proBDNF在二种神经精神疾病中表达的研究
摘要
研究背景：
酒精中毒和抑郁症均是神经退行性疾病,其共同特征均是在特定脑区出现大量神经元凋亡,并伴随神经再生减少。并且,酒精中毒和抑郁症表现出很高的共病率。临床证据表明,抑郁症状常出现在慢性酒精中毒的戒断过程中,并且对戒断后复饮有很大的影响。虽然没有一种单一的神经生物学机制可以解释这2种对大脑均有巨大破坏性疾病的发生,但不断有证据提示该2种疾病均与神经再生减少有关。
脑源性神经营养因子(BDNF)能够影响中枢神经系统内神经元的发育和存活。许多研究提示酒精中毒和抑郁症均是成年期海马的神经再生发生了改变引起的。由此,我们提出这样一个设想：神经元再生的改变是否就是这2种神经精神疾病——酒精中毒和抑郁症共同的神经生物学机制。因此,本实验的主要内容包括：BDNF和proBDNF及其受体分别在抑郁症和酒精中毒中表达的变化,并探讨在酒精戒断过程中出现抑郁症状时这些因子的变化及2种疾病的相互作用。
方法：
1. proBDNF及其受体在人类抑郁症及酒精中毒中表达的研究：
抽取2010年至2011年在云南省精神病医院住院的满足ICD-10对抑郁症(40例)及慢性酒中毒(30例)诊断标准的病人血样以及与其相匹配的正常人血样男女各50例。从中分离血清,并提取RNA和蛋白质,通过western blotting、 RT-qPCR和ELISA等技术,观察proBDNF、 BDNF、 p75NTR、 sotilin及TrkB这5个因子与这2种疾病的关系。同时,在酒精中毒实验中,我们在酒精戒断后采用PANSS量表对酒精中毒患者的阳性和阴性症状做出评价,利用其中的抑郁因子得分比较酒精戒断后的抑郁症状,探讨当酒精戒断伴随抑郁症状出现时proBDNF及其受体的变化。
2. proBDNF及其受体在慢性酒中毒小鼠中表达的研究：
以50例小鼠为研究对象,建立慢性酒中毒小鼠模型,分为正常对照组、慢性酒中毒组、酒精戒断1天组(简称戒断1天组),酒精戒断3天组(简称戒断3天组)和慢性酒中毒侧脑室注射anti-proBDNF组(简称侧脑室注射anti-proBDNF组)。观察BDNF. proBDNF因子及其受体和慢性酒中毒的关系。并且观察连续酒精戒断3天内小鼠的抑郁行为,探讨当酒精戒断过程中出现抑郁症状时proBDNF及其受体的变化。
结果：
1.重症抑郁患者及慢性酒精中毒患者与正常对照组比较,proBDNF, sortilin和p75NTR的蛋白水平较高,而TrkB的蛋白质水平降低。proBDNF,p75NTR,sortilin和TrkB表达的血.清蛋白水平与淋巴细胞蛋白水平的趋势是一致的。
2.在重症抑郁患者中,BDNF,TrkB和p75NTR在mRNA水平的改变与其在蛋白水平的改变一致。重症抑郁症患者中,血清中mBDNF浓度明显低于正常对照组的水平(P<0.05)。且在重症抑郁症患者中,血清中proBNDF的表达水平与血清mBDNF的水平呈反比。
3. proBDNF、 p75NTR及sortilin在淋巴细胞蛋白及血清中的表达与重症抑郁程度(HRSD-21项评分)呈正相关：而mBDNF及TrkB与HRDS-21项的得分呈负相关。
4.在人类血液样本中,慢性酒中毒患者酒精戒断前无论是淋巴细胞蛋白还是血清中的proBDNF, sortilin和p75NTR的表达水平均高于正常对照组,而nBDNF和TrkB的水平较低。在进行了一周的戒断治疗后,proBDNF,sortilin和p75NTR的表达水平较戒断前明显降低了,而mBDNF和TrkB的水平则明显升高。通过ELISA检测时发现血清中mBDNF的水平在酒精戒断前较正常对照组低,而戒断一周后其水平就明显增加了。比较戒断前proBDNF和mBDNF的表达比例时发现,在慢性酒中毒患者中proBDNF/mBDNF的平衡被打破了。
5.人类血液样本中,mBDNF和TrkB的表达水平与慢性酒中毒患者平均每天酒精消耗量呈负相关,proBDNF,p75NTR和sortilin的表达水平与慢性酒中毒患者平均每天酒精消耗量呈正相关。
6.酒精戒断1周后,酒精中毒患者的抑郁症状较戒断前及正常对照组明显,但未达到统计学意义。
7.通过行为学检查发现,经过56天的慢性酒精溶液灌胃后实验组小鼠的体重、毛色、精神状态、水平动机活动、探究行为及认知功能都有明显改变,可以说明慢性酒精中毒小鼠造模成功。
8.戒断的行为学实验发现,随着戒断时间的延长,戒断组小鼠水平动机活动、探究行为及认知功能都逐渐恢复,有的已经接近或超过正常对照组。但戒断1天时,强迫游泳实验中戒断组小鼠的绝对不动时间最长,与慢性酒中毒组和正常对照组均有统计学差异。随着戒断时间的延长,戒断组小鼠的绝对不动时间有所减少,但仍比正常对照组小鼠长。
9.侧脑室注射anti-proBDNF实验中,侧脑室注射anti-proBDNF组小鼠的认知功能较慢性酒中毒组明显改善,但仍未达到正常水平。10.慢性酒中毒组小鼠中proBDNF、 sortilin和p75NTR的脑蛋白水平高于戒断组及正常对照组,而mBDNF和TrkB水平较低。且随着戒断时间的延长,戒断组小鼠proBDNF、 sortilin、 p75NTR和TrkB水平都逐渐恢复,有的已经接近或超过正常对照组。侧脑室注射anti-proBDNF实验中,侧脑室注射anti-proBDNF组小鼠脑蛋白proBDNF、 sortilin、 p75NTR和TrkB的表达水平都有所恢复,但仍未达到正常水平。
11.实时荧光定量PCR的结果发现,鼠脑BDNF、 sortilin、 p75NTR和TrkB的mRNA表达水平与其蛋白表达水平一致。即戒断后小鼠BDNF和TrkB的mRNA表达较慢性酒中毒组有所升高,但未恢复到正常水平；sortilin和p75NTR的mRNA表达较慢性酒中毒组有所降低,但未恢复到正常水平。
结论：
1.我们的初步研究结果显示,在重症抑郁患者和慢性酒精中毒患者中proBDNF及其受体p75NTR和sortilin的表达上调,而TrkB和BDNF的水平下调了。也就是,在proBDNF/p75NTR/sortilin和mBDNF/TrkB信号途径之间的平衡被破坏了。尽管我们的研究存在许多局限性,但其研究结果表明,在重症抑郁和慢性酒中毒中proBDNF/p75NTR/sortilin信号途径发挥着潜在的作用。也表明,抑郁症和酒精中毒的发病存在共同的分子机制,这可能也是2种疾病共病的分子基础。但这仅仅只是一个研究的开始,关于BDNF在抑郁症和慢性酒中毒中的作用还需要进一步的深入研究,以便更多地认识抑郁症和酒中毒这2种神经精神疾病,为其治疗提供新的方向及靶点。2.无论在人类慢性酒中毒样本还是小鼠慢性酒精中毒模型中我们均发现proBDNF/p75NTR/soritlin信号通路的表达增强了,由此引发了慢性酒中毒小鼠的海马及前额叶皮层等脑区的功能障碍。而通过对他们进行干预(戒断或侧脑室注射anti-proBDNF)后,减弱了proBDNF/p75NTR/soritlin信号通路对神经元发生的抑制作用,且mBDNF和TrkB的表达水平却能够明显回升,促进了大脑中神经元的再生,也改善慢性酒中毒引起的认知功能及行为能力障碍。
3.无论在人类慢性酒中毒样本还是小鼠慢性酒精中毒模型中,在酒精戒断后均出现了抑郁样症状或行为。这可能是由于在慢性酒精中毒的发展过程中,proBDNF/mBDNF的平衡失调,超过了机体的可调节范围,使得脑内神经发生被明显抑制。但随着酒精戒断的时间逐渐延长,机体的代偿功能逐渐恢复,神经元再生也开始增多,抑郁症状才逐步减轻。
Background:
Alcoholism and depression are all neurodegenerative diseases, which have common features of a large number neuronal apoptosis in specific brain regions, accompanied by reduced nerve regeneration. Also, alcoholism and depression showed a high rate of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in neurogenesis.
Brain-derived neurotrophic factor (BDNF) can affect the neuronal development and survival in the central nervous system. Many studies have suggested alcoholism and depression are caused by changes of adult hippocampal neurogenesis. Thus, we propose such an idea:changes of neurogenesis are the common neurobiological mechanisms of these two neuropsychiatric disorders-alcoholism and depression. Therefore, this study mainly covers: the expressions of BDNF and proBDNF and their receptors in depression and alcoholism, and to explore the depression symptoms occurred during the process of the alcohol withdrawal; the last are the interactions of the2diseases.
Methods:
1. The association studies of proBDNF and its receptors in human depression and alcoholism:
40female depression patients and30male alcoholism patients were recruited from Yunnan Mental Hospital, which were all met the1CD-10diagnosis criteria of depression and alcoholism in the year from2010to2011. The control groups were the matched men and women50cases respectly. The serum, RNA and protein were extracted from the blood samples, and the proBDNF, BDNF, p75NTR, sotilin and TrkB factors were assayed by western blotting, RT-qPCR and ELISA techniques and the relationships between the factors and the two kinds of diseases were observation. Meanwhile the PANSS were used to evaluate the depression scores in the alcoholism patients before and after alcohol withdrawal and discuss the expression changes of proBDNF and its receptor.
2. The researches of the expressions of proBDNF and its receptors in the chronic alcoholism mice model:
50mice were used to establish a chronic alcoholism mouse model. And all the mice were divided into normal control group, group of chronic alcoholism, alcohol withdrawal one day group, alcohol withdrawal3days group and anti-proBDNF group. The chronic alcoholism mouse model was used to observe the changes of expressions of BDNF, proBDNF and their receptors. Then the FST test was used to explore the depression behaviors after alcohol withdrawal.
Results:
1. ProBDNF, sortilin and p75NTR protein levels were higher in major depression and chronic alcoholism patients than in control groups and TrkB protein level was decreased. The expression trends of proBDNF, p75NTR, sortilin and TrkB levels in the serum were consistent with the changes of lymophocytes protein levels.
2. In major depressive patients, the expression levels of BDNF, TrkB and p75NTR at the mRNA level changed consistently with their trends in protein levels. The serum concentrations in the major depressive patients were significantly higher than in the control group's (P<0.05). In the major depressive patients, the proBDNF levels in the serum had negative relationship with the mBDNF levels in the serum.
3. In the major depressive patients, the expressions of proBDNF, p75NTR and sortilin in lymphocytes and serum had positive correlations with the extent of depression (HRSD-21score); while the serum levels of mBDNF and TrkB were negatively correlated with HRDS-21item scores
4. In the human blood samples, before alcohol withdrawal, either in lymophocytes or in serum, the expression levels of proBDNF, sortilin and p75NTR were higher in chronic alcoholism group than in the control group, while mBDNF and TrkB levels were lower in patients'group. After a week of abstinence, proBDNF, sortilin and p75NTR expression levels were significantly reduced in chronic alcoholism group when compared with control group and mBDNF and TrkB levels were significantly increased. Through ELISA test, serum mBDNF level was found reduced before the alcohol withdrawal when compared with normal control group, but a week after the withdrawal it significantly increased. proBDNF/mBDNF balance was broken in patients with chronic alcoholism.
5. In the human blood samples, mBDNF and TrkB expression levels in patients with chronic alcoholism were negatively correlated with average daily alcohol consumption; proBDNF, p75NTR and sortilin expression levels in chronic alcoholism patients were positively correlated with average daily alcohol consumption.
6. In the human samples, the depression symptoms during alcohol withdrawal were more abvious after one week's alcohol withdrawal than before abstinence and control group, but the significance did not reach statistical significance.
7. Through behavioral tests, we found that after56days of chronic alcohol solution intragastric administration, the mice body weight, hair color, mental status, level of motivation activity, exploratory behavior, and cognitive function all significantly changed, it suggested that chronic alcoholism mice model was successfully established.
8. Withdrawal behavioral experiments of mice, we found that with the withdrawal time, the level of motivation activities, explore behaviour and cognitive functions were gradually restored after alcohol abstinence, and some results had been close to or more than the normal control group. But after one day's abstinence, the absolute immobility time was the longest among three days FST in the chronic alcohohlism group. With the withdrawal time, the absolute immobility time decreased in chronic alcoholism group, but still longer than normal control mice.
9. In the intracerebroventricular injection of anti-proBDNF experiment, after icv anti-proBDNF, cognitive function in the chronic alcoholism group was significantly improved, but had not yet reached the normal levels.
10. The proBDNF, sortilin and p75NTR protein levels in mice brain were the highest in the chronic alcoholism group than in the withdrawal group and the normal control group, while mBDNF and TrkB level were the lowest. And with the withdrawal time, the proBDNF, sortilin, p75NTR and TrkB levels were gradually restored, and some had been close to or more than the normal control group. After intracerebroventricular injection of anti-proBDNF, proBDNF, sortilin, p75NTR and TrkB expression levels were all recovered, but had not yet reached normal levels.
11. The real-time quantitative PCR results showed that BDNF, sortilin, p75NTR and TrkB mRNA levels in mice brain were consistent with their protein expression levels. That was after the withdrawal, BDNF and TrkB mRNA levels were increased, but did not return to the normal levels; sortilin and p75NTR mRNA levels were decreased, but did not return to normal levels.
Conlusions:
1. Our preliminary findings showed that in major depressive patients and chronic alcoholism patients, proBDNF and its receptors p75NTR and sortilin were upregulated, and TrkB and BDNF levels lowered. That was that the balance between proBDNF/p75NTR/sortilin and mBDNF/TrkB signaling pathways was destroyed. Although there are many limitations of our study, but the results suggested that in major depressive patients and chronic alcoholism patients, the proBDNF/p75NTR/sortilin signaling pathway played a potential role in the neuropsychiatries disorders. It also suggested that there was common molecular mechanism in the pathology of depression and alcoholism, which might also be the two molecular basis of the comorbidity of these two diseases. But this was just a start of the study, the role of BDNF in depression and chronic alcoholism still require further in-depth study in order to know more about the two diseases and provide a new treatment direction.
2. Whether chronic alcohol intoxication in humans or mice model, we had found that proBDNF/p75NTR/soritlin signaling pathway expression increased, which led to dysfunctios of hippocampus and prefrontal cortex and other brain regions in chronic alcoholism mice. Through the intervention (withdrawal or intracerebroventricular injection of anti-proBDNF), the weakened proBDNF/p75NTR/soritlin signaling pathway had less inhibition of neurogenesis and mBDNF and TrkB expression level was able to rebound significantly so that to promoted regeneration of neurons in the brain, but also to improve cognitive and behavioral skills caused by chronic alcohol poisoning.
