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系統識別號 U0026-1407201120423900
論文名稱(中文) 血管內皮生長因子在海馬迴突觸功能中扮演的角色
論文名稱(英文) The role of vascular endothelial growth factor signaling pathway in hippocampal synaptic function
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 黃鈺斐
研究生(英文) Yu-Fei Huang
學號 S58941206
學位類別 博士
語文別 英文
論文頁數 164頁
口試委員 指導教授-許桂森
召集委員-莊季瑛
口試委員-戴明泓
口試委員-陳慶鏗
口試委員-華瑜
中文關鍵字 血管內皮生長因子  海馬迴  突觸  抗憂鬱藥 
英文關鍵字 VEGF  Hippocampus  dendritic spine  antidepressant 
學科別分類
中文摘要 血管內皮生長因子(VEGF, vascular endothelial growth factor)除了促進血管新生的重要角色外,在中樞神經系統中還有神經滋養的作用。研究證據證明血管內皮生長因子具有調控神經細胞的增生,神經束的生長以及預防缺血或創傷性腦損傷的神經保護能力。除此之外,血管內皮生長因子與其接受體被發現廣泛地分佈於神經細胞,而且它們的表現會受到局部的神經活性所調控,這也顯示血管內皮生長因子在調控神經系統的突觸功能上扮演著某些角色。我們的研究發現增加血管內皮生長因子的合成可以增加海馬迴中興奮性神經突觸的傳遞。在神經系統的研究顯示血管內皮生長因子在缺氧的情況下會受到第一型缺氧誘發因子(HIF-1 alpha, hypoxia- inducible factor-1 alpha)所調控。而我們的研究利用藥物刺激與基因轉殖的方式的確影響了第一型缺氧誘發因子的表現進而透過調控血管內皮生長因子的表現而增強海馬迴興奮性神經突觸的傳遞。實驗結果顯示在海馬迴神經細胞中,胰島素樣生長因子(IGF-1, insulin-like growth factor-1)對於誘發第一型缺氧誘發因子蛋白質的表現與其下游基因血管內皮生長因子的轉錄會隨著給藥時間與劑量而逐漸增加。此外,直接外送持續活化態的第一型缺氧誘發因子至神經細胞中也可產生類似胰島素樣生長因子對神經細胞產生的作用。這些結果顯示增加局部血管內皮生長因子的合成可改變海馬迴興奮性神經突觸的傳遞。
最近的研究也指出血管內皮生長因子可能與豐富的環境(EE, enriched environment)及抗憂鬱藥產生的海馬迴突觸塑性的改變有關。除此之外,憂鬱症相關的疾病也被認為是由於血管內皮生長因子或腦衍生神經滋長因子(BDNF, brain-derived neurotrophic factor)的缺失引起的海馬迴突觸結構改變所致,並且遭受憂鬱症的病人由於某些未知的原因其憂鬱程度被發現與海馬迴結構萎縮相關。所以,我們進一步探討經過豐富環境的刺激後,血管內皮生長因子調控海馬迴突觸塑性與行為改變的角色為何?並進一步研究調控血管內皮生長因子可能的機制。如同我們的發現,成年的小鼠飼養在豐富的環境7天後,很快的就有類似抗憂鬱行為的表現,而且在海馬迴CA1腦區的神經細胞也有明顯的突觸數目增加的現象。這種快速的產生類似抗憂鬱的作用主要是透過第一型缺氧誘發因子調控而增加血管內皮生長因子的表現所致。更重要的是我們發現豐富的環境增加第一型缺氧誘發因子的表現伴隨著明顯的miR-107的減少。在海馬迴大量表現miR-107則能完全地阻斷豐富的環境引起的第一型缺氧誘發因子的產生與抗憂鬱的作用。
以上這些結果,我們發現了血管內皮生長因子可以直接作用神經細胞並對於調節海馬迴興奮性神經突觸傳遞有重要的角色;此外豐富的環境刺激,可以藉由降低miR-107對於第一型缺氧誘發因子抑制的作用,而影響血管內皮生長因子來促進突觸新生的作用(spinogenesis)以產生快速的抗憂鬱的效果。
英文摘要 Vascular endothelial growth factor (VEGF), in addition to its essential role in the promoting of vascularization and angiogenesis, exerts direct neurotrophic effects in the central nervous system. Numerous evidence has been provided to show the role of VEGF in modulation of neuronal proliferation, neurite outgrowth and its neuroprotective ability against ischemia or traumatic brain injuries. VEGF and its receptors have been found to be extensively expressed in neuronal cells and their expression levels can be regulated by changes in local neuronal activity, which implied that there could be certain roles for VEGF on the regulation of synaptic function in the nervous system. We found an increase in VEGF synthesis could result in changes of excitatory synaptic transmission in cultured hippocampal neurons. In the neuronal system, it has been shown that VEGF can be regulated by transcription factors such as hypoxia-inducible factor-1 (HIF-1) under hypoxic situations. We found either pharmacological or genetic accumulation of HIF-1 alpha enhances excitatory synaptic transmission in hippocampal neurons through the production of VEGF. Treatment with IGF-1 resulted in a time and dose-dependent increase in HIF-1 alpha and its downstream VEGF transcription in hippocampal cultured neurons. In addition, direct transfection of constitutively active HIF-1 alpha (CA- HIF-1 alpha) into neurons mimicked the effects of IGF-1 treatment. All these results suggest that increase in regional VEGF synthesis could result in changes of excitatory synaptic transmission in hippocampal neurons.
