PTSD大鼠模型不同脑区谷氨酸受体的表达变化
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摘要
创伤后应激障碍(Post-traumatie stress disorder，PTSD)是指对亲身经历或目睹的异乎寻常的威胁性、灾难性事件的剧烈反应。人们对创伤后应激障碍的认识已有100余年历史，曾被冠名为“炮弹休克”、“战争神经症”等。在美国精神障碍诊断与统计手册第三版(DSM-Ⅲ)中首次定义PTSD，并描述了其重新体验创伤、回避、过度警觉等三组主要症状。重新体验创伤症状包括梦魇、闪回记忆、创伤幻觉重现；回避症状包括故意遗忘、不愿谈论或回想；过度警觉症状包括严重的惊恐反应、睡眠障碍、注意力难以集中等。
目前研究PTSD最多的是采用脑功能成像技术，主要用PET和fMRI。有的研究认为PTSD患者的海马体积变小，且与PTSD症状的严重程度成正相关；而有的认为PTSD患者海马体积没有变化。还有的研究发现PTSD患者晚期左侧杏仁核变小但活动增强，而早期右侧杏仁核反应降低。PTSD患者的前额叶体积似乎更小，在相关的认知任务试验中反应低下。
谷氨酸受体家族分为离子型谷氨酸受体和代谢型谷氨酸受体两大类。离子型谷氨酸受体根据选择性激动剂的不同又可分为NMDA受体、AMPA受体和KA受体。离子型谷氨酸受体介导中枢神经系统的兴奋性突触传递。NMDA受体是由NR1、NR2或NR3亚单位组成的异聚体分子。已知NR1亚单位是NMDA受体的必需组分，不同的NR2亚单位与NR1装配形成了具有不同通道特征的NMDA受体亚型。NMDA受体是一类电压依赖的配体门控型离子通道，通道开放不仅需要谷氨酸和甘氨酸的共同结合，还需解除Mg~(2+)对通道阻滞作用。AMPA受体主要是由GluR1、GluR2、GluR3和GluR4四种亚单位组成，目前认为AMPA受体是由四个亚单位组成的四聚体，既可以形成同聚体也可以形成异聚体。AMPA受体主要介导了中枢神经系统快速的兴奋性突触传递。AMPA受体激活引起细胞膜部分去极化，当去极化达到一定程度时解除Mg~(2+)对NMDA受体通道的阻滞作用。研究表明，NMDA受体通道的激活有助于AMPA受体插入到树突棘的膜表面，从而使突触传递效能明显增强。
目前没有治疗PTSD的特效药，仅限于用其他精神疾病的药物来替代治疗。先前的药理学研究表明阻断AMPA受体可以缓解PTSD的症状，但是具体哪个或者哪几个脑区参与其中，以及可能的分子机制尚不清楚。根据功能影像学研究，PTSD患者可能存在杏仁核、海马、前额叶皮层几个脑区结构和功能的改变。已知谷氨酸受体在突触可塑性和学习记忆方面起着重要作用，而PTSD与恐惧记忆密切相关。因此，在本研究中我们通过研究PTSD大鼠模型谷氨酸受体在海马、前额叶皮层、杏仁核这三个脑区的表达变化，来探究PTSD敏感化症状的分子机制，为临床治疗PTSD提供一定的理论依据。
到现在为止，还没有能完全模拟人类PTSD疾病的动物模型，只能模拟PTSD的某个症状。我们根据Rau V，DeCola JP的研究建立了PTSD大鼠模型(该模型能有效模拟PTSD重要特征之一—敏感化)；将大鼠断颈处死，立即取脑，在冰上分离出海马、前额叶皮层、杏仁核；根据经典的方法提取脑组织总蛋白和膜蛋白；免疫印迹反应检测NR1、GluR1的含量。我们发现：(1)在海马部位，PTSD组膜蛋白GluR1含量显著升高，且维持在高水平。提示PTSD可能影响了海马的突触结构和功能，从而导致了行为敏感化。(2)在前额叶皮，PTSD组和Control组神经元细胞膜表面AMPA受体和NMDA受体含量均显著低于Naive组，这个结果提示应激可能引起前额叶皮层的活动降低，与影象学的结果一致。(3)在杏仁核，PTSD组NR1含量较Control组升高，PTSD组总蛋白中NR1的增加可能与其恐惧记忆相关。
Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been know over a hundrand years, ever been named as "shell shock"or "war neurosis". PTSD is characterized in the DSM-III by a phenomenological triad incorporating the symptoms of re-experiencing, avoidance and hyperarousal. The re-experiencing symptoms of PTSD include nightmares, intrusive memories and flashbacks of the trauma. The avoidance symptoms Neurobiology of posttraumatic stress disorder include amnesia for the trauma or a reluctance to discuss or think about the trauma. Finally, the hyperarousal symptoms include an exaggerated startle response, fitful sleep and poor concentration.
Most functional brain imaging studies in PTSD have used either PET or fMRI. Imaging studies in PTSD patients have demonstrated volume reductions in the hippocampus that appear correlated with illness severity and the degree of cognitive deficit, although there is evidence of decreased hippocampal volume predating PTSD. PTSD subjects also showed a small but significant enhancement in left amygdala activity, most apparent during the late phase, but reduction in Early right amygdala response. In contrast, prefrontal cortex appears to be volumetrically smaller and is hyporesponsive during symptomatic states and the performance of
cognitive tasks in PTSD.
Glutamate receptors are classified into two groups: ionotropic and metabotropic receptor families. There are three major types of ionotropic glutamate receptors (iGluRs), which are named after reasonably selective agonists, thus, called N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) and 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine (kainate) receptors. Ionotropic glutamate receptors mediate the vast majority of fast excitatory synaptic transmission in the CNS. NMDA receptors are heteromeric complexes incorporating different subunits within a repertoire of three subtypes: NR1, NR2 and NR3. It is widely recognized that the NR1 subunit is essential to the functional NMDA receptor channels, while various combinations of NR2 and NR1 subunits could endow NMDA receptor channel with different functional properties. NMDA receptor is a voltage-dependent ligand-gated ion channel. Activation of NMDA receptor not only requires to bind with glutamate and glycine, but also need to remove Mg~(2+) from NMDA receptor channel by membrane depolarization. AMPA receptors can exist as either homomeric or heteromeric assemblies of GluR1-4 receptor. AMPA receptors are the principal molecular units for fast excitatory synaptic transmission in the central nervous system. Activation AMPA receptor cause local membrane depolarization, which can release Mg~(2+) from nearby NMDA channel. Previous studies indicated, activation of NMDA receptor can induce AMPA receptors to insert into cell membrane of dendrite spine and enhance the synapse transmission efficiency.
