronized oscillation of intracellular calcium in rat hippocampal neuronal networks and represses spontaneous synaptic activities in terms of spontaneous synaptic currents (SSC) and spontaneous excitatory postsynaptic currents (sEPSC). Moreover, pretreatment with PIP expects protective effect on glutamate-induced decrease of cell viability and apoptosis of hippocampal neurons. These data suggest that the neuroprotective effects of PIP might be associated with suppression of synchronization of neuronal networks, presynaptic glutamic acid release, and Ca(2+) overloading.

  14. Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

    2016-03-15

    Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.

  15. Hippocampal volume in relation to clinical and cognitive outcome after electroconvulsive therapy in depression

    Nordanskog, P; Larsson, M R; Larsson, E-M; Johanson, A

    2014-01-01

    Objective In a previous magnetic resonance imaging (MRI) study, we found a significant increase in hippocampal volume immediately after electroconvulsive therapy (ECT) in patients with depression. The aim of this study was to evaluate hippocampal volume up to 1 year after ECT and investigate its possible relation to clinical and cognitive outcome. Method Clinical and cognitive outcome in 12 in-patients with depression receiving antidepressive pharmacological treatment referred for ECT were investigated with the Montgomery–Asberg Depression Rating Scale (MADRS) and a broad neuropsychological test battery within 1 week before and after ECT. The assessments were repeated 6 and 12 months after baseline in 10 and seven of these patients, respectively. Hippocampal volumes were measured on all four occasions with 3 Tesla MRI. Results Hippocampal volume returned to baseline during the follow-up period of 6 months. Neither the significant antidepressant effect nor the significant transient decrease in executive and verbal episodic memory tests after ECT could be related to changes in hippocampal volume. No persistent cognitive side effects were observed 1 year after ECT. Conclusion The immediate increase in hippocampal volume after ECT is reversible and is not related to clinical or cognitive outcome. PMID:23745780

  16. Autopsy-confirmed hippocampal-sparing Alzheimer's disease with delusional jealousy as initial manifestation.

    Fujishiro, Hiroshige; Iritani, Shuji; Hattori, Miho; Sekiguchi, Hirotaka; Matsunaga, Shinji; Habuchi, Chikako; Torii, Youta; Umeda, Kentaro; Ozaki, Norio; Yoshida, Mari; Fujita, Kiyoshi

    2015-09-01

    Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre-dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single-photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD.

  17. Gentianine protects hippocampal neurons in a rat model of recurrent febrile convulsion

    Xuewei Liu; Shumin Liu; Na Wang; Fang Lu; Min Cao

    2011-01-01

    Gentianine has been shown to have a protective effect on hippocampal CA1 neurons in rats subjected to recurrent febrile convulsion (FC).The present study sought to explore the possible mechanism of gentianine by intraperitoneally injecting gentianine into rats with warm water-induced FC.The results revealed that neuronal organelle injury was slightly ameliorated in the hippocampal CA1 region.The level of glutamate was decreased,but the level of γ-aminobutyric acid was increased,as detected by ninhydrin staining.In addition,glutamate acid decarboxylase expression in hippocampal CA1 was increased,as determined by immunohistochemistry.The results demonstrated that gentianine can ameliorate FC-induced neuronal injury by enhancing glutamate acid decarboxylase activity,decreasing glutamate levels and increasing γ-aminobutyric acid levels.

  18. Porcupine Controls Hippocampal AMPAR Levels, Composition, and Synaptic Transmission

    Nadine Erlenhardt

    2016-02-01

    Full Text Available AMPA receptor (AMPAR complexes contain auxiliary subunits that modulate receptor trafficking and gating. In addition to the transmembrane AMPAR regulatory proteins (TARPs and cornichons (CNIH-2/3, recent proteomic studies identified a diverse array of additional AMPAR-associated transmembrane and secreted partners. We systematically surveyed these and found that PORCN and ABHD6 increase GluA1 levels in transfected cells. Knockdown of PORCN in rat hippocampal neurons, which express it in high amounts, selectively reduces levels of all tested AMPAR complex components. Regulation of AMPARs is independent of PORCN’s membrane-associated O-acyl transferase activity. PORCN knockdown in hippocampal neurons decreases AMPAR currents and accelerates desensitization and leads to depletion of TARP γ-8 from AMPAR complexes. Conditional PORCN knockout mice also exhibit specific changes in AMPAR expression and gating that reduce basal synaptic transmission but leave long-term potentiation intact. These studies define additional roles for PORCN in controlling synaptic transmission by regulating the level and composition of hippocampal AMPAR complexes.

  19. Hippocampal adult neurogenesis: Does the immune system matter?

    de Miranda, Aline Silva; Zhang, Cun-Jin; Katsumoto, Atsuko; Teixeira, Antônio Lúcio

    2017-01-15

    Adult hippocampal neurogenesis involves proliferation, survival, differentiation and integration of newborn neurons into pre-existing neuronal networks. Although its functional significance in the central nervous system (CNS) has not comprehensively elucidated, adult neurogenesis has been attributed a role in cognition, learning and memory. There is a growing body of evidence that CNS resident as well as peripheral immune cells participate in regulating hippocampal adult neurogenesis. Microglial cells are closely associated with neural stem/progenitor cell (NSPC) in the neurogenic niche engaged in a bidirectional communication with neurons, which may be important for adult neurogenesis. Microglial and neuronal crosstalk is mediated in part by CX3CL1/CX3CR1 signaling and a disruption in this pathway has been associated with impaired neurogenesis. It has been also reported that microglial neuroprotective or neurotoxic effects in adult neurogenesis occur in a context-dependent manner. Apart from microglia other brain resident and peripheral immune cells including pericytes, perivascular macrophages, mast cells and T-cells also modulate this phenomenon. It is worth mentioning that under some physiological circumstances such as normal aging there is a significant decrease in hippocampal neurogenesis. A role for innate and adaptive immune system in adult neurogenesis has been also reported during aging. Here, we review the current evidence regarding neuro-immune interactions in the regulation of neurogenesis under distinct conditions, including aging.

  20. Maternal vitamin C deficiency does not reduce hippocampal volume and beta-tubulin III intensity in prenatal Guinea pigs

    Hansen, Stine Normann; Schjoldager, Janne Gram; Paidi, Maya Devi

    2016-01-01

    the observed deficits remain largely unknown. We hypothesized that vitC deficiency in utero may lead to a decreased neuronal maturation and increased cellular death giving rise to alterations of the hippocampal morphology in a guinea pig model. Brains from prenatal guinea pig pups (n = 9-10 in each group...... study found that hippocampal volume and beta-tubulin isotype III intensity in the prenatal guinea pig were influenced by gestational day but not by maternal vitC intake...

  1. Effect of Acute and Fractionated Irradiation on Hippocampal Neurogenesis

    Jin Kyu Kim

    2012-08-01

    Full Text Available Ionizing radiation has become an inevitable health concern emanating from natural sources like space travel and from artificial sources like medical therapies. In general, exposure to ionizing radiation such as γ-rays is one of the methods currently used to stress specific model systems. In this study, we elucidated the long-term effect of acute and fractionated irradiation on DCX-positive cells in hippocampal neurogenesis. Groups of two-month-old C57BL/6 female mice were exposed to whole-body irradiation at acute dose (5 Gy or fractional doses (1 Gy × 5 times and 0.5 Gy × 10 times. Six months after exposure to γ-irradiation, the hippocampus was analyzed. Doublecortin (DCX immunohistochemistry was used to measure changes of neurogenesis in the subgranular zone (SGZ of the hippocampal dentate gyrus (DG. The number of DCX-positive cells was significantly decreased in all acute and fractionally irradiation groups. The long-term changes in DCX-positive cells triggered by radiation exposure showed a very different pattern to the short-term changes which tended to return to the control level in previous studies. Furthermore, the number of DCX-positive cells was relatively lower in the acute irradiation group than the fractional irradiation groups (approximately 3.6-fold, suggesting the biological change on hippocampal neurogenesis was more susceptible to being damaged by acute than fractional irradiation. These results suggest that the exposure to γ-irradiation as a long-term effect can trigger biological responses resulting in the inhibition of hippocampal neurogenesis.

  2. Theta Oscillations and Reactivity of Hippocampal Stratum Oriens Neurons

    Valentina F. Kitchigina

    2010-01-01

    Full Text Available The supposition was advanced that the neuronal theta rhythmicity is the key mode of signal selection at the hippocampal level. To address this hypothesis, the experimental data on the responses of putative hippocampal interneurons of the stratum oriens CA1-CA3 to stimulation during enhanced theta rhythm and after its blockade are reviewed. Both a strong increase and a decrease of the natural theta rhythm disturbed the reactions of hippocampal neurons; during theta augmentation, the responses were masked or disappeared, and after theta blockade, they lost the ability to habituate. In both cases, two important events were broken: the resetting of the background activity and the phase-locking of theta cycles to stimulus. These data allow one to suppose that only important stimuli are normally capable to evoke these events and these stimuli are selected for recording. When the response to a significant stimulus occurs, the following theta prevents the responses to other stimuli. This probably protects the hippocampal activity from interference from irrelevant signals. Presumably, the absence of the theta deprives the hippocampus of this protection. During enhanced and persistent theta oscillations, the reset disappeared and theta bursts were generated without stimulus locking. In this state, the system is probably closed and the information cannot be recorded. During the theta blockade, the reset was too long and did not habituate. In this case, the system is open for any signals and the hippocampus loses the ability to select signal. This analysis suggests that information selection in the hippocampus may be performed with the participation of nonpyramidal neurons.

  3. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression.

    Huijbers, Willem; Mormino, Elizabeth C; Schultz, Aaron P; Wigman, Sarah; Ward, Andrew M; Larvie, Mykol; Amariglio, Rebecca E; Marshall, Gad A; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A

    2015-04-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  4. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

    Mormino, Elizabeth C.; Schultz, Aaron P.; Wigman, Sarah; Ward, Andrew M.; Larvie, Mykol; Amariglio, Rebecca E.; Marshall, Gad A.; Rentz, Dorene M.; Johnson, Keith A.; Sperling, Reisa A.

    2015-01-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity—consistent with findings in genetic at-risk populations—and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer’s disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  5. Negative rebound in hippocampal neurogenesis following exercise cessation.

    Nishijima, Takeshi; Kamidozono, Yoshika; Ishiizumi, Atsushi; Amemiya, Seiichiro; Kita, Ichiro

    2017-03-01

    Physical exercise can improve brain function, but the effects of exercise cessation are largely unknown. This study examined the time-course profile of hippocampal neurogenesis following exercise cessation. Male C57BL/6 mice were randomly assigned to either a control (Con) or an exercise cessation (ExC) group. Mice in the ExC group were reared in a cage with a running wheel for 8 wk and subsequently placed in a standard cage to cease the exercise. Exercise resulted in a significant increase in the density of doublecortin (DCX)-positive immature neurons in the dentate gyrus (at week 0). Following exercise cessation, the density of DCX-positive neurons gradually decreased and was significantly lower than that in the Con group at 5 and 8 wk after cessation, indicating that exercise cessation leads to a negative rebound in hippocampal neurogenesis. Immunohistochemistry analysis suggests that the negative rebound in neurogenesis is caused by diminished cell survival, not by suppression of cell proliferation and neural maturation. Neither elevated expression of ΔFosB, a transcription factor involved in neurogenesis regulation, nor increased plasma corticosterone, were involved in the negative neurogenesis rebound. Importantly, exercise cessation suppressed ambulatory activity, and a significant correlation between change in activity and DCX-positive neuron density suggested that the decrease in activity is involved in neurogenesis impairment. Forced treadmill running following exercise cessation failed to prevent the negative neurogenesis rebound. This study indicates that cessation of exercise or a decrease in physical activity is associated with an increased risk for impaired hippocampal function, which might increase vulnerability to stress-induced mood disorders.

  6. Vulnerability of hippocampal GABA-ergic interneurons to kainate-induced excitotoxic injury during old age.

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

    2009-08-01

    Hippocampal inhibitory interneurons expressing glutamate decarboxylase-67 (GAD-67) considerably decline in number during old age. Studies in young adult animals further suggest that hippocampal GAD-67+ interneuron population is highly vulnerable to excitotoxic injury. However, the relative susceptibility of residual GAD-67+ interneurons in the aged hippocampus to excitotoxic injury is unknown. To elucidate this, using both adult and aged F344 rats, we performed stereological counting of GAD-67+ interneurons in different layers of the dentate gyrus and CA1 & CA3 sub-fields, at 3 months post-excitotoxic hippocampal injury inflicted through an intracerebroventricular administration of kainic acid (KA). Substantial reductions of GAD-67+ interneurons were found in all hippocampal layers and sub-fields after KA-induced injury in adult animals. Contrastingly, there was no significant change in GAD-67+ interneuron population in any of the hippocampal layers and sub-fields following similar injury in aged animals. Furthermore, the stability of GAD-67+ interneurons in aged rats after KA was not attributable to milder injury, as the overall extent of KA-induced hippocampal principal neuron loss was comparable between adult and aged rats. Interestingly, because of the age-related disparity in vulnerability of interneurons to injury, the surviving GAD-67+ interneuron population in the injured aged hippocampus remained comparable to that observed in the injured adult hippocampus despite enduring significant reductions in interneuron number with aging. Thus, unlike in the adult hippocampus, an excitotoxic injury to the aged hippocampus does not result in significantly decreased numbers of GAD-67+ interneurons. Persistence of GAD-67+ interneuron population in the injured aged hippocampus likely reflects an age-related change in the response of GAD-67+ interneurons to excitotoxic hippocampal injury. These results have implications towards understanding mechanisms underlying the

  7. α-Calcium calmodulin kinase II modulates the temporal structure of hippocampal bursting patterns.

    Jeiwon Cho

    Full Text Available The alpha calcium calmodulin kinase II (α-CaMKII is known to play a key role in CA1/CA3 synaptic plasticity, hippocampal place cell stability and spatial learning. Additionally, there is evidence from hippocampal electrophysiological slice studies that this kinase has a role in regulating ion channels that control neuronal excitability. Here, we report in vivo single unit studies, with α-CaMKII mutant mice, in which threonine 305 was replaced with an aspartate (α-CaMKII(T305D mutants, that indicate that this kinase modulates spike patterns in hippocampal pyramidal neurons. Previous studies showed that α-CaMKII(T305D mutants have abnormalities in both hippocampal LTP and hippocampal-dependent learning. We found that besides decreased place cell stability, which could be caused by their LTP impairments, the hippocampal CA1 spike patterns of α-CaMKII(T305D mutants were profoundly abnormal. Although overall firing rate, and overall burst frequency were not significantly altered in these mutants, inter-burst intervals, mean number of intra-burst spikes, ratio of intra-burst spikes to total spikes, and mean intra-burst intervals were significantly altered. In particular, the intra burst intervals of place cells in α-CaMKII(T305D mutants showed higher variability than controls. These results provide in vivo evidence that besides its well-known function in synaptic plasticity, α-CaMKII, and in particular its inhibitory phosphorylation at threonine 305, also have a role in shaping the temporal structure of hippocampal burst patterns. These results suggest that some of the molecular processes involved in acquiring information may also shape the patterns used to encode this information.

  8. Hippocampal volumes are important predictors for memory function in elderly women

    Adolfsdottir Steinunn

    2009-08-01

    Full Text Available Abstract Background Normal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years. Methods Brain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT. To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis. Results APOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results. Conclusion Gender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.

  9. BDNF Regains Function in Hippocampal Long-Term Potentiation Deficits Caused by Diencephalic Damage

    Vedder, Lindsey C.; Savage, Lisa M.

    2017-01-01

    Thiamine deficiency (TD), commonly associated with chronic alcoholism, leads to diencephalic damage, hippocampal dysfunction, and spatial learning and memory deficits. We show a decrease in the magnitude of long-term potentiation (LTP) and paired-pulse facilitation (PPF) at CA3-CA1 synapses, independent of sex, following diencephalic damage…

  10. Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease

    Ericksen Mielle Borba

    2016-12-01

    Full Text Available Background/Aims: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD pathology. Serum brain-derived neurotrophic factor (BDNF reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]. Methods: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®. Results: MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. Discussion: The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction.

  11. Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease

    Borba, Ericksen Mielle; Duarte, Juliana Avila; Bristot, Giovana; Scotton, Ellen; Camozzato, Ana Luiza; Chaves, Márcia Lorena Fagundes

    2016-01-01

    Background/Aims Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). Methods Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®. Results MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. Discussion The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction. PMID:28101102

  12. Age-Associated Increase in BMP Signaling Inhibits Hippocampal Neurogenesis.

    Yousef, Hanadie; Morgenthaler, Adam; Schlesinger, Christina; Bugaj, Lukasz; Conboy, Irina M; Schaffer, David V

    2015-05-01

    Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, although evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone morphogenetic protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline.

  13. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice.

    Ramírez-Rodríguez, Gerardo; Vega-Rivera, Nelly Maritza; Oikawa-Sala, Julián; Gómez-Sánchez, Ariadna; Ortiz-López, Leonardo; Estrada-Camarena, Erika

    2014-05-01

    Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (29%), survival (>39%), and the absolute number of -associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

  14. Updating the Lamellar Hypothesis of Hippocampal Organization

    Robert S Sloviter; Terje eLømo

    2012-01-01

    In 1971, Andersen and colleagues proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a trisynaptic circuit lying within transverse hippocampal slices or lamellae [Andersen, Bliss, and Skrede. 1971. Lamellar organization of hippocampal pathways. Exp Brain Res 13, 222-238]. In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly i...

  15. Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin.

    Yau, Suk Yu; Li, Ang; Hoo, Ruby L C; Ching, Yick Pang; Christie, Brian R; Lee, Tatia M C; Xu, Aimin; So, Kwok-Fai

    2014-11-04

    Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood-brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exercise-induced reduction in depression-like behaviors was abrogated in ADN-deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression.

  16. Role of dorsal hippocampal orexin-1 receptors in associating morphine reward with contextual stimuli.

    Riahi, Esmail; Khodagholi, Fariba; Haghparast, Abbas

    2013-08-01

    In this study, we evaluated the role of orexin receptors in the dorsal hippocampus (dHPC) in the development of morphine-induced conditioned place preference (CPP) and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels. Orexin-A (0.5, 5, and 50 pmol) and the orexin-1 receptor antagonist, SB334867 (10, 20, and 40 nmol), were bilaterally infused into the dHPC immediately before conditioning with morphine (0.5 or 7.5 mg/kg) using the CPP task. Western blotting was then used to measure the protein levels of c-Fos, total CREB, and phosphorylated CREB (pCREB) in the hippocampus. Orexin did not enhance the rewarding efficacy of morphine (0.5 mg/kg), but caused a reduction in hippocampal c-Fos. Successful conditioning with morphine (7.5 mg/kg) was associated with increased levels of hippocampal c-Fos and CREB, but with decreased CREB phosphorylation. Intrahippocampal administration of SB334867 before conditioning sessions disrupted the rewarding effect of morphine (7.5 mg/kg) and blocked morphine-induced increases in hippocampal CREB protein levels. The results suggest that orexin signaling within the dHPC is necessary for the development of morphine CPP. Morphine reward is related to altered levels of hippocampal c-Fos and CREB. Inhibition of morphine-induced increases in CREB levels might be the underlying mechanism for the disruption of morphine CPP.

  17. Noradrenergic mechanism involved in the nociceptive modulation of hippocampal CA3 region of normal rats.

    Jin, Hua; Teng, Yueqiu; Zhang, Xuexin; Yang, Chunxiao; Xu, Manying; Yang, Lizhuang

    2014-06-27

    Norepinephrine (NE) is an important neurotransmitter in the brain, and regulates antinociception. However, the mechanism of action of NE on pain-related neurons in the hippocampal CA3 region is not clear. This study examines the effects of NE, phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of rats. Trains of electric impulses applied to the right sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in the hippocampal CA3 region were recorded by using a glass microelectrode. Our results revealed that, in the hippocampal CA3 region, the intra-CA3 region microinjection of NE decreased the pain-evoked discharged frequency and prolonged the discharged latency of PEN, and increased the pain-evoked discharged frequency and shortened discharged inhibitory duration (ID) of PIN, exhibiting the specific analgesic effect of NE. While intra-CA3 region microinjection of phentolamine produced the opposite response. It implies that phentolamine can block the effect of endogenous NE to cause the enhanced response of PEN and PIN to noxious stimulation. On the basis of above findings we can deduce that NE, phentolamine and alpha-adrenoceptor are involved in the modulation of nociceptive information transmission in the hippocampal CA3 region.

  18. Apoptosis and autophagy control cell proliferation in the dentate gyrus following hippocampal lesion

    Ju Zhou; Wei Peng; Qi Zhu; Shan Gong; Lidong Shan; Tadashi Hisamitsu; Shiyu Guo; Xinghong Jiang

    2010-01-01

    Brain injuries often result in the promotion of cell proliferation in the hippocampal dentate gyrus(DG),but the number of newborn cells declines with time.However,the cause of this decline remains poorly understood.Elucidation of the fate of these newborn cells will further the understanding of the pathological process and treatment of brain injury.In the present study,the number of newborn cells was quantitatively analyzed using an unbiased stereological method following hippocampal lesion by kainic acid,in combination with detection of apoptosis and autophagy.Results revealed that hippocampal lesion resulted in a significantly increased number of 5-bromo-2-deoxyuridine(BrdU)-positive cells in the DG,which subsequently decreased with time.BrdU/cleaved caspase-3 double-labeled cells were detected in the granular cell layer and hilus of DG.However,expressions of LC3-11,Beclin 1,and p53 were upregulated,and pro-caspase-3 and Bcl-2 were downregulated.Results indicated that hippocampal lesion in adult rats resulted in significant cell proliferation in the DG,which subsequently reduced with time.In addition,results suggested that apoptosis and autophagic processes could regulate cell proliferation in the DG following hippocampal lesion.

  19. Chrysophanol attenuates lead exposure-induced injury to hippocampal neurons in neonatal mice

    Ji Zhang; Chunlin Yan; Shu Wang; Yong Hou; Guiping Xue; Li Zhang

    2014-01-01

    Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrys-ophanol can alleviate learning and memory dysfunction and hippocampal neuronal injury in lead-exposed neonatal mice. At the end of lactation, chrysophanol (0.1, 1.0, 10.0 mg/kg) was administered to the neonatal mice by intraperitoneal injection for 15 days. Chrysophanol signifi-cantly alleviated injury to hippocampal neurons and improved learning and memory abilities in the lead-poisoned neonatal mice. Chrysophanol also significantly decreased lead content in blood, brain, heart, spleen, liver and kidney in the lead-exposed neonatal mice. The levels of malondialdehyde in the brain, liver and kidney were significantly reduced, and superoxide dismutase and glutathione peroxidase activities were significantly increased after chrysophanol treatment. Collectively, these findings indicate that chrysophanol can significantly reduce damage to hippocampal neurons in lead-exposed neonatal mice.

  20. Inhibition of TYRO3/Akt signaling participates in hypoxic injury in hippocampal neurons

    Yan-zhen Zhu; Wei Wang; Na Xian; Bing Wu

    2016-01-01

    In this study, we investigated the role of the TYRO3/Akt signaling pathway in hypoxic injury to hippocampal neurons. 3-(4,5-Dimethylth-iazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that hypoxia inhibited the proliferation and viability of hippocampal neurons. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay demonstrated that hypoxia induced neuronal apoptosis in a time-dependent manner, with a greater number of apoptotic cells with longer hypoxic exposure. Immunolfuorescence labeling revealed that hypoxia suppressed TYRO3 expression. Western blot assay showed that hypoxia decreased Akt phosphorylation levels in a time-de-pendent manner. Taken together, these ifndings suggest that hypoxia inhibits the proliferation of hippocampal neurons and promotes apoptosis, and that the inhibition of the TYRO3/Akt signaling pathway plays an important role in hypoxia-induced neuronal injury.

  1. Comparison of mesencephalic free-floating tissue culture grafts and cell suspension grafts in the 6-hydroxydopamine-lesioned rat

    Meyer, Morten; Widmer, H R; Wagner, B;

    1998-01-01

    . The amphetamine-induced rotational behavior of all 6-OHDA-lesioned animals was monitored at various time points from 18 days before transplantation and up to 80 days after transplantation. Tyrosine hydroxylase (TH) immunostaining of the histologically processed brains served to assess the long-term survival...... improvements in terms of significant reductions in amphetamine-induced rotations were observed in rats grafted with FFRT cultures (127%) and rats grafted with cell suspensions (122%), while control animals showed no normalization of rotational behavior. At 84 days after transplantation, there were similar...

  2. Fate of (D-Ala2-deltorphin-I-like immunoreactive neurons in 6-hydroxydopamine lesioned rat brain

    A Casini

    2009-06-01

    Full Text Available The use of a polyclonal antiserum specific to C-terminal tetrapeptide amide of (D-Ala2deltorphin-I, a naturally occurring amphibian skin opioid peptide, has already demonstrated the presence of immunoreactive neurons in rat midbrain. Double immunostaining identified these neurons as a subpopulation of the mesencephalic dopaminergic neurons that were also tyrosine hydroxylase-immunopositive and calbindin- D28kD- negative, namely, the neurons predominantly affected in Parkinson disease. We followed the fate of these neurons after a monolateral injection of 6-hydroxy-dopamine into rat brain. Almost all the immunopositive neurons and their nigrostriatal, mesolimbic and mesocortical projections on the side ipsilateral to the lesion disappeared. Only a few scattered immunopositive neurons within the substantia nigra, pars compacta, and those of supramammillary nucleus remained unaffected. The consistent overlap of dopamine and this new molecule provides a further key to identifying the mammalian counterpart of these amphibian skin opioid peptides.

  3. Treatment with a substance P receptor antagonist is neuroprotective in the intrastriatal 6-hydroxydopamine model of early Parkinson's disease.

    Emma Thornton

    Full Text Available Neuroinflammation and blood brain barrier (BBB dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD. The neuropeptide substance P (SP is an important mediator of both neuroinflammation and BBB dysfunction through its NK1 receptor in a process known as neurogenic inflammation. Increased SP content has previously been reported following 6-OHDA treatment in vitro, with the levels of SP correlating with cell death. The present study used an in vivo 6-OHDA lesion model to determine if dopaminergic degeneration was associated with increased SP in the substantia nigra and whether this degeneration could be prevented by using a SP, NK1 receptor antagonist. Unilateral, intrastriatal 6-OHDA lesions were induced and SP (10 µg/2 µL or the NK1 receptor antagonists, N-acetyl-L-tryptophan (2 µL at 50 nM or L-333,060 (2 µL at 100 nM, administered immediately after the neurotoxin. Nigral SP content was then determined using immunohistochemical and ELISA methods, neuroinflammation and barrier integrity was assessed using Iba-1, ED-1, GFAP and albumin immunohistochemistry, while dopaminergic cell loss was assessed with tyrosine hydroxylase immunohistochemistry. Motor function in all animals was assessed using the rotarod task. Intrastriatal 6-OHDA lesioning produced an early and sustained increase in ipsilateral nigral SP content, along with a breakdown of the BBB and activation of microglia and astrocytes. Further exacerbation of SP levels accelerated disease progression, whereas NK1 receptor antagonist treatment protected dopaminergic neurons, preserved barrier integrity, reduced neuroinflammation and significantly improved motor function. We propose that neurogenic inflammation contributes to dopaminergic degeneration in early experimental PD and demonstrate that an NK1 receptor antagonist may represent a novel neuroprotective therapy.

  4. Hippocampal EEG and behaviour in dog. II. Hippocampal EEG correlates with elementary motor acts

    Arnolds, D.E.A.T.; Lopes da Silva, F.H.; Aitink, J.W.; Kamp, A.

    1979-01-01

    A positive correlation has been shown between the speed of forced stepping on a conveyor belt and the amplitude and frequency of the concomitant hippocampal EEG. Significant modulation in the spectral properties of the dog's hippocampal EEG has been found in relation to 3 elementary motor acts: ste

  5. Dynamics and heterogeneity of bovine hippocampal membranes: role of cholesterol and proteins.

    Mukherjee, Soumi; Kombrabail, Mamata; Krishnamoorthy, G; Chattopadhyay, Amitabha

    2007-09-01

    The structural and dynamic consequence of alterations in membrane lipid composition (specifically cholesterol) in neuronal membranes is poorly understood. Previous work from our laboratory has established bovine hippocampal membranes as a convenient natural source for studying neuronal receptors. In this paper, we have explored the role of cholesterol and proteins in the dynamics and heterogeneity of bovine hippocampal membranes using fluorescence lifetime distribution analysis of the environment-sensitive fluorescent probe Nile Red incorporated into such membranes by the maximum entropy method (MEM), and time-resolved fluorescence anisotropy measurements. The peak position and the width of the lifetime distribution of Nile Red show a progressive reduction with increasing cholesterol depletion from native hippocampal membranes indicating that the extent of heterogeneity decreases with decrease in membrane cholesterol content. This is accompanied by a concomitant decrease of the fluorescence anisotropy and rotational correlation time. Our results point out that the microenvironment experienced by Nile Red is relatively insensitive to the presence of proteins in hippocampal membranes. Interestingly, Nile Red lifetime distribution in liposomes of lipid extracts is similar to that of native membranes indicating that proteins do not contribute significantly to the high level of heterogeneity observed in native membranes. These results could be relevant in understanding the neuronal diseases characterized by defective membrane lipid metabolism.

  6. Hippocampal atrophy rates in Alzheimer disease

    Henneman, W J.P.; Sluimer, J D.; Barnes, J; van der Flier, W M.; Sluimer, I C.; Fox, N C.; Scheltens, P; Vrenken, H; Barkhof, F

    2009-01-01

    Objective: To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls. Methods: We included 64 patients with AD (67 ± 9 years; F/M 38/26), 44 patients with MCI (71 ± 6 years; 21/23), and 34 controls (67 ± 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 ± 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools. Results: All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5–22.2]), hippocampal atrophy rate (5.2 [1.9–14.3]), and whole brain atrophy rate (2.8 [1.1–7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1–606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression. Conclusion: Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD. GLOSSARY AD = Alzheimer disease; BET = brain

  7. Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats.

    Wu, Zhong-Min; Yang, Li-Hua; Cui, Rong; Ni, Gui-Lian; Wu, Feng-Tian; Liang, Yong

    2017-05-01

    One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT3 receptor in the development of PTSD, even though 5-HT3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.

  8. Treadmill Exercise Induces Hippocampal Astroglial Alterations in Rats

    Caren Bernardi

    2013-01-01

    Full Text Available Physical exercise effects on brain health and cognitive performance have been described. Synaptic remodeling in hippocampus induced by physical exercise has been described in animal models, but the underlying mechanisms remain poorly understood. Changes in astrocytes, the glial cells involved in synaptic remodeling, need more characterization. We investigated the effect of moderate treadmill exercise (20 min/day for 4 weeks on some parameters of astrocytic activity in rat hippocampal slices, namely, glial fibrillary acidic protein (GFAP, glutamate uptake and glutamine synthetase (GS activities, glutathione content, and S100B protein content and secretion, as well as brain-derived neurotrophic factor (BDNF levels and glucose uptake activity in this tissue. Results show that moderate treadmill exercise was able to induce a decrease in GFAP content (evaluated by ELISA and immunohistochemistry and an increase in GS activity. These changes could be mediated by corticosterone, whose levels were elevated in serum. BDNF, another putative mediator, was not altered in hippocampal tissue. Moreover, treadmill exercise caused a decrease in NO content. Our data indicate specific changes in astrocyte markers induced by physical exercise, the importance of studying astrocytes for understanding brain plasticity, as well as reinforce the relevance of physical exercise as a neuroprotective strategy.

  9. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour.

    Snyder, Jason S; Soumier, Amélie; Brewer, Michelle; Pickel, James; Cameron, Heather A

    2011-08-03

    Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

  10. Hippocampal place cells, context, and episodic memory.

    Smith, David M; Mizumori, Sheri J Y

    2006-01-01

    Although most observers agree that the hippocampus has a critical role in learning and memory, there remains considerable debate about the precise functional contribution of the hippocampus to these processes. Two of the most influential accounts hold that the primary function of the hippocampus is to generate cognitive maps and to mediate episodic memory processes. The well-documented spatial firing patterns (place fields) of hippocampal neurons in rodents, along with the spatial learning impairments observed with hippocampal damage support the cognitive mapping hypothesis. The amnesia for personally experienced events seen in humans with hippocampal damage and the data of animal models, which show severe memory deficits associated with hippocampal lesions, support the episodic memory account. Although an extensive literature supports each of these hypotheses, a specific contribution of place cells to episodic memory has not been clearly demonstrated. Recent data from our laboratory, together with previous findings, indicate that hippocampal place fields and neuronal responses to task-relevant stimuli are highly sensitive to the context, even when the contexts are defined by abstract task demands rather than the spatial geometry of the environment. On the basis of these findings, it is proposed that place fields reflect a more general context processing function of the hippocampus. Hippocampal context representations could serve to differentiate contexts and prime the relevant memories and behaviors. Since episodic memories, by definition, include information about the time and place where the episode occurred, contextual information is a necessary prerequisite for any episodic memory. Thus, place fields contribute importantly to episodic memory as part of the needed context representations. Additionally, recent findings indicate that hippocampal neurons differentiate contexts at progressively finer levels of detail, suggesting a hierarchical coding scheme which

  11. A Hopfield-like hippocampal CA3 neural network model for studying associative memory in Alzheimer's disease

    Wangxiong Zhao; Qingli Qiao; Dan Wang

    2010-01-01

    Associative memory, one of the major cognitive functions in the hippocampal CA3 region, includes auto-associative memory and hetero-associative memory. Many previous studies have shown that Alzheimer's disease (AD) can lead to loss of functional synapses in the central nervous system, and associative memory functions in patients with AD are often impaired, but few studies have addressed the effect of AD on hetero-associative memory in the hippocampal CA3 region. In this study, based on a simplified anatomical structure and synaptic connections in the hippocampal CA3 region, a three-layered Hopfield-like neural network model of hippocampal CA3 was proposed and then used to simulate associative memory functions in three circumstances: normal, synaptic deletion and synaptic compensation, according to Ruppin's synaptic deletion and compensation theory. The influences of AD on hetero-associative memory were further analyzed. The simulated results showed that the established three-layered Hopfield-like neural network model of hippocampal CA3 has both auto-associative and hetero-associative memory functions. With increasing synaptic deletion level, both associative memory functions were gradually impaired and the mean firing rates of the neurons within the network model were decreased. With gradual increasing synaptic compensation, the associative memory functions of the network were improved and the mean firing rates were increased. The simulated results suggest that the Hopfield-like neural network model can effectively simulate both associative memory functions of the hippocampal CA3 region. Synaptic deletion affects both auto-associative and hetero-associative memory functions in the hippocampal CA3 region, and can also result in memory dysfunction. To some extent, synaptic compensation measures can offset two kinds of associative memory dysfunction caused by synaptic deletion in the hippocampal CA3 area.

  12. Intervention effects of ganoderma lucidum spores on epileptiform discharge hippocampal neurons and expression of neurotrophin-4 and N-cadherin.

    Shu-Qiu Wang

    Full Text Available Epilepsy can cause cerebral transient dysfunctions. Ganoderma lucidum spores (GLS, a traditional Chinese medicinal herb, has shown some antiepileptic effects in our previous studies. This was the first study of the effects of GLS on cultured primary hippocampal neurons, treated with Mg(2+ free medium. This in vitro model of epileptiform discharge hippocampal neurons allowed us to investigate the anti-epileptic effects and mechanism of GLS activity. Primary hippocampal neurons from <1 day old rats were cultured and their morphologies observed under fluorescence microscope. Neurons were confirmed by immunofluorescent staining of neuron specific enolase (NSE. Sterile method for GLS generation was investigated and serial dilutions of GLS were used to test the maximum non-toxic concentration of GLS on hippocampal neurons. The optimized concentration of GLS of 0.122 mg/ml was identified and used for subsequent analysis. Using the in vitro model, hippocampal neurons were divided into 4 groups for subsequent treatment i control, ii model (incubated with Mg(2+ free medium for 3 hours, iii GLS group I (incubated with Mg(2+ free medium containing GLS for 3 hours and replaced with normal medium and incubated for 6 hours and iv GLS group II (neurons incubated with Mg(2+ free medium for 3 hours then replaced with a normal medium containing GLS for 6 hours. Neurotrophin-4 and N-Cadherin protein expression were detected using Western blot. The results showed that the number of normal hippocampal neurons increased and the morphologies of hippocampal neurons were well preserved after GLS treatment. Furthermore, the expression of neurotrophin-4 was significantly increased while the expression of N-Cadherin was decreased in the GLS treated group compared with the model group. This data indicates that GLS may protect hippocampal neurons by promoting neurotrophin-4 expression and inhibiting N-Cadherin expression.

  13. Developmental changes in hippocampal associative coding.

    Goldsberry, Mary E; Kim, Jangjin; Freeman, John H

    2015-03-11

    Behavioral analyses of the ontogeny of memory have shown that hippocampus-dependent learning emerges relatively late in postnatal development compared with simple associative learning. Maturation of hippocampal mnemonic mechanisms has been hypothesized to underlie the development of the later emerging learning processes. However, the role of hippocampal maturation in learning has not been examined directly. The goal of the present study was to examine developmental changes in hippocampal neuronal coding during acquisition of a hippocampus-dependent learning task. We recorded activity from CA1 pyramidal cells in rat pups while they were trained on trace eyeblink conditioning. Trace eyeblink conditioning is a Pavlovian conditioning task that involves the association of a conditioned stimulus (CS) with an unconditioned stimulus over a stimulus-free trace interval. The inclusion of the trace interval is what makes the task hippocampus dependent. In the present study, rats were trained at 21-23, 24-26, and 31-33 d of age. Previous research from our laboratory and others shows that trace conditioning begins to emerge during the third postnatal week. The results indicate that hippocampal neurons show a substantial increase in responsiveness to task-relevant events during development. Moreover, there is an age-related increase in the proportion of neurons that respond to a combination of trial events (e.g., CS and trace). Our findings indicate that the developmental emergence of hippocampally mediated learning is related to increases in the strength and complexity of CA1 associative coding.

  14. Regional hippocampal volumes and development predict learning and memory.

    Tamnes, Christian K; Walhovd, Kristine B; Engvig, Andreas; Grydeland, Håkon; Krogsrud, Stine K; Østby, Ylva; Holland, Dominic; Dale, Anders M; Fjell, Anders M

    2014-01-01

    The hippocampus is an anatomically and functionally heterogeneous structure, but longitudinal studies of its regional development are scarce and it is not known whether protracted maturation of the hippocampus in adolescence is related to memory development. First, we investigated hippocampal subfield development using 170 longitudinally acquired brain magnetic resonance imaging scans from 85 participants aged 8-21 years. Hippocampal subfield volumes were estimated by the use of automated segmentation of 7 subfields, including the cornu ammonis (CA) sectors and the dentate gyrus (DG), while longitudinal subfield volumetric change was quantified using a nonlinear registration procedure. Second, associations between subfield volumes and change and verbal learning/memory across multiple retention intervals (5 min, 30 min and 1 week) were tested. It was hypothesized that short and intermediate memory would be more closely related to CA2-3/CA4-DG and extended, remote memory to CA1. Change rates were significantly different across hippocampal subfields, but nearly all subfields showed significant volume decreases over time throughout adolescence. Several subfield volumes were larger in the right hemisphere and in males, while for change rates there were no hemisphere or sex differences. Partly in support of the hypotheses, greater volume of CA1 and CA2-3 was related to recall and retention after an extended delay, while longitudinal reduction of CA2-3 and CA4-DG was related to learning. This suggests continued regional development of the hippocampus across adolescence and that volume and volume change in specific subfields differentially predict verbal learning and memory over different retention intervals, but future high-resolution studies are called for.

