高唤醒对创伤后应激障碍形成发展的影响及其神经机制

高唤醒是创伤后应激障碍(PTSD)的主要症状之一, 对创伤后应激障碍的形成与发展起核心作用。急性应激期产生的高唤醒可以预测其后PTSD的回避与麻木、再体验等症状的形成, 在创伤后早期, 降低唤醒程度可以减轻PTSD相关的症状表现。下丘脑-垂体-肾上腺轴异常变化会导致去甲肾上腺素(NE)、促肾上腺皮质激素释放因子(CRF)过度释放, 同时皮质醇(酮)水平下降, 这二者是高唤醒产生与维持的主要原因。另外, 5-羟色胺(5-HT)系统的高度激活也影响了高唤醒的形成。食欲素神经肽与NE、CRF与5-HT系统有密切的神经联系, 可能参与高唤醒的调节, 是近年来研究的一个热点。     

创伤后应激障碍的动物模型及其神经生物学机制

创伤后应激障碍是指个体由于经历对生命具有威胁的事件或严重的创伤,导致症状长期持续的精神障碍。研究创伤后应激障碍的主要动物模型为条件性恐惧和应激敏感化模型。研究表明,创伤后应激障碍中长时程留存的恐惧性记忆、高唤醒等症状与大脑杏仁核、内侧前额叶皮层和海马三个脑区及下丘脑-垂体-肾上腺轴负反馈功能增强密切相关。其中杏仁核活动增强是条件性恐惧记忆获得、保持和表达的关键神经基础。内侧前额叶皮层对杏仁核的去抑制及海马向杏仁核传递的威胁性环境信息,促进创伤后应激障碍症状的出现。在经历创伤应激后糖皮质激素受体的上调及多巴胺活动的增强是创伤后应激障碍产生的主要神经基础。对创伤后应激障碍的药物治疗研究证明多巴胺D2受体在改善患者症状中的作用比较重要,但仍需作更深入的探索     

雄性HSF1基因缺陷小鼠的行为改变

为研究HSF1基因缺陷小鼠的行为特征,探索HSF1基因在小鼠行为表现中的作用。选取6~7个月大雄性HSF1基因缺陷小鼠39只及野生型小鼠36只进行情绪性评分、旷场实验、高架十字迷宫实验、简易迷津实验、T-CAT实验、独木桥实验和悬挂实验以观察其情绪性唤醒水平、焦虑水平、探索行为、工作记忆能力和运动能力。结果表明HSF1基因缺陷小鼠的情绪唤醒水平和焦虑水平较低、探索行为减少、T-CAT中转换率较低,提示小鼠的情绪、探索动机和工作记忆受HSF1基因的调控     

急性心理性应激诱发的神经内分泌反应及其影响因素

急性心理性应激源分别通过下丘脑-脑垂体-肾上腺轴(hypothalamus–pituitary–adrenal axis,HPAA)和交感神经-肾上腺髓质轴(sympathetic-adrenal medulla axis)诱发神经内分泌反应。唾液皮质醇被认为是检测急性心理性应激所诱发的HPA轴反应的稳定指标。以特里尔社会应激测试(Trier Social Stress Test,TSST)及其变式作为应激源, 以HPA轴的反应作为应激指标, 影响个体在急性心理性应激情境中发生特异性神经内分泌反应的因素主要包括人口统计学、环境和应激频率三大方面, 未来应加强急性心理性应激所诱发的神经内分泌反应的纵向研究。     