Until now, there is no wonder drug which can be used for PTSD medications and other mental disorder is always clinically used instead. Pevious pharmacological studies indicated that inhibition of AMPA receptor can ameliorate the symptom of PTSD, whereas the brain regions and mechanisms which are involved in PTSD are unknown. According to brain imaging studies, the brain regions involved in PTSD may include hippocampus, prefrontal cortex and amygdala, which may change functionally and structurally. It is well known that glutamate receptors play a key role in synaptic plasticity. In additon, PTSD is associated with fear memory and
synaptic plasticity in these brain regions. Therefore, in this study, to explore the sensitization mechanism of PTSD, we examined the expression level of the glutamate receptors in the hippocampus, prefrontal cortex and amylgada regions of PTSD model. It may aid to understand the underlying mechanism of PTSD sensitization and provide value for clinical therapy.
So far, there is no any animal model of PTSD which can mimic human symptom. According to Rau V's study, we established an animal model of PTSD, which successfully mimic the sensitizaiton, one of the important symptoms of PTSD. Exposure therapy (extinction) and amnestic (NMDA antagonist) treatment have no effect on this PTSD model. After treatment described as above, animals were sacrificed immediately. Hippocampus, prefrontal cortex and amygdala were dissected on ice. Total protein and membrane protein extraction were carried out using techniques described previously. Then, we examined the expression of NR1 and GluRl by Semi-quantitative Western blotting analysis. We found that hippocampal GluRl in membrane fraciton of PTSD group increased and maintained at hight level compared with control group. It suggests that trauma event may effect on synaptic structure and founction in hippocampus, thus result in behavioral sensitization. Moreover, our results indicate that, in stress groups, expression of NR1 and GluRl decreased compared with Naive group, which suggests stress reduced activity, and is consistent with neruoimaging. Finaly, NR1 amygdaloid totl lysis of PTSD group is increased. It suggests that NR1 increase may be related with fear memory of PTSD.
目前研究PTSD最多的是采用脑功能成像技术，主要用PET和fMRI。有的研究认为PTSD患者的海马体积变小，且与PTSD症状的严重程度成正相关；而有的认为PTSD患者海马体积没有变化。还有的研究发现PTSD患者晚期左侧杏仁核变小但活动增强，而早期右侧杏仁核反应降低。PTSD患者的前额叶体积似乎更小，在相关的认知任务试验中反应低下。
谷氨酸受体家族分为离子型谷氨酸受体和代谢型谷氨酸受体两大类。离子型谷氨酸受体根据选择性激动剂的不同又可分为NMDA受体、AMPA受体和KA受体。离子型谷氨酸受体介导中枢神经系统的兴奋性突触传递。NMDA受体是由NR1、NR2或NR3亚单位组成的异聚体分子。已知NR1亚单位是NMDA受体的必需组分，不同的NR2亚单位与NR1装配形成了具有不同通道特征的NMDA受体亚型。NMDA受体是一类电压依赖的配体门控型离子通道，通道开放不仅需要谷氨酸和甘氨酸的共同结合，还需解除Mg~(2+)对通道阻滞作用。AMPA受体主要是由GluR1、GluR2、GluR3和GluR4四种亚单位组成，目前认为AMPA受体是由四个亚单位组成的四聚体，既可以形成同聚体也可以形成异聚体。AMPA受体主要介导了中枢神经系统快速的兴奋性突触传递。AMPA受体激活引起细胞膜部分去极化，当去极化达到一定程度时解除Mg~(2+)对NMDA受体通道的阻滞作用。研究表明，NMDA受体通道的激活有助于AMPA受体插入到树突棘的膜表面，从而使突触传递效能明显增强。
目前没有治疗PTSD的特效药，仅限于用其他精神疾病的药物来替代治疗。先前的药理学研究表明阻断AMPA受体可以缓解PTSD的症状，但是具体哪个或者哪几个脑区参与其中，以及可能的分子机制尚不清楚。根据功能影像学研究，PTSD患者可能存在杏仁核、海马、前额叶皮层几个脑区结构和功能的改变。已知谷氨酸受体在突触可塑性和学习记忆方面起着重要作用，而PTSD与恐惧记忆密切相关。因此，在本研究中我们通过研究PTSD大鼠模型谷氨酸受体在海马、前额叶皮层、杏仁核这三个脑区的表达变化，来探究PTSD敏感化症状的分子机制，为临床治疗PTSD提供一定的理论依据。
到现在为止，还没有能完全模拟人类PTSD疾病的动物模型，只能模拟PTSD的某个症状。我们根据Rau V，DeCola JP的研究建立了PTSD大鼠模型(该模型能有效模拟PTSD重要特征之一—敏感化)；将大鼠断颈处死，立即取脑，在冰上分离出海马、前额叶皮层、杏仁核；根据经典的方法提取脑组织总蛋白和膜蛋白；免疫印迹反应检测NR1、GluR1的含量。我们发现：(1)在海马部位，PTSD组膜蛋白GluR1含量显著升高，且维持在高水平。提示PTSD可能影响了海马的突触结构和功能，从而导致了行为敏感化。(2)在前额叶皮，PTSD组和Control组神经元细胞膜表面AMPA受体和NMDA受体含量均显著低于Naive组，这个结果提示应激可能引起前额叶皮层的活动降低，与影象学的结果一致。(3)在杏仁核，PTSD组NR1含量较Control组升高，PTSD组总蛋白中NR1的增加可能与其恐惧记忆相关。
Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been know over a hundrand years, ever been named as "shell shock"or "war neurosis". PTSD is characterized in the DSM-III by a phenomenological triad incorporating the symptoms of re-experiencing, avoidance and hyperarousal. The re-experiencing symptoms of PTSD include nightmares, intrusive memories and flashbacks of the trauma. The avoidance symptoms Neurobiology of posttraumatic stress disorder include amnesia for the trauma or a reluctance to discuss or think about the trauma. Finally, the hyperarousal symptoms include an exaggerated startle response, fitful sleep and poor concentration.
Most functional brain imaging studies in PTSD have used either PET or fMRI. Imaging studies in PTSD patients have demonstrated volume reductions in the hippocampus that appear correlated with illness severity and the degree of cognitive deficit, although there is evidence of decreased hippocampal volume predating PTSD. PTSD subjects also showed a small but significant enhancement in left amygdala activity, most apparent during the late phase, but reduction in Early right amygdala response. In contrast, prefrontal cortex appears to be volumetrically smaller and is hyporesponsive during symptomatic states and the performance of
cognitive tasks in PTSD.
Glutamate receptors are classified into two groups: ionotropic and metabotropic receptor families. There are three major types of ionotropic glutamate receptors (iGluRs), which are named after reasonably selective agonists, thus, called N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) and 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine (kainate) receptors. Ionotropic glutamate receptors mediate the vast majority of fast excitatory synaptic transmission in the CNS. NMDA receptors are heteromeric complexes incorporating different subunits within a repertoire of three subtypes: NR1, NR2 and NR3. It is widely recognized that the NR1 subunit is essential to the functional NMDA receptor channels, while various combinations of NR2 and NR1 subunits could endow NMDA receptor channel with different functional properties. NMDA receptor is a voltage-dependent ligand-gated ion channel. Activation of NMDA receptor not only requires to bind with glutamate and glycine, but also need to remove Mg~(2+) from NMDA receptor channel by membrane depolarization. AMPA receptors can exist as either homomeric or heteromeric assemblies of GluR1-4 receptor. AMPA receptors are the principal molecular units for fast excitatory synaptic transmission in the central nervous system. Activation AMPA receptor cause local membrane depolarization, which can release Mg~(2+) from nearby NMDA channel. Previous studies indicated, activation of NMDA receptor can induce AMPA receptors to insert into cell membrane of dendrite spine and enhance the synapse transmission efficiency.