  15. Antenatal glucocorticoid treatment affects hippocampal development in mice.

    Cornelle W Noorlander

    Full Text Available Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

  16. Antenatal glucocorticoid treatment affects hippocampal development in mice.

    Noorlander, Cornelle W; Tijsseling, Deodata; Hessel, Ellen V S; de Vries, Willem B; Derks, Jan B; Visser, Gerard H A; de Graan, Pierre N E

    2014-01-01

    Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

  17. Differential response of hippocampal subregions to stress and learning.

    Darby F Hawley

    Full Text Available The hippocampus has two functionally distinct subregions-the dorsal portion, primarily associated with spatial navigation, and the ventral portion, primarily associated with anxiety. In a prior study of chronic unpredictable stress (CUS in rodents, we found that it selectively enhanced cellular plasticity in the dorsal hippocampal subregion while negatively impacting it in the ventral. In the present study, we determined whether this adaptive plasticity in the dorsal subregion would confer CUS rats an advantage in a spatial task-the radial arm water maze (RAWM. RAWM exposure is both stressful and requires spatial navigation, and therefore places demands simultaneously upon both hippocampal subregions. Therefore, we used Western blotting to investigate differential expression of plasticity-associated proteins (brain derived neurotrophic factor [BDNF], proBDNF and postsynaptic density-95 [PSD-95] in the dorsal and ventral subregions following RAWM exposure. Lastly, we used unbiased stereology to compare the effects of CUS on proliferation, survival and neuronal differentiation of cells in the dorsal and ventral hippocampal subregions. We found that CUS and exposure to the RAWM both increased corticosterone, indicating that both are stressful; nevertheless, CUS animals had significantly better long-term spatial memory. We also observed a subregion-specific pattern of protein expression following RAWM, with proBDNF increased in the dorsal and decreased in the ventral subregion, while PSD-95 was selectively upregulated in the ventral. Finally, consistent with our previous study, we found that CUS most negatively affected neurogenesis in the ventral (compared to the dorsal subregion. Taken together, our data support a dual role for the hippocampus in stressful experiences, with the more resilient dorsal portion undergoing adaptive plasticity (perhaps to facilitate escape from or neutralization of the stressor, and the ventral portion involved in

  18. Zinc chelation reduces hippocampal neurogenesis after pilocarpine-induced seizure.

    Jin Hee Kim

    Full Text Available Several studies have shown that epileptic seizures increase hippocampal neurogenesis in the adult. However, the mechanism underlying increased neurogenesis after seizures remains largely unknown. Neurogenesis occurs in the subgranular zone (SGZ of the hippocampus in the adult brain, although an understanding of why it actively occurs in this region has remained elusive. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ. Previously, we demonstrated that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia. Using a lithium-pilocarpine model, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after seizure. Then, we injected the zinc chelator, clioquinol (CQ, 30 mg/kg, into the intraperitoneal space to reduce brain zinc availability. Neuronal death was detected with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after seizure. The total number of degenerating and live neurons was similar in vehicle and in CQ treated rats at 1 week after seizure. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX immunostaining 1 week after seizure. The number of BrdU, Ki67 and DCX positive cell was increased after seizure. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. Intracellular zinc chelator, N,N,N0,N-Tetrakis (2-pyridylmethyl ethylenediamine (TPEN, also reduced seizure-induced neurogenesis in the hippocampus. The present study shows that zinc chelation does not prevent neurodegeneration but does reduce seizure-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal neurogenesis after seizure.

  19. Growth hormone rescues hippocampal synaptic function after sleep deprivation

    Kim, EunYoung; Grover, Lawrence M; Bertolotti, Don; Green, Todd L.

    2010-01-01

    Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-d-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone l...

  20. Effects of diazepam on glutamatergic synaptic transmission in the hippocampal CA1 area of rats with traumatic brain injury.

    Cao, Lei; Bie, Xiaohua; Huo, Su; Du, Jubao; Liu, Lin; Song, Weiqun

    2014-11-01

    The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after fluid percussion injury. Diazepam can inhibit the hyperexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment significantly increased the slope of input-output curves in rat neurons after fluid percussion injury. Diazepam significantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 μmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the fluid percussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area.

  1. Effects of diazepam on glutamatergic synaptic transmission in the hippocampal CA1 area of rats with traumatic brain injury

    Lei Cao; Xiaohua Bie; Su Huo; Jubao Du; Lin Liu; Weiqun Song

    2014-01-01

    The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after lfuid percussion injury. Diazepam can inhibit the hy-perexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment signiifcantly increased the slope of input-output curves in rat neurons after lfuid per-cussion injury. Diazepam signiifcantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 μmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the lfuid per-cussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area.

  2. Time window characteristics of cultured rat hippocampal neurons subjected to ischemia and reperfusion

    XU Zhong; XU Ru-xiang; LIU Bao-song; JIANG Xiao-dan; HUANG Tao; DING Lian-shu; YUAN Jun

    2005-01-01

    Objective: To explore cell death and apoptosis in rat hippocampal neurons at different time points after ischemia, hypoxia and reperfusion injury and to elucidate time window characteristics in ischemia neuronal injury.Methods: Hippocampal neurons were obtained from rat embryo and were cultured in vitro. The ischemia and reperfusion of cultured rat hippocampal neurons were simulated by oxygen-glucose deprivation (OGD) and recovery. OGD at different time points (0.25 h to 3.0 h) and then the same recovery (24 h) were prepared. Annexin V-PI staining and flow cytometry examined neuron death and apoptosis at different time after injury. Results: After OGD and recovery, both necrosis and apoptosis were observed. At different times after OGD, there were statistically significant differences in neuron necrosis rate (P0.05). At recovery, survival rate of hippocampal neurons further decreased while apoptosis rate increased. Furthermore, apoptosis rates of different time differed greatly (P<0.05). Apoptosis rate gradually increased with significant difference among those of different time points (P<0.05). However, 2 h after ischemia, apoptosis rate decreased markedly.Conclusions: Apoptosis is an important pathway of delayed neuron death. The therapeutic time window should be within 2 h after cerebral ischemia and hypoxia.

  3. A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis

    Xiqing Chai; Weina Kong; Lingyun Liu; Wenguo Yu; Zhenqing Zhang; Yimin Sun

    2014-01-01

    Hypoxia-inducible factor 1 (HIF-1) attenuates amyloid-beta protein neurotoxicity and decreases apoptosis induced by oxidative stress or hypoxia in cortical neurons. In this study, we construct-ed a recombinant adeno-associated virus (rAAV) vector expressing the human HIF-1αgene (rAAV-HIF-1α), and tested the assumption that rAAV-HIF-1αrepresses hippocampal neuronal apoptosis induced by amyloid-beta protein. Our results conifrmed that rAAV-HIF-1αsigniifcant-ly reduces apoptosis induced by amyloid-beta protein in primary cultured hippocampal neurons. Direct intracerebral rAAV-HIF-1αadministration also induced robust and prolonged HIF-1αproduction in rat hippocampus. Single rAAV-HIF-1αadministration resulted in decreased apoptosis of hippocampal neurons in an Alzheimer’s disease rat model established by intrace-rebroventricular injection of aggregated amyloid-beta protein (25-35). Our in vitro and in vivo ifndings demonstrate that HIF-1 has potential for attenuating hippocampal neuronal apoptosis induced by amyloid-beta protein, and provides experimental support for treatment of neurode-generative diseases using gene therapy.

  4. Dissociation of dorsal hippocampal regional activation under the influence of stress in freely behaving rats

    Johannes ePassecker

    2011-10-01

    Full Text Available Stress has deleterious effects on brain, body and behaviour in humans and animals alike. The present work investigated how 30-minute acute photic stress exposure impacts on spatial information processing in the main subregions of the dorsal hippocampal formation (CA1, CA3 and Dentate Gyrus, a brain structure prominently implicated in memory and spatial representation. Recordings were performed from spatially tuned hippocampal and dentate gyrus cells in rats while animals foraged in a square arena for food. The stress procedure induced a decrease in firing frequencies in CA1 and CA3 place cells while sparing locational characteristics. In contrast to the CA1-CA3 network, acute stress failed to induce major changes in the DG neuronal population. These data demonstrate a clear dissociation of the effects of stress on the main hippocampal sub-regions. Our findings further support the notion of decreased hippocampal excitability arising from stress in areas CA1 and CA3, but not in dentate gyrus.

  5. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Yun-fengLI; You-zhiZHANG; Yan-qinLIU; Heng-linWANG; LiYUAN; Zhi-puLUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC 12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μnol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40 mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  6. Chronic stress impairs learning and hippocampal cell proliferation in senescence-accelerated prone mice.

    Yan, Weihong; Zhang, Ting; Jia, Weiping; Sun, Xiaojiang; Liu, Xueyuan

    2011-02-25

    Chronic stress can induce cognitive impairment. It is unclear whether a higher susceptibility to chronic stress is associated with the progression of pathological brain aging. Senescence-accelerated prone mouse 8 (SAMP8) is a naturally occurring animal model of accelerated brain aging. Senescence-accelerated resistant mouse 1 (SAMR1) is usually used as the normal control. In this study, we examined the effects of chronic restraint stress (CRS) on learning in the Y-maze, hippocampal cell proliferation, and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of 4-month-old SAMP8 and SAMR1. The results showed that exposure to CRS impaired learning and hippocampal cell proliferation in SAMP8 and SAMR1 but to a much greater extent in SAMP8. Furthermore, CRS significantly decreased the expression of BDNF protein and mRNA in the hippocampus of SAMP8 and SAMR1. These data indicated that SAMP8 is more sensitive to the deleterious effects of CRS on learning than SAMR1. A greater decrease in hippocampal cell proliferation caused by chronic stress may be part of the underlying mechanism for the more severe learning deficit observed in SAMP8. In addition, our findings suggested a role of BDNF in the stress-induced impairment of learning and hippocampal cell proliferation in both strains.

  7. Effects of GSM 1800 MHz on dendritic development of cultured hippo-campal neurons

    Wei NING; Shu-jun XU; Huai CHIANG; Zheng-ping XU; Su-ya ZHOU; Wei YANG; Jian-hong LUO

    2007-01-01

    Aim: To evaluate the effects of global system for mobile communications (GSM)1800 MHz microwaves on dendritic filopodia, dendritic arborization, and spine maturation during development in cultured hippocampal neurons in rats. Methods: The cultured hippocampal neurons were exposed to GSM 1800 MHz microwaves with 2.4 and 0.8 W/kg, respectively, for 15 min each day from 6 days in vitro (DIV6) to DIV14. The subtle structures of dendrites were displayed by transfection with farnesylated enhanced green fluorescent protein (F-GFP) and GFP-actin on DIV5 into the hippocampal neurons. Results: There was a significant decrease in the density and mobility of dendritic filopodia at DIV8 and in the density of mature spines at DIV14 in the neurons exposed to GSM 1800 MHz microwaves with 2.4 W/kg. In addition, the average length of dendrites per neuron at DIV10 and DIV14 was decreased, while the dendritic arborization was unaltered in these neurons. However, there were no significant changes found in the neurons ex- posed to the GSM 1800 MHz microwaves with 0.8 W/kg. Conclusion: These data indicate that the chronic exposure to 2.4 W/kg GSM 1800 MHz micro- waves during the early developmental stage may affect dendritic development and the formation of excitatory synapses of hippocampal neurons in culture.

  8. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Yun-feng LI; You-zhi ZHANG; Yan-qin LIU; Heng-lin WANG; Li YUAN; Zhi-pu LUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μmol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  9. Depressive Symptoms and Small Hippocampal Volume Accelerate the Progression to Dementia from Mild Cognitive Impairment.

    Chung, Jun Ku; Plitman, Eric; Nakajima, Shinichiro; Chakravarty, M Mallar; Caravaggio, Fernando; Takeuchi, Hiroyoshi; Gerretsen, Philip; Iwata, Yusuke; Patel, Raihaan; Mulsant, Benoit H; Graff-Guerrero, Ariel

    2016-01-01

    Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimer's Disease Neuroimaging Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (p = 0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non-converters over the 2-year period (p = 0.003, p = 0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia.

  10. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons.

    Magariños, A M; Li, C J; Gal Toth, J; Bath, K G; Jing, D; Lee, F S; McEwen, B S

    2011-03-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF(±) ) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF(±) mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF(±) mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling.

  11. α2-containing GABAA receptors expressed in hippocampal region CA3 control fast network oscillations.

    Heistek, Tim S; Ruiperez-Alonso, Marta; Timmerman, A Jaap; Brussaard, Arjen B; Mansvelder, Huibert D

    2013-02-15

    GABA(A) receptors are critically involved in hippocampal oscillations. GABA(A) receptor α1 and α2 subunits are differentially expressed throughout the hippocampal circuitry and thereby may have distinct contributions to oscillations. It is unknown which GABA(A) receptor α subunit controls hippocampal oscillations and where these receptors are expressed. To address these questions we used transgenic mice expressing GABA(A) receptor α1 and/or α2 subunits with point mutations (H101R) that render these receptors insensitive to allosteric modulation at the benzodiazepine binding site, and tested how increased or decreased function of α subunits affects hippocampal oscillations. Positive allosteric modulation by zolpidem prolonged decay kinetics of hippocampal GABAergic synaptic transmission and reduced the frequency of cholinergically induced oscillations. Allosteric modulation of GABAergic receptors in CA3 altered oscillation frequency in CA1, while modulation of GABA receptors in CA1 did not affect oscillations. In mice having a point mutation (H101R) at the GABA(A) receptor α2 subunit, zolpidem effects on cholinergically induced oscillations were strongly reduced compared to wild-type animals, while zolpidem modulation was still present in mice with the H101R mutation at the α1 subunit. Furthermore, genetic knockout of α2 subunits strongly reduced oscillations, whereas knockout of α1 subunits had no effect. Allosteric modulation of GABAergic receptors was strongly reduced in unitary connections between fast spiking interneurons and pyramidal neurons in CA3 of α2H101R mice, but not of α1H101R mice, suggesting that fast spiking interneuron to pyramidal neuron synapses in CA3 contain α2 subunits. These findings suggest that α2-containing GABA(A) receptors expressed in the CA3 region provide the inhibition that controls hippocampal rhythm during cholinergically induced oscillations.

  12. Neuromorphic VLSI realization of the hippocampal formation.

    Aggarwal, Anu

    2016-05-01

    The medial entorhinal cortex grid cells, aided by the subicular head direction cells, are thought to provide a matrix which is utilized by the hippocampal place cells for calculation of position of an animal during spatial navigation. The place cells are thought to function as an internal GPS for the brain and provide a spatiotemporal stamp on episodic memories. Several computational neuroscience models have been proposed to explain the place specific firing patterns of the cells of the hippocampal formation - including the GRIDSmap model for grid cells and Bayesian integration for place cells. In this work, we present design and measurement results from a first ever system of silicon circuits which successfully realize the function of the hippocampal formation of brain based on these models.

  13. Localized gene transfer into organotypic hippocampal slice cultures and acute hippocampal slices

    Casaccia-Bonnefil, P; Benedikz, Eirikur; Shen, H;

    1993-01-01

    Viral vectors derived from herpes simplex virus, type-1 (HSV), can transfer and express genes into fully differentiated, post-mitotic neurons. These vectors also transduce cells effectively in organotypic hippocampal slice cultures. Nanoliter quantities of a virus stock of HSVlac, an HSV vector...... or hippocampal slices. The rapid expression of beta-gal by HSVlac allowed efficient transduction of acute hippocampal slices. Many genes have been transduced and expressed using HSV vectors; therefore, this microapplication method can be applied to many neurobiological questions....

  14. Adult hippocampal neurogenesis and cognitive aging

    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.

  15. Age-related changes of NGF, BDNF, parvalbumin and neuronal nitric oxide synthase immunoreactivity in the mouse hippocampal CA1 sector.

    Hayakawa, Natsumi; Abe, Manami; Eto, Risa; Kato, Hiroyuki; Araki, Tsutomu

    2008-06-01

    We investigated the age-related alterations in nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), parvalbumin and neuronal nitric oxide synthase (nNOS) immunoreactivity of the mouse hippocampal CA1 sector. NGF and BDNF immunoreactivity was unchanged in the hippocampal CA1 pyramidal neurons from 2 to 50-59 weeks of birth. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector from 40-42 to 50-59 weeks of birth. On the other hand, the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. Our results indicate that NGF and BDNF immunoreactivity was unaltered in the hippocampal CA1 pyramidal neurons during aging processes. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector during aging processes. The present study also shows that the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. These results demonstrate that the expression of glial NGF and BDNF may play a key role for helping survival and maintenance of pyramidal neurons and neuronal functions in the hippocampal CA1 sector during aging processes. Furthermore, our findings suggest that parvalbumin- and nNOS-positive interneurons in the hippocampal CA1 sector are resistant to aging processes. Moreover, our findings suggest that nitric oxide synthesized by the nNOS may play some role for neuronal growth during postnatal development.

  16. Rat hippocampal GABAergic molecular markers are differentially affected by ageing.

    Vela, José; Gutierrez, Antonia; Vitorica, Javier; Ruano, Diego

    2003-04-01

    We previously reported that the pharmacological properties of the hippocampal GABAA receptor and the expression of several subunits are modified during normal ageing. However, correlation between these post-synaptic modifications and pre-synaptic deficits were not determined. To address this issue, we have analysed the mRNA levels of several GABAergic molecular markers in young and old rat hippocampus, including glutamic acid decarboxylase enzymes, parvalbumin, calretinin, somatostatin, neuropeptide Y and vasoactive intestinal peptide (VIP). There was a differential age-related decrease in these interneuronal mRNAs that was inversely correlated with up-regulation of the alpha1 GABA receptor subunit. Somatostatin and neuropeptide Y mRNAs were most frequently affected (75% of the animals), then calretinin and VIP mRNAs (50% of the animals), and parvalbumin mRNA (25% of the animals) in the aged hippocampus. This selective vulnerability was well correlated at the protein/cellular level as analysed by immunocytochemistry. Somatostatin interneurones, which mostly innervate principal cell distal dendrites, were more vulnerable than calretinin interneurones, which target other interneurones. Parvalbumin interneurones, which mostly innervate perisomatic domains of principal cells, were preserved. This age-dependent differential reduction of specific hippocampal inteneuronal subpopulations might produce functional alterations in the GABAergic tone which might be compensated, at the post-synaptic level, by up-regulation of the expression of the alpha1 GABAA receptor subunit.

  17. Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents.

    Martin, Mauricio G; Ahmed, Tariq; Korovaichuk, Alejandra; Venero, Cesar; Menchón, Silvia A; Salas, Isabel; Munck, Sebastian; Herreras, Oscar; Balschun, Detlef; Dotti, Carlos G

    2014-05-30

    Cognitive decline is one of the many characteristics of aging. Reduced long-term potentiation (LTP) and long-term depression (LTD) are thought to be responsible for this decline, although the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, which leads to PI3K/Akt phosphorylation. Given that Akt de-phosphorylation is required for glutamate receptor internalization and LTD, we hypothesized that the decrease in cholesterol in neuronal membranes may contribute to the deficits in LTD typical of aging. Here, we show that cholesterol loss triggers p-Akt accumulation, which in turn perturbs the normal cellular and molecular responses induced by LTD, such as impaired AMPA receptor internalization and its reduced lateral diffusion. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Accordingly, cholesterol replenishment in aging animals improves hippocampal-dependent learning and memory in the water maze test.

  18. Enhanced Glutamatergic Synaptic Plasticity in the Hippocampal CA1 Field of Food-Restricted Rats: Involvement of CB1 Receptors.

    Talani, Giuseppe; Licheri, Valentina; Biggio, Francesca; Locci, Valentina; Mostallino, Maria Cristina; Secci, Pietro Paolo; Melis, Valentina; Dazzi, Laura; Carta, Gianfranca; Banni, Sebastiano; Biggio, Giovanni; Sanna, Enrico

    2016-04-01

    The endogenous endocannabinoid system has a crucial role in regulating appetite and feeding behavior in mammals, as well as working memory and reward mechanisms. In order to elucidate the possible role of cannabinoid type-1 receptors (CB1Rs) in the regulation of hippocampal plasticity in animals exposed to food restriction (FR), we limited the availability of food to a 2-h daily period for 3 weeks in Sprague-Dawley rats. FR rats showed a higher long-term potentiation at hippocampal CA1 excitatory synapses with a parallel increase in glutamate release when compared with animals fed ad libitum. FR rats showed a significant increase in the long-term spatial memory determined by Barnes maze. FR was also associated with a decreased inhibitory effect of the CB1R agonist win55,212-2 on glutamatergic field excitatory postsynaptic potentials, together with a decrease in hippocampal CB1R protein expression. In addition, hippocampal brain-derived neurotrophic factor protein levels and mushroom dendritic spine density were significantly enhanced in FR rats. Altogether, our data suggest that alterations of hippocampal CB1R expression and function in FR rats are associated with dendritic spine remodeling and functional potentiation of CA1 excitatory synapses, and these findings are consistent with increasing evidence supporting the idea that FR may improve cognitive functions.

  19. Beyond dizziness: virtual navigation, spatial anxiety and hippocampal volume in bilateral vestibulopathy

    Olympia eKremmyda

    2016-03-01

    Full Text Available Bilateral vestibulopathy (BVP is defined as the impairment or loss of function of either the labyrinths or the eighth nerves. Patients with total BVP due to bilateral vestibular nerve section exhibit difficulties in spatial memory and navigation and show a loss of hippocampal volume. In clinical practice, most patients do not have a complete loss of function but rather an asymmetrical residual functioning of the vestibular system. The purpose of the current study was to investigate navigational ability and hippocampal atrophy in BVP patients with residual vestibular function. Fifteen patients with BVP and a group of age- and gender- matched healthy controls were examined. Self-reported questionnaires on spatial anxiety and wayfinding were used to assess the applied strategy of wayfinding and quality of life. Spatial memory and navigation were tested directly using a virtual Morris Water Maze Task. The hippocampal volume of these two groups was evaluated by voxel-based morphometry. In the patients, the questionnaire showed a higher spatial anxiety and the Morris Water Maze Task a delayed spatial learning performance. MRI revealed a significant decrease in the gray matter mid-hippocampal volume (Left: p = 0.006, Z = 4.58, Right: p < 0.001, Z = 3.63 and posterior parahippocampal volume (Right: p = 0.005, Z = 4.65, Left: p < 0.001, Z = 3.87 compared to those of healthy controls. In addition, a decrease in hippocampal formation volume correlated with a more dominant route-finding strategy. Our current findings demonstrate that even partial bilateral vestibular loss leads to anatomical and functional

  20. Protective roles of heat stress on the neurons in hippocampal CA1 region of mice

    WANG Chunxu; WANG Hanxing

    2007-01-01

    The effects of heat stress on the neurons in hippocampal CA1 region of brain ischemia/reperfusion were explored.The mice were pretreated with heat stress followed by ischemia/reperfusion by clipping bilateral cervical common arteries for 7 min.Mice were divided randomly into four groups as follows:(1)normal control group;(2)heat stress pretreated subsequent to ischemia/reperfusion group (HS/IR);(3)ischemia/reperfusion group(IR);and(4)heat stress group(HS).Animals in the last three groups were subdivided into three subgroups:1 d,4 d,14 d respectively.The Morris water maze was used to test the ability of learning and memorizing,Nissl staining was used to count the average number of survived neurons in hippocampal CA1 region,and immunohistochemistry combined with image analysis system to detect the changes of Microtubule associated protein 2 (MAP-2)expression.The results showed that mice in IR group exhibited increased escape latency when compared with that of normal,HS and HS/IR groups(P<0.01),and the mice in IR group adopted an inefficient search strategy,major in circling and restricted searching manners.Nissl staining results showed a significant reduction in the number of pyramidal neurons in hippocampal CA1 regions in HS/IR and IR groups,with a decrease in IR group(P<0.01).Compared with normal group,the expression of MAP-2 in hippocampal CA1 region obviously decreased in IR group(P<0.05).The present results indicate that heat stress pretreatment can improve the spatial learning and memorizing function through protection to hippocampal neurons.

  1. Decreasing relative risk premium

    Hansen, Frank

    2007-01-01

    such that the corresponding relative risk premium is a decreasing function of present wealth, and we determine the set of associated utility functions. We find a new characterization of risk vulnerability and determine a large set of utility functions, closed under summation and composition, which are both risk vulnerable...... and have decreasing relative risk premium. We finally introduce the notion of partial risk neutral preferences on binary lotteries and show that partial risk neutrality is equivalent to preferences with decreasing relative risk premium...

  2. Influence of BclI C/G (rs41423247) on hippocampal shape and white matter integrity of the parahippocampal cingulum in major depressive disorder.

    Won, Eunsoo; Kang, June; Kim, Aram; Choi, Sunyoung; Han, Kyu-Man; Tae, Woo Suk; Chang, Hun Soo; Son, Kyu Ri; Greenberg, Tsafrir; Joe, Sook-Haeng; Lee, Min-Soo; Ham, Byung-Joo

    2016-10-01

    We investigated the interactive effects of BclI C/G (rs41423247) allelic variants and the diagnosis of major depressive disorder (MDD) on hippocampal shape and integrity of the left parahippocampal subdivision of the cingulum. Fifty-two patients with MDD and 52 healthy controls (HCs) underwent T1-weighted structural magnetic resonance imaging and BclI C/G (rs41423247) genotyping. We analyzed hippocampal shape using the FIRST module of FSL and analyzed white matter (WM) integrity using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS). Significant alterations in left hippocampal shape and decreased fractional anisotropy (FA) values of the left parahippocampal cingulum were observed in MDD patients, compared to HCs. In addition, MDD patients of the BclI minor (G-) allele carrier group showed significant alterations in left hippocampal shape and decreased FA values of the left parahippocampal cingulum compared to BclI minor (G-) allele carrier HCs. No significant differences between diagnostic subgroups of the C/C homozygotes were observed. Our study provides evidence for alterations in hippocampal shape and decreased integrity of the WM region associated with the hippocampus in MDD, and for the possible influence of BclI C/G polymorphism (rs41423247) on hippocampal shape and integrity of the parahippocampal subdivision of the cingulum in depression.

  3. Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl phthalate in male Long Evans rats.

    Catherine A Smith

    Full Text Available Early developmental exposure to di(2-ethylhexyl phthalate (DEHP has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats.

  4. Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl) phthalate in male Long Evans rats.

    Smith, Catherine A; Holahan, Matthew R

    2014-01-01

    Early developmental exposure to di(2-ethylhexyl) phthalate (DEHP) has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats.

  5. Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression

    Zhang, Kuo; Pan, Xing; Wang, Fang; Ma, Jie; Su, Guangyue; Dong, Yingxu; Yang, Jingyu; Wu, Chunfu

    2016-01-01

    Antidepressants increase hippocampal neurogenesis by activating the glucocorticoid receptor (GR), but excessive GR activation impairs hippocampal neurogenesis, suggesting that normal GR function is crucial for hippocampal neurogenesis. Baicalin was reported to regulate the expression of GR and facilitate hippocampal neurogenesis, but the underlying molecular mechanisms are still unknown. In this study, we used the chronic corticosterone (CORT)-induced mouse model of anxiety/depression to assess antidepressant-like effects of baicalin and illuminate possible molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis. We found that oral administration of baicalin (40, 80 or 160 mg/kg) for 4 weeks alleviated several chronic CORT-induced anxiety/depression-like behaviors. Baicalin also increased Ki-67- and DCX-positive cells to restore chronic CORT-induced suppression of hippocampal neurogenesis. Moreover, baicalin normalized the chronic CORT-induced decrease in GR protein levels, the increase in GR nuclear translocation and the increase in GR phosphorylation at Ser203 and Ser211. Finally, chronic CORT exposure increased the level of FK506-binding protein 51 (FKBP5) and of phosphorylated serum- and glucocorticoid-inducible kinase 1 (SGK1) at Ser422 and Thr256, whereas baicalin normalized these changes. Together, our findings suggest that baicalin improves anxiety/depression-like behaviors and promotes hippocampal neurogenesis. We propose that baicalin may normalize GR function through SGK1- and FKBP5-mediated GR phosphorylation. PMID:27502757

  6. Nocturnal Mnemonics: Sleep and Hippocampal Memory Processing

    Jared M. Saletin

    2012-05-01

    Full Text Available As critical as waking brain function is to learning and memory, an established literature now describes an equally important yet complementary role for sleep in information processing. This overview examines the specific contribution of sleep to human hippocampal memory processing; both the detriments caused by a lack of sleep, and conversely, the proactive benefits that develop following the presence of sleep. First, a role for sleep before learning is discussed, preparing the hippocampus for initial memory encoding. Second, a role for sleep after learning is considered, modulating the post-encoding consolidation of hippocampal-dependent memory. Third, a model is outlined in which these encoding and consolidation operations are symbiotically accomplished, associated with specific NREM sleep physiological oscillations. As a result, the optimal network outcome is achieved, increasing hippocampal independence and hence overnight consolidation, while restoring next-day sparse hippocampal encoding capacity for renewed learning ability upon awakening. Finally, emerging evidence is considered suggesting that, unlike previous conceptions, sleep does not universally consolidate all information equally. Instead, and based on explicit as well as motivational cues during initial encoding, sleep executes the discriminatory offline consolidation only of select information. Consequently, sleep promotes the targeted strengthening of some memories while actively forgetting others; a proposal with significant theoretical and clinical ramifications.

  7. Stimulus Configuration, Classical Conditioning, and Hippocampal Function.

    Schmajuk, Nestor A.; DiCarlo, James J.

    1991-01-01

    The participation of the hippocampus in classical conditioning is described in terms of a multilayer network portraying stimulus configuration. A model of hippocampal function is presented, and computer simulations are used to study neural activity in the various brain areas mapped according to the model. (SLD)

  8. Glucocorticoid receptor knockdown and adult hippocampal neurogenesis

    Hooijdonk, Leonarda Wilhelmina Antonia van

    2010-01-01

    The research in this thesis is aimed at the elucidation of the role of the glucocorticoid receptor (GR) in hippocampal neuroplasticity and functioning. To achieve this, we have developed a novel method to specifically knockdown GR in a discrete cell population of the mouse brain. In this thesis I r

  9. Food restriction modifies ultrastructure of hippocampal synapses.

    Babits, Réka; Szőke, Balázs; Sótonyi, Péter; Rácz, Bence

    2016-04-01

    Consumption of high-energy diets may compromise health and may also impair cognition; these impairments have been linked to tasks that require hippocampal function. Conversely, food restriction has been shown to improve certain aspects of hippocampal function, including spatial memory and memory persistence. These diet-dependent functional changes raise the possibility that the synaptic structure underlying hippocampal function is also affected. To examine how short-term food restriction (FR) alters the synaptic structure of the hippocampus, we used quantitative electron microscopy to analyze the organization of neuropil in the CA1 stratum radiatum of the hippocampus in young rats, consequent to reduced food. While four weeks of FR did not modify the density, size, or shape of postsynaptic spines, the synapses established by these spines were altered, displaying increased mean length, and more frequent perforations of postsynaptic densities. That the number of perforated synapses (believed to be an indicator of synaptic enhancement) increased, and that the CA1 spine population had on average significantly longer PSDs suggests that synaptic efficacy of axospinous synapses also increased in the CA1. Taken together, our ultrastructural data reveal previously unrecognized structural changes at hippocampal synapses as a function of food restriction, supporting a link between metabolic balance and synaptic plasticity.

  10. Relationships between hippocampal activity and breathing patterns

    Harper, R M; Poe, G R; Rector, D M;

    1998-01-01

    Single cell discharge, EEG activity, and optical changes accompanying alterations in breathing patterns, as well as the knowledge that respiratory musculature is heavily involved in movement and other behavioral acts, implicate hippocampal regions in some aspects of breathing control. The control...

  11. Impact of neonatal anoxia on adult rat hippocampal volume, neurogenesis and behavior.

    Takada, Silvia Honda; Motta-Teixeira, Lívia Clemente; Machado-Nils, Aline Vilar; Lee, Vitor Yonamine; Sampaio, Carlos Alberto; Polli, Roberson Saraiva; Malheiros, Jackeline Moraes; Takase, Luiz Fernando; Kihara, Alexandre Hiroaki; Covolan, Luciene; Xavier, Gilberto Fernando; Nogueira, Maria Inês

    2016-01-01

    Neonates that suffer oxygen deprivation during birth can have long lasting cognitive deficits, such as memory and learning impairments. Hippocampus, one of the main structures that participate in memory and learning processes, is a plastic and dynamic structure that conserves during life span the property of generating new cells which can become neurons, the so-called neurogenesis. The present study investigated whether a model of rat neonatal anoxia, that causes only respiratory distress, is able to alter the hippocampal volume, the neurogenesis rate and has functional implications in adult life. MRI analysis revealed significant hippocampal volume decrease in adult rats who had experienced neonatal anoxia compared to control animals for rostral, caudal and total hippocampus. In addition, these animals also had 55.7% decrease of double-labelled cells to BrdU and NeuN, reflecting a decrease in neurogenesis rate. Finally, behavioral analysis indicated that neonatal anoxia resulted in disruption of spatial working memory, similar to human condition, accompanied by an anxiogenic effect. The observed behavioral alterations caused by oxygen deprivation at birth might represent an outcome of the decreased hippocampal neurogenesis and volume, evidenced by immunohistochemistry and MRI analysis. Therefore, based on current findings we propose this model as suitable to explore new therapeutic approaches.

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

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

    2016-12-01

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

  13. Microelectrode array recordings of excitability of low Mg2+-induced acute hippocampal slices

    Fan Yang; Xinwei Gong; Haiqing Gong; Puming Zhang; Peiji Liang; Qinchi LU

    2010-01-01

    Neuronal connections can be detected by neuronal network discharges in hippocampal neurons cultured on multi-electrodes.However,the multi-electrode-array(MEA)has not been widely used in hippocampal slice culture studies focused on epilepsy.The present study induced spontaneous synchronous epileptiform activity using low Mg2+artificial cerebrospinal fluid on acute hippocampal slices to record hippocampal discharges with MEA.Results showed that burst duration and average number of spikes in a burst were significantly greater in the CA3 compared with dentate gyrus and CA1 areas.In Schaffer cut-off group,CA1 area discharges disappeared,but synchronous discharges remained in the CA3 area.Moreover,synchronous discharge frequency in the Schaffer cut-off group was similar to control.However,burst duration and average number of spikes in a burst were significantly decreased compared with control(P < 0.05).Results demonstrated that highest neuronal excitability occurred in the CA3 area,and synchronous discharges induced by low Mg2+originated from the CA3 region.

  14. Intracerebroventricular administration of okadaic acid induces hippocampal glucose uptake dysfunction and tau phosphorylation.

    Broetto, Núbia; Hansen, Fernanda; Brolese, Giovana; Batassini, Cristiane; Lirio, Franciane; Galland, Fabiana; Dos Santos, João Paulo Almeida; Dutra, Márcio Ferreira; Gonçalves, Carlos-Alberto

    2016-06-01

    Intraneuronal aggregates of neurofibrillary tangles (NFTs), together with beta-amyloid plaques and astrogliosis, are histological markers of Alzheimer's disease (AD). The underlying mechanism of sporadic AD remains poorly understood, but abnormal hyperphosphorylation of tau protein is suggested to have a role in NFTs genesis, which leads to neuronal dysfunction and death. Okadaic acid (OKA), a strong inhibitor of protein phosphatase 2A, has been used to induce dementia similar to AD in rats. We herein investigated the effect of intracerebroventricular (ICV) infusion of OKA (100 and 200ng) on hippocampal tau phosphorylation at Ser396, which is considered an important fibrillogenic tau protein site, and on glucose uptake, which is reduced early in AD. ICV infusion of OKA (at 200ng) induced a spatial cognitive deficit, hippocampal astrogliosis (based on GFAP increment) and increase in tau phosphorylation at site 396 in this model. Moreover, we observed a decreased glucose uptake in the hippocampal slices of OKA-treated rats. In vitro exposure of hippocampal slices to OKA altered tau phosphorylation at site 396, without any associated change in glucose uptake activity. Taken together, these findings further our understanding of OKA neurotoxicity, in vivo and vitro, particularly with regard to the role of tau phosphorylation, and reinforce the importance of the OKA dementia model for studying the neurochemical alterations that may occur in AD, such as NFTs and glucose hypometabolism.

  15. Chronic Psychosocial Stress and Negative Feedback Inhibition: Enhanced Hippocampal Glucocorticoid Signaling despite Lower Cytoplasmic GR Expression.

    Füchsl, Andrea M; Reber, Stefan O

    2016-01-01

    Chronic subordinate colony housing (CSC), a pre-clinically validated mouse model for chronic psychosocial stress, results in increased basal and acute stress-induced plasma adrenocorticotropic hormone (ACTH) levels. We assessed CSC effects on hippocampal glucocorticoid (GC) receptor (GR), mineralocorticoid receptor (MR), and FK506 binding protein (FKBP51) expression, acute heterotypic stressor-induced GR translocation, as well as GC effects on gene expression and cell viability in isolated hippocampal cells. CSC mice showed decreased GR mRNA and cytoplasmic protein levels compared with single-housed control (SHC) mice. Basal and acute stress-induced nuclear GR protein expression were comparable between CSC and SHC mice, as were MR and FKBP51 mRNA and/or cytoplasmic protein levels. In vitro the effect of corticosterone (CORT) on hippocampal cell viability and gene transcription was more pronounced in CSC versus SHC mice. In summary, CSC mice show an, if at all, increased hippocampal GC signaling capacity despite lower cytoplasmic GR protein expression, making negative feedback deficits in the hippocampus unlikely to contribute to the increased ACTH drive following CSC.

  16. Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade

    Tope eLanre-Amos

    2010-09-01

    Full Text Available Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the basolateral amygdala which causes cell-type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity—theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala-hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments.

  17. 5-Hydroxymethylfurfural from wine-processed Fructus corni inhibits hippocampal neuron apoptosis***

    Hai Gu; Zequn Jiang; Mingyan Wang; Haiying Jiang; Fengming Zhao; Xia Ding; Baochang Cai; Zhen Zhan

    2013-01-01

    Previous studies have shown that 5-hydroxymethylfurfural, a compound extracted from wine- pro-cessed Fructus corni, has a protective effect on hippocampal neurons. The present study was de-signed to explore the related mechanisms. Our study revealed that high and medium doses (10, 1μmol/L) of 5-hydroxymethylfurfural could improve the morphology of H2O2-treated rat hippocampal neurons as revealed by inverted phase-contrast microscopy and transmission electron microscopy. MTT results showed that incubation with high and medium doses of 5-hydroxymethylfurfural caused a significant increase in the viability of neuronal cells injured by H2O2. Flow cytometry assays con-firmed that H2O2 could induce cellapoptosis, while high and medium doses of 5-hydroxymethylfurfural had a visible protective effect on apoptotic rat hippocampal neurons. Re-al-time PCR and western blot analysis showed that high and medium doses of 5-hydroxymethylfurfural prevented H2O2-induced up-regulation of p53, Bax and caspase-3 and antagonized the down-regulation of Bcl-2 induced by H2O2 treatment. These results suggested that 5-hydroxymethylfurfural could inhibit apoptosis of cultured rat hippocampal neurons injured by H2O2 via increase in Bcl-2 levels and decrease in p53, Bax and caspase-3 protein expression lev-els.

  18. Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation.

