抑郁大鼠嗅球神经发生与凋亡研究
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摘要
研究背景
抑郁症是常见的精神疾病,终生患病率高达16%,其发病机制未明。大量临床和基础研究发现,海马神经发生障碍与抑郁症有关。最新研究发现,抑郁模型小鼠侧脑室下区存在神经发生障碍,提示抑郁症除海马外,成年其他神经发生脑区也可能存在神经发生障碍。
嗅球是嗅觉传导的第一中继站,成年哺乳动物嗅球终生进行神经发生以维持嗅觉。嗅球神经发生障碍是否存在于抑郁症发生、发展过程中目前还不清楚,但是许多临床研究发现抑郁症患者嗅觉敏感性降低,并且最新研究发现抑郁症患者嗅球体积减小,提示在嗅球可能存在细胞和分子水平的改变。
目的
本实验基于前期研究抑郁症与神经发生的基础,应用神经科学的研究思路和方法,观察抑郁大鼠嗅球神经发生情况,进一步探讨神经发生与抑郁症的关系,以及抑郁症患者嗅觉敏感性降低和嗅球体积减小的可能原因。同时观察抑郁大鼠嗅球凋亡情况,多角度探索临床现象的细胞和分子机制。
方法
本实验分为二部分：第一部分,抑郁大鼠嗅球神经发生的研究；
第二部分,抑郁大鼠嗅球凋亡的研究。
主要方法和技术路线：
1.构建慢性不可预见性温和刺激抑郁大鼠动物模型,并进行嗅觉测试,检测抑郁大鼠嗅觉是否存在障碍。
2.运用嗅球连续矢状切片,计算大鼠嗅球体积,检测抑郁大鼠嗅球体积是否减小。
3.运用免疫组织化学、western blot等方法,检测抑郁大鼠嗅球未成熟神经元标志物多唾液酸-神经细胞粘附分子(PSA-NCAM)和成熟神经元标志物神经元核抗原(NeuN)阳性细胞数和蛋白表达情况,观察抑郁大鼠神经发生是否存在改变。
4.运用western blot、RT-PCR等方法,检测抑郁大鼠嗅球突触前膜功能相关蛋白突触素和突触融合蛋白的表达,观察抑郁大鼠突触前膜功能是否存在障碍。
5.运用脱氧核苷酸末端转移酶介导的dUTP缺口末端标记技术(TUNEl)检测抑郁大鼠嗅球凋亡情况,观察抑郁大鼠是否存在凋亡增多。
6.运用western blot检测抑郁大鼠嗅球促凋亡蛋白bax和抑凋亡蛋白bcl-2的表达,进一步探讨抑郁大鼠凋亡增多可能的分子机制。
结果
1.埋藏食物小球法嗅觉测试结果显示抑郁大鼠找到食物时间较正常对照明显延长。
2.抑郁大鼠较正常对照嗅球体积减小了21.3%。
3.免疫组织化学显示抑郁大鼠嗅球室管膜下区PSA-NCAM阳性细胞数明显减少,western blot进一步印证嗅球PSA-NCAM蛋白表达量减少。
4.免疫组织化学显示抑郁大鼠嗅球小球层NeuN阳性细胞数明显减少,western blot进一步印证嗅球NeuN蛋白表达量减少。
5.抑郁大鼠嗅球突触前膜功能相关蛋白突触素表达减少,突触融合蛋白表达增多；这两种蛋白mRNA水平并没有发现有明显改变。
6.抑郁大鼠嗅球小球层TUNEL阳性细胞数量较正常对照明显增多。
7.抑郁大鼠嗅球促凋亡蛋白bax表达增多,抑凋亡蛋白bcl-2表达减少。
结论
1.抑郁大鼠嗅球神经发生减少,同时伴有突触前膜功能障碍、嗅球体积减小和嗅觉功能降低。嗅球神经发生障碍可能是临床抑郁症患者嗅觉功能减退和嗅球体积减小的原因之一,同时突触前膜功能障碍可能是抑郁患者嗅觉功能减退的分子机制之一。
2.抑郁大鼠嗅球凋亡增多。促凋亡蛋白bax增多,抑凋亡蛋白bcl-2减少,可能是其潜在的分子机制之一。
Background
Major depression is a common mental disorder and has a lifetime prevalence rates as high as 16%, yet the pathogenesis of this mental disorder is poorly understood. Clinical findings show that hippocampal atrophy exists in the depressed patients, and a variety of evidence has a connection with hippocampal neurogenesis in the pathophysiology of depression. In addition, another adult mammalian brain neurogenesis area, namely, the subventricular zone, was also observed decreased neurogenesis in a mouse model of depression. However, whether other neurogenic regions in the adult central nervous system would be involved with depression is an interesting question. Olfactory bulb (OB) is the first relay station of olfactory transduction pathway, and one of the post-developmental neurogenesis areas in the adult mammalian brain. Reduced OB volume as well as, respectly, olfactory sensitivity was observed in patients with depressive disorder, nevertheless, the molecular and cellular mechanisms is unclear.
Objective
Based on previous series of studies of depressive disorder, the purposes of present study was to detect neurogenesis and apoptosis in the OB of a rat model of depression by means of neurological idea and methods, and investigate the possible reasons for the reduced OB volume and olfactory sensitivity in depressed patients.
Methods
The experiment consistes of two parts:the first part focuses on the OB neurogenesis in the rat model of depression; the second part concentrates to the apoptosis of the rat model. The main methods and technology:
1. Construction of chronic unpredictable mild stress (CUMS) rat model of depression, and then conducting the olfactory test to detecting whether the CUMS rat would exist olfactory dysfunction.
2. Calculating the OB volume by means of continuous sagittal slices to detect the alteration of OB volume in the CUMS rat.
3. Detecting the number of immature neurons marked by polysialylated neural cell adhesion molecule and mature neurons labeled by Neuronal Nuclei in the OB of rat after 4 weeks chronic stress treatment by means of immunohistochemistry and western blot.
4. Detecting the expression of the pre-synaptic proteins synaptophsin and syntaxin in the OB of the rat model by way of western blot and RT-PCR.
5. Investigating the apoptosis in the OB of the rat model using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method.
6. Detecting the expression of pro-apoptotic protein bax and anti-apoptotic protein bcl-2 in the OB of the rat model furtherly to investigate possible molecular mechanism of the apoptosis.