Until now, there is no wonder drug which can be used for PTSD medications and other mental disorder is always clinically used instead. Pevious pharmacological studies indicated that inhibition of AMPA receptor can ameliorate the symptom of PTSD, whereas the brain regions and mechanisms which are involved in PTSD are unknown. According to brain imaging studies, the brain regions involved in PTSD may include hippocampus, prefrontal cortex and amygdala, which may change functionally and structurally. It is well known that glutamate receptors play a key role in synaptic plasticity. In additon, PTSD is associated with fear memory and
synaptic plasticity in these brain regions. Therefore, in this study, to explore the sensitization mechanism of PTSD, we examined the expression level of the glutamate receptors in the hippocampus, prefrontal cortex and amylgada regions of PTSD model. It may aid to understand the underlying mechanism of PTSD sensitization and provide value for clinical therapy.
So far, there is no any animal model of PTSD which can mimic human symptom. According to Rau V's study, we established an animal model of PTSD, which successfully mimic the sensitizaiton, one of the important symptoms of PTSD. Exposure therapy (extinction) and amnestic (NMDA antagonist) treatment have no effect on this PTSD model. After treatment described as above, animals were sacrificed immediately. Hippocampus, prefrontal cortex and amygdala were dissected on ice. Total protein and membrane protein extraction were carried out using techniques described previously. Then, we examined the expression of NR1 and GluRl by Semi-quantitative Western blotting analysis. We found that hippocampal GluRl in membrane fraciton of PTSD group increased and maintained at hight level compared with control group. It suggests that trauma event may effect on synaptic structure and founction in hippocampus, thus result in behavioral sensitization. Moreover, our results indicate that, in stress groups, expression of NR1 and GluRl decreased compared with Naive group, which suggests stress reduced activity, and is consistent with neruoimaging. Finaly, NR1 amygdaloid totl lysis of PTSD group is increased. It suggests that NR1 increase may be related with fear memory of PTSD.
引文
[1] McNally RJ. (2002) Progress and controversy in the study of posttraumatic stress disorder. Annu Rev Psychol, 54:229-52.
[2] Terence M. Keane, Amy D. Marshall, and Casey T. Taft. (2006) POST-TRAUMATIC STRESS DISORDER: Etiology, Epidemiology, and Treatment Outcome. Annu. Rev. Clin. Psychol, 2:161-97.
[3] Foa EB, Meadows EA. (1997) Psychosocial treatments for posttraumatic stress disorder: a critical review. Annual review of psychology, 48:449-80.
[4] Broekman BF, Olff M, Boer F. (2007) The genetic background to PTSD. Neurosci Biobehav Rev, 31 (3):348-62.
[5] Hull AM. (2002) Neuroirnaging findings in post-traumatic stress disorder. Systematic review. The British journal of psychiatry, 181: 102-10.
[6] Kasai K, Yamasue H. (2005) Neuroimaging in posttraumatic stress disorder. No To Shinkei, 57(4):285-90.
[7] Corbo V, Clement MH, Armony JL, Pruessner JC, Brunet A.(2005) Size versus shape differences: contrasting voxel-based and volumetric analyses of the anterior cingulate cortex in individuals with acute posttraumatic stress disorder. Biol Psychiatr, 15;58(2): 119-24.
[8] Li Z, Zhou Q, Li L, Mao R, Wang M, Peng W, Dong Z, Xu L, Cao J. (2005) Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CA1 area in vivo. Hippocampus, 15(6):815-24.
[9] Bruening S, Oh E, Hetzenauer A, Escobar-Alvarez S, Westphalen RI, Hemmings HC Jr, Singewald N, Shippenberg T, Toth M. (2006) The anxiety-like phenotype of 5-HT receptor null mice is associated with genetic background-specific perturbations in the prefrontal cortex GABA-glutamate system. J Neurochem, 99(3):892-9.
[10] Harvey BH, Bothma T, Nel A, Wegener G, Stein DJ. (2005) Involvement of the NMDA receptor, NO-cyclic GMP and nuclear factor K-beta in an animal model of repeated trauma. Hum Psychopharmacol, 20(5):367-73.
[11] Harvey BH, Oosthuizen F, Brand L, Wegener G, Stein DJ. (2004) Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl), 175(4):494-502.
[12] Cohen H, Kaplan Z, Kotler M. (1999) CCK-antagonists in a rat exposed to acute stress: implication for anxiety associated with post-traumatic stress disorder. Depress Anxiety, 10(1):8-17.
[13] Uys JD, Muller CJ, Marais L, Harvey BH, Stein DJ, Daniels WM. (2006) Early life trauma decreases glucocorticoid receptors in rat dentate gyms upon adult re-stress: reversal by escitalopram. Neuroscience, 137(2):619-25.
[14] Scoville WB, Milner B. (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry, 20(1): 11-21.
[15] Barski JJ, Lewin-Kowalik J, Sieron AL. (1992) Current views on the structure and function of the hippocampus. Neurol Neurochir Po., 26(2):224-31.
[16] Ridderinkhof KR, van den Wildenberg WP, Segalowitz SJ, Carter CS. (2004) Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain Cogn, 56(2): 129-40.
[17] Bussey TJ, Wise SP, Murray EA. (2001) The role of ventral and orbital prefrontal cortex in conditional visuomotor learning and strategy use in rhesus monkeys (Macaca mulatta). Behav Neurosci,115(5):971-82.
[18] Funahashi S, Kubota K. (1994) Working memory and prefrontal cortex. Neurosci Res, 21(1):1-11.
[19] D'Esposito M, Aguirre GK, Zarahn E, Ballard D, Shin RK, Lease J. (1998) Functional MRI studies of spatial and nonspatial working memory. Brain Res Cogn Brain Res, 7(1):1-13.
[20] Ferbinteanu J, Kennedy PJ, Shapiro ML. (2006) Episodic memory-from brain to mind. Hippocampus, 16(9):691-703.
[21] Torras M, Portell I, Morgado I. (2001) The amigdaloid body: functional implications. Rev Neurol, 33(5):471-6.
[22] Fox RJ, Sorenson CA. (1994) Bilateral lesions of the amygdala attenuate analgesia induced by diverse environmental challenges. Brain Res, 648(2):215-21.
[23] Wallace KJ, Rosen JB. (2001) Neurotoxic lesions of the lateral nucleus of the amygdala decrease conditioned fear but not unconditioned fear of a predator odor: comparison with electrolytic lesions. J Neurosc, 21 (10):3619-27.
[24] Davis M. (1997) Neurobiology of fear responses: the role of the amygdala. J Neuropsychiatry Clin Neurosci, 9(3):382-402.