    Favre, G; Banta Lavenex, P; Lavenex, P

    2012-10-23

    The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

  19. Updating the lamellar hypothesis of hippocampal organization

    Robert S Sloviter

    2012-12-01

    Full Text Available In 1971, Andersen and colleagues proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a trisynaptic circuit lying within transverse hippocampal slices or lamellae [Andersen, Bliss, and Skrede. 1971. Lamellar organization of hippocampal pathways. Exp Brain Res 13, 222-238]. In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly infinite variety of unique outputs. The lamellar hypothesis derives primary support from the lamellar distribution of dentate granule cell axons (the mossy fibers, which innervate dentate hilar neurons and area CA3 pyramidal cells and interneurons within the confines of a thin transverse hippocampal segment. Following the initial formulation of the lamellar hypothesis, anatomical studies revealed that unlike granule cells, hilar mossy cells, CA3 pyramidal cells, and Layer II entorhinal cells all form axonal projections that are more divergent along the longitudinal axis than the clearly lamellar mossy fiber pathway. The existence of pathways with translamellar distribution patterns has been interpreted, incorrectly in our view, as justifying outright rejection of the lamellar hypothesis [Amaral and Witter. 1989. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571-591]. We suggest that the functional implications of longitudinally-projecting axons depend not on whether they exist, but on what they do. The observation that focal granule cell layer discharges normally inhibit, rather than excite, distant granule cells suggests that longitudinal axons in the dentate gyrus may mediate "lateral" inhibition and define lamellar function, rather than undermine it. In this review, we attempt a reconsideration of the evidence that most directly impacts the physiological concept of hippocampal lamellar

  20. Acupuncture effects on the hippocampal cholinergic system in a rat model of neuropathic pain

    Junying Wang; Junling Liu; Shuping Chen; Yonghui Gao; Fanying Meng; Lina Qiao

    2012-01-01

    The present study observed the effects of repeated electroacupuncture of Zusanli (ST36) and Yanglingquan (GB34) on expression of hippocampal acetylcholinesterase, vesicular acetylcholine transporter, and muscarinic M1 receptor mRNA in chronic constrictive injury (neuropathic pain) and/or ovariotomy rats. Results demonstrated increased expression of hippocampal acetylcholinesterase, vesicular acetylcholine transporter, and muscarinic M1 receptor mRNA, as well as decreased pain threshold, in a rat model of chronic neuropathic pain after electroacupuncture. The effects of electroacupuncture increased with prolonged time, but the above-mentioned effects decreased in memory-deficient animals. Results indicated that repeated electroacupuncture has a cumulative analgesic effect, which is closely associated with upregulation of acetylcholinesterase and vesicular acetylcholine transporter activity, as well as M1 receptor mRNA expression and memory.

  1. More vulnerability of left than right hippocampal damage in right-handed patients with post-traumatic stress disorder.

    Shu, Xi-Ji; Xue, Li; Liu, Wei; Chen, Fu-Yin; Zhu, Cheng; Sun, Xiao-Hai; Wang, Xiao-Ping; Liu, Zhong-Cun; Zhao, Hu

    2013-06-30

    Previous studies have shown hippocampal abnormalities in people with post-traumatic stress disorder (PTSD), but findings of diminished volume in shortages in the hippocampus have been inconsistent. In this study, we investigated changes in hippocampal volume and neuronal metabolites in right-handed PTSD patients to determine their possible relationship(s) with PTSD severity. We performed a case-control study of 11 right-handed PTSD patients and 11 healthy controls using magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H MRS). Hippocampal volume and metabolite ratios of N-acetylaspartate (NAA) to creatine (Cr) (NAA/Cr) and choline compounds (Cho) to Cr (Cho/Cr) were calculated. The severity of PTSD was evaluated by the Clinician-Administered PTSD Scale (CAPS). Significantly decreased left and total normalized hippocampal volumes were found in PTSD patients compared with controls (6.6% for the left hippocampus, 5.5% for total hippocampus). Also, the bilateral hippocampal NAA/Cr ratio of PTSD patients was significantly reduced compared with controls. The volume of the left hippocampus was negatively correlated to the CAPS total and CPAS-C scores. The left hippocampal NAA/Cr ratio was negatively correlated to the CAPS-total, CAPS-B, CAPS-C, and CAPS-D scores. The CAPS total and the CAPS-B scores were positively correlated to the Cho/Cr ratio of the right hippocampus. Our results indicate that hippocampal dysfunction is asymmetric in right-handed PTSD patients, with the left side affected more than the right.

  2. Hippocampal neurogenesis in the new model of global cerebral ischemia

    Kisel, A. A.; Chernysheva, G. A.; Smol'yakova, V. I.; Savchenko, R. R.; Plotnikov, M. B.; Khodanovich, M. Yu.

    2015-11-01

    The study aimed to evaluate the changes of hippocampal neurogenesis in a new model of global transient cerebral ischemia which was performed by the occlusion of the three main vessels (tr. brachiocephalicus, a. subclavia sinistra, and a. carotis communis sinistra) branching from the aortic arch and supplying the brain. Global transitory cerebral ischemia was modeled on male rats (weight = 250-300 g) under chloral hydrate with artificial lung ventilation. Animals after the same surgical operation without vessel occlusion served as sham-operated controls. The number of DCX-positive (doublecortin, the marker of immature neurons) cells in dentate gyrus (DG) and CA1-CA3 fields of hippocampus was counted at the 31st day after ischemia modeling. It was revealed that global cerebral ischemia decreased neurogenesis in dentate gyrus in comparison with the sham-operated group (Pneurogenesis in CA1-CA3 fields was increased as compared to the control (P<0.05).

  3. Decreasing Relative Risk Premium

    Hansen, Frank

    We consider the risk premium demanded by a decision maker with wealth x in order to be indifferent between obtaining a new level of wealth y1 with certainty, or to participate in a lottery which either results in unchanged present wealth or a level of wealth y2 > y1. We define the relative risk...... premium as the quotient between the risk premium and the increase in wealth y1–x which the decision maker puts on the line by choosing the lottery in place of receiving y1 with certainty. We study preferences such that the relative risk premium is a decreasing function of present wealth, and we determine...... relative risk premium in the small implies decreasing relative risk premium in the large, and decreasing relative risk premium everywhere implies risk aversion. We finally show that preferences with decreasing relative risk premium may be equivalently expressed in terms of certain preferences on risky...

  4. Decreasing Serial Cost Sharing

    Hougaard, Jens Leth; Østerdal, Lars Peter

    The increasing serial cost sharing rule of Moulin and Shenker [Econometrica 60 (1992) 1009] and the decreasing serial rule of de Frutos [Journal of Economic Theory 79 (1998) 245] have attracted attention due to their intuitive appeal and striking incentive properties. An axiomatic characterization...... of the increasing serial rule was provided by Moulin and Shenker [Journal of Economic Theory 64 (1994) 178]. This paper gives an axiomatic characterization of the decreasing serial rule...

  5. Moderate Hypothermia Significantly Decreases Hippocampal Cell Death Involving Autophagy Pathway after Moderate Traumatic Brain Injury.

    Jin, Yichao; Lin, Yingying; Feng, Jun-feng; Jia, Feng; Gao, Guo-yi; Jiang, Ji-yao

    2015-07-15

    Here, we evaluated changes in autophagy after post-traumatic brain injury (TBI) followed by moderate hypothermia in rats. Adult male Sprague-Dawley rats were randomly divided into four groups: sham injury with normothermia group (37 °C); sham injury with hypothermia group (32 °C); TBI with normothermia group (TNG; 37 °C); and TBI with hypothermia group (THG; 32 °C). Injury was induced by a fluid percussion TBI device. Moderate hypothermia (32 °C) was achieved by partial immersion in a water bath (0 °C) under general anesthesia for 4 h. All rats were killed at 24 h after fluid percussion TBI. The ipsilateral hippocampus in all rats was analyzed with hematoxylin and eosin staining; terminal deoxynucleoitidyl transferase-mediated nick end labeling staining was used to determine cell death in ipsilateral hippocampus. Immunohistochemistry and western blotting of microtubule-associated protein light chain 3 (LC3), Beclin-1, as well as transmission electron microscopy performed to assess changes in autophagy. At 24 h after TBI, the cell death index was 27.90 ± 2.36% in TNG and 14.90 ± 1.52% in THG. Expression level of LC3 and Beclin-1 were significantly increased after TBI and were further up-regulated after post-TBI hypothermia. Further, ultrastructural observations showed that there was a marked increase of autophagosomes and autolysosomes in ipsilateral hippocampus after post-TBI hypothermia. Our data demonstrated that moderate hypothermia significantly attenuated cell death and increased autophagy in ipsilateral hippocampus after fluid percussion TBI. In conclusion, autophagy pathway may participate in the neuroprotective effect of post-TBI hypothermia.

  6. Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress

    Dagyte, Girstaute; Crescente, Ilaria; Postema, Folkert; Seguin, Laure; Gabriel, Cecilia; Mocaer, Elisabeth; Den Boer, Johan A.; Koolhaas, Jaap M.; Dagytė, Girstautė

    2011-01-01

    The antidepressant agomelatine is a MT1/MT2 receptor agonist and 5-HT2C antagonist. Its antidepressant activity is proposed to result from the synergy between these sets of receptors. Agomelatine-induced changes in the brain have been reported under basal conditions. Yet, little is known about its e

  7. Exercise enhances hippocampal recovery following binge ethanol exposure.

    Mark E Maynard

    Full Text Available Binge drinking damages the brain, and although a significant amount of recovery occurs with abstinence, there is a need for effective strategies to maximize neurorestoration. In contrast to binge drinking, exercise promotes brain health, so the present study assessed whether it could counteract ethanol-induced damage by augmenting natural self-repair processes following one or more binge exposures. Adult female rats were exposed to 0 (control, 1 or 2 binges, using an established 4-day model of binge-induced neurodegeneration. Half of the animals in each group remained sedentary, or had running wheel access beginning 7 days after the final binge, and were sacrificed 28 days later. To assess binge-induced hippocampal damage and exercise restoration, we quantified volume of the dentate gyrus and number of granule neurons. We found that a single binge exposure significantly decreased the volume of the dentate gyrus and number of granule neurons. A second binge did not exacerbate the damage. Exercise completely restored baseline volume and granule neuron numbers. To investigate a potential mechanism of this restoration, we administered IdU (a thymidine analog in order to label cells generated after the first binge. Previous studies have shown that neurogenesis in the dentate gyrus is decreased by binge alcohol exposure, and that the hippocampus responds to this insult by increasing cell genesis during abstinence. We found increased IdU labeling in binge-exposed animals, and a further increase in binged animals that exercised. Our results indicate that exercise reverses long-lasting hippocampal damage by augmenting natural self-repair processes.

  8. Fractalkine and CX3CR1 regulate hippocampal neurogenesis in adult and aged rats

    Bachstetter, Adam D.; Morganti, Josh M.; Jernberg, Jennifer; Schlunk, Andrea; Mitchell, Staten H.; Brewster, Kaelin W.; Hudson, Charles E.; Cole, Michael J; Harrison, Jeffrey K.; Bickford, Paula C.; Gemma, Carmelina

    2010-01-01

    Microglia have neuroprotective capacities, yet chronic activation can promote neurotoxic inflammation. Neuronal fractalkine (FKN), acting on CX3CR1, has been shown to suppress excessive microglia activation. We found that disruption in FKN/ CX3CR1 signaling in young adult rodents decreased survival and proliferation of neural progenitor cells through IL-1β. Aged rats were found to have decreased levels of hippocampal FKN protein; moreover, interruption of CX3CR1 function in these animals did not affect neurogenesis. The age-related loss of FKN could be restored by exogenous FKN reversing the age-related decrease in hippocampal neurogenesis. There were no measureable changes in young animals by the addition of exogenous FKN. The results suggest that FKN/ CX3CR1 signaling has a regulatory role in modulating hippocampal neurogenesis via mechanisms that involve indirect modification of the niche environment. As elevated neuroinflammation is associated with many age-related neurodegenerative diseases, enhancing FKN/ CX3CR1 interactions could provide an alternative therapeutic approach to slow age-related neurodegeneration. PMID:20018408

  9. Effects of intracerebroventricular injection of histamine on memory deficits induced by hippocampal lesions in rats.

    Kamei, C; Chen, Z; Nakamura, S; Sugimoto, Y

    1997-05-01

    The influence of bilateral hippocampal lesions on active avoidance response was studied in rats, as well as the effect of intracerebroventricular (i.c.v.) injection of histamine on memory deficits caused by hippocampectomy. Retardation of learning acquisition was produced by lesioning of the bilateral dorsal hippocampus in active avoidance response. Memory retention was also impaired by hippocampectomy. Although locomotor activity and rearing behavior measured by open-field test increased after hippocampal lesions, there was no relation between impairment of learning and increase in exploratory behavior. I.c.v. injection of histamine and i.p. injection of histidine resulted in an improvement of memory deficits (not only learning acquisition but also memory retrieval) induced by hippocampal lesions in rats. Histamine contents of the hippocampus and hypothalamus decreased after hippocampectomy, and a decrease in histamine contents of both areas was restored by histamine (i.c.v.) and histidine (i.p.) injection. In addition, a close relationship was found between decrease in response latency of avoidance response and an increase in histamine content of the hippocampus and hypothalamus after histamine injection.

  10. In vitro ischemia triggers a transcriptional response to down-regulate synaptic proteins in hippocampal neurons.

    Joana Fernandes

    Full Text Available Transient global cerebral ischemia induces profound changes in the transcriptome of brain cells, which is partially associated with the induction or repression of genes that influence the ischemic response. However, the mechanisms responsible for the selective vulnerability of hippocampal neurons to global ischemia remain to be clarified. To identify molecular changes elicited by ischemic insults, we subjected hippocampal primary cultures to oxygen-glucose deprivation (OGD, an in vitro model for global ischemia that resulted in delayed neuronal death with an excitotoxic component. To investigate changes in the transcriptome of hippocampal neurons submitted to OGD, total RNA was extracted at early (7 h and delayed (24 h time points after OGD and used in a whole-genome RNA microarray. We observed that at 7 h after OGD there was a general repression of genes, whereas at 24 h there was a general induction of gene expression. Genes related with functions such as transcription and RNA biosynthesis were highly regulated at both periods of incubation after OGD, confirming that the response to ischemia is a dynamic and coordinated process. Our analysis showed that genes for synaptic proteins, such as those encoding for PICK1, GRIP1, TARPγ3, calsyntenin-2/3, SAPAP2 and SNAP-25, were down-regulated after OGD. Additionally, OGD decreased the mRNA and protein expression levels of the GluA1 AMPA receptor subunit as well as the GluN2A and GluN2B subunits of NMDA receptors, but increased the mRNA expression of the GluN3A subunit, thus altering the composition of ionotropic glutamate receptors in hippocampal neurons. Together, our results present the expression profile elicited by in vitro ischemia in hippocampal neurons, and indicate that OGD activates a transcriptional program leading to down-regulation in the expression of genes coding for synaptic proteins, suggesting that the synaptic proteome may change after ischemia.

  11. Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer’s disease

    J. Carson eSmith

    2014-04-01

    Full Text Available We examined the impact of physical activity (PA on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimer’s disease (AD. Hippocampal volume was measured from structural magnetic resonance imaging (MRI scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-ε4 allele. Four subgroups were studied: Low Risk/High PA (n = 24, Low Risk/Low PA (n = 34, High Risk/High PA (n = 22, and High Risk/Low PA (n = 17. Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, precentral gyrus, caudal middle frontal gyrus, cortical white matter, and total grey matter. These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories.

  12. Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus.

    Xiang Gao

    Full Text Available Hippocampal injury-associated learning and memory deficits are frequent hallmarks of brain trauma and are the most enduring and devastating consequences following traumatic brain injury (TBI. Several reports, including our recent paper, showed that TBI brought on by a moderate level of controlled cortical impact (CCI induces immature newborn neuron death in the hippocampal dentate gyrus. In contrast, the majority of mature neurons are spared. Less research has been focused on these spared neurons, which may also be injured or compromised by TBI. Here we examined the dendrite morphologies, dendritic spines, and synaptic structures using a genetic approach in combination with immunohistochemistry and Golgi staining. We found that although most of the mature granular neurons were spared following TBI at a moderate level of impact, they exhibited dramatic dendritic beading and fragmentation, decreased number of dendritic branches, and a lower density of dendritic spines, particularly the mushroom-shaped mature spines. Further studies showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced. The electrophysiological activity of neurons was impaired as well. These results indicate that TBI not only induces cell death in immature granular neurons, it also causes significant dendritic and synaptic degeneration in pathohistology. TBI also impairs the function of the spared mature granular neurons in the hippocampal dentate gyrus. These observations point to a potential anatomic substrate to explain, in part, the development of posttraumatic memory deficits. They also indicate that dendritic damage in the hippocampal dentate gyrus may serve as a therapeutic target following TBI.

  13. Comparison between visual assessment of MTA and hippocampal volumes in an elderly, non-demented population

    Cavallin, Lena; Axelsson, Rimma [CLINTEC, Div. of Medical Imaging and Technology, Karolinska Inst., Karolinska Univ. Hospital, Stockholm (Sweden); Dept. of Radiology, Karolinska Univ. Hospital, Stockholm (Sweden)], e-mail: lena.cavallin@karolinska.se; Bronge, Lena [CLINTEC, Div. of Medical Imaging and Technology, Karolinska Inst., Karolinska Univ. Hospital, Stockholm (Sweden); Aleris Diagnostics, Stockholm (Sweden); Zhang, Yi [NVS, Novum, Karolinska Inst., Karolinska Univ. Hospital, Stockholm (Sweden); Oeksengaard, Anne-Rita [NVS, Novum, Karolinska Inst., Karolinska Univ. Hospital, Stockholm (Sweden); Ulleval Univ. Hospital and Asker and Baerum Hospital, Oslo (Norway); Wahlund, Lars-Olof [NVS, Novum, Karolinska Inst., Karolinska Univ. Hospital, Stockholm (Sweden); Swedish Brain Power, Karolinska Univ. Hospital, Stockholm (Sweden); Fratiglioni, Laura [ARC Karolinska Inst. Stockholm (Sweden)

    2012-06-15

    Background: It is important to have a replicable easy method for monitoring atrophy progression in Alzheimer's disease. Volumetric methods for calculating hippocampal volume are time-consuming and commonly used in research. Visual assessments of medial temporal lobe atrophy (vaMTA) is a rapid method for clinical use. This method has not been tested in a large non-demented population in comparison with volumetry measurements. Since hippocampal volume decreases with time even in normal aging there is also a need to study the normal age differences of medial temporal lobe atrophy. Purpose: To compare visual assessment of medial temporal lobe atrophy (vaMTA) with hippocampal volume in a healthy, non-demented elderly population. To describe normal ageing using vaMTA. Material and Methods: Non-demented individuals aged 60, 66, 72, 78, 81, 84, and {>=}87 years old were recruited from the Swedish National study on Ageing and Care in Kungsholmen (SNAC-K), Sweden. Standard magnetic resonance imaging (MRI) scans, vaMTA, and calculations of hippocampal volumes were performed in 544 subjects. Results: Significant correlation (rs = -0.32, P < 0.001, sin; and rs = -0.26, P < 0.001, dx) was found between hippocampal volume measurements and vaMTA. In normal ageing, almost 95% of {<=}66-year-olds had a medial temporal lobe atrophy (MTA) score {<=}1, with possible scores ranging from 0 to 4. Subjects aged 72, 78, and 81 years scored {<=}2, while the two oldest age groups had scores {<=}3. Conclusion: There was a highly significant correlation between volumetric measurements of the hippocampus and MTA scoring. In normal ageing, there is increasing MTA score. For non-demented elderly individuals {<=}70 years, an MTA score of 0-1 may be considered normal, compared with MTA {<=}2 for 70-80-years and MTA 3 for >80-year-old individuals.

  14. Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis

    Thomas eGrüter

    2015-05-01

    Full Text Available Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signalling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR results in similar molecular, cellular, cognitive and behavioural changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A, and increase in GABA(B-receptor-expression in PFC, along with a significant increase of GABA(B- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry.

  15. Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

    Jukić, M M; Opel, N; Ström, J; Carrillo-Roa, T; Miksys, S; Novalen, M; Renblom, A; Sim, S C; Peñas-Lledó, E M; Courtet, P; Llerena, A; Baune, B T; de Quervain, D J; Papassotiropoulos, A; Tyndale, R F; Binder, E B; Dannlowski, U; Ingelman-Sundberg, M

    2016-11-29

    The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.Molecular Psychiatry advance online publication, 29 November 2016; doi:10.1038/mp.2016.204.

  16. Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis

    Grüter, Thomas; Wiescholleck, Valentina; Dubovyk, Valentyna; Aliane, Verena; Manahan-Vaughan, Denise

    2015-01-01

    Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioral changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse (PP) facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry. PMID:26042007

  17. n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

    Debora eCutuli

    2014-08-01

    Full Text Available As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations found in n-3 PUFA supplemented mice also pointed towards an effective neuroprotection.On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging.

  18. ZD7288, a selective hyperpolarization-activated cyclic nucleotide-gated channel blocker, inhibits hippocampal synaptic plasticity

    Xiao-xue Zhang; Xiao-chun Min; Xu-lin Xu; Min Zheng; Lian-jun Guo

    2016-01-01

    The selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker 4-(N-ethyl-N-phenylamino)-1,2-dimeth-yl-6-(methylamino) pyrimidinium chloride (ZD7288) blocks the induction of long-term potentiation in the perforant path–CA3 region in rat hippocampusin vivo. To explore the mechanisms underlying the action of ZD7288, we recorded excitatory postsynaptic potentials in perforant path–CA3 synapses in male Sprague-Dawley rats. We measured glutamate content in the hippocampus and in cultured hip-pocampal neurons using high performance liquid chromatography, and determined intracellular Ca2+ concentration ([Ca2+]i) using Fura-2. ZD7288 inhibited the induction and maintenance of long-term potentiation, and these effects were mirrored by the nonspeciifc HCN channel blocker cesium. ZD7288 also decreased glutamate release in hippocampal tissue and in cultured hippocampal neurons. Further-more, ZD7288 attenuated glutamate-induced rises in [Ca2+]i in a concentration-dependent manner and reversed 8-Br-cAMP-mediated facilitation of these glutamate-induced [Ca2+]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both gluta-mate release and resultant [Ca2+]i increases in rat hippocampal neurons.

  19. Early life inflammatory pain induces long-lasting deficits in hippocampal-dependent spatial memory in male and female rats.

    Henderson, Yoko O; Victoria, Nicole C; Inoue, Kiyoshi; Murphy, Anne Z; Parent, Marise B

    2015-02-01

    The present experiment tested the hypothesis that neonatal injury disrupts adult hippocampal functioning and that normal aging or chronic stress during adulthood, which are known to have a negative impact on hippocampal function, exacerbate these effects. Male and female Sprague-Dawley rats were given an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth and their memory was tested in the hippocampal-dependent spatial water maze in adulthood and again in middle age. We found that neonatal injury impaired hippocampal-dependent memory in adulthood, that the effects of injury on memory were more pronounced in middle-aged male rats, and that chronic stress accelerated the onset of these memory deficits. Neonatal injury also decreased glucocorticoid receptor mRNA in the dorsal CA1 area of middle-aged rats, a brain region critical for spatial memory. Morphine administration at the time of injury completely reversed injury-induced memory deficits, but neonatal morphine treatments in the absence of injury produced significant memory impairments in adulthood. Collectively, these findings are consistent with our hypothesis that neonatal injury produces long-lasting disruption in adult hippocampal functioning.

  20. Manipulating Decisiveness in Decision Making: Effects of Clonidine on Hippocampal Search Strategies.

    Amemiya, Seiichiro; Redish, A David

    2016-01-20

    Decisiveness is the ability to commit to a decision quickly and efficiently; in contrast, indecision entails the repeated consideration of multiple alternative possibilities. In humans, the α2-adrenergic receptor agonist clonidine increases decisiveness in tasks that require planning through unknown neural mechanisms. In rats, indecision is manifested as reorienting behaviors at choice points (vicarious trial and error [VTE]), during which hippocampal representations alternate between prospective options. To determine whether the increase in decisiveness driven by clonidine also entails changes in hippocampal search processes, we compared the effect of clonidine on spatial representations in hippocampal neural ensembles as rats passed through a T-shaped decision point. Consistent with previous experiments, hippocampal representations reflected both chosen and unchosen paths during VTE events under saline control conditions. Also, consistent with previous experiments, hippocampal representations reflected the chosen path more than the unchosen path when the animal did not show VTE at the choice point. Injection of clonidine suppressed the spatial representation of the unchosen path at the choice point on VTE laps and hastened the differentiation of spatial representations of the chosen path from the unchosen path on non-VTE laps to appear before reaching the choice point. These results suggest that the decisiveness seen under clonidine is due to limited exploration of potential options in hippocampus, and suggest novel roles for noradrenaline as a modulator of the hippocampal search processes. Significance statement: Clonidine, an α2-adrenergic receptor agonist, which decreases the level of noradrenaline in vivo, has an interesting effect in humans and other animals: it makes them more decisive. However, the mechanisms by which clonidine makes them more decisive remain unknown. Researchers have speculated that clonidine limits the amount of mental search that

  1. Neural stem cell activation and glial proliferation in the hippocampal CA3 region of posttraumatic epileptic rats

    Yuanxiang Lin; Kun Lin; Dezhi Kang; Feng Wang

    2011-01-01

    The present study observed the dynamic expression of CD133, nuclear factor-κB and glial fibrillary acidic protein in the hippocampal CA3 area of the experimental posttraumatic epilepsy rats to investigate whether gliosis occurs after posttraumatic epilepsy. CD133 and nuclear factor-κB expression was increased at 1 day after posttraumatic epilepsy, peaked at 7 days, and gradually decreased up to 14 days, as seen by double-immunohistochemical staining. Glial fibrillary acidic protein/nuclear factor-κB double-labeled cells increased with time and peaked at 14 days after posttraumatic epilepsy. Results show that activation of hippocampal neural stem cells and glial proliferation after posttraumatic epilepsy-induced oxidative stress increases hippocampal glial cell density.

  2. GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor.

    Marty, S; Berninger, B; Carroll, P; Thoenen, H

    1996-03-01

    Gamma-Aminobutyric acid (GABA) switches from enhancing to repressing brain-derived neurotrophic factor (BDNF) mRNA synthesis during the maturation of hippocampal neurons in vitro. Interneurons do not produce BDNF themselves, but BDNF enhances their differentiation. Therefore, the question arose whether hippocampal interneurons regulate their phenotype by regulating BDNF expression and release from adjacent cells. The GABA(A) receptor agonist muscimol and BDNF increased the size and neuropeptide Y (NPY) immunoreactivity of hippocampal interneurons. However, GABAergic stimulation failed to increase NPY immunoreactivity in cultures from BDNF knockout embryos. At later developmental stages, when GABA represses BDNF synthesis, treatment with muscimol induced a decrease in cell size and NPY immunoreactivity of interneurons. Interneurons might thus control their phenotype through the regulation of BDNF synthesis in, and release from, their target neurons.

  3. Decreasing strabismus surgery

    Arora, A; Williams, B; Arora, A K; McNamara, R; Yates, J; Fielder, A

    2005-01-01

    Aim: To determine whether there has been a consistent change across countries and healthcare systems in the frequency of strabismus surgery in children over the past decade. Methods: Retrospective analysis of data on all strabismus surgery performed in NHS hospitals in England and Wales, on children aged 0–16 years between 1989 and 2000, and between 1994 and 2000 in Ontario (Canada) hospitals. These were compared with published data for Scotland, 1989–2000. Results: Between 1989 and 1999–2000 the number of strabismus procedures performed on children, 0–16 years, in England decreased by 41.2% from 15 083 to 8869. Combined medial rectus recession with lateral rectus resection decreased from 5538 to 3013 (45.6%) in the same period. Bimedial recessions increased from 489 to 762, oblique tenotomies from 43 to 121, and the use of adjustable sutures from 29 to 44, in 2000. In Ontario, operations for squint decreased from 2280 to 1685 (26.1%) among 0–16 year olds between 1994 and 2000. Conclusion: The clinical impression of decrease in the frequency of paediatric strabismus surgery is confirmed. In the authors’ opinion this cannot be fully explained by a decrease in births or by the method of healthcare funding. Two factors that might have contributed are better conservative strabismus management and increased subspecialisation that has improved the quality of surgery and the need for re-operation. This finding has a significant impact upon surgical services and also on the training of ophthalmologists. PMID:15774914

  4. Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

    Eun Joo Bae; Seongkweon Hong; Dong Won Kim; Jun Hwi Cho; Yun Lyul Lee; Moo-Ho Won; Joon Ha Park; Bai Hui Chen; Bing Chun Yan; Bich Na Shin; Jeong Hwi Cho; In Hye Kim; Ji Hyeon Ahn; Jae Chul Lee; Hyun-Jin Tae

    2015-01-01

    The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we ifrst compared ischemia-in-duced effects on p63 expression in the hippocampal regions (CA1–3) between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was signiifcantly slow compared with that in the adult gerbils after transient global cerebral ischemia. p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was signiifcantly low compared with that in the sham-operated adult group. p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was signiifcantly decreased at 4 days post-ischemia;however, p63 immunoreactivity in the ischemia-operated young group was signiifcantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These ifndings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.

  5. Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

    Eun Joo Bae

    2015-01-01

    Full Text Available The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions (CA1- 3 between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia. p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group. p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.

  6. Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats.

    Suk-Yu Yau

    Full Text Available Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg of corticosterone (CORT for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog /doublecortin (immature neuronal marker showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract

  7. Hippocampal Neurogenesis and Dendritic Plasticity Support Running-Improved Spatial Learning and Depression-Like Behaviour in Stressed Rats

    Tong, Jian-Bin; Wong, Richard; Ching, Yick-Pang; Qiu, Guang; Tang, Siu-Wa; Lee, Tatia M. C.; So, Kwok-Fai

    2011-01-01

    Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress. PMID:21935393

  8. A Compressed Sensing Perspective of Hippocampal Function

    Panagiotis ePetrantonakis

    2014-08-01

    Full Text Available Hippocampus is one of the most important information processing units in the brain. Input from the cortex passes through convergent axon pathways to the downstream hippocampal subregions and, after being appropriately processed, is fanned out back to the cortex. Here, we review evidence of the hypothesis that information flow and processing in the hippocampus complies with the principles of Compressed Sensing (CS. The CS theory comprises a mathematical framework that describes how and under which conditions, restricted sampling of information (data set can lead to condensed, yet concise, forms of the initial, subsampled information entity (i.e. of the original data set. In this work, hippocampus related regions and their respective circuitry are presented as a CS-based system whose different components collaborate to realize efficient memory encoding and decoding processes. This proposition introduces a unifying mathematical framework for hippocampal function and opens new avenues for exploring coding and decoding strategies in the brain.

  9. Prediction of dementia by hippocampal shape analysis

    Achterberg, Hakim C.; van der Lijn, Fedde; den Heijer, Tom;

    2010-01-01

    This work investigates the possibility of predicting future onset of dementia in subjects who are cognitively normal, using hippocampal shape and volume information extracted from MRI scans. A group of 47 subjects who were non-demented normal at the time of the MRI acquisition, but were diagnosed...... and, if necessary, manually corrected by a trained observer. From this data a statistical model of hippocampal shape was constructed, using an entropy-based particle system. This shape model provided the input for a Support Vector Machine classifier to predict dementia. Cross validation experiments...... showed that shape information can predict future onset of dementia in this dataset with an accuracy of 70%. By incorporating both shape and volume information into the classifier, the accuracy increased to 74%....

  10. Inhibitory microcircuit modules in hippocampal learning.

    Caroni, Pico

    2015-12-01

    It has recently become possible to investigate connectivities and roles of identified hippocampal GABAergic interneurons (INs) in behaving rodents. INs targeting distinct pyramidal neuron subcompartments are recruited dynamically at defined phases of behavior and learning. They include Parvalbumin Axo-axonic and perisomatic Basket cells, and Somatostatin radiatum-oriens and oriens-lacunosum moleculare cells. Each IN is in turn either activated or inhibited upon specific behavioral and network state requirements through specific inputs and neuromodulators. Subpopulations of these principal neurons and INs interconnect selectively, suggesting selective processing and routing of alternate information streams. First canonical functional modules have emerged, which will have to be further defined and linked to identified afferents and efferents towards a circuit understanding of how hippocampal networks support behavior.

  11. Hippocampal Processing of Ambiguity Enhances Fear Memory.

    Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth; Baratta, Michael V; Goosens, Ki A

    2017-02-01

    Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, in which dangerous situations can lead to unpleasant outcomes in unpredictable ways. In the current experiments, we varied the timing of aversive events after predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of cornu ammonis 1 cells during aversive negative prediction errors prevented this enhancement of fear without affecting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial-reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning.

  12. Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy

    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.

  13. Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial.

    Wagner, Gerd; Herbsleb, Marco; de la Cruz, Feliberto; Schumann, Andy; Brünner, Franziska; Schachtzabel, Claudia; Gussew, Alexander; Puta, Christian; Smesny, Stefan; Gabriel, Holger W; Reichenbach, Jürgen R; Bär, Karl-Jürgen

    2015-10-01

    Interventional studies suggest that changes in physical fitness affect brain function and structure. We studied the influence of high intensity physical exercise on hippocampal volume and metabolism in 17 young healthy male adults during a 6-week exercise program compared with matched controls. We further aimed to relate these changes to hypothesized changes in exercised-induced brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). We show profound improvement of physical fitness in most subjects and a positive correlation between the degree of fitness improvement and increased BDNF levels. We unexpectedly observed an average volume decrease of about 2%, which was restricted to right hippocampal subfields CA2/3, subiculum, and dentate gyrus and which correlated with fitness improvement and increased BDNF levels negatively. This result indicates that mainly those subjects who did not benefit from the exercise program show decreased hippocampal volume, reduced BDNF levels, and increased TNF-α concentrations. While spectroscopy results do not indicate any neuronal loss (unchanged N-acetylaspartate levels) decreased glutamate-glutamine levels were observed in the right anterior hippocampus in the exercise group only. Responder characteristics need to be studied in more detail. Our results point to an important role of the inflammatory response after exercise on changes in hippocampal structure.

  14. Decreasing serial cost sharing

    Hougaard, Jens Leth; Østerdal, Lars Peter Raahave

    2009-01-01

    The increasing serial cost sharing rule of Moulin and Shenker (Econometrica 60:1009-1037, 1992) and the decreasing serial rule of de Frutos (J Econ Theory 79:245-275, 1998) are known by their intuitive appeal and striking incentive properties. An axiomatic characterization of the increasing serial...

  15. Decreasing Serial Cost Sharing

    Hougaard, Jens Leth; Østerdal, Lars Peter

    The increasing serial cost sharing rule of Moulin and Shenker [Econometrica 60 (1992) 1009] and the decreasing serial rule of de Frutos [Journal of Economic Theory 79 (1998) 245] have attracted attention due to their intuitive appeal and striking incentive properties. An axiomatic characterization...

  16. Tuberous sclerosis complex coexistent with hippocampal sclerosis.

    Lang, Min; Prayson, Richard A

    2016-02-01

    Tuberous sclerosis and hippocampal sclerosis are both well-defined entities associated with medically intractable epilepsy. To our knowledge, there has been only one prior case of these two pathologies being co-existent. We report a 7-month-old boy who presented with intractable seizures at 2 months of age. MRI studies showed diffuse volume loss in the brain with bilateral, multiple cortical tubers and subcortical migration abnormalities. Subependymal nodules were noted without subependymal giant cell astrocytoma. Genetic testing revealed TSC2 and PRD gene deletions. Histopathology of the hippocampus showed CA1 sclerosis marked by loss of neurons in the CA1 region. Sections from the temporal, parietal and occipital lobes showed multiple cortical tubers characterized by cortical architectural disorganization, gliosis, calcifications and increased number of large balloon cells. Focal white matter balloon cells and spongiform changes were also present. The patient underwent resection of the right fronto-parietal lobe and a subsequent resection of the right temporal, parietal and occipital lobes. The patient is free of seizures on anti-epileptic medication 69 months after surgery. Although hippocampal sclerosis is well documented to be associated with coexistent focal cortical dysplasia, the specific co-existence of cortical tubers and hippocampal sclerosis appears to be rare.

  17. Updating the lamellar hypothesis of hippocampal organization.

    Sloviter, Robert S; Lømo, Terje

    2012-01-01

    Andersen et al. (1971) proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a "trisynaptic circuit" lying within transverse hippocampal "slices" or "lamellae." In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly infinite variety of unique outputs. The lamellar hypothesis derives primary support from the "lamellar" distribution of dentate granule cell axons (the mossy fibers), which innervate dentate hilar neurons and area CA3 pyramidal cells and interneurons within the confines of a thin transverse hippocampal segment. Following the initial formulation of the lamellar hypothesis, anatomical studies revealed that unlike granule cells, hilar mossy cells, CA3 pyramidal cells, and Layer II entorhinal cells all form axonal projections that are more divergent along the longitudinal axis than the clearly "lamellar" mossy fiber pathway. The existence of pathways with "translamellar" distribution patterns has been interpreted, incorrectly in our view, as justifying outright rejection of the lamellar hypothesis (Amaral and Witter, 1989). We suggest that the functional implications of longitudinally projecting axons depend not on whether they exist, but on what they do. The observation that focal granule cell layer discharges normally inhibit, rather than excite, distant granule cells suggests that longitudinal axons in the dentate gyrus may mediate "lateral" inhibition and define lamellar function, rather than undermine it. In this review, we attempt a reconsideration of the evidence that most directly impacts the physiological concept of hippocampal lamellar organization.

  18. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat.

    Ego-Stengel, Valérie; Wilson, Matthew A

    2010-01-01

    The hippocampus plays a key role in the acquisition of new memories for places and events. Evidence suggests that the consolidation of these memories is enhanced during sleep. At the neuronal level, reactivation of awake experience in the hippocampus during sharp-wave ripple events, characteristic of slow-wave sleep, has been proposed as a neural mechanism for sleep-dependent memory consolidation. However, a causal relation between sleep reactivation and memory consolidation has not been established. Here we show that disrupting neuronal activity during ripple events impairs spatial learning. We trained rats daily in two identical spatial navigation tasks followed each by a 1-hour rest period. After one of the tasks, stimulation of hippocampal afferents selectively disrupted neuronal activity associated with ripple events without changing the sleep-wake structure. Rats learned the control task significantly faster than the task followed by rest stimulation, indicating that interfering with hippocampal processing during sleep led to decreased learning.

  19. Muscarinic modulation of sodium current by activation of protein kinase C in rat hippocampal neurons.

    Cantrell, A R; Ma, J Y; Scheuer, T; Catterall, W A

    1996-05-01

    Phosphorylation of brain Na+ channels by protein kinase C (PKC) decreases peak Na+ current and slows macroscopic inactivation, but receptor-activated modulation of Na+ currents via the PKC pathway has not been demonstrated. We have examined modulation of Na+ channels by activation of muscarinic receptors in acutely-isolated hippocampal neurons using whole-cell voltage-clamp recording. Application of the muscarinic agonist carbachol reduced peak Na+ current and slowed macroscopic inactivation at all potentials, without changing the voltage-dependent properties of the channel. These effects were mediated by PKC, since they were eliminated when the specific PKC inhibitor (PKCI19-36) was included in the pipette solution and mimicked by the extracellular application of the PKC activator, OAG. Thus, activation of endogenous muscarinic receptors on hippocampal neurons strongly modulates Na+ channel activity by activation of PKC. Cholinergic input from basal forebrain neurons may have this effect in the hippocampus in vivo.

  20. Microbats appear to have adult hippocampal neurogenesis, but post-capture stress causes a rapid decline in the number of neurons expressing doublecortin.

    Chawana, R; Alagaili, A; Patzke, N; Spocter, M A; Mohammed, O B; Kaswera, C; Gilissen, E; Bennett, N C; Ihunwo, A O; Manger, P R

    2014-09-26

    A previous study investigating potential adult hippocampal neurogenesis in microchiropteran bats failed to reveal a strong presence of this neural trait. As microchiropterans have a high field metabolic rate and a small body mass, it is possible that capture/handling stress may lead to a decrease in the detectable presence of adult hippocampal neurogenesis. Here we looked for evidence of adult hippocampal neurogenesis using immunohistochemical techniques for the endogenous marker doublecortin (DCX) in 10 species of microchiropterans euthanized and perfusion fixed at specific time points following capture. Our results reveal that when euthanized and perfused within 15 min of capture, abundant putative adult hippocampal neurogenesis could be detected using DCX immunohistochemistry. Between 15 and 30 min post-capture, the detectable levels of DCX dropped dramatically and after 30 min post-capture, immunohistochemistry for DCX could not reveal any significant evidence of putative adult hippocampal neurogenesis. Thus, as with all other mammals studied to date apart from cetaceans, bats, including both microchiropterans and megachiropterans, appear to exhibit substantial levels of adult hippocampal neurogenesis. The present study underscores the concept that, as with laboratory experiments, studies conducted on wild-caught animals need to be cognizant of the fact that acute stress (capture/handling) may induce major changes in the appearance of specific neural traits.