Results
1. CUMS rat took significantly longer time to locate the food than control rat.
2. Compared with control group, the OB volume of CUMS rat decreased by 21.3%.
3. Results of immunohistochemistry and western blot analysis showed a dramatic reduction of immature neurons marked by polysialylated neural cell adhesion molecule in the OB of rat after 4 weeks chronic stress treatment.
4. Results of immunohistochemistry and western blot analysis showed a dramatic reduction of mature neurons labeled by Neuronal Nuclei in the OB of rat after 4 weeks chronic stress treatment.
5. Data of western blot analysis showed that chronic stress reduced expression of synaptophysin but increased expression of syntaxin in the OB, while significant variation at these mRNA level was not observed.
6. TUNEL-positive cells increased in the glomerular layer in the OB of the CUMS rat.
7. Down-regulated expression of bcl-2 protein companying with up-regulated expression of bax protein in the OB of the CUMS rat.
Conclusion
1. Reduced OB neurogenesis did present in the CUMS rat model of depression. Simultaneously, impaired neurogenesis accompanied with pre-synaptic dysfunction, reduced OB volume and decreased olfactory sensitivity in the CUMS rat model of depression. Reduced OB neurogenesis may be one of the reasons for the reduced OB volume and olfactory sensitivity in the depressed patients, and the pre-synaptic dysfunction may be the underlying molecular mechanism for it.
2. Increased apoptosis did exist in the OB of the CUMS rats. Furthermore, up-regulated expression of bax protein and down-regulated expression of bcl-2 protein might function to some extend in the increased apoptosis in the OB of the CUMS rats.
抑郁症是常见的精神疾病,终生患病率高达16%,其发病机制未明。大量临床和基础研究发现,海马神经发生障碍与抑郁症有关。最新研究发现,抑郁模型小鼠侧脑室下区存在神经发生障碍,提示抑郁症除海马外,成年其他神经发生脑区也可能存在神经发生障碍。
嗅球是嗅觉传导的第一中继站,成年哺乳动物嗅球终生进行神经发生以维持嗅觉。嗅球神经发生障碍是否存在于抑郁症发生、发展过程中目前还不清楚,但是许多临床研究发现抑郁症患者嗅觉敏感性降低,并且最新研究发现抑郁症患者嗅球体积减小,提示在嗅球可能存在细胞和分子水平的改变。
目的
本实验基于前期研究抑郁症与神经发生的基础,应用神经科学的研究思路和方法,观察抑郁大鼠嗅球神经发生情况,进一步探讨神经发生与抑郁症的关系,以及抑郁症患者嗅觉敏感性降低和嗅球体积减小的可能原因。同时观察抑郁大鼠嗅球凋亡情况,多角度探索临床现象的细胞和分子机制。
方法
本实验分为二部分：第一部分,抑郁大鼠嗅球神经发生的研究；
第二部分,抑郁大鼠嗅球凋亡的研究。
主要方法和技术路线：
1.构建慢性不可预见性温和刺激抑郁大鼠动物模型,并进行嗅觉测试,检测抑郁大鼠嗅觉是否存在障碍。
2.运用嗅球连续矢状切片,计算大鼠嗅球体积,检测抑郁大鼠嗅球体积是否减小。
3.运用免疫组织化学、western blot等方法,检测抑郁大鼠嗅球未成熟神经元标志物多唾液酸-神经细胞粘附分子(PSA-NCAM)和成熟神经元标志物神经元核抗原(NeuN)阳性细胞数和蛋白表达情况,观察抑郁大鼠神经发生是否存在改变。
4.运用western blot、RT-PCR等方法,检测抑郁大鼠嗅球突触前膜功能相关蛋白突触素和突触融合蛋白的表达,观察抑郁大鼠突触前膜功能是否存在障碍。
5.运用脱氧核苷酸末端转移酶介导的dUTP缺口末端标记技术(TUNEl)检测抑郁大鼠嗅球凋亡情况,观察抑郁大鼠是否存在凋亡增多。
6.运用western blot检测抑郁大鼠嗅球促凋亡蛋白bax和抑凋亡蛋白bcl-2的表达,进一步探讨抑郁大鼠凋亡增多可能的分子机制。
结果
1.埋藏食物小球法嗅觉测试结果显示抑郁大鼠找到食物时间较正常对照明显延长。
2.抑郁大鼠较正常对照嗅球体积减小了21.3%。
3.免疫组织化学显示抑郁大鼠嗅球室管膜下区PSA-NCAM阳性细胞数明显减少,western blot进一步印证嗅球PSA-NCAM蛋白表达量减少。
4.免疫组织化学显示抑郁大鼠嗅球小球层NeuN阳性细胞数明显减少,western blot进一步印证嗅球NeuN蛋白表达量减少。
5.抑郁大鼠嗅球突触前膜功能相关蛋白突触素表达减少,突触融合蛋白表达增多；这两种蛋白mRNA水平并没有发现有明显改变。
6.抑郁大鼠嗅球小球层TUNEL阳性细胞数量较正常对照明显增多。
7.抑郁大鼠嗅球促凋亡蛋白bax表达增多,抑凋亡蛋白bcl-2表达减少。
结论
1.抑郁大鼠嗅球神经发生减少,同时伴有突触前膜功能障碍、嗅球体积减小和嗅觉功能降低。嗅球神经发生障碍可能是临床抑郁症患者嗅觉功能减退和嗅球体积减小的原因之一,同时突触前膜功能障碍可能是抑郁患者嗅觉功能减退的分子机制之一。
2.抑郁大鼠嗅球凋亡增多。促凋亡蛋白bax增多,抑凋亡蛋白bcl-2减少,可能是其潜在的分子机制之一。
Background
Major depression is a common mental disorder and has a lifetime prevalence rates as high as 16%, yet the pathogenesis of this mental disorder is poorly understood. Clinical findings show that hippocampal atrophy exists in the depressed patients, and a variety of evidence has a connection with hippocampal neurogenesis in the pathophysiology of depression. In addition, another adult mammalian brain neurogenesis area, namely, the subventricular zone, was also observed decreased neurogenesis in a mouse model of depression. However, whether other neurogenic regions in the adult central nervous system would be involved with depression is an interesting question. Olfactory bulb (OB) is the first relay station of olfactory transduction pathway, and one of the post-developmental neurogenesis areas in the adult mammalian brain. Reduced OB volume as well as, respectly, olfactory sensitivity was observed in patients with depressive disorder, nevertheless, the molecular and cellular mechanisms is unclear.