Recent studies have demonstrated that VEGF might be involved in the effects of enriched environment (EE) and antidepressants on the hippocampal synaptic plasticity. Depressive-related disorders with loss of VEGF or BDNF signaling are linked to structurally plasticity changes in the hippocampus, and the depressive scores in the suffered patients somehow correlate to the shrinkage in the volume of hippocampus. We further investigated the role of VEGF in the regulation of hippocampal structural plasticity and behavioral changes after EE stimulation and further studied its underlying mechanisms involved in the regulation of VEGF. We found that adult mice housed in an EE cage for 7 days displayed a rapid antidepressant-like phenotype and a significant increase in dendritic spine density in hippocampal CA1 pyramidal neurons. This rapid antidepressant-like effect could be primarily attributed to increased VEGF expression through a HIF-1 alpha-mediated transcriptional mechanism. More importantly, the increase in HIF-1 alpha expression in the hippocampus induced by EE was accompanied by a significant reduction in miR-107 levels. Overexpression of miR-107 in the hippocampus completely blocked EE-induced HIF-1 alpha production and the antidepressive effect.
Our results reveal a novel role of VEGF in regulating excitatory synaptic transmission in hippocampal neurons and support a model in which, miR-107, acting through HIF-1 alpha, mediates VEGF-dependent spinogenesis to underlie the antidepressive effect of EE.
論文目次 Abstract in Chinese...........................2
Abstract in English...........................5
Contents......................................8
Figure List..................................11
Chapter I: Introduction......................15
1.1 The properties of VEGF family
1.2 VEGF and brain functions
1.3 Regulation of VEGF in the central nervous system
1.4 VEGF and its regulation of synaptic transmission
1.5 The regulation of VEGF in structural plasticity
1.6 The expression level of VEGF correlates to the
actions of antidepressant treatment
1.7 Regulation of hippocampal functions by enriched
environment stimulation

Chapter II: Materials and Methods............26
2.1 Animals
2.2 Standard and enriched housing conditions
2.3 Establishment and maintenance of hippocampal neuron
cultures
2.4 Drug treatment
2.5 Construction and production of engineered
lentiviruses
2.6 Performance of dual-luciferase reporter assay
2.7 Western blotting analysis
2.8 Quantitative real-time reverse-transcription (RT)-
PCR analysis
2.9 Electrophysiological recordings
2.10 Chromatin immunoprecipitation (ChIP) assay
2.11 Quantification of VEGF secretion by ELISA
2.12 Human embryonic kidney 293 cell culture,
transfection, and morphology analysis
2.13 Lactate dehydrogenase release analysis
2.14 DNA fragmentation analysis
2.15 Superoxide dismutase activity analysis
2.16 Glutathione assay
2.17 Immunofluorescence staining
2.18 Stereotaxic viruses injection
2.19 Golgi impregnation
2.20 Construction of lentiviral vectors expressing
miRNAs and antagomiRs
2.21 Tail suspension test
2.22 Open field test
2.23 Sucrose preference test
2.24 Forced swimming test
2.25 Transient transfection and VEGF stimulation in
cultured neurons
2.26 Immunohistochemistry
2.27 Image acquisition and quantification
2.28 Statistical analysis