  1. Diazinon and diazoxon impair the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons

    Pizzurro, Daniella M.; Dao, Khoi [Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA (United States); Costa, Lucio G. [Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA (United States); Department of Neuroscience, University of Parma, Parma (Italy)

    2014-02-01

    Evidence from in vivo and epidemiological studies suggests that organophosphorus insecticides (OPs) are developmental neurotoxicants, but possible underlying mechanisms are still unclear. Astrocytes are increasingly recognized for their active role in normal neuronal development. This study sought to investigate whether the widely-used OP diazinon (DZ), and its oxygen metabolite diazoxon (DZO), would affect glial–neuronal interactions as a potential mechanism of developmental neurotoxicity. Specifically, we investigated the effects of DZ and DZO on the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons. The results show that both DZ and DZO adversely affect astrocyte function, resulting in inhibited neurite outgrowth in hippocampal neurons. This effect appears to be mediated by oxidative stress, as indicated by OP-induced increased reactive oxygen species production in astrocytes and prevention of neurite outgrowth inhibition by antioxidants. The concentrations of OPs were devoid of cytotoxicity, and cause limited acetylcholinesterase inhibition in astrocytes (18 and 25% for DZ and DZO, respectively). Among astrocytic neuritogenic factors, the most important one is the extracellular matrix protein fibronectin. DZ and DZO decreased levels of fibronectin in astrocytes, and this effect was also attenuated by antioxidants. Underscoring the importance of fibronectin in this context, adding exogenous fibronectin to the co-culture system successfully prevented inhibition of neurite outgrowth caused by DZ and DZO. These results indicate that DZ and DZO increase oxidative stress in astrocytes, and this in turn modulates astrocytic fibronectin, leading to impaired neurite outgrowth in hippocampal neurons. - Highlights: • DZ and DZO inhibit astrocyte-mediated neurite outgrowth in rat hippocampal neurons. • Oxidative stress is involved in inhibition of neuritogenesis by DZ and DZO. • DZ and DZO decrease expression of the neuritogenic

  2. Involvement of the GABAergic septo-hippocampal pathway in brain stimulation reward.

    Germán Vega-Flores

    Full Text Available The hippocampus is a structure related to several cognitive processes, but not very much is known about its putative involvement in positive reinforcement. In its turn, the septum has been related to instrumental brain stimulation reward (BSR by its electrical stimulation with trains of pulses. Although the anatomical relationships of the septo-hippocampal pathway are well established, the functional relationship between these structures during rewarding behaviors remains poorly understood. To explore hippocampal mechanisms involved in BSR, CA3-evoked field excitatory and inhibitory postsynaptic potentials (fEPSPs, fIPSPs were recorded in the CA1 area during BSR in alert behaving mice. The synaptic efficiency was determined from changes in fEPSP and fIPSP amplitudes across the learning of a BSR task. The successive BSR sessions evoked a progressive increase of the performance in inverse relationship with a decrease in the amplitude of fEPSPs, but not of fIPSPs. Additionally, we evaluated CA1 local field potentials (LFPs during a preference task, comparing 8-, 20-, and 100-Hz trains of septal BSR. We corroborate a clear preference for BSR at 100 Hz (in comparison with BSR at 20 Hz or 8 Hz, in parallel with an increase in the spectral power of the low theta band, and a decrease in the gamma. These results were replicated by intrahippocampal injections of a GABAB antagonist. Thus, the GABAergic septo-hippocampal pathway seems to carry information involved in the encoding of reward properties, where GABAB receptors seem to play a key role. With regard to the dorsal hippocampus, fEPSPs evoked at the CA3-CA1 synapse seem to reflect the BSR learning process, while hippocampal rhythmic activities are more related to reward properties.

  3. Leptin-induced downregulation of the rat hippocampal somatostatinergic system may potentiate its anorexigenic effects.

    Perianes-Cachero, Arancha; Burgos-Ramos, Emma; Puebla-Jiménez, Lilian; Canelles, Sandra; Viveros, María Paz; Mela, Virginia; Chowen, Julie A; Argente, Jesús; Arilla-Ferreiro, Eduardo; Barrios, Vicente

    2012-12-01

    The learning and memory mechanisms in the hippocampus translate hormonal signals of energy balance into behavioral outcomes involved in the regulation of food intake. As leptin and its receptors are expressed in the hippocampus and somatostatin (SRIF), an orexigenic neuropeptide, may inhibit leptin-mediated suppression of food intake in other brain areas, we asked whether chronic leptin infusion induces changes in the hippocampal somatostatinergic system and whether these modifications are involved in leptin-mediated effects. We studied 18 male Wistar rats divided into three groups: controls (C), treated intracerebroventricularly (icv) with leptin (12 μg/day) for 14 days (L) and a pair-fed group (PF) that received the same amount of food consumed by the L group. Food restriction increased whereas leptin decreased the hippocampal SRIF receptor density, due to changes in SRIF receptor 2 protein levels. These changes in the PF group were concurrent with an increase of hippocampal G protein-coupled receptor kinase 2 protein levels and activation of Akt and cyclic AMP response element binding protein. The inhibitory effect of SRIF on adenylyl cyclase (AC) activity, however, was decreased in L rats, coincident with lower G inhibitory α3 and higher AC-I levels as well as signal transducer and activator of transcription factor 3 activation. In addition, 20 male Wistar rats were included to analyze whether the leptin antagonist L39A/D40A/F41A and the SRIF receptor agonist SMS 201-995 modify SRIF signaling and food intake, respectively. Administration of L39A/D40A/F41A reversed changes in SRIF signaling, whereas SMS 201-995 ameliorated food consumption in L. Altogether, these results suggest that increased somatostatinergic tone in PF rats may be a mechanism to improve the hippocampal orexigenic effects in a situation of metabolic demand, whereas down-regulation of this system in L rats may represent a mechanism to enhance the anorexigenic effects of leptin.

  4. Neuroligin-1 knockdown reduces survival of adult-generated newborn hippocampal neurons

    Eric eSchnell

    2014-04-01

    Full Text Available Survival of adult-born hippocampal granule cells is modulated by neural activity, and thought to be enhanced by excitatory synaptic signaling. Here, we report that a reduction in the synaptogenic protein neuroligin-1 in adult-born neurons in vivo decreased their survival, but surprisingly, this effect was independent of changes in excitatory synaptic function. Instead, the decreased survival was associated with unexpected changes in dendrite and spine morphology during granule cell maturation, suggesting a link between cell growth and survival.

  5. Ethanol impairs muscarinic receptor-induced neuritogenesis in rat hippocampal slices: Role of astrocytes and extracellular matrix proteins.

    Giordano, Gennaro; Guizzetti, Marina; Dao, Khoi; Mattison, Hayley A; Costa, Lucio G

    2011-12-01

    In an in vitro co-culture system of astrocytes and neurons, stimulation of cholinergic muscarinic receptors in astrocytes had been shown to cause neuritogenesis in hippocampal neurons, and this effect was inhibited by ethanol. The present study sought to confirm these earlier findings in a more complex system, in vitro rat hippocampal slices in culture. Exposure of hippocampal slices to the cholinergic agonist carbachol (1mM for 24h) induced neurite outgrowth in hippocampal pyramidal neurons, which was mediated by activation of muscarinic M3 receptors. Specifically, carbachol induced a >4-fold increase in the length of the longest neurite, and a 4-fold increase in the length of minor neurites and in the number of branches. Co-incubation of carbachol with ethanol (50mM) resulted in significant inhibition of the effects induced by carbachol on all parameters measured. Neurite outgrowth in CNS neurons is dependent on various permissive factors that are produced and released by glial cells. In hippocampal slices carbachol increased the levels of two extracellular matrix protein, fibronectin and laminin-1, by 1.6-fold, as measured by Western blot. Co-incubation of carbachol with ethanol significantly inhibited these increases. Carbachol-induced increases in levels of extracellular matrix proteins were antagonized by a M3 muscarinic receptor antagonist. Furthermore, function-blocking fibronectin or laminin-1 antibodies antagonized the effect of carbachol on neurite outgrowth. These results indicate that in hippocampal slices stimulation of muscarinic M3 receptors induces neurite outgrowth, which is mediated by fibronectin and laminin-1, two extracellular matrix proteins released by astrocytes. By decreasing fibronectin and laminin levels ethanol prevents carbachol-induced neuritogenesis. These findings highlight the importance of glial-neuronal interactions as important targets in the developmental neurotoxicity of alcohol.

  6. Anterior Thalamic Lesions Alter Both Hippocampal-Dependent Behavior and Hippocampal Acetylcholine Release in the Rat

    Savage, Lisa M.; Hall, Joseph M.; Vetreno, Ryan P.

    2011-01-01

    The anterior thalamic nuclei (ATN) are important for learning and memory as damage to this region produces a persistent amnestic syndrome. Dense connections between the ATN and the hippocampus exist, and importantly, damage to the ATN can impair hippocampal functioning. Acetylcholine (ACh) is a key neurotransmitter in the hippocampus, and in vivo…

  7. Aberrant hippocampal neurogenesis after limbic kindling: Relationship to BDNF and hippocampal-dependent memory.

    Botterill, J J; Brymer, K J; Caruncho, H J; Kalynchuk, L E

    2015-06-01

    Seizures dramatically increase the number of adult generated neurons in the hippocampus. However, it is not known whether this effect depends on seizures that originate in specific brain regions or whether it is nonspecific to seizure activity regardless of origin. We used kindling of different brain sites to address this question. Rats received 99 kindling stimulations of the basolateral amygdala, dorsal hippocampus, or caudate nucleus over a 6-week period. After kindling, we counted the number of adult generated hippocampal neurons that were birth-dated with the proliferative marker bromodeoxyuridine (BrdU) to evaluate cell proliferation and survival under conditions of repeated seizures. Next, we counted the number of doublecortin immunoreactive (DCX-ir) cells and evaluated their dendritic complexity to determine if limbic and nonlimbic seizures have differential effects on neuronal maturation. We also quantified hippocampal brain-derived neurotrophin factor (BDNF) protein levels using an ELISA kit and assessed memory performance using a hippocampal-dependent fear conditioning paradigm. We found that limbic, but not nonlimbic, seizures dramatically increased hippocampal cell proliferation and the number of hilar-CA3 ectopic granule cells. Further, limbic kindling promoted dendritic outgrowth of DCX-ir cells and the number of DCX-ir cells containing basal dendrites. Limbic kindling also enhanced BDNF protein levels throughout the entire hippocampus and impaired the retrieval of fear memories. Collectively, our results suggest a relationship between limbic seizures, neurogenesis, BDNF protein, and cognition.

  8. The Impact of Sleep Loss on Hippocampal Function

    Prince, Toni-Moi; Abel, Ted

    2013-01-01

    Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are targeted by sleep…

  9. SU-E-T-449: Hippocampal Sparing Radiotherapy Using Intensity Modulated Radiotherapy and Volumetric Modulated Arc Therapy

    Moon, S [Korea University, Seoul (Korea, Republic of); Kyung Hee University Hospital at Gangdong, Gangdong-gu (Korea, Republic of); Kim, D; Chung, W [Kyung Hee University Hospital at Gangdong, Gangdong-gu (Korea, Republic of); Yoon, M [Korea University, Seoul (Korea, Republic of)

    2015-06-15

    Purpose: The hippocampus sparing during the cranial irradiation has become interesting because it may mitigate radiation-induced neurocognitive toxicity. Herein we report our preliminary study for sparing the hippocampus with and without tilling condition for patient with brain metastases. Methods: Ten patients previously treated with whole brain were reviewed. Five patients tilted the head to around 30 degrees and others were treated without tilting. Treatment plans of linear accelerator (Linac)-based volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) were generated for prescription dose of 30 Gy in 15 fractions. Hippocampal avoidance regions were created with 5-mm volumetric expansion around the hippocampus. Whole brain, hippocampus and hippocampal avoidance volume were 1372cm3, 6cm3 and 30cm3 and hippocampal avoidance volume was 2.2% of the whole brain planned target volume in average. Organs at risk (OARs) are hippocampus, eyes, lens, and cochleae. Coverage index (CVI), conformity index (CI), homogeneity index (HI) and mean dose to OARs were used to compare dose characteristic of tilted and non-tilted cases. Results: In IMRT, when CI, CVI and HI of whole brain were 0.88, 0.09 and 0.98 in both tilted and non-tilted cases, absorbed dose of hippocampal avoidance volume in tilted cases were 10% lower than non-tilted cases. Doses in other OARs such as eyes, lens, and cochleae were also decreased about 20% when tilting the head. When CI, HI and CVI in VMAT were 0.9, 0.08 and 0.99, the dose-decreased ratio of OARs in both with and without tilting cases were almost the same with IMRT. But absolute dose of hippocampal avoidance volume in VMAT was 30% lower than IMRT. Conclusion: This study confirms that dose to hippocampus decreases if patients tilt the head. When treating the whole brain with head tilted, patients can acquire the same successful treatment Result and also preserve their valuable memory.

  10. Influence of morphine on levels of type Ⅱ inhibitory guanine nucleotide binding protein in primary hippocampal neurons

    Qinghua Wu; Qiang Fu; Xinhua Wang; Jianhua Zhao; Liwei Liu; Shirong Tang

    2008-01-01

    BACKGROUND: The pharmacological action of opioid drugs is related to signal transduction of inhibitory guanine nucleotide binding protein.OBJECTIVE: To quantitatively and qualitatively analyze the influence of morphine on levels of type Ⅱ inhibitory guanine nucleotide binding protein (Gi2 protein) in primary cultured hippocampal neurons at different time points.DESIGN, TIME AND SETTING: A randomized controlled study, which was performed at the Department of Neurobiology, Changzheng Hospital, Second Military Medical University of Chinese PLA between September 2002 and March 2004.MATERIALS: Cerebral hippocampal neurons were obtained from newborn SD rats at 1-2 days of age. Biotin-antibody Ⅱ-avidin fluorescein isothiocyanate (Avidin-FITC) was purchased from Sigma Company (USA) and the Gi2 protein polyclonal antibody from Santa Cruz Biochemistry Company (USA).METHODS: Seven days after culture, mature hippocampal neurons were randomly divided into six groups: 4-, 8-, 16-, 24-, and 48-hour morphine groups, and a blank control group. Neurons in the morphine groups Received morphine (10μmol/L), which could cause alterations of G-protein mRNA and cAMP expression in the prefrontal cortex. Neurons in the blank control group were given the same volume of saline.MAIN OUTCOME MEASURES: Gi2 protein levels were detected by an immunofluorescence technique, and were analyzed by the image analytic system with the use of green fluorescence intensity.RESULTS: Gi2 protein levels in hippocampal neurons gradually decreased in the 4-, 8-, 16-, 24-, and 48-hour morphine groups. In particular, Gi2 protein levels in the 16-, 24-, and 48-hour morphine groups were significantly lower than that in the blank control group (P<0.05-0.01).CONCLUSION: Morphine may decrease Gi2 protein level in primary hippocampal neurons, and the decreasing trend is positively related to morphine-induced time.

  11. Chemotherapy, cognitive impairment and hippocampal toxicity.

    Dietrich, J; Prust, M; Kaiser, J

    2015-11-19

    Cancer therapies can be associated with significant central nervous system (CNS) toxicity. While radiation-induced brain damage has been long recognized both in pediatric and adult cancer patients, CNS toxicity from chemotherapy has only recently been acknowledged. Clinical studies suggest that the most frequent neurotoxic adverse effects associated with chemotherapy include memory and learning deficits, alterations of attention, concentration, processing speed and executive function. Preclinical studies have started to shed light on how chemotherapy targets the CNS both on cellular and molecular levels to disrupt neural function and brain plasticity. Potential mechanisms include direct cellular toxicity, alterations in cellular metabolism, oxidative stress, and induction of pro-inflammatory processes with subsequent disruption of normal cellular and neurological function. Damage to neural progenitor cell populations within germinal zones of the adult CNS has been identified as one of the key mechanisms by which chemotherapy might exert long-lasting and progressive neurotoxic effects. Based on the important role of the hippocampus for maintenance of brain plasticity throughout life, several experimental studies have focused on the study of chemotherapy effects on hippocampal neurogenesis and associated learning and memory. An increasing body of literature from both animal studies and neuroimaging studies in cancer patients suggests a possible relationship between chemotherapy induced hippocampal damage and the spectrum of neurocognitive deficits and mood alterations observed in cancer patients. This review aims to briefly summarize current preclinical and neuroimaging studies that are providing a potential link between the neurotoxic effects of chemotherapy and hippocampal dysfunction, highlighting challenges and future directions in this field of investigation.

  12. Control of noradrenaline release from hippocampal synaptosomes

    West, D.P.; Fillenz, M.

    1981-10-01

    Potassium-evoked tritiated noradrenaline (NA) release from hippocampal synaptosomes was measured with a superfusion method. A single 2-min high-K+ pulse released 39% of the vesicular NA by a Ca2+-dependent mechanism: the Ca2+-independent release was negligible. After changing the vesicular NA store size by pretreating rats with either alpha-methyl-para-tyrosine, 500 mg/kg, or tranylcypromine, 10 mg/kg, a single K+ pulse released a constant percentage of the vesicular NA. With two K+ pulses, however, there was a reduction in the percentage of vesicular NA released in response to the second pulse.

  13. EFFECT OF MOBILE PHONE RADIOFREQUENCY ON HIPPOCAMPAL CA3 NEURONS

    Srinivas Rao Bolla

    2015-09-01

    Full Text Available Objective: The purpose of the study is to investigate the effects of mobile phone [MP] radiofrequency electromagnetic fields (RF-EMF exposure for different durations on dendritic morphology and nerve cell damage in CA3 sub region of Hippocampus in Swiss albino mice. Materials &Methods: Total 70 Swiss albino mice of both sexes were used in the study. Animals were divided into 10 groups randomly. Five groups (n=6 were used for assessment of neuronal damage by cresyl violet staining. Another five groups (n=8 were used for assessment of dendritic morphology by Golgi- Cox staining. Groups were divided by exposure duration (15, 30, 45 and 60 minutes/ per day for 30 days; age matched unexposed groups served as controls. Results: Results of the study have shown that there was decrease in the number of viable neurons and dendritic arborization in CA3 sub region of hippocampus in 30, 45 and 60 min exposed groups. Conclusions: Increased neuronal damage and decreased dendritic arborization of hippocampal CA3 neurons was found with increase in exposure duration of MPRF-EMF.

  14. Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat.

    Gui, Z H; Zhang, Q J; Liu, J; Zhang, L; Ali, U; Hou, C; Fan, L L; Sun, Y N; Wu, Z H; Hui, Y P

    2011-10-01

    5-Hydroxytryptamine(1A) (5-HT(1A)) receptors are expressed in the prefrontal cortical interneurons. Among these interneurons, calcium-binding protein parvalbumin (PV)-positive fast spiking (FS) interneurons play an important role in regulatory function of the prefrontal cortex. In the present study, the response of medial prefrontal cortex (mPFC) FS interneurons to the selective 5-HT(1A) receptor agonist 8-OH-DPAT and change in expression of 5-HT(1A) receptor on PV-positive neurons were examined in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by using extracellular recording and double-labeling immunofluorescence histochemistry. Systemic administration of 8-OH-DPAT (1-243 μg/kg, i.v.) dose-dependently inhibited the mean firing rate of the FS interneurons in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition in the lesioned rats (243 μg/kg) was significantly higher than that of sham-operated rats (27 μg/kg). Furthermore, the local application of 8-OH-DPAT (0.01 μg) in the mPFC inhibited the FS interneurons in sham-operated rats, while having no effect on firing rate of the FS interneurons in the lesioned rats. In contrast to sham-operated rats, the lesion of the SNc in rats did not cause the change of PV-positive neurons in the prelimbic prefrontal cortex, a subregion of the mPFC, whereas the lesion of the SNc markedly reduced in percentage of PV-positive neurons expressing 5-HT(1A) receptors. Our results indicate that degeneration of the nigrostriatal pathway results in the decreased response of FS interneurons in the mPFC to 5-HT(1A) receptor stimulation, which attributes to down-regulation of 5-HT(1A) receptor expression in these interneurons.

  15. Exercise can rescue recognition memory impairment in a model with reduced adult hippocampal neurogenesis

    Pauline Lafenetre

    2010-02-01

    Full Text Available Running is a potent stimulator of cell proliferation in the adult dentate gyrus and these newly generated hippocampal neurons seem to be implicated in memory functions. Here we have used a mouse model expressing activated Ras under the direction of the neuronal Synapsin I promoter (named synRas mice. These mice develop down-regulated proliferation of adult hippocampal precursor cells and show decreased short-term recognition memory performances. Voluntary physical activity reversed the genetically blocked generation of hippocampal proliferating cells and enhanced the dendritic arborisation of the resulting doublecortin newly generated neurons. Moreover, running improved novelty recognition in both wild type and synRas littermates, compensating their memory deficits. Brain-derived neurotrophic factor (BDNF has been proposed to be a potential mediator of physical exercise acting in the hippocampus on dentate neurons and their precursors. This was confirmed here by the identification of doublecortin-immunoreactive cells expressing TrkB BDNF receptor. While no difference in BDNF levels were detected in basal conditions between the synRas mice and their wild type littermates, running was associated with enhanced BDNF expression levels. Thus increased BDNF signalling is a candidate mechanism to explain the observed effects of running. Our studies demonstrate that voluntary physical activity has a robust beneficial effect even in mice with genetically restricted neurogenesis and cognition.

  16. Astragaloside Ⅳ inhibits spontaneous synaptic transmission and synchronized Ca2+ oscillations on hippocampal neurons

    Shao-qing ZHU; Lei QI; Yan-fang RUI; Ru-xin LI; Xiang-ping HE; Zuo-ping XIE

    2008-01-01

    Aim: To investigate the changes in the spontaneous neuronal excitability in-duced by astragaloside Ⅳ (AGS-Ⅳ) in the cultured hippocampal network. Methods: Hippocampal neurons in culture for 9-11 d were used for this study. The sponta-neous synaptic activities of these hippocampal neurons were examined by Ca2+ imaging and whole-cell patch-clamp techniques. In total, 40 mg/L AGS-Ⅳ dis-solved in DMSO and 2 mL/L DMSO were applied to the neurons under a micro-scope while the experiments were taking place. Results: AGS-Ⅳ inhibited the frequencies of synchronized spontaneous Ca2+ oscillations to 59.39%+3.25% (mean+SEM), the spontaneous postsynaptic currents to 43.78%±7.72% (mean±SEM), and the spontaneous excitatory postsynaptic currents to 49.25%±7.06% (mean±SEM) of those of the control periods, respectively, at 16 min after the AGS-Ⅳ applications. AGS-Ⅳ also decreased the peak values of the voltage-gated K+ and Na+ channel currents at that time point. Conclusion: These results indicate that AGS-Ⅳ suppresses the spontaneous neuronal excitabilities effectively. Such a modulation of neuronal activity could represent new evidence for AGS-Ⅳ as a neuroprotector.

  17. Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone.

    Shende, Vishvesh H; McArthur, Simon; Gillies, Glenda E; Opacka-Juffry, Jolanta

    2015-01-01

    The long-term effects of antenatal dexamethasone treatment on brain remodelling in 3-month-old male Sprague Dawley rats whose mothers had been treated with dexamethasone were investigated in the present study. Dorsal hippocampus, basolateral amygdala and nucleus accumbens volume, cell numbers, and GFAP-immunoreactive astroglial cell morphology were analysed using stereology. Total brain volume as assessed by micro-CT was not affected by the treatment. The relative volume of the dorsal hippocampus (% of total brain volume) showed a moderate, by 8%, but significant reduction in dexamethasone-treated versus control animals. Dexamethasone had no effect on the total and GFAP-positive cell numbers in the hippocampal subregions, basolateral amygdala, and nucleus accumbens. Morphological analysis indicated that numbers of astroglial primary processes were not affected in any of the hippocampal subregions analysed but significant reductions in the total primary process length were observed in CA1 by 32%, CA3 by 50%, and DG by 25%. Mean primary process length values were also significantly decreased in CA1 by 25%, CA3 by 45%, and DG by 25%. No significant astroglial morphological changes were found in basolateral amygdala and nucleus accumbens. We propose that the dexamethasone-dependent impoverishment of hippocampal astroglial morphology is the case of maladaptive glial plasticity induced prenatally.

  18. Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone

    Vishvesh H. Shende

    2015-01-01

    Full Text Available The long-term effects of antenatal dexamethasone treatment on brain remodelling in 3-month-old male Sprague Dawley rats whose mothers had been treated with dexamethasone were investigated in the present study. Dorsal hippocampus, basolateral amygdala and nucleus accumbens volume, cell numbers, and GFAP-immunoreactive astroglial cell morphology were analysed using stereology. Total brain volume as assessed by micro-CT was not affected by the treatment. The relative volume of the dorsal hippocampus (% of total brain volume showed a moderate, by 8%, but significant reduction in dexamethasone-treated versus control animals. Dexamethasone had no effect on the total and GFAP-positive cell numbers in the hippocampal subregions, basolateral amygdala, and nucleus accumbens. Morphological analysis indicated that numbers of astroglial primary processes were not affected in any of the hippocampal subregions analysed but significant reductions in the total primary process length were observed in CA1 by 32%, CA3 by 50%, and DG by 25%. Mean primary process length values were also significantly decreased in CA1 by 25%, CA3 by 45%, and DG by 25%. No significant astroglial morphological changes were found in basolateral amygdala and nucleus accumbens. We propose that the dexamethasone-dependent impoverishment of hippocampal astroglial morphology is the case of maladaptive glial plasticity induced prenatally.

  19. Extracellular calcium modulates persistent sodium current-dependent burst-firing in hippocampal pyramidal neurons.

    Su, H; Alroy, G; Kirson, E D; Yaari, Y

    2001-06-15

    The generation of high-frequency spike bursts ("complex spikes"), either spontaneously or in response to depolarizing stimuli applied to the soma, is a notable feature in intracellular recordings from hippocampal CA1 pyramidal cells (PCs) in vivo. There is compelling evidence that the bursts are intrinsically generated by summation of large spike afterdepolarizations (ADPs). Using intracellular recordings in adult rat hippocampal slices, we show that intrinsic burst-firing in CA1 PCs is strongly dependent on the extracellular concentration of Ca(2+) ([Ca(2+)](o)). Thus, lowering [Ca(2+)](o) (by equimolar substitution with Mn(2+) or Mg(2+)) induced intrinsic bursting in nonbursters, whereas raising [Ca(2+)](o) suppressed intrinsic bursting in native bursters. The induction of intrinsic bursting by low [Ca(2+)](o) was associated with enlargement of the spike ADP. Low [Ca(2+)](o)-induced intrinsic bursts and their underlying ADPs were suppressed by drugs that reduce the persistent Na(+) current (I(NaP)), indicating that this current mediates the slow burst depolarization. Blocking Ca(2+)-activated K(+) currents with extracellular Ni(2+) or intracellular chelation of Ca(2+) did not induce intrinsic bursting. This and other evidence suggest that lowering [Ca(2+)](o) may induce intrinsic bursting by augmenting I(NaP). Because repetitive neuronal activity in the hippocampus is associated with marked decreases in [Ca(2+)](o), the regulation of intrinsic bursting by extracellular Ca(2+) may provide a mechanism for preferential recruitment of this firing mode during certain forms of hippocampal activation.

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

    Kevin T Gobeske

    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.

  1. Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice

    Dawe Gavin S

    2009-06-01

    Full Text Available Abstract Background Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. Running is a robust inducer of adult hippocampal neurogenesis. This study aims to address the effect of running on hippocampal neurogenesis in lesioned mice, where septohippocampal cholinergic neurones have been selectively eliminated in the medial septum and diagonal band of Broca of the basal forebrain by infusion of mu-p75-saporin immunotoxin. Results Running increased the number of newborn cells in the dentate gyrus of the hippocampus in cholinergic denervated mice compared to non-lesioned mice 24 hours after injection of bromodeoxyuridine (BrdU. Although similar levels of surviving cells were present in cholinergic depleted animals and their respective controls four weeks after injection of BrdU, the majority of progenitors that proliferate in response to the initial period of running were not able to survive beyond one month without cholinergic input. Despite this, the running-induced increase in the number of surviving neurones was not affected by cholinergic depletion. Conclusion The lesion paradigm used here models aspects of the cholinergic deficits associated with Alzheimer's Disease and aging. We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease.

  2. Interactions of the hippocampal system and the prefrontal cortex in learning language-like rules.

    Opitz, Bertram; Friederici, Angela D

    2003-08-01

    One of the most influential views on the hippocampal function suggests that this brain region is critically involved in relational memory processing, that is, binding converging inputs to mediate the representation of relationships among the constituents of episodes. It has been proposed that this binding is automatic and obligatory during learning and remembering In addition, neuroimaging studies have highlighted the importance of the prefrontal cortex, in learning, memory, and language processing. However, the posited importance of hippocampal-prefrontal interaction remains to be empirically tested. In the present study we used functional magnetic resonance imaging to examine in detail this interaction by assessing learning-related changes in hemodynamic activity during artificial language acquisition. It has been shown previously that artificial grammar systems might be learned by evaluating pattern-based relations in word sequences and generalizing beyond specific word order, that is, rule abstraction. During scanning, participants learned an artificial language whose miniature grammar meets the universal principles of a natural language. Increased proficiency level of the artificial language is associated with decreased left hippocampal activity. In contrast, we observed an increased recruitment of the left inferior frontal gyrus (Broca's area), a region that contributes to syntax processing in natural language. The present results, therefore, indicate a learning-related change in brain circuitry underlying relational processes of language learning, with a transition from a similarity-based learning system in the medial temporal lobes to a language-related processing system in the left prefrontal cortex.

  3. Somatosensory stimulation suppresses the excitability of pyramidal cells in the hippocampal CA1 region in rats

    Yang Wang; Zhouyan Feng; Jing Wang; Xiaojing Zheng

    2014-01-01

    The hippocampal region of the brain is important for encoding environment inputs and memory formation. However, the underlying mechanisms are unclear. To investigate the behavior of indi-vidual neurons in response to somatosensory inputs in the hippocampal CA1 region, we recorded and analyzed changes in local ifeld potentials and the ifring rates of individual pyramidal cells and interneurons during tail clamping in urethane-anesthetized rats. We also explored the mechanisms underlying the neuronal responses. Somatosensory stimulation, in the form of tail clamping, chan-ged local ifeld potentials into theta rhythm-dominated waveforms, decreased the spike ifring of py-ramidal cells, and increased interneuron ifring. In addition, somatosensory stimulation attenuated orthodromic-evoked population spikes. These results suggest that somatosensory stimulation sup-presses the excitability of pyramidal cells in the hippocampal CA1 region. Increased inhibition by local interneurons might underlie this effect. These ifndings provide insight into the mechanisms of signal processing in the hippocampus and suggest that sensory stimulation might have thera-peutic potential for brain disorders associated with neuronal hyperexcitability.

  4. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons.

    Murphy, D D; Cole, N B; Segal, M

    1998-09-15

    Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons.

  5. Parkia biglobosa Improves Mitochondrial Functioning and Protects against Neurotoxic Agents in Rat Brain Hippocampal Slices

    Kayode Komolafe

    2014-01-01

    Full Text Available Objective. Methanolic leaf extracts of Parkia biglobosa, PBE, and one of its major polyphenolic constituents, catechin, were investigated for their protective effects against neurotoxicity induced by different agents on rat brain hippocampal slices and isolated mitochondria. Methods. Hippocampal slices were preincubated with PBE (25, 50, 100, or 200 µg/mL or catechin (1, 5, or 10 µg/mL for 30 min followed by further incubation with 300 µM H2O2, 300 µM SNP, or 200 µM PbCl2 for 1 h. Effects of PBE and catechin on SNP- or CaCl2-induced brain mitochondrial ROS formation and mitochondrial membrane potential (ΔΨm were also determined. Results. PBE and catechin decreased basal ROS generation in slices and blunted the prooxidant effects of neurotoxicants on membrane lipid peroxidation and nonprotein thiol contents. PBE rescued hippocampal cellular viability from SNP damage and caused a significant boost in hippocampus Na+, K+-ATPase activity but with no effect on the acetylcholinesterase activity. Both PBE and catechin also mitigated SNP- or CaCl2-dependent mitochondrial ROS generation. Measurement by safranine fluorescence however showed that the mild depolarization of the ΔΨm by PBE was independent of catechin. Conclusion. The results suggest that the neuroprotective effect of PBE is dependent on its constituent antioxidants and mild mitochondrial depolarization propensity.

  6. Risk assessment for the combinational effects of food color additives: neural progenitor cells and hippocampal neurogenesis.

    Park, Mikyung; Park, Hee Ra; Kim, So Jung; Kim, Min-Sun; Kong, Kyoung Hye; Kim, Hyun Soo; Gong, Ein Ji; Kim, Mi Eun; Kim, Hyung Sik; Lee, Byung Mu; Lee, Jaewon

    2009-01-01

    In 2006, the Korea Food and Drug Administration reported that combinations of dietary colors such as allura red AC (R40), tartrazine (Y4), sunset yellow FCF (Y5), amaranth (R2), and brilliant blue FCF (B1) are widely used in food manufacturing. Although individual tar food colors are controlled based on acceptable daily intake (ADI), there is no apparent information available for how combinations of these additives affect food safety. In the current study, the potencies of single and combination use of R40, Y4, Y5, R2, and B1 were examined on neural progenitor cell (NPC) toxicity, a biomarker for developmental stage, and neurogenesis, indicative of adult central nervous system (CNS) functions. R40 and R2 reduced NPC proliferation and viability in mouse multipotent NPC, in the developing CNS model. Among several combinations tested in mouse model, combination of Y4 and B1 at 1000-fold higher than average daily intake in Korea significantly decreased numbers of newly generated cells in adult mouse hippocampus, indicating potent adverse actions on hippocampal neurogenesis. However, other combinations including R40 and R2 did not affect adult hippocampal neurogenesis in the dentate gyrus. Evidence indicates that single and combination use of most tar food colors may be safe with respect to risk using developmental NPC and adult hippocampal neurogenesis. However, the response to excessively high dose combination of Y4 and B1 is suggestive of synergistic effects to suppress proliferation of NPC in adult hippocampus. Data indicated that combinations of tar colors may adversely affect both developmental and adult hippocampal neurogenesis; thus, further extensive studies are required to assess the safety of these additive combinations.

  7. Loss of hippocampal function impairs pattern separation on a mouse touch-screen operant paradigm.

    Josey, Megan; Brigman, Jonathan L

    2015-11-01

    The hippocampus is heavily involved in the learning and memory processes necessary to successfully encode environmental stimuli and representations over time. Impairment of hippocampal function is associated with numerous neuropsychiatric diseases and can lead to detriments in the quality of life. In order to take full advantage of preclinical models of these disorders, there is a need for the development of more refined measures of clinically relevant hippocampal behaviors. While arena-based navigation tasks have provided fundamental information regarding the role of the hippocampus in spatial memory, the development of automated operant variants have had mixed results. Recently, an automated touch-screen paradigm has been shown to be highly sensitive to hippocampal function in the rat and eliminated mediating strategies that arose in previous tasks. Here we show that mice with lesions encompassing the entire ventral portion of the dorsal hippocampus are impaired on pattern separation behavior using a delayed nonmatching-to-location (TUNL) adapted for mice. Lesioned mice readily acquired the task at control rates when separations were maximal and delay periods were short while decreasing separations significantly impaired lesion mice. However, in contrast to previously reported results in the rat, consistently increasing delays did not significantly impair performance in the lesion group. Presentation of a variable delay within a session significantly impaired performance in lesion mice across delay periods. The current results demonstrate the utility of a touch-screen paradigm for measuring hippocampal-dependent pattern separation in the mouse and establish the paradigm as an important platform for future studies in disease models.

  8. Penicillin-induced epilepsy model in rats: dose-dependant effect on hippocampal volume and neuron number.

    Akdogan, Ilgaz; Adiguzel, Esat; Yilmaz, Ismail; Ozdemir, M Bulent; Sahiner, Melike; Tufan, A Cevik

    2008-10-22

    This study was designed to evaluate the penicillin-induced epilepsy model in terms of dose-response relationship of penicillin used to induce epilepsy seizure on hippocampal neuron number and hippocampal volume in Sprague-Dawley rats. Seizures were induced with 300, 500, 1500 and 2000IU of penicillin-G injected intracortically in rats divided in four experimental groups, respectively. Control group was injected intracortically with saline. Animals were decapitated on day 7 of treatment and brains were removed. The total neuron number of pyramidal cell layer from rat hippocampus was estimated using the optical fractionator method. The volume of same hippocampal areas was estimated using the Cavalieri method. Dose-dependent decrease in hippocampal neuron number was observed in three experimental groups (300, 500 and 1500IU of penicillin-G), and the effects were statistically significant when compared to the control group (P<0.009). Dose-dependent decrease in hippocampal volume, on the other hand, was observed in all three of these groups; however, the difference compared to the control group was only statistically significant in 1500IU of penicillin-G injected group (P<0.009). At the dose of 2000IU penicillin-G, all animals died due to status seizures. These results suggest that the appropriate dose of penicillin has to be selected for a given experimental epilepsy study in order to demonstrate the relevant epileptic seizure and its effects. Intracortical 1500IU penicillin-induced epilepsy model may be a good choice to practice studies that investigate neuroprotective mechanisms of the anti-epileptic drugs.

  9. White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy.

    Fiford, Cassidy M; Manning, Emily N; Bartlett, Jonathan W; Cash, David M; Malone, Ian B; Ridgway, Gerard R; Lehmann, Manja; Leung, Kelvin K; Sudre, Carole H; Ourselin, Sebastien; Biessels, Geert Jan; Carmichael, Owen T; Fox, Nick C; Cardoso, M Jorge; Barnes, Josephine

    2017-03-01

    This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5-T MRI. CSF Aβ42 and total tau were measured (n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Aβ42 and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (P = 0.002) and MCI subjects (P = 0.03), and with brain atrophy rate in controls (P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

  10. Cortisol, Cytokines, and Hippocampal Volume in the Elderly

    Keith Daniel Sudheimer

    2014-07-01

    Full Text Available Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  11. Intercellular adhesion molecule-1 expression in the hippocampal CA1 region of hyperlipidemic rats with chronic cerebral ischemia

    Yingying Cheng; Ying Zhang; Hongmei Song; Jiachun Feng

    2012-01-01

    Chronic cerebral ischemia is a pathological process in many cerebrovascular diseases and it is induced by long-term hyperlipidemia, hypertension and diabetes mellitus. After being fed a high-fat diet for 4 weeks, rats were subjected to permanent occlusion of bilateral common carotid arteries to establish rat models of chronic cerebral ischemia with hyperlipidemia. Intercellular adhesion molecule-1 expression in rat hippocampal CA1 region was determined to better understand the mechanism underlying the effects of hyperlipidemia on chronic cerebral ischemia. Water maze test results showed that the cognitive function of rats with hyperlipidemia or chronic cerebral ischemia, particularly in rats with hyperlipidemia combined with chronic cerebral ischemia, gradually decreased between 1 and 4 months after occlusion of the bilateral common carotid arteries. This correlated with pathological changes in the hippocampal CA1 region as detected by hematoxylin-eosin staining. Immunohistochemical staining showed that intercellular adhesion molecule-1 expression in the hippocampal CA1 region was noticeably increased in rats with hyperlipidemia or chronic cerebral ischemia, in particular in rats with hyperlipidemia combined with chronic cerebral ischemia. These findings suggest that hyperlipidemia aggravates chronic cerebral ischemia-induced neurological damage and cognitive impairment in the rat hippocampal CA1 region, which may be mediated, at least in part, by up-regulated expression of intercellular adhesion molecule-1.

  12. Carboxypeptidase E protects hippocampal neurons during stress in male mice by up-regulating prosurvival BCL2 protein expression.