Objective
Based on previous series of studies of depressive disorder, the purposes of present study was to detect neurogenesis and apoptosis in the OB of a rat model of depression by means of neurological idea and methods, and investigate the possible reasons for the reduced OB volume and olfactory sensitivity in depressed patients.
Methods
The experiment consistes of two parts:the first part focuses on the OB neurogenesis in the rat model of depression; the second part concentrates to the apoptosis of the rat model. The main methods and technology:
1. Construction of chronic unpredictable mild stress (CUMS) rat model of depression, and then conducting the olfactory test to detecting whether the CUMS rat would exist olfactory dysfunction.
2. Calculating the OB volume by means of continuous sagittal slices to detect the alteration of OB volume in the CUMS rat.
3. Detecting the number of immature neurons marked by polysialylated neural cell adhesion molecule and mature neurons labeled by Neuronal Nuclei in the OB of rat after 4 weeks chronic stress treatment by means of immunohistochemistry and western blot.
4. Detecting the expression of the pre-synaptic proteins synaptophsin and syntaxin in the OB of the rat model by way of western blot and RT-PCR.
5. Investigating the apoptosis in the OB of the rat model using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method.
6. Detecting the expression of pro-apoptotic protein bax and anti-apoptotic protein bcl-2 in the OB of the rat model furtherly to investigate possible molecular mechanism of the apoptosis.
Results
1. CUMS rat took significantly longer time to locate the food than control rat.
2. Compared with control group, the OB volume of CUMS rat decreased by 21.3%.
3. Results of immunohistochemistry and western blot analysis showed a dramatic reduction of immature neurons marked by polysialylated neural cell adhesion molecule in the OB of rat after 4 weeks chronic stress treatment.
4. Results of immunohistochemistry and western blot analysis showed a dramatic reduction of mature neurons labeled by Neuronal Nuclei in the OB of rat after 4 weeks chronic stress treatment.
5. Data of western blot analysis showed that chronic stress reduced expression of synaptophysin but increased expression of syntaxin in the OB, while significant variation at these mRNA level was not observed.
6. TUNEL-positive cells increased in the glomerular layer in the OB of the CUMS rat.
7. Down-regulated expression of bcl-2 protein companying with up-regulated expression of bax protein in the OB of the CUMS rat.
Conclusion
1. Reduced OB neurogenesis did present in the CUMS rat model of depression. Simultaneously, impaired neurogenesis accompanied with pre-synaptic dysfunction, reduced OB volume and decreased olfactory sensitivity in the CUMS rat model of depression. Reduced OB neurogenesis may be one of the reasons for the reduced OB volume and olfactory sensitivity in the depressed patients, and the pre-synaptic dysfunction may be the underlying molecular mechanism for it.
2. Increased apoptosis did exist in the OB of the CUMS rats. Furthermore, up-regulated expression of bax protein and down-regulated expression of bcl-2 protein might function to some extend in the increased apoptosis in the OB of the CUMS rats.
引文
[1]Jacobs BL, van PH, Gage FH. Adult brain neurogenesis and psychiatry:a novel theory of depression. Mol Psychiatry.2000.5(3):262-9.
[2]Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007.10(9):1110-5.
-[3] Rajkowska G Depression:what we can learn from postmortem studies. Neuroscientist.2003.9(4):273-84.
[4]Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in patients suffering from depression:a meta-analysis. Am J Psychiatry.2004. 161(4):598-607.
[5]Videbech P, Ravnkilde B. Hippocampal volume and depression:a meta-analysis of MRI studies. Am J Psychiatry.2004.161(11):1957-66.
[6]MacQueen GM, Campbell S, McEwen BS, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003.100(3):1387-92.
[7]Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci.2000.20(24): 9104-10.
[8]Perera TD, Coplan JD, Lisanby SH, et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci.2007.27(18):4894-901.
[9]Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science.2003.301(5634):805-9.
[10]Mu J, Xie P, Yang ZS, et al.1H magnetic resonance spectroscopy study of thalamus in treatment resistant depressive patients. Neurosci Lett.2007.425(1):49-52.
[1 l]Mu J, Xie P, Yang ZS, et al. Neurogenesis and major depression:implications from proteomic analyses of hippocampal proteins in a rat depression model. Neurosci Lett.2007.416(3):252-6. [12]Duman RS. Structural alterations in depression:cellular mechanisms underlying pathology and treatment of mood disorders. CNS Spectr.2002.7(2):140-2,144-7.
[13]Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med.2001.7(5):541-7.
[14]Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron.2002.34(1):13-25.
[15]Mineur YS, Belzung C, Crusio WE. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience.2007.150(2): 251-9.
[16]Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat RevNeurosci.2006.7(3):179-93.
[17]Lledo PM, Saghatelyan A. Integrating new neurons into the adult olfactory bulb: joining the network, life-death decisions, and the effects of sensory experience. Trends Neurosci.2005.28(5):248-54.
[18]Atanasova B, Graux J, El HW, Hommet C, Camus V, Belzung C. Olfaction:a potential cognitive marker of psychiatric disorders. Neurosci Biobehav Rev.2008. 32(7):1315-25.
[19]Buschhuter D, Smitka M, Puschman.n S, et al. Correlation between olfactory bulb volume and olfactory function. Neuroimage.2008.42(2):498-502.
[20]Haehner A, Rodewald A, Gerber JC, Hummel T. Correlation of olfactory function with changes in the volume of the human olfactory bulb. Arch Otolaryngol Head Neck Surg.2008.134(6):621-4.
[21]Negoias S, Croy I, Gerber J, et al. Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience.2010.169(1): 415-21.
[22]Song C, Leonard BE. The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev.2005.29(4-5):627-47.
[23]Benn SC, Woolf CJ. Adult neuron survival strategies-slamming on the brakes. Nat Rev Neurosci.2004.5(9):686-700.
[24]Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell.1997.88(3):347-54.
[25]McKernan DP, Dinan TG, Cryan JF. "Killing the Blues":a role for cellular suicide (apoptosis) in depression and the antidepressant response. Prog Neurobiol.2009. 88(4):246-63.