Chapter III: Results.........................49
3.1 Pharmacological and genetic accumulation of HIF-1
alpha enhances excitatory synaptic transmission in
hippocampal neurons through the production of VEGF
3.2 VEGF-dependent spinogenesis underlies rapid
antidepressive effect of enriched environment

Chapter IV: Discussion.......................72
4.1 The role of VEGF in regulation of synaptic
transmission in hippocampal neurons
4.2 VEGF-dependent spinogenesis underlies rapid
antidepressive effect of enriched environment

Chapter V: Conclusion........................84
Chapter VI: Figures and Legends..............87
Chapter VII: References.....................144
參考文獻 Abu-Elneel K, Ochiishi T, Medina M, Remedi M, Gastaldi L, Caceres A, Kosik KS (2008) A delta-catenin signaling pathway leading to dendritic protrusions. J Biol Chem 283:32781-32791.
Adamcio B, Sperling S, Hagemeyer N, Walkinshaw G, Ehrenreich H (2010) Hypoxia inducible factor stabilization leads to lasting improvement of hippocampal memory in healthy mice. Behav Brain Res 208: 80-84.
Ayala de la Pena F, Kanasaki K, Kanasaki M, Tangirala N, Maeda G, Kalluri R (2011) Loss of p53 and Acquisition of Angiogenic MicroRNA Profile Are Insufficient to Facilitate Progression of Bladder Urothelial Carcinoma in Situ to Invasive Carcinoma. J Biol Chem 286: 20778-20787.
Balkowiec A, Katz DM (2002) Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J Neurosci 22: 10399-10407.
Banasr, M, Duman, RS (2008) Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 64: 863-870.
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136: 215-233.
Belaiba RS, Bonello S, Zahringer C, Schmidt S, Hess J, Kietzmann T, Gorlach A (2007) Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells. Mol Biol Cell 18: 4691-4697.
Bermont L, Lamielle F, Lorchel F, Fauconnet S, Esumi H, Weisz A, Adessi GL (2001) Insulin up-regulates vascular endothelial growth factor and stabilizes its messengers in endometrial adenocarcinoma cells. J Clin Endocrinol Metab 86: 363-368.
Bilkei-Gorzo A, Racz I, Michel K, Zimmer A (2002) Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J Neurosci 22: 10046-10052.
Bindu B, Alladi PA, Mansooralikhan BM, Srikumar BN, Raju TR, Kutty BM (2007) Short-term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions. Neuroscience 144: 412-423.
Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, Harris AL, Gleadle JM, Ragoussis J (2008) hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res 14: 1340-1348.
Canabal DD, Potian JG, Duran RG, McArdle JJ, Routh VH (2007) Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol 293: R592-600.
Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ (2004) VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 36: 827-835.
Cascio S, D'Andrea A, Ferla R, Surmacz E, Gulotta E, Amodeo V, Bazan V, Gebbia N, Russo A (2010) miR-20b modulates VEGF expression by targeting HIF-1 alpha and STAT3 in MCF-7 breast cancer cells. J Cell Physiol 224: 242-249.
Chao HW, Hong CJ, Huang TN, Lin YL, Hsueh YP (2008) SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis. J Cell Biol 182: 141-155.
Chen J, Zhao S, Nakada K, Kuge Y, Tamaki N, Okada F, Wang J, Shindo M, Higashino F, Takeda K, Asaka M, Katoh H, Sugiyama T, Hosokawa M, Kobayashi M (2003) Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am J Pathol 162: 1283-1291.