生活应激诱发大学生抑郁症状及轻生意念预警模型

用“大学生人格问卷”(UPI)和“学生生活应激量表”(SLSI)检测大学生3558例,并用回归分析和路经分析探讨其应激过程(应激源—应激反应)诱发抑郁症状及轻生意念的预警模型。结果显示,大学生生活中所承受的挫折、压力、变化和自我强加是预警抑郁症状产生的主要应激源;情绪反应、生理反应、行为反应和认知反应是预警抑郁症状产生的主要应激反应;大学生抑郁症状诱发轻生意念的预测正确率为97.0%,发生比(OR)或危险率1.86倍于非抑郁症状者,其中女生抑郁症状诱发轻生意念的危险率近2倍于无此症状者;应激源直接引起应激反应,应激反应直接诱发抑郁症状,抑郁症状直接引发轻生意念,应激源和应激反应不直接影响轻生意念,而通过诱发抑郁症状间接影响轻生意念。此预警模型为大学生危机心理鉴别干预提供了临床心理学依据和参数。     

自闭症谱系障碍者抑制控制的影响因素及神经机制

自闭症谱系障碍(ASD)是一种起源于儿童期的神经发育障碍, ASD的重复刻板行为与其抑制控制发展有密切关系。使用Go/No-go、Flanker及Stroop等范式的研究发现, ASD者抑制控制受损主要表现为反应抑制和干扰抑制能力存在缺陷; 其主要影响因素是任务状态、被试年龄及取样; 涉及的脑区和脑网络集中在前额皮层、前扣带回和基底神经节; 涉及的基因集中在谷氨酸盐、γ-氨基丁酸与5-羟色胺三种神经递质。未来应从脑机制研究入手, 综合考虑任务状态、个体特征对研究结果造成的影响, 并着力开发更有效的干预模式。     

损毁下丘脑弓状核、中缝背核和蓝斑对大鼠应激镇痛的影响

本文用不能躲避的间歇脚底电刺激引起大鼠应激,用电刺激鼠尾-嘶叫法测定镇痛效应,研究下丘脑弓状核(脑内β-内啡肽能神经元胞体集中的部位)、中缝背核(脑内5-羟色胺能神经元胞体主要集中的部位之一)和蓝斑(脑内去甲肾上腺素能神经元胞体主要集中的部位之一)与应激镇痛的关系。 用新生大鼠腹腔注射谷氨酸-钠的方法损毁弓状核后,用海人酸和电解两种方法损毁中缝背核或蓝斑后,应激镇痛效应均明显减弱。由于谷氨酸-钠和海人酸只选择性地损毁神经元胞体,故认为脑内的β-内啡肽能神经元、5-羟色胺能神经元和去甲肾上腺素能神经元均参与应激的行为镇痛。     

自立人格与心身症状：特质-应激-症状相符中介模型的检验

自立人格是新近提出的一种新的心身症状的保护性人格因素。为了探索自立人格抵御心身症状的机制, 提出了特质-应激-症状相符中介模型。该模型涉及应激中介模型假设、特质-应激相符假设、特质-症状相符假设三个理论假设。使用青少年学生自立人格量表、青少年生活事件量表和症状自评量表3种问卷对674名有效被试进行了调查, 以检验该模型。结果发现：①应激调节模型不被支持, 自立人格特质是通过应激的中介作用来负向预测心身症状; ②人际自立对心身症状的负向预测能力明显大于个人自立, 人际自立对人际性和个人性症状均有独立的预测能力, 个人自立则对人际性症状没有独立的预测能力; ③个人自立对应激的预测能力大于人际自立, 个人自立对人际和个人应激均有独立的预测能力, 人际自立则对个人应激没有独立的预测能力; ④修正后的自立人格的特质-应激-症状相符中介模型能够获得支持。总之, 本研究的结果显示：人际自立主要通过人际应激的中介作用负向预测心身症状总分; 个人自立则通过应激(包括人际与个人应激)的中介作用负向预测个人性症状。     

心理理论的遗传基础初探

心理理论在社会交往中起着关键作用,其认知过程包括对自我和他人的心理状态进行推断及预测下一步行为.心理理论在不同个体间具有差异,这种差异可能部分归因于与心理理论相关的神经化学物质如多巴胺、五羟色胺、催产素、血管加压素等.来自不同群体的研究结果还发现,与这些神经化学物质有关的基因多态性,如儿茶酚胺氧位甲基转移酶、多巴胺D4受体基因、5-羟色胺受体基因、催产素受体基因等都与心理理论的表现有关.     