[26]Lucassen PJ, Muller MB, Holsboer F, et al. Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol.2001.158(2):453-68.
[27]Luo C, Xu H, Li XM. Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons:effect of chronic administration of olanzapine. Brain Res. 2004.1025(1-2):194-202.
[28]Weaver IC, Grant RJ, Meaney MJ. Maternal behavior regulates long-term hippocampal expression of BAX and apoptosis in the offspring. J Neurochem.2002. 82(4):998-1002.
[1]Kessler RC, Berglund P, Dernier 0, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-1V disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry.2005.62(6):593-602.
[2]Dranovsky A, Hen R. Hippocampal neurogenesis:regulation by stress and antidepressants. Biol Psychiatry.2006.59(12):1136-43.
[3]Mineur YS, Belzung C, Crusio WE. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience.2007.150(2): 251-9.
[4]Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci.2006.7(3):179-93.
[5][5] Atanasova B, Graux J, El HW, Hommet C, Camus V, Belzung C. Olfaction:a potential cognitive marker of psychiatric disorders. Neurosci Biobehav Rev.2008. 32(7):1315-25.
[6]Negoias S, Croy I, Gerber J, et al. Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience.2010.169(1): 415-21.
[7]Buschhuter D, Smitka M, Puschmann S, et al. Correlation between olfactory bulb volume and olfactory function. Neuroimage.2008.42(2):498-502.
[8]Haehner A, Rodewald A, Gerber JC, Hummel T. Correlation of olfactory function with changes in the volume of the human olfactory bulb. Arch Otolaryngol Head Neck Surg.2008.134(6):621-4.
[9]Mu J, Yang ZS, Xie P. Proteomic analysis of a rat model of depression. Expert Rev Proteomics.2008.5(2):315-20.
[10]Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci.2005.28:223-50.
[11]Mu J, Xie P, Yang ZS, et al. Neurogenesis and major depression:implications from proteomic analyses of hippocampal proteins in a rat depression model. Neurosci Lett.2007.416(3):252-6.
[12]Nathan BP, Yost J, Litherland MT, Struble RG, Switzer PV. Olfactory function in apoE knockout mice. Behav Brain Res.2004.150(1-2):1-7.
[13]Luo DD, An SC, Zhang X. Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress. Brain Res Bull.2008. 77(1):8-12.
[14]Mirich JM, Williams NC, Berlau DJ, Brunjes PC. Comparative study of aging in the mouse olfactory bulb. J Comp Neurol.2002.454(4):361-72.
[15]Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci.2005.28:223-50.
[16]Jin K, Peel AL, Mao XO, et al. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A.2004.101(1):343-7.
[17]Kempermann G, Jessberger S, Steiner B, Kronenberg G Milestones of neuronal development in the adult hippocampus. Trends Neurosci.2004.27(8):447-52.
[18]Curtis MA, Kam M, Nannmark U, et al. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science.2007.315(5816):1243-9.
[19]Gao Z, Ure K, Abies JL, et al. Neurodl is essential for the survival and maturation of adult-born neurons. Nat Neurosci.2009.12(9):1090-2.
[20]Ma DK, Jang MH, Guo JU, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science.2009.323(5917): 1074-7.
[21]Imayoshi I, Sakamoto M, Ohtsuka T, et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci.2008.11(10): 1153-61.
[22]Hack MA, Saghatelyan A, de Chevigny A, et al. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci.2005.8(7):865-72.
[23]Dranovsky A, Hen R. Hippocampal neurogenesis:regulation by stress and antidepressants. Biol Psychiatry.2006.59(12):1136-43. [24]Edelmann L, Hanson PI, Chapman ER, Jahn R. Synaptobrevin binding to synaptophysin:a potential mechanism for controlling the exocytotic fusion machine. EMBOJ.1995.14(2):224-31.
[25]Tarsa L, Goda Y. Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A.2002.99(2):1012-6.
[26]Hu JY, Meng X, Schacher S. Redistribution of syntaxin mRNA in neuronal cell bodies regulates protein expression and transport during synapse formation and long-term synaptic plasticity. JNeurosci.2003.23(5):1804-15.
[27]Aguado F, Majo G, Ruiz-Montasell B, Llorens J, Marsal J, Blasi J. Syntaxin 1A and 1B display distinct distribution patterns in the rat peripheral nervous system. Neuroscience.1999.88(2):437-46.
[28]Nakayama T, Matsuoka R, Kimura M, et al. Hemizygous deletion of the HPC-1/syntaxin 1A gene (STX1A) in patients with Williams syndrome. Cytogenet Cell Genet.1998.82(1-2):49-51.
[29]Thome J, Pesold B, Baader M, et al. Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biol Psychiatry.2001.50(10): 809-12.
[30]Carboni L, Piubelli C, Pozzato C, et al. Proteomic analysis of rat hippocampus after repeated psychosocial stress. Neuroscience.2006.137(4):1237-46.
[31]Crawley JN. Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res.1999.835(1):18-26.
[32]Fleming SM, Tetreault NA, Mulligan CK, Hutson CB, Masliah E, Chesselet MF. Olfactory deficits in mice overexpressing human wildtype alpha-synuclein. Eur J Neurosci.2008.28(2):247-56.
[33]Pause BM, Miranda A, Goder R; Aldenhoff JB, Ferstl R. Reduced olfactory performance in patients with major depression. J Psychiatr Res.2001.35(5):271-7.
[34]Rochefort C, Gheusi G, Vincent JD, Lledo PM. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J Neurosci.2002.22(7):2679-89.
[35]Gheusi G, Cremer H, McLean H, Chazal G, Vincent JD, Lledo PM. Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci U S A.2000.97(4):1823-8.
[36]Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci.2004.24(38): 8354-65.
[1]Czeh B, Lucassen PJ. What causes the hippocatnpal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated. Eur Arch Psychiatry Clin Neurosci.2007.257(5):250-60.
[2]McKernan DP, Dinan TG, Cry an JF. "Killing the Blues":a role for cellular suicide (apoptosis) in depression and the antidepressant response. Prog Neurobiol.2009. 88(4):246-63.
[3]Lucassen PJ, Muller MB, Holsboer F, et al. Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol.2001.158(2):453-68.