Ciucci F, Putignano E, Baroncelli L, Landi S, Berardi N, Maffei L (2007) Insulin-like growth factor 1 (IGF-1) mediates the effects of enriched environment (EE) on visual cortical development. PLoS One 2: e475.
Collins PD, Connolly DT, Williams TJ (1993) Characterization of the increase in vascular permeability induced by vascular permeability factor in vivo. Br J Pharmacol 109: 195-199.
Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84: 1470-1478.
Cooper DC, Klipec WD, Fowler MA, Ozkan ED (2006) A role for the subiculum in the brain motivation/reward circuitry. Behav Brain Res 174: 225-231.
Croll SD, Goodman JH, Scharfman HE (2004) Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword. Adv Exp Med Biol 548: 57-68.
Cryan JF, O'Leary OF (2010) Neuroscience. A glutamate pathway to faster-acting antidepressants? Science 329: 913-914.
De Foubert G, Carney SL, Robinson CS, Destexhe EJ, Tomlinson R, Hicks CA, Murray TK, Gaillard JP, Deville C, Xhenseval V, Thomas CE, O'Neill MJ, Zetterström TS (2004) Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. Neuroscience 128: 597-604.
Diamond DM, Campbell AM, Park CR, Woodson JC, Conrad CD, Bachstetter AD, Mervis RF (2006) Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 16: 571-576.
Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67: 793-802.
Dolt KS, Mishra MK, Karar J, Baig MA, Ahmed Z, Pasha MA (2007) cDNA cloning, gene organization and variant specific expression of HIF-1 alpha in high altitude yak (Bos grunniens). Gene 386: 73-80.
During MJ, Cao L (2006) VEGF, a mediator of the effect of experience on hippocampal neurogenesis. Curr Alzheimer Res 3: 29-33.
Eckert MJ, Bilkey DK, Abraham WC (2010) Altered plasticity in hippocampal CA1, but not dentate gyrus, following long-term environmental enrichment. J Neurophysiol 103: 3320-3329.
Faherty CJ, Kerley D, Smeyne RJ (2003) A Golgi-Cox morphological analysis of neuronal changes induced by environmental enrichment. Brain Res Dev Brain Res 141: 55-61.
Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273: 18623-18632.
Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18: 4-25.
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9: 669-676.
Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161: 851-858.
Fiore R, Khudayberdiev S, Christensen M, Siegel G, Flavell SW, Kim TK, Greenberg ME, Schratt G (2008) Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels. EMBO J 28: 697-710.
Fournier NM, Duman RS (2011) Role of vascular endothelial growth factor in adult hippocampal neurogenesis: Implications for the pathophysiology and treatment of depression. Behav Brain Res doi: 10.1016/j.bbr.2011.04.022.
Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 3rd ed. (Amsterdam ; New York: Elsevier/Academic Press).
Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL (2002) Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 277: 38205-38211.
Garrett TA, Van Buul JD, Burridge K (2007) VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. Exp Cell Res 313: 3285-3297.
Ghosh A, Carnahan J, Greenberg ME (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263: 1618-1623.
Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12: 502-513.
Gonzalez-Perez RR, Xu Y, Guo S, Watters A, Zhou W, Leibovich SJ (2010) Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation. Cell Signal 22: 1350-1362.
Greene J, Banasr M, Lee B, Warner-Schmidt J, Duman RS (2009) Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: pharmacological and cellular characterization. Neuropsychopharmacology 34: 2459-2468.
Greenwood BN, Fleshner M (2008) Exercise, learned helplessness, and the stress-resistant brain. Neuromolecular Med 10: 81-98.
Gruden G, Araf S, Zonca S, Burt D, Thomas S, Gnudi L, Viberti G (2003) IGF-I induces vascular endothelial growth factor in human mesangial cells via a Src-dependent mechanism. Kidney Int 63: 1249-1255.
Hajszan T, Dow A, Warner-Schmidt JL, Szigeti-Buck K, Sallam NL, Parducz A, Leranth C, Duman RS (2009) Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry 65: 392-400.