[25] Pare D, Quirk GJ, (2004) Ledoux JE. New vistas on amygdala networks in conditioned fear. J Neurophysiol, 92(1): 1-9.
[26] Watkins JC, Jane DE. (2006) The glutamate story. Br J Pharmacol., 147 Suppl 1 :S100-8.
[27] Cull-Candy S, Brickley S, Farrant M. (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol, 11 (3):327-35.
[28] Collingridge GL, Isaac JT, Wang YT. (2004) Receptor trafficking and synaptic plasticity. Nat Rev Neurosci, 5(12):952-62.
[29] Dingledine R, Borges K Traynelis SF, Bowie D. (1999) The glutamate receptor ion channels. Pharmacol Rev, 51 (1):7-61.
[30] Kuba K, Kumamoto E. (1990) Long-term potentiations in vertebrate synapses: a variety of cascades with common subprocesses. Prog Neurobiol, 34(3): 197-269.
[31] Artola A, Singer W. (1993)Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends in neurosciences, 16(11):480-7.
[32] Hawkins RD, Kandel ER, Siegelbaum SA. (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annu Rev Neurosci, 16:625-65.
[33] Hollmann M, Heinemann S.(1994) Cloned glutamate receptors. Annu Rev Neurosc, 17:31-108.
[34] Tanaka H, Grooms SY, Bennett MV, Zukin RS. (2000) The AMPAR subunit GluR2: still front and center-stage. Brain Res, 886(1-2): 190-207.
[35] Wenthold RJ, Petralia RS, Blahos J II, Niedzielski AS. (1996) Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J Neurosci,16(6): 1982-9.
[36] Lin H, Huganir R, Liao D. (2004) Temporal dynamics of NMDA receptor-induced changes in spine morphology and AMPA receptor recruitment to spines. Biochem Biophys Res Commun, 316(2):501-11.
[37] Lee HK, Takamiya K, Han JS, Man H, Kim CH, Rumbaugh G, Yu S, Ding L, He C, Petralia RS, Wenthold RJ, Gallagher M, Huganir RL. (2003) Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell, 112(5):631-43.
[38] Reisel D, Bannerman DM, Schmitt WB, Deacon RM, Flint J, Borchardt T, Seeburg PH, Rawlins JN. (2002) Spatial memory dissociations in mice lacking GluR1. Nat Neurosci, 5(9):868-73.
[39] Zullino DF, Krenz S, Besson J. (2003) AMPA blockade may be the mechanism underlying the efficacy of topiramate in PTSD. J Clin Psychiatry, 64(2):219-20.
[40] Rau V, DeCola JP, Fanselow MS. (2005) Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci Biobehav Rev, 29(8):1207-23.
[41] Fanselow, M. S., (1994) Neural organization of the defensive behavior system responsible for fear. Psychon. Bull. Rev, 1 (4), 429-438.
[42] Fanselow, M. S., 1980. Conditional and unconditional components of postshock freezing. Pavlov. J. Biol. Sci,15 (4), 177-182.
[43] George Paxinos, Charles Watson. (1997) The Rat Brainin Stereotaxic Coordinates
[44] Luo J, Wang Y, Yasuda RP, Dunah AW, Wolfe BB. (1997) The majority of N-methyl-D-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR 1/NR2A/NR2B). Mol Pharmaco, 51 (1):79-86.
[45] Zhu LJ, Chen Z, Zhang LS, Xu SJ, Xu AJ, Luo JH. (2004) Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. Neurosci Lett, 356(1):53-6.
[46] Chklovskii DB, Mel BW, Svoboda K. (2004) Cortical rewiring and information storage. Nature, 431 (7010):782-8.
[47] Khan S, Liberzon I. (2004) Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology, 172(2):225-9.
[48] Umegaki H, Yamamoto A, Suzuki Y, Iguchi A. (2006) Stimulation of the hippocampal glutamate receptor systems induces stress-like responses. Neuro Endocrinol Lett, 27(3):339-43.
[49] Pickering C, Gustafsson L, Cebere A, Nylander I, Liljequist S. (2006) Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex. Brain Res, 1099(1):101-8. Epub 2006 Jun 19.
[50] Pavic L, Gregurek R, Rados M, Brkljacic B, Brajkovic L, Simetin-Pavic I, Ivanac G, Pavlisa G, Kalousek V. (2007) Smaller right hippocampus in war veterans with posttraumatic stress disorder. Psychiatry Res, 154(2):191-8.
[51] Bremner JD. (2006) Stress and brain atrophy. CNS Neurol Disord Drug Targett, (5):503-12.
[52] Bremner JD. (2006) The relationship between cognitive and brain changes in posttraumatic stress disorder. Ann N Y Acad Sci, 1071:80-6.
[53] Liberzon I, Phan KL. (2003) Brain-imaging studies of posttraumatic stress disorder. CNS Spect, 8(9):641-50.
[54] Bartanusz V, Aubry JM, Pagliusi S, Jezova D, Baffi J, Kiss JZ. (2006) Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscienc, 66(2):247-52.
[55] Zhong W, Dong Z, Tian M, Cao J, Xu T, Xu L, Luo J. (2006) Opiate withdrawal induces dynamic expressions of AMPA receptors and its regulatory molecule CaMKIIalpha in hippocampal synapses. Life Sci, 79(9): 861-9.
[56] Schwendt M, Jezova D. (2000) Gene expression of two glutamate receptor subunits in response to repeated stress exposure in rat hippocampus. Cell Mol Neurobio., 20(3):319-29.
[57] Adamec RE, Burton P, Shallow T, Budgell J. (1999) NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure — implications for anxiety associated with posttraumatic stress disorder. Physiol Behav, 65(4-5):723-37.
[58] Lukoyanov NV, Paula-Barbosa MM. (2000) A single high dose of dizocilpine produces long-lasting impairment of the water maze performance in adult rats. Neurosci Lett, 285(2): 139-42.
[59] Reed JM, Squire LR. (1997) Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behav Neurosci.111(4):667-75.
[60] 徐淑君等．(2003)大鼠海马NMDA受体NR1亚单位蛋白的基础表达量与学习记忆相关．浙江大学学报(医学版)，32(6)：465-9
[61] Son GH, Geum D, Chung S, Kim EJ, Jo JH, Kim CM, Lee KH, Kim H, Choi S, Kim HT, Lee CJ, Kim K. (2006) Maternal stress produces learning deficits associated with impairment of NMDA receptor-mediated synaptic plasticity. J Neurosci, 26(12):3309-18.
[62] Williams LM, Kemp AH, Felmingham K, Barton M, Olivieri G, Peduto A, Gordon E, Bryant RA. (2006) Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. Neuroimage, 29(2):347-57.
[63] Matsuo K, Taneichi K, Matsumoto A, Ohtani T, Yamasue H, Sakano Y, Sasaki T, Sadamatsu M, Kasai K, Iwanami A, Asukai N, Kato N, Kato T. (2003) Hypoactivation of the prefrontal cortex during verbal fluency test in PTSD: a near-infrared spectroscopy study. Psychiatry Res, 124(1): 1-10
[64] Moghaddam B. (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem, 60(5): 1650-7.