[4]Luo C, Xu H, Li XM. Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons:effect of chronic administration of olanzapine. Brain Res. 2004.1025(1-2):194-202.
[5]Weaver IC, Grant RJ, Meaney MJ. Maternal behavior regulates long-term hippocampal expression of BAX and apoptosis in the offspring. J Neurochem.2002. 82(4):998-1002.
[6]Kosten TA, Galloway MP, Duman RS, Russell DS, D'Sa C. Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures. Neuropsychopharmacology.2008.33(7):1545-58.
[7]Fiske BK, Brunjes PC. Cell death in the developing and sensory-deprived rat olfactory bulb. J Comp Neurol.2001.431(3):311-9.
[8]Najbauer J, Leon M. Olfactory experience modulated apoptosis in the developing olfactory bulb. Brain Res.1995.674(2):245-51.
[9]Pomeroy SL, LaMantia AS, Purves D. Postnatal construction of neural circuitry in the mouse olfactory bulb. J Neurosci.1990.10(6):1952-66.
[10]Lazarini F, Lledo PM. Is adult neurogenesis essential for olfaction. Trends Neurosci. 2011.34(1):20-30.
[11]Johnson BA, Leon M. Odorant molecular length:one aspect of the olfactory code. J Comp Neurol.2000.426(2):330-8.
[12]Johnson BA, Leon M. Modular representations of odorants in the glomerular layer of the rat olfactory bulb and the effects of stimulus concentration. J Comp Neurol. 2000.422(4):496-509.
[13]Uchida N, Takahashi YK, Tanifuji M, Mori K. Odor maps in the mammalian olfactory bulb:domain organization and odorant structural features. Nat Neurosci. 2000.3(10):1035-43.
[14]Belluscio L, Katz LC. Symmetry, stereotypy, and topography of odorant representations in mouse olfactory bulbs. J Neurosci.2001.21(6):2113-22.
[15]lgarashi KM, Mori K. Spatial representation of hydrocarbon odorants in the ventrolateral zones of the rat olfactory bulb. J Neurophysiol.2005.93(2):1007-19.
[16]Wachowiak M, Cohen LB. Representation of odorants by receptor neuron input to the mouse olfactory bulb. Neuron.2001.32(4):723-35.
[17]Friedrich RW, Korsching SI. Chemotopic, combinatorial, and noncombinatorial odorant representations in the olfactory bulb revealed using a voltage-sensitive axon tracer. J Neurosci.1998.18(23):9977-88.
[18]Adams JM, Cory S. Life-or-death decisions by the Bcl-2 protein family. Trends BiochemSci.2001.26(1):61-6.
[19]Borner C. The Bcl-2 protein family:sensors and checkpoints for life-or-death decisions. Mol Immunol.2003.39(11):615-47.
[20]Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem.1999.274(4):2225-33.
[21]Kuwana T, Mackey MR, Perkins G, et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell.2002.111(3): 331-42.
[22]Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2:release of cytochrome c from mitochondria blocked. Science.1997.275(5303):1129-32.
[23]Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ.2000.7(12):1182-91.
[24]Weaver IC, Grant RJ, Meaney MJ. Maternal behavior regulates long-term hippocampal expression of BAX and apoptosis in the offspring. J Neurochem.2002. 82(4):998-1002.
[1]Kaplan MS, Bell DH. Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus. J Neurosci.1984.4(6):1429-41.
[2]Stanfield BB, Trice JE. Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res.1988.72(2):399-406.
[3]Cameron HA, Woolley CS, McEwen BS, Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience.1993.56(2): 337-44.
[4]Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996.16(6):2027-33.
[5]Galea LAM, Tanapat P, Gould E (1996) Exposure to predator odor suppresses cell proliferation in the dentate gyrus of adult rats via a cholinergic mechanism. Soc Neurosci Abstr 22:1196.
[6]Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci.1997.17(7):2492-8.
[7]Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A.1998.95(6):3168-71.
[8]Heine VM, Maslam S, Zareno J, Joels M, Lucassen PJ. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Eur J Neurosci.2004.19(1):131-44.
[9]Dagyte G, Crescente I, Postema F, et al. Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress. Behav Brain Res.2011. 218(1):121-8.
[10]Gould E, Cameron HA. Regulation of neuronal birth, migration and death in the rat dentate gyrus. Dev Neurosci.1996.18(1-2):22-35.
[11]Qiu G, Helmeste DM, Samaranayake AN, et al. Modulation of the suppressive effect of corticosterone on adult rat hippocampal cell proliferation by paroxetine. Neurosci Bull.2007.23(3):131-6.
[12]Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci.2000.20(24): 9104-10.
[13]Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry.2004.56(8):570-80.
[14]Wang JW, David DJ, Monckton JE, Battaglia F, Hen R. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci.2008.28(6):1374-84.
[15]Boldrini M, Underwood MD, Hen R, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology.2009. 34(11):2376-89.
[16]Chen H, Pandey GN, Dwivedi Y. Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport.2006.17(9):863-7.
[17]Liu Q, Yu J, Mao-Ying QL, et al. Repeated clomipramine treatment reversed the inhibition of cell proliferation in adult hippocampus induced by chronic unpredictable stress. Pharmacogenomics J.2008.8(6):375-83.
[18]Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science.2003.301(5634):805-9.
[19]David DJ, Samuels BA, Rainer Q, et al. Neurogenesis-dependent and-independent effects of fluoxetine in an animal model of anxiety/depression. Neuron.2009.62(4): 479-93.
[20]Martinez-Turrillas R, Del RJ, Frechilla D. Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment. Neuropharmacology.2005.49(8):1178-88.
[21]Martinez-Turrillas R, Del RJ, Frechilla D. Neuronal proteins involved in synaptic targeting of AMPA receptors in rat hippocampus by antidepressant drugs. Biochem Biophys Res Commun.2007.353(3):750-5.
[22]Banasr M, Hery M, Printemps R, Daszuta A. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology.2004.29(3):450-60.
[23]Donati RJ, Rasenick MM. G protein signaling and the molecular basis of antidepressant action. Life Sci.2003.73(1):1-17.
[24]Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem.1989.53(5):1644-7.
[25]Perez J, Tinelli D, Brunello N, Racagni G. cAMP-dependent phosphorylation of soluble and crude microtubule fractions of rat cerebral cortex after prolonged desmethylimipramine treatment. Eur J Pharmacol.1989.172(3):305-16.