Hajszan T, Szigeti-Buck K, Sallam NL, Bober J, Parducz A, Maclusky NJ, Leranth C, Duman RS (2010) Effects of estradiol on learned helplessness and associated remodeling of hippocampal spine synapses in female rats. Biol Psychiatry 67: 168-174.
Hattori S, Hashimoto R, Miyakawa T, Yamanaka H, Maeno H, Wada K, Kunugi H (2007) Enriched environments influence depression-related behavior in adult mice and the survival of newborn cells in their hippocampi. Behav Brain Res 180: 69-76.
Hayashi T, Abe K, Suzuki H, Itoyama Y (1997) Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 28: 2039-2044.
Hirsila M, Koivunen P Xu L, Seeley T, Kivirikko KI, Myllyharju J (2005) Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J 19: 1308-1310.
Hoffman AF, Lupica CR (2001) Direct actions of cannabinoids on synaptic transmission in the nucleus accumbens: a comparison with opioids. J Neurophysiol 85: 72-83.
Hua Z, Lv Q, Ye W, Wong CK, Cai G, Gu D, Ji Y, Zhao C, Wang J, Yang BB, Zhang Y (2006) MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS One 1: e116.
Huang CC, Chou PH, Yang CH, Hsu KS (2005) Neonatal isolation accelerates the developmental switch in the signalling cascades for long-term potentiation induction. J Physiol 569: 789-799.
Huang YF, Yang CH, Huang CC, Tai MH, Hsu KS (2010) Pharmacological and genetic accumulation of hypoxia-inducible factor-1alpha enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth factor. J Neurosci 30: 6080-6093.
Ickes BR, Pham TM, Sanders LA, Albeck DS, Mohammed AH, Granholm AC (2000) Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp Neurol 164: 45-52.
Iwata M, Shirayama Y, Ishida H, Kawahara R (2006) Hippocampal synapsin I, growth-associated protein-43, and microtubule-associated protein-2 immunoreactivity in learned helplessness rats and antidepressant-treated rats. Neuroscience 141: 1301-1313.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468-472.
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A 99: 11946-11950.
Jin KL, Mao XO, Greenberg DA (2000) Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci U S A 97: 10242-10247.
Kai ZS, Pasquinelli AE (2010) MicroRNA assassins: factors that regulate the disappearance of miRNAs. Nat Struct Mol Biol 17: 5-10.
Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L (1997) Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci U S A 94: 5667-5672.
Katz B (1969) The release of neural transmitter substances. ([Liverpool]: Liverpool Univ. Press).
Kazi AA, Jones JM, Koos RD (2005) Chromatin immunoprecipitation analysis of gene expression in the rat uterus in vivo: estrogen-induced recruitment of both estrogen receptor alpha and hypoxia-inducible factor 1 to the vascular endothelial growth factor promoter. Mol Endocrinol 19: 2006-2019.
Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70: 1469-1480.
Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386: 493-495.
Kilic E, Kilic U, Wang Y, Bassetti CL, Marti HH, Hermann DM (2006) The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. FASEB J 20: 1185-1187.
Kim BW, Choi M, Kim YS, Park H, Lee HR, Yun CO, Kim EJ, Choi JS, Kim S, Rhim H, Kaang BK, Son H (2008) Vascular endothelial growth factor (VEGF) signaling regulates hippocampal neurons by elevation of intracellular calcium and activation of calcium/calmodulin protein kinase II and mammalian target of rapamycin. Cell Signal 20: 714-725.
Kjeldsen T, Andersen AS, Wiberg FC, Rasmussen JS, Schaffer L, Balschmidt P, Moller KB, Moller NP (1991) The ligand specificities of the insulin receptor and the insulin-like growth factor I receptor reside in different regions of a common binding site. Proc Natl Acad Sci U S A 88: 4404-4408.
Klein SL, Lambert KG, Durr D, Schaefer T, Waring RE (1994) Influence of environmental enrichment and sex on predator stress response in rats. Physiol Behav 56: 291-297.
Knierim JJ, Lee I, Hargreaves EL (2006) Hippocampal place cells: parallel input streams, subregional processing, and implications for episodic memory. Hippocampus 16: 755-764.