    Murthy, S R K; Thouennon, E; Li, W-S; Cheng, Y; Bhupatkar, J; Cawley, N X; Lane, M; Merchenthaler, I; Loh, Y P

    2013-09-01

    Prolonged chronic stress causing elevated plasma glucocorticoids leads to neurodegeneration. Adaptation to stress (allostasis) through neuroprotective mechanisms can delay this process. Studies on hippocampal neurons have identified carboxypeptidase E (CPE) as a novel neuroprotective protein that acts extracellularly, independent of its enzymatic activity, although the mechanism of action is unclear. Here, we aim to determine if CPE plays a neuroprotective role in allostasis in mouse hippocampus during chronic restraint stress (CRS), and the molecular mechanisms involved. Quantitative RT-PCR/in situ hybridization and Western blots were used to assay for mRNA and protein. After mild CRS (1 h/d for 7 d), CPE protein and mRNA were significantly elevated in the hippocampal CA3 region, compared to naïve littermates. In addition, luciferase reporter assays identified a functional glucocorticoid regulatory element within the cpe promoter that mediated the up-regulation of CPE expression in primary hippocampal neurons following dexamethasone treatment, suggesting that circulating plasma glucocorticoids could evoke a similar effect on CPE in the hippocampus in vivo. Overexpression of CPE in hippocampal neurons, or CRS in mice, resulted in elevated prosurvival BCL2 protein/mRNA and p-AKT levels in the hippocampus; however, CPE(-/-) mice showed a decrease. Thus, during mild CRS, CPE expression is up-regulated, possibly contributed by glucocorticoids, to mediate neuroprotection of the hippocampus by enhancing BCL2 expression through AKT signaling, and thereby maintaining allostasis.

  13. MRI and 1H-MRS detects volumetric and metabolic abnormalities of hippocampal sclerosis in temporal lobe epilepsy

    2007-01-01

    Objective:To further investigate the ability of MRI and 1H-MRS techniques for presurgical evaluation of hippocampal sclerosis. Methods:MRI and 1H-MRS were performed on 30 healthy subjects to determine the confidence levels. Eight patients who were pathologically confirmed hippocampal sclerosis were then studied using the same protocols. The difference of hippocampal formation (DHF) was used to determine atrophy of hippocampus. Areas under the peak of N-acetylaspartate(NAA) ,Creatine(Cr) and Choline (Cho) were measured, and the ratios of NAA/Cr, Cho/Cr, and NAA/Cr+Cho were calculated. NAA/Cr+Cho value was applied to localize the seizure focus. Results:Two patients showed hippocampal atrophy according to DHF value. NAA/Cr ratio decreased significantly in ipsilateral hippocampus compared to that in contralateral hippocampus and control subjects(P<0.01). Cho/Cr value increased in both ipsi-and contralateral hippocampus in comparison with that in control subjects(P<0.01). NAA/Cr+Cho ratio, however, significantly reduced in both ipsi-and contralateral hippocampus(P<0.01) with lowest NAA/Cr+Cho ratio in seizure foci. Six patients could be lateralized by reduced and/or asymmetric NAA/Cr+Cho value. Conclusion:1H-MRS should be a promising diagnostic tool to detect neuron abnormality.1H-MRS and MRI complement each other hi presurgical lateralization of epileptogenic lesion in epilepsy patients.

  14. A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells.

    Green, Holly F; Treacy, Eimear; Keohane, Aoife K; Sullivan, Aideen M; O'Keeffe, Gerard W; Nolan, Yvonne M

    2012-03-01

    Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1β (IL-1β) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessed the effect of IL-1β on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1β treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1β, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1β exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1β signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired.

  15. Exploring the potential relationship between Notch pathway genes expression and their promoter methylation in mice hippocampal neurogenesis.

    Zhang, Zhen; Gao, Feng; Kang, Xiaokui; Li, Jia; Zhang, Litong; Dong, Wentao; Jin, Zhangning; Li, Fan; Gao, Nannan; Cai, Xinwang; Yang, Shuyuan; Zhang, Jianning; Ren, Xinliang; Yang, Xinyu

    2015-04-01

    The Notch pathway is a highly conserved pathway that regulates hippocampal neurogenesis during embryonic development and adulthood. It has become apparent that intracellular epigenetic modification including DNA methylation is deeply involved in fate specification of neural stem cells (NSCs). However, it is still unclear whether the Notch pathway regulates hippocampal neurogenesis by changing the Notch genes' DNA methylation status. Here, we present the evidence from DNA methylation profiling of Notch1, Hes1 and Ngn2 promoters during neurogenesis in the dentate gyrus (DG) of postnatal, adult and traumatic brains. We observed the expression of Notch1, Hes1 and Ngn2 in hippocampal DG with qPCR, Western blot and immunofluorescence staining. In addition, we investigated the methylation status of Notch pathway genes using the bisulfite sequencing PCR (BSP) method. The number of Notch1 or Hes1 (+) and BrdU (+) cells decreased in the subgranular zone (SGZ) of the DG in the hippocampus following TBI. Nevertheless, the number of Ngn2-positive cells in the DG of injured mice was markedly higher than in the DG of non-TBI mice. Accordingly, the DNA methylation level of the three gene promoters changed with their expression in the DG. These findings suggest that the strict spatio-temporal expression of Notch effector genes plays an important role during hippocampal neurogenesis and suggests the possibility that Notch1, Hes1 and Ngn2 were regulated by changing some specific CpG sites of their promoters to further orchestrate neurogenesis in vivo.

  16. Protective mechanisms of microRNA-27a against oxygen-glucose deprivation-induced injuries in hippocampal neurons

    Qun Cai; Ting Wang; Wen-jie Yang; Xing Fen

    2016-01-01

    Hypoxic injuries during fetal distress have been shown to cause reduced expression of microRNA-27a (miR-27a), which regulates sensi-tivity of cortical neurons to apoptosis. We hypothesized that miR-27a overexpression attenuates hypoxia-and ischemia-induced neuronal apoptosis by regulating FOXO1, an important transcription factor for regulating the oxidative stress response. miR-27a mimic was transfected into hippocampal neurons to overexpress miR-27a. Results showed increased hippocampal neuronal viability and decreased caspase-3 ex-pression. The luciferase reporter gene system demonstrated that miR-27a directly binded to FOXO1 3′UTR in hippocampal neurons and inhibited FOXO1 expression, suggesting that FOXO1 was the target gene for miR-27a. These ifndings conifrm that miR-27a protects hippo-campal neurons against oxygen-glucose deprivation-induced injuries. The mechanism might be mediated by modulation of FOXO1 and apoptosis-related gene caspase-3 expression.

  17. Elemental changes in the hippocampal formation following two different formulas of ketogenic diet: an X-ray fluorescence microscopy study.

    Chwiej, J; Patulska, A; Skoczen, A; Janeczko, K; Ciarach, M; Simon, R; Setkowicz, Z

    2015-12-01

    The main purpose of the following study was the determination of elemental changes occurring within hippocampal formation as a result of high-fat and carbohydrate-restricted ketogenic diet (KD). To realize it, X-ray fluorescence microscopy was applied for topographic and quantitative analysis of P, S, K, Ca, Fe, Cu, Zn and Se in hippocampal formations taken from rats fed with two different KDs and naive controls. The detailed comparisons were done for sectors 1 and 3 of the Ammon's, the dentate gyrus and hilus of dentate gyrus. The results of elemental analysis showed that the KDs induced statistically significant changes in the accumulation of P, K, Ca, Zn and Se in particular areas of hippocampal formation and these alterations strongly depended on the composition of the diets. Much greater influence on the hippocampal areal densities of examined elements was found for the KD which was characterized by a lower content of carbohydrates, higher content of fats and increased proportion of unsaturated fatty acids. The levels of P, K and Zn decreased whilst those of Ca and Se increased as a result of the treatment with the KDs.

  18. Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons.

    Pugazhenthi, Subbiah; Nesterova, Albina; Jambal, Purevsuren; Audesirk, Gerald; Kern, Marcey; Cabell, Leigh; Eves, Eva; Rosner, Marsha R; Boxer, Linda M; Reusch, Jane E-B

    2003-03-01

    Generation of oxidative stress/reactive oxygen species (ROS) is one of the causes of neuronal apoptosis. We have examined the effects of ROS at the transcriptional level in an immortalized hippocampal neuronal cell line (H19-7) and in rat primary hippocampal neurons. Treatment of H19-7 cells with hydrogen peroxide (150 micro m) resulted in a 40% decrease in Bcl-2 protein and a parallel decrease in bcl-2 mRNA levels. H19-7 cells overexpressing bcl-2 were found to be resistant to ROS-induced apoptosis. We had previously shown that bcl-2 promoter activity is positively regulated by the transcription factor cyclic AMP response element binding protein (CREB) in neurons. In the present study, we demonstrate that ROS decreases the activity of luciferase reporter gene driven by a cyclic AMP response element site containing bcl-2 promoter. Exposure of neurons to ROS for 6 h resulted in basal and fibroblast growth factor-2-stimulated phosphorylation/activation of CREB. Chronic 24 h treatment with ROS led to a significant (p < 0.01) decrease in CREB protein and CREB mRNA levels. Adenoviral overexpression of wild type CREB in H19-7 cells resulted in significant (p < 0.01) protection against ROS-induced apoptosis through up-regulation of Bcl-2 expression whereas dominant negative CREB exaggerated the injury. These findings demonstrate that loss of CREB function contributes to oxidative stress-induced neuronal dysfunction.

  19. Hippocampal Sclerosis After Febrile Status Epilepticus: The FEBSTAT Study

    Lewis, Darrell V.; Shinnar, Shlomo; Hesdorffer, Dale C.; Bagiella, Emilia; Bello, Jacqueline A.; Chan, Stephen; Xu, Yuan; MacFall, James; Gomes, William A.; Moshé, Solomon L.; Mathern, Gary W.; Pellock, John M.; Nordli, Douglas R.; Frank, L. Matthew; Provenzale, James; Shinnar, Ruth C.; Epstein, Leon G.; Masur, David; Litherland, Claire; Sun, Shumei

    2014-01-01

    Objective Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine if FSE produces acute hippocampal injury that evolves to HS. Methods FEBSTAT and two affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute MRIs and follow-up MRIs were obtained at approximately 1 year later in the majority. Visual interpretation by two neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intra-hippocampal distribution of T2 signal, and apparent diffusion coefficients. Results Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRIs obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRIs had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially and reduced hippocampal growth. Interpretation Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after one year. Furthermore, impaired growth of normal appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE. PMID:24318290

  20. Early detection of Alzheimer's disease using MRI hippocampal texture

    Sørensen, Lauge; Igel, Christian; Hansen, Naja Liv

    2016-01-01

    Cognitive impairment in patients with Alzheimer's disease (AD) is associated with reduction in hippocampal volume in magnetic resonance imaging (MRI). However, it is unknown whether hippocampal texture changes in persons with mild cognitive impairment (MCI) that does not have a change...... applied to score independent data sets from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and the Metropolit 1953 Danish Male Birth Cohort (Metropolit). Hippocampal texture was superior to volume reduction as predictor of MCI-to-AD conversion in ADNI (area under...

  1. Atorvastatin increases dynamin 1 expression in hippocampal CA1 region in a rat model of vascular dementia

    Qinghua Li; Wensheng Zhou

    2011-01-01

    The current study examined a rat model of vascular dementia. The model rats exhibited obvious morphological and ultrastructural changes in neurons in the brain, and significantly reduced dynamin 1 expression in hippocampal CA1 region along with decreased learning and memory performance. Following atorvastatin treatment, the morphology and ultrastructure of cells in the model rat brain were significantly improved, dynamin 1 expression in hippocampal CA1 region was significantly enhanced, and learning and memory ability was significantly improved. The results demonstrated that impaired learning and memory abilities in vascular dementia model rats were closely correlated with decreased dynamin 1 expression. These findings indicate that atorvastatin can protect model rats against cognitive impairment by increasing dynamin 1 expression.

  2. Partial loss of parvalbumin-containing hippocampal interneurons in dementia with Lewy bodies.

    Bernstein, Hans-Gert; Johnson, Mary; Perry, Robert H; LeBeau, Fiona E N; Dobrowolny, Henrik; Bogerts, Bernhard; Perry, Elaine K

    2011-02-01

    Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. Among many other neuropathological changes in DLB, brain region-specific cellular deficits have been reported. They include decreases in motor neuron and pyramidal cell densities, while neocortical parvalbumin (parv)-containing neurons are thought to be free of Lewy bodies and spared in DLB. However, elevated parv levels are found in the cerebrospinal fluid of patients suffering from dementia with Lewy bodies. We performed an immunohistochemical analysis of hippocampal parv-immunoreactive neurons in well-characterised DLB cases and from controls using a specific antibody against the calcium binding protein. In addition, an analysis of the regional and cellular distribution of alpha-synuclein was carried out. Subfield and laminar distribution of parv-immunoreactive (ir) neurons on the hippocampus in subjects with DLB and controls were present exclusively as non-granule cells of the dentate gyrus (DG)/hilus and non-pyramidal cells of CA1, CA2, CA3 and CA4 areas of the hippocampus. The distribution patterns did not differ qualitatively between DLB and controls. Quantitative estimation of parv-ir neuron density revealed significant decreases in the dentate (DG)/hilus region as well as in the CA1 subfield. Double immunolabelling experiments showed that only 2% of parv expressing interneurons were laden with alpha-synuclein immunoreactive material. No significant changes were found for the total neuron densities in DLB cases. Our results show a partial loss of parv-expressing hippocampal interneurons in DLB, which might be the result of long-lasting calcium overload in combination with a proposed impaired mitochondrial function. It remains to be elucidated if the numerical decrease of this particular subset of hippocampal interneurons has consequences for the gamma (20-80 Hz) frequency activity in DLB patients.

  3. MEK inhibitor PD98059 acutely inhibits synchronized spontaneous Ca2+ oscillations in cultured hippocampal networks

    Yan-fang RUI; Zhao-hui SUN; Jia-ping GU; Zhong-hua SHENG; Xiang-ping HE; Zuo-ping XIE

    2006-01-01

    Aim: To investigate the changes in synchronized spontaneous Ca2+ oscillations induced by mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 at different concentrations in cultured hippocampal network. Methods: Hippocampal neurons in culture for 1-2 weeks were used for this study. Spontaneous synaptic activities of these hippocampal neurons were examined by Ca2+ imaging using calcium-sensitive dye. MEK inhibitor PD98059 (10,30, and 60 μmol/L) and SB202474 (10 and 60 μmol/L), a negative control for mitogen-activated protein kinase (MAPK) cascade study, were applied to the cells under the microscope while imaging was taking place. Results: PD98059 at a lower concentration of 10 μmol/L had little effect on the Ca2+ oscillation. At the higher concentration of 30 μmol/L, 5 min after application of PD98059, the spike frequency was decreased to 25.38%±7.40% (mean±SEM, n=16, F<0.01 vs medium control) of that of the control period. At an even higher concentration of 60 μmol/L, 5 min after application of PD98059, the spike frequency was decreased to 14.53%±5.34% (mean±SEM, n=16, P<0.01 vs medium control) of that of the control period. The spike amplitude underwent a corresponding decrease. However, the negative control SB202474 at concentrations of 10 and 60 μmol/L had little inhibition effect on the Ca2+ oscillation. Conclusion: These results indicate that PD98059 inhibits synchronized spontaneous Ca2+ oscillation through inhibition of MEK, which hints that the MAPK cascade is required to maintain synchronized spontaneous Ca2+ oscillation.

  4. Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval

    Ishikawa, Rie; Fukushima, Hotaka; Frankland, Paul W; Kida, Satoshi

    2016-01-01

    Forgetting of recent fear memory is promoted by treatment with memantine (MEM), which increases hippocampal neurogenesis. The approaches for treatment of post-traumatic stress disorder (PTSD) using rodent models have focused on the extinction and reconsolidation of recent, but not remote, memories. Here we show that, following prolonged re-exposure to the conditioning context, enhancers of hippocampal neurogenesis, including MEM, promote forgetting of remote contextual fear memory. However, these interventions are ineffective following shorter re-exposures. Importantly, we find that long, but not short re-exposures activate gene expression in the hippocampus and induce hippocampus-dependent reconsolidation of remote contextual fear memory. Furthermore, remote memory retrieval becomes hippocampus-dependent after the long-time recall, suggesting that remote fear memory returns to a hippocampus dependent state after the long-time recall, thereby allowing enhanced forgetting by increased hippocampal neurogenesis. Forgetting of traumatic memory may contribute to the development of PTSD treatment. DOI: http://dx.doi.org/10.7554/eLife.17464.001 PMID:27669409

  5. Hippocampal kindling alters the concentration of glial fibrillary acidic protein and other marker proteins in rat brain

    Hansen, A; Jørgensen, Ole Steen; Bolwig, T G;

    1990-01-01

    The effect of hippocampal kindling on neuronal and glial marker proteins was studied in the rat by immunochemical methods. In hippocampus, pyriform cortex and amygdala there was an increase in glial fibrillary acidic protein (GFAP), indicating reactive gliosis, and an increase in the glycolytic...... enzyme NSE, suggesting increased anaerobic metabolism. Neuronal cell adhesion molecule (NCAM) decreased in pyriform cortex and amygdala of kindled rats, indicating neuronal degeneration....

  6. Restoration of Akt activity by the bisperoxovanadium compound bpV(pic) attenuates hippocampal apoptosis in experimental neonatal pneumococcal meningitis.

    Sury, Matthias D; Vorlet-Fawer, Lorianne; Agarinis, Claudia; Yousefi, Shida; Grandgirard, Denis; Leib, Stephen L; Christen, Stephan

    2011-01-01

    Pneumococcal meningitis causes apoptosis of developing neurons in the dentate gyrus of the hippocampus. The death of these cells is accompanied with long-term learning and memory deficits in meningitis survivors. Here, we studied the role of the PI3K/Akt (protein kinase B) survival pathway in hippocampal apoptosis in a well-characterized infant rat model of pneumococcal meningitis. Meningitis was accompanied by a significant decrease of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and of phosphorylated (i.e., activated) Akt in the hippocampus. At the cellular level, phosphorylated Akt was decreased in both the granular layer and the subgranular zone of the dentate gyrus, the region where the developing neurons undergo apoptosis. Protein levels and activity of PTEN, the major antagonist of PI3K, were unaltered by infection, suggesting that the observed decrease in PIP(3) and Akt phosphorylation is a result of decreased PI3K signaling. Treatment with the PTEN inhibitor bpV(pic) restored Akt activity and significantly attenuated hippocampal apoptosis. Co-treatment with the specific PI3K inhibitor LY294002 reversed the restoration of Akt activity and attenuation of hippocampal apoptosis, while it had no significant effect on these parameters on its own. These results indicate that the inhibitory effect of bpV(pic) on apoptosis was mediated by PI3K-dependent activation of Akt, strongly suggesting that bpV(pic) acted on PTEN. Treatment with bpV(pic) also partially inhibited the concentration of bacteria and cytokines in the CSF, but this effect was not reversed by LY294002, indicating that the effect of bpV(pic) on apoptosis was independent of its effect on CSF bacterial burden and cytokine levels. These results indicate that the PI3K/Akt pathway plays an important role in the death and survival of developing hippocampal neurons during the acute phase of pneumococcal meningitis.

  7. Staining protocol for organotypic hippocampal slice cultures.

    Gogolla, Nadine; Galimberti, Ivan; DePaola, Vincenzo; Caroni, Pico

    2006-01-01

    This protocol details a method to immunostain organotypic slice cultures from mouse hippocampus. The cultures are based on the interface method, which does not require special equipment, is easy to execute and yields slice cultures that can be imaged repeatedly, from the time of isolation at postnatal day 6-9 up to 6 months in vitro. The preserved tissue architecture facilitates the analysis of defined hippocampal synapses, cells and entire projections. Time-lapse imaging is based on transgenes expressed in the mice or on constructs introduced through transfection or viral vectors; it can reveal processes that develop over periods ranging from seconds to months. Subsequent to imaging, the slices can be processed for immunocytochemistry to collect further information about the imaged structures. This protocol can be completed in 3 d.

  8. Spatial relational memory requires hippocampal adult neurogenesis.

    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.

  9. Cocaine depresses GABAA current of hippocampal neurons.

    Ye, J H; Liu, P L; Wu, W H; McArdle, J J

    1997-10-01

    Although blockade of dopamine re-uptake and the resulting elevation of excitatory agonists is commonly thought the primary mechanism of cocaine-induced seizures, it is possible that other neurotransmitters such as gamma-aminobutyric acid (GABA) are involved. To examine this possibility, the effects of cocaine on the whole cell GABA current (IGABA) of freshly isolated rat hippocampal neurons were investigated with the patch-clamp technique. Preincubation or acute application of cocaine reversibly suppressed IGABA. The IC50 was 127 microM when cocaine was applied before the application of GABA. The concentration-response relations of cocaine in various GABA concentrations revealed that cocaine inhibited IGABA non-competitively. This effect of cocaine appeared to be independent of voltage. The present study suggests that the GABA receptor/channel complex is also a target for cocaine's action. The suppression of IGABA may contribute to cocaine-induced seizures.

  10. Correlation between phosphorylation level of a hippocampal 86kDa protein and extinction of a behaviour in a model of Wernicke-Korsakoff syndrome.

    Pires, Rita G W; Pereira, Sílvia R C; Carvalho, Fabiana M; Oliveira-Silva, Ieda F; Ferraz, Vany P; Ribeiro, Angela M

    2007-06-04

    The effects of chronic ethanol and thiamine deficiency, alone or associated, on hippocampal protein phosphorylation profiles ranging in molecular weight from 30 to 250kDa molecular weight, in stimulated (high K(+) concentration) and unstimulated (basal) conditions were investigated. These treatments significantly changed the phosphorylation level of an 86kDa phosphoprotein. Thiamine deficiency, but not chronic ethanol, induced a decrease in a behavioural extinction index, which is significantly correlated to the phosphorylation level of the p86 protein. These data add to and extend previous findings by our laboratory implicating the involvement of hippocampal neurotransmission components in extinction of a behaviour which involves learning of environmental spatial cues.

  11. Glucocorticoid effects on hippocampal protein synthesis

    Schlatter, L.K.

    1988-01-01

    Following subcutaneous injection of rats with 5 mg corticosterone, hippocampal slices in vitro show increased ({sup 35}S)-methionine labeling of a cytosolic protein with an apparent molecular weight (M{sub r}) of 35,000 and an isoelectric point (IEP) of 6.6. This labeling is temporally consistent with a transcriptional event, and is steroid- and tissue-specific. The pear serum concentration of steroid occurs one hour or less following the injection. Maximal labeling of this protein is reached whenever serum corticosterone values are approximately 100 ng/ml. When endogenous corticosterone levels are elevated to 100 ng/ml through stressors or exogenous ACTH injections the same maximal increase in synthesis of the 35,000 M{sub r} protein is observed. Adrenalectomy prevents the observed response from occurring following stressor application or ACTH injections. Comparison of the increases observed after administration of the type 2 receptor agonist RU 28362 and aldosterone, which has a higher affinity for the type 1 receptor, shows a 50-fold greater sensitivity of the response to the type 2 receptor agonist. Synthesis of this protein following serum increases of steroid possibly correlates to the theorized function of the type 2 receptor feedback regulation. The similar protein in the liver has an IEP of 6.8 and a slightly higher M{sub r}. A second hippocampal protein with an M{sub r} of 46,000 and an IEP of 6.2 is also increased in labeling. Two additional liver proteins, one of Mr 53,000 (IEP of 6.2) and the other with an M{sub r} of 45,000 (IEP of 8.7-7.8) are increased in the liver following glucocorticoid administration.

  12. Hippocampal sharp waves: their origin and significance.

    Buzsáki, G

    1986-11-29

    This study investigated the spatial distribution and cellular-synaptic generation of hippocampal sharp waves (SPW) in the dorsal hippocampus of the awake rat. Depth analyses of SPWs were performed by stepping the recording electrode in 82.5 microns increments. SPWs were present during slow wave sleep, awake immobility, drinking, grooming and eating (0.01-2/s). The largest negative SPWs were recorded from the middle part of the stratum radiatum of CA1, the stratum lucidum of CA3, the inner molecular layer of the dentate gyrus and from layer I of the subiculum, in that order. The polarity of the SPWs was positive in layers II-IV of the subiculum, in stratum oriens and stratum pyramidale of CA1 and CA3, and in the hilus of the dentate gyrus. The electrical gradients across the null zones of the field SPWs were as large as 8-14 mV/mm. SPWs were associated with population bursts of pyramidal cells and increased discharges of interneurons and granule cells. During the SPW the excitability of granule cells and pyramidal cells to afferent volleys increased considerably. Picrotoxin and atropine and aspiration lesion of the fimbria-fornix increased either the amplitude or the frequency of SPWs. Diazepam and Nembutal could completely abolish SPWs. It is suggested that: hippocampal SPWs are triggered by a population burst of CA3 pyramidal cells as a result of temporary disinhibition from afferent control; and field SPWs represent summed extracellular PSPs of CA1 and subicular pyramidal cells, and dentate granular cells induced by the Schaffer collaterals and the associational fibers of hilar cells, respectively. The relevance of the physiological SPWs to epileptic interictal spikes and long-term potentiation is discussed.

  13. Rhinal-hippocampal EEG coherence is reduced during human sleep.

    Fell, J.; Staedtgen, M.; Burr, W.; Kockelmann, E.; Helmstaedter, C.; Schaller, C.; Elger, C.E.; Fernandez, G.S.E.

    2003-01-01

    The deficiency of declarative memory compared with waking state is an often overlooked characteristic of sleep. Here, we investigated whether rhinal-hippocampal coherence, an electrophysiological correlate of declarative memory formation, is significantly altered during sleep as compared with waking

  14. Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects.

    Geil, Chelsea R; Hayes, Dayna M; McClain, Justin A; Liput, Daniel J; Marshall, S Alex; Chen, Kevin Y; Nixon, Kimberly

    2014-10-03

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may be one route by which alcohol produces hippocampal neuropathology. Alcohol is a pharmacologically promiscuous drug capable of interfering with adult neurogenesis through multiple mechanisms. This review will discuss the primary mechanisms underlying alcohol-induced changes in adult hippocampal neurogenesis including alcohol's effects on neurotransmitters, CREB and its downstream effectors, and the neurogenic niche.

  15. Segmentation of the mouse hippocampal formation in magnetic resonance images.

    Richards, Kay; Watson, Charles; Buckley, Rachel F; Kurniawan, Nyoman D; Yang, Zhengyi; Keller, Marianne D; Beare, Richard; Bartlett, Perry F; Egan, Gary F; Galloway, Graham J; Paxinos, George; Petrou, Steven; Reutens, David C

    2011-10-01

    The hippocampal formation plays an important role in cognition, spatial navigation, learning, and memory. High resolution magnetic resonance (MR) imaging makes it possible to study in vivo changes in the hippocampus over time and is useful for comparing hippocampal volume and structure in wild type and mutant mice. Such comparisons demand a reliable way to segment the hippocampal formation. We have developed a method for the systematic segmentation of the hippocampal formation using the perfusion-fixed C57BL/6 mouse brain for application in longitudinal and comparative studies. Our aim was to develop a guide for segmenting over 40 structures in an adult mouse brain using 30 μm isotropic resolution images acquired with a 16.4 T MR imaging system and combined using super-resolution reconstruction.

  16. Neuroprotection of n-Butanol Extract from Roots of Potentilla anserina on Hypoxic Injury in Primary Hippocampal Neurons

    QIN Xiao-jing; LI Ling-zhi; LV Qi; YU Bao-guo; YANG Shu-wang; HE Tao; ZHANG Yong-liang

    2012-01-01

    Objective To investigate the protective effect of n-butanol extract from the roots of Potentilla anserina (NP) on hypoxic hippocampal neurons in neonatal rats.Methods Primary cultured hippocampal neurons were pretreated with different concentration of NP (0.25,0.0625,and 0.0156 mg/mL) before incubation in a low oxygen (0.1%) environment for 4 h.Cell viability was evaluated by Trypan blue staining assay.Lactate dehydrogenase (LDH) released by neurons into the medium was measured.The activity of superoxide dismutase (SOD) in cell cytosol was determined using nitroblue tetrazolium.Morphological changes and mitochondrial function were observed by transmission electron microscopy.Results Hypoxic injury could decrease the cells viability of neuron,enhance LDH release (P < 0.05),decrease SOD activity,and increase mitochondrial injury.Pretreatment with NP significantly increased cell viability,decreased LDH release (P < 0.05),promoted SOD activity (P < 0.05),and remarkably improved cellular ultra-microstructure compared with the model group.Conclusion NP could protect the primary hippocampal neurons from hypoxic injury by attenuating mitochondrial cell death.

  17. Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype.

    Guiard, Bruno P; David, Denis J P; Deltheil, Thierry; Chenu, Franck; Le Maître, Erwan; Renoir, Thibault; Leroux-Nicollet, Isabelle; Sokoloff, Pierre; Lanfumey, Laurence; Hamon, Michel; Andrews, Anne M; Hen, René; Gardier, Alain M

    2008-02-01

    Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.

  18. Perforated patch-clamp analysis of the passive membrane properties of three classes of hippocampal neurons.

    Spruston, N; Johnston, D

    1992-03-01

    1. Perforated patch-clamp recordings were made from the three major classes of hippocampal neurons in conventional in vitro slices prepared from adult guinea pigs. This technique provided experimental estimates of passive membrane properties (input resistance, RN, and membrane time constant, tau m) determined in the absence of the leak conductance associated with microelectrode impalement or the washout of cytoplasmic constituents associated with conventional whole-cell recordings. 2. To facilitate comparison of our data with previous results and to determine the passive membrane properties under conditions as physiological as possible, recordings were made at the resting potential, in physiological saline, and without any added blockers of voltage-dependent conductances. 3. Membrane-potential responses to current steps were analyzed, and four criteria were used to identify voltage responses that were the least affected by activation of voltage-dependent conductances. tau m was estimated from the slowest component (tau 0) of multiexponential fits of responses deemed passive by these criteria. RN was estimated from the slope of the linear region in the hyperpolarizing direction of the voltage-current relation. 4. It was not possible to measure purely passive membrane properties that were completely independent of membrane potential in any of the three classes of hippocampal neurons. Changing the membrane potential by constant current injection resulted in changes in RN and tau 0; subthreshold depolarization produced an increase, and hyperpolarization a decrease, in both RN and tau 0 for all three classes of hippocampal neurons. 5. Each of the three classes of hippocampal neurons also displayed a depolarizing "sag" during larger hyperpolarizing voltage transients. To evaluate the effect of the conductances underlying this sag on passive membrane properties, 2-5 mM Cs+ was added to the physiological saline. Extracellular Cs+ effectively blocked the sag in all three

  19. Hippocampal impairments are associated with intermittent hypoxia of obstructive sleep apnea

    FENG Jing; WU Qi; ZHANG Dan; CHEN Bao-yuan

    2012-01-01

    Obstructive sleep apnea (OSA),which is the most common sleep-related breathing disorder,is characterized as frequent upper airway collapse and obstruction.It is a treatable disorder but if left untreated is associated with complications in several organ systems.The health risk to OSA patients shows a strong association with acute cardiovascular events,and with chronic conditions.To the central nervous system,OSA causes behavioral and neuropsychologic deficits including daytime sleepiness,depression,impaired memory,mood disorders,cognition deficiencies,language comprehension and expression deficiencies,all of which are compatible with impaired hippocampal function.Furthermore,there exists a significant correlation between disease severity and cognitive deficits in OSA.Children with severe OSA have significantly lower intelligence quotient (IQ) and executive control functions compared to normal children matched for age,gender and ethnicity.This corroborates the findings of several pediatric studies of cognition in childhood OSA,where deficits are reported in general intelligence and some measures of executive function.In studies of OSA,it is difficult to differentiate the effects of its two main pathologic traits,intermittent hypoxia (IH) and sleep fragmentation.Many OSA studies,utilize IH as the only exposure factor in OSA studies.These approaches simplify research process and attain most of the academic goals.IH,continuous hypoxia and intermittent continuous hypoxia can all result in decreases in arterial O2.There are striking differences to them in the response of physiological systems.There are multiple studies showing that IH treatment in a rodent model of OSA can impair performance of standard water maze tests associated with deficits in spatial learning and memory which most likely are hippocampal-dependent.Cellular damage to the hippocampal cornuammonis 1 (CA1) region likely contributes to neuropsychological impairment among OSA patients,since neural circuits

  20. Intracellular activities related to in vitro hippocampal sharp waves are altered in CA3 pyramidal neurons of aged mice.

    Moradi-Chameh, H; Peng, J; Wu, C; Zhang, L

    2014-09-26

    Pyramidal neurons in the hippocampal CA3 area interconnect intensively via recurrent axonal collaterals, and such CA3-to-CA3 recurrent circuitry plays important roles in the generation of hippocampal network activities. In particular, the CA3 circuitry is able to generate spontaneous sharp waves (SPWs) when examined in vitro. These in vitro SPWs are thought to result from the network activity of GABAergic inhibitory interneurons as SPW-correlating intracellular activities are featured with strong IPSPs in pyramidal neurons and EPSPs or spikes in GABAergic interneurons. In view of accumulating evidence indicating a decrease in subgroups of hippocampal GABAergic interneurons in aged animals, we test the hypothesis that the intracellular activities related to in vitro SPWs are altered in CA3 pyramidal neurons of aged mice. Hippocampal slices were prepared from adult and aged C57 black mice (ages 3-6 and 24-28months respectively). Population and single-cell activities were examined via extracellular and whole-cell patch-clamp recordings. CA3 SPW frequencies were not significantly different between the slices of adult and aged mice but SPW-correlating intracellular activities featured weaker IPSC components in aged CA3 pyramidal neurons compared to adult neurons. It was unlikely that this latter phenomenon was due to general impairments of GABAergic synapses in the aged CA3 circuitry as evoked IPSC responses and pharmacologically isolated IPSCs were observed in aged CA3 pyramidal neurons. In addition, aged CA3 pyramidal neurons displayed more positive resting potentials and had a higher propensity of burst firing than adult neurons. We postulate that alterations of GABAergic network activity may explain the reduced IPCS contributions to in vitro SPWs in aged CA3 pyramidal neurons. Overall, our present observations are supportive of the notion that excitability of hippocampal CA3 circuitry is increased in aged mice.

  1. Zinc chelation reduces traumatic brain injury-induced neurogenesis in the subgranular zone of the hippocampal dentate gyrus.

    Choi, Bo Young; Kim, Jin Hee; Kim, Hyun Jung; Lee, Bo Eun; Kim, In Yeol; Sohn, Min; Suh, Sang Won

    2014-10-01

    Numerous studies have demonstrated that traumatic brain injury (TBI) increases hippocampal neurogenesis in the rodent brain. However, the mechanisms underlying increased neurogenesis after TBI remain unknown. Continuous neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in the adult brain. The mechanism that maintains active neurogenesis in the hippocampal area is not known. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ (mossy fiber). The mossy fiber of dentate granular cells contains high levels of chelatable zinc in their terminal vesicles, which can be released into the extracellular space during neuronal activity. Previously, our lab presented findings indicating that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia or epilepsy. Using a weight drop animal model to mimic human TBI, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after TBI. Thus, we injected a zinc chelator, clioquinol (CQ, 30mg/kg), into the intraperitoneal space to reduce brain zinc availability twice per day for 1 week. Neuronal death was evaluated with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after TBI. The number of degenerating neurons (FJB (+)) and live neurons (NeuN (+)) was similar in vehicle and in CQ-treated rats at 1 week after TBI. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX) immunostaining 1 week after TBI. The number of BrdU, Ki67 and DCX positive cell was increased after TBI. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. The present study shows that zinc chelation did not prevent neurodegeneration but did reduce TBI-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal

  2. Hippocampal Theta Dysfunction after Lateral Fluid Percussion Injury

    2010-01-01

    Chronic memory deficits are a major cause of morbidity following traumatic brain injury (TBI). In the rat, the hippocampal theta rhythm is a well-studied correlate of memory function. This study sought to investigate disturbances in hippocampal theta rhythm following lateral fluid percussion injury in the rat. A total of 13 control rats and 12 TBI rats were used. Electrodes were implanted in bilateral hippocampi and an electroencephalogram (EEG) was recorded while the rats explored a new envi...

  3. Alcohol and adult hippocampal neurogenesis: Promiscuous drug, wanton effects

    Geil, Chelsea R.; Hayes, Dayna M.; McClain, Justin A.; Liput, Daniel J.; Marshall, S. Alex; Chen, Kevin Y.; Nixon, Kimberly

    2014-01-01

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may...

  4. Adult hippocampal neurogenesis of mammals: evolution and life history

    Amrein, I.; Lipp, H. P.

    2009-01-01

    Substantial production of new neurons in the adult mammalian brain is restricted to the olfactory system and the hippocampal formation. Its physiological and behavioural role is still debated. By comparing adult hippocampal neurogenesis (AHN) across many mammalian species, one might recognize a common function. AHN is most prominent in rodents, but shows considerable variability across species, being lowest or missing in primates and bats. The latter finding argues against a critical role of ...

  5. Novel anticonvulsive effects of progesterone in a mouse model of hippocampal electrical kindling.

    Jeffrey, M; Lang, M; Gane, J; Chow, E; Wu, C; Zhang, L

    2014-01-17

    Progesterone is a known anticonvulsant, with its inhibitory effects generally attributed to its secondary metabolite, 5α,3α-tetrahydroprogesterone (THP), and THP's enhancement of GABAA receptor activity. Accumulating evidence, however, suggests that progesterone may have non-genomic actions independent of the GABAA receptor. In this study, we explored THP/GABAA-independent anticonvulsive actions of progesterone in a mouse model of hippocampal kindling and in mouse entorhinal slices in vitro. Specifically, we examined the effects of progesterone in kindled mice with or without pretreatments with finasteride, a 5α-reductase inhibitor known to block the metabolism of progesterone to THP. In addition, we examined the effects of progesterone on entorhinal epileptiform potentials in the presence of a GABAA receptor antagonist picrotoxin and finasteride. Adult male mice were kindled via a daily stimulation protocol. Electroencephalographic (EEG) discharges were recorded from the hippocampus or cortex to assess "focal" or "generalized" seizure activity. Kindled mice were treated with intra-peritoneal injections of progesterone (10, 35, 100 and 160mg/kg) with or without finasteride pretreatment (50 or 100mg/kg), THP (1, 3.5, 10 and 30mg/kg), midazolam (2mg/kg) and carbamazepine (50mg/kg). Entorhinal cortical slices were prepared from naïve young mice, and repetitive epileptiform potentials were induced by 4-aminopyridine (100μM), picrotoxin (100μM) and finasteride (1μM). Pretreatment with finasteride did not abolish the anticonvulsant effects of progesterone. In finasteride-pretreated mice, progesterone at 100 and 160mg/kg decreased cortical but not hippocampal afterdischarges (ADs). Carbamazepine mimicked the effects of progesterone with finasteride pretreatments in decreasing cortical discharges and motor seizures, whereas midazolam produced effects similar to progesterone alone or THP in decreasing hippocampal ADs and motor seizures. In brain slices, progesterone

  6. Effect of clausenamide on hippocampal neuron apoptosis induced by sodium nitroprusside

    Yongjun Liu; Qifeng Zhu

    2007-01-01

    chromatometry; levels of mRNA of hippocampal neuron bcl-2 and bax gene were detected with reverse transcription polymerase chain reaction (RT-PCR); expression of hippocampal neuron Bcl-2 and Bax protein was measured with Western blot technique.MAIN OUTCOME MEASURES: ① Effect of (-) clausenamide on survival rate of SNP-induced hippocampal neuron apoptosis; ② bcl-2 and bax mRNA and protein expression of hippocampal neurons.RESULTS: ① Survival rate ofhippocampal neurons: Survival rate of hippocampal neurons affected by 0.4 - 1.6 μ mol/L ( - ) clausenamide was higher in the experimental group than the model group (P < 0.01),and the survival rate was increased with the larger volume of (-) clausenamide. Survival rate was the highest when hippocampal neurons were induced by 1.6 μ mol/L, and it had obvious dosage dependence (P <0.01). ② Expression of bcl-2 and bar mRNA: Hippocampal neurons were pretreated with 0.2 - 1.6 μ mol/L( - ) clausenamide for 6 hours in the experimental group and strap of PCR product of bcl-2 gene was brightened gradually. This suggested that, with the increase of concentration, expression of bcl-2 mRNA was increased simultaneously. However, when strap of PCR product of bax gene was darkened, expression of bax was decreased with the increase of concentration. ③ Expression of Bcl-2 and Bax protein: Hippocampal neurons were pretreated with 0.2 - 1.6 μ mol/L ( - ) clausenamide for 6 hours in the experimental group and strap of PCR product of Bcl-2 protein was thickened gradually. This suggested that, with the increase of concentration, expression of Bcl-2 protein was increased simultaneously. However, when strap of PCR product of Bax protein was thinned, expression of Bax protein was decreased with the increase of concentration.CONCLUSION: ( - ) clausenamide can resist neurotoxic effect of SNP through dosage dependence, and the mechanism may be related to promoting expression of anti-apoptotic bcl-2 gene and inhibiting expression of pro

  7. The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity

    Yves eKellner

    2014-03-01

    Full Text Available The fine tuning of neural networks during development and learning relies upon both functional and structural plastic processes. Changes in the number as well as in the size and shape of dendritic spines are associated to long-term activity-dependent synaptic plasticity. However, the molecular mechanisms translating functional into structural changes are still largely unknown. In this context, neurotrophins, like Brain-Derived Neurotrophic Factor (BDNF, are among promising candidates. Specifically BDNF-TrkB receptor signaling is crucial for activity-dependent strengthening of synapses in different brain regions. BDNF application has been shown to positively modulate dendritic and spine architecture in cortical and hippocampal neurons as well as structural plasticity in vitro. However, a global BDNF deprivation throughout the central nervous system (CNS resulted in very mild structural alterations of dendritic spines, questioning the relevance of the endogenous BDNF signaling in modulating the development and the mature structure of neurons in vivo. Here we show that a loss-of-function approach, blocking BDNF results in a significant reduction in dendritic spine density, associated with an increase in spine length and a decrease in head width. These changes are associated with a decrease in F-actin levels within spine heads. On the other hand, a gain-of-function approach, applying exogenous BDNF, could not reproduce the increase in spine density or the changes in spine morphology previously described. Taken together, we show here that the effects exerted by BDNF on the dendritic architecture of hippocampal neurons are dependent on the neuron’s maturation stage. Indeed, in mature hippocampal neurons in vitro as shown in vivo BDNF is specifically required for the activity-dependent maintenance of the mature spine phenotype.

