Glucocorticoids accelerate ATP loss following metabolic insults in cultured hippocampal neurons

Glucocorticoids (GCs), adrenal steroids released during stress, can damage the hippocampus outright and increase hippocampal vulnerability to metabolic insults. Changes in ATP levels were measured in response to aglycemia and to cyanide in cultured hippocampal neurons that had been exposed to high- and low-GC conditions. GCs did not depress baseline ATP levels but did accelerate the rate of the decline in ATP concentrations observed during the metabolic insults. These results support the hypothesis that GCs increase neuronal vulnerability by disrupting cellular metabolism and agree with similar findings in hippocampal astrocytes.     

Glucocorticoids worsen excitotoxin-induced expression of pro-inflammatory cytokines in hippocampal cultures

Glucocorticoids (GCs), the adrenal steroid hormones released during stress, have well-known anti-inflammatory actions. Despite that, there is increasing evidence that GCs are not uniformly anti-inflammatory in the injured nervous system and, in fact, can be pro-inflammatory. The present report continues this theme. Primary hippocampal cultures were treated with GC concentrations approximating basal, acute (1 h) stress or chronic (24 h) stress conditions and were then exposed to the excitotoxin kainic acid (KA). KA induced expression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha, and chronic high dose GC exposure excacerbated this induction. In a second study, cultures were exposed to the physiological range of GC concentrations for 24 h prior to KA treatment. Low- to mid-range GC concentrations were anti-inflammatory, decreasing expression of IL-1 beta and TNF-alpha, while the highest GC doses either failed to be anti-inflammatory or even potentiated expression further. These findings add to the growing picture of these classically anti-inflammatory hormones potentially having pro-inflammatory effects in the injured CNS.     

Glucocorticoids and serotonin alter glucocorticoid receptor (GR) but not mineralocorticoid receptor (MR) mRNA levels in fetal mouse hippocampal neurons, in vitro

Studies utilizing rats and guinea pigs have demonstrated that the hypothalamo-pituitary-adrenal (HPA) axis can be programmed by glucocorticoids during fetal life. Such programming is believed to occur, at least partially, at the level of hippocampal glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). Studies have also demonstrated that serotonin up regulates GR levels within the developing hippocampus. However, the cell type in which these changes take place has not been determined. We hypothesized that dexamethasone, corticosterone and serotonin exposure modify GR and MR mRNA levels in fetal mouse hippocampal cultures, and that these effects are confined to neurons. Cultures were derived from CD1 mouse fetuses on day 18 of gestation (n=8 dams). Fetal hippocampi were dissected, then mechanically and chemically dispersed. Cultures were exposed to dexamethasone, corticosterone or serotonin (1-100 nM) for 4 days. Levels of GR and MR mRNA were examined by in situ hybridization and high-resolution silver emulsion autoradiography. Four days exposure to dexamethasone or corticosterone (10 or 100 nM) decreased levels of GR mRNA within neurons. There was no significant change in MR mRNA in either experiment. Exposure to serotonin (100 nM) significantly increased expression of GR mRNA in hippocampal neurons. MR mRNA levels were unaffected by serotonin treatment. Dexamethasone, corticosterone or serotonin exposure did not alter expression of GR mRNA within glial cells. We conclude that synthetic and endogenous glucocorticoids, as well as serotonin, can influence neuronal levels of GR mRNA during hippocampal development. However, whether these effects are permanent remains to be determined.     

Glucocorticoids Decrease Hippocampal and Prefrontal Activation during Declarative Memory Retrieval in Young Men

Glucocorticoids (GCs, cortisol in human) are associated with impairments in declarative memory retrieval. Brain regions hypothesized to mediate these effects are the hippocampus and prefrontal cortex (PFC). Our aim was to use fMRI in localizing the effects of GCs during declarative memory retrieval. Therefore, we tested memory retrieval in 21 young healthy males in a randomized placebo-controlled crossover design. Participants encoded word lists containing neutral and emotional words 1 h prior to ingestion of 20 mg hydrocortisone. Memory retrieval was tested using an old/new recognition paradigm in a rapid event-related design. It was found that hydrocortisone decreased brain activity in both the hippocampus and PFC during successful retrieval of neutral words. These observations are consistent with previous animal and human studies suggesting that glucocorticoids modulate both hippocampal and prefrontal brain regions that are crucially involved in memory processing. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