Ko HM, Seo KH, Han SJ, Ahn KY, Choi IH, Koh GY, Lee HK, Ra MS, Im SY (2002) Nuclear factor kappaB dependency of platelet-activating factor-induced angiogenesis. Cancer Res 62: 1809-1814.
Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65: 9047-9055.
Krum JM, Khaibullina A (2003) Inhibition of endogenous VEGF impedes revascularization and astroglial proliferation: roles for VEGF in brain repair. Exp Neurol 181: 241-257.
Kutner RH, Zhang XY, Reiser J (2009) Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors. Nat Protoc 4: 495-505.
Kuzumaki N, Ikegami D, Tamura R, Hareyama N, Imai S, Narita M, Torigoe K, Niikura K, Takeshima H, Ando T, Igarashi K, Kanno J, Ushijima T, Suzuki T, Narita M (2011) Hippocampal epigenetic modification at the brain-derived neurotrophic factor gene induced by an enriched environment. Hippocampus 21: 127-132.
Landgren, S, Simms, JA, Thelle, DS, Strandhagen, E, Bartlett, SE, Engel, JA, and Jerlhag, E (2011) The ghrelin signalling system is involved in the consumption of sweets. PLoS One 6: e18170.
Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295: 858-861.
Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ (2004) Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am J Psychiatry 161: 1848-1855.
Lee CC, Huang CC, Wu MY, Hsu KS (2005) Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J Biol Chem 280: 18543-18550.
Lee JS, Jang DJ, Lee N, Ko HG, Kim H, Kim YS, Kim B, Son J, Kim SH, Chung H, Lee MY, Kim WR, Sun W, Zhuo M, Abel T, Kaang BK, Son H (2009) Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors. J Neurosci 29: 8493-8505.
Lei Z, Li B, Yang Z, Fang H, Zhang GM, Feng ZH, Huang B (2009) Regulation of HIF-1alpha and VEGF by miR-20b tunes tumor cells to adapt to the alteration of oxygen concentration. PLoS One 4: e7629.
Lennmyr F, Ata KA, Funa K, Olsson Y, Terent A (1998) Expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1) following permanent and transient occlusion of the middle cerebral artery in the rat. J Neuropathol Exp Neurol 57: 874-882.
Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell. 119: 873-887.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329: 959-964.
Lisman JE, Grace AA (2005) The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 46: 703-713.
Llorens-Martin MV, Rueda N, Martinez-Cue C, Torres-Aleman I, Florez J, Trejo JL (2007) Both increases in immature dentate neuron number and decreases of immobility time in the forced swim test occurred in parallel after environmental enrichment of mice. Neuroscience 147: 631-638.
Lunn JS, Sakowski SA, Kim B, Rosenberg AA, Feldman EL (2009) Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration. Dev Neurobiol 69: 871-884.
Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS Jr, Mayo MW (2000) Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol 20: 1626-1638.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20: 9104-9110.
Malykhin NV, Carter R, Seres P, Coupland NJ (2010) Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment. J Psychiatry Neurosci 35: 337-343.
Marashi V, Barnekow A, Ossendorf E, Sachser N (2003) Effects of different forms of environmental enrichment on behavioral, endocrinological, and immunological parameters in male mice. Horm Behav 43: 281-292.
Martello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, Enzo E, Guzzardo V, Rondina M, Spruce T, Parenti AR, Daidone MG, Bicciato S, Piccolo S (2010) A MicroRNA targeting dicer for metastasis control. Cell 141: 1195-1207.
Martin D, Galisteo R, Gutkind JS (2009) CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NFkappaB through the CBM (Carma3/Bcl10/Malt1) complex. J Biol Chem 284: 6038-6042.
Matsunaga Y, Yamazaki Y, Suzuki H, Morita T (2009) VEGF-A and VEGF-F evoke distinct changes in vascular ultrastructure. Biochem Biophys Res Commun 379: 872-875.
Matsuzaki H, Tamatani M, Yamaguchi A, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M (2001) Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. FASEB J 15: 1218-1220.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271-275.
McCloskey DP, Croll SD, Scharfman HE (2005) Depression of synaptic transmission by vascular endothelial growth factor in adult rat hippocampus and evidence for increased efficacy after chronic seizures. J Neurosci 25: 8889-8897.
McCloskey DP, Hintz TM, Scharfman HE (2008) Modulation of vascular endothelial growth factor (VEGF) expression in motor neurons and its electrophysiological effects. Brain Res Bull 76: 36-44.
McEwen BS (2003) Sex, stress and the hippocampus: allostasis, allostatic load and the aging process. Neurobiol Aging 23: 921-939.
Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576-579.
Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72: 835-846.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34: 13-25.
Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, Duman RS (2003) Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci 23: 10841-10851.
Ni J, Takayama K, Inoshima N, Uchino J, Harada A, Minami T, Harada T, Zhou C, Nakanishi Y (2005) Gene transfer of inhibitor kappaB in human lung cancer cell line NCI-H460 inhibits tumorigenesis and angiogenesis in vivo. Anticancer Res 25: 69-77.
Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15: 7539-7547.
Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7: 697-709.
Norrholm SD, Ouimet CC (2001) Altered dendritic spine density in animal models of depression and in response to antidepressant treatment. Synapse 42: 151-163.
Ogunshola OO, Antic A, Donoghue MJ, Fan SY, Kim H, Stewart WB, Madri JA, Ment LR (2002) Paracrine and autocrine functions of neuronal vascular endothelial growth factor (VEGF) in the central nervous system. J Biol Chem 277: 11410-11415.
Parrizas M, Gazit A, Levitzki A, Wertheimer E, LeRoith D (1997) Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. Endocrinology 138: 1427-1433.
Pati S, Orsi SA, Moore AN, Dash PK (2009) Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory. Brain Res 1256: 85-91.
Plaschke K, Staub J, Ernst E, Marti HH (2008) VEGF overexpression improves mice cognitive abilities after unilateral common carotid artery occlusion. Exp Neurol 214: 285-292.
Porsolt, RD, Le Pichon, M, and Jalfre, M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730-732.
Punglia RS, Lu M, Hsu J, Kuroki M, Tolentino MJ, Keough K, Levy AP, Levy NS, Goldberg MA, D'Amato RJ, Adamis AP (1997) Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. Diabetes 46: 1619-1626.
Ramanathan M, Pinhal-Enfield G, Hao I, Leibovich SJ (2007) Synergistic up-regulation of vascular endothelial growth factor (VEGF) expression in macrophages by adenosine A2A receptor agonists and endotoxin involves transcriptional regulation via the hypoxia response element in the VEGF promoter. Mol Biol Cell 18: 14-23.
Rampon C, Jiang CH, Dong H, Tang YP, Lockhart DJ, Schultz PG, Tsien JZ, Hu Y (2000) Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci U S A 97:12880-12884.
Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114: 853-865.
Rosenstein JM, Mani N, Khaibullina A, Krum JM (2003) Neurotrophic effects of vascular endothelial growth factor on organotypic cortical explants and primary cortical neurons. J Neurosci 23: 11036-11044.
Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270: 815-822.
Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272: 22642-22647.
Sandau KB, Zhou J, Kietzmann T, Brune B (2001) Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. J Biol Chem 276: 39805-39811.
Scherr M, Venturini L, Battmer K, Schaller-Schoenitz M, Schaefer D, Dallmann I, Ganser A, Eder M (2007) Lentivirus-mediated antagomir expression for specific inhibition of miRNA function. Nucleic Acids Res 35: e149.
Schloesser RJ, Lehmann M, Martinowich K, Manji HK, Herkenham M (2010) Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol Psychiatry 15: 1152-1163.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439: 283-289.
Semenza GL, Agani F, Iyer N, Jiang BH, Leung S, Wiener C, Yu A (1998) Hypoxia-inducible factor 1: from molecular biology to cardiopulmonary physiology. Chest 114: 40S-45S.
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376: 62-66.
Sharp FR, Bernaudin M (2004) HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5: 437-448.