  8. Global changes in the hippocampal proteome following exposure to an enriched environment.

    McNair, K; Broad, J; Riedel, G; Davies, C H; Cobb, S R

    2007-03-16

    Exposure to an enriched environment promotes neurochemical, structural and neurophysiological changes in the brain and is associated with enhanced synaptic plasticity and improved hippocampal-dependent learning. Using a global proteomics-based approach we have now been able to reveal the altered expression of a diverse range of hippocampal proteins following exposure to an enriched environment. Male Hooded Lister rats (8 weeks) were subjected to a 6-week regimen in which they were housed in either non-enriched (open field) or enriched conditions (toys, wheels etc.). Whole protein extracts from stratum pyramidale and stratum radiatum of area CA1 were then isolated and subjected to differential gel electrophoresis [McNair K, Davies CH, Cobb SR (2006) Plasticity-related regulation of the hippocampal proteome. Eur J Neurosci 23(2):575-580]. Of the 2469 resolvable protein spots detected in this study, 42 spots (1.7% of the detectable proteome) derived from predominantly somatic fractions and 32 proteins spots from dendritic fractions (1.3% of detectable proteome) were significantly altered in abundance following exposure to an enriched environment (somatic: 14 increased/28 decreased abundance, range -1.5 to +1.4-fold change; dendritic: 16 increased, 16 decreased abundance, range -1.6 to +3.0-fold change). Following in-gel tryptic digestion and Maldi-Tof/Q-star mass spectrometry, database searching revealed the identity of 50 protein spots displaying environmental enrichment-related modulation of expression. Identified proteins belonged to a variety of functional classes with gene ontology analysis revealing the majority (>70%) of regulated proteins to be part of the energy metabolism, cytoplasmic organization/biogenesis and signal transduction processes.

  9. Multi-walled carbon nanotube inhibits CA1 glutamatergic synaptic transmission in rat's hippocampal slices.

    Chen, Ting; Yang, Jiajia; Zhang, Hui; Ren, Guogang; Yang, Zhuo; Zhang, Tao

    2014-09-17

    The purpose of the study was to investigate the neurotoxic effect of multi-walled carbon nanotubes (MWCNTs) on the properties of glutamatergic synaptic transmission in rat's hippocampal slices using whole-cell patch clamp technique. The amplitude and frequency of excitatory postsynaptic current (EPSC) were accessed on the hippocampal pyramidal neurons. The alterations of glutamatergic synaptic transmission in CA3-CA1 were examined by measuring both the amplitude of evoked excitatory postsynaptic current (eEPSC) and paired-pulse ratio (PPR). The data showed that the amplitude of either spontaneous excitatory postsynaptic current (sEPSC) or miniature excitatory postsynaptic current (mEPSC) was significantly inhibited by 1 μg/mL MWCNTs. However, it was found that there was a trend of different change on the frequency index. When 1 μg/mL MWCNTs was applied, there were a decreased frequency of mEPSC and an increased frequency of sEPSC, which might be due to the effect of action potential. Furthermore, the amplitudes of eEPSC at CA3-CA1 synapses were remarkably decreased. And the mean amplitude of AMPAR-mediated eEPSC was significantly reduced as well. Meanwhile, a majority of PPRs data were greater than one. There were no significant differences of PPRs between control and MWCNTs states, but an increased trend of paired-pulse facilitation was found. These results suggested that MWCNT markedly inhibited hippocampal CA1 glutamatergic synaptic transmission in vitro, which provided new insights into the MWCNT toxicology on CNS at cellular level.

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

    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.

  11. Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

    Paula Patricia Perissinotti

    2015-01-01

    Full Text Available Kelch-like 1 (KLHL1 is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type and CaV3.2 (α1H T-type calcium channels; KLHL1 knockdown experiments (KD cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014. Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT; and PQ-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were reduced in the KO hippocampus; cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

  12. Melatonin increases dendritogenesis in the hilus of hippocampal organotypic cultures.

    Domínguez-Alonso, Aline; Ramírez-Rodríguez, Gerardo; Benítez-King, Gloria

    2012-05-01

    Neuropsychiatric disorders are characterized by hippocampus decreased volume and loss of dendrite arborizations in the subiculum and prefrontal cortex. These structural changes are associated with diminished memory performance. Hilar neurons of the hippocampus integrate spatial memory and are lost in dementia. They receive information from dentate gyrus neurons through dendrites, while they send axonal tracts to the CA3 region. Dendrites are complex structures of neurons that receive chemical information from presynaptic and postsynaptic terminals. Melatonin, the main product of the pineal gland, has neuroprotective actions through its free radical-scavenging properties and decreases neuronal apoptosis. Recently, we found that melatonin increases dendrite maturation and complexity in new neurons formed in the dentate gyrus of mice. In addition, in N1E-115 cultured cells, the indole stimulates early stages of neurite formation, a process that is known to antecede dendrite formation and maturation. Thus, in this study, we explored whether melatonin stimulates dendrite formation and complexity in the adult rat hippocampus in organotypic slice cultures, which is a model that preserves the hippocampal circuitry and their tridimensional organizations of connectivity. The effects of melatonin were studied in nonpathological conditions and in the absence of harmful agents. The results showed that the indole at nocturnal concentrations reached in the cerebrospinal fluid stimulates dendritogenesis at formation, growth, and maturation stages. Also, data showed that dendrites formed became competent to form presynaptic specializations. Evidence strongly suggests that melatonin may be useful in the treatment of neuropsychiatric diseases to repair the loss of dendrites and re-establish lost synaptic connections.

  13. Neurotoxicity of perfluorooctane sulfonate to hippocampal cells in adult mice.

    Yan Long

    Full Text Available Perfluorooctane sulfonate (PFOS is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA and 3,4-dihydrophenylacetic acid (DOPAC in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase, Herc5 (hect domain and RLD 5 isoform 2 and Tyro3 (TYRO3 protein tyrosine kinase 3 were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit, Gzma (Isoform HF1 of Granzyme A precursor, Plau (Urokinase-type plasminogen activator precursor and Lig4 (DNA ligase 4 were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice.

  14. Assessment of PET & ASL metabolism in the hippocampal subfields of MCI and AD using simultaneous PET-MR

    Goubran, Maged; Douglas, David; Chao, Steven; Quon, Andrew; Tripathi, Pragya; Holley, Dawn; Vasanawala, Minal; Zaharchuk, Greg; Zeineh, Michael [Stanford University (United States)

    2015-05-18

    Alzheimer’s disease (AD) has been reported to show decreased metabolic activity in the hippocampus using FDG PET-MR. Histological data suggests that the hippocampal subfields are selectively affected in AD. Given the simultaneous imaging nature of integrated PET-MR scanners and the multimodal capabilities of PET-MR, our purpose here is to assess FDG activity, as well as ASL perfusion in the subfields of MCI and AD patients. 10 consecutive subjects were recruited for this study 3 MCI, 3 AD patients and 4 age-matched controls. The scanning was performed on a simultaneous 3T PET/MR scanner. To delineate the hippocampal subfields, automatic segmentation of hippocampal subfields (ASHS) was employed. Static FDG-PET series were reconstructed for analysis at 45-75 min for all subjects. All imaging sequences were automatically registered to the oblique coronal T2-weighted images (segmentation space). PET standardized uptake values (SUV) in the hippocampal subfields were normalized by the pons. FDG PET metabolism was reduced significantly in AD, as well as MCI patients as compared to controls, with the highest effect demonstrated in the CA3/DG and CA1/2 (p = 0.047, subfields. Patients (MCI and AD combined) had decreased metabolism as compared to controls in CA1/2 and significantly smaller volumes the Subiculum. When assessing CBF across groups, a significant decrease in CBF was found in the Subiculum. Our preliminary results demonstrate that PET-MRI may potentially be a sensitive biomarker and tool for early diagnosis of AD. They also confirm the importance of assessing metabolic and structural changes of neurodegenerative diseases at the subfield level.

  15. Phenotypic Alterations in Hippocampal NPY- and PV-Expressing Interneurons in a Presymptomatic Transgenic Mouse Model of Alzheimer’s Disease

    Mahar, Ian; Albuquerque, Marilia Silva; Mondragon-Rodriguez, Siddhartha; Cavanagh, Chelsea; Davoli, Maria Antonietta; Chabot, Jean-Guy; Williams, Sylvain; Mechawar, Naguib; Quirion, Rémi; Krantic, Slavica

    2017-01-01

    Interneurons, key regulators of hippocampal neuronal network excitability and synchronization, are lost in advanced stages of Alzheimer’s disease (AD). Given that network changes occur at early (presymptomatic) stages, we explored whether alterations of interneurons also occur before amyloid-beta (Aβ) accumulation. Numbers of neuropeptide Y (NPY) and parvalbumin (PV) immunoreactive (IR) cells were decreased in the hippocampus of 1 month-old TgCRND8 mouse AD model in a sub-regionally specific manner. The most prominent change observed was a decrease in the number of PV-IR cells that selectively affected CA1/2 and subiculum, with the pyramidal layer (PY) of CA1/2 accounting almost entirely for the reduction in number of hippocampal PV-IR cells. As PV neurons were decreased selectively in CA1/2 and subiculum, and given that they are critically involved in the control of hippocampal theta oscillations, we then assessed intrinsic theta oscillations in these regions after a 4-aminopyridine (4AP) challenge. This revealed increased theta power and population bursts in TgCRND8 mice compared to non-transgenic (nTg) controls, suggesting a hyperexcitability network state. Taken together, our results identify for the first time AD-related alterations in hippocampal interneuron function as early as at 1 month of age. These early functional alterations occurring before amyloid deposition may contribute to cognitive dysfunction in AD. PMID:28154533

  16. The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise.

    Cai, Ming; Wang, Hong; Li, Jing-Jing; Zhang, Yun-Li; Xin, Lei; Li, Feng; Lou, Shu-Jie

    2016-10-01

    significantly decreased proBDNF-the precursor of mature BDNF, but also attenuated p38/ERK-CREB signaling pathways and activated NLRP3-IL-1β pathways in obese rats. These results were associated with reduced BDNF and SYN protein production. However, these adverse changes were obviously reversed by aerobic exercise intervention through activating the Nrf2-HO-1 pathways. These results suggest that dietary obesity could induce hippocampal ERS in male SD rats, and excessive hippocampal ERS plays a critical role in decreasing the levels of BDNF and SYN. Moreover, aerobic exercise could activate hippocampal Nrf2 and HO-1 to relieve ERS and heighten BDNF and SYN production in obese rats.

  17. Hippocampal sclerosis in dementia, epilepsy, and ischemic injury: differential vulnerability of hippocampal subfields.

    Hatanpaa, Kimmo J; Raisanen, Jack M; Herndon, Emily; Burns, Dennis K; Foong, Chan; Habib, Amyn A; White, Charles L

    2014-02-01

    Severe neuronal loss in the hippocampus, that is, hippocampal sclerosis (HS), can be seen in 3 main clinical contexts: dementia (particularly frontotemporal lobar degeneration [FTLD]), temporal lobe epilepsy (TLE), and hippocampal ischemic injury (H-I). It has been suggested that shared pathogenetic mechanisms may underlie selective vulnerability of the hippocampal subfields such as the CA1 in these conditions. We determined the extent of neuronal loss in cases of HS-FTLD (n=14), HS-TLE (n=35), and H-I (n=20). Immunohistochemistry for zinc transporter 3 was used to help define the CA3/CA2 border in the routinely processed human autopsy tissue samples. The subiculum was involved in 57% of HS-FTLD, 10% of H-I, and 0% of HS-TLE cases (p<0.0001). The CA regions other than CA1 were involved in 57% of HS-TLE, 30% of H-I, and 0% of HS-FTLD cases (p=0.0003). The distal third of CA1 was involved in 79% of HS-FTLD, 35% of H-I, and 37% of HS-TLE cases (p=0.02). The distal third of CA1 was the only area involved in 29% of HS-FTLD, 3% of HS-TLE, and 0% of H-I cases (p=0.019). The proximal-middle CA1 was the only area affected in 50% of H-I, 29% of HS-TLE, and 0% of HS-FTLD cases (p=0.004). These findings support heterogeneity in the pathogenesis of HS.

  18. Changes in mitochondrial function in primary culture of rat’s hippocampal neurons after exposure to electromagnetic field

    Ming-yue QU

    2014-10-01

    Full Text Available Objective To investigate the changes in mitochondrial function in rat's hippocampal neurons of primary culture after exposure to electromagnetic field (EMF. Methods Rat's hippocampal neurons of primary culture were exposed to EMF irradiation (2.45GHz with average power density of 5, 10, 30 and 60 mW/cm2 for 10 minutes. CCK-8 kit and LDH kit were used to determine the injurious effects on rat hippocampal neurons at 0, 3, 6, 12, 24 and 48 hours after irradiation. Reactive oxygen species (ROS were detected using fluorescent probe DCFH-DA, mitochondrial membrane potential (ΔΨm was assessed using fluorescent probe JC-1, mitochondrial permeability transition pore (mPTP opening was determined by calcein-fluorescence quenching method, and the intracellular ATP levels were determined by ATP detection kit at 12 hours after irradiation. Results  Hippocampal neuron damage was found after EMF irradiation, and it was aggravated by an increase in power density. Compared with the control, the viability of hippocampal neurons decreased significantly at 12, 24 and 48 h (P<0.05, and LDH levels increased at 24 and 48 h (P<0.05 after 10 mW/cm2 irradiation, while their viability decreased at 3, 6, 12, 24 and 48 h (P<0.05, P<0.01, and LDH levels increased at 6, 12, 24 and 48 h (P<0.05, P<0.01 after 30 and 60 mW/cm2 irradiation. Compared with the control, the mitochondrial ROS level was elevated significantly (P<0.05, P<0.01 after 5, 10, 30 and 60 mW/cm2 irradiation, while ΔΨm and ATP levels lowered and mPTP was obviously opened and activated (P<0.05, P<0.01 after 10, 30 and 60 mW/cm2 irradiation. Conclusion EMF irradiation may induce damage to rat's hippocampal neurons of primary culture in dose- and time-dependent manners, and mitochondrial dysfunction occurs during the exposure. DOI: 10.11855/j.issn.0577-7402.2014.08.12

  19. Effects of Regular Treadmill Exercise on a DNA Oxidative-Damage Marker and Total Antioxidant Capacity in Rat Hippocampal Tissue

    Mahjoub, Soleiman; Ghadi, Arezoo; Pourbagher, Roghayeh; Hajian-Tilaki, Karimollah

    2016-01-01

    Background and Purpose Regular exercise can result in changes in the levels of oxidative stress in the hippocampus; however, little attention has been paid to physical-activity-induced neuronal protection to exposure to lead compounds. This study investigated the effects of regular treadmill exercise on a DNA oxidative-damage marker [8-hydroxy-2'-deoxyguanosine (8-OHdG)] and the total antioxidant capacity (TAC) of hippocampal tissue in lead-acetate exposed rats. Methods This study investigated the effects of 8 weeks of regular treadmill exercise on 8-OHdG and the TAC of hippocampal tissue in lead-acetate-exposed rats. Wistar rats were randomly divided into four groups: baseline, sham (control), lead, and exercise+lead. The exercise program involved running on a treadmill with increasing intensity five times a week for 8 weeks. Animals in the lead and exercise+lead groups received lead acetate at 20 mg/kg body weight intraperitoneally three times weekly for 8 weeks. Animals in the sham group received solvent (ethyl oleate) at 30 mg/kg body weight three times weekly for 8 weeks. TAC and 8-OHdG were measured by spectrophotometric and ELISA techniques, respectively. Data were analyzed by ANOVA and Tukey's post-hoc test with a significance cutoff of p≤0.05. Results The level of 8-OHdG and the TAC were significantly higher and lower, respectively, in the lead group than in the baseline and sham groups (p<0.01). However, the 8-OHdG level and TAC value in hippocampal tissue were significantly decreased and increased, respectively, in the exercise+lead group relative to the lead group (p<0.05). Conclusions The TAC of hippocampal tissue may be directly associated with neural protection mechanisms of exercise following lead acetate injection, and the beneficial effects of regular exercise in preventing hippocampal neuronal damage could be due to decreased hippocampal oxidative stress such as reflected by a lower 8-OHdG level and increased TAC.

  20. Influence of Ginkgo Biloba extract on beta-secretase in rat hippocampal neuronal cultures following chronic hypoxic and hypoglycemic conditions

    Xueneng Guan; Fuling Yan

    2008-01-01

    BACKGROUND: Preparation of Ginkgo leaf has been widely used to improve cognitive deficits and dementia, in particular in Alzheimer's disease patients. However, the precise mechanism of action of Ginkgo leaf remains unclear.OBJECTIVE: To explore the effect of Ginkgo Biloba extract (Egb761), Ginaton, on β-secretase expression in rat hippocampal neuronal cultures following chronic hypoxic and hypoglycemic conditions.DESIGN, TIME AND SETTNG: Completely by randomized, grouping study. The experiment was performed at the Laboratory of Molecular Imaging, Southeast University between August 2006 and August 2007.MATERIALS: A total of 128 Wistar rats aged 24 hours were selected, and hippocampal neurons were harvested for primary cultures.METHODS: On day 7, primary hippocampal neuronal cultures were treated with Egb761 (0, 25, 50, 100, 150, and 200 μ g/mL) under hypoxic/hypoglycemic or hypoglycemic culture conditions for 12, 24, and 36 hours, respectively. Hippocampal neurons cultured in primary culture medium served as control.MAIN OUTCOME MEASURES: Cell viability was assayed using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); fluorescence detection of β-secretase activity was performed; Western Blot was used to measure β -secretase expression.RESULTS: Cell viability under hypoxic/hypoglycemic or hypoglycemic culture conditions was significantly less than control cells (P 25 μ g/mL Egb761 induced greater cell viability (P 0.05). Α -secretase activity was increased after 12 hours in hypoxic/hypoglycemic culture (P 0.05). Β -secretase activity was greater after 12, 24, and 36 hours in hypoxic/hypoglycemic culture conditions, compared with control conditions (P < 0.05). Β-secretase activity was significantly decreased in neurons treated with Egb761 for 12, 24, or 36 hours, compared with the hypoxic/hypoglycemic group (P < 0.05).β-secretase protein expression was significantly up-regulated in neurons cultured in hypoxic/hypoglycemic conditions for

  1. Role of hippocampal dentate gyrus neurons in the protective effects of heat shock factor 1 on working memory

    Min Peng; Xiongzhao Zhu; Ming Cheng; Xiangyi Chen; Shuqiao Yao

    2011-01-01

    Increasing evidence suggests that heat shock factor 1 exerts endogenous protective effects on working memory under conditions of chronic psychological stress. However, the precise underlying mechanisms remain poorly understood. This study examined the protective factors affecting working memory in heat shock transcription factor 1 gene knockout mice. The results indicated that the number of correct T maze alternations decreased following mild chronic psychological stress in knockout mice. This change was accompanied by a decrease in neurogenesis and an increase in neuronal apoptosis in the hippocampal dentate gyrus. The number of correct T maze alternations was positively correlated with neurogenesis in hippocampal dentate gyrus, and negatively correlated with neuronal apoptosis. In wild type mice, no significant difference was detected in the number of correct T maze alternations or neuronal apoptosis in hippocampal dentate gyrus. These results indicate that the heat shock factor 1 gene has an endogenous protective role in working memory during mild chronic psychological stress associated with dentate gyrus neuronal apoptosis.Moreover, dentate gyrus neurogenesis appears to participate in the protective mechanism.

  2. Prenatal Stress Produces Persistence of Remote Memory and Disrupts Functional Connectivity in the Hippocampal-Prefrontal Cortex Axis.

    Negrón-Oyarzo, Ignacio; Neira, David; Espinosa, Nelson; Fuentealba, Pablo; Aboitiz, Francisco

    2015-09-01

    Prenatal stress is a risk factor for the development of neuropsychiatric disorders, many of which are commonly characterized by an increased persistence of aversive remote memory. Here, we addressed the effect of prenatal stress on both memory consolidation and functional connectivity in the hippocampal-prefrontal cortex axis, a dynamical interplay that is critical for mnemonic processing. Pregnant mice of the C57BL6 strain were subjected to restraint stressed during the last week of pregnancy, and male offspring were behaviorally tested at adulthood for recent and remote spatial memory performance in the Barnes Maze test under an aversive context. Prenatal stress did not affect the acquisition or recall of recent memory. In contrast, it produced the persistence of remote spatial memory. Memory persistence was not associated with alterations in major network rhythms, such as hippocampal sharp-wave ripples (SWRs) or neocortical spindles. Instead, it was associated with a large decrease in the basal discharge activity of identified principal neurons in the medial prefrontal cortex (mPFC) as measured in urethane anesthetized mice. Furthermore, functional connectivity was disrupted, as the temporal coupling between neuronal discharge in the mPFC and hippocampal SWRs was decreased by prenatal stress. These results could be relevant to understand the biological basis of the persistence of aversive remote memories in stress-related disorders.

  3. Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons.

    Rombo, Diogo M; Dias, Raquel B; Duarte, Sofia T; Ribeiro, Joaquim A; Lamsa, Karri P; Sebastião, Ana M

    2016-03-01

    Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A1 receptor (A1R). The presynaptic inhibitory action of adenosine A1R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABAA receptor (GABAAR)-mediated tonic, but not phasic, transmission is suppressed by A1R in hippocampal neurons. Adenosine A1R activation strongly inhibits GABAAR agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A1R suppresses tonic GABAAR currents measured in the presence of elevated ambient GABA as well as in naïve slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABAAR δ-subunit expression. On the contrary, no A1R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A1R modulates extrasynaptic rather than synaptic GABAAR-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABAAR signaling by adenosine A1R in specific neuron types may regulate neuronal gain and excitability in the hippocampus.

  4. Reduction of rat hippocampal calcium-binding protein following commissural, amygdala, septal, perforant path, and olfactory bulb kindling.

    Baimbridge, K G; Mody, I; Miller, J J

    1985-01-01

    The calcium-binding protein (CaBP) content of the hippocampal formation was determined by radioimmunoassay in control and kindled rats. Kindling of a number of different sites resulted in a reduction in the CaBP content of the hippocampal formation, which was shown immunohistochemically to be restricted to the dentate granule cells and their processes. The maximum decline in CaBP varied with the different kindling sites: perforant path, 33%; commissural path, 32%; septum, 30%; amygdala, 18%; and olfactory bulbs, 15%. There were no changes in the CaBP content of the stimulated areas themselves. In cases where the kindling stimulus was delivered unilaterally (perforant path and amygdala), the maximum decrease in hippocampal CaBP was observed ipsilateral to the site of stimulation when the criterion for full kindling was established (six consecutive stage 5 motor seizures). Further kindling trials were required to produce a similar magnitude decrease in the CaBP content of the contralateral hippocampus. These observations are discussed both in relation to the possible role of CaBP in the establishment of a seizure response to kindling and also as a potential compensatory mechanism that may serve to overcome the epileptogenic effects of kindling.

  5. Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons

    Ernest Palomer

    2016-09-01

    Full Text Available Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.

  6. Effects of combined nicotine and fluoxetine treatment on adult hippocampal neurogenesis and conditioned place preference.

    Faillace, M P; Zwiller, J; Bernabeu, R O

    2015-08-06

    Adult neurogenesis occurs in mammals within the dentate gyrus, a hippocampal subarea. It is known to be induced by antidepressant treatment and reduced in response to nicotine administration. We checked here whether the antidepressant fluoxetine would inverse the decrease in hippocampal neurogenesis caused by nicotine. It is shown that repeated, but not a single injection of rats with fluoxetine was able to abolish the decrease in adult dentate cell proliferation produced by nicotine treatment. We measured the expression of several biochemical parameters known to be associated with neurogenesis in the dentate gyrus. Both drugs increased the expression of p75 neurotrophin receptor, which promotes proliferation and early maturation of dentate gyrus cells. Using the conditioned place preference (CPP) paradigm, we also gave both drugs in a context in which their rewarding properties could be measured. Fluoxetine produced a significant but less robust CPP than nicotine. A single injection of fluoxetine was found to reduce nicotine-induced CPP. Moreover, the rewarding properties of nicotine were completely abolished in response to repeated fluoxetine injections. Expression of nicotine-induced CPP was accompanied by an increase of phospho-CREB (cyclic AMP-responsive element-binding protein) and HDAC2 (histone deacetylase 2) expression in the nucleus accumbens. The data suggest that fluoxetine reward, as opposed to nicotine reward, depends on dentate gyrus neurogenesis. Since fluoxetine was able to disrupt the association between nicotine and the environment, this antidepressant may be tested as a treatment for nicotine addiction using cue exposure therapy.

  7. Antidepressant behavior in thyroidectomized Wistar rats is induced by hippocampal hypothyroidism.

    da Conceição, Rodrigo Rodrigues; Laureano-Melo, Roberto; Oliveira, Kelen Carneiro; de Carvalho Melo, Maria Clara; Kasamatsu, Tereza Sayoko; de Barros Maciel, Rui Monteiro; de Souza, Janaina Sena; Giannocco, Gisele

    2016-04-01

    Thyroidectomy is a surgical procedure indicated in cases of several maligned or benign thyroid diseases, thus, the aim of our study was to verify how the hypothyroidism induced by thyroidectomy influences behavioral parameters and its relation to thyroid hormones metabolism and neurogenesis at hippocampus. For this purpose, Adult male Wistar rats underwent to thyroidectomy to induce hypothyroidism. Behavioral tests, the thyroid profile and hippocampal gene expression were evaluated in control and in thyroidectomized animals. It was observed that thyroidectomized group had a significant increasing in serum thyroid-stimulating hormone (TSH) and a decreasing in thyroxine (T4) levels as well as in triiodothyronine (T3) serum level. It was also observed reduction of the monocarboxylate transporter 8 (Mct8), thyroid hormone receptor alfa (Trα1), deiodinase type 2 (Dio2), ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2) and brain-derived neurotrophic factor (Bdnf) mRNA expression in hippocampus of thyroidectomized animals. In the forced swimming test, it was verified that thyroidectomy promotes a decrease in time of immobility and climbing when compared with the control group. In summary, we demonstrated that antidepressant behavior in thyroidectomized Wistar rats is induced by hippocampal hypothyroidism. This effect could be associated to an impaired neuronal activity in acute stress response as it is observed in forced swimming paradigm.

  8. Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging.

    Gebara, Elias; Sultan, Sebastien; Kocher-Braissant, Jacqueline; Toni, Nicolas

    2013-01-01

    Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain plasticity involved in learning and memory. The proliferation of adult neural stem or progenitor cells is regulated by several extrinsic factors such as experience, disease or aging and intrinsic factors originating from the neurogenic niche. Microglia is very abundant in the dentate gyrus (DG) and increasing evidence indicates that these cells mediate the inflammation-induced reduction in neurogenesis. However, the role of microglia in neurogenesis in physiological conditions remains poorly understood. In this study, we monitored microglia and the proliferation of adult hippocampal stem/progenitor cells in physiological conditions known to increase or decrease adult neurogenesis, voluntary running and aging respectively. We found that the number of microglia in the DG was strongly inversely correlated with the number of stem/progenitor cells and cell proliferation in the granule cell layer. Accordingly, co-cultures of decreasing neural progenitor/glia ratio showed that microglia but not astroglia reduced the number of progenitor cells. Together, these results suggest that microglia inhibits the proliferation of neural stem/progenitor cells despite the absence of inflammatory stimulus.

  9. Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging.

    Elias Georges Gebara

    2013-08-01

    Full Text Available Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain plasticity involved in learning and memory. The proliferation of adult neural stem or progenitor cells is regulated by several extrinsic factors such as experience, disease or aging and intrinsic factors originating from the neurogenic niche. Microglia is very abundant in the dentate gyrus and increasing evidence indicates that these cells mediate the inflammation-induced reduction in neurogenesis. However, the role of microglia in neurogenesis in physiological conditions remains poorly understood. In this study, we monitored microglia and the proliferation of adult hippocampal stem/progenitor cells in physiological conditions known to increase or decrease adult neurogenesis, voluntary running and aging respectively. We found that the number of microglia in the dentate gyrus was strongly inversely correlated with the number of stem/progenitor cells and cell proliferation in the granule cell layer. Accordingly, co-cultures of decreasing neural progenitor/glia ratio showed that microglia but not astroglia reduced the number of progenitor cells. Together, these results suggest that microglia inhibits the proliferation of neural stem/progenitor cells despite the absence of inflammatory stimulus.

  10. The effects of hippocampal lesions on MRI measures of structural and functional connectivity.

    Henson, Richard N; Greve, Andrea; Cooper, Elisa; Gregori, Mariella; Simons, Jon S; Geerligs, Linda; Erzinçlioğlu, Sharon; Kapur, Narinder; Browne, Georgina

    2016-11-01

    Focal lesions can affect connectivity between distal brain regions (connectional diaschisis) and impact the graph-theoretic properties of major brain networks (connectomic diaschisis). Given its unique anatomy and diverse range of functions, the hippocampus has been claimed to be a critical "hub" in brain networks. We investigated the effects of hippocampal lesions on structural and functional connectivity in six patients with amnesia, using a range of magnetic resonance imaging (MRI) analyses. Neuropsychological assessment revealed marked episodic memory impairment and generally intact performance across other cognitive domains. The hippocampus was the only brain structure exhibiting reduced grey-matter volume that was consistent across patients, and the fornix was the only major white-matter tract to show altered structural connectivity according to both diffusion metrics. Nonetheless, functional MRI revealed both increases and decreases in functional connectivity. Analysis at the level of regions within the default-mode network revealed reduced functional connectivity, including between nonhippocampal regions (connectional diaschisis). Analysis at the level of functional networks revealed reduced connectivity between thalamic and precuneus networks, but increased connectivity between the default-mode network and frontal executive network. The overall functional connectome showed evidence of increased functional segregation in patients (connectomic diaschisis). Together, these results point to dynamic reorganization following hippocampal lesions, with both decreased and increased functional connectivity involving limbic-diencephalic structures and larger-scale networks. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

  11. Afadin regulates puncta adherentia junction formation and presynaptic differentiation in hippocampal neurons.

    Daisaku Toyoshima

    Full Text Available The formation and remodeling of mossy fiber-CA3 pyramidal cell synapses in the stratum lucidum of the hippocampus are implicated in the cellular basis of learning and memory. Afadin and its binding cell adhesion molecules, nectin-1 and nectin-3, together with N-cadherin, are concentrated at puncta adherentia junctions (PAJs in these synapses. Here, we investigated the roles of afadin in PAJ formation and presynaptic differentiation in mossy fiber-CA3 pyramidal cell synapses. At these synapses in the mice in which the afadin gene was conditionally inactivated before synaptogenesis by using nestin-Cre mice, the immunofluorescence signals for the PAJ components, nectin-1, nectin-3 and N-cadherin, disappeared almost completely, while those for the presynaptic components, VGLUT1 and bassoon, were markedly decreased. In addition, these signals were significantly decreased in cultured afadin-deficient hippocampal neurons. Furthermore, the interevent interval of miniature excitatory postsynaptic currents was prolonged in the cultured afadin-deficient hippocampal neurons compared with control neurons, indicating that presynaptic functions were suppressed or a number of synapse was reduced in the afadin-deficient neurons. Analyses of presynaptic vesicle recycling and paired recordings revealed that the cultured afadin-deficient neurons showed impaired presynaptic functions. These results indicate that afadin regulates both PAJ formation and presynaptic differentiation in most mossy fiber-CA3 pyramidal cell synapses, while in a considerable population of these neurons, afadin regulates only PAJ formation but not presynaptic differentiation.

  12. Afadin Regulates Puncta Adherentia Junction Formation and Presynaptic Differentiation in Hippocampal Neurons

    Toyoshima, Daisaku; Mandai, Kenji; Maruo, Tomohiko; Supriyanto, Irwan; Togashi, Hideru; Inoue, Takahito; Mori, Masahiro; Takai, Yoshimi

    2014-01-01

    The formation and remodeling of mossy fiber-CA3 pyramidal cell synapses in the stratum lucidum of the hippocampus are implicated in the cellular basis of learning and memory. Afadin and its binding cell adhesion molecules, nectin-1 and nectin-3, together with N-cadherin, are concentrated at puncta adherentia junctions (PAJs) in these synapses. Here, we investigated the roles of afadin in PAJ formation and presynaptic differentiation in mossy fiber-CA3 pyramidal cell synapses. At these synapses in the mice in which the afadin gene was conditionally inactivated before synaptogenesis by using nestin-Cre mice, the immunofluorescence signals for the PAJ components, nectin-1, nectin-3 and N-cadherin, disappeared almost completely, while those for the presynaptic components, VGLUT1 and bassoon, were markedly decreased. In addition, these signals were significantly decreased in cultured afadin-deficient hippocampal neurons. Furthermore, the interevent interval of miniature excitatory postsynaptic currents was prolonged in the cultured afadin-deficient hippocampal neurons compared with control neurons, indicating that presynaptic functions were suppressed or a number of synapse was reduced in the afadin-deficient neurons. Analyses of presynaptic vesicle recycling and paired recordings revealed that the cultured afadin-deficient neurons showed impaired presynaptic functions. These results indicate that afadin regulates both PAJ formation and presynaptic differentiation in most mossy fiber-CA3 pyramidal cell synapses, while in a considerable population of these neurons, afadin regulates only PAJ formation but not presynaptic differentiation. PMID:24587018

  13. Nonlinear dynamical analysis of carbachol induced hippocampal oscillations in mice

    Metin AKAY; Kui WANG; Yasemin M AKAY; Andrei DRAGOMIR; Jie WU

    2009-01-01

    Aim: Hippocampal neuronal network and synaptic impairment underlie learning and memory deficit in Alzheimer's disease (AD) patients and animal models. In this paper, we analyzed the dynamics and complexity of hippocampal neuronal network synchronization induced by acute exposure to carbachol, a nicotinic and muscarinic receptor co-agonist, using the nonlinear dynamical model based on the Lempel-Ziv estimator. We compared the dynamics of hippocampal oscillations between wild-type (WT) and triple-transgenic (3xTg) mice, as an AD animal model. We also compared these dynamic alterations between different age groups (5 and 10 months). We hypothesize that there is an impairment of complexity of CCh-induced hippocampal oscillations in 3xTg AD mice compared to WT mice, and that this impairment is age-dependent. Methods: To test this hypothesis, we used electrophysiological recordings (field potential) in hippocampal slices. Results: Acute exposure to 100 nmol/L CCh induced field potential oscillations in hippocampal CA1 region, which exhibited three distinct patterns: (1) continuous neural firing, (2) repeated burst neural firing and (3) the mixed (continuous and burst) pattern in both WT and 3xTg AD mice. Based on Lempel-Ziv estimator, pattern (2) was significantly lower than patterns (1) and (3) in 3xTg AD mice compared to WT mice (P<0.001), and also in 10-month old WT mice compared to those in 5-month old WT mice (P<0.01).Conclusion: These results suggest that the burst pattern (theta oscillation) of hippocampal network is selectively impaired in 3xTg AD mouse model, which may reflect a learning and memory deficit in the AD patients.

  14. Associative reinstatement memory measures hippocampal function in Parkinson's Disease.

    Cohn, Melanie; Giannoylis, Irene; De Belder, Maya; Saint-Cyr, Jean A; McAndrews, Mary Pat

    2016-09-01

    In Parkinson's Disease (PD), hippocampal atrophy is associated with rapid cognitive decline. Hippocampal function is typically assessed using memory tests but current clinical tools (e.g., free recall) also rely on executive functions or use material that is not optimally engaging hippocampal memory networks. Because of the ubiquity of executive dysfunction in PD, our ability to detect true memory deficits is suboptimal. Our previous behavioural and neuroimaging work in other populations suggests that an experimental memory task - Associative Reinstatement Memory (ARM) - may prove useful in investigating hippocampal function in PD. In this study, we investigated whether ARM is compromised in PD and we assessed its convergent and divergent validity by comparing it to standardized measures of memory and of attention and executive functioning in PD, respectively. Using fMRI, we also investigated whether performance in PD relates to degree of hippocampal engagement. Fifteen participants with PD and 13 age-matched healthy controls completed neuropsychological testing as well as an ARM fMRI recognition paradigm in which they were instructed to identify word pairs comprised of two studied words (intact or rearranged pairs) and those containing at least one new word (new or half new pairs). ARM is measured by the differences in hit rates between intact and rearranged pairs. Behaviourally, ARM was poorer in PD relative to controls and was correlated with verbal memory measures, but not with attention or executive functioning in the PD group. Hippocampal activation associated with ARM was reduced in PD relative to controls and covaried with ARM scores in both groups. To conclude, ARM is a sensitive measure of hippocampal memory function that is unaffected by attention or executive dysfunction in PD. Our study highlights the benefit of integrating cognitive neuroscience frameworks and novel experimental tasks to improve the practice of clinical neuropsychology in PD.

  15. Early life stress and hippocampal neurogenesis in the neonate: sexual dimorphism, long term consequences and possible mediators. A minireview.

    Naima eLajud

    2015-02-01

    Full Text Available Adverse early life experience decreases adult hippocampal neurogenesis and results in increased vulnerability to neuropsychiatric disorders. Despite that the effects of postnatal stress on neurogenesis have been widely studied in adult individuals, few efforts have been done to evaluate its immediate effects on the developing hippocampus. Moreover, it is not clear whether postnatal stress causes a differential impact in hippocampus development in male and female neonates that could be related to emotional deficits in adulthood. It has been proposed that the long term effects of early stress exposure rise from a persistent HPA axis activation during sensitive time windows; nevertheless the exact mechanisms and mediators remain unknown. Here, we summarize the immediate and late effects of early life stress on hippocampal neurogenesis in male and female rat pups, compare its later consequences in emotionality, and highlight some relevant mediator peptides that could be potentially involved in programming.

  16. Effect of Opioid on Adult Hippocampal Neurogenesis

    Yue Zhang

    2016-01-01

    Full Text Available During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs’ effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal’s opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

  17. Hippocampal CA1 Ripples as Inhibitory Transients.

    Paola Malerba

    2016-04-01

    Full Text Available Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  18. Hippocampal CA1 Ripples as Inhibitory Transients.

    Malerba, Paola; Krishnan, Giri P; Fellous, Jean-Marc; Bazhenov, Maxim

    2016-04-01

    Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  19. Dendritic potassium channels in hippocampal pyramidal neurons.