[26]Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants:a critical overview. Pharmacol Rev.2006.58(1): 115-34.
[27]Blendy JA. The role of CREB in depression and antidepressant treatment. Biol Psychiatry.2006.59(12):1144-50.
[28]Tiraboschi E, Tardito D, Kasahara J, et al. Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology.2004.29(10):1831-40.
[29]Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci.2002.22(8):3251-61.
[30]Sairanen M, Lucas G, Ernfors P, Castren M, Castren E. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci.2005. 25(5):1089-94.
[31]Doetsch F. A niche for adult neural stem cells. Curr Opin Genet Dev.2003.13(5): 543-50.
[32]Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol.2000.425(4):479-94.
[33]Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol.2000.425(4):479-94.
[34]Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A.2007.104(11): 4647-52.
[35]Atanasova B, Graux J, El HW, Hommet C, Camus V, Belzung C. Olfaction:a potential cognitive marker of psychiatric disorders. Neurosci Biobehav Rev.2008. 32(7):1315-25.
[36]Negoias S, Croy I, Gerber J, et al. Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience.2010.169(1): 415-21.
[37]Buschhuter D, Smitka M, Puschmann S, et al. Correlation between olfactory bulb volume and olfactory function. Neuroimage.2008.42(2):498-502.
[38]Haehner A, Rodewald A, Gerber JC, Hummel T. Correlation of olfactory function with changes in the volume of the human olfactory bulb. Arch Otolaryngol Head Neck Surg.2008.134(6):621-4.
[39]Mineur YS, Belzung C, Crusio WE. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience.2007.150(2): 251-9.
[2]Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007.10(9):1110-5.
-[3] Rajkowska G Depression:what we can learn from postmortem studies. Neuroscientist.2003.9(4):273-84.
[4]Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in patients suffering from depression:a meta-analysis. Am J Psychiatry.2004. 161(4):598-607.
[5]Videbech P, Ravnkilde B. Hippocampal volume and depression:a meta-analysis of MRI studies. Am J Psychiatry.2004.161(11):1957-66.
[6]MacQueen GM, Campbell S, McEwen BS, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003.100(3):1387-92.
[7]Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci.2000.20(24): 9104-10.
[8]Perera TD, Coplan JD, Lisanby SH, et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci.2007.27(18):4894-901.
[9]Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science.2003.301(5634):805-9.
[10]Mu J, Xie P, Yang ZS, et al.1H magnetic resonance spectroscopy study of thalamus in treatment resistant depressive patients. Neurosci Lett.2007.425(1):49-52.
[1 l]Mu J, Xie P, Yang ZS, et al. Neurogenesis and major depression:implications from proteomic analyses of hippocampal proteins in a rat depression model. Neurosci Lett.2007.416(3):252-6. [12]Duman RS. Structural alterations in depression:cellular mechanisms underlying pathology and treatment of mood disorders. CNS Spectr.2002.7(2):140-2,144-7.
[13]Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med.2001.7(5):541-7.
[14]Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron.2002.34(1):13-25.
[15]Mineur YS, Belzung C, Crusio WE. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience.2007.150(2): 251-9.
[16]Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat RevNeurosci.2006.7(3):179-93.
[17]Lledo PM, Saghatelyan A. Integrating new neurons into the adult olfactory bulb: joining the network, life-death decisions, and the effects of sensory experience. Trends Neurosci.2005.28(5):248-54.
[18]Atanasova B, Graux J, El HW, Hommet C, Camus V, Belzung C. Olfaction:a potential cognitive marker of psychiatric disorders. Neurosci Biobehav Rev.2008. 32(7):1315-25.
[19]Buschhuter D, Smitka M, Puschman.n S, et al. Correlation between olfactory bulb volume and olfactory function. Neuroimage.2008.42(2):498-502.
[20]Haehner A, Rodewald A, Gerber JC, Hummel T. Correlation of olfactory function with changes in the volume of the human olfactory bulb. Arch Otolaryngol Head Neck Surg.2008.134(6):621-4.
[21]Negoias S, Croy I, Gerber J, et al. Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience.2010.169(1): 415-21.
[22]Song C, Leonard BE. The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev.2005.29(4-5):627-47.
[23]Benn SC, Woolf CJ. Adult neuron survival strategies-slamming on the brakes. Nat Rev Neurosci.2004.5(9):686-700.
[24]Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell.1997.88(3):347-54.
[25]McKernan DP, Dinan TG, Cryan JF. "Killing the Blues":a role for cellular suicide (apoptosis) in depression and the antidepressant response. Prog Neurobiol.2009. 88(4):246-63.
[26]Lucassen PJ, Muller MB, Holsboer F, et al. Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol.2001.158(2):453-68.
[27]Luo C, Xu H, Li XM. Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons:effect of chronic administration of olanzapine. Brain Res. 2004.1025(1-2):194-202.
[28]Weaver IC, Grant RJ, Meaney MJ. Maternal behavior regulates long-term hippocampal expression of BAX and apoptosis in the offspring. J Neurochem.2002. 82(4):998-1002.
[1]Kessler RC, Berglund P, Dernier 0, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-1V disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry.2005.62(6):593-602.
[2]Dranovsky A, Hen R. Hippocampal neurogenesis:regulation by stress and antidepressants. Biol Psychiatry.2006.59(12):1136-43.
[3]Mineur YS, Belzung C, Crusio WE. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience.2007.150(2): 251-9.
[4]Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci.2006.7(3):179-93.
[5][5] Atanasova B, Graux J, El HW, Hommet C, Camus V, Belzung C. Olfaction:a potential cognitive marker of psychiatric disorders. Neurosci Biobehav Rev.2008. 32(7):1315-25.
[6]Negoias S, Croy I, Gerber J, et al. Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience.2010.169(1): 415-21.
[7]Buschhuter D, Smitka M, Puschmann S, et al. Correlation between olfactory bulb volume and olfactory function. Neuroimage.2008.42(2):498-502.
[8]Haehner A, Rodewald A, Gerber JC, Hummel T. Correlation of olfactory function with changes in the volume of the human olfactory bulb. Arch Otolaryngol Head Neck Surg.2008.134(6):621-4.