母孕期应激对后代海马神经生物学影响的研究进展

流行病学及动物研究均表明,母孕期遭受的应激对后代认知功能存在远期影响,并增加后代精神障碍与躯体疾病的患病风险。母孕期应激对后代神经生物学方面的影响,尤其是对海马系统的影响日益成为国内外学者研究的重点。现就母孕期遭受应激导致后代海马相关神经生物学变化做一综述。     

慢性应激对大鼠海马CA3区锥体细胞顶树突细胞骨架的效应及其机制研究

目的 探讨慢性强迫游泳应激对大鼠海马CA3区锥体细胞顶树突细胞骨架的效应及可能的机制.方法 将16只雄性Sprague-Dawley大鼠(2月龄),随机分为对照组和应激组(强迫游泳,20 min/d,共4周),每组8只.用常规透射电镜观察两组大鼠海马CA3区锥体细胞顶树突细胞骨架,用免疫组织化学方法定量测定锥体细胞内磷酸化微管相关蛋白2(MAP2)表达水平.结果 (1)海马CA3区锥体细胞顶树突内细胞骨架的变化:对照组纵切面显示微管排列整齐、连续,呈平行状;横切面显示环状微管完整、规则,分布均匀;线粒体嵴清晰.应激组纵切面显示微管断裂,平行微管间距离变宽;横切面显示微管环不完整,单体分布不均匀;线粒体嵴模糊,偶见空泡样变性.(2)海马CA3区锥体细胞磷酸化MAP2的表达:应激组大鼠平均灰度值(145.0±4.4)低于对照组(149.3±1.8)(P＜0.05),表达的阳性细胞数[(40.36±1.36)个/视野]少于对照组[(42.73±1.56)个/视野;P＜0.01].结论 慢性强迫游泳应激可导致大鼠海马CA3区锥体细胞顶树突内细胞骨架的损害,这一效应可能通过增加磷酸化MAP2的表达实现.     

Plasticity in the propagation of hippocampal stimulation-induced activity: a [C]2-deoxyglucose mapping study

Previous work has suggested that the rewarding effect of hippocampal stimulation develops only as a consequence of neuroplastic change resulting from repeated stimulation experience: naive rats will not initiate self-stimulation for several dats, but a prior program of hippocampal kindling greatly facilitates acquisition of self-stimulation. In the current study, the metabolic tracer [¹⁴C]2-deoxyglucose was used to measure functional activity during a session of repeated electrical stimulation of the hippocampus to determine whether the resulting activation propagates more widely in experienced hippocampal self-stimulators than in naive rats receiving the same programmed stimulation. a control group of naive unstimulated rats was also included. The results indicated that dorsal CA3 stimulation in naive rats failed to increase metabolic activity in the hippocampus, while in experienced rats, the stimulation produced significant bilateral activation of CA1, Ca3, and the ventral subiculum. These results provide support for the hypothesis that development of the rewarding effect of hippocampal stimulation is associated with more widespread propagation of stimulation-induced activity.     

慢性应激对大鼠海马CA3区锥体细胞顶树突及血清皮质酮浓度的影响

目的探讨慢性应激对大鼠海马CA3区锥体细胞结构和血清皮质酮浓度的影响。方法将20只雄性Sprague-Dawley大鼠按体质量随机分为应激组和对照组,每组10只。采用高尔基染色法及酶联免疫分析方法,观察慢性强迫游泳应激对大鼠海马CA3区锥体细胞顶树突和血清皮质酮浓度的影响。结果应激组大鼠海马CA3区锥体细胞顶树突的总长度[(112±10)μm]短于对照组[(168±34)μm],差异有统计学意义(P<0.01);一级树突直径[(9.0±1.1)μm]大于对照组[(5.7±0.9)μm],差异有统计学意义(P<0.01);血清皮质酮浓度[(13±14)μg/L]低于对照组[(30±16)μg/L],差异有统计学意义(P<0.05)。结论慢性强迫游泳可引起大鼠海马CA3区锥体细胞顶树突及血清皮质酮浓度的改变。     

Loss of parvalbumin immunoreactivity defines selectively vulnerable thalamic reticular nucleus neurons following cardiac arrest in the rat