3. Whether in human chronic alcoholism blood samples or chronic alcoholism mice model, the depression symptoms occurred during alcohol abstinence. The reason might be the balance of proBDNF/mBDNF was broken during chronic alcohol intoxication, which beyond the ability of the body and led to the inhibition of neurogenesis in the brain. However, with the abstinence time, the compensation functions of the body recovered and the neuroregeneration began, so the depression symptoms alleviated.
酒精中毒和抑郁症均是神经退行性疾病,其共同特征均是在特定脑区出现大量神经元凋亡,并伴随神经再生减少。并且,酒精中毒和抑郁症表现出很高的共病率。临床证据表明,抑郁症状常出现在慢性酒精中毒的戒断过程中,并且对戒断后复饮有很大的影响。虽然没有一种单一的神经生物学机制可以解释这2种对大脑均有巨大破坏性疾病的发生,但不断有证据提示该2种疾病均与神经再生减少有关。
脑源性神经营养因子(BDNF)能够影响中枢神经系统内神经元的发育和存活。许多研究提示酒精中毒和抑郁症均是成年期海马的神经再生发生了改变引起的。由此,我们提出这样一个设想：神经元再生的改变是否就是这2种神经精神疾病——酒精中毒和抑郁症共同的神经生物学机制。因此,本实验的主要内容包括：BDNF和proBDNF及其受体分别在抑郁症和酒精中毒中表达的变化,并探讨在酒精戒断过程中出现抑郁症状时这些因子的变化及2种疾病的相互作用。
方法：
1. proBDNF及其受体在人类抑郁症及酒精中毒中表达的研究：
抽取2010年至2011年在云南省精神病医院住院的满足ICD-10对抑郁症(40例)及慢性酒中毒(30例)诊断标准的病人血样以及与其相匹配的正常人血样男女各50例。从中分离血清,并提取RNA和蛋白质,通过western blotting、 RT-qPCR和ELISA等技术,观察proBDNF、 BDNF、 p75NTR、 sotilin及TrkB这5个因子与这2种疾病的关系。同时,在酒精中毒实验中,我们在酒精戒断后采用PANSS量表对酒精中毒患者的阳性和阴性症状做出评价,利用其中的抑郁因子得分比较酒精戒断后的抑郁症状,探讨当酒精戒断伴随抑郁症状出现时proBDNF及其受体的变化。
2. proBDNF及其受体在慢性酒中毒小鼠中表达的研究：
以50例小鼠为研究对象,建立慢性酒中毒小鼠模型,分为正常对照组、慢性酒中毒组、酒精戒断1天组(简称戒断1天组),酒精戒断3天组(简称戒断3天组)和慢性酒中毒侧脑室注射anti-proBDNF组(简称侧脑室注射anti-proBDNF组)。观察BDNF. proBDNF因子及其受体和慢性酒中毒的关系。并且观察连续酒精戒断3天内小鼠的抑郁行为,探讨当酒精戒断过程中出现抑郁症状时proBDNF及其受体的变化。
结果：
1.重症抑郁患者及慢性酒精中毒患者与正常对照组比较,proBDNF, sortilin和p75NTR的蛋白水平较高,而TrkB的蛋白质水平降低。proBDNF,p75NTR,sortilin和TrkB表达的血.清蛋白水平与淋巴细胞蛋白水平的趋势是一致的。
2.在重症抑郁患者中,BDNF,TrkB和p75NTR在mRNA水平的改变与其在蛋白水平的改变一致。重症抑郁症患者中,血清中mBDNF浓度明显低于正常对照组的水平(P<0.05)。且在重症抑郁症患者中,血清中proBNDF的表达水平与血清mBDNF的水平呈反比。
3. proBDNF、 p75NTR及sortilin在淋巴细胞蛋白及血清中的表达与重症抑郁程度(HRSD-21项评分)呈正相关：而mBDNF及TrkB与HRDS-21项的得分呈负相关。
4.在人类血液样本中,慢性酒中毒患者酒精戒断前无论是淋巴细胞蛋白还是血清中的proBDNF, sortilin和p75NTR的表达水平均高于正常对照组,而nBDNF和TrkB的水平较低。在进行了一周的戒断治疗后,proBDNF,sortilin和p75NTR的表达水平较戒断前明显降低了,而mBDNF和TrkB的水平则明显升高。通过ELISA检测时发现血清中mBDNF的水平在酒精戒断前较正常对照组低,而戒断一周后其水平就明显增加了。比较戒断前proBDNF和mBDNF的表达比例时发现,在慢性酒中毒患者中proBDNF/mBDNF的平衡被打破了。
5.人类血液样本中,mBDNF和TrkB的表达水平与慢性酒中毒患者平均每天酒精消耗量呈负相关,proBDNF,p75NTR和sortilin的表达水平与慢性酒中毒患者平均每天酒精消耗量呈正相关。
6.酒精戒断1周后,酒精中毒患者的抑郁症状较戒断前及正常对照组明显,但未达到统计学意义。
7.通过行为学检查发现,经过56天的慢性酒精溶液灌胃后实验组小鼠的体重、毛色、精神状态、水平动机活动、探究行为及认知功能都有明显改变,可以说明慢性酒精中毒小鼠造模成功。
8.戒断的行为学实验发现,随着戒断时间的延长,戒断组小鼠水平动机活动、探究行为及认知功能都逐渐恢复,有的已经接近或超过正常对照组。但戒断1天时,强迫游泳实验中戒断组小鼠的绝对不动时间最长,与慢性酒中毒组和正常对照组均有统计学差异。随着戒断时间的延长,戒断组小鼠的绝对不动时间有所减少,但仍比正常对照组小鼠长。
9.侧脑室注射anti-proBDNF实验中,侧脑室注射anti-proBDNF组小鼠的认知功能较慢性酒中毒组明显改善,但仍未达到正常水平。10.慢性酒中毒组小鼠中proBDNF、 sortilin和p75NTR的脑蛋白水平高于戒断组及正常对照组,而mBDNF和TrkB水平较低。且随着戒断时间的延长,戒断组小鼠proBDNF、 sortilin、 p75NTR和TrkB水平都逐渐恢复,有的已经接近或超过正常对照组。侧脑室注射anti-proBDNF实验中,侧脑室注射anti-proBDNF组小鼠脑蛋白proBDNF、 sortilin、 p75NTR和TrkB的表达水平都有所恢复,但仍未达到正常水平。
11.实时荧光定量PCR的结果发现,鼠脑BDNF、 sortilin、 p75NTR和TrkB的mRNA表达水平与其蛋白表达水平一致。即戒断后小鼠BDNF和TrkB的mRNA表达较慢性酒中毒组有所升高,但未恢复到正常水平；sortilin和p75NTR的mRNA表达较慢性酒中毒组有所降低,但未恢复到正常水平。
结论：
1.我们的初步研究结果显示,在重症抑郁患者和慢性酒精中毒患者中proBDNF及其受体p75NTR和sortilin的表达上调,而TrkB和BDNF的水平下调了。也就是,在proBDNF/p75NTR/sortilin和mBDNF/TrkB信号途径之间的平衡被破坏了。尽管我们的研究存在许多局限性,但其研究结果表明,在重症抑郁和慢性酒中毒中proBDNF/p75NTR/sortilin信号途径发挥着潜在的作用。也表明,抑郁症和酒精中毒的发病存在共同的分子机制,这可能也是2种疾病共病的分子基础。但这仅仅只是一个研究的开始,关于BDNF在抑郁症和慢性酒中毒中的作用还需要进一步的深入研究,以便更多地认识抑郁症和酒中毒这2种神经精神疾病,为其治疗提供新的方向及靶点。2.无论在人类慢性酒中毒样本还是小鼠慢性酒精中毒模型中我们均发现proBDNF/p75NTR/soritlin信号通路的表达增强了,由此引发了慢性酒中毒小鼠的海马及前额叶皮层等脑区的功能障碍。而通过对他们进行干预(戒断或侧脑室注射anti-proBDNF)后,减弱了proBDNF/p75NTR/soritlin信号通路对神经元发生的抑制作用,且mBDNF和TrkB的表达水平却能够明显回升,促进了大脑中神经元的再生,也改善慢性酒中毒引起的认知功能及行为能力障碍。
3.无论在人类慢性酒中毒样本还是小鼠慢性酒精中毒模型中,在酒精戒断后均出现了抑郁样症状或行为。这可能是由于在慢性酒精中毒的发展过程中,proBDNF/mBDNF的平衡失调,超过了机体的可调节范围,使得脑内神经发生被明显抑制。但随着酒精戒断的时间逐渐延长,机体的代偿功能逐渐恢复,神经元再生也开始增多,抑郁症状才逐步减轻。
Background:
Alcoholism and depression are all neurodegenerative diseases, which have common features of a large number neuronal apoptosis in specific brain regions, accompanied by reduced nerve regeneration. Also, alcoholism and depression showed a high rate of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in neurogenesis.
Brain-derived neurotrophic factor (BDNF) can affect the neuronal development and survival in the central nervous system. Many studies have suggested alcoholism and depression are caused by changes of adult hippocampal neurogenesis. Thus, we propose such an idea:changes of neurogenesis are the common neurobiological mechanisms of these two neuropsychiatric disorders-alcoholism and depression. Therefore, this study mainly covers: the expressions of BDNF and proBDNF and their receptors in depression and alcoholism, and to explore the depression symptoms occurred during the process of the alcohol withdrawal; the last are the interactions of the2diseases.
Methods:
1. The association studies of proBDNF and its receptors in human depression and alcoholism:
40female depression patients and30male alcoholism patients were recruited from Yunnan Mental Hospital, which were all met the1CD-10diagnosis criteria of depression and alcoholism in the year from2010to2011. The control groups were the matched men and women50cases respectly. The serum, RNA and protein were extracted from the blood samples, and the proBDNF, BDNF, p75NTR, sotilin and TrkB factors were assayed by western blotting, RT-qPCR and ELISA techniques and the relationships between the factors and the two kinds of diseases were observation. Meanwhile the PANSS were used to evaluate the depression scores in the alcoholism patients before and after alcohol withdrawal and discuss the expression changes of proBDNF and its receptor.
2. The researches of the expressions of proBDNF and its receptors in the chronic alcoholism mice model:
50mice were used to establish a chronic alcoholism mouse model. And all the mice were divided into normal control group, group of chronic alcoholism, alcohol withdrawal one day group, alcohol withdrawal3days group and anti-proBDNF group. The chronic alcoholism mouse model was used to observe the changes of expressions of BDNF, proBDNF and their receptors. Then the FST test was used to explore the depression behaviors after alcohol withdrawal.
Results:
1. ProBDNF, sortilin and p75NTR protein levels were higher in major depression and chronic alcoholism patients than in control groups and TrkB protein level was decreased. The expression trends of proBDNF, p75NTR, sortilin and TrkB levels in the serum were consistent with the changes of lymophocytes protein levels.
2. In major depressive patients, the expression levels of BDNF, TrkB and p75NTR at the mRNA level changed consistently with their trends in protein levels. The serum concentrations in the major depressive patients were significantly higher than in the control group's (P<0.05). In the major depressive patients, the proBDNF levels in the serum had negative relationship with the mBDNF levels in the serum.
3. In the major depressive patients, the expressions of proBDNF, p75NTR and sortilin in lymphocytes and serum had positive correlations with the extent of depression (HRSD-21score); while the serum levels of mBDNF and TrkB were negatively correlated with HRDS-21item scores
4. In the human blood samples, before alcohol withdrawal, either in lymophocytes or in serum, the expression levels of proBDNF, sortilin and p75NTR were higher in chronic alcoholism group than in the control group, while mBDNF and TrkB levels were lower in patients'group. After a week of abstinence, proBDNF, sortilin and p75NTR expression levels were significantly reduced in chronic alcoholism group when compared with control group and mBDNF and TrkB levels were significantly increased. Through ELISA test, serum mBDNF level was found reduced before the alcohol withdrawal when compared with normal control group, but a week after the withdrawal it significantly increased. proBDNF/mBDNF balance was broken in patients with chronic alcoholism.
5. In the human blood samples, mBDNF and TrkB expression levels in patients with chronic alcoholism were negatively correlated with average daily alcohol consumption; proBDNF, p75NTR and sortilin expression levels in chronic alcoholism patients were positively correlated with average daily alcohol consumption.
6. In the human samples, the depression symptoms during alcohol withdrawal were more abvious after one week's alcohol withdrawal than before abstinence and control group, but the significance did not reach statistical significance.
7. Through behavioral tests, we found that after56days of chronic alcohol solution intragastric administration, the mice body weight, hair color, mental status, level of motivation activity, exploratory behavior, and cognitive function all significantly changed, it suggested that chronic alcoholism mice model was successfully established.
8. Withdrawal behavioral experiments of mice, we found that with the withdrawal time, the level of motivation activities, explore behaviour and cognitive functions were gradually restored after alcohol abstinence, and some results had been close to or more than the normal control group. But after one day's abstinence, the absolute immobility time was the longest among three days FST in the chronic alcohohlism group. With the withdrawal time, the absolute immobility time decreased in chronic alcoholism group, but still longer than normal control mice.
9. In the intracerebroventricular injection of anti-proBDNF experiment, after icv anti-proBDNF, cognitive function in the chronic alcoholism group was significantly improved, but had not yet reached the normal levels.
10. The proBDNF, sortilin and p75NTR protein levels in mice brain were the highest in the chronic alcoholism group than in the withdrawal group and the normal control group, while mBDNF and TrkB level were the lowest. And with the withdrawal time, the proBDNF, sortilin, p75NTR and TrkB levels were gradually restored, and some had been close to or more than the normal control group. After intracerebroventricular injection of anti-proBDNF, proBDNF, sortilin, p75NTR and TrkB expression levels were all recovered, but had not yet reached normal levels.
11. The real-time quantitative PCR results showed that BDNF, sortilin, p75NTR and TrkB mRNA levels in mice brain were consistent with their protein expression levels. That was after the withdrawal, BDNF and TrkB mRNA levels were increased, but did not return to the normal levels; sortilin and p75NTR mRNA levels were decreased, but did not return to normal levels.
Conlusions:
1. Our preliminary findings showed that in major depressive patients and chronic alcoholism patients, proBDNF and its receptors p75NTR and sortilin were upregulated, and TrkB and BDNF levels lowered. That was that the balance between proBDNF/p75NTR/sortilin and mBDNF/TrkB signaling pathways was destroyed. Although there are many limitations of our study, but the results suggested that in major depressive patients and chronic alcoholism patients, the proBDNF/p75NTR/sortilin signaling pathway played a potential role in the neuropsychiatries disorders. It also suggested that there was common molecular mechanism in the pathology of depression and alcoholism, which might also be the two molecular basis of the comorbidity of these two diseases. But this was just a start of the study, the role of BDNF in depression and chronic alcoholism still require further in-depth study in order to know more about the two diseases and provide a new treatment direction.