    Johnston, D; Hoffman, D A; Magee, J C; Poolos, N P; Watanabe, S; Colbert, C M; Migliore, M

    2000-05-15

    Potassium channels located in the dendrites of hippocampal CA1 pyramidal neurons control the shape and amplitude of back-propagating action potentials, the amplitude of excitatory postsynaptic potentials and dendritic excitability. Non-uniform gradients in the distribution of potassium channels in the dendrites make the dendritic electrical properties markedly different from those found in the soma. For example, the influence of a fast, calcium-dependent potassium current on action potential repolarization is progressively reduced in the first 150 micrometer of the apical dendrites, so that action potentials recorded farther than 200 micrometer from the soma have no fast after-hyperpolarization and are wider than those in the soma. The peak amplitude of back-propagating action potentials is also progressively reduced in the dendrites because of the increasing density of a transient potassium channel with distance from the soma. The activation of this channel can be reduced by the activity of a number of protein kinases as well as by prior depolarization. The depolarization from excitatory postsynaptic potentials (EPSPs) can inactivate these A-type K+ channels and thus lead to an increase in the amplitude of dendritic action potentials, provided the EPSP and the action potentials occur within the appropriate time window. This time window could be in the order of 15 ms and may play a role in long-term potentiation induced by pairing EPSPs and back-propagating action potentials.

  20. Neuroprotection against diisopropylfluorophosphate in acute hippocampal slices

    Ferchmin, P. A.; Pérez, Dinely; Cuadrado, Brenda L.; Carrasco, Marimée; Martins, Antonio H.; Eterović, Vesna A.

    2015-01-01

    Diisopropylfluorophosphate (DFP) is an irreversible inhibitor of acetylcholine esterase (AChE) and a surrogate of the organophosphorus (OP) nerve agent sarin. The neurotoxicity of DFP was assessed as a reduction of population spike (PS) area elicited by synaptic stimulation in acute hippocampal slices. Two classical antidotes, atropine, and pralidoxime, and two novel antidotes, 4R-cembranotriene-diol (4R) and a caspase 9 inhibitor, were tested. Atropine, pralidoxime, and 4R significantly protected when applied 30 min after DFP. The caspase inhibitor was neuroprotective when applied 5–10 min before or after DFP, suggesting that early synaptic apoptosis is responsible for the loss of PSs. It is likely that apoptosis starts at the synapses and, if antidotes are not applied, descends to the cell bodies, causing death. The acute slice is a reliable tool for mechanistic studies, and the assessment of neurotoxicity and neuroprotection with PS areas is, in general, pharmacologically congruent with in vivo results and predicts the effect of drugs in vivo. 4R was first found to be neuroprotective in slices and later we demonstrated that 4R is neuroprotective in vivo. The mechanism of neurotoxicity of OPs is not well understood, and there is a need for novel antidotes that could be discovered using acute slices. PMID:26438150

  1. The effects of prenatal methylmercury exposure on trace element and antioxidant levels in rats following 6-hydroxydopamine-induced neuronal insult.

    Mohamed Moosa, Zulfiah; Daniels, Willie M U; Mabandla, Musa V

    2014-06-01

    Methylmercury (MeHg) is a metal toxin found commonly in the environment. Studies have shown severe neurotoxic effects of MeHg poisoning especially during pregnancy where it crosses the foetoplacental and the blood brain barrier of the foetus leading to neurodevelopmental deficits in the offspring. These deficits may predispose offspring to neurodegenerative diseases later in life. In this study we investigated the effects of prenatal methylmercury exposure (2.5 mg/L in drinking water from GND 1-GND 21) on the trace element status in the brain of adolescent offspring (PND 28). Total antioxidant capacity (TAC) was measured in their blood plasma. In a separate group of animals that was also exposed prenatally to MeHg, 6-hydroydopamine (6-OHDA) was administered at PND 60 as a model of neuronal insult. Trace element and TAC levels were compared before and after 6-OHDA exposure. Prenatal MeHg treatment alone resulted in significantly higher concentrations of zinc, copper, manganese and selenium in the brain of offspring at PND 28 (p levels in MeHg-exposed adolescent offspring were significantly lower than their controls (p levels of iron, zinc, copper and manganese were increased compared to sham-lesioned offspring (p levels thereby promoting toxicity (p levels were higher in adult male rats than in female rats during adolescence however male rats that had been exposed to MeHg in utero failed to show this increase at PND 74. Prenatal MeHg exposure results in trace element dyshomeostasis in the brain of offspring and reduces total antioxidant capacity. This may reflect a mechanism by which methylmercury exerts its neurotoxicity and/or predispose offspring to further neurological insults during adulthood.

  2. Studies of ATP sensitive potassium channels on 6 - hydroxydopamine and haloperidol rat models of Parkinson' s disease: Implications for treating Parkinson' s disease?

    WANGSen; YANGYong; DINGJian-Hua; HUGang

    2004-01-01

    Parkinson' s disease is a common neurodegenerative movement disease that affects more than 1% of the elderly population, characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta. Although during the past score, major biochemistry process such as mitochondrial dysfunction, oxidative stress and glutamate toxicity

  3. Effect of acute and repeated restraint stress on glucose oxidation to CO2 in hippocampal and cerebral cortex slices

    Torres I.L.S.

    2001-01-01

    Full Text Available It has been suggested that glucocorticoids released during stress might impair neuronal function by decreasing glucose uptake by hippocampal neurons. Previous work has demonstrated that glucose uptake is reduced in hippocampal and cerebral cortex slices 24 h after exposure to acute stress, while no effect was observed after repeated stress. Here, we report the effect of acute and repeated restraint stress on glucose oxidation to CO2 in hippocampal and cerebral cortex slices and on plasma glucose and corticosterone levels. Male adult Wistar rats were exposed to restraint 1 h/day for 50 days in the chronic model. In the acute model there was a single exposure. Immediately or 24 h after stress, the animals were sacrificed and the hippocampus and cerebral cortex were dissected, sliced, and incubated with Krebs buffer, pH 7.4, containing 5 mM glucose and 0.2 µCi D-[U-14C] glucose. CO2 production from glucose was estimated. Trunk blood was also collected, and both corticosterone and glucose were measured. The results showed that corticosterone levels after exposure to acute restraint were increased, but the increase was smaller when the animals were submitted to repeated stress. Blood glucose levels increased after both acute and repeated stress. However, glucose utilization, measured as CO2 production in hippocampal and cerebral cortex slices, was the same in stressed and control groups under conditions of both acute and chronic stress. We conclude that, although stress may induce a decrease in glucose uptake, this effect is not sufficient to affect the energy metabolism of these cells.

  4. Reducing central serotonin in adulthood promotes hippocampal neurogenesis.

    Song, Ning-Ning; Jia, Yun-Fang; Zhang, Lei; Zhang, Qiong; Huang, Ying; Liu, Xiao-Zhen; Hu, Ling; Lan, Wei; Chen, Ling; Lesch, Klaus-Peter; Chen, Xiaoyan; Xu, Lin; Ding, Yu-Qiang

    2016-02-03

    Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER(T2) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.

  5. Amyloid Beta Peptide Slows Down Sensory-Induced Hippocampal Oscillations

    Fernando Peña-Ortega

    2012-01-01

    Full Text Available Alzheimer’s disease (AD progresses with a deterioration of hippocampal function that is likely induced by amyloid beta (Aβ oligomers. Hippocampal function is strongly dependent on theta rhythm, and disruptions in this rhythm have been related to the reduction of cognitive performance in AD. Accordingly, both AD patients and AD-transgenic mice show an increase in theta rhythm at rest but a reduction in cognitive-induced theta rhythm. We have previously found that monomers of the short sequence of Aβ (peptide 25–35 reduce sensory-induced theta oscillations. However, considering on the one hand that different Aβ sequences differentially affect hippocampal oscillations and on the other hand that Aβ oligomers seem to be responsible for the cognitive decline observed in AD, here we aimed to explore the effect of Aβ oligomers on sensory-induced theta rhythm. Our results show that intracisternal injection of Aβ1–42 oligomers, which has no significant effect on spontaneous hippocampal activity, disrupts the induction of theta rhythm upon sensory stimulation. Instead of increasing the power in the theta band, the hippocampus of Aβ-treated animals responds to sensory stimulation (tail pinch with an increase in lower frequencies. These findings demonstrate that Aβ alters induced theta rhythm, providing an in vivo model to test for therapeutic approaches to overcome Aβ-induced hippocampal and cognitive dysfunctions.

  6. Altered hippocampal morphology in unmedicated patients with major depressive illness

    Carrie E Bearden

    2009-11-01

    Full Text Available Despite converging evidence that major depressive illness is associated with both memory impairment and hippocampal pathology, findings vary widely across studies and it is not known whether these changes are regionally specific. In the present study we acquired brain MRIs (magnetic resonance images from 31 unmedicated patients with MDD (major depressive disorder; mean age 39.2±11.9 years; 77% female and 31 demographically comparable controls. Three-dimensional parametric mesh models were created to examine localized alterations of hippocampal morphology. Although global volumes did not differ between groups, statistical mapping results revealed that in MDD patients, more severe depressive symptoms were associated with greater left hippocampal atrophy, particularly in CA1 (cornu ammonis 1 subfields and the subiculum. However, previous treatment with atypical antipsychotics was associated with a trend towards larger left hippocampal volume. Our findings suggest effects of illness severity on hippocampal size, as well as a possible effect of past history of atypical antipsychotic treatment, which may reflect prolonged neuroprotective effects. This possibility awaits confirmation in longitudinal studies.

  7. The Form and Function of Hippocampal Context Representations

    Smith, David M.; Bulkin, David A.

    2014-01-01

    Context is an essential component of learning and memory processes, and the hippocampus is critical for encoding contextual information. However, connecting hippocampal physiology with its role in context and memory has only recently become possible. It is now clear that contexts are represented by coherent ensembles of hippocampal neurons and new optogenetic stimulation studies indicate that activity in these ensembles can trigger the retrieval of context appropriate memories. We interpret these findings in light of recent evidence that the hippocampus is critically involved in using contextual information to prevent interference, and propose a theoretical framework for understanding contextual influence of memory retrieval. When a new context is encountered, a unique hippocampal ensemble is recruited to represent it. Memories for events that occur in the context become associated with the hippocampal representation. Revisiting the context causes the hippocampal context code to be re-expressed and the relevant memories are primed. As a result, retrieval of appropriate memories is enhanced and interference from memories belonging to other contexts is minimized. PMID:24462752

  8. Qualitative and Quantitative Hippocampal MRI Assessments in Intractable Epilepsy

    Paramdeep Singh

    2013-01-01

    Full Text Available Aims. To acquire normative data of hippocampal volumes and T2 relaxation times, to evaluate and compare qualitative and quantitative assessments in evaluating hippocampi in patients with different durations of intractable epilepsy, and to propose an imaging protocol based on performance of these techniques. Methods. MRI analysis was done in 50 nonepileptic controls and 30 patients with intractable epilepsy on 1.5T scanner. Visual assessment and hippocampal volumetry were done on oblique coronal IR/T2W and T1W MP-RAGE images, respectively. T2 relaxation times were measured using 16-echo Carr-Purcell-Meiboom-Gill sequence. Volumetric data was normalized for variation in head size between individuals. Patients were divided into temporal ( and extratemporal ( groups based on clinical and EEG localization. Results. In controls, right hippocampal volume was slightly more than the left with no effect of age or gender. In TLE patients, hippocampal volumetry provided maximum concordance with EEG. Visual assessment of unilateral pathology concurred well with measured quantitative values but poorly in cases with bilateral pathologies. There were no significant differences of mean values between extratemporal group and controls group. Quantitative techniques detected mild abnormalities, undetected on visual assessment. Conclusions. Quantitative techniques are more sensitive to diagnose bilateral and mild unilateral hippocampal abnormalities.

  9. Hippocampal CA1 transcriptional profile of sleep deprivation: relation to aging and stress.

    Nada M Porter

    Full Text Available BACKGROUND: Many aging changes seem similar to those elicited by sleep-deprivation and psychosocial stress. Further, sleep architecture changes with age suggest an age-related loss of sleep. Here, we hypothesized that sleep deprivation in young subjects would elicit both stress and aging-like transcriptional responses. METHODOLOGY/PRINCIPAL FINDINGS: F344 rats were divided into control and sleep deprivation groups. Body weight, adrenal weight, corticosterone level and hippocampal CA1 transcriptional profiles were measured. A second group of animals was exposed to novel environment stress (NES, and their hippocampal transcriptional profiles measured. A third cohort exposed to control or SD was used to validate transcriptional results with Western blots. Microarray results were statistically contrasted with prior transcriptional studies. Microarray results pointed to sleep pressure signaling and macromolecular synthesis disruptions in the hippocampal CA1 region. Animals exposed to NES recapitulated nearly one third of the SD transcriptional profile. However, the SD-aging relationship was more complex. Compared to aging, SD profiles influenced a significant subset of genes. mRNA associated with neurogenesis and energy pathways showed agreement between aging and SD, while immune, glial, and macromolecular synthesis pathways showed SD profiles that opposed those seen in aging. CONCLUSIONS/SIGNIFICANCE: We conclude that although NES and SD exert similar transcriptional changes, selective presynaptic release machinery and Homer1 expression changes are seen in SD. Among other changes, the marked decrease in Homer1 expression with age may represent an important divergence between young and aged brain response to SD. Based on this, it seems reasonable to conclude that therapeutic strategies designed to promote sleep in young subjects may have off-target effects in the aged. Finally, this work identifies presynaptic vesicular release and intercellular

  10. Cholecystokinin-octapeptide restored morphine-induced hippocampal long-term potentiation impairment in rats.

    Wen, Di; Zang, Guoqing; Sun, DongLei; Yu, Feng; Mei, Dong; Ma, Chunling; Cong, Bin

    2014-01-24

    Cholecystokinin-octapeptide (CCK-8), which is a typical brain-gut peptide, exerts a wide range of biological activities on the central nervous system. We have previously reported that CCK-8 significantly alleviated morphine-induced amnesia and reversed spine density decreases in the CA1 region of the hippocampus in morphine-treated animals. Here, we investigated the effects of CCK-8 on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of rat dentate gyrus (DG) in acute saline or morphine-treated rats. Population spikes (PS), which were evoked by stimulation of the LPP, were recorded in the DG region. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and CCK-8 (1μg, i.c.v.) restored the amplitude of PS that was attenuated by morphine injection. Furthermore, microinjection of CCK-8 (0.1 and 1μg, i.c.v.) also significantly augmented hippocampal LTP in saline-treated (1ml/kg, s.c.) rats. Pre-treatment of the CCK2 receptor antagonist L-365,260 (10μg, i.c.v) reversed the effects of CCK-8, but the CCK1 receptor antagonist L-364,718 (10μg, i.c.v) did not. The present results demonstrate that CCK-8 attenuates the effect of morphine on hippocampal LTP through CCK2 receptors and suggest an ameliorative function of CCK-8 on morphine-induced memory impairment.

  11. Effect of forced exercise and exercise withdrawal on memory, serum and hippocampal corticosterone levels in rats.

    Radahmadi, Maryam; Alaei, Hojjatallah; Sharifi, Mohammad Reza; Hosseini, Nasrin

    2015-10-01

    Evidence suggests that there are positive effects of exercise on learning and memory. Moreover, some studies have demonstrated that forced exercise plays the role of a stressor. This study was aimed at investigating the effects of different timing of exercise and exercise withdrawal on memory, and serum and hippocampal corticosterone (CORT) levels. Wistar rats were randomly divided into five groups: control, sham, exercise-rest (exercise withdrawal), rest-exercise (exercised group), and exercise-exercise (continuous exercise). Rats were forced to run on a treadmill for 1 h/day at a speed 20-21-m/min. Memory function was evaluated by the passive avoidance test in different intervals (1, 7 and 21 days) after foot shock. Findings showed that after the exercise withdrawal, short-term and mid-term memories, had significant enhancement compared to the control group, while the long-term memory did not present this result. In addition, the serum and hippocampal CORT levels were at the basal levels after the rest period in the exercise-rest group. In the rest-exercise group, exercise improved mid- and long-term memories, whereas continuous exercise improved all types short-, mid- and long-term memories, particularly the mid-term memory. Twenty-one and forty-two days of exercise significantly decreased the serum and hippocampal CORT levels. It seems that exercise for at least 21 days with no rest could affect biochemical factors in the brain. Also, regular continuous exercise plays an important role in memory function. Hence, the duration and withdraw of exercise are important factors for the neurobiological aspects of the memory responses.

  12. Structural hippocampal anomalies in a schizophrenia population correlate with navigation performance on a wayfinding task

    Andrée-Anne eLedoux

    2014-03-01

    Full Text Available Episodic memory, related to the hippocampus, has been found to be impaired in schizophrenia. Further, hippocampal anomalies have also been observed in schizophrenia. This study investigated whether average hippocampal grey matter (GM would differentiate performance on a hippocampus-dependent memory task in patients with schizophrenia and healthy controls. Twenty-one patients with schizophrenia and twenty-two control participants were scanned with an MRI while being tested on a wayfinding task in a virtual town (e.g., find the grocery store from the school. Regressions were performed for both groups individually and together using GM and performance on the wayfinding task. Results indicate that controls successfully completed the task more often than patients, took less time, and made fewer errors. Additionally, controls had significantly more hippocampal GM than patients. Poor performance was associated with a GM decrease in the right hippocampus for both groups. Within group regressions found an association between right hippocampi GM and performance in controls and an association between the left hippocampi GM and performance in patients. A second analysis revealed that different anatomical GM regions, known to be associated with the hippocampus, such as the parahippocampal cortex, amygdala, medial and orbital prefrontal cortices, covaried with the hippocampus in the control group. Interestingly, the cuneus and cingulate gyrus also covaried with the hippocampus in the patient group but the orbital frontal cortex did not, supporting the hypothesis of impaired connectivity between the hippocampus and the frontal cortex in schizophrenia. These results present important implications for creating intervention programs aimed at measuring functional and structural changes in the hippocampus in schizophrenia.

  13. Persistent reduction of hippocampal glutamine synthetase expression after status epilepticus in immature rats.

    van der Hel, W Saskia; Hessel, Ellen V S; Bos, Ineke W M; Mulder, Sandra D; Verlinde, Suzanne A M W; van Eijsden, Pieter; de Graan, Pierre N E

    2014-12-01

    Mesiotemporal sclerosis (MTS), the most frequent form of drug-resistant temporal lobe epilepsy, often develops after an initial precipitating injury affecting the immature brain. To analyse early processes in epileptogenesis we used the juvenile pilocarpine model to study status epilepticus (SE)-induced changes in expression of key components in the glutamate-glutamine cycle, known to be affected in MTS patients. SE was induced by Li(+) /pilocarpine injection in 21-day-old rats. At 2-19 weeks after SE hippocampal protein expression was analysed by immunohistochemistry and neuron damage by FluoroJade staining. Spontaneous seizures occurred in at least 44% of animals 15-18 weeks after SE. As expected in this model, we did not observe loss of principal hippocampal neurons. Neuron damage was most pronounced in the hilus, where we also detected progressive loss of parvalbumin-positive GABAergic interneurons. Hilar neuron loss (or end-folium sclerosis), a common feature in patients with MTS, was accompanied by a progressively decreased glutamine synthetase (GS)-immunoreactivity from 2 (-15%) to 19 weeks (-33.5%) after SE. Immunoreactivity for excitatory amino-acid transporters, vesicular glutamate transporter 1 and glial fibrillary acidic protein was unaffected. Our data show that SE elicited in 21-day-old rats induces a progressive reduction in hilar GS expression without affecting other key components of the glutamate-glutamine cycle. Reduced expression of glial enzyme GS was first detected 2 weeks after SE, and thus clearly before spontaneous recurrent seizures occurred. These results support the hypothesis that reduced GS expression is an early event in the development of hippocampal sclerosis in MTS patients and emphasize the importance of astrocytes in early epileptogenesis.

  14. Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons.

    Gill, Raminder; Chang, Philip K-Y; Prenosil, George A; Deane, Emily C; McKinney, Rebecca A

    2013-12-01

    Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.

  15. Exploration of the Brn4-regulated genes enhancing adult hippocampal neurogenesis by RNA sequencing.

    Guo, Jingjing; Cheng, Xiang; Zhang, Lei; Wang, Linmei; Mao, Yongxin; Tian, Guixiang; Xu, Wenhao; Wu, Yuhao; Ma, Zhi; Qin, Jianbing; Tian, Meiling; Jin, Guohua; Shi, Wei; Zhang, Xinhua

    2017-02-18

    Adult hippocampal neurogenesis is essential for learning and memory, and its dysfunction is involved in neurodegenerative diseases. However, the molecular mechanisms underlying adult hippocampal neurogenesis are still largely unknown. Our previous studies indicated that the transcription factor Brn4 was upregulated and promoted neuronal differentiation of neural stem cells (NSCs) in the surgically denervated hippocampus in rats. In this study, we use high-throughput RNA sequencing to explore the molecular mechanisms underlying the enhancement of adult hippocampal neurogenesis induced by lentivirus-mediated Brn4 overexpression in vivo. After 10 days of the lentivirus injection, we found that the expression levels of genes related to neuronal development and maturation were significantly increased and the expression levels of genes related to NSC maintenance were significantly decreased, indicating enhanced neurogenesis in the hippocampus after Brn4 overexpression. Through RNA sequencing, we found that 658 genes were differentially expressed in the Brn4-overexpressed hippocampi compared with GFP-overexpressed controls. Many of these differentially expressed genes are involved in NSC division and differentiation. By using quantitative real-time PCR, we validated the expression changes of three genes, including Ctbp2, Notch2, and Gli1, all of which are reported to play key roles in neuronal differentiation of NSCs. Importantly, the expression levels of Ctbp2 and Notch2 were also significantly changed in the hippocampus of Brn4 KO mice, which indicates that the expression levels of Ctbp2 and Notch2 may be directly regulated by Brn4. Our current study provides a solid foundation for further investigation and identifies Ctbp2 and Notch2 as possible downstream targets of Brn4. © 2017 Wiley Periodicals, Inc.

  16. Neonatal isoflurane exposure induces neurocognitive impairment and abnormal hippocampal histone acetylation in mice.

    Tao Zhong

    Full Text Available Neonatal exposure to isoflurane may induce long-term memory impairment in mice. Histone acetylation is an important form of chromatin modification that regulates the transcription of genes required for memory formation. This study investigated whether neonatal isoflurane exposure-induced neurocognitive impairment is related to dysregulated histone acetylation in the hippocampus and whether it can be attenuated by the histone deacetylase (HDAC inhibitor trichostatin A (TSA.C57BL/6 mice were exposed to 0.75% isoflurane three times (each for 4 h at postnatal days 7, 8, and 9. Contextual fear conditioning (CFC was tested at 3 months after anesthesia administration. TSA was intraperitoneally injected 2 h before CFC training. Hippocampal histone acetylation levels were analyzed following CFC training. Levels of the neuronal activation and synaptic plasticity marker c-Fos were investigated at the same time point.Mice that were neonatally exposed to isoflurane showed significant memory impairment on CFC testing. These mice also exhibited dysregulated hippocampal H4K12 acetylation and decreased c-Fos expression following CFC training. TSA attenuated isoflurane-induced memory impairment and simultaneously increased histone acetylation and c-Fos levels in the hippocampal cornu ammonis (CA1 area 1 h after CFC training.Memory impairment induced by repeated neonatal exposure to isoflurane is associated with dysregulated histone H4K12 acetylation in the hippocampus, which probably affects downstream c-Fos gene expression following CFC training. The HDAC inhibitor TSA successfully rescued impaired contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression.

  17. Base excision repair activities in organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation.

    Rolseth, Veslemøy; Rundén-Pran, Elise; Neurauter, Christine Gran; Yndestad, Arne; Luna, Luisa; Aukrust, Pål; Ottersen, Ole Petter; Bjørås, Magnar

    2008-06-01

    The capacity for DNA repair is likely to be one of the factors that determine the vulnerability of neurons to ischemic stress and may influence the pathological outcome of stroke. In this report, initiation of base excision repair (BER) was assessed by analysis of enzyme activity and gene expression level of DNA glycosylases and AP-endonucleases in rat organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation (OGD) - an in vitro model of stroke. Under basal conditions, AP-endonuclease activity and base removal of ethenoadenine and 8-oxoguanine (8-oxoG) were higher (by approximately 20-35 %) in CA3/fascia dentata (FD) than in CA1. Base removal of uracil did not differ between the two hippocampal regions, while removal of 5-hydroxyuracil (5-OHU) was slightly less efficient in CA3/FD than in CA1. Analyses performed immediately after 30 min of OGD revealed a decreased AP-endonuclease activity (by approximately 20%) in CA1 as well as CA3/FD, and an increased ethenoadenine activity (by approximately 25%) in CA1. Activities for 8-oxoG, 5-OHU and uracil showed no significant changes at this time point. At 8h after OGD, none of the enzyme activities differed from control values. Real-time RT-PCR showed that transcription of DNA glycosylases, including Ogg1, Nth1, Ung, Aag, Neil1 and Neil2 were not changed in response to OGD treatment (t=0 h). The hippocampal expression of Neil2 was low compared with the other DNA glycosylases. These data indicate that CA1 has a lower capacity than CA3/FD for removal of base lesions under basal conditions. The relatively low capacity for BER in basal conditions and the apparent failure to upregulate repair of oxidative damage after OGD might contribute to the high vulnerability of CA1 to ischemic injury.

  18. Regulation of extracellular signal-regulated kinase 1/2 inlfuences hippocampal neuronal survival in a rat model of diabetic cerebral ischemia

    Yaning Zhao; Jianmin Li; Qiqun Tang; Pan Zhang; Liwei Jing; Changxiang Chen; Shuxing Li

    2014-01-01

    Activation of extracellular signal-regulated kinase 1/2 has been demonstrated in acute brain ischemia. We hypothesized that activated extracellular signal-regulated kinase 1/2 can protect hippocampal neurons from injury in a diabetic model after cerebral ischemia/reperfusion. In this study, transient whole-brain ischemia was induced by four-vessel occlusion in normal and diabetic rats, and extracellular signal-regulated kinase 1/2 inhibitor (U0126) was administered into diabetic rats 30 minutes before ischemia as a pretreatment. Results showed that the number of surviving neurons in the hippocampal CA1 region was reduced, extracellular signal-regulated kinase 1/2 phosphorylation and Ku70 activity were decreased, and pro-apoptotic Bax expression was upregulated after intervention using U0126. These ifndings demonstrate that inhibition of extracellular signal-regulated kinase 1/2 activity aggravated neuronal loss in the hippocampus in a diabetic rat after cerebral ischemia/reperfusion, further decreased DNA repairing ability and ac-celerated apoptosis in hippocampal neurons. Extracellular signal-regulated kinase 1/2 activation plays a neuroprotective role in hippocampal neurons in a diabetic rat after cerebral ischemia/reperfusion.

  19. The influence of electric fields on hippocampal neural progenitor cells.

    Ariza, Carlos Atico; Fleury, Asha T; Tormos, Christian J; Petruk, Vadim; Chawla, Sagar; Oh, Jisun; Sakaguchi, Donald S; Mallapragada, Surya K

    2010-12-01

    The differentiation and proliferation of neural stem/progenitor cells (NPCs) depend on various in vivo environmental factors or cues, which may include an endogenous electrical field (EF), as observed during nervous system development and repair. In this study, we investigate the morphologic, phenotypic, and mitotic alterations of adult hippocampal NPCs that occur when exposed to two EFs of estimated endogenous strengths. NPCs treated with a 437 mV/mm direct current (DC) EF aligned perpendicularly to the EF vector and had a greater tendency to differentiate into neurons, but not into oligodendrocytes or astrocytes, compared to controls. Furthermore, NPC process growth was promoted perpendicularly and inhibited anodally in the 437 mV/mm DC EF. Yet fewer cells were observed in the DC EF, which in part was due to a decrease in cell viability. The other EF applied was a 46 mV/mm alternating current (AC) EF. However, the 46 mV/mm AC EF showed no major differences in alignment or differentiation, compared to control conditions. For both EF treatments, the percent of mitotic cells during the last 14 h of the experiment were statistically similar to controls. Reported here, to our knowledge, is the first evidence of adult NPC differentiation affected in an EF in vitro. Further investigation and application of EFs on stem cells is warranted to elucidate the utility of EFs to control phenotypic behavior. With progress, the use of EFs may be engineered to control differentiation and target the growth of transplanted cells in a stem cell-based therapy to treat nervous system disorders.

  20. The Antidepressant-Like Effect of Fish Oil: Possible Role of Ventral Hippocampal 5-HT1A Post-synaptic Receptor.

    Carabelli, Bruno; Delattre, Ana Marcia; Pudell, Claudia; Mori, Marco Aurélio; Suchecki, Deborah; Machado, Ricardo B; Venancio, Daniel Paulino; Piazzetta, Sílvia Regina; Hammerschmidt, Ivilim; Zanata, Sílvio M; Lima, Marcelo M S; Zanoveli, Janaína Menezes; Ferraz, Anete Curte

    2015-08-01

    The pathophysiology of depression is not completely understood; nonetheless, numerous studies point to serotonergic dysfunction as a possible cause. Supplementation with fish oil rich docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) during critical periods of development produces antidepressant effects by increasing serotonergic neurotransmission, particularly in the hippocampus. In a previous study, the involvement of 5-HT1A receptors was demonstrated and we hypothesized that fish oil supplementation (from conception to weaning) alters the function of post-synaptic hippocampal 5-HT1A receptors. To test this hypothesis, female rats were supplemented with fish oil during habituation, mating, gestation, and lactation. The adult male offspring was maintained without supplementation until 3 months of age, when they were subjected to the modified forced swimming test (MFST) after infusion of vehicle or the selective 5-HT1A antagonist, WAY100635, and frequency of swimming, immobility, and climbing was recorded for 5 min. After the behavioral test, the hippocampi were obtained for quantification of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and for 5-HT1A receptor expression by Western blotting analysis. Fish oil-supplemented offspring displayed less depressive-like behaviors in the MFST reflected by decreased immobility and increased swimming and higher 5-HT hippocampal levels. Although there was no difference in the expression of hippocampal 5-HT1A receptors, intra-hippocampal infusion of a sub-effective dose of 8-OH-DPAT enhanced the antidepressant effect of fish oil in supplemented animals. In summary, the present findings suggest that the antidepressant-like effects of fish oil supplementation are likely related to increased hippocampal serotonergic neurotransmission and sensitization of hippocampal 5-HT1A receptors.

  1. Effect of acetylcholine receptors on the pain-related electrical activities in the hippocampal CA3 region of morphine-addicted rats

    Guan Zeng Li

    2015-07-01

    Full Text Available Objective(s:To determine the effect of acetylcholine (ACh, pilocarpine, and atropine on pain evoked responses of pain excited neurons (PEN and pain inhibited neurons (PIN in hippocampal CA3 region of morphine addicted rats. Materials and Methods:Female Wistar rats, weighing between 230-260 g were used in this study. Morphine addicted rats were generated by subcutaneous injection of increasing concentrations of morphine hydrochloride for six days. Trains of electrical impulses applied to the sciatic nerve were used as noxious stimulation and the evoked electrical activities of PEN or PIN in hippocampal CA3 area were recorded using extracellular electrophysiological recording techniques in hippocampal slices. The effect of acetylcholine receptor stimulation byACh, the muscarinic agonist pilocarpine, and the muscarinic antagonist atropine on the pain evoked responses of pain related electrical activities was analyzed in hippocampal CA3 area of morphine addicted rats. Results:Intra-CA3 microinjection of ACh (2 μg/1 μl or pilocarpine (2 μg/1 μl decreased the discharge frequency and prolonged the firing latency of PEN, but increased the discharge frequency and shortened the firing inhibitory duration (ID of PIN. The intra-CA3 administration of atropine (0.5 μg/1 μl produced opposite effect. The peak activity of cholinergic modulators was 2 to 4 min later in morphine addicted rats compared to peak activity previously observed in normal rats. Conclusion: ACh dependent modulation of noxious stimulation exists in hippocampal CA3 area of morphine addicted rats. Morphine treatment may shift the sensitivity of pain related neurons towards a delayed response to muscarinergic neurotransmission in hippocampal CA3 region.

  2. Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB.

    Qiao, Feng; Gao, Xiu-Ping; Yuan, Li; Cai, Hong-Yan; Qi, Jin-Shun

    2014-01-01

    Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+/calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4.

  3. MR-determined hippocampal asymmetry in full-term and preterm neonates.

    Thompson, Deanne K; Wood, Stephen J; Doyle, Lex W; Warfield, Simon K; Egan, Gary F; Inder, Terrie E

    2009-02-01

    Hippocampi are asymmetrical in children and adults, where the right hippocampus is larger. To date, no literature has confirmed that hippocampal asymmetry is evident at birth. Furthermore, gender differences have been observed in normal hippocampal asymmetry, but this has not been examined in neonates. Stress, injury, and lower IQ have been associated with alterations to hippocampal asymmetry. These same factors often accompany preterm birth. Therefore, prematurity is possibly associated with altered hippocampal asymmetry. There were three aims of this study: First, we assessed whether hippocampi were asymmetrical at birth, second whether there was a gender effect on hippocampal asymmetry, and third whether the stress of preterm birth altered hippocampal asymmetry. This study utilized volumetric magnetic resonance imaging to compare left and right hippocampal volumes in 32 full-term and 184 preterm infants at term. Full-term infants demonstrated rightward hippocampal asymmetry, as did preterm infants. In the case of preterm infants, hippocampal asymmetry was proportional to total hemispheric asymmetry. This study is the first to demonstrate that the normal pattern of hippocampal asymmetry is present this early in development. We did not find gender differences in hippocampal asymmetry at term. Preterm infants tended to have less asymmetrical hippocampi than full-term infants, a difference which became significant after correcting for hemispheric brain tissue volumes. This study may suggest that hippocampal asymmetry develops in utero and is maintained into adulthood in infants with a normal neurological course.

  4. Maternal exposure to hexachlorophene targets intermediate-stage progenitor cells in the hippocampal neurogenesis involving myelin vacuolation of cholinergic and glutamatergic inputs in mice.

    Kato, Mizuho; Abe, Hajime; Itahashi, Megu; Kikuchihara, Yoh; Kimura, Masayuki; Mizukami, Sayaka; Yoshida, Toshinori; Shibutani, Makoto

    2016-02-01

    Hexachlorophene (HCP) has been shown to induce myelin vacuolation due to intramyelinic edema of the nerve fibers in animal neural tissue. We investigated the maternal exposure effect of HCP on hippocampal neurogenesis in the offspring of pregnant mice supplemented with 0 (control), 33 or 100 ppm HCP in diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, offspring as examined in males exhibited decreased granule cell lineage populations expressing paired box 6, sex-determining region Y-box 2 and eomesodermin in the hippocampal subgranular zone (SGZ) accompanied by myelin vacuolation involving white matter tracts of the hippocampal fimbria at ≥ 33 ppm. However, SGZ cellular populations expressing brain lipid binding protein and doublecortin were unchanged at any dose. Transcript expression of cholinergic receptor genes, Chrna4 and Chrnb2, and glutamate receptor genes, Grm1 and Grin2d, examined at 100 ppm, decreased in the dentate gyrus. HCP exposure did not alter the number of proliferating or apoptotic cells in the SGZ, or reelin- or calcium-binding protein-expressing γ-aminobutyric acid (GABA)ergic interneurons in the dentate hilus, on PND 21 and PND 77. All neurogenesis-related changes observed in HCP-exposed offspring on PND 21 disappeared on PND 77, suggesting that maternal HCP exposure at ≥ 33 ppm reversibly decreased type 2 intermediate-stage progenitor cells in the hippocampal neurogenesis. Myelin vacuolation might be responsible for changes in neurogenesis possibly by reducing nerve conduction velocity of cholinergic inputs from the septal-hippocampal pathway to granule cell lineages and/or GABAergic interneurons, and of glutamatergic inputs to granule cell lineages.

  5. Differential modulation of changes in hippocampal-septal synaptic excitability by the amygdala as a function of either elemental or contextual fear conditioning in mice.

    Desmedt, A; Garcia, R; Jaffard, R

    1998-01-01

    Recent data obtained using a classic fear conditioning paradigm showed a dissociation between the retention of associations relative to contextual information (dependent on the hippocampal formation) and the retention of elemental associations (dependent on the amygdala). Furthermore, it was reported that conditioned emotional responses (CERs) could be dissociated from the recollection of the learning experience (declarative memory) in humans and from modifications of the hippocampal-septal excitability in animals. Our aim was to determine whether these two systems ("behavioral expression" system and "factual memory" system) interact by examining the consequences of amygdalar lesions (1) on the modifications of hippocampal-septal excitability and (2) on the behavioral expression of fear (freezing) resulting from an aversive conditioning during reexposure to conditional stimuli (CSs). During conditioning, to modulate the predictive nature of the context and of a discrete stimulus (tone) on the unconditional stimulus (US) occurrence, the phasic discrete CS was paired with the US or randomly distributed with regard to the US. After the lesion, the CER was dramatically reduced during reexposure to the CSs, whatever the type of acquisition. However, the changes in hippocampal-septal excitability persisted but were altered. For controls, a decrease in septal excitability was observed during reexposure to the conditioning context only for the "unpaired group" (predictive context case). Conversely, among lesioned subjects this decrease was observed in the "paired group" (predictive discrete CS case), whereas this decrease was significantly reduced in the unpaired group with respect to the matched control group. The amplitude and the direction of these modifications suggest a differential modulation of hippocampal-septal excitability by the amygdala to amplify the contribution of the more predictive association signaling the occurrence of the aversive event.

  6. Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis***

    Zhihong Chen; Songhe Yang; Yaqiang He; Chengjun Song; Yongping Liu

    2013-01-01

    Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mel itus. In this study, a rat type 2 diabetes mel itus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, fol owing which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to al eviate hippocampal damage in diabetic rats.

  7. The Yin and Yang of Memory Consolidation: Hippocampal and Neocortical

    Rossato, Janine I.; Jacobse, Justin; Grieves, Roddy M.; Spooner, Patrick A.; Battaglia, Francesco P.; Fernández, Guillen; Morris, Richard G. M.

    2017-01-01

    While hippocampal and cortical mechanisms of memory consolidation have long been studied, their interaction is poorly understood. We sought to investigate potential interactions with respect to trace dominance, strengthening, and interference associated with postencoding novelty or sleep. A learning procedure was scheduled in a watermaze that placed the impact of novelty and sleep in opposition. Distinct behavioural manipulations—context preexposure or interference during memory retrieval—differentially affected trace dominance and trace survival, respectively. Analysis of immediate early gene expression revealed parallel up-regulation in the hippocampus and cortex, sustained in the hippocampus in association with novelty but in the cortex in association with sleep. These findings shed light on dynamically interacting mechanisms mediating the stabilization of hippocampal and neocortical memory traces. Hippocampal memory traces followed by novelty were more dominant by default but liable to interference, whereas sleep engaged a lasting stabilization of cortical traces and consequent trace dominance after preexposure. PMID:28085883

  8. Hippocampal unit activity during classical aversive and appetitive conditioning.

    Segal, M; Disterhoft, J F; Olds, J

    1972-02-18

    Rats were trained with a tone being followed by either food or electric shock, on alternate days. Unit activity during application of the conditioned stimulus was recorded from the dorsal hippocampus. The results indicate differentiation of the hippocampal system. Dentate units respond by augmentation to a conditioned stimulus which leads to food and by inhibition to the same stimulus when it precedes electric shock. The hippocampus proper responds by augmentation in both situations. The intensity of the hippocampal response to the conditioned stimulus on the first day of training is higher if the unconditioned stimulus is food than if it is electric shock. These data cast light on the functions of the dorsal dentate-hippocampal connections and the hippocampus proper during aversive and appetitive conditioning.