The thalamic reticular nucleus (NRT) is one of the most vulnerable structures to selective neuronal damage both in human cardiac arrest patients and in experimental rodent global cerebral ischemia models. The detailed distribution of neuronal injury within the NRT was examined following 10-min cardiac arrest in the rat with conventional Nissl staining, ⁴⁵Ca autoradiography and immunocytochemistry of the calcium binding proteins parvalbumin (PV) and calretinin (CR). While Nissl staining was almost unable to show the exact boundary of the nucleus and of the lesion, immunocytochemistry of PV proved to be the most useful index of the exact location and extent of neuronal loss in the NRT after ischemia. Calcium autoradiography was a sensitive method for detecting the lesion, and showed a similar distribution to the loss of PV staining, but did not give optimal spatial resolution. Quantitative analysis of PV staining at 7 days of recirculation demonstrated cell loss restricted to the lateral aspect of the middle segment of the NRT, identical with the distribution of large fusiform neurons in the somatosensory component of the nucleus. CR-positive neurons in the NRT were completely spared, although not all surviving neurons contained CR. These studies provide the first detailed characterization of the distribution of vulnerable neurons within the NRT after experimental ischemia and suggest that immunocytochemistry of PV is a useful tool for quantitative analysis of the lesion for use in further experiments to elucidate the mechanisms of selective vulnerability of the NRT.     

Volumetric MRI analysis of hippocampal subregions in Cushing's disease: A model for glucocorticoid neural modulation

Several preclinical studies have demonstrated neuronal effects of glucocorticoids on the hippocampus (HC), a limbic structure with anterior-posterior anatomical and functional segmentation. We propose a volumetric magnetic resonance imaging analysis of hippocampus head (HH), body (HB) and tail (HT) using Cushing's disease (CD) as model, to investigate whether there is a differential sensitivity to glucocorticoid neuronal damage in these segments. We found a significant difference in the HH bilaterally after 12 months from trans-sphenoidal surgical selective resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary micro-adenomas. This pre-post surgery difference could contribute to better understand the pathopysiology of CD as an in vivo model for stress-related hypercortisolemic neuropsychiatric disorders.     

Glucocorticoids are involved in the long-term effects of a single immobilization stress on the hypothalamic-pituitary-adrenal axis

We have previously observed that a single exposure to a severe stressor such as immobilization (IMO) induces long-lasting desensitization of the responsiveness of the hypothalamic–pituitary–adrenal (HPA) axis to the same stressor that enhances rather than dissipates with time (days). As this desensitization of the HPA axis was not observed in response to a novel stressor, we suggested this might be a particular type of learning linked to severe stressful situations. Taking into account the evidence that glucocorticoids are involved in learning and memory, the present study addresses the role of glucocorticoids in the induction of long-term effects of an acute exposure to IMO. Three different experimental approaches were used: (i) blockade of stress-induced corticosterone release by using adrenalectomized rats supplemented with a low dose of corticosterone in the drinking saline (ADX+B); (ii) blockade of corticosterone synthesis during the first exposure to IMO with the 11-β-hydroxylase inhibitor metyrapone (200 mg/kg); and (iii) administration of the glucocorticoid receptor antagonist RU486 (100 mg/kg). Previous exposure to IMO resulted in an enhanced post-stress recovery of the HPA response to the same stressor 1 week later. These long-term effects of IMO were blocked in ADX+B rats, were partially reduced in metyrapone-treated rats and only modestly affected by RU486 administration. These data suggest that glucocorticoids play a partial role in the induction of long-term effects of IMO on the HPA responsiveness to the same stressor, although the weak effect of RU486 suggests that non-classical corticosteroid receptors may be involved. The role of glucocorticoids in the expression of the phenomenon is suggested by the full blockade of the phenomenon in ADX+B rats, but further studies are needed. As blockade of corticosterone synthesis only partially blunted the long-term effect of IMO, it appears that full induction of the long-term effects of acute exposure to IMO on the HPA axis is only achieved by the concerted action of several endocrine (or neurochemical) factors.     

Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume

Smaller hippocampal volume has been consistently observed as a biomarker of posttraumatic stress disorder (PTSD). However, less is known about individual volumes of the subfields composing the hippocampus such as the dentate gyrus and cornu ammonis (CA) fields 1–4 in PTSD. The aim of the present study was to examine the hypothesis that volume of the dentate gyrus, a region putatively involved in distinctive encoding of similar events, is smaller in individuals with PTSD versus trauma-exposed controls. Ninety-seven recent war veterans underwent structural imaging on a 3T scanner and were assessed for PTSD using the Clinician-Administered PTSD Scale. The hippocampal subfield automated segmentation program available through FreeSurfer was used to segment the CA4/dentate gyrus, CA1, CA2/3, presubiculum, and subiculum of the hippocampus. Results showed that CA4/dentate gyrus subfield volume was significantly smaller in veterans with PTSD and scaled inversely with PTSD symptom severity. These results support the view that dentate gyrus abnormalities are associated with symptoms of PTSD, although additional evidence is necessary to determine whether these abnormalities underlie fear generalization and other memory alterations in PTSD.     

Effects of low intensity radiofrequency electromagnetic fields on electrical activity in rat hippocampal slices

Slices of rat hippocampus were exposed to 700 MHz continuous wave radiofrequency (RF) fields (25.2-71.0 V m(-1), 5-15 min exposure) in a stripline waveguide. At low field intensities, the predominant effect on the electrically evoked field potential in CA1 was a potentiation of the amplitude of the population spike by up to 20%, but higher intensity fields could produce either increases or decreases of up to 120 and 80%, respectively, in the amplitude of the population spike. To eliminate the possibility of RF-induced artefacts due to the metal stimulating electrode, the effect of RF exposure on spontaneous epileptiform activity induced in CA3 by 4-aminopyridine (50-100 microM) was investigated. Exposure to RF fields (50.0 V m(-1)) reduced or abolished epileptiform bursting in 36% of slices tested. The maximum field intensity used in these experiments, 71.0 V m(-1), was calculated to produce a specific absorption rate (SAR) of between 0.0016 and 0.0044 W kg(-1) in the slices. Measurements with a Luxtron fibreoptic probe confirmed that there was no detectable temperature change (+/- 0.1 degrees C) during a 15 min exposure to this field intensity. Furthermore, imposed temperature changes of up to 1 degrees C failed to mimic the effects of RF exposure. These results suggest that low-intensity RF fields can modulate the excitability of hippocampal tissue in vitro in the absence of gross thermal effects. The changes in excitability may be consistent with reported behavioural effects of RF fields.     

不同刺激对条件性恐惧大鼠行为及海马CA1区突触可塑性的影响

目的研究不同刺激对条件性恐惧大鼠的行为、海马CA1区兴奋性突触后电位（EPSP）的长时程增强（LTP）及长时程抑制（LTD）的影响。方法将106只大鼠分为7个实验组和4个行为对照组，检测其活体海马CA1区EPSP的LTP和LTD。（1）应激：①空白对照组（11只）除外，将6个实验组大鼠分别在A箱（应激箱）和B箱（非应激箱）中适应2d，第3天在A箱中给予20个条件性光刺激（CS）和足底电击（应激），将②急性应激组（8只）在应激后立即检测，③无暴露组（11只）在应激后24h后检测；（2）行为学观察：第4天将其余4组分别暴露于A箱（④A暴露组，17只）和B箱（⑤B暴露组，11只）中，并在不同刺激下（⑥A暴露＋1CS组，10只；⑦B暴露＋1CS组，11只）观察其僵住行为（共1h，分3个连续时相，每个时相20min；自第3个时相开始时给予或不给予1次CS）。随后进行检测。相应的4个行为对照组大鼠接受与④一⑦组同样的处理，但不予电击和EPSP检测。结果（1）僵住行为：各实验组在3个时相中的僵住时间比例均高于各自的对照组（P≤O．01）。在第3个时相中，A暴露组、A暴露＋1CS组、B暴露＋1CS组的僵住时间比例均高于B暴露组（P≤0．01）。（2）EPSP：经高频刺激，除急性应激组和A暴露＋1CS组外，空白对照组、无暴露组、A暴露组、B暴露组和B暴露＋1CS组均诱导出m（P〈0．01和P〈0．05）。经低频刺激后，急性应激组和A暴露＋1CS组大鼠的海马CA1区可稳定地诱导出LTD（P〈O．01和P〈0．05）。结论不同刺激可引起条件性恐惧大鼠长时间的僵住行为，其海马CA1区突触可塑性发生异质性改变。     

Restriction of environmental space attenuates locomotor activity and hippocampal acetylcholine release in male rats