CRF受体对五羟色胺系统的调节作用及早期环境因素的影响

早期环境因素持续影响脑与行为的发展,增加个体成年后应激相关精神疾病患病的易感性.应激反应的中枢启动因子促肾上腺皮质激素释放因子(corticotropin-releasing factor,CRF)通过两种受体CRF1和CRF2调节中缝背核(dorsal raphe nucleus,DRN)-五-羟色胺(serotonin,5-HT)系统,后者已被证实在应激相关情绪疾患发病和治疗过程中发挥重要作用.已知CRF受体以相互影响相互拮抗的方式动态调节DRN-5-HT系统,提示这两种受体相对作用的调节对于协调复杂环境中DRN-5-HT系统的应激反应过程起着关键性作用.早期环境因素和遗传因素交互作用导致CRF受体的分布和反应性持续改变并造成DRN-5-HT系统反应异常,可能是导致应激反应和精神疾病易感性个体差异的重要神经基础.     

Glucocorticoids are required for extinction of predator stress-induced hyperarousal

Background

The role of glucocorticoids in extinction of traumatic memories has not been fully characterized despite its potential as a therapeutic target for acquired posttraumatic stress disorder (PTSD). The predator stress paradigm allows us to determine whether glucocorticoids mediate the extinction of both context-dependent and context-independent fear memories.

Methods

Male C57BL/6J mice were exposed to a predator (cat) then repeatedly exposed to the predator stress context in the absence of the cat. Context-dependent (associative) fear memory was assessed as suppression of activity during re-exposure to the predator stress context without the cat (extinction trials). Context-independent fear (non-associative) was assessed seven days after extinction trials using measures of hyperarousal and anxiety-like behaviours in environments unlike the predator stress context. To assess the role of glucocorticoids, mice were injected with metyrapone (50 mg/kg) 90 min prior to extinction trials in predator stressed mice and context-dependent and context-independent fear memories were assessed. Finally, metyrapone-treated predator stressed mice were injected with corticosterone (5 or 10 mg/kg) immediately following extinction trials and context-dependent and context-independent fear memories were assessed.

Results

Repeated re-exposure to the predator stress context without the cat present extinguished context-dependent fear memory, and also reduced hyperarousal, a generalized, chronic PTSD-like symptom. We show that extinction of context-independent predator stress-induced hyperarousal is dependent on endogenous glucocorticoids during the extinction trials. Furthermore, the inhibition of extinction by metyrapone on startle amplitude was reduced by exogenous administration of corticosterone following extinction trials. Overall, these data implicate glucocorticoids in the extinction of hyperarousal, a core symptom of PTSD.     

Improvements in hippocampal-dependent learning and decremental attention in 5-HT(3) receptor overexpressing mice

The 5-HT3 receptor for serotonin is expressed within limbic structures and is known to modulate neurotransmitter release, suggesting that this receptor may influence learning and memory. Perturbations in serotonergic neurotransmission lead to changes in the ability to attend, learn, and remember. To examine the role of 5-HT3 receptors in learning, memory, and attention, 5-HT3 receptor overexpressing (5-HT3-OE) transgenic mice and their wild-type littermates (WT) were tested in Pavlovian contextual and cued fear conditioning, fear extinction, and latent inhibition (LI) paradigms. Prepulse inhibition (PPI) was assessed to reveal changes in sensorimotor gating. Additionally, anxious behaviors, shock sensitivity, and reactions to novel stimuli were evaluated. 5-HT3-OE mice displayed enhanced contextual conditioning, whereas cued conditioning remained the same as that of WT mice. 5-HT3-OE mice did not differ from WT in extinction rates to either the context or cue. LI was enhanced for 5-HT3-OE mice compared to WT. PPI remained unchanged. No differences in sensitivity to footshock or startle were found. However, 5-HT3-OE mice demonstrated heightened exploratory behavior in response to novel environmental stimuli and decreased anxiety as measured in the elevated plus-maze. Results indicate that overexpression of the 5-HT3 receptor in mouse forebrain results in enhanced hippocampal-dependent learning and attention. Enhanced inspective behavior in response to novelty may contribute to the observed improvements in learning, memory, and attention due to 5-HT3 receptor overexpression.     

Psychometric properties of the Impact of Event Scale - Revised

This study investigated the psychometric properties of the Impact of Event Scale—Revised (IES-R) in two samples of male Vietnam veterans: a treatment-seeking sample with a confirmed posttraumatic stress disorder (PTSD) diagnosis (N=120) and a community sample with varying levels of traumatic stress symptomatology (N=154). The scale showed high internal consistency (alpha=0.96). Confirmatory factor analysis did not provide support for a three-factor solution corresponding to the three subscales of intrusion, avoidance, and hyperarousal. Exploratory factor analysis suggested that either a single, or a two-factor solution (intrusion/hyperarousal and avoidance), provided the best account of the data. However, correlations among the subscales were higher in the community sample than in the treatment sample, suggesting that the IES-R may be sensitive to a more general construct of traumatic stress in those with lower symptom levels. The correlation between the IES-R and the PTSD Checklist was high (0.84) and a cutoff of 1.5 (equivalent to a total score of 33) was found to provide the best diagnostic accuracy.     

Selective blockade of 5-HT2A receptors attenuates the increased temperature response in brown adipose tissue to restraint stress in rats

Previous studies have demonstrated that 5-HT2A receptors may be involved in the central control of thermoregulation and of the cardiovascular system. Our aim was to test whether these receptors mediate thermogenic and tachycardiac responses induced by acute psychological stress. Three groups of adult male Hooded Wistar rats were instrumented with: (i) a thermistor in the interscapular area (for recording brown adipose tissue temperature) and an ultrasound Doppler probe (to record tail blood flow); (ii) temperature dataloggers to record core body temperature; (iii) ECG electrodes. On the day of the experiment, rats were subjected to a 30-min restraint stress preceded by s.c. injection of either vehicle or SR-46349B (a serotonin 2A receptor antagonist) at doses of 0.01, 0.1 and 1.0 mg/kg. The restraint stress caused a rise in brown adipose tissue temperature (from, mean +/- s.e.m., 36.6 +/- 0.2 to 38.0 +/- 0.2 degrees C), transient cutaneous vasoconstriction (tail blood flow decreased from 12 +/- 2 to 5 +/- 1 cm/s), increase in heart rate (from 303 +/- 15 to 453 +/- 15 bpm at the peak, then reduced to 393 +/- 12 bpm at the steady state), and defaecation (6 +/- 1 pellets per restraint session). The core body temperature was not affected by the restraint. Blockade of 5-HT2A receptors attenuated the increase in brown adipose tissue temperature and transient cutaneous vasoconstriction, but not tachycardia and defaecation elicited by restraint stress. These results indicate that psychological stress causes activation of 5-HT2A receptors in neural pathways that control thermogenesis in the brown adipose tissue and facilitate cutaneous vasoconstriction.     

Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent

Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2?h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, na?ve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33?mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress.     

Pituitary-adrenal activity in acute and chronically stressed male and female mice lacking the 5-HT-3A receptor

The serotonin (5-HT)-3A receptor has been localized in limbic and brainstem structures that regulate hypothalamic--pituitary--adrenal (HPA) activity. We previously showed that 5-HT-3A receptor knock-out (KO) male mice displayed lower ACTH responses to acute restraint or lipopolysaccharide administration compared to age-matched wild-type (WT) males. In the present study, we found that pituitary-adrenal responses to acute stress were not different in female WT and KO mice. Furthermore, we examined the role of the 5-HT-3A receptor in regulation of chronic stress-induced HPA activity in both male and female WT and KO mice. The results show that ACTH, but not corticosterone, responses to novel restraint are lower in chronically cold stressed females compared to non-stressed control females but no effect of 5-HT-3A receptor deletion was observed. In contrast, male mice showed facilitated responses to novel restraint after chronic cold stress and this facilitation produced sex differences in ACTH responses to novel restraint between male and female chronically stressed KO mice. Together, these results indicate that there are sex differences in HPA responses to novel restraint in chronically stressed mice and these differences are partly related to 5-HT-3A receptor function.     

母亲消极教养、同伴侵害与FKBP5基因对青少年抑郁的影响

累积压力假说与匹配-不匹配假说均可解释远端和近端逆境对个体抑郁的影响, 但鲜有研究考察遗传基因在其中的调节作用。采用问卷法和DNA分型技术, 对970名青少年进行间隔3年的追踪调查。分别以母亲消极教养、同伴侵害为远端和近端压力指标, FKBP5基因多位点累加得分为遗传指标, 考察三者对青少年抑郁的交互作用及性别差异。结果发现, 在男青少年中, E × E × G显著。当累加得分较高、同伴侵害水平较高时, 母亲消极教养显著负向预测抑郁, 符合匹配-不匹配假说; 累加得分较低时, E × E不显著, 但倾向于以累积压力假说的方式发挥作用。女青少年中, E × E × G不显著。研究结果提示, 在男青少年中, 累积压力假说与匹配-不匹配假说均可阐明抑郁的发生机制, 分别适用于携带不同FKBP5基因多位点累加得分的个体。     

惊反射在创伤后应激障碍研究中的应用:高唤醒与恐惧抑制

创伤后应激障碍(PTSD)是唯一在诊断标准中包含惊反射改变的精神疾病.相比自我报告法,对惊反射的实验室测量与总体症状关联更紧密,并已积累了较多神经机制研究成果,可作为连接前临床与临床研究的桥梁.在惊反射应用于PTSD研究的初期,它主要作为PTSD患者高唤醒症状的客观指标,但是尚未发现惊反射强度的变化与总体症状的明确关系.近年来,惊反射与情境性焦虑、恐惧抑制等新范式结合,发现特定情境下惊反射改变是PTSD患者特有的表现.惊反射在创伤应激障碍研究中所取得的新进展对PTSD病理机制的探索和临床诊断都有所启发和推进.     

Long-term effects of footshock and social defeat on anxiety-like behaviours in rats: Relationships to pre-stressor plasma corticosterone concentration

We compared the consequences of two stressors, 'unnatural' inescapable footshocks (IFSs) and 'natural' social defeat (SD), on behaviours typically sensitive to stress [sucrose preference, open field (OF), elevated plus maze (EPM) and acoustic startle responses (ASRs)] and the association with pre-stressor plasma corticosterone concentration. After initial blood sampling, rats (n?=?20 per group) were exposed to either 10 IFSs (1?mA intensity, 5?s duration each) or to 1?h SD (defeat by an aggressive resident male rat and further exposure but separated in a small cage) or to control procedures (handling). Rats were tested once for ASR (day 19), while the other behavioural tests were applied once weekly for 3 weeks. Both stress groups showed short-lasting lowered sucrose preference, and in the EPM they showed shorter total distance moved, shorter distance moved on open arms and less time on open arms compared to controls. In the OF test, IFS rats showed shorter total distance moved up to 2 weeks after stress. The SD group showed shorter total distance moved in the OF, which was only significant 2 weeks after stress. Low pre-stressor plasma corticosterone concentration was only associated with defecation (IFS rats) and latency to enter open arms in the EPM (all low corticosterone subgroups, n?=?10 per subgroup). SD rats with high initial plasma corticosterone concentration showed enhanced ASR compared to the other subgroups with high initial plasma corticosterone concentration (n?=?9 per subgroup). The results indicate that footshock and SD, while generally leading to an increase in anxiety behaviours, represent qualitatively different stressors.