  9. Unstable periodic orbits in human epileptic hippocampal slices.

    Pen-Ning Yu; Min-Chi Hsiao; Dong Song; Liu, Charles Y; Heck, Christi N; Millett, David; Berger, Theodore W

    2014-01-01

    Inter-ictal activity is studied in hippocampal slices resected from patients with epilepsy using local field potential recording. Inter-ictal activity in the dentate gyrus (DG) is induced by high-potassium (8 mM), low-magnesium (0.25 mM) aCSF with additional 100 μM 4-aminopyridine(4-AP). The dynamics of the inter-ictal activity is investigated by developing the first return map with inter-pulse intervals. Unstable periodic orbits (UPOs) are detected in the hippocampal slice at the DG area according to both the topological recurrence method and the periodic orbit transform method. Surrogate analysis suggests the presence of UPOs in hippocampal slices from patients with epilepsy. This finding also suggests that inter-ictal activity is a chaotic system and will allow us to apply chaos control techniques to manipulate inter-ictal activity.

  10. Effect of Xingnaojing Injection (醒脑静注射液) on Hippocampal N-methyl-D-aspartic Acid Receptors of Focal Cerebral Ischemia in Rats

    沈思钰; 蔡定芳; 陈伟华; 刘静; 陈虎; 应健

    2003-01-01

    Objective: To observe and elucidate the neuroprotective effect of Xingnaojing (XNJ) injection on hippocampal N-methyl-D-aspartic acid (NMDA) receptors of focal cerebral ischemia in rats. Methods: Cerebral ischemia was established by occluding the middle cerebral artery with an intraluminal suture technique in rats. Neurological deficit score, infarct volume and quantity of NMDA receptors were estimated in all groups and compared. Results: After being treated with XNJ, the score decreased in the initial 6 hours and infarct volume decreased in 24 hours. And within 24 hours,the quantity of NMDA receptors obviously decreased compared with the model group(P<0.01). It indicated that XNJ could ameliorate neurological behavior of middle cerebral artery occlusion rats and down-regulate the expression of hippocampal NMDA receptors. Conclusion: The neuroprotective effect of XNJ on focal cerebral ischemia is possibly related to down-regulating the expression of NMDA receptors in rats.

  11. Hippocampal expression of synaptic structural proteins and phosphorylated cAMP response element-binding protein in a rat model of vascular dementia induced by chronic cerebral hypoperfusion

    Hui Zhao; Zhiyong Li; Yali Wang; Qiuxia Zhang

    2012-01-01

    The present study established a rat model of vascular dementia induced by chronic cerebral hy-poperfusion through permanent ligation of bilateral common carotid arteries. At 60 days after mod-eling, escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group. In addition, the number of accurate crossings over the original platform significantly decreased, hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased, cAMP response element-binding protein expression remained unchanged, and phosphorylated cAMP response element-binding protein expression significantly decreased. Results suggested that abnormal expression of hippo-campal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion.

  12. Effects of pharmacological treatments on hippocampal NCAM1 and ERK2 expression in epileptic rats with cognitive dysfunction

    Kong, Qingxia; Min, Xia; Sun, Ran; Gao, Jianying; Liang, Ruqing; Li, Lei; Chu, Xu

    2016-01-01

    The present study aimed to investigate the effects of various pharmacological agents on the hippocampal expression of neural cell adhesion molecule 1 (NCAM1) and extracellular signal-regulated kinase 2 (ERK2) in epileptic rats with cognitive dysfunction. The experiments were conducted using 120 Wistar rats: 20 controls and 100 with pilocarpine-induced status epilepticus (SE). The SE rats were randomly assigned to 5 groups (n=20/group) that received daily treatments for 1 month with one of the following: (i) saline (no effect on epilepsy); (ii) carbamazepine (an anticonvulsant); (iii) oxcarbazepine (an anticonvulsant); (iv) aniracetam (a nootropic); or (v) donepezil (an acetylcholinesterase inhibitor). Spatial learning and memory were assessed using a Morris Water Maze (MWM). Hippocampal tissue was assessed for NCAM1 and ERK2 messenger RNA (mRNA) expression by reverse transcription polymerase chain reaction, and protein expression by immunochemistry. The results revealed that SE rats had significantly poorer MWM performances compared with controls (P<0.01). Performance in SE rats was improved with donepezil treatment (P<0.01), but declined with carbamazepine (P<0.01). Compared with controls, saline-treated SE rats exhibited increased hippocampal NCAM1 mRNA expression (P<0.01). Among SE rats, NCAM1 mRNA expression was highest in those treated with donepezil, followed by aniracetam-, saline-, oxcarbazepine- and carbamazepine-treated rats. Compared to controls, saline-treated SE rats exhibited decreased hippocampal ERK2 mRNA expression (P<0.01). Among SE rats, ERK2 mRNA expression was highest in those treated with donepezil, followed by aniracetam, saline, oxcarbazepine and carbamazepine. NCAM1 and ERK2 protein expression levels were parallel to those of the mRNA. In saline-treated SE rats, hippocampal ERK2 expression was decreased and NCAM1 expression was increased; thus, these two molecules may be involved in the impairment of spatial memory. Carbamazepine augmented

  13. Hippocampal granule cells opt for early retirement.

    Alme, C B; Buzzetti, R A; Marrone, D F; Leutgeb, J K; Chawla, M K; Schaner, M J; Bohanick, J D; Khoboko, T; Leutgeb, S; Moser, E I; Moser, M-B; McNaughton, B L; Barnes, C A

    2010-10-01

    Increased excitability and plasticity of adult-generated hippocampal granule cells during a critical period suggests that they may "orthogonalize" memories according to time. One version of this "temporal tag" hypothesis suggests that young granule cells are particularly responsive during a specific time period after their genesis, allowing them to play a significant role in sculpting CA3 representations, after which they become much less responsive to any input. An alternative possibility is that the granule cells active during their window of increased plasticity, and excitability become selectively tuned to events that occurred during that time and participate in later reinstatement of those experiences, to the exclusion of other cells. To discriminate between these possibilities, rats were exposed to different environments at different times over many weeks, and cell activation was subsequently assessed during a single session in which all environments were revisited. Dispersing the initial experiences in time did not lead to the increase in total recruitment at reinstatement time predicted by the selective tuning hypothesis. The data indicate that, during a given time frame, only a very small number of granule cells participate in many experiences, with most not participating significantly in any. Based on these and previous data, the small excitable population of granule cells probably correspond to the most recently generated cells. It appears that, rather than contributing to the recollection of long past events, most granule cells, possibly 90-95%, are effectively "retired." If granule cells indeed sculpt CA3 representations (which remains to be shown), then a possible consequence of having a new set of granule cells participate when old memories are reinstated is that new representations of these experiences might be generated in CA3. Whatever the case, the present data may be interpreted to undermine the standard "orthogonalizer" theory of the role of

  14. Mixed neurotransmission in the hippocampal mossy fibers

    Agnieszka eMuenster-Wandowski

    2013-11-01

    Full Text Available The hippocampal mossy fibers (MFs, the axons of the granule cells of the dentate gyrus, innervate mossy cells and interneurons in the hilus on its way to CA3 where they innervate interneurons and pyramidal cells. Synapses on each target cell have distinct anatomical and functional characteristics. In recent years, the paradigmatic view of the MF synapses being only glutamatergic and, thus, excitatory has been questioned. Several laboratories have provided data supporting the hypothesis that the MFs can transiently release GABA during development and, in the adult, after periods of enhanced excitability. This transient glutamate-GABA co-transmission coincides with the transient expression of the machinery for the synthesis and release of GABA in the glutamatergic granule cells. Although some investigators have deemed this evidence controversial, new data has appeared with direct evidence of co-release of glutamate and GABA from single, identified MF boutons. However, this must still be confirmed by other groups and with other methodologies. A second, intriguing observation is that MF activation produced fast spikelets followed by excitatory postsynaptic potentials in a number of pyramidal cells, which, unlike the spikelets, underwent frequency potentiation and were strongly depressed by activation of metabotropic glutamate receptors. The spikelets persisted during blockade of chemical transmission and were suppressed by the gap junction blocker carbenoxolone. These data is consistent with the hypothesis of mixed electrical-chemical synapses between MFs and some pyramidal cells. Dye coupling between these types of principal cells and ultrastructural studies showing the co-existence of AMPA receptors and connexin 36 in this synapse corroborate their presence. A deeper consideration of mixed neurotransmission taking place in this synapse may expand our search and understanding of communication channels between different regions of the mammalian CNS.

  15. Long-term effects of amygdala GABA receptor blockade on specific subpopulations of hippocampal interneurons.

    Berretta, Sabina; Lange, Nicholas; Bhattacharyya, Sujoy; Sebro, Ronnie; Garces, Jessica; Benes, Francine M

    2004-01-01

    Growing evidence indicates that the amygdala modulates hippocampal functions. To test the hypothesis that this modulation may involve long-lasting effects on interneuronal networks in the hippocampus, changes in the expression of neurochemical markers specific for different interneuronal subpopulations were assessed in adult rats 96 h following acute infusion of low doses of the GABAA receptor antagonist picrotoxin into the amygdala. The numerical density (Nd) of somata showing immunoreactivity (IR) for parvalbumin (PVB) was decreased in dentate gyrus (DG) and the CA4-2 region, while that of calretinin (CR)-IR was decreased in DG and CA2. The Nd of calbindin D28k (CB)-IR somata was decreased in CA3-2. The densities of axon terminals arising from PVB-IR and cholecystokinin (CCK)-IR basket neurons were also altered, with those of CCK-IR terminals increased across all sectors, while PVB-IR terminals were decreased only in the CA region. Increases in CCK-IR terminals were paralleled by increases of terminals with IR for the 65-kD isoform of glutamate decarboxylase (GAD65). Mixed-effects statistical models, adapted specifically for these analyses, indicated that perturbations of amygdalar inputs to the hippocampus significantly alter the drive that hippocampal PVB-, CR-, and CB-IR neurons within the dentate gyrus/CA4 region exercise on CCK-IR terminals within the same region as well as in CA3-1. These results suggest that amygdalar modulation of specific neuronal subpopulations may induce lasting and far-reaching changes in the hippocampus during normal functioning, as well as in diseases involving a disruption of amygdalar activity. In particular, changes in specific interneuronal markers within selective hippocampal sectors detected in the present results are strikingly similar to those reported in this region in schizophrenia. These similarities suggest that, in this disease, a disruption of GABAergic transmission within the amygdala may play a significant role in

  16. Repeated exposure to neurotoxic levels of chlorpyrifos alters hippocampal expression of neurotrophins and neuropeptides.

    Lee, Young S; Lewis, John A; Ippolito, Danielle L; Hussainzada, Naissan; Lein, Pamela J; Jackson, David A; Stallings, Jonathan D

    2016-01-18

    Chlorpyrifos (CPF), an organophosphorus pesticide (OP), is one of the most widely used pesticides in the world. Subchronic exposures to CPF that do not cause cholinergic crisis are associated with problems in cognitive function (i.e., learning and memory deficits), but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of subchronic CPF neurotoxicity, adult male Long Evans (LE) rats were administered CPF at 3 or 10mg/kg/d (s.c.) for 21 days. We quantified mRNA and non-coding RNA (ncRNA) expression profiles by RNA-seq, microarray analysis and small ncRNA sequencing technology in the CA1 region of the hippocampus. Hippocampal slice immunohistochemistry was used to determine CPF-induced changes in protein expression and localization patterns. Neither dose of CPF caused overt clinical signs of cholinergic toxicity, although after 21 days of exposure, cholinesterase activity was decreased to 58% or 13% of control levels in the hippocampus of rats in the 3 or 10mg/kg/d groups, respectively. Differential gene expression in the CA1 region of the hippocampus was observed only in the 10mg/kg/d dose group relative to controls. Of the 1382 differentially expressed genes identified by RNA-seq and microarray analysis, 67 were common to both approaches. Differential expression of six of these genes (Bdnf, Cort, Crhbp, Nptx2, Npy and Pnoc) was verified in an independent CPF exposure study; immunohistochemistry demonstrated that CRHBP and NPY were elevated in the CA1 region of the hippocampus at 10mg/kg/d CPF. Gene ontology enrichment analysis suggested association of these genes with receptor-mediated cell survival signaling pathways. miR132/212 was also elevated in the CA1 hippocampal region, which may play a role in the disruption of neurotrophin-mediated cognitive processes after CPF administration. These findings identify potential mediators of CPF-induced neurobehavioral deficits following subchronic exposure to CPF at

  17. SPECT and MRI study in patients with temporal lobe epilepsy caused by hippocampal sclerosis

    Le GUAN

    2015-11-01

    Full Text Available Objective To analyze the changes of hippocampus blood perfusion and hippocampal volume in patients with temporal lobe epilepsy (TLE caused by hippocampal sclerosis (HS using single-photon emission-computed tomography (SPECT and MRI, so as to explore the effect on localization of epileptogenic focus in TLE patients.  Methods Eighteen TLE patients and 3 healthy controls underwent 99Tcm-ethyl cysteinate dimer (99Tcm-ECD SPECT. Eighteen TLE patients and 21 healthy controls were performed MRI. The relative cerebral blood flow (rCBF and hippocampal volume were calculated and compared between 2 groups. The correlation between rCBF in ipsilateral hippocampus and hippocampal volume of TLE patients was analyzed. Results SPECT showed rCBF in ipsilateral hippocampus [(46.04 ± 7.94 ml/(100 g·min] was significantly decreased compared with contralateral hippocampus in TLE patients [(54.76 ± 9.62 ml/(100 g·min; t = -2.966, P = 0.005] and bilateral hippocampus in healthy controls [(64.87 ± 7.28 ml/(100 g·min; t = -4.824, P = 0.000]. The volume of ipsilateral hippocampus [(1.69 ± 0.39 cm3] was significantly smaller than that of contralateral hippocampus in TLE patients [(2.68 ± 0.41 cm3; t = -7.410, P = 0.000] and bilateral hippocampus in healthy controls [(3.50 ± 0.39 cm3; t = -16.340, P = 0.000]. The rCBF of ipsilateral hippocampus had positive correlation with the volume of corresponding hippocampus in TLE patients (r = 0.394, P = 0.017.  Conclusions Both rCBF and the volume of ipsilateral hippocampus were reduced in patients with TLE caused by HS, and there was positive correlation between the two. It was helpful for preoperative localization of epileptogenic focus to combine SPECT with MRI. DOI: 10.3969/j.issn.1672-6731.2015.11.007

  18. Mild hypothermia, but not propofol, is neuroprotective in organotypic hippocampal cultures.

    Feiner, John R; Bickler, Philip E; Estrada, Sergio; Donohoe, Paul H; Fahlman, Christian S; Schuyler, Jennifer A

    2005-01-01

    The neuroprotective potency of anesthetics such as propofol compared to mild hypothermia remains undefined. Therefore, we determined whether propofol at two clinically relevant concentrations is as effective as mild hypothermia in preventing delayed neuron death in hippocampal slice cultures (HSC). Survival of neurons was assessed 2 and 3 days after 1 h oxygen and glucose deprivation (OGD) either at 37 degrees C (with or without 10 or 100 microM propofol) or at an average temperature of 35 degrees C during OGD (mild hypothermia). Cell death in CA1, CA3, and dentate neurons in each slice was measured with propidium iodide fluorescence. Mild hypothermia eliminated death in CA1, CA3, and dentate neurons but propofol protected dentate neurons only at a concentration of 10 microM; the more ischemia vulnerable CA1 and CA3 neurons were not protected by either 10 microM or 100 microM propofol. In slice cultures, the toxicity of 100 muM N-methyl-D-aspartate (NMDA), 500 microM glutamate, and 20 microM alpha-amino-5-methyl-4-isoxazole propionic acid (AMPA) was not reduced by 100 microM propofol. Because propofol neuroprotection may involve gamma-aminobutyric acid (GABA)-mediated indirect inhibition of glutamate receptors (GluRs), the effects of propofol on GluR activity (calcium influx induced by GluR agonists) were studied in CA1 neurons in HSC, in isolated CA1 neurons, and in cortical brain slices. Propofol (100 and 200 microM, approximate burst suppression concentrations) decreased glutamate-mediated [Ca2+]i increases (Delta[Ca2+]i) responses by 25%-35% in isolated CA1 neurons and reduced glutamate and NMDA Delta[Ca2+]i in acute and cultured hippocampal slices by 35%-50%. In both CA1 neurons and cortical slices, blocking GABAA receptors with picrotoxin reduced the inhibition of GluRs substantially. We conclude that mild hypothermia, but not propofol, protects CA1 and CA3 neurons in hippocampal slice cultures subjected to oxygen and glucose deprivation. Propofol was not

  19. Differential Conditioning of Associative Synaptic Enhancement in Hippocampal Brain Slices

    Kelso, Stephen R.; Brown, Thomas H.

    1986-04-01

    An electrophysiological stimulation paradigm similar to one that produces Pavlovian conditioning was applied to synaptic inputs to pyramidal neurons of hippocampal brain slices. Persistent synaptic enhancement was induced in one of two weak synaptic inputs by pairing high-frequency electrical stimulation of the weak input with stimulation of a third, stronger input to the same region. Forward (temporally overlapping) but not backward (temporally separate) pairings caused this enhancement. Thus hippocampal synapses in vitro can undergo the conditional and selective type of associative modification that could provide the substrate for some of the mnemonic functions in which the hippocampus is thought to participate.

  20. Presynaptic Modulation of the Hippocampal Mossy Fiber Synapse.

    1992-09-14

    0.19 pg Dyn B-LI/ at least 48 h after KA injection. Intracerebroventricular min/mg protein compared to 3.81 ± 0.26 pg Dyn B/min/ administration of KA...guinea pig hippocampal MF administration and colchioine-induced neurotoxicity. Proc. Natl. synaptosomes is selectively depressed by K, but not p Acad. Sci...Exp. Ther. 255:900-905. tamate exocytosis from rat hippocampal mossy fiber synaptosomes. 20. Perry, D. C., and Grimes, L. M. 1989. Administration of

  1. Hippocampal volume and serotonin transporter polymorphism in major depressive disorder

    Ahdidan, Jamila; Foldager, Leslie; Rosenberg, Raben;

    2013-01-01

    Objective: The main aim of the present study was to replicate a previous finding in major depressive disorder (MDD) of association between reduced hippocampal volume and the long variant of the di- and triallelic serotonin transporter polymorphism in SLC6A4 on chromosome 17q11.2. Secondarily, we...... that we aimed to replicate, and no significant associations with the serotonin transporter polymorphism were found. Conclusions: The present quantitative and morphometric MRI study was not able to replicate the previous finding of association between reduced hippocampal volume in depressed patients...

  2. Delayed hippocampal damage in humans following cardiorespiratory arrest.

    Petito, C K; Feldmann, E; Pulsinelli, W A; Plum, F

    1987-08-01

    Transient ischemia in animals produces delayed cell death in vulnerable hippocampal neurons. To see if this occurs in humans, we reexamined brain slides from all patients with anoxic-ischemic encephalopathy and a well-documented cardiorespiratory arrest. Eight patients dying 18 hours or less after cardiac arrest had minimal damage in hippocampus and moderate damage in cerebral cortex and putamen. Six patients living 24 hours or more had severe damage in all four regions. The increase in damage with time postarrest was significant only in the hippocampus. Delayed hippocampal injury now documented in humans provides a target for possible therapy that can be initiated after cardiopulmonary resuscitation.

  3. Trimethyltin (TMT) neurotoxicity in organotypic rat hippocampal slice cultures

    Noraberg, J; Gramsbergen, J B; Fonnum, F;

    1998-01-01

    The neurotoxic effects of trimethyltin (TMT) on the hippocampus have been extensively studied in vivo. In this study, we examined whether the toxicity of TMT to hippocampal neurons could be reproduced in organotypic brain slice cultures in order to test the potential of this model for neurotoxico......The neurotoxic effects of trimethyltin (TMT) on the hippocampus have been extensively studied in vivo. In this study, we examined whether the toxicity of TMT to hippocampal neurons could be reproduced in organotypic brain slice cultures in order to test the potential of this model...

  4. Roles of PTEN-induced putative kinase 1 and dynamin-related protein 1 in transient global ischemia-induced hippocampal neuronal injury

    Chen, Shang-Der, E-mail: chensd@adm.cgmh.org.tw [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Lin, Tsu-Kung [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Yang, Ding-I. [Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan (China); Lee, Su-Ying [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Shaw, Fu-Zen [Department of Psychology, National Cheng Kung University, Tainan, Taiwan (China); Liou, Chia-Wei [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Chuang, Yao-Chung, E-mail: ycchuang@adm.cgmh.org.tw [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China)

    2015-05-01

    Recent studies showed that increased mitochondrial fission is an early event of cell death during cerebral ischemia and dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, which may be regulated by PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase thought to protect cells from stress-induced mitochondrial dysfunction and regulate mitochondrial fission. However, the roles of PINK1 and Drp1 in hippocampal injury caused by transient global ischemia (TGI) remain unknown. We therefore tested the hypothesis that TGI may induce PINK1 causing downregulation of Drp1 phosphorylation to enhance hippocampal neuronal survival, thus functioning as an endogenous neuroprotective mechanism. We found progressively increased PINK1 expression in the hippocampal CA1 subfield1-48 h following TGI, reaching the maximal level at 4 h. Despite lack of changes in the expression level of total Drp1 and phosphor-Drp1 at Ser637, TGI induced a time-dependent increase of Drp1 phosphorlation at Ser616 that peaked after 24 h. Notably, PINK1-siRNA increased p-Drp1(Ser616) protein level in hippocampal CA1 subfield 24 h after TGI. The PINK1 siRNA also aggravated the TGI-induced oxidative DNA damage with an increased 8-hydroxy-deoxyguanosine (8-OHdG) content in hippocampal CA1 subfield. Furthermore, PINK1 siRNA also augmented TGI-induced apoptosis as evidenced by the increased numbers of TUNEL-positive staining and enhanced DNA fragmentation. These findings indicated that PINK1 is an endogenous protective mediator vital for neuronal survival under ischemic insult through regulating Drp1 phosphorylation at Ser616. - Highlights: • Transient global ischemia increases expression of PINK1 and p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA decreases PINK1 expression but increases p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA augments oxidative stress and neuronal damage in hippocampal CA1 subfield.

  5. Xiangshao Granule Exerts Antidepressive Effects in a Depression Mouse Model by Ameliorating Deficits in Hippocampal BDNF and TrkB

    Yi Chen

    2013-01-01

    Full Text Available This study explores the therapeutic effects of Xiangshao granules in a mouse depression model and examines the potential molecular mechanisms involved. After 21 consecutive days of chronic stress challenge, all mice were divided into three groups: control group, depression group, and Xiangshao granule treatment group. On the 22nd day, rats in the Xiangshao granule treatment group received Xiangshao granules via gastrogavage for 3 consecutive weeks. Depression group mice showed a significant reduction of crossings (P<0.01 but not rearings (P<0.05. Serum CRH, CORT, and ACTH levels were significantly increased in depression mice compared with control (P<0.05 and the expression levels of hippocampal BDNF and TrkB were reduced in the model group (P<0.05. However, Xiangshao granule treatment remarkably rescued the decrease in the body weight (P<0.05, increased crossings in the open field test (P<0.05, upregulated the expression of hippocampal BDNF and TrkB expression, and reduced the serum CRH, CORT, and ACTH concentrations compared with the depression group (P<0.05. Collectively, these results demonstrated that Xiangshao granule could effectively induce antidepressive effects in the depression mouse model by ameliorating the expression of hippocampal BDNF and TrkB.

  6. Aluminum alters NMDA receptor 1A and 2A/B expression on neonatal hippocampal neurons in rats

    Yuan Chia-Yi

    2011-11-01

    Full Text Available Abstract Background High aluminum (Al content in certain infant formula raises the concern of possible Al toxicity on brain development of neonates during their vulnerable period of growing. Results of in vivo study showed that Al content of brain tissues reached to 74 μM when oral intake up to 1110 μM, 10 times of that in the hi-Al infant formula. Methods Utilizing a cultured neuron cells in vitro model, we have assessed Al influence on neuronal specific gene expression alteration by immunoblot and immunohistochemistry and neural proliferation rate changes by MTT assay. Results Microscopic images showed that the neurite outgrowth of hippocampal neurons increased along with the Al dosages (37, 74 μM Al (AlCl3. MTT results also indicated that Al increased neural cell viability. On the other hand, the immunocytochemistry staining suggested that the protein expressions of NMDAR 1A and NMDAR 2A/B decreased with the Al dosages (p Conclusion Treated hippocampal neurons with 37 and 74 μM of Al for 14 days increased neural cell viability, but hampered NMDAR 1A and NMDAR 2A/B expressions. It was suggested that Al exposure might alter the development of hippocampal neurons in neonatal rats.

  7. Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF.

    Moy, Gregory A; McNay, Ewan C

    2013-01-17

    Obesity, high-fat diets, and subsequent type 2 diabetes (T2DM) are associated with cognitive impairment. Moreover, T2DM increases the risk of Alzheimer's disease (AD) and leads to abnormal elevation of brain beta-amyloid levels, one of the hallmarks of AD. The psychoactive alkaloid caffeine has been shown to have therapeutic potential in AD but the central impact of caffeine has not been well-studied in the context of a high-fat diet. Here we investigated the impact of caffeine administration on metabolism and cognitive performance, both in control rats and in rats placed on a high-fat diet. The effects of caffeine were significant: caffeine both (i) prevented the weight-gain associated with the high-fat diet and (ii) prevented cognitive impairment. Caffeine did not alter hippocampal metabolism or insulin signaling, likely because the high-fat-fed animals did not develop full-blown diabetes; however, caffeine did prevent or reverse a decrease in hippocampal brain-derived neurotrophic factor (BDNF) seen in high-fat-fed animals. These data confirm that caffeine may serve as a neuroprotective agent against cognitive impairment caused by obesity and/or a high-fat diet. Increased hippocampal BDNF following caffeine administration could explain, at least in part, the effects of caffeine on cognition and metabolism.

  8. Underlying mechanism of protection from hypoxic injury seen with n-butanol extract of Potentilla anserine L. in hippocampal neurons

    Xiaojing Qin; Lingzhi Li; Qi Lv; Baoguo Yu; Shuwang Yang; Tao He; Yongliang Zhang

    2012-01-01

    The alcohol and n-butanol extract of Potentilla anserine L.significantly protects myocardium from acute ischemic injury.However,its effects on rat hippocampal neurons and the mechanism of protection remain unclear.In this study,primary cultured hippocampal neurons from neonatal rats were incubated in 95% N2 and 5% CO2 for 4 hours.Results indicated that hypoxic injury decreased the viability of neurons,increased the expression levels of caspase-9 and caspase-3 mRNA,as well as cytochrome c,Caspase-9,and Caspase-3 protein.Pretreatment with 0.25,0.0625,0.0156 mg/mL n-butanol extract of Potentilla anserine L.led to a significant increase in cell viability.Expression levels of caspase-9 and caspase-3 mRNA,as well as cytochrome c,Caspase-9,andCaspase-3 protein,were attenuated.The neuroprotective effect of n-butanol extract of Potentillaanserine L.was equivalent to tanshinone IIA.Our data suggest that the n-butanol extract of Potentilla anserine L.could protect primary hippocampal neurons from hypoxic injury by deactivating mitochondrial cell death.

  9. Nox-2-mediated phenotype loss of hippocampal parvalbumin interneurons might contribute to postoperative cognitive decline in aging mice

    lili qiu

    2016-10-01

    Full Text Available Postoperative cognitive decline (POCD is a common complication following anesthesia and surgery, especially in elderly patients; however, the precise mechanisms of POCD remain unclear. Here, we investigated whether nicotinamide adenine dinucleotide phosphate (NADPH oxidase mediated-abnormalities in parvalbumin (PV interneurons play an important role in the pathophysiology of POCD. The animal model was established using isoflurane anesthesia and exploratory laparotomy in sixteen-month-old male C57BL/6 mice. For interventional experiments, mice were chronically treated with the NADPH oxidase inhibitor apocynin (APO. Open field and fear conditioning behavioral tests were performed on day 6 and 7 post-surgery, respectively. In a separate experiment, brain tissue was harvested and subjected to biochemical analysis. Primary hippocampal neurons challenged with lipopolysaccharide in vitro were used to investigate the mechanisms underlying the oxidative stress-induced abnormalities in PV interneurons. Our results showed that anesthesia and surgery induced significant hippocampus-dependent memory impairment, which was accompanied by PV interneuron phenotype loss and increased expression of interleukin-1β, markers of oxidative stress, and NADPH oxidase 2 (Nox2 in the hippocampus. In addition, lipopolysaccharide exposure increased Nox2 level and decreased the expression of PV and the number of excitatory synapses onto PV interneurons in the primary hippocampal neurons. Notably, treatment with APO reversed these abnormalities. Our study suggests that Nox2-derived ROS production triggers, at least in part, anesthesia- and surgery-induced hippocampal PV interneuron phenotype loss and consequent cognitive impairment in aging mice.

  10. Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia.

    Chou, Shinnyi; Jones, Sean; Li, Ming

    2015-08-27

    Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidylic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed a similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5'-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation. The implications of the relationship between behavioral and neurobiological results are discussed.

  11. Effects of prolonged abstinence from METH on the hippocampal BDNF levels, neuronal numbers and apoptosis in methamphetamine-sensitized rats.

    Hajheidari, Samira; Sameni, Hamid Reza; Bandegi, Ahmad Reza; Miladi-Gorji, Hossein

    2017-04-03

    Methamphetamine (METH) use is associated with neuronal damage in various regions of brain, while effects of prolonged abstinence on METH-induced damage are not quite clear. This study evaluated serum and hippocampal BDNF levels, neuronal numbers and apoptosis in METH-sensitized and abstinent rats. Rats were sensitized to METH (2mg/kg, daily/18 days, s.c.). All rats were evaluated for neuron counting, the TUNEL test and serum and hippocampal BDNF levels after 30 days of forced abstinence from METH. The results showed that increased BDNF levels in the hippocampus and serum of METH-sensitized rats returned to control level after 30 days of abstinence. The number of neurons in the DG and CA1 of hippocampus and also, the total hippocampal perimeter and area in METH-sensitized rats were significantly lower than the saline rats. While, the number of neurons was not significantly increased in the hippocampus after prolonged abstinence from METH. Also, METH-sensitized rats showed a significant increase in TUNEL-positive cells, whereas METH-abstinent rats showed a slight but significant decrease in TUNEL-positive cells in the DG and CA3 of hippocampus. These results suggest that despite the reduction in BDNF levels, reducing the number of neurons, perimeter and area of the hippocampus were stable after abstinence. Thus, the degenerative effects of METH have been sustained even after prolonged abstinence in the hippocampus.

  12. Administration of copper reduced the hyper-excitability of neurons in CA1 hippocampal slices from epileptic rats.

    Leiva, Juan; Infante, Claudio

    2016-04-01

    Copper as a trace metal is involved in several neurodegenerative illnesses, such as Menkes, Wilson's, Alzheimer's, amyotrophic lateral sclerosis (ALS), and Creutzfeldt-Jakob. Electrophysiological evidence indicates that acute perfusion of copper can inhibit long-term synaptic potentiation in hippocampal slices. The objective of this work is to determine whether Cu perfusion can perturb synaptic transmission in hippocampal slices derived from pilocarpine treated epileptic rats. Field potential (FP) recordings of the CA1 neurons of rats with chronic epilepsy showed voltage and response duration decrease following copper sulfate perfusion. However, voltage and response duration were higher after removing copper by washing. The discharge frequency of the CA1 neurons of hippocampal slices from non-epileptic control rats was increased after acute perfusion of 10 μM of pilocarpine. This increase was blocked by administering copper sulphate 10 μM. Krebs-Ringer solution washing re-established the discharges, with a higher frequency than that provoked by pilocarpine perfusion. We discuss the blocking effect of copper and the synaptic hyper-excitability generated by its removal.

  13. Intellectual impairment and brain MRI findings in myotonic dystrophy. With a special reference to hippocampal atrophy and white matter lesions

    Kato, Etsuko; Takahashi, Satoshi; Yonezawa, Hisashi [Iwate Medical Univ., Morioka (Japan). School of Medicine

    1995-08-01

    We performed a correlative study between intellectual impairment, CTG repeat expansion and magnetic resonance imaging (MRI) abnormalities, including hippocampal atrophy, white matter lesions and ventricular dilatation in 15 patients with myotonic dystrophy (MD). They included 4 males and 11 females aged from 20 to 66 years, averaging 43 years of age and 15 years of duration of illness. Nine patients had intellectual impairment (WAIS-R<80). Negative correlations were found between full scale IQ (FSIQ), duration of illness (p<0.05) and CTG repeat expansion (p<0.05). Compared with normal controls, the patients with MD showed a significant reduction in size of the hippocampal head (p<0.01), which was positively correlated to FSIQ, verbal IQ and performance IQ levels (p<0.05). Ten patients had white matter lesions. Severer white matter lesions tended to be recognized in patients with longer duration of illness and with decreased FSIQ level. These results suggest that hippocampal atrophy and white matter lesions are related to intellectual impairment in patients with MD. (author).

  14. Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

    Ine Rayen

    Full Text Available Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day or vehicle beginning on postnatal day 1 (P1. Adolescent male and female offspring were divided into 4 groups: 1 prenatal stress+fluoxetine exposure, 2 prenatal stress+vehicle, 3 fluoxetine exposure alone, and 4 vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

  15. Cytomorphometric changes in hippocampal CA1 neurons exposed to simulated microgravity using rats as model

    Amit eRanjan

    2014-05-01

    Full Text Available Microgravity and sleep loss lead to cognitive and learning deficits. These behavioral alterations are likely to be associated with cytomorphological changes and loss of neurons. To understand the phenomenon, we exposed rats (225-275g to 14 days simulated microgravity (SMg and compared its effects on CA1 hippocampal neuronal plasticity, with that of normal cage control rats. We observed that the mean area, perimeter, synaptic cleft and length of active zone of CA1 hippocampal neurons significantly decreased while dendritic arborization and number of spines significantly increased in SMg group as compared with controls. The mean thickness of the post synaptic density and total dendritic length remained unaltered. The changes may be a compensatory effect induced by exposure to microgravity; however, the effects may be transient or permanent, which need further study. These findings may be useful for designing effective prevention for those, including the astronauts, exposed to microgravity. Further, subject to confirmation we propose that SMg exposure might be useful for recovery of stroke patients.

  16. Retinoids and glucocorticoids target common genes in hippocampal HT22 cells.

    Brossaud, Julie; Roumes, Hélène; Moisan, Marie-Pierre; Pallet, Véronique; Redonnet, Anabelle; Corcuff, Jean-Benoît

    2013-05-01

    Vitamin A metabolite retinoic acid (RA) plays a major role in the aging adult brain plasticity. Conversely, chronic excess of glucocorticoids (GC) elicits some deleterious effects in the hippocampus. We questioned here the involvement of RA and GC in the expression of target proteins in hippocampal neurons. We investigated proteins involved either in the signaling pathways [RA receptor β (RARβ) and glucocorticoid receptor (GR)] or in neuron differentiation and plasticity [tissue transglutaminase 2 (tTG) and brain-derived neurotrophic factor (BDNF)] in a hippocampal cell line, HT22. We applied RA and/or dexamethasone (Dex) as activators of the pathways and investigated mRNA and protein expression of their receptors and of tTG and BDNF as well as tTG activity and BDNF secretion. Our results confirm the involvement of RA- and GC-dependent pathways and their interaction in our neuronal cell model. First, both pathways regulate the transcription and expression of own and reciprocal receptors: RA and Dex increased RARβ and decreased GR expressions. Second, Dex reduces the expression of tTG when associated with RA despite stimulating its expression when used alone. Importantly, when they are combined, RA counteracts the deleterious effect of glucocorticoids on BDNF regulation and thus may improve neuronal plasticity under stress conditions. In conclusion, GC and RA both interact through regulations of the two receptors, RARβ and GR. Furthermore, they both act, synergistically or oppositely, on other target proteins critical for neuronal plasticity, tTG and BDNF.

  17. Mechanism underlying blockade of voltage-gated calcium channels by agmatine in cultured rat hippocampal neurons

    Jian-quan ZHENG; Xie-chuan WENG; Xiao-dan GAI; Jin LI; Wen-bin XIAO

    2004-01-01

    AIM: To investigate whether agmatine could selectively block a given type of the voltage-gated calcium channels (VGCC) and whether related receptors are involved in the blocking effect of agmatine on VGCC. METHODS: The whole-cell patch recording technique was performed to record VGCC currents in the cultured neonatal rat hippocampal neurons. RESULTS: Verapamil (100 μmol/L), a selective blocker of L-type calcium channel, significantly inhibited VGCC current by 80 %± 7 %. Agmatine (100 μmol/L) could further depress the remained currents by 25 %±6 %. The α2-adrenoceptor antagonist yohimbine (10 μmol/L) and the I2 imidazoline receptor antagonist idazoxon (10 and 40 μmol/L) had no significant effect on VGCC currents when used respectively. When the mixture of yohimbine and agmatine was applied, VGCC currents were still depressed remarkably. However, the blocking effect of agmatine was decreased by 29 %± 8 % in the presence of idazoxon (10 μmol/L). The effect of idazoxon did not increase at a higher concentration (40 μmol/L). CONCLUSION: Agmatine could block the L- and other types of VGCC currents in the cultured rat hippocampal neurons. Blocking effect of agmatine on VGCC was partially related to I2 imidazoline receptor and had no relationship with α2-adrenoceptors.

  18. Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats

    Jiro Kasahara

    2016-01-01

    Full Text Available Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine. The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them.

  19. Dissociating hippocampal and basal ganglia contributions to category learning using stimulus novelty and subjective judgments.

    Seger, Carol A; Dennison, Christina S; Lopez-Paniagua, Dan; Peterson, Erik J; Roark, Aubrey A

    2011-04-15

    We identified factors leading to hippocampal and basal ganglia recruitment during categorization learning. Subjects alternated between blocks of a standard trial and error category learning task and a subjective judgment task. In the subjective judgments task subjects categorized the stimulus and then instead of receiving feedback they indicated the basis of their response using 4 options: Remember: Conscious episodic memory of previous trials. Know-Automatic: Automatic, rapid response accompanied by conscious awareness of category membership. Know-Intuition: A "gut feeling" without fully conscious knowledge of category membership. Guess: Guessing. In addition, new stimuli were introduced throughout the experiment to examine effects of novelty. Categorization overall recruited both the basal ganglia and posterior hippocampus. However, basal ganglia activity was found during Know judgments (both Automatic and Intuition), whereas posterior hippocampus activity was found during Remember judgments. Granger causality mapping indicated interactions between the basal ganglia and hippocampus, with the putamen exerting directed influence on the posterior hippocampus, which in turn exerted directed influence on the posterior caudate nucleus. We also found a region of anterior hippocampus that showed decreased activity relative to baseline during categorization overall, and showed a strong novelty effect. Our results indicate that subjective measures may be effective in dissociating basal ganglia from hippocampal dependent learning, and that the basal ganglia are involved in both conscious and unconscious learning. They also indicate a dissociation within the hippocampus, in which the anterior regions are sensitive to novelty, and the posterior regions are involved in memory based categorization learning.

  20. Enhancement of CA3 hippocampal network activity by activation of group II metabotropic glutamate receptors.

    Ster, Jeanne; Mateos, José María; Grewe, Benjamin Friedrich; Coiret, Guyllaume; Corti, Corrado; Corsi, Mauro; Helmchen, Fritjof; Gerber, Urs

    2011-06-14

    Impaired function or expression of group II metabotropic glutamate receptors (mGluRIIs) is observed in brain disorders such as schizophrenia. This class of receptor is thought to modulate activity of neuronal circuits primarily by inhibiting neurotransmitter release. Here, we characterize a postsynaptic excitatory response mediated by somato-dendritic mGluRIIs in hippocampal CA3 pyramidal cells and in stratum oriens interneurons. The specific mGluRII agonists DCG-IV or LCCG-1 induced an inward current blocked by the mGluRII antagonist LY341495. Experiments with transgenic mice revealed a significant reduction of the inward current in mGluR3(-/-) but not in mGluR2(-/-) mice. The excitatory response was associated with periods of synchronized activity at theta frequency. Furthermore, cholinergically induced network oscillations exhibited decreased frequency when mGluRIIs were blocked. Thus, our data indicate that hippocampal responses are modulated not only by presynaptic mGluRIIs that reduce glutamate release but also by postsynaptic mGluRIIs that