[65] Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N. (2007) The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci, 27(11):2781-7.
[66] Vouimba RM, Yaniv D, Diamond D, Richter-Levin G. (2004) Effects of inescapable stress on LTP in the amygdala versus the dentate gyrus of freely behaving rats. Eur J Neurosci, 19(7): 1887-94.
[1] Foa EB, Meadows EA. (1997) Psychosocial treatments for posttraumatic stress disorder: a critical review. Annual review of psychology, 48:449-80,
[2] 许绍芬．神经生物学．第二版．上海医学大学出版社，1999，403．
[3] Hull AM. (2002) Neuroimaging findings in post-traumatic stress disorder. Systematic review. The British journal of psychiatry, 181: 102-10.
[4] Villarreal G, Hamilton DA, Petropoulos H, Driscoll I, Rowland LM, Griego JA, Kodituwakku PW, Hart BL, Escalona R, Brooks WM. (2002) Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder. Biological psychiatry, 52(2): 119-25.
[5] Pitman RK, Shin LM, Rauch SL. (2001) Investigating the pathogenesis of posttraumatic stress disorder with neuroimaging. The Journal of clinical psychiatry, 62 Suppl 17:47-54.
[6] Schuff N, Neylan TC, Lenoci MA, Du AT, Weiss DS, Marmar CR, Weiner MW. (2001) Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder. Biological psychiatry, 50(12):952-9.
[7] Thome J, Pesold B, Baader M, Hu M, Gewirtz JC, Duman RS, Henn FA. (2001) Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biological psychiatry, 50(10): 809-12.
[8] Arnsten AFT. (1998) Catecholamine modulation of prefrontal cognitive function. Trends of Cognitive Science, 2 (5): 436.
[9] Gilboa A, Shalev AY, Laor L, Lester H, Louzoun Y, Chisin R, Bonne O. (2004) Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biological psychiatry, 55(3):263-72.
[10] Swanson LW, Petrovich GD. (1998) What is the amygdala? Trends in neurosciences, 21 (8):323-31.
[11] De Bellis MD, Keshavan MS, Clark DB, Casey BJ, Giedd JN, Boring AM, Frustaci K, Ryan ND.(1999) A. E. Bennett Research Award. Developmental traumatology. Part Ⅱ: Brain development. Biological psychiatry, 45(10):1271-84.
[12] Lanius RA, Williamson PC, Densmore M, Boksman K, Gupta MA, Neufeld RW, Gati JS, Menon RS. (2001) Neural correlates of traumatic memories in posttraumatic stress disorder : a functional MRI investigation. The American journal of psychiatry, 158 :1920-1922.
[13] Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, et al. (1999) Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. American Journal of Psychiatry, 156: 585—8.
[14] Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, et al. (1997) Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. American Journal of Psychiatry, 154:624-9.
[15] Bremner JD, Vythilingam M, Anderson G, Vermetten E, McGlashan T, Heninger G, et al. (2003a) Assessment of the hypothalamic-pituitary-adrenal axis over a 24-hour diurnal period and in response to neuroendocrine challenges in women with and without childhood sexual abuse and posttraumatic stress disorder. Biological Psychiatry, 54:710-8.
[16] Yehuda R, Halligan SL, Grossman R, Golier JA, Wong C. (2002) The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder. Biological Psychiatry, 52(5):393-403.
[17] Yehuda R. (2001) Biology of posttraumatic stress disorder. The Journal of clinical psychiatry, 17:41-6
[18] Avital A, Segal M, Richter-Levin G (2006) Contrasting roles of corticosteroid receptors in hippocampal plasticity. The Journal of neuroscience, 26(36):9130-4.
[19] Conrad CD. (2006) What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus? Behavioral and cognitive neuroscience reviews, 5(1):41-60.
[20] Rau V, DeCola JP, Fanselow MS. (2005) Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neuroscience and biobehavioral reviews, 29(8): 1207-23
[21] Bliss TVP, Lomo T. (1973) Long-lasting potentiation of synaptic transmission in the dentate gyrus of the anesthetized rabbit following stimulation of the perforant path. J Physiol(Lond), 232:331-356
[22] Huang YY, Kandel ER, Varshavsky L, Brandon EP, Qi M, Idzerda RL, McKnight GS, Bourtchouladze R. (1995) A genetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell, 83(7):1211-22.
[23] Gustafsson B, Wigstrom H, Abraham WC, Huang YY. (1987) Long-term potentiation in the hippocampus using depolarizing current pulses as the conditioning stimulus to single volley synaptic potentials. J Neurosci, 7(3):774-80.
[24] Zalutsky RA, Nicoll RA. (1990) Comparison of two forms of long-term potentiation in single hippocampal neurons. Science, 248(4963): 1619-24.
[25] Kuba K, Kumamoto E. (1990) Long-term potentiations in vertebrate synapses: a variety of cascades with common subprocesses. Prog Neurobiol, 34(3): 197-269.
[26] Ito M, Kano M. (1982) Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci Lett, 33(3):253-8.
[27] Ito M. (2002) The molecular organization of cerebellar long-term depression. Nature reviews. Neuroscience, 3(11):896-902.
[28] Shi S, Hayashi Y, Esteban JA, Malinow R. (2001) Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell, 105(3):331-43.
[29] Anwyl R. (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev, 29(1):83-120.
[30] Dudek, S.M. and Bear, M.F. (1992) Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-Daspartate receptor blockade. Proc. Natl. Acad. Sci., 89, 4363-4367
[31] Bear, M. F. and Abraham, W. C. (1996) Long-term depression in hippocampus. Annu. Rev. Neurosci, 19, 437-462
[32] Artola A, Singer W. (1993)Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends in neurosciences, 16(11):480-7
[33] Hawkins RD, Kandel ER, Siegelbaum SA. (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annu Rev Neurosci, 16:625-65.
[34] 寿天德(主编)．神经生物学．北京高等教育出版社，2000，374-395
[35] Malenka RC, Bear MF. (2004) LTP and LTD: an embarrassment of riches. Neuron, 44:5-21.
[36] Collingridge GL, Randall AD, Davies CH, Alford S. (1992) The synaptic activation of NMDA receptors and Ca2+ signalling in neurons. Ciba Foundation symposium, 164:162-71; discussion 172-5.
[37] Nishizawa Y. (2001) Glutamate release and neuronal damage in ischemia. Life sciences, 69(4):369-81
[38] Adamec RE, Blundell J, Collins A. (2001)Neural plasticity and stress induced changes in defense in the rat. Neuroscience and biobehavioral reviews, 25(7-8):721-44.
[39] Adamec RE, Burton P, Shallow T, Budgell J. (1999) NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure-implications for anxiety associated with posttraumatic stress disorder. Physiol Behav, 65(4-5):723-37.
[40] Adamec RE, Shallow T, Budgell J. (1997) Blockade of CCK(B) but not CCK(A) receptors before and after the stress of predator exposure prevents lasting increases in anxiety-like behavior: implications for anxiety associated with posttraumatic stress disorder. Behav Neurosci, 111 (2):435-49.