We examined the effects of the restriction of environmental space on hippocampal acetylcholine release and spontaneous locomotor activity. Four days after the housing in a large or small cage, sampling for microdialysis study was begun. The locomotor activity counts exhibited significant daily changes in all rats in either the large or small cage. But, the mean locomotor activity counts in rats in the small cage was significantly less than that in the large cage. In contrast, the amount of acetylcholine collected per 20-min sample exhibited significant diurnal changes in all six rats in the large cage and in 5 of 6 rats in the small cage. The mean acetylcholine release in the rat in the small cage was significantly lower than that in the rat in the large cage during the dark phase, but not during the light phase. In addition, during the dark phase, hippocampal acetylcholine release was closely associated with spontaneous activity in all six rats in the large cage but not in 3 of 6 rats in the small cage. The present study suggests that the restriction of environmental space somehow interfere with the spontaneous locomotor activity and hippocampal acetylcholine release during the dark phase.     

应激对大鼠海马谷氨酸、天冬氨酸和γ-氨基丁酸含量的影响

目的　探讨应激对大鼠海马谷氨酸、天冬氨酸和γ 氨基丁酸 (GABA)含量的动态影响。方法　将 72只健康雄性大鼠随机分为 5个应激暴露不同时间组和对照组 ,每组 12只。利用高效液相色谱仪 紫外检测法 ,分别于应激第 1,3,7,14和 2 8天观察应激对大鼠海马谷氨酸、天冬氨酸及GABA含量的影响。结果　应激第 1天组大鼠海马谷氨酸和天冬氨酸含量与对照组相比 ,差异无显著性 ;但GABA含量 [(2 74 7± 0 339) μmol/g]低于对照组 [(3 719± 0 5 2 8) μmol/g;P <0 0 5 ]。应激第 3,7,14和 2 8天组谷氨酸含量 [分别为 (7 818± 0 799) μmol/g ,(9 0 0 7± 0 5 2 0 ) μmol/g,(8 0 4 9± 0 733) μmol/g和 (8 12 9± 1 5 5 6 ) μmol/g]高于对照组 [(6 4 11± 0 6 38) μmol/g];天冬氨酸含量 [分别为 (2 717± 0 2 5 8)μmol/g,(2 6 96± 0 317) μmol/g,(2 82 8± 0 4 6 8) μmol/g和 (4 6 4 9± 0 6 37) μmol/g]也高于对照组 [(2 0 0 3± 0 2 71) μmol/g];均P <0 0 1。应激第 14天组和 2 8天组GABA含量 [分别为 (4 4 6 2± 0 883) μmol/g和(4 4 97± 0 85 7) μmol/g]高于对照组 (P <0 0 5～0 .0 0 1) ,应激第 3天组和 7天组的GABA含量与对照组间的差异无显著性。结论　应激第 3天开始     

海马NMDA受体调节严重烫伤应激后HPA轴兴奋性的相关机制研究

目的探寻海马N-甲基-D-天冬氨酸(NMDA)受体调节严重创伤应激后HPA轴过度兴奋的可能机制。方法以30%总体表面积(TBSA)Ⅲ度烫伤应激作为严重创伤应激模型,先通过地塞米松抑制试验检测严重烫伤应激后糖皮质激素(GC)负反馈功能的变化,再利用RT-PCR技术检测烫伤应激后海马糖皮质激素受体(GR)mRNA水平(其水平与负反馈功能密切相关)的变化特点,并观察烫伤应激前腹腔注射NMDA受体拮抗剂MK-801对烫伤应激后2hGRmRNA水平的影响。结果30%TBSAⅢ度烫伤应激后地塞米松抑制试验阴性,GC负反馈功能下降;烫伤应激后0.5、2、8、24、48h海马GRmRNA水平皆明显降低,尤以伤后2h最明显;与烫伤应激组相比,MK-8013mg/kg组GRmRNA水平显著上升,MK-8016mg/kg组海马GRmRNA水平进一步上升,盐水组GRmRNA水平无明显变化。结论海马NMDA受体调节严重烫伤应激后HPA轴的亢进是通过下调海马GR从而影响了GC在海马水平的负反馈引起的。     