Shen BQ, Lee DY, Zioncheck TF (1999) Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem 274: 33057-33063.
Shibuya M, Ito N, Claesson-Welsh L (1999) Structure and function of vascular endothelial growth factor receptor-1 and -2. Curr Top Microbiol Immunol 237: 59-83.
Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M, Khudayberdiev S, Leuschner PF, Busch CJ, Kane C, Hübel K, Dekker F, Hedberg C, Rengarajan B, Drepper C, Waldmann H, Kauppinen S, Greenberg ME, Draguhn A, Rehmsmeier M, Martinez J, Schratt GM (2009) A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 11: 705-716.
Sondell M, Sundler F, Kanje M (2000) Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci 12: 4243-4254.
Southwick SM, Vythilingam M, Charney DS (2005) The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol 1: 255-291.
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85: 367-370.
Surdziel E, Eder M, Scherr M (2010) Lentivirus-mediated antagomir expression. Methods Mol Biol 667: 237-248.
Sutter CH, Laughner E, Semenza GL (2000) Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc Natl Acad Sci U S A 97: 4748-4753.
Suzuki K, Ikegaya Y, Matsuura S, Kanai Y, Endou H, Matsuki N (2001) Transient upregulation of the glial glutamate transporter GLAST in response to fibroblast growth factor, insulin-like growth factor and epidermal growth factor in cultured astrocytes. J Cell Sci 114: 3717-3725.
Taguchi A, Yanagisawa K, Tanaka M, Cao K, Matsuyama Y, Goto H, Takahashi T (2008) Identification of hypoxia-inducible factor-1 alpha as a novel target for miR-17-92 microRNA cluster. Cancer Res 68: 5540-5545.
Tolosa L, Mir M, Asensio VJ, Olmos G, Llado J (2008) Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3-kinase. J Neurochem 105: 1080-1090.
Treins C, Giorgetti-Peraldi S, Murdaca J, Monthouel-Kartmann MN, Van Obberghen E (2005) Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I. Mol Endocrinol 19: 1304-1317.
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, STAR*D Study Team (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163: 28-40.
Veena J, Srikumar BN, Raju TR, Shankaranarayana Rao BS (2009) Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats. Neurosci Lett 455: 178-182.
Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran -4-one (LY294002). J Biol Chem 269: 5241-5248.
Wang GS, Hong CJ, Yen TY, Huang HY, Ou Y, Huang TN, Jung WG, Kuo TY, Sheng M, Wang TF, Hsueh YP (2004) Transcriptional modification by a CASK-interacting nucleosome assembly protein. Neuron 42: 113-128.
Warner-Schmidt JL, Duman RS (2007) VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A 104: 4647-4652.
Whittles CE, Pocock TM, Wedge SR, Kendrew J, Hennequin LF, Harper SJ, Bates DO (2002) ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity. Microcirculation 9: 513-522.
Widenfalk J, Lipson A, Jubran M, Hofstetter C, Ebendal T, Cao Y, Olson L (2003) Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury. Neuroscience 120: 951-960.
Winter C, von Rumohr A, Mundt A, Petrus D, Klein J, Lee T, Morgenstern R, Kupsch A, Juckel G (2007) Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats. Behav Brain Res 184: 133-141.
Wittert GA, Livesey JH, Espiner EA, Donald RA (1996) Adaptation of the hypothalamopituitary adrenal axis to chronic exercise stress in humans. Med Sci Sports Exerc 28: 1015-1019.
Wright RL, Conrad CD (2008) Enriched environment prevents chronic stress-induced spatial learning and memory deficits. Behav Brain Res 187: 41-47.
Yamakuchi M, Lotterman CD, Bao C, Hruban RH, Karim B, Mendell JT, Huso D, Lowenstein CJ (2010) P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proc Natl Acad Sci U S A 107: 6334-6339.
Young D, Lawlor PA, Leone P, Dragunow M, During MJ (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 5: 448-453.
Zachary I (2005) Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals 14: 207-221.
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63: 856-864.
Zhu Y, Jin K, Mao XO, Greenberg, DA (2003) Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J 17: 186-193.
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