2. Whether chronic alcohol intoxication in humans or mice model, we had found that proBDNF/p75NTR/soritlin signaling pathway expression increased, which led to dysfunctios of hippocampus and prefrontal cortex and other brain regions in chronic alcoholism mice. Through the intervention (withdrawal or intracerebroventricular injection of anti-proBDNF), the weakened proBDNF/p75NTR/soritlin signaling pathway had less inhibition of neurogenesis and mBDNF and TrkB expression level was able to rebound significantly so that to promoted regeneration of neurons in the brain, but also to improve cognitive and behavioral skills caused by chronic alcohol poisoning.
3. Whether in human chronic alcoholism blood samples or chronic alcoholism mice model, the depression symptoms occurred during alcohol abstinence. The reason might be the balance of proBDNF/mBDNF was broken during chronic alcohol intoxication, which beyond the ability of the body and led to the inhibition of neurogenesis in the brain. However, with the abstinence time, the compensation functions of the body recovered and the neuroregeneration began, so the depression symptoms alleviated.
引文
[1]Miller H.L., Delgado P.L., Salomon R.M., et al. Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry,1996,53:117-128.
[2]Schuckit M.A, Tipp J.E., Bergman M., et al. Comparison of induced and independent major depressive disorders in 2,945 alcoholics. Am J Psychiatry,1997,154:948-957.
[3]Pettinati H.M. Antidepressant treatment of co-occurring depression and alcohol dependence. Biol Psychiatry,2004,56:785-792.
[4]Grant B.F. Comorbidity between DSM-IV drug use disorders and major depression:results of a national survey of adults. J Subst Abuse,1995,7:481-497.
[5]Kessler R.C., Crum R.M., Warner L.A., et al. Lifetime co-occurrence of DSM-Ⅲ-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry, 1997,54:313-321.
[6]Lynskey M.T. The comorbidity of alcohol dependence and affective disorders:treatment implications. Drug Alcohol Depend,1998,52:201-209.
[7]Garbutt J.C., West S.L., Carey T.S., et al. Pharmacological treatment of alcohol dependence:a review of the evidence. JAMA,1999,281:1318-1325.
[8]Greenfield S.F., Weiss R.D., Muenz L.R., et al. The effect of depression on return to drinking:a prospective study. Arch Gen Psychiatry,1998,55:259-265.
[9]Mueller T.I., Lavori P.W., Keller M.B., et al. Prognostic effect of the variable course of alcoholism on the 10-year course of depression. Am J Psychiatry,1994,151:701-706.
[10]Crews F.T., Nixon K.., Wilkie M.E. Exercise reverses ethanol inhibition of neural stem cell proliferation. Alcohol,2004,33:63-71.
[11]Duman R.S., Malberg J., Nakagawa S., et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry,2000,48:732-739.
[12]Malberg J.E., Eisch A.J., Nestler E.J., et al. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci,2000,20:9104-9110.
[13]Santarelli L., Saxe M., Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science,2003,301:805-809.
[14]Warner-Schmidt J.L., Duman R.S. Hippocampal neurogenesis:opposing effects of stress and antidepressant treatment. Hippocampus,2006,16:239-249.
[15]Gregus A., Wintink A.J., Davis A.C., et al. Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav Brain Res,2005,156:105-114.
[16]Malberg J.E., Duman R.S. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology,2003,28:1562-1571.
[17]Tanapat P., Hastings N.B., Rydel T.A., et al. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J Comp Neurol,2001, 437:496-504.
[18]He J., Nixon K., Shetty A.K., et al. Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons. Eur J Neurosci,2005,21:2711-2720.
[19]Nixon K., Crews F.T.. Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J Neurochem,2002,83:1087-1093.
[20]Sheline Y.I., Sanghavi M, Mintun M.A., et al. Depression durationbut not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci,1999, 19:5034-5043.
[21]Sheline Y.I., Wang P.W., Gado M.H., et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA,1996,93:3908-3913.
[22]Mowla S. J., Pareek S., Farhadi H.F., et al. Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J. Neurosci,1999,19(6):2069-2080.
[23]Lee R., Kermani P., Teng K.K., et al. Regulation of cell survival by secreted proneurotrophins. Science,2001,294:1945-1948.
[24]Matsumoto, T., Rauskolb, S., Polack, M., et al.. Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not proBDNF. Nat. Neurosci.2008,11(2):131-133.
[25]Nagappan G., Zaitsev E., Vladimir V., et al.. Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc. Natl. Acad. Sci. U. S. A.,2009,106(4):1267-1272.
[26]Yang F., Je H.S., Ji Y., et al.. ProBDNF-induced synaptic depression and retraction at developing neuromuscular synapses. J. Cell Biol,2009,182(4):727-741.
[27]Pang P.T., H.K. Teng, E. Zaitsev, et al.. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science,2004,306:487-491.
[28]Lu B., Pang P.T., Woo N.H. The yin and yang of neurotrophin action. Nat Rev Neurosci,2005, 6:603-614.
[29]Lazic S.E., Grote H.E., Armstrong R.J.,et al. Decreased hippocampal cell proliferation in R6/1 Huntington's mice. Neuroreport,2004,15:811-813.
[30]Barbara L. Hempstead. Dissecting the diversse actions of pro-and mature neurotrophins. Current Alzheimer Research,2006,3:19-24.
[31]Huang E.J., Reichardt L.F. Neurotrophins:roles in neuronal development and function. Annu Rev Neurosci,2001,24:677-736.
[32]Chao M.V., Rajagopal R., Lee F.S.. Neurotrophin signalling in health and disease. Clin Sci (Lond), 2006,110:167-173.
[33]Allen S.J., Dawbarn D.. Clinical relevance of the neurotrophins and their receptors. Clin Sci (Lond), 2006,110:175-191
[34]Levi-Montalcini R., Aloe L. and Alleva E.. A role for nerve growth factor in nervous, endocrine and immune systems. Prog Neurol Endocrinol Immunol,1990,3:1-10.
[35]Barde Y.A.. Neurotrophins:a family of proteins supporting the survival of neurons. Prog Clin Biol Res,1994,390:45-56.
[36]Schwartz M., Kipnis J.. Protective autoimmunity:regulation andprospects for vaccination after brain and spinal cord injuries. Trends Mol. Med,2001,7:252-258.
[37]Hauben E., Butovsky O., Nevo U., et al. Passive or active immunization withmyelin basic protein promotes recovery from spinal cord contusion.J. Neurosci,2000,20:6421-6430.
[38]Schwartz M., Moalem G., Leibowitz-Amit R., et al. Innate and adaptive immune responses can be beneficial for CNS repair. TINS,1999,22:295-299.
[39]Barouch R., Appel E., Kazimirsky G., et al. Macrophages express neurotrophins and neurotrophin receptors-regulation of nitric oxide production by NT-3. J. Neuroimmunol,2001,112:72-77.
[40]Hammarberg H., Lidman O., Lundberg C., et al. Neuroprotection by encephalomyelitis:rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J. Neurosci,2000,20:5283-5291.
[41]Kerschensteiner M., Gallmeier E., Behrens L., et al. Activated human T cells, B cells, and monocytes produce brain derived neurotrophic factor in vitro and in inflammatory brain lesions:a neuroprotective role of inflammation? J. Exp. Med,1999,189:865-870.
[42]Muhallab S., Lundberg C., Gielen A.W., et al. Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis. Scand. J. Immunol,2002, 55:264-273.
[43]Schulte-Herbruggen O., Nassenstein C.,Lommatzsch M., et al. Tumor necrosis factor-alpha and interleukin-6 regulate secretion of brain-derived neurotrophic factor in human monocytes. J. Neuroimmunol,2005,160:204-209.
[44]Stadelmann C, Kerschensteiner M., Misgeld T., et al. BDNF and gp145trkB in multiple sclerosis brain lesions:neuroprotective interactions between immune and neuronal cells? Brain,2002,125: 75-85.
[45]Shuang Y., Holsboer F., Osborne F.X. Neuronal actions of glucocorticoids:Focus on depression [J]. J Steroid Biochem Mol Biol,2008,108 (3/5):300-309.
[46]Mathers C, Loncar D.. Projections of global mortality and burden of disease from 2002 to 2030 [J]. PLoSMed,2006,3(11):e442.
[47]Kessler R.C., Berglund P., Demler O., et al. The epidemiology of major depressive disorder:results from the National Comorbidity Survey Replication (NCS-R). JAMA,2003,289:3095-3105.
[48]John M. The medical management of depression. N Engl J Med,2005,353:1819-1834.
[49]Yogesh D., Hooriyah S. R., Robert R. C, et al. Altered Gene Expression of Brain-Derived Neurotrophic Factor and Receptor Tyrosine Kinase B in Postmortem Brain of Suicide Subjects Arch Ge Psychiatry,2003,60:804-815.
[50]李云峰,罗质璞.抑郁症发病机制及治疗药物.神经药理学新论.北京：人民卫生出版社,2004,1-20.
[51]Kempermann G., Kuhn H.G., Gage F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature,1997,386:493-495.
[52]Nibuya M., Morinobu S., Duman R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci,1997,15:7539-7547
[53]Duman R.S. Pathophysiology of depression:the concept of synaptic plasticity. Eur Psychiatry,2002, 17 Suppl,3:306-310.
[54]Tapia-Aiancibia L., Rage F., Givalois L., et al. Physiology of BDNF:focus on hypothalamic function. Front Neuroendocrinol,2004,25:77-107.
[55]Castren E., Voikar V., Rantamaki T. Role of neurotrophic factors in depression. Curr Opin Pharmacol, 2007,7:18-21.
[56]Peng S., Wuu J., Mufson E. J., et al. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J. Neuropath. Exp.Neuron,2004,63:641-649.
[57]Harrington A.W., Leiner B., Blechschmitt C, et al. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc, Nat. Acad. Sci. USA,2004,101(16):6226-6230.
[58]Srinivasan B., Roque C. H., Hempstead B.L., et al. Microglia-derived pronerve growth factor promotes photoreceptor cell death via p75 neurotrophin receptor. J. Biol. Chem.,2004,279:41839-41845.
[59]Martinowich K., Manji H., Lu B.. New insights into BDNF function in depression and anxiety. Nature Neuroscience,2007,10:1089-1093.
[60]Fauchais, A.L., Lalloue, F., Lise,M.C, et al. Role of Endogenous Brain-Derived Neurotrophic Factor and Sortilin in B Cell Survival. J Immunol,2008,181(5):3027-3038.
[61]Karege F., Bondolfi G., Gervasoni N., et al. Low brain-derived neurotrophic factor(BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity[J]. Biol Psychiatry,2005, (57):1068-1072.
[62]李欣,李海红,方泽漫,等.白介素-1β对原代培养海马神经元毒性的研究.中华行为医学和脑科学杂志,2009,(12)：1061-1063.
[63]Lee B. H, Kim H., Park S. H., et al. Decreased plasma BDNF level in depressive patients [J].Journal of Affective Disorders,2007, (101):239-244.
[64]Molendijk M.L., Bus B.A., Spinhoven P., et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder:state-trait issues, clinical features and pharmacological treatment. Mol. Psychiat,2011,16:1088-1095.
[65]Xu Z.Q., Sun Y., Li H.Y., et al. Endogenous proBDNF is a negative regulator of migration of cerebellar granule cells in neonatal mice. Eur. J. Neurosci,2011,33(8):1376-1384.
[66]Sun Y., Lim Y., Li F., et al. ProBDNF Collapses Neurite Outgrowth of Primary Neurons by Activating RhoA. PLoS ONE,2012,7(4):e35883.
[67]Woo N.H., H.K. Teng, C.J. Siao, et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat. Neurosci,2005,8:1069-1077.
[68]Zagrebelsky M., Holz A., Dechant G., et al. The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J.Neurosci,2005,25(43):9989-9999.
[69]Bachis A., Avdoshina V., Zecca L., et al.. Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. J. Neurosci,2012,32(28):9477-9484.
[70]Le A.P., Friedman W. J. Matrix Metalloproteinase-7 Regulates Cleavage of Pro-Nerve Growth Factor and Is Neuroprotective following Kainic Acid-Induced Seizures. J. Neurosci,2012,32(2):703-712.
[71]Karege F., Perret G., Bondolfib G., et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiat. Res,2002,109(2):143-148.
[72]Shimizu E., Hashimoto K., Okamura N., et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiat, 2003,54(1):70-75.
[73]Poduslo J.F. C.G. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res,1996,36(2):280-286.
[74]Pan W. B.W., Fasold M.B., Bluth J., et al. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology,1998,37(12):1553-1561.
[75]Brunoni A. R., Lopes M., Fregni F.. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels:implications for the role of neuroplasticity in depression. Int. J. Neuropsychoph,2008,11(8):1169-1180.
[76]张玉梅,张志塘,沙维等.抑郁症患者治疗前后血清脑源性神经营养因子水平变化及相关因素分析.中华精神科杂志,2009,42(4)：210-214.
[77]Gonul A.S., Akdeniz F., Taneli F., et al. Effect of treatment on serum brain-derived neurotmphic factor levels in depressed patients. Eur. Arch. Psychiatry Clin. Neurosci,2005,255:381-386.
[78]Bus B.A., Molendijk M.L., Penninx B.J., et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrino,2011,36(2):228-239.
[79]Ozana E., Okurb H., Ekerc C., et al. The effect of depression, BDNF gene va166met polymorphism and gender on serum BDNF levels. Brain Res. Bull,2010,81(1):61-65.
[80]Bocchio-Chiavetto, L., Bagnardi, V., Zanardini, R., et al. Serum and plasma BDNF levels in major depression:a replication study and meta-analyses. World J, Biol. Psychia,2010,11(6):763-773.
[81]沈渔邮.精神病学.第三版.人民卫生出版社,1980,527.
[82]Abel E.L. Fetal alcohol syndrome:a cautionary note. Curr Pharm Des,2006,12:1521-1529.
[83]Mancinelli R., Ceccanti M., Laviola G. Fetal alcohol spectrum disorders (FASD):from experimental biology to the search for treatment. Neurosci Biobehav Rev,2007,31:165-167.
[84]Niccols A. Fetal alcohol syndrome and the developing socio-emotional brain. Brain Cogn,2007, 65:135-142.
[85]Kubota M, Nakazaki S, Hirai S., et al. Alcohol consumption and frontal lobe shrinkage:study of 1432 non-alcoholic subjects. J Neurol Neurosurg Psychiatry,2001,71:104-106.
[86]Sullivan E.V., Pfefferbaum A.. Neurocircuitry in alcoholism:a substrate of disruption and repair. Psychopharmacology,2005,180:583-594.
[87]Crews F. T., Collins M. A., Dlugos C, et al. Alcohol-Induced Neurodegeneration:When, Where and Why? ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH,2004, (28)2:350-364.
[88]Gabbard G. O. Treatments of Psychiatric Disorders.3rd Ed. v2. Washington:American Psychiatric Publishing,2001, Treatments of psychiatric disorders (3 ed.). Washington, DC:American Psychiatric Press. ISBN 978-0-88048-910-2.1447-1482; 1587-1622
[89]Gro Harlem Brundtland (19 February 2001). "WHO European Ministerial Conference on Young People and Alcohol". World Health Organization.
[90]刘兆玺,张敬悬,翁正.山东省慢性酒中毒流行病学十年对比研究.J.中国行为医学科学,1999,84：293-295.
[91]Malyutina S., Bobak M., Kurilovitch S., et al. Trends in alcohol intake by education and martial status in urburn population Russian between mid 1980s and the mid 1990s [J]. Alcohol Alcoholism,2004, 39(1):64-69.
[92]Gallup Poll, annual surverys taken between 1935 and July 12-15,2007, as found on http:// www.galluppoll.com/content
[93]Yamashita M., Yamamoto T.. Wernicke encephalopathy with symmetric pericentral involvement:MR findings [J]. J Compute Assist Tomogr,1995,19(2):306-308.
[94]Napper R.M., West J.R.. Permanent neuronal cell loss in the cerebellum or rats exposed to continuous low blood alcohol levels during the brain growth spurt:a stereological investigation. J Comp Neurol, 1995,362:283-292.
[95]Lewin G.R., Barde Y.A. Physiology of the neurotrophins. Annu. Rev. Neurosci,1996,19:289-317.
[96]Mitchell J.J., Paiva M., Moore D.B., et al. A comparative study of ethanol, hypoglycemia, hypoxia and neurotrophic factor interactions with fetal rat hippocampal neurons:a multi-factor in vitro model for developmental ethanol effects. Dev Brain Res,1998,105:241-250.
[97]Hall J., Thomas K. L. and Everitt B. J. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nature Neuroscience,2000,3:533-535.
[98]Hyman C, Hofer M., Barde Y. A. et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature,1991,350:230-232.
[99]Li Y. X., Zhang Y., Lester H. A., et al.. Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. The Journal of Neuroscience, 1998,18:10231-10240.
[100]Lyons W. E., Mamounas L. A., Ricaurte G. A. et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proceedings of the National Academy of Sciences of the United States of America,1999,96: 15239-15244.
[101]Guillin O., Diaz J., Carroll P., et al. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature,2001,411:86-89.
[102]Horger B.A., lyasere C.A., Berhow M.T., et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J Neurosi,1999, 19(10):4110-4122.
[103]McGough N.N., He D.Y., Logrip M.L., et al. RACK1 and brain-derived neurotrophic factor:a homeostatic pathway that regulates alcohol addiction. J Neurosci,2004,24:10542-10552.
[104]Uhl G. R., Liu Q. R., Walther D., et al. Polysubstance abuse-vulnerability genes:genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am. J. Hum. Genet, 2001,69:1290-1300.
[105]Matsushita S., Kimura M., Miyakawa T., et al. Association study of brain-derived neurotrophic factor gene polymorphism and alcoholism. Alcohol. Clin. Exp. Res,2004,28:1609-1612.
[106]Bolanos C. A. and Nestler E. J. Neurotrophic mechanisms in drug addiction. Neuromolecular Med,2004,5:69-83.
[107]Berhow M. T., Russell D. S., Terwilliger R. Z., et al. Influence of neurotrophic factors on morphine-and cocaine-induced biochemical changes in the mesolimbic dopamine system. Neuroscience,1995,68:969-979.
[108]Le F. B., Diaz J., and Sokoloff P. A single cocaine exposure increases BDNF and D3 receptor expression:implications for drug-conditioning. Neuroreport,2005,16:175-178.
[109]Liu Q. R., Lu L., Zhu X. G., et al. Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res,2006,1067:1-12.
[110]Meredith G. E., Callen S., and Scheuer D. A. Brain-derived neurotrophic factor expression is increased in the rat amygdala, piriform cortex and hypothalamus following repeated amphetamine administration. Brain Res,2002,949:218-227.
[111]Zhang D., Zhang L., Lou D. W., et al. The dopamine Dl receptor is a critical mediator for cocaine-induced gene expression. J. Neurochem,2002,82:1453-1464.
[112]Grimm, J. W., Lu, L., Hayashi, T., et al. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopa-mine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci,2003,23:742-747.
[113]Tapia-Arancibia L., Rage F., Givalois L., et al. Effects of alcohol on brain-derived neurotrophic factor mRNA expression in discrete regions of the rat hippocampus and hypothalamus. J. Neurosci. Res,2001,63:200-208.
[114]Hensler J. G., Ladenheim E. E., and Lyons W. E. Ethanol consumption and serotonin-lA (5-HT1A) receptor function in heterozygous BDNF (+/-) mice. J. Neurochem,2003,85:1139-1147.
[115]Pandey S. C, Roy A., Zhang H., et al. Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors. J. Neurosci,2004,24:5022-5030.
[116]Pandey S. C, Zhang H., Roy A., et al. Central and medial amygdaloid brain-derived neurotrophic factor signaling plays a critical role in alcohol-drinking and anxiety-like behaviors. J. Neurosci,2006,26:8320-8331.
[117]Hall F. S., Drgonova J., Goeb M., et al. Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuro psychopharmacology,2003, 28:1485-1490.
[118]Teng H.K., Teng K.K., Lee R., et al. ProBDNF induces neuronal apoptosis via activation of a receptor. J Neurosci,2005,25(22):5455-5463.
[119]Lu B. Pro-region of neurotrophins:role in synaptic modulation. Neuron,2003,39:735-738.
[120]Paul C.A., Au R., Fredman L., et al. Association of alcohol consumption with brain volume in the Framingham study. Arch Neurol,2008,65(10):1363-1367.
[121]Tsai G. and Coyle J. T.. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annual Review of Medicine,1998,49:173-184.
[122]Littleton J. M., Lovinger D., Liljequist S., et al. Role of polyamines and NMDA receptors in ethanol dependence and withdrawal. Alcoholism:Clinical and Experimental Research,2001,25(5 suppl):132S-136S.
[123]Nixon, K. and Crews, F. T.. Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence fromalcohol. The Journal of Neuroscience,2004,24: 9714-9722.
[124]MacLennan A.J., Lee N., and Walker D.W.. Chronic ethanol administration decreases brainderived neurotrophic factor gene expression in the rat hippocampus. Neurosci Lett,1995, 197(2):105-108.
[125]Radka S.F., Holst P.A., Fritsche M., et al. Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res, 1996,709(1):122-301.
[126]Mori T., Shimizu K., Hayashi M.. Levels in serum brain-derived neurotrophic factor in primates. Primates,2003,44:167-169.
[127]Heberlein A., Muschler M., Wilhelm J., et al. BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal. Prog Neuropsychopharmacol Biol Psychiatry,2010, 34(6):1060-1064.
[128]Huang M.C., Chen C.H., et al. Alterations of serum brain-derived neurotrophic factor levels in early alcohol withdrawal. Alcohol Alcohol,2008,43(3):241-245.
[129]Zhou L, Xiong J, Lim Y, et al. Upregulation of blood proBDNF and its receptors in major depression. Journal of Affective Disorders,2013,150:776-778.
[130]Jeanblanc J., He D., McGough N., et al. Evidence that BDNF regulation of ethanol consumption is mediated by the dopamine D 3 receptor in the dorsal striatum. Program,2005,797.
[131]Hasin D., Liu X., Nunes E., et al. Effects of major depression on remission and relapse of substance dependence. Arch Gen Psychiatry,2002,59:375-380.
[132]Stevenson J. R., Schroeder J. P, and Nixon K. Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice. Neuropsychopharmacology,2009,34(5):1209-1222.
[133]Ostacher M.J. Comorbid alcohol and substance abuse dependence in depression:impact on the outcome of antidepressant treatment. Psychiatr Clin North Am,2007,30:69-76.
[134]Le Fauve C.E., Litten R.Z., Randall C.L., et al. Pharmacological treatment of alcohol abuse/dependence with psychiatric comorbidity. Alcohol Clin Exp Res,2004,28:302-312.
[135]Haynes L. E., Barber D. and Mitchell I. J.. Chronic antidepressant medication attenuates dexamethasone-induced neuronal death and sublethal neuronal damage in the hippocampus and striatum.Brain Research,2004,1026:157-167.
[136]Hyman S. E., Malenka R. C, and Nestler E. J.. Neural mechanisms of addiction:the role of reward-related learning and memory. Annu Rev Neurosci,2006,29:565-598.
[137]Koob, G. F. Alcoholism:allostasis and beyond. Alcohol Clin Exp Res,2003,27:232-243.
[138]Fumagalli F., Di Pasquale L., Caffino L., et al. Repeated exposure to cocaine differently modulates BDNF mRNA and protein levels in rat striatum and prefrontal cortex. Eur. J. Neurosci, 2007,26:2756-2763.
[139]Logrip, M. L., Janak, P. H., and Ron, D. Escalating ethanol intake is associated with altered corticostriatal BDNF expression. J. Neurochem,2009,109:1459-1468.
[140]Yoon S. J., Roh S., Lee H. et al. Possible role of nerve growth factor in the pathogenesis of alcohol dependence. Alcohol Clin. Exp. Res,2006,30:1060-1065.
[141]Jeanblanc J., He D. Y., McGough N. N., et al. The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J. Neurosci,2006,26:1457-1464.
[142]Prakash A., Zhang H. and Pandey S. C. Innate differences in the expression of brain-derived neurotrophic factor in the regions within the extended amygdala between alcohol preferring and nonpreferring rats. Alcohol. Clin. Exp. Res,2008,32:909-920.
[143]Goodlett C.R., Horn K.H. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res Health,2001,25:175-184.
[144]Luo J., Miller M.W.. Growth factor-mediated neural proliferation:target of ethanol toxicity. Brain Res Brain Res Rev,1998,27:157-167.
[145]Harper C The neuropathology of alcohol-related brain damage. Alcohol Alcohol,2009, 44:136-140.
[146]Mowla S.J., Farhadi H.F., Pareek S., et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem,2001,276:12660-12666.
[147]Heaton M.B., Paiva M., Madorsky I., et al. Ethanol effects on neonatal rat cortex:comparative analyses of neurotrophic factors, apoptosis-related proteins, and oxidative processes during vulnerable and resistant periods. Brain Res Dev,2003,145:249-262.
[148]Miller M.W., Mooney S.M. Chronic exposure to ethanol alters neurotrophin content in the basal forebrain-cortex system in the mature rat:effects on autocrine-paracrine mechanisms. J Neurobiol, 2004.60:490-498.
[149]Malinowska B., Napiorkowska-Pawlak D., Pawlak R., et al. Ifenprodil influences changes in mouse behaviour related to acute and chronic ethanol administration. Eur J Pharmacol; 1999,377: 13-19.
[150]Kernie S.G., Liebl D.J., Parada L.F. BDNF regulates eating behavior and locomotor activity in mice. Embo. J,2000,19(6):1290-1300.
[151]Fox E.A. and Byerly M.S.. A mechanism underlying mature-onset obesity:evidence from the hyperphagic phenotype of brain-derived neurotrophic factor mutants. Am. J. Physiol. Regul. Integr. Comp. Physiol,2004,286:R994-1004.
[152]Cunha C, Angelucci A., D'Antoni A., et al. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiology of Disease, 2009,33:358-368.
[153]Morris RGM. Spatial localization does not require the presence of local cues. J. Learn Motiv, 1981,12:239.
[154]Doremus T. L., Brunell S. C, Rajendran P. et al. Factors Influencing Elevated Ethanol Consumption in Adolescent Relative to Adult Rats. Alcoholism:Clinical and Experimental Research, 2005,29:1796-1808.
[155]Liu I. Y., Lyons W. E., Mamounas L. A., et al. Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning. J. Neurosci,2004,24:7958-7963.
[156]Linnarsson S., Bjorklund A., and Ernfors, P. Learning deficit in BDNF mutant mice. Eur. J. Neurosci,1997,9:2581-2587.
[157]Yamada K. and Nabeshima T.. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J. Pharmacol. Sci,2003,91:267-270.
[158]Pandey S.C., Zhang D., Mittal N., et al. Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal related anxiety. J Pharmacol Exp Ther,1999,282(2):866-878.
[159]Coffey S.F., Dansky B.S., Carrigan M.H., et al. Acute and protracted cocaine abstinence in an outpatient population:a prospective study of mood, sleep and withdrawal symptoms. Drug Alcohol Depend,2000,59:277-286.
[160]Crews F.T., Nixon K. Alcohol, neural stem cells, and adult neurogenesis. Alcohol Res Health, 2003,27:197-204.
[161]Carlezon W.A. Jr., Duman R.S. and Nestler E.J. The many faces of CREB. Trends Neurosci, 2005,28:436-445.
[162]Johnson S.A., Fournier N.M., Kalynchuk L.E. Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res,2006, 168:280-288.
[163]胡建,刘薇,夏炎等.慢性酒中毒患者大脑萎缩的CT研究.中国行为医学科学,2005,14(11)：984-985.
[164]Namura I., Hishikawa Y.. Cerebal damages in alcoholic patients visualized by MRI:With special reference to frontal atrophy, basal ganglia and white matter lesion. Nippon Rinsho,1997,55 Suppl: 288.
[165]Pfefferbaum A., Sullivan E.V., Mathalon D.H., et al. Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapse alcoholics. Alcohol Clin Exp Res,1995, 19:1177.
[166]Pierce C. R., Audrey F. P., and Balakrishna M. P.. Neurotrophin-3 Contributes to the Initiation of Behavioral Sensitization to Cocaine by Activating the Ras/Mitogen-Activated Protein Kinase Signal Transduction Cascade. The Journal of Neuroscience,1999,19(19):8685-8695.
[167]Cirulli F., Berry A., Chiarotti F., et al., Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze. Hippocampus,2004,14(7):802-807.
[168]Mizuno M., Yamada K., Olariu A., et al. Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J. Neurosci,2000,20(18): 7116-7121.
[169]Jonathan L. C. Lee. Barry J. Everitt. Kerrie L. Thomas. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science,2004,304,839-843.
[170]Rattiner L.M., Davis M., French C.T., et al. Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. J. Neurosci,2004, 24(20):4796-4806.
[171]Rattiner L.M., Davis M., Ressler K.J.. Brain-derived neurotrophic factor in amygdala-dependent learning. Neuroscientist,2005,11(14):323-333.
[172]Alonso M, Vianna M.R., Depino A.M., et al. BDNF-triggered events in the rat hippocampus are required for both short-and long-term memory formation. Hippocampus,2002,12(4):551-560.
[173]Alonso M., Bekinschtein P., Cammarota M., et al. Endogenous BDNF is required for long-term memory formation in the rat parietal cortex. Learn. Mem,2005,12(4):504-510.
[174]Bekinschtein P., Cammarota M., Igaz L.M., et al. Persistence of long-term memory storage requires a late protein synthesis-and BDNF-dependent phase in the hippocampus. Neuron,2007, 53(2):261-277.
[175]Tyler W.J., Alonso M., Bramham C.R., et al. From acquisition to consolidation:on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn. Mem,2002, 9(5):224-237.
[176]Mu J.S., Li W.P., Yao Z.B., et al. Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain. Res,1999,835(2):259-265.
[177]Moonat S., Sakharkar A.J., Zhang H.B. et al. The role of amygdaloid brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein and dendritic spines in anxiety and alcoholism. Addiction Biology,2010,16:238-250.
[178]Altar C.A., Cai N., Bliven T.T., et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature,1997,389:856-860.
[179]Pandey S.C., Zhang H., Ugale R., et al. Effector immediate-early gene Arc in the amygdala plays a critical role in alcoholism. The Journal of Neuroscience,2008,28(10):2589-2600.
[180]Miller R., King M. A., Heaton M. B., et al. The effects of chronic ethanol consumption on neurotrophins and their receptors in the rat hippocampus and basal forebrain. Brain Res,2002,950: 137-147.
[181]Okamoto H., Miki T., Lee K. Y., et al. Effects of chronic ethanol administration on the expression levels of neurotrophic factors in the rat hippocampus. Okajimas Folia Anat Jpn,2006,83:1-6.
[182]Heaton M. B., Kim D. S., and Paiva, M. Neurotrophic factor protection against ethanol toxicity in rat cerebellar granule cell cultures requires phosphatidylinositol 3-kinase activation. Neurosci Lett, 2000,291:121-125.
[183]Bonthius D. J., Karacay B., Dai D., et al. FGF-2, NGF and IGF-1, but not BDNF, utilize a nitric oxide pathway to signal neurotrophic and neuroprotective effects against alcohol toxicity in cerebellar granule cell cultures. Brain Res Dev Brain Res,2003,140:15-28.
[1]Shuang Y., Holsboer F., Osborne F.X. Neuronal actions of glucocorticoids:Focus on dep ression [J]. J Steroid BiochemMolBiol,2008,108 (3/5):300-309.
[2]Mathers C, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030 [J]. PLoSMed,2006,3 (11):e442.
[3]Kessler R.C., Berglund P., Demler O., et al. The epidemiology of major depressive disorder:results from the National Comorbidity Survey Replication (NCS-R). JAMA,2003,289:3095-3105.
[4]John M. The medical management of depression. N Engl J Med,2005,353:1819-1834.
[5]Bradvik L., Berglund M. Suicidal ideation in severe depression. Eur Arch Psychiatry Clin Neurosci, 2000,250:139-143.
[6]McEwen B.S. Stress and hippocampal plasticity. Annu Rev Neurosci,1999,22:105-122.
[7]Gould E., Tanapat P., McEwen B.S., et al. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA,1998,95:3168-3171.
[8]Erickson P.S., Perfilieva E., Bjork-Erikkson T., et al. Neurogenesis in the adult human hippocampus. Nat Med,1998,4:1313-1317.
[9]Rupshi M., Karan S., Karen J.P., et al. Social stress related behavior affects hippocampal cell proliferation in mice. Physiology& Behavior,2006,89:123-127.
[10]Santarelli L., Saxe M., Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science,2003,301:805-809.
[11]Huang E.J., Reichardt L.F. Neurotrophins:roles in neuronal development and function. Annu Rev Neurosci,2001,24:677-736.
[12]Karege F., Bondolfi G, Gervasoni N., et al. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry,2005,57(9):1068-1072.
[13]Thoenen H. Neurotrophins and neuronal plasticity. Science,1995,270:593-598.
[14]Altar C.A., Cai N., Bliven T., et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature,1997,389:856-860.
[15]Bartrup J.T., Moorman J.M., Newberry N.R. BDNF enhances neuronal growth and synaptic activity in hippocampal cell cultures. Neuroreport,1997,8:3791-3794.
[16]Acheson A., Conover J.C., Fandl J.P., et al. A BDNF autocrine loop in adult sensory neurons prevents cell death". Nature,1995,374 (6521):450-453.
[17]Yamada K., Nabeshima T. Brain-derived neurotrophic factor/TrkB signaling in memory processes". J. Pharmacol. Sci,2003,91 (4):267-270.
[18]Bekinschtein P., Cammarota M, Katche C, et al. BDNF is essential to promote persistence of long-term memory storage, Proc. Natl. Acad. Sci. U.S.A.,2008,105 (7):2711-2716.
[19]Zigova T., Pencea V., Wiegand S.J., et al. Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol. Cell. Neurosci,1998,11 (4): 234-245.
[20]Benraiss A., Chmielnicki E., Lerner K., et al. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J. Neurosci,2001,21 (17):6718-6731.
[21]Pencea V., Bingaman K.D., Wiegand S.J., et al. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J. Neurosci,2001,21 (17):6706-6717.
[22]Ernfors P., Kucera J., Lee K.F., et al. Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice. Int. J. Dev. Biol.,1995,39 (5):799-807.
[23]Kafitz K.W., Rose C.R., Thoenen H., et al. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature,1999,401:918-921.
[24]Yogesh D., Hooriyah S. R., Robert R. C, et al. Altered Gene Expression of Brain-Derived Neurotrophic Factor and Receptor Tyrosine Kinase B in Postmortem Brain of Suicide Subjects. Arch Ge Psychiatry,2003,60:804-815.
[25]Warner-Schmidt J.L., Duman R.S. Hippocampal neurogenesis:opposing effects of stress and antidepressant treatment. Hippocampus,2006,16:239-249.
[26]Molteni R., Calabrese F., Bedogni F., et al. Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions. Neuropsychopharmacology,2005,22:1-11.
[27]Brown C.M., Cooper-Kuhn G., Kempermann H., et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci.,2003,17:2042-2046.
[28]Helen S., Jeffrey G., Adam M., et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Experimental Neurology,2005,192:348-356.
[29]李云峰,罗质璞.抑郁症发病机制及治疗药物.神经药理学新论.北京：人民卫生出版社,2004,1-20.
[30]Kempermann G., Kuhn H.G., Gage F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature,1997,386:493-495.
[31]Nibuya M., Morinobu S., Duman R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci,1997,15:7539-7547.
[32]Tuomisto J., Tukiainen E. Decreased uptake of 5-hydroxytryptamine in blood platelets from depressed patients. Nature,1976,262:596-598.
[33]Mowla S.J., Pareek S., Farhadi H.F., et al. Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J Neurosci,1999,19:2069-2080.
[34]Balkowiec A., Katz D.M. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J Neurosci,2002,22:10399-10407.
[35]Heymach J.V., Jr, Kruttgen A., et al. The regulated secretion and vectorial targeting of neurotrophins in neuroendocrine and epithelial cells. J Biol Chem,1996,271:25430-25437.
[36]Teng H.K., Teng K.K., Lee R., et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci,2005,25:5455-5463.
[37]Woo N.H., Teng H.K., Siao C.J., et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat. Neurosci,2005,8:1069-1077.
[38]Seidah N.G., et al. Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett,1996,379:247-250.
[39]Mowla S.J., Farhadi H.F., Pareek S., et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem,2001,276(16):12660-12666.
[40]Lee R., Kermani P., Teng K.K., et al. Regulation of cell survival by secreted proneurotrophins. Science,2001,294:1945-1948.
[41]Pang P.T., H.K. Teng, E. Zaitsev, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science,2004,306:487-491.
[42]Lu B., Pang P.T., Woo N.H. The yin and yang of neurotrophin action. Nat Rev Neurosci,2005, 6:603-614.
[43]Rosch H., Schweigreiter R., Bonhoeffer T., et al. The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc. Natl. Acad. Sci. USA.,2005,102:7362-7367.
[44]Korte M., Carroll P., Wolf E., et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA.,1995,92:8856-8860.
[45]Figurov A., Pozzo-Miller L.D., Olafsson P., et al. Regulation of synaptic responses,to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature,1996,381:706-709.
[46]Patterson S.L., Abel T., Deuel T.A., et al. Recombinant BDNF rescues decits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron,1996,16:1137-1145.
[47]Yang J., Siao C.J., Nagappan G, et al. Neuronal release of proBDNF. Nat. Neurosci,2009, 12:113-115.
[48]Matsumoto T., Rauskolb S., Polack,M. et al. Biosynthesis and processing of endogenous BDNF:CNS neurons store and secrete BDNF, not proBDNF. Nat. Neurosci,2008,11:131-133.
[49]Nagappan G, E. Zaitsev, V.V. Senatorov Jr., et al. Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc. Natl. Acad. Sci. USA.,2009,106:1267-1272.
[50]Deppmann C.D., Mihalas S., Sharma N., et al. A model for neuronal competition during development. Science,2008,320:369-373.
[51]Martinowich K., Manji H., Lu B. New insights into BDNF function in depression and anxiety. Nature Neuroscience,2007,10:1089-1093.
[52]Chen Z.Y., Patel P.D., Sant G., et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci,2004,24:4401-4411.
[53]Egan M.F., Kojima M., Callicott J.H., et al. The BDNF va166met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell,2003, 112:257-269.
[54]Hashimoto R., Moriguchi Y., Yamashita F., et al. Dose-dependent effect of the Va166Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity. Neurosci Res.,2008,61:360-367.
[55]Gong P., Zheng A., Chen D., et al. Effect of BDNF Va166Met polymorphism on digital working memory and spatial localization in a healthy Chinese Han population. J Mol Neurosci,2009, 38:250-256.
[56]Hariri A.R., Goldberg T.E., Mattay V.S., et al. Brain-derived neurotrophic factor va166met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci,2003,23:6690-6694.
[57]Montag C, Weber B., Fliessbach K., et al. The BDNF Va166Met polymorphism impacts parahippocampal and amygdala volume in healthy humans:incremental support for a genetic risk factor for depression. Psychol Med,2009,39:1831-1839.
[58]Matsuo K., Walss-Bass C, Nery F.G., et al. Neuronal correlates of brain-derived neurotrophic factor Va166Met polymorphism and morphometric abnormalities in bipolar disorder. Neuropsychopharmacology,2009,34:1904-1913.
[59]Green E., Craddock N. Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: evidence, limitations, and implications. Curr Psychiatry Rep.,2003,5:469-476.
[60]Karege F., Perret G., Bondolfi G., et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res.,2002,109:143-148.
[61]Duman R.S., Vaidya V.A. Molecular and cellular actions of chronic electroconvulsive seizures. J ECT. 1998,14:181-193.
[62]Chen B., Dowlatshahi D., MacQueen G.M., et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry,2001,50:260-265.
[63]Shirayama Y., Chen A.C., Nakagawa S., et al. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci,2002,22:3251-3261.
[64]Siuciak J.A., Lewis D.R., Wiegand S.J., et al. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav.,1997,56:131-137.
[65]Stern A.J., Savostyanova A.A., Goldman A., et al. Impact of the brain-derived neurotrophic factor Va166Met polymorphism on levels of hippocampal N-acetyl-aspartate assessed by magnetic resonance spectroscopic imaging at 3 Tesla. Biol Psychiatry,2008,64:856-862.
[66]Pezawas L., Verchinski B.A., Mattay V.S., et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci.,2004,24:10099-10102.
[67]Bueller J.A., Aftab M., Sen S., et al. BDNF Va166Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry,2006,59:812-815.
[68]Nemoto K.., Ohnishi T., Mori T., et al. The Va166Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett.,2006,397:25-29.
[69]Vollmayr B., Keck S., Henn F.A., et al. Acute stress decreases serotonin transporter mRNA in the raphe pontis but not in other raphe nuclei of the rat. Neurosci Lett.,2000,290:109-112.
[70]Frodl T., Schiile C, Schmitt G, et al. Association of the brain-derived neurotrophic factor va166met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry,2007, 64:410-416.
[71]Yulay B., Ozan E., Aydin N., et al. Brain-derived neurotrophic polymorphism:more than a prognostic factor during depression? J Neuropsychiatry Clin Neurosci,2009,21:471-472.
[72]Jiang X., Xu K., Hoberman J., et al. BDNF variation and mood disorders:a novel functional promoter polymorphism and Va166Met are associated with anxiety but have opposing effects. Neuropsychophannacology,2005,30:1353-1361.
[73]Hall D., Dhilla A., Charalambous A., et al. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet, 2003,73370-73376.
[74]Sklar P., Gabriel S. B., Mclnnis M.G., et al. Family-based association study of 76 candidate genes in bipolar disorder:BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry, 2002,7579-7593.
[75]Neves-Pereira M., Mundo E., Muglia P., et al. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder:evidence from a family-based association study. Am J Hum Genet, 2002,71651-71655.
[76]Geller B., Badner J.A., Tillman R., et al. Linkage disequilibrium of the brain-derived neurotrophic factor Va166Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry,2004,16:11698-1700.
[77]Sen S., Nesse R. M., Stoltenberg S. F., et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology, 2003,28:397-401.
[78]Kang R.H., Chang H.S., Wong ML., et al. Brain-derived neurotrophic factor gene polymorphisms and mirtazapine responses in Koreans with major depression. Journal of Psychopharmacology,2009, doi:10.1177/0269881109105457
[79]Tsai S. J., Hong C. J., Yu Y. W. et al. Association Study of a Brain-Derived Neurotrophic Factor (BDNF) Va166Met Polymorphism and Personality Trait and Intelligence in Healthy Young Females. Neuropsychobiology,2004,49:13-16.
[80]Taylor Warren D., Zuchner Stephan, McQuoid Douglas R. B.S., et al. Differences in the Brain-Derived Neurotrophic Factor Va166Met Polymorphism in Late-Life Depression. American Journal of Geriatric Psychiatry,2007,10:850-857.
[81]Hwang J.P., Tsai S.J., Hong C.J., et al. The Va166Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging,2006, 27:1834-1837.
[82]Tsai S.J., Cheng C.Y., Yu Y.W., et al. Association study of brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet,2003,123:19-22.
[83]Hong C.J., Huo S.J., Yen F.C., et al. Association study of brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology,2003, 48:186-189.
[84]Willis-Owen SAG, Fullerton J., Surtees P.G., et al. The Va166Met coding variant of the brain-derived neurotrophic factor (BDNF) gene does not contribute toward variation in the personality trait neuroticism. Biol Psychiatry,2005,58:738-742.
[85]Paul G. Surtees, Nicholas W.J. Wainwright, Saffron A.G. Willis-Owen, et al. No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults. Journal of Psychiatric Research,2007,5:404-409.
[86]Gratacos M., Gonzalez J.R., Mercader J.M., et al. Brain-derived neurotrophic factor Val66Met and psychiatric disorders:Meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry,2007,61:911-922.
[87]Verhagen M., van der Meij A., van Deurzen P.A., et al. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder:Effects of gender and ethnicity. Mol Psychiatry, 2010,15(3):260-271.
[88]Chao M. V. Neurotrophins and their receptors:a convergence point for many signalling pathways. Nat Rev Neurosci,2003,4:299-309.
[89]Friedman W. J, Greene L. A. Neurotrophin signaling via Trks and p75. Exp Cell Res,1999,25: 3131-3142.
[90]Beattie M. S., Harrington A.W., Lee R., et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron,2002,36:375-386.
[91]Bui N. T., Konig H. G., Culmsee C, et al. p75 neurotrophin receptor is required for constitutive and NGF-induced survival signaling in PC12 cells and rat hippocampal neurons. J Neuro chem.,2002, 8:594-605.
[92]Lu B. Pro-region of neurotrophins:role in synaptic modulation. Neuron,2003,3;735-738.
[93]Licinio J., Dong C, Wong M.L. Novel sequence variations in the brain-derived,neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry,2009,66:488-497.
[2]Schuckit M.A, Tipp J.E., Bergman M., et al. Comparison of induced and independent major depressive disorders in 2,945 alcoholics. Am J Psychiatry,1997,154:948-957.
[3]Pettinati H.M. Antidepressant treatment of co-occurring depression and alcohol dependence. Biol Psychiatry,2004,56:785-792.
[4]Grant B.F. Comorbidity between DSM-IV drug use disorders and major depression:results of a national survey of adults. J Subst Abuse,1995,7:481-497.
[5]Kessler R.C., Crum R.M., Warner L.A., et al. Lifetime co-occurrence of DSM-Ⅲ-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry, 1997,54:313-321.
[6]Lynskey M.T. The comorbidity of alcohol dependence and affective disorders:treatment implications. Drug Alcohol Depend,1998,52:201-209.
[7]Garbutt J.C., West S.L., Carey T.S., et al. Pharmacological treatment of alcohol dependence:a review of the evidence. JAMA,1999,281:1318-1325.
[8]Greenfield S.F., Weiss R.D., Muenz L.R., et al. The effect of depression on return to drinking:a prospective study. Arch Gen Psychiatry,1998,55:259-265.
[9]Mueller T.I., Lavori P.W., Keller M.B., et al. Prognostic effect of the variable course of alcoholism on the 10-year course of depression. Am J Psychiatry,1994,151:701-706.
[10]Crews F.T., Nixon K.., Wilkie M.E. Exercise reverses ethanol inhibition of neural stem cell proliferation. Alcohol,2004,33:63-71.
[11]Duman R.S., Malberg J., Nakagawa S., et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry,2000,48:732-739.
[12]Malberg J.E., Eisch A.J., Nestler E.J., et al. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci,2000,20:9104-9110.
[13]Santarelli L., Saxe M., Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science,2003,301:805-809.
[14]Warner-Schmidt J.L., Duman R.S. Hippocampal neurogenesis:opposing effects of stress and antidepressant treatment. Hippocampus,2006,16:239-249.
[15]Gregus A., Wintink A.J., Davis A.C., et al. Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav Brain Res,2005,156:105-114.
[16]Malberg J.E., Duman R.S. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology,2003,28:1562-1571.
[17]Tanapat P., Hastings N.B., Rydel T.A., et al. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J Comp Neurol,2001, 437:496-504.
[18]He J., Nixon K., Shetty A.K., et al. Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons. Eur J Neurosci,2005,21:2711-2720.
[19]Nixon K., Crews F.T.. Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J Neurochem,2002,83:1087-1093.
[20]Sheline Y.I., Sanghavi M, Mintun M.A., et al. Depression durationbut not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci,1999, 19:5034-5043.
[21]Sheline Y.I., Wang P.W., Gado M.H., et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA,1996,93:3908-3913.
[22]Mowla S. J., Pareek S., Farhadi H.F., et al. Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J. Neurosci,1999,19(6):2069-2080.
[23]Lee R., Kermani P., Teng K.K., et al. Regulation of cell survival by secreted proneurotrophins. Science,2001,294:1945-1948.
[24]Matsumoto, T., Rauskolb, S., Polack, M., et al.. Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not proBDNF. Nat. Neurosci.2008,11(2):131-133.
[25]Nagappan G., Zaitsev E., Vladimir V., et al.. Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc. Natl. Acad. Sci. U. S. A.,2009,106(4):1267-1272.
[26]Yang F., Je H.S., Ji Y., et al.. ProBDNF-induced synaptic depression and retraction at developing neuromuscular synapses. J. Cell Biol,2009,182(4):727-741.
[27]Pang P.T., H.K. Teng, E. Zaitsev, et al.. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science,2004,306:487-491.
[28]Lu B., Pang P.T., Woo N.H. The yin and yang of neurotrophin action. Nat Rev Neurosci,2005, 6:603-614.
[29]Lazic S.E., Grote H.E., Armstrong R.J.,et al. Decreased hippocampal cell proliferation in R6/1 Huntington's mice. Neuroreport,2004,15:811-813.
[30]Barbara L. Hempstead. Dissecting the diversse actions of pro-and mature neurotrophins. Current Alzheimer Research,2006,3:19-24.
[31]Huang E.J., Reichardt L.F. Neurotrophins:roles in neuronal development and function. Annu Rev Neurosci,2001,24:677-736.
[32]Chao M.V., Rajagopal R., Lee F.S.. Neurotrophin signalling in health and disease. Clin Sci (Lond), 2006,110:167-173.
[33]Allen S.J., Dawbarn D.. Clinical relevance of the neurotrophins and their receptors. Clin Sci (Lond), 2006,110:175-191
[34]Levi-Montalcini R., Aloe L. and Alleva E.. A role for nerve growth factor in nervous, endocrine and immune systems. Prog Neurol Endocrinol Immunol,1990,3:1-10.
[35]Barde Y.A.. Neurotrophins:a family of proteins supporting the survival of neurons. Prog Clin Biol Res,1994,390:45-56.
[36]Schwartz M., Kipnis J.. Protective autoimmunity:regulation andprospects for vaccination after brain and spinal cord injuries. Trends Mol. Med,2001,7:252-258.
[37]Hauben E., Butovsky O., Nevo U., et al. Passive or active immunization withmyelin basic protein promotes recovery from spinal cord contusion.J. Neurosci,2000,20:6421-6430.
[38]Schwartz M., Moalem G., Leibowitz-Amit R., et al. Innate and adaptive immune responses can be beneficial for CNS repair. TINS,1999,22:295-299.
[39]Barouch R., Appel E., Kazimirsky G., et al. Macrophages express neurotrophins and neurotrophin receptors-regulation of nitric oxide production by NT-3. J. Neuroimmunol,2001,112:72-77.
[40]Hammarberg H., Lidman O., Lundberg C., et al. Neuroprotection by encephalomyelitis:rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J. Neurosci,2000,20:5283-5291.
[41]Kerschensteiner M., Gallmeier E., Behrens L., et al. Activated human T cells, B cells, and monocytes produce brain derived neurotrophic factor in vitro and in inflammatory brain lesions:a neuroprotective role of inflammation? J. Exp. Med,1999,189:865-870.
[42]Muhallab S., Lundberg C., Gielen A.W., et al. Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis. Scand. J. Immunol,2002, 55:264-273.
[43]Schulte-Herbruggen O., Nassenstein C.,Lommatzsch M., et al. Tumor necrosis factor-alpha and interleukin-6 regulate secretion of brain-derived neurotrophic factor in human monocytes. J. Neuroimmunol,2005,160:204-209.
[44]Stadelmann C, Kerschensteiner M., Misgeld T., et al. BDNF and gp145trkB in multiple sclerosis brain lesions:neuroprotective interactions between immune and neuronal cells? Brain,2002,125: 75-85.
[45]Shuang Y., Holsboer F., Osborne F.X. Neuronal actions of glucocorticoids:Focus on depression [J]. J Steroid Biochem Mol Biol,2008,108 (3/5):300-309.
[46]Mathers C, Loncar D.. Projections of global mortality and burden of disease from 2002 to 2030 [J]. PLoSMed,2006,3(11):e442.
[47]Kessler R.C., Berglund P., Demler O., et al. The epidemiology of major depressive disorder:results from the National Comorbidity Survey Replication (NCS-R). JAMA,2003,289:3095-3105.
[48]John M. The medical management of depression. N Engl J Med,2005,353:1819-1834.
[49]Yogesh D., Hooriyah S. R., Robert R. C, et al. Altered Gene Expression of Brain-Derived Neurotrophic Factor and Receptor Tyrosine Kinase B in Postmortem Brain of Suicide Subjects Arch Ge Psychiatry,2003,60:804-815.
[50]李云峰,罗质璞.抑郁症发病机制及治疗药物.神经药理学新论.北京：人民卫生出版社,2004,1-20.
[51]Kempermann G., Kuhn H.G., Gage F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature,1997,386:493-495.
[52]Nibuya M., Morinobu S., Duman R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci,1997,15:7539-7547
[53]Duman R.S. Pathophysiology of depression:the concept of synaptic plasticity. Eur Psychiatry,2002, 17 Suppl,3:306-310.
[54]Tapia-Aiancibia L., Rage F., Givalois L., et al. Physiology of BDNF:focus on hypothalamic function. Front Neuroendocrinol,2004,25:77-107.
[55]Castren E., Voikar V., Rantamaki T. Role of neurotrophic factors in depression. Curr Opin Pharmacol, 2007,7:18-21.
[56]Peng S., Wuu J., Mufson E. J., et al. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J. Neuropath. Exp.Neuron,2004,63:641-649.
[57]Harrington A.W., Leiner B., Blechschmitt C, et al. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc, Nat. Acad. Sci. USA,2004,101(16):6226-6230.
[58]Srinivasan B., Roque C. H., Hempstead B.L., et al. Microglia-derived pronerve growth factor promotes photoreceptor cell death via p75 neurotrophin receptor. J. Biol. Chem.,2004,279:41839-41845.
[59]Martinowich K., Manji H., Lu B.. New insights into BDNF function in depression and anxiety. Nature Neuroscience,2007,10:1089-1093.
[60]Fauchais, A.L., Lalloue, F., Lise,M.C, et al. Role of Endogenous Brain-Derived Neurotrophic Factor and Sortilin in B Cell Survival. J Immunol,2008,181(5):3027-3038.
[61]Karege F., Bondolfi G., Gervasoni N., et al. Low brain-derived neurotrophic factor(BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity[J]. Biol Psychiatry,2005, (57):1068-1072.
[62]李欣,李海红,方泽漫,等.白介素-1β对原代培养海马神经元毒性的研究.中华行为医学和脑科学杂志,2009,(12)：1061-1063.
[63]Lee B. H, Kim H., Park S. H., et al. Decreased plasma BDNF level in depressive patients [J].Journal of Affective Disorders,2007, (101):239-244.
[64]Molendijk M.L., Bus B.A., Spinhoven P., et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder:state-trait issues, clinical features and pharmacological treatment. Mol. Psychiat,2011,16:1088-1095.
[65]Xu Z.Q., Sun Y., Li H.Y., et al. Endogenous proBDNF is a negative regulator of migration of cerebellar granule cells in neonatal mice. Eur. J. Neurosci,2011,33(8):1376-1384.
[66]Sun Y., Lim Y., Li F., et al. ProBDNF Collapses Neurite Outgrowth of Primary Neurons by Activating RhoA. PLoS ONE,2012,7(4):e35883.
[67]Woo N.H., H.K. Teng, C.J. Siao, et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat. Neurosci,2005,8:1069-1077.
[68]Zagrebelsky M., Holz A., Dechant G., et al. The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J.Neurosci,2005,25(43):9989-9999.
[69]Bachis A., Avdoshina V., Zecca L., et al.. Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. J. Neurosci,2012,32(28):9477-9484.
[70]Le A.P., Friedman W. J. Matrix Metalloproteinase-7 Regulates Cleavage of Pro-Nerve Growth Factor and Is Neuroprotective following Kainic Acid-Induced Seizures. J. Neurosci,2012,32(2):703-712.
[71]Karege F., Perret G., Bondolfib G., et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiat. Res,2002,109(2):143-148.
[72]Shimizu E., Hashimoto K., Okamura N., et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiat, 2003,54(1):70-75.
[73]Poduslo J.F. C.G. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res,1996,36(2):280-286.
[74]Pan W. B.W., Fasold M.B., Bluth J., et al. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology,1998,37(12):1553-1561.
[75]Brunoni A. R., Lopes M., Fregni F.. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels:implications for the role of neuroplasticity in depression. Int. J. Neuropsychoph,2008,11(8):1169-1180.
[76]张玉梅,张志塘,沙维等.抑郁症患者治疗前后血清脑源性神经营养因子水平变化及相关因素分析.中华精神科杂志,2009,42(4)：210-214.
[77]Gonul A.S., Akdeniz F., Taneli F., et al. Effect of treatment on serum brain-derived neurotmphic factor levels in depressed patients. Eur. Arch. Psychiatry Clin. Neurosci,2005,255:381-386.
[78]Bus B.A., Molendijk M.L., Penninx B.J., et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrino,2011,36(2):228-239.
[79]Ozana E., Okurb H., Ekerc C., et al. The effect of depression, BDNF gene va166met polymorphism and gender on serum BDNF levels. Brain Res. Bull,2010,81(1):61-65.
[80]Bocchio-Chiavetto, L., Bagnardi, V., Zanardini, R., et al. Serum and plasma BDNF levels in major depression:a replication study and meta-analyses. World J, Biol. Psychia,2010,11(6):763-773.
[81]沈渔邮.精神病学.第三版.人民卫生出版社,1980,527.
[82]Abel E.L. Fetal alcohol syndrome:a cautionary note. Curr Pharm Des,2006,12:1521-1529.
[83]Mancinelli R., Ceccanti M., Laviola G. Fetal alcohol spectrum disorders (FASD):from experimental biology to the search for treatment. Neurosci Biobehav Rev,2007,31:165-167.
[84]Niccols A. Fetal alcohol syndrome and the developing socio-emotional brain. Brain Cogn,2007, 65:135-142.
[85]Kubota M, Nakazaki S, Hirai S., et al. Alcohol consumption and frontal lobe shrinkage:study of 1432 non-alcoholic subjects. J Neurol Neurosurg Psychiatry,2001,71:104-106.
[86]Sullivan E.V., Pfefferbaum A.. Neurocircuitry in alcoholism:a substrate of disruption and repair. Psychopharmacology,2005,180:583-594.
[87]Crews F. T., Collins M. A., Dlugos C, et al. Alcohol-Induced Neurodegeneration:When, Where and Why? ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH,2004, (28)2:350-364.
[88]Gabbard G. O. Treatments of Psychiatric Disorders.3rd Ed. v2. Washington:American Psychiatric Publishing,2001, Treatments of psychiatric disorders (3 ed.). Washington, DC:American Psychiatric Press. ISBN 978-0-88048-910-2.1447-1482; 1587-1622
[89]Gro Harlem Brundtland (19 February 2001). "WHO European Ministerial Conference on Young People and Alcohol". World Health Organization.
[90]刘兆玺,张敬悬,翁正.山东省慢性酒中毒流行病学十年对比研究.J.中国行为医学科学,1999,84：293-295.
[91]Malyutina S., Bobak M., Kurilovitch S., et al. Trends in alcohol intake by education and martial status in urburn population Russian between mid 1980s and the mid 1990s [J]. Alcohol Alcoholism,2004, 39(1):64-69.
[92]Gallup Poll, annual surverys taken between 1935 and July 12-15,2007, as found on http:// www.galluppoll.com/content
[93]Yamashita M., Yamamoto T.. Wernicke encephalopathy with symmetric pericentral involvement:MR findings [J]. J Compute Assist Tomogr,1995,19(2):306-308.
[94]Napper R.M., West J.R.. Permanent neuronal cell loss in the cerebellum or rats exposed to continuous low blood alcohol levels during the brain growth spurt:a stereological investigation. J Comp Neurol, 1995,362:283-292.
[95]Lewin G.R., Barde Y.A. Physiology of the neurotrophins. Annu. Rev. Neurosci,1996,19:289-317.
[96]Mitchell J.J., Paiva M., Moore D.B., et al. A comparative study of ethanol, hypoglycemia, hypoxia and neurotrophic factor interactions with fetal rat hippocampal neurons:a multi-factor in vitro model for developmental ethanol effects. Dev Brain Res,1998,105:241-250.
[97]Hall J., Thomas K. L. and Everitt B. J. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nature Neuroscience,2000,3:533-535.
[98]Hyman C, Hofer M., Barde Y. A. et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature,1991,350:230-232.
[99]Li Y. X., Zhang Y., Lester H. A., et al.. Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. The Journal of Neuroscience, 1998,18:10231-10240.
[100]Lyons W. E., Mamounas L. A., Ricaurte G. A. et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proceedings of the National Academy of Sciences of the United States of America,1999,96: 15239-15244.
[101]Guillin O., Diaz J., Carroll P., et al. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature,2001,411:86-89.
[102]Horger B.A., lyasere C.A., Berhow M.T., et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J Neurosi,1999, 19(10):4110-4122.
[103]McGough N.N., He D.Y., Logrip M.L., et al. RACK1 and brain-derived neurotrophic factor:a homeostatic pathway that regulates alcohol addiction. J Neurosci,2004,24:10542-10552.
[104]Uhl G. R., Liu Q. R., Walther D., et al. Polysubstance abuse-vulnerability genes:genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am. J. Hum. Genet, 2001,69:1290-1300.
[105]Matsushita S., Kimura M., Miyakawa T., et al. Association study of brain-derived neurotrophic factor gene polymorphism and alcoholism. Alcohol. Clin. Exp. Res,2004,28:1609-1612.
[106]Bolanos C. A. and Nestler E. J. Neurotrophic mechanisms in drug addiction. Neuromolecular Med,2004,5:69-83.
[107]Berhow M. T., Russell D. S., Terwilliger R. Z., et al. Influence of neurotrophic factors on morphine-and cocaine-induced biochemical changes in the mesolimbic dopamine system. Neuroscience,1995,68:969-979.
[108]Le F. B., Diaz J., and Sokoloff P. A single cocaine exposure increases BDNF and D3 receptor expression:implications for drug-conditioning. Neuroreport,2005,16:175-178.
[109]Liu Q. R., Lu L., Zhu X. G., et al. Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res,2006,1067:1-12.
[110]Meredith G. E., Callen S., and Scheuer D. A. Brain-derived neurotrophic factor expression is increased in the rat amygdala, piriform cortex and hypothalamus following repeated amphetamine administration. Brain Res,2002,949:218-227.
[111]Zhang D., Zhang L., Lou D. W., et al. The dopamine Dl receptor is a critical mediator for cocaine-induced gene expression. J. Neurochem,2002,82:1453-1464.
[112]Grimm, J. W., Lu, L., Hayashi, T., et al. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopa-mine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci,2003,23:742-747.
[113]Tapia-Arancibia L., Rage F., Givalois L., et al. Effects of alcohol on brain-derived neurotrophic factor mRNA expression in discrete regions of the rat hippocampus and hypothalamus. J. Neurosci. Res,2001,63:200-208.
[114]Hensler J. G., Ladenheim E. E., and Lyons W. E. Ethanol consumption and serotonin-lA (5-HT1A) receptor function in heterozygous BDNF (+/-) mice. J. Neurochem,2003,85:1139-1147.
[115]Pandey S. C, Roy A., Zhang H., et al. Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors. J. Neurosci,2004,24:5022-5030.
[116]Pandey S. C, Zhang H., Roy A., et al. Central and medial amygdaloid brain-derived neurotrophic factor signaling plays a critical role in alcohol-drinking and anxiety-like behaviors. J. Neurosci,2006,26:8320-8331.
[117]Hall F. S., Drgonova J., Goeb M., et al. Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuro psychopharmacology,2003, 28:1485-1490.
[118]Teng H.K., Teng K.K., Lee R., et al. ProBDNF induces neuronal apoptosis via activation of a receptor. J Neurosci,2005,25(22):5455-5463.
[119]Lu B. Pro-region of neurotrophins:role in synaptic modulation. Neuron,2003,39:735-738.
[120]Paul C.A., Au R., Fredman L., et al. Association of alcohol consumption with brain volume in the Framingham study. Arch Neurol,2008,65(10):1363-1367.
[121]Tsai G. and Coyle J. T.. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annual Review of Medicine,1998,49:173-184.
[122]Littleton J. M., Lovinger D., Liljequist S., et al. Role of polyamines and NMDA receptors in ethanol dependence and withdrawal. Alcoholism:Clinical and Experimental Research,2001,25(5 suppl):132S-136S.
[123]Nixon, K. and Crews, F. T.. Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence fromalcohol. The Journal of Neuroscience,2004,24: 9714-9722.
[124]MacLennan A.J., Lee N., and Walker D.W.. Chronic ethanol administration decreases brainderived neurotrophic factor gene expression in the rat hippocampus. Neurosci Lett,1995, 197(2):105-108.
[125]Radka S.F., Holst P.A., Fritsche M., et al. Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res, 1996,709(1):122-301.
[126]Mori T., Shimizu K., Hayashi M.. Levels in serum brain-derived neurotrophic factor in primates. Primates,2003,44:167-169.
[127]Heberlein A., Muschler M., Wilhelm J., et al. BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal. Prog Neuropsychopharmacol Biol Psychiatry,2010, 34(6):1060-1064.
[128]Huang M.C., Chen C.H., et al. Alterations of serum brain-derived neurotrophic factor levels in early alcohol withdrawal. Alcohol Alcohol,2008,43(3):241-245.
[129]Zhou L, Xiong J, Lim Y, et al. Upregulation of blood proBDNF and its receptors in major depression. Journal of Affective Disorders,2013,150:776-778.
[130]Jeanblanc J., He D., McGough N., et al. Evidence that BDNF regulation of ethanol consumption is mediated by the dopamine D 3 receptor in the dorsal striatum. Program,2005,797.
[131]Hasin D., Liu X., Nunes E., et al. Effects of major depression on remission and relapse of substance dependence. Arch Gen Psychiatry,2002,59:375-380.
[132]Stevenson J. R., Schroeder J. P, and Nixon K. Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice. Neuropsychopharmacology,2009,34(5):1209-1222.
[133]Ostacher M.J. Comorbid alcohol and substance abuse dependence in depression:impact on the outcome of antidepressant treatment. Psychiatr Clin North Am,2007,30:69-76.
[134]Le Fauve C.E., Litten R.Z., Randall C.L., et al. Pharmacological treatment of alcohol abuse/dependence with psychiatric comorbidity. Alcohol Clin Exp Res,2004,28:302-312.
[135]Haynes L. E., Barber D. and Mitchell I. J.. Chronic antidepressant medication attenuates dexamethasone-induced neuronal death and sublethal neuronal damage in the hippocampus and striatum.Brain Research,2004,1026:157-167.
[136]Hyman S. E., Malenka R. C, and Nestler E. J.. Neural mechanisms of addiction:the role of reward-related learning and memory. Annu Rev Neurosci,2006,29:565-598.
[137]Koob, G. F. Alcoholism:allostasis and beyond. Alcohol Clin Exp Res,2003,27:232-243.
[138]Fumagalli F., Di Pasquale L., Caffino L., et al. Repeated exposure to cocaine differently modulates BDNF mRNA and protein levels in rat striatum and prefrontal cortex. Eur. J. Neurosci, 2007,26:2756-2763.
[139]Logrip, M. L., Janak, P. H., and Ron, D. Escalating ethanol intake is associated with altered corticostriatal BDNF expression. J. Neurochem,2009,109:1459-1468.
[140]Yoon S. J., Roh S., Lee H. et al. Possible role of nerve growth factor in the pathogenesis of alcohol dependence. Alcohol Clin. Exp. Res,2006,30:1060-1065.
[141]Jeanblanc J., He D. Y., McGough N. N., et al. The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J. Neurosci,2006,26:1457-1464.
[142]Prakash A., Zhang H. and Pandey S. C. Innate differences in the expression of brain-derived neurotrophic factor in the regions within the extended amygdala between alcohol preferring and nonpreferring rats. Alcohol. Clin. Exp. Res,2008,32:909-920.
[143]Goodlett C.R., Horn K.H. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res Health,2001,25:175-184.
[144]Luo J., Miller M.W.. Growth factor-mediated neural proliferation:target of ethanol toxicity. Brain Res Brain Res Rev,1998,27:157-167.
[145]Harper C The neuropathology of alcohol-related brain damage. Alcohol Alcohol,2009, 44:136-140.
[146]Mowla S.J., Farhadi H.F., Pareek S., et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem,2001,276:12660-12666.
[147]Heaton M.B., Paiva M., Madorsky I., et al. Ethanol effects on neonatal rat cortex:comparative analyses of neurotrophic factors, apoptosis-related proteins, and oxidative processes during vulnerable and resistant periods. Brain Res Dev,2003,145:249-262.
[148]Miller M.W., Mooney S.M. Chronic exposure to ethanol alters neurotrophin content in the basal forebrain-cortex system in the mature rat:effects on autocrine-paracrine mechanisms. J Neurobiol, 2004.60:490-498.
[149]Malinowska B., Napiorkowska-Pawlak D., Pawlak R., et al. Ifenprodil influences changes in mouse behaviour related to acute and chronic ethanol administration. Eur J Pharmacol; 1999,377: 13-19.
[150]Kernie S.G., Liebl D.J., Parada L.F. BDNF regulates eating behavior and locomotor activity in mice. Embo. J,2000,19(6):1290-1300.
[151]Fox E.A. and Byerly M.S.. A mechanism underlying mature-onset obesity:evidence from the hyperphagic phenotype of brain-derived neurotrophic factor mutants. Am. J. Physiol. Regul. Integr. Comp. Physiol,2004,286:R994-1004.
[152]Cunha C, Angelucci A., D'Antoni A., et al. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiology of Disease, 2009,33:358-368.
[153]Morris RGM. Spatial localization does not require the presence of local cues. J. Learn Motiv, 1981,12:239.
[154]Doremus T. L., Brunell S. C, Rajendran P. et al. Factors Influencing Elevated Ethanol Consumption in Adolescent Relative to Adult Rats. Alcoholism:Clinical and Experimental Research, 2005,29:1796-1808.
[155]Liu I. Y., Lyons W. E., Mamounas L. A., et al. Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning. J. Neurosci,2004,24:7958-7963.
[156]Linnarsson S., Bjorklund A., and Ernfors, P. Learning deficit in BDNF mutant mice. Eur. J. Neurosci,1997,9:2581-2587.
[157]Yamada K. and Nabeshima T.. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J. Pharmacol. Sci,2003,91:267-270.
[158]Pandey S.C., Zhang D., Mittal N., et al. Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal related anxiety. J Pharmacol Exp Ther,1999,282(2):866-878.
[159]Coffey S.F., Dansky B.S., Carrigan M.H., et al. Acute and protracted cocaine abstinence in an outpatient population:a prospective study of mood, sleep and withdrawal symptoms. Drug Alcohol Depend,2000,59:277-286.
[160]Crews F.T., Nixon K. Alcohol, neural stem cells, and adult neurogenesis. Alcohol Res Health, 2003,27:197-204.
[161]Carlezon W.A. Jr., Duman R.S. and Nestler E.J. The many faces of CREB. Trends Neurosci, 2005,28:436-445.
[162]Johnson S.A., Fournier N.M., Kalynchuk L.E. Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res,2006, 168:280-288.
[163]胡建,刘薇,夏炎等.慢性酒中毒患者大脑萎缩的CT研究.中国行为医学科学,2005,14(11)：984-985.
[164]Namura I., Hishikawa Y.. Cerebal damages in alcoholic patients visualized by MRI:With special reference to frontal atrophy, basal ganglia and white matter lesion. Nippon Rinsho,1997,55 Suppl: 288.
[165]Pfefferbaum A., Sullivan E.V., Mathalon D.H., et al. Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapse alcoholics. Alcohol Clin Exp Res,1995, 19:1177.
[166]Pierce C. R., Audrey F. P., and Balakrishna M. P.. Neurotrophin-3 Contributes to the Initiation of Behavioral Sensitization to Cocaine by Activating the Ras/Mitogen-Activated Protein Kinase Signal Transduction Cascade. The Journal of Neuroscience,1999,19(19):8685-8695.
[167]Cirulli F., Berry A., Chiarotti F., et al., Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze. Hippocampus,2004,14(7):802-807.
[168]Mizuno M., Yamada K., Olariu A., et al. Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J. Neurosci,2000,20(18): 7116-7121.
[169]Jonathan L. C. Lee. Barry J. Everitt. Kerrie L. Thomas. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science,2004,304,839-843.
[170]Rattiner L.M., Davis M., French C.T., et al. Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. J. Neurosci,2004, 24(20):4796-4806.
[171]Rattiner L.M., Davis M., Ressler K.J.. Brain-derived neurotrophic factor in amygdala-dependent learning. Neuroscientist,2005,11(14):323-333.
[172]Alonso M, Vianna M.R., Depino A.M., et al. BDNF-triggered events in the rat hippocampus are required for both short-and long-term memory formation. Hippocampus,2002,12(4):551-560.
[173]Alonso M., Bekinschtein P., Cammarota M., et al. Endogenous BDNF is required for long-term memory formation in the rat parietal cortex. Learn. Mem,2005,12(4):504-510.
[174]Bekinschtein P., Cammarota M., Igaz L.M., et al. Persistence of long-term memory storage requires a late protein synthesis-and BDNF-dependent phase in the hippocampus. Neuron,2007, 53(2):261-277.
[175]Tyler W.J., Alonso M., Bramham C.R., et al. From acquisition to consolidation:on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn. Mem,2002, 9(5):224-237.
[176]Mu J.S., Li W.P., Yao Z.B., et al. Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain. Res,1999,835(2):259-265.
[177]Moonat S., Sakharkar A.J., Zhang H.B. et al. The role of amygdaloid brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein and dendritic spines in anxiety and alcoholism. Addiction Biology,2010,16:238-250.
[178]Altar C.A., Cai N., Bliven T.T., et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature,1997,389:856-860.
[179]Pandey S.C., Zhang H., Ugale R., et al. Effector immediate-early gene Arc in the amygdala plays a critical role in alcoholism. The Journal of Neuroscience,2008,28(10):2589-2600.
[180]Miller R., King M. A., Heaton M. B., et al. The effects of chronic ethanol consumption on neurotrophins and their receptors in the rat hippocampus and basal forebrain. Brain Res,2002,950: 137-147.
[181]Okamoto H., Miki T., Lee K. Y., et al. Effects of chronic ethanol administration on the expression levels of neurotrophic factors in the rat hippocampus. Okajimas Folia Anat Jpn,2006,83:1-6.
[182]Heaton M. B., Kim D. S., and Paiva, M. Neurotrophic factor protection against ethanol toxicity in rat cerebellar granule cell cultures requires phosphatidylinositol 3-kinase activation. Neurosci Lett, 2000,291:121-125.
[183]Bonthius D. J., Karacay B., Dai D., et al. FGF-2, NGF and IGF-1, but not BDNF, utilize a nitric oxide pathway to signal neurotrophic and neuroprotective effects against alcohol toxicity in cerebellar granule cell cultures. Brain Res Dev Brain Res,2003,140:15-28.
[1]Shuang Y., Holsboer F., Osborne F.X. Neuronal actions of glucocorticoids:Focus on dep ression [J]. J Steroid BiochemMolBiol,2008,108 (3/5):300-309.
[2]Mathers C, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030 [J]. PLoSMed,2006,3 (11):e442.
[3]Kessler R.C., Berglund P., Demler O., et al. The epidemiology of major depressive disorder:results from the National Comorbidity Survey Replication (NCS-R). JAMA,2003,289:3095-3105.
[4]John M. The medical management of depression. N Engl J Med,2005,353:1819-1834.
[5]Bradvik L., Berglund M. Suicidal ideation in severe depression. Eur Arch Psychiatry Clin Neurosci, 2000,250:139-143.
[6]McEwen B.S. Stress and hippocampal plasticity. Annu Rev Neurosci,1999,22:105-122.
[7]Gould E., Tanapat P., McEwen B.S., et al. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA,1998,95:3168-3171.
[8]Erickson P.S., Perfilieva E., Bjork-Erikkson T., et al. Neurogenesis in the adult human hippocampus. Nat Med,1998,4:1313-1317.
[9]Rupshi M., Karan S., Karen J.P., et al. Social stress related behavior affects hippocampal cell proliferation in mice. Physiology& Behavior,2006,89:123-127.
[10]Santarelli L., Saxe M., Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science,2003,301:805-809.
[11]Huang E.J., Reichardt L.F. Neurotrophins:roles in neuronal development and function. Annu Rev Neurosci,2001,24:677-736.
[12]Karege F., Bondolfi G, Gervasoni N., et al. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry,2005,57(9):1068-1072.
[13]Thoenen H. Neurotrophins and neuronal plasticity. Science,1995,270:593-598.
[14]Altar C.A., Cai N., Bliven T., et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature,1997,389:856-860.
[15]Bartrup J.T., Moorman J.M., Newberry N.R. BDNF enhances neuronal growth and synaptic activity in hippocampal cell cultures. Neuroreport,1997,8:3791-3794.
[16]Acheson A., Conover J.C., Fandl J.P., et al. A BDNF autocrine loop in adult sensory neurons prevents cell death". Nature,1995,374 (6521):450-453.
[17]Yamada K., Nabeshima T. Brain-derived neurotrophic factor/TrkB signaling in memory processes". J. Pharmacol. Sci,2003,91 (4):267-270.
[18]Bekinschtein P., Cammarota M, Katche C, et al. BDNF is essential to promote persistence of long-term memory storage, Proc. Natl. Acad. Sci. U.S.A.,2008,105 (7):2711-2716.
[19]Zigova T., Pencea V., Wiegand S.J., et al. Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol. Cell. Neurosci,1998,11 (4): 234-245.
[20]Benraiss A., Chmielnicki E., Lerner K., et al. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J. Neurosci,2001,21 (17):6718-6731.
[21]Pencea V., Bingaman K.D., Wiegand S.J., et al. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J. Neurosci,2001,21 (17):6706-6717.
[22]Ernfors P., Kucera J., Lee K.F., et al. Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice. Int. J. Dev. Biol.,1995,39 (5):799-807.
[23]Kafitz K.W., Rose C.R., Thoenen H., et al. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature,1999,401:918-921.
[24]Yogesh D., Hooriyah S. R., Robert R. C, et al. Altered Gene Expression of Brain-Derived Neurotrophic Factor and Receptor Tyrosine Kinase B in Postmortem Brain of Suicide Subjects. Arch Ge Psychiatry,2003,60:804-815.
[25]Warner-Schmidt J.L., Duman R.S. Hippocampal neurogenesis:opposing effects of stress and antidepressant treatment. Hippocampus,2006,16:239-249.
[26]Molteni R., Calabrese F., Bedogni F., et al. Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions. Neuropsychopharmacology,2005,22:1-11.
[27]Brown C.M., Cooper-Kuhn G., Kempermann H., et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci.,2003,17:2042-2046.
[28]Helen S., Jeffrey G., Adam M., et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Experimental Neurology,2005,192:348-356.
[29]李云峰,罗质璞.抑郁症发病机制及治疗药物.神经药理学新论.北京：人民卫生出版社,2004,1-20.
[30]Kempermann G., Kuhn H.G., Gage F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature,1997,386:493-495.
[31]Nibuya M., Morinobu S., Duman R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci,1997,15:7539-7547.
[32]Tuomisto J., Tukiainen E. Decreased uptake of 5-hydroxytryptamine in blood platelets from depressed patients. Nature,1976,262:596-598.
[33]Mowla S.J., Pareek S., Farhadi H.F., et al. Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J Neurosci,1999,19:2069-2080.
[34]Balkowiec A., Katz D.M. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J Neurosci,2002,22:10399-10407.
[35]Heymach J.V., Jr, Kruttgen A., et al. The regulated secretion and vectorial targeting of neurotrophins in neuroendocrine and epithelial cells. J Biol Chem,1996,271:25430-25437.
[36]Teng H.K., Teng K.K., Lee R., et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci,2005,25:5455-5463.
[37]Woo N.H., Teng H.K., Siao C.J., et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat. Neurosci,2005,8:1069-1077.
[38]Seidah N.G., et al. Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett,1996,379:247-250.
[39]Mowla S.J., Farhadi H.F., Pareek S., et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem,2001,276(16):12660-12666.
[40]Lee R., Kermani P., Teng K.K., et al. Regulation of cell survival by secreted proneurotrophins. Science,2001,294:1945-1948.
[41]Pang P.T., H.K. Teng, E. Zaitsev, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science,2004,306:487-491.
[42]Lu B., Pang P.T., Woo N.H. The yin and yang of neurotrophin action. Nat Rev Neurosci,2005, 6:603-614.
[43]Rosch H., Schweigreiter R., Bonhoeffer T., et al. The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc. Natl. Acad. Sci. USA.,2005,102:7362-7367.
[44]Korte M., Carroll P., Wolf E., et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA.,1995,92:8856-8860.
[45]Figurov A., Pozzo-Miller L.D., Olafsson P., et al. Regulation of synaptic responses,to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature,1996,381:706-709.
[46]Patterson S.L., Abel T., Deuel T.A., et al. Recombinant BDNF rescues decits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron,1996,16:1137-1145.
[47]Yang J., Siao C.J., Nagappan G, et al. Neuronal release of proBDNF. Nat. Neurosci,2009, 12:113-115.
[48]Matsumoto T., Rauskolb S., Polack,M. et al. Biosynthesis and processing of endogenous BDNF:CNS neurons store and secrete BDNF, not proBDNF. Nat. Neurosci,2008,11:131-133.
[49]Nagappan G, E. Zaitsev, V.V. Senatorov Jr., et al. Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc. Natl. Acad. Sci. USA.,2009,106:1267-1272.
[50]Deppmann C.D., Mihalas S., Sharma N., et al. A model for neuronal competition during development. Science,2008,320:369-373.
[51]Martinowich K., Manji H., Lu B. New insights into BDNF function in depression and anxiety. Nature Neuroscience,2007,10:1089-1093.
[52]Chen Z.Y., Patel P.D., Sant G., et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci,2004,24:4401-4411.
[53]Egan M.F., Kojima M., Callicott J.H., et al. The BDNF va166met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell,2003, 112:257-269.
[54]Hashimoto R., Moriguchi Y., Yamashita F., et al. Dose-dependent effect of the Va166Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity. Neurosci Res.,2008,61:360-367.
[55]Gong P., Zheng A., Chen D., et al. Effect of BDNF Va166Met polymorphism on digital working memory and spatial localization in a healthy Chinese Han population. J Mol Neurosci,2009, 38:250-256.
[56]Hariri A.R., Goldberg T.E., Mattay V.S., et al. Brain-derived neurotrophic factor va166met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci,2003,23:6690-6694.
[57]Montag C, Weber B., Fliessbach K., et al. The BDNF Va166Met polymorphism impacts parahippocampal and amygdala volume in healthy humans:incremental support for a genetic risk factor for depression. Psychol Med,2009,39:1831-1839.
[58]Matsuo K., Walss-Bass C, Nery F.G., et al. Neuronal correlates of brain-derived neurotrophic factor Va166Met polymorphism and morphometric abnormalities in bipolar disorder. Neuropsychopharmacology,2009,34:1904-1913.
[59]Green E., Craddock N. Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: evidence, limitations, and implications. Curr Psychiatry Rep.,2003,5:469-476.
[60]Karege F., Perret G., Bondolfi G., et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res.,2002,109:143-148.
[61]Duman R.S., Vaidya V.A. Molecular and cellular actions of chronic electroconvulsive seizures. J ECT. 1998,14:181-193.
[62]Chen B., Dowlatshahi D., MacQueen G.M., et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry,2001,50:260-265.
[63]Shirayama Y., Chen A.C., Nakagawa S., et al. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci,2002,22:3251-3261.
[64]Siuciak J.A., Lewis D.R., Wiegand S.J., et al. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav.,1997,56:131-137.
[65]Stern A.J., Savostyanova A.A., Goldman A., et al. Impact of the brain-derived neurotrophic factor Va166Met polymorphism on levels of hippocampal N-acetyl-aspartate assessed by magnetic resonance spectroscopic imaging at 3 Tesla. Biol Psychiatry,2008,64:856-862.
[66]Pezawas L., Verchinski B.A., Mattay V.S., et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci.,2004,24:10099-10102.
[67]Bueller J.A., Aftab M., Sen S., et al. BDNF Va166Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry,2006,59:812-815.
[68]Nemoto K.., Ohnishi T., Mori T., et al. The Va166Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett.,2006,397:25-29.
[69]Vollmayr B., Keck S., Henn F.A., et al. Acute stress decreases serotonin transporter mRNA in the raphe pontis but not in other raphe nuclei of the rat. Neurosci Lett.,2000,290:109-112.
[70]Frodl T., Schiile C, Schmitt G, et al. Association of the brain-derived neurotrophic factor va166met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry,2007, 64:410-416.
[71]Yulay B., Ozan E., Aydin N., et al. Brain-derived neurotrophic polymorphism:more than a prognostic factor during depression? J Neuropsychiatry Clin Neurosci,2009,21:471-472.
[72]Jiang X., Xu K., Hoberman J., et al. BDNF variation and mood disorders:a novel functional promoter polymorphism and Va166Met are associated with anxiety but have opposing effects. Neuropsychophannacology,2005,30:1353-1361.
[73]Hall D., Dhilla A., Charalambous A., et al. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet, 2003,73370-73376.
[74]Sklar P., Gabriel S. B., Mclnnis M.G., et al. Family-based association study of 76 candidate genes in bipolar disorder:BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry, 2002,7579-7593.
[75]Neves-Pereira M., Mundo E., Muglia P., et al. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder:evidence from a family-based association study. Am J Hum Genet, 2002,71651-71655.
[76]Geller B., Badner J.A., Tillman R., et al. Linkage disequilibrium of the brain-derived neurotrophic factor Va166Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry,2004,16:11698-1700.
[77]Sen S., Nesse R. M., Stoltenberg S. F., et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology, 2003,28:397-401.
[78]Kang R.H., Chang H.S., Wong ML., et al. Brain-derived neurotrophic factor gene polymorphisms and mirtazapine responses in Koreans with major depression. Journal of Psychopharmacology,2009, doi:10.1177/0269881109105457
[79]Tsai S. J., Hong C. J., Yu Y. W. et al. Association Study of a Brain-Derived Neurotrophic Factor (BDNF) Va166Met Polymorphism and Personality Trait and Intelligence in Healthy Young Females. Neuropsychobiology,2004,49:13-16.
[80]Taylor Warren D., Zuchner Stephan, McQuoid Douglas R. B.S., et al. Differences in the Brain-Derived Neurotrophic Factor Va166Met Polymorphism in Late-Life Depression. American Journal of Geriatric Psychiatry,2007,10:850-857.
[81]Hwang J.P., Tsai S.J., Hong C.J., et al. The Va166Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging,2006, 27:1834-1837.
[82]Tsai S.J., Cheng C.Y., Yu Y.W., et al. Association study of brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet,2003,123:19-22.
[83]Hong C.J., Huo S.J., Yen F.C., et al. Association study of brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology,2003, 48:186-189.
[84]Willis-Owen SAG, Fullerton J., Surtees P.G., et al. The Va166Met coding variant of the brain-derived neurotrophic factor (BDNF) gene does not contribute toward variation in the personality trait neuroticism. Biol Psychiatry,2005,58:738-742.
[85]Paul G. Surtees, Nicholas W.J. Wainwright, Saffron A.G. Willis-Owen, et al. No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults. Journal of Psychiatric Research,2007,5:404-409.
[86]Gratacos M., Gonzalez J.R., Mercader J.M., et al. Brain-derived neurotrophic factor Val66Met and psychiatric disorders:Meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry,2007,61:911-922.
[87]Verhagen M., van der Meij A., van Deurzen P.A., et al. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder:Effects of gender and ethnicity. Mol Psychiatry, 2010,15(3):260-271.
[88]Chao M. V. Neurotrophins and their receptors:a convergence point for many signalling pathways. Nat Rev Neurosci,2003,4:299-309.
[89]Friedman W. J, Greene L. A. Neurotrophin signaling via Trks and p75. Exp Cell Res,1999,25: 3131-3142.
[90]Beattie M. S., Harrington A.W., Lee R., et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron,2002,36:375-386.
[91]Bui N. T., Konig H. G., Culmsee C, et al. p75 neurotrophin receptor is required for constitutive and NGF-induced survival signaling in PC12 cells and rat hippocampal neurons. J Neuro chem.,2002, 8:594-605.
[92]Lu B. Pro-region of neurotrophins:role in synaptic modulation. Neuron,2003,3;735-738.
[93]Licinio J., Dong C, Wong M.L. Novel sequence variations in the brain-derived,neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry,2009,66:488-497.