[41] McEwen BS. (1999) Stress and hippocampal plasticity. Annu Rev Neurosci, 22:105-122.
[42] Li Z, Zhou Q, Li L, Mao R, Wang M, Peng W, Dong Z, Xu L, Cao J. (2005) Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CA1 area in vivo. Hippocampus, 15(6):815-24.
[43] Richter-Levin G. (1998) Acute and long-term behavioral correlates of underwater trauma-potential relevance to stress and post-stress syndromes. Psychiatr Res, 79, 73-83.
[44] Wang J, Akirav I, Richter-Levin G.(2000) Short-term behavioral and electrophysiological consequences of underwater trauma. Physiol Behav, 70(3-4):327-32.
[45] Paul S, Olausson P, Venkitaramani DV, Ruchkina I, Moran TD, Tronson N, Mills E, Hakim S, Salter MW, Taylor JR, Lombroso PJ. (2006) The Striatal-Enriched Protein Tyrosine Phosphatase Gates Long-Term Potentiation and Fear Memory in the Lateral Amygdala. Biol Psychiatry, (in press)
[46] Van der Kolk BA. (1994) The body keeps the score: memory; the evolving psychobiology of posttraumatic stress disorder. Harvard Rev. Psychiatry, 253-265.
[2] Terence M. Keane, Amy D. Marshall, and Casey T. Taft. (2006) POST-TRAUMATIC STRESS DISORDER: Etiology, Epidemiology, and Treatment Outcome. Annu. Rev. Clin. Psychol, 2:161-97.
[3] Foa EB, Meadows EA. (1997) Psychosocial treatments for posttraumatic stress disorder: a critical review. Annual review of psychology, 48:449-80.
[4] Broekman BF, Olff M, Boer F. (2007) The genetic background to PTSD. Neurosci Biobehav Rev, 31 (3):348-62.
[5] Hull AM. (2002) Neuroirnaging findings in post-traumatic stress disorder. Systematic review. The British journal of psychiatry, 181: 102-10.
[6] Kasai K, Yamasue H. (2005) Neuroimaging in posttraumatic stress disorder. No To Shinkei, 57(4):285-90.
[7] Corbo V, Clement MH, Armony JL, Pruessner JC, Brunet A.(2005) Size versus shape differences: contrasting voxel-based and volumetric analyses of the anterior cingulate cortex in individuals with acute posttraumatic stress disorder. Biol Psychiatr, 15;58(2): 119-24.
[8] Li Z, Zhou Q, Li L, Mao R, Wang M, Peng W, Dong Z, Xu L, Cao J. (2005) Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CA1 area in vivo. Hippocampus, 15(6):815-24.
[9] Bruening S, Oh E, Hetzenauer A, Escobar-Alvarez S, Westphalen RI, Hemmings HC Jr, Singewald N, Shippenberg T, Toth M. (2006) The anxiety-like phenotype of 5-HT receptor null mice is associated with genetic background-specific perturbations in the prefrontal cortex GABA-glutamate system. J Neurochem, 99(3):892-9.
[10] Harvey BH, Bothma T, Nel A, Wegener G, Stein DJ. (2005) Involvement of the NMDA receptor, NO-cyclic GMP and nuclear factor K-beta in an animal model of repeated trauma. Hum Psychopharmacol, 20(5):367-73.
[11] Harvey BH, Oosthuizen F, Brand L, Wegener G, Stein DJ. (2004) Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl), 175(4):494-502.
[12] Cohen H, Kaplan Z, Kotler M. (1999) CCK-antagonists in a rat exposed to acute stress: implication for anxiety associated with post-traumatic stress disorder. Depress Anxiety, 10(1):8-17.
[13] Uys JD, Muller CJ, Marais L, Harvey BH, Stein DJ, Daniels WM. (2006) Early life trauma decreases glucocorticoid receptors in rat dentate gyms upon adult re-stress: reversal by escitalopram. Neuroscience, 137(2):619-25.
[14] Scoville WB, Milner B. (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry, 20(1): 11-21.
[15] Barski JJ, Lewin-Kowalik J, Sieron AL. (1992) Current views on the structure and function of the hippocampus. Neurol Neurochir Po., 26(2):224-31.
[16] Ridderinkhof KR, van den Wildenberg WP, Segalowitz SJ, Carter CS. (2004) Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain Cogn, 56(2): 129-40.
[17] Bussey TJ, Wise SP, Murray EA. (2001) The role of ventral and orbital prefrontal cortex in conditional visuomotor learning and strategy use in rhesus monkeys (Macaca mulatta). Behav Neurosci,115(5):971-82.
[18] Funahashi S, Kubota K. (1994) Working memory and prefrontal cortex. Neurosci Res, 21(1):1-11.
[19] D'Esposito M, Aguirre GK, Zarahn E, Ballard D, Shin RK, Lease J. (1998) Functional MRI studies of spatial and nonspatial working memory. Brain Res Cogn Brain Res, 7(1):1-13.
[20] Ferbinteanu J, Kennedy PJ, Shapiro ML. (2006) Episodic memory-from brain to mind. Hippocampus, 16(9):691-703.
[21] Torras M, Portell I, Morgado I. (2001) The amigdaloid body: functional implications. Rev Neurol, 33(5):471-6.
[22] Fox RJ, Sorenson CA. (1994) Bilateral lesions of the amygdala attenuate analgesia induced by diverse environmental challenges. Brain Res, 648(2):215-21.
[23] Wallace KJ, Rosen JB. (2001) Neurotoxic lesions of the lateral nucleus of the amygdala decrease conditioned fear but not unconditioned fear of a predator odor: comparison with electrolytic lesions. J Neurosc, 21 (10):3619-27.
[24] Davis M. (1997) Neurobiology of fear responses: the role of the amygdala. J Neuropsychiatry Clin Neurosci, 9(3):382-402.
[25] Pare D, Quirk GJ, (2004) Ledoux JE. New vistas on amygdala networks in conditioned fear. J Neurophysiol, 92(1): 1-9.
[26] Watkins JC, Jane DE. (2006) The glutamate story. Br J Pharmacol., 147 Suppl 1 :S100-8.
[27] Cull-Candy S, Brickley S, Farrant M. (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol, 11 (3):327-35.
[28] Collingridge GL, Isaac JT, Wang YT. (2004) Receptor trafficking and synaptic plasticity. Nat Rev Neurosci, 5(12):952-62.
[29] Dingledine R, Borges K Traynelis SF, Bowie D. (1999) The glutamate receptor ion channels. Pharmacol Rev, 51 (1):7-61.
[30] Kuba K, Kumamoto E. (1990) Long-term potentiations in vertebrate synapses: a variety of cascades with common subprocesses. Prog Neurobiol, 34(3): 197-269.
[31] Artola A, Singer W. (1993)Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends in neurosciences, 16(11):480-7.
[32] Hawkins RD, Kandel ER, Siegelbaum SA. (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annu Rev Neurosci, 16:625-65.
[33] Hollmann M, Heinemann S.(1994) Cloned glutamate receptors. Annu Rev Neurosc, 17:31-108.