[9]Mu J, Yang ZS, Xie P. Proteomic analysis of a rat model of depression. Expert Rev Proteomics.2008.5(2):315-20.
[10]Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci.2005.28:223-50.
[11]Mu J, Xie P, Yang ZS, et al. Neurogenesis and major depression:implications from proteomic analyses of hippocampal proteins in a rat depression model. Neurosci Lett.2007.416(3):252-6.
[12]Nathan BP, Yost J, Litherland MT, Struble RG, Switzer PV. Olfactory function in apoE knockout mice. Behav Brain Res.2004.150(1-2):1-7.
[13]Luo DD, An SC, Zhang X. Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress. Brain Res Bull.2008. 77(1):8-12.
[14]Mirich JM, Williams NC, Berlau DJ, Brunjes PC. Comparative study of aging in the mouse olfactory bulb. J Comp Neurol.2002.454(4):361-72.
[15]Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci.2005.28:223-50.
[16]Jin K, Peel AL, Mao XO, et al. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A.2004.101(1):343-7.
[17]Kempermann G, Jessberger S, Steiner B, Kronenberg G Milestones of neuronal development in the adult hippocampus. Trends Neurosci.2004.27(8):447-52.
[18]Curtis MA, Kam M, Nannmark U, et al. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science.2007.315(5816):1243-9.
[19]Gao Z, Ure K, Abies JL, et al. Neurodl is essential for the survival and maturation of adult-born neurons. Nat Neurosci.2009.12(9):1090-2.
[20]Ma DK, Jang MH, Guo JU, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science.2009.323(5917): 1074-7.
[21]Imayoshi I, Sakamoto M, Ohtsuka T, et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci.2008.11(10): 1153-61.
[22]Hack MA, Saghatelyan A, de Chevigny A, et al. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci.2005.8(7):865-72.
[23]Dranovsky A, Hen R. Hippocampal neurogenesis:regulation by stress and antidepressants. Biol Psychiatry.2006.59(12):1136-43. [24]Edelmann L, Hanson PI, Chapman ER, Jahn R. Synaptobrevin binding to synaptophysin:a potential mechanism for controlling the exocytotic fusion machine. EMBOJ.1995.14(2):224-31.
[25]Tarsa L, Goda Y. Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A.2002.99(2):1012-6.
[26]Hu JY, Meng X, Schacher S. Redistribution of syntaxin mRNA in neuronal cell bodies regulates protein expression and transport during synapse formation and long-term synaptic plasticity. JNeurosci.2003.23(5):1804-15.
[27]Aguado F, Majo G, Ruiz-Montasell B, Llorens J, Marsal J, Blasi J. Syntaxin 1A and 1B display distinct distribution patterns in the rat peripheral nervous system. Neuroscience.1999.88(2):437-46.
[28]Nakayama T, Matsuoka R, Kimura M, et al. Hemizygous deletion of the HPC-1/syntaxin 1A gene (STX1A) in patients with Williams syndrome. Cytogenet Cell Genet.1998.82(1-2):49-51.
[29]Thome J, Pesold B, Baader M, et al. Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biol Psychiatry.2001.50(10): 809-12.
[30]Carboni L, Piubelli C, Pozzato C, et al. Proteomic analysis of rat hippocampus after repeated psychosocial stress. Neuroscience.2006.137(4):1237-46.
[31]Crawley JN. Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res.1999.835(1):18-26.
[32]Fleming SM, Tetreault NA, Mulligan CK, Hutson CB, Masliah E, Chesselet MF. Olfactory deficits in mice overexpressing human wildtype alpha-synuclein. Eur J Neurosci.2008.28(2):247-56.
[33]Pause BM, Miranda A, Goder R; Aldenhoff JB, Ferstl R. Reduced olfactory performance in patients with major depression. J Psychiatr Res.2001.35(5):271-7.
[34]Rochefort C, Gheusi G, Vincent JD, Lledo PM. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J Neurosci.2002.22(7):2679-89.
[35]Gheusi G, Cremer H, McLean H, Chazal G, Vincent JD, Lledo PM. Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci U S A.2000.97(4):1823-8.
[36]Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci.2004.24(38): 8354-65.
[1]Czeh B, Lucassen PJ. What causes the hippocatnpal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated. Eur Arch Psychiatry Clin Neurosci.2007.257(5):250-60.
[2]McKernan DP, Dinan TG, Cry an JF. "Killing the Blues":a role for cellular suicide (apoptosis) in depression and the antidepressant response. Prog Neurobiol.2009. 88(4):246-63.
[3]Lucassen PJ, Muller MB, Holsboer F, et al. Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol.2001.158(2):453-68.
[4]Luo C, Xu H, Li XM. Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons:effect of chronic administration of olanzapine. Brain Res. 2004.1025(1-2):194-202.
[5]Weaver IC, Grant RJ, Meaney MJ. Maternal behavior regulates long-term hippocampal expression of BAX and apoptosis in the offspring. J Neurochem.2002. 82(4):998-1002.
[6]Kosten TA, Galloway MP, Duman RS, Russell DS, D'Sa C. Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures. Neuropsychopharmacology.2008.33(7):1545-58.
[7]Fiske BK, Brunjes PC. Cell death in the developing and sensory-deprived rat olfactory bulb. J Comp Neurol.2001.431(3):311-9.
[8]Najbauer J, Leon M. Olfactory experience modulated apoptosis in the developing olfactory bulb. Brain Res.1995.674(2):245-51.
[9]Pomeroy SL, LaMantia AS, Purves D. Postnatal construction of neural circuitry in the mouse olfactory bulb. J Neurosci.1990.10(6):1952-66.
[10]Lazarini F, Lledo PM. Is adult neurogenesis essential for olfaction. Trends Neurosci. 2011.34(1):20-30.
[11]Johnson BA, Leon M. Odorant molecular length:one aspect of the olfactory code. J Comp Neurol.2000.426(2):330-8.
[12]Johnson BA, Leon M. Modular representations of odorants in the glomerular layer of the rat olfactory bulb and the effects of stimulus concentration. J Comp Neurol. 2000.422(4):496-509.
[13]Uchida N, Takahashi YK, Tanifuji M, Mori K. Odor maps in the mammalian olfactory bulb:domain organization and odorant structural features. Nat Neurosci. 2000.3(10):1035-43.
[14]Belluscio L, Katz LC. Symmetry, stereotypy, and topography of odorant representations in mouse olfactory bulbs. J Neurosci.2001.21(6):2113-22.
[15]lgarashi KM, Mori K. Spatial representation of hydrocarbon odorants in the ventrolateral zones of the rat olfactory bulb. J Neurophysiol.2005.93(2):1007-19.
[16]Wachowiak M, Cohen LB. Representation of odorants by receptor neuron input to the mouse olfactory bulb. Neuron.2001.32(4):723-35.
[17]Friedrich RW, Korsching SI. Chemotopic, combinatorial, and noncombinatorial odorant representations in the olfactory bulb revealed using a voltage-sensitive axon tracer. J Neurosci.1998.18(23):9977-88.
[18]Adams JM, Cory S. Life-or-death decisions by the Bcl-2 protein family. Trends BiochemSci.2001.26(1):61-6.
[19]Borner C. The Bcl-2 protein family:sensors and checkpoints for life-or-death decisions. Mol Immunol.2003.39(11):615-47.
[20]Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem.1999.274(4):2225-33.
[21]Kuwana T, Mackey MR, Perkins G, et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell.2002.111(3): 331-42.
[22]Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2:release of cytochrome c from mitochondria blocked. Science.1997.275(5303):1129-32.
[23]Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ.2000.7(12):1182-91.
[24]Weaver IC, Grant RJ, Meaney MJ. Maternal behavior regulates long-term hippocampal expression of BAX and apoptosis in the offspring. J Neurochem.2002. 82(4):998-1002.
[1]Kaplan MS, Bell DH. Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus. J Neurosci.1984.4(6):1429-41.
[2]Stanfield BB, Trice JE. Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res.1988.72(2):399-406.
[3]Cameron HA, Woolley CS, McEwen BS, Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience.1993.56(2): 337-44.
[4]Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996.16(6):2027-33.
[5]Galea LAM, Tanapat P, Gould E (1996) Exposure to predator odor suppresses cell proliferation in the dentate gyrus of adult rats via a cholinergic mechanism. Soc Neurosci Abstr 22:1196.
[6]Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci.1997.17(7):2492-8.
[7]Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A.1998.95(6):3168-71.
[8]Heine VM, Maslam S, Zareno J, Joels M, Lucassen PJ. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Eur J Neurosci.2004.19(1):131-44.
[9]Dagyte G, Crescente I, Postema F, et al. Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress. Behav Brain Res.2011. 218(1):121-8.
[10]Gould E, Cameron HA. Regulation of neuronal birth, migration and death in the rat dentate gyrus. Dev Neurosci.1996.18(1-2):22-35.
[11]Qiu G, Helmeste DM, Samaranayake AN, et al. Modulation of the suppressive effect of corticosterone on adult rat hippocampal cell proliferation by paroxetine. Neurosci Bull.2007.23(3):131-6.
[12]Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci.2000.20(24): 9104-10.
[13]Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry.2004.56(8):570-80.
[14]Wang JW, David DJ, Monckton JE, Battaglia F, Hen R. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci.2008.28(6):1374-84.
[15]Boldrini M, Underwood MD, Hen R, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology.2009. 34(11):2376-89.
[16]Chen H, Pandey GN, Dwivedi Y. Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport.2006.17(9):863-7.
[17]Liu Q, Yu J, Mao-Ying QL, et al. Repeated clomipramine treatment reversed the inhibition of cell proliferation in adult hippocampus induced by chronic unpredictable stress. Pharmacogenomics J.2008.8(6):375-83.
[18]Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science.2003.301(5634):805-9.
[19]David DJ, Samuels BA, Rainer Q, et al. Neurogenesis-dependent and-independent effects of fluoxetine in an animal model of anxiety/depression. Neuron.2009.62(4): 479-93.
[20]Martinez-Turrillas R, Del RJ, Frechilla D. Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment. Neuropharmacology.2005.49(8):1178-88.
[21]Martinez-Turrillas R, Del RJ, Frechilla D. Neuronal proteins involved in synaptic targeting of AMPA receptors in rat hippocampus by antidepressant drugs. Biochem Biophys Res Commun.2007.353(3):750-5.
[22]Banasr M, Hery M, Printemps R, Daszuta A. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology.2004.29(3):450-60.
[23]Donati RJ, Rasenick MM. G protein signaling and the molecular basis of antidepressant action. Life Sci.2003.73(1):1-17.
[24]Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem.1989.53(5):1644-7.
[25]Perez J, Tinelli D, Brunello N, Racagni G. cAMP-dependent phosphorylation of soluble and crude microtubule fractions of rat cerebral cortex after prolonged desmethylimipramine treatment. Eur J Pharmacol.1989.172(3):305-16.
[26]Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants:a critical overview. Pharmacol Rev.2006.58(1): 115-34.
[27]Blendy JA. The role of CREB in depression and antidepressant treatment. Biol Psychiatry.2006.59(12):1144-50.
[28]Tiraboschi E, Tardito D, Kasahara J, et al. Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology.2004.29(10):1831-40.
[29]Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci.2002.22(8):3251-61.
[30]Sairanen M, Lucas G, Ernfors P, Castren M, Castren E. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci.2005. 25(5):1089-94.
[31]Doetsch F. A niche for adult neural stem cells. Curr Opin Genet Dev.2003.13(5): 543-50.
[32]Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol.2000.425(4):479-94.
[33]Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol.2000.425(4):479-94.
[34]Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A.2007.104(11): 4647-52.
[35]Atanasova B, Graux J, El HW, Hommet C, Camus V, Belzung C. Olfaction:a potential cognitive marker of psychiatric disorders. Neurosci Biobehav Rev.2008. 32(7):1315-25.
[36]Negoias S, Croy I, Gerber J, et al. Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience.2010.169(1): 415-21.
[37]Buschhuter D, Smitka M, Puschmann S, et al. Correlation between olfactory bulb volume and olfactory function. Neuroimage.2008.42(2):498-502.
[38]Haehner A, Rodewald A, Gerber JC, Hummel T. Correlation of olfactory function with changes in the volume of the human olfactory bulb. Arch Otolaryngol Head Neck Surg.2008.134(6):621-4.
[39]Mineur YS, Belzung C, Crusio WE. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience.2007.150(2): 251-9.