电针及氟西汀对抑郁大鼠行为学及海马神经元凋亡的影响

目的 探究电针及氟西汀对慢性应激抑郁大鼠行为学及海马神经元凋亡的影响.方法 65只Sprague-Dawley雄性大鼠,按随机数字表随机分为空白组、空白电针组、模型组、电针组、氟西汀组,每组13只.慢性应激后进行行为学评价;采用膜联蛋白V-异硫氰酸荧光素/碘化丙啶双染法检测海马神经元凋亡率;采用免疫组织化学方法检测海马bcl-2蛋白表达.结果 模型组大鼠旷场试验水平穿越格数[(1.6±1.3)格]、竖立次数[(0.4 ±0.2)次]、体质量增加量[(34±18)g]均明显低于空白组[分别为(51.1 ±22.3)格、(13.2±4.6)次、(128 ±21)g],P均＜0.05;海马神经元细胞凋亡率[(67±10)%]高于空白组[(53±13)%],P＜0.05;海马组织bcl-2蛋白阳性细胞计数[(28±10)个/mm<'2>]低于空白组[(78±22)个/mm<'2>],P＜0.05.电针组[分别为(39.3 ±14.3)格,(9.6 ±4.1)次,(81±43)g]、氟西汀组[分别为(37.2±15.1)格,(9.3±4.6)次,(80 ±35)g]上述指标均明显高于模型组(P＜0.05);海马神经元细胞凋亡率[电针组(30±9)%,氟西汀组(51±13)%]均低于模型组(P＜0.05);海马组织bcl-2蛋白阳性细胞计数[电针组(56±18)个/mm<'2>,氟西汀组(62±24)个/mm<'2>]均高于模型组(P＜0.05),而电针组与氟西汀组间的差异无统计学意义(P＞0.05).结论 电针和氟西汀可改善抑郁大鼠行为学症状,这种改善与海马细胞凋亡机制有一定相关性.     

捕食应激致大鼠持续性情绪唤醒障碍时血浆皮质酮及海马皮质类固醇受体表达变化

目的 探讨严重心理应激所致情感行为异常的相关神经生物学机制.方法 将136只雄性Wistar大鼠随机分为捕食应激组(以下简称应激组)和正常对照组(以下简称对照组),每组68只.以放射免疫分析法检测应激后1 h、1 d、1周,以及1,2,4个月时血浆皮质酮水平,并采用免疫组化和蛋白质免疫印迹法,检测海马糖皮质激素受体(GR)及盐皮质激素受体(MR)表达的变化规律.结果 (1)血浆皮质酮水平:应激后1 h应激组[(44.5±9.3)μg/L]高于对照组[(22.6±4.0)μg/L,P＜0.01],但应激后1 d降至正常水平,而应激后1周至4个月则明显低于对照组[应激组分别为(μg/L)12.4±2.5,9.8±2.1,8.7±2.1,10.1±2.3,对照组分别为(μg/L)20.8±3.9,21.1±4.2,16.6±3.6及20.2±4.0;P＜0.01].(2)海马GR和MR阳性免疫反应信号:应激后1 d免疫组化研究显示,应激大鼠海马及额叶皮层GR均较对照组增强(P＜0.01),其中以海马结构的改变更明显(P＜0.05);而MR则显著降低(P＜0.01).海马免疫印迹检测进一步揭示,应激组海马GR表达于应激后1 d至4个月明显增高(P＜0.05),而MR表达则于应激后1 h至1个月显著低于对照组(P＜0.05).结论 捕食应激后大鼠出现血浆皮质酮双向变化、海马GR和MR失衡以及不同的变化规律,这种严重的心理应激在引发大鼠持续性情绪唤醒障碍中可能有重要作用.     

Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice

Whether benzodiazepines (BZDs) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain. The present study designed four preclinical experiments to determine the effects of BZDs using chronic unpredictable stress model. In Experiment 1, several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests (FST and TST) as well as hippocampal structural plasticity markers. Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 wk. In Experiment 2, mice received p.o. administration of three diazepam dosages prior to each variate stress session for 4 wk. This treatment significantly antagonized the elevation of stress-induced corticosterone levels. Only low- (0.5 mg/kg) and medium-dose (1 mg/kg) diazepam blocked the detrimental effects of chronic stress. In Experiment 3, after 7 wk of stress sessions, daily p.o. diazepam administration during 1 wk recovery phase dose-dependently accelerated the recovery of stressed mice. In Experiment 4, 1 wk diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect, whereas 4 wk diazepam administration produced opposite effects. Hence, diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones. Considering the adverse effect of long-term diazepam administration on hippocampal plasticity, the preventive effects of diazepam may depend on the proper dose. Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress.