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。     

应激性抑郁样行为发生中眶额叶5-HT1A受体对谷氨酸和γ-氨基丁酸的调节

5-羟色胺(5-hydroxytryptamine,5-HT)在抑郁症的发生及治疗中起着极其重要的作用,谷氨酸(glutamic acid,Glu)过度释放是应激性抑郁发生的重要原因。为了证明应激性抑郁样行为发生中眶额叶(orbitofrontal cortex,OFC)5-HT1A受体是否通过对Glu和γ-氨基丁酸(gamma-aminobutyric acid,GABA)的调节而发挥作用。本研究通过建立慢性不可预见性温和应激(chronic unpredictable mild stress,CUMS)抑郁模型,结合OFC区分别微量注射5-HT1A受体激动剂8-OH-DPAT和拮抗剂WAY100635,采用糖水偏爱率测试、旷场测试及悬尾测试检测动物的行为学表现,并通过高效液相色谱法(high-performance liquid chromatography,HPLC)分别检测了OFC区5-HT、Glu和GABA的含量。结果显示,CUMS组和注射WAY100635组大鼠较对照组表现出明显的抑郁样行为,且Glu含量显著升高,但5-HT水平和GABA含量均未有显著性变化。微量注射8-OH-DPAT后,能够显著改善大鼠的抑郁样行为,且Glu显著降低,但5-HT水平和GABA含量仍未发生显著性变化。结果表明,慢性不可预见性温和应激所引起的抑郁样行为,并不是由于眶额叶5-HT水平的降低,而可能是由于5-HT不能满足应激状态下调节Glu能神经的需要,或可能是OFC区Glu能神经元上5-HT1A受体功能的降低,导致Glu水平过高所致。眶额叶5-HT1A受体在Glu合成与释放中发挥重要调节作用。     

早年应激影响成年海马神经元再生的机制

成年海马神经元再生是指齿状回颗粒下区的神经干细胞发育为功能性神经元的过程。在生命的早期经历应激事件可损害成年期海马神经元再生,并引起学习记忆障碍。然而,目前关于早年应激影响成年海马神经元再生的机制研究主要集中在糖皮质激素及受体系统,其相关调节分子与机制有待深入研究。本文阐述了主要的应激因子(包括促肾上腺皮质激素释放激素及其受体等系统)在早年应激介导的成年海马神经元再生异常和海马重塑中的潜在作用。     

应激性抑郁样行为发生中海马5-羟色胺1A受体的作用及其对NMDA受体和AMPA受体的调节

为探讨慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)诱发抑郁样行为发生中海马5-羟色胺1A受体(5-hydroxytryptamine receptor 1A, 5-HT1AR)表达与作用, 及其对谷氨酸N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体和α-氨基羟甲基异恶唑丙酸(α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid, AMPA)受体的影响。通过建立CUMS动物模型, 给应激抑郁模型大鼠海马微量注射5-HT1A受体激动剂、给正常大鼠海马微量注射5-HT1A受体拮抗剂, 测量大鼠体重变化率, 并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测, 运用Western blot和ELISA方法检测大鼠海马组织中5-HT1AR和NMDAR和AMPAR的关键亚基的表达以及磷酸化水平。结果显示, 与对照组相比, CUMS组大鼠表现出抑郁样行为, 海马5-HT1AR、AMPA受体的GluR2/3亚基表达及磷酸化明显降低, NMDA受体的NR1和NR2B亚基表达及磷酸化显著增加; 正常大鼠海马微量注射5-HT1A受体拮抗剂WAY100635, 动物行为学表现及AMPA受体、NMDA受体表达及磷酸化水平均与CUMS组相同; 注射5-HT1A受体激动剂8-OH-DPAT能逆转应激诱导的上述改变。以上结果表明, CUMS诱发抑郁样行为与海马5-HT1AR表达下降, AMPAR表达量及磷酸化水平降低, NMDAR表达量及磷酸化水平升高有关。5-HT通过5-HT1AR产生抗抑郁作用。5-HT1AR激动剂抗抑郁作用与降低NMDAR表达量及磷酸化水平, 提高AMPAR表达量及磷酸化水平密切相关。     

急性应激与风险倾向：兴奋易感性的调节作用

为探索应激对决策的作用机理及其个体差异,减少工程作业中因应激导致的决策失误,本研究采用特里尔社会应激测试和气球模拟风险任务考察应激反应与应激下风险倾向的关系,并探索兴奋易感性在其中的调节作用。研究结果表明,应激下个体的皮质醇反应越大,行为越冒险。且这一作用受到兴奋易感性的调节：兴奋易感性较高的个体,应激下皮质醇反应越大,行为越冒险;而兴奋易感性较低的个体,其皮质醇变化不能预测风险倾向。该发现提示了兴奋易感性在应激影响中的重要作用,也为高压岗位的人员选拔提供了科学启示。     

中枢免疫失衡与认知功能障碍:聚焦TNFα的作用

中枢免疫对于神经系统内稳态的维持意义重大。免疫活性分子TNFα及其受体系统参与神经发育、突触可塑性和认知功能调节;其表达异常,无论过度或者不足都可能导致对脑功能和行为的不良影响。应激,尤其是发育早期应激可能通过影响中枢TNFα的动态发展过程从而造成其功能的持续改变,并与后期免疫相关的心理病理发生密切相关。未来研究需拓展中枢免疫与认知功能障碍之间的因果联系,建立基于免疫调节的疾病防治新策略。     

内质网应激和胰岛素抵抗

2型糖尿病的发病机制主要涉及胰岛素抵抗.近年来研究表明内质网应激可诱导胰岛素抵抗的形成,并使与改善胰岛素受体敏感性相关的内质网应激标志物分子氧调节蛋白150和转录因子X盒结合蛋白-1表达增强,表明内质网应激对细胞具有双重作用,一方面可诱导胰岛素抵抗,另一方面激发对应激的适应反应.     

应激神经成像的研究述评

HPA轴(hypothalamic-pituitary-adrenal cortex axis)是人体的重要内分泌应激系统, 大脑通过控制HPA轴活动影响机体在应激情境中皮质醇(cortisol)的分泌, 同时皮质醇分泌对大脑也具有负反馈作用, 影响着大脑边缘系统的重塑; 海马、杏仁核、前额叶皮层和脑干都参与了应激反应中的皮质醇调节; 未来研究要进一步对应激源细化分类, 并且试图找到适合事件相关电位技术的社会心理性应激实验范式。     

成瘾与应激的关系及治疗

成瘾严重危害个体的心身健康,造成许多家庭和社会问题。成瘾与应激有着密切的关系。最新研究发现下丘脑-垂体-肾上腺（HPA）轴、促肾上腺皮质激素调节因子（CRF）和糖皮质激素在成瘾与应激中发挥重要作用。由于对成瘾和应激的机制尚未完全阐明,目前无特效治疗。采取缓解应激源、预防精神活性物质的使用、预防复发、让患者回归社会等综合措施使复发率明显降低。     

早期应激对抑郁相关行为及神经内分泌反应的长期影响

临床研究发现,早期创伤性经历是导致成年抑郁症易感性增加的高风险因素之一。但早期应激通过何种途径对抑郁发病产生长期的影响,目前尚不清楚。本文综述了近年来有关的实验动物研究,从早期应激的动物模型建立、早期应激对成年动物抑郁相关行为及神经内分泌反应的长期影响等方面进行了系统论述和分析,进而提出了早期应激并不影响动物的本能行为,但早期应激影响与行为动机和应激应对等认知相关的行为的观点,进一步论证了早期应激是通过增加个体潜在的易患病素质对抑郁症发病产生影响     

Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety

Stress initiates a series of neuronal responses that prepare an organism to adapt to new environmental challenges. However, chronic stress may lead to maladaptive responses that can result in psychiatric syndromes such as anxiety and depressive disorders. Corticotropin-releasing factor (CRF) has been identified as a key neuropeptide responsible for initiating many of the endocrine, autonomic and behavioral responses to stress. The amygdala expresses high concentrations of CRF receptors and is itself a major extrahypothalamic source of CRF containing neurons. Within the amygdala, the basolateral nucleus (BLA) has an important role in regulating anxiety and affective responses. During periods of stress, CRF is released into the amygdala and local CRF receptor activation has been postulated as a substrate for stress-induced alterations in affective behavior. Previous studies have suggested that synaptic plasticity in the BLA contributes to mechanisms underlying long-term changes in the regulation of affective behaviors. Several studies have shown that acute glutamate receptor-mediated activation, by either GABA-mediated disinhibition or CRF-mediated excitation, induces long-term synaptic plasticity and increases the excitability of BLA neurons. This review summarizes some of the data supporting the hypotheses that stress induced plasticity within the amygdala may be a critical step in the pathophysiology of the development of chronic anxiety states. It is further proposed that such a change in the limbic neural circuitry is involved in the transition from normal vigilance responses to pathological anxiety, leading to syndromes such as panic and post-traumatic stress disorders.     

Brain and peripheral angiotensin II play a major role in stress

Angiotensin II (Ang II), the active principle of the renin-angiotensin system (RAS), was discovered as a vasoconstrictive, fluid retentive circulating hormone. It was revealed later that there are local RAS in many organs, including the brain. The physiological receptor for Ang II, the AT(1) receptor type, was found to be highly expressed in many tissues and brain areas involved in the hypothalamic-pituitary-adrenal axis response to stress and in the sympathoadrenal system. The production of circulating and local Ang II, and the expression of AT(1) receptors increase during stress. Blockade of peripheral and brain AT(1) receptors with receptor antagonists administered peripherally prevented the hormonal and sympathoadrenal response to isolation stress, the stress-related alterations in cortical CRF(1) and benzodiazepine receptors, part of the GABA(A) complex, and reduced anxiety in rodents. AT(1) receptor blockade prevented the ulcerations of the gastric mucosa produced by cold-restraint stress, by preservation of the gastric blood flow, prevention of the stress-induced inflammatory response of the gastric mucosa, and partial blockade of the sympathoadrenal response to the stress. Our observations demonstrate that Ang II is an important stress hormone, and that blockade of AT(1) receptors could be proposed as a potentially useful therapy for stress-induced disorders.     

New lessons from knockout mice: The role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders

Serotonin (5-HT) modulates numerous processes in the central nervous system that are relevant to neuropsychiatric function and dysfunction. It exerts significant effects on anxiety, mood, impulsivity, sleep, ingestive behavior, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several psychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of 5-HT as well as several enzymes that control its synthesis and metabolism. Pharmacologic agents that target specific receptors have provided clues regarding the function of these receptors in the human brain. 5-HT is also an important modulator of neural development and several groups have employed a genetic strategy relevant to behavior. Several inactivation mutations of specific 5-HT receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases, knockout mice have been used to confirm what has already been suspected based on pharmacologic studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior.     

5-羟色胺基因缺陷增强急性应激后高唤醒状态

剧烈的应激刺激会引起持续的高唤醒状态, 是多种应激障碍的核心症状, 并推进其他症状的发生发展。本研究关注5-羟色胺在应激诱发高唤醒的发生、发展中的作用, 通过测量听觉惊吓反射水平反映高唤醒状态, 考察色氨酸羟化酶-2基因缺陷小鼠在天敌或电击应激前后高唤醒的变化。研究发现, 雄性基因缺陷小鼠在应激后出现持续一周以上的高唤醒表现, 而野生型小鼠高唤醒状态很快恢复。结果提示, 基因缺陷引起的5-羟色胺降低可能是强应激诱发的持续高唤醒的易感因素。     

Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala

There is growing interest in the role that the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA), components of the extended amygdala, play in drug addiction. Within the BNST and CeA, there is an extensive system of intrinsic, primarily GABAergic, interconnections known to synthesize a variety of neuropeptides, including corticotrophin-releasing factor (CRF). The actions of CRF at extrahypothalamic sites,including the BNST and CeA, have been implicated in stress responses and in the aversive effects of withdrawal from drugs of abuse. Most recently, we have shown a critical role for extrahypothalamic CRF in stress-induced reinstatement of drug seeking in rats. In attempting to determine which brain circuitry mediates the effect of stress on relapse and, more specifically, where in the brain CRF acts to initiate the behaviours involved in relapse, we focused on the BNST and CeA. In the present paper, we summarize studies we have conducted that explore the role of these brain sites in stress-induced relapse to heroin and cocaine seeking, and then consider how our findings can be understood within the more general context of what is known about the role of the BNST and CeA in stress-related and general approach behaviours, such as drug seeking.     

5-HT2A: its role in frontally mediated executive function and related psychopathology

Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.     

Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala

The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA.     

The role of the glutamatergic system in posttraumatic stress disorder

Antiglutamatergic agents, such as lamotrigine, have been used successfully for the treatment of posttraumatic stress disorder (PTSD). They could be potentially acting through the stabilization of the corticotropin-releasing factor (CRF) systems. Glutamate mediates CRF release in various brain regions involved in the pathophysiology of PTSD, antiglutamatergic agents could stabilize the CRF system and, thereby, improve the symptom complex of PTSD (reexperiencing, hyperarousal, and avoidance). The role of glutamate and CRF in PTSD and other anxiety disorders are still being elucidated. However, it is clear that the glutamatergic systems play a role in the pathophysiology of PTSD.