[34] Tanaka H, Grooms SY, Bennett MV, Zukin RS. (2000) The AMPAR subunit GluR2: still front and center-stage. Brain Res, 886(1-2): 190-207.
[35] Wenthold RJ, Petralia RS, Blahos J II, Niedzielski AS. (1996) Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J Neurosci,16(6): 1982-9.
[36] Lin H, Huganir R, Liao D. (2004) Temporal dynamics of NMDA receptor-induced changes in spine morphology and AMPA receptor recruitment to spines. Biochem Biophys Res Commun, 316(2):501-11.
[37] Lee HK, Takamiya K, Han JS, Man H, Kim CH, Rumbaugh G, Yu S, Ding L, He C, Petralia RS, Wenthold RJ, Gallagher M, Huganir RL. (2003) Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell, 112(5):631-43.
[38] Reisel D, Bannerman DM, Schmitt WB, Deacon RM, Flint J, Borchardt T, Seeburg PH, Rawlins JN. (2002) Spatial memory dissociations in mice lacking GluR1. Nat Neurosci, 5(9):868-73.
[39] Zullino DF, Krenz S, Besson J. (2003) AMPA blockade may be the mechanism underlying the efficacy of topiramate in PTSD. J Clin Psychiatry, 64(2):219-20.
[40] Rau V, DeCola JP, Fanselow MS. (2005) Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci Biobehav Rev, 29(8):1207-23.
[41] Fanselow, M. S., (1994) Neural organization of the defensive behavior system responsible for fear. Psychon. Bull. Rev, 1 (4), 429-438.
[42] Fanselow, M. S., 1980. Conditional and unconditional components of postshock freezing. Pavlov. J. Biol. Sci,15 (4), 177-182.
[43] George Paxinos, Charles Watson. (1997) The Rat Brainin Stereotaxic Coordinates
[44] Luo J, Wang Y, Yasuda RP, Dunah AW, Wolfe BB. (1997) The majority of N-methyl-D-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR 1/NR2A/NR2B). Mol Pharmaco, 51 (1):79-86.
[45] Zhu LJ, Chen Z, Zhang LS, Xu SJ, Xu AJ, Luo JH. (2004) Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. Neurosci Lett, 356(1):53-6.
[46] Chklovskii DB, Mel BW, Svoboda K. (2004) Cortical rewiring and information storage. Nature, 431 (7010):782-8.
[47] Khan S, Liberzon I. (2004) Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology, 172(2):225-9.
[48] Umegaki H, Yamamoto A, Suzuki Y, Iguchi A. (2006) Stimulation of the hippocampal glutamate receptor systems induces stress-like responses. Neuro Endocrinol Lett, 27(3):339-43.
[49] Pickering C, Gustafsson L, Cebere A, Nylander I, Liljequist S. (2006) Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex. Brain Res, 1099(1):101-8. Epub 2006 Jun 19.
[50] Pavic L, Gregurek R, Rados M, Brkljacic B, Brajkovic L, Simetin-Pavic I, Ivanac G, Pavlisa G, Kalousek V. (2007) Smaller right hippocampus in war veterans with posttraumatic stress disorder. Psychiatry Res, 154(2):191-8.
[51] Bremner JD. (2006) Stress and brain atrophy. CNS Neurol Disord Drug Targett, (5):503-12.
[52] Bremner JD. (2006) The relationship between cognitive and brain changes in posttraumatic stress disorder. Ann N Y Acad Sci, 1071:80-6.
[53] Liberzon I, Phan KL. (2003) Brain-imaging studies of posttraumatic stress disorder. CNS Spect, 8(9):641-50.
[54] Bartanusz V, Aubry JM, Pagliusi S, Jezova D, Baffi J, Kiss JZ. (2006) Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscienc, 66(2):247-52.
[55] Zhong W, Dong Z, Tian M, Cao J, Xu T, Xu L, Luo J. (2006) Opiate withdrawal induces dynamic expressions of AMPA receptors and its regulatory molecule CaMKIIalpha in hippocampal synapses. Life Sci, 79(9): 861-9.
[56] Schwendt M, Jezova D. (2000) Gene expression of two glutamate receptor subunits in response to repeated stress exposure in rat hippocampus. Cell Mol Neurobio., 20(3):319-29.
[57] Adamec RE, Burton P, Shallow T, Budgell J. (1999) NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure — implications for anxiety associated with posttraumatic stress disorder. Physiol Behav, 65(4-5):723-37.
[58] Lukoyanov NV, Paula-Barbosa MM. (2000) A single high dose of dizocilpine produces long-lasting impairment of the water maze performance in adult rats. Neurosci Lett, 285(2): 139-42.
[59] Reed JM, Squire LR. (1997) Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behav Neurosci.111(4):667-75.
[60] 徐淑君等．(2003)大鼠海马NMDA受体NR1亚单位蛋白的基础表达量与学习记忆相关．浙江大学学报(医学版)，32(6)：465-9
[61] Son GH, Geum D, Chung S, Kim EJ, Jo JH, Kim CM, Lee KH, Kim H, Choi S, Kim HT, Lee CJ, Kim K. (2006) Maternal stress produces learning deficits associated with impairment of NMDA receptor-mediated synaptic plasticity. J Neurosci, 26(12):3309-18.
[62] Williams LM, Kemp AH, Felmingham K, Barton M, Olivieri G, Peduto A, Gordon E, Bryant RA. (2006) Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. Neuroimage, 29(2):347-57.
[63] Matsuo K, Taneichi K, Matsumoto A, Ohtani T, Yamasue H, Sakano Y, Sasaki T, Sadamatsu M, Kasai K, Iwanami A, Asukai N, Kato N, Kato T. (2003) Hypoactivation of the prefrontal cortex during verbal fluency test in PTSD: a near-infrared spectroscopy study. Psychiatry Res, 124(1): 1-10
[64] Moghaddam B. (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem, 60(5): 1650-7.
[65] Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N. (2007) The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci, 27(11):2781-7.
[66] Vouimba RM, Yaniv D, Diamond D, Richter-Levin G. (2004) Effects of inescapable stress on LTP in the amygdala versus the dentate gyrus of freely behaving rats. Eur J Neurosci, 19(7): 1887-94.
[1] Foa EB, Meadows EA. (1997) Psychosocial treatments for posttraumatic stress disorder: a critical review. Annual review of psychology, 48:449-80,
[2] 许绍芬．神经生物学．第二版．上海医学大学出版社，1999，403．
[3] Hull AM. (2002) Neuroimaging findings in post-traumatic stress disorder. Systematic review. The British journal of psychiatry, 181: 102-10.
[4] Villarreal G, Hamilton DA, Petropoulos H, Driscoll I, Rowland LM, Griego JA, Kodituwakku PW, Hart BL, Escalona R, Brooks WM. (2002) Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder. Biological psychiatry, 52(2): 119-25.
[5] Pitman RK, Shin LM, Rauch SL. (2001) Investigating the pathogenesis of posttraumatic stress disorder with neuroimaging. The Journal of clinical psychiatry, 62 Suppl 17:47-54.
[6] Schuff N, Neylan TC, Lenoci MA, Du AT, Weiss DS, Marmar CR, Weiner MW. (2001) Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder. Biological psychiatry, 50(12):952-9.
[7] Thome J, Pesold B, Baader M, Hu M, Gewirtz JC, Duman RS, Henn FA. (2001) Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biological psychiatry, 50(10): 809-12.
[8] Arnsten AFT. (1998) Catecholamine modulation of prefrontal cognitive function. Trends of Cognitive Science, 2 (5): 436.
[9] Gilboa A, Shalev AY, Laor L, Lester H, Louzoun Y, Chisin R, Bonne O. (2004) Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biological psychiatry, 55(3):263-72.
[10] Swanson LW, Petrovich GD. (1998) What is the amygdala? Trends in neurosciences, 21 (8):323-31.
[11] De Bellis MD, Keshavan MS, Clark DB, Casey BJ, Giedd JN, Boring AM, Frustaci K, Ryan ND.(1999) A. E. Bennett Research Award. Developmental traumatology. Part Ⅱ: Brain development. Biological psychiatry, 45(10):1271-84.
[12] Lanius RA, Williamson PC, Densmore M, Boksman K, Gupta MA, Neufeld RW, Gati JS, Menon RS. (2001) Neural correlates of traumatic memories in posttraumatic stress disorder : a functional MRI investigation. The American journal of psychiatry, 158 :1920-1922.
[13] Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, et al. (1999) Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. American Journal of Psychiatry, 156: 585—8.
[14] Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, et al. (1997) Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. American Journal of Psychiatry, 154:624-9.
[15] Bremner JD, Vythilingam M, Anderson G, Vermetten E, McGlashan T, Heninger G, et al. (2003a) Assessment of the hypothalamic-pituitary-adrenal axis over a 24-hour diurnal period and in response to neuroendocrine challenges in women with and without childhood sexual abuse and posttraumatic stress disorder. Biological Psychiatry, 54:710-8.
[16] Yehuda R, Halligan SL, Grossman R, Golier JA, Wong C. (2002) The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder. Biological Psychiatry, 52(5):393-403.
[17] Yehuda R. (2001) Biology of posttraumatic stress disorder. The Journal of clinical psychiatry, 17:41-6
[18] Avital A, Segal M, Richter-Levin G (2006) Contrasting roles of corticosteroid receptors in hippocampal plasticity. The Journal of neuroscience, 26(36):9130-4.
[19] Conrad CD. (2006) What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus? Behavioral and cognitive neuroscience reviews, 5(1):41-60.
[20] Rau V, DeCola JP, Fanselow MS. (2005) Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neuroscience and biobehavioral reviews, 29(8): 1207-23
[21] Bliss TVP, Lomo T. (1973) Long-lasting potentiation of synaptic transmission in the dentate gyrus of the anesthetized rabbit following stimulation of the perforant path. J Physiol(Lond), 232:331-356
[22] Huang YY, Kandel ER, Varshavsky L, Brandon EP, Qi M, Idzerda RL, McKnight GS, Bourtchouladze R. (1995) A genetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell, 83(7):1211-22.
[23] Gustafsson B, Wigstrom H, Abraham WC, Huang YY. (1987) Long-term potentiation in the hippocampus using depolarizing current pulses as the conditioning stimulus to single volley synaptic potentials. J Neurosci, 7(3):774-80.
[24] Zalutsky RA, Nicoll RA. (1990) Comparison of two forms of long-term potentiation in single hippocampal neurons. Science, 248(4963): 1619-24.
[25] Kuba K, Kumamoto E. (1990) Long-term potentiations in vertebrate synapses: a variety of cascades with common subprocesses. Prog Neurobiol, 34(3): 197-269.
[26] Ito M, Kano M. (1982) Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci Lett, 33(3):253-8.
[27] Ito M. (2002) The molecular organization of cerebellar long-term depression. Nature reviews. Neuroscience, 3(11):896-902.
[28] Shi S, Hayashi Y, Esteban JA, Malinow R. (2001) Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell, 105(3):331-43.
[29] Anwyl R. (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev, 29(1):83-120.
[30] Dudek, S.M. and Bear, M.F. (1992) Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-Daspartate receptor blockade. Proc. Natl. Acad. Sci., 89, 4363-4367
[31] Bear, M. F. and Abraham, W. C. (1996) Long-term depression in hippocampus. Annu. Rev. Neurosci, 19, 437-462
[32] Artola A, Singer W. (1993)Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends in neurosciences, 16(11):480-7
[33] Hawkins RD, Kandel ER, Siegelbaum SA. (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annu Rev Neurosci, 16:625-65.
[34] 寿天德(主编)．神经生物学．北京高等教育出版社，2000，374-395
[35] Malenka RC, Bear MF. (2004) LTP and LTD: an embarrassment of riches. Neuron, 44:5-21.
[36] Collingridge GL, Randall AD, Davies CH, Alford S. (1992) The synaptic activation of NMDA receptors and Ca2+ signalling in neurons. Ciba Foundation symposium, 164:162-71; discussion 172-5.
[37] Nishizawa Y. (2001) Glutamate release and neuronal damage in ischemia. Life sciences, 69(4):369-81
[38] Adamec RE, Blundell J, Collins A. (2001)Neural plasticity and stress induced changes in defense in the rat. Neuroscience and biobehavioral reviews, 25(7-8):721-44.
[39] Adamec RE, Burton P, Shallow T, Budgell J. (1999) NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure-implications for anxiety associated with posttraumatic stress disorder. Physiol Behav, 65(4-5):723-37.
[40] Adamec RE, Shallow T, Budgell J. (1997) Blockade of CCK(B) but not CCK(A) receptors before and after the stress of predator exposure prevents lasting increases in anxiety-like behavior: implications for anxiety associated with posttraumatic stress disorder. Behav Neurosci, 111 (2):435-49.
[41] McEwen BS. (1999) Stress and hippocampal plasticity. Annu Rev Neurosci, 22:105-122.
[42] Li Z, Zhou Q, Li L, Mao R, Wang M, Peng W, Dong Z, Xu L, Cao J. (2005) Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CA1 area in vivo. Hippocampus, 15(6):815-24.
[43] Richter-Levin G. (1998) Acute and long-term behavioral correlates of underwater trauma-potential relevance to stress and post-stress syndromes. Psychiatr Res, 79, 73-83.
[44] Wang J, Akirav I, Richter-Levin G.(2000) Short-term behavioral and electrophysiological consequences of underwater trauma. Physiol Behav, 70(3-4):327-32.
[45] Paul S, Olausson P, Venkitaramani DV, Ruchkina I, Moran TD, Tronson N, Mills E, Hakim S, Salter MW, Taylor JR, Lombroso PJ. (2006) The Striatal-Enriched Protein Tyrosine Phosphatase Gates Long-Term Potentiation and Fear Memory in the Lateral Amygdala. Biol Psychiatry, (in press)
[46] Van der Kolk BA. (1994) The body keeps the score: memory; the evolving psychobiology of posttraumatic stress disorder. Harvard Rev. Psychiatry, 253-265.