恐惧记忆相关神经环路的PET分子影像研究

发布时间：2018-05-12 23:35

本文选题：正电子发射断层显像 + 创伤后应激障碍　；参考：《浙江大学》2017年博士论文

【摘要】：近年来,随着自然环境持续恶化,人与自然之间的不和谐因素增多,使得全球自然灾害频发,突发性灾害性事件难以避免。灾难不仅吞噬了大量生命,也对幸存者的身心造成了重大创伤和痛苦。大部分的人面对重大灾难时会产生程度不等的恐惧反应与心理创伤,轻者属于一种生理防御反应,症状轻微而短暂,能逐渐缓解;重者若不及时干预可能会出现应激相关的疾病,如创伤后应激障碍(post-traumatic stress disorder,PTSD)和焦虑障碍(anxiety disorders)等。目前,临床上用于治疗PTSD和焦虑障碍的药物并不能完全缓解患者的症状,治疗效果有限。越来越多的研究显示认知行为疗法(cognitive behavioral therapy)对PTSD的疗效要优于药物治疗,但其神经机制并未完全阐明。暴露疗法与动物恐惧记忆的消退具有相似的神经生物学机制,我们设想,利用小动物PET(microPET)的灵敏度高,可定量以及可直接转化临床的优点,从神经影像方法入手,研究大鼠恐惧记忆获得与消退的神经机制;即利用18F标记的氟代脱氧葡萄糖(2-deoxy-2-[18F]fuoro-d-glucose,[18F]FDG)作为 PET 显像剂,活体检测恐惧记忆获得与消退时脑内葡萄糖代谢的变化,并结合免疫组化技术深入研究恐惧形成和消退的神经机制。另外,为了研究焦虑的神经机制,我们利用microPET检测大鼠在场景恐惧形成和场景恐惧记忆提取时,脑内[18F]FDG摄取的变化。第一部分条件恐惧记忆形成和消退的PET分子影像研究目的:为了研究PTSD的发病机制以及暴露疗法的神经机制,本研究利用microPET检测大鼠在条件恐惧形成和消退过程中,脑内[18F]FDG摄取的变化。方法:大鼠进行为期5天的条件恐惧和消退训练:第一天只给予声音(作为对照);第二天给予声音和电击刺激,建立条件恐惧;第三天和第四天进行消退训练;第五天检测消退记忆的形成。分别在第一、第二和第五天大鼠训练结束后,进行[18F]FDGmicroPET扫描。同时,用免疫组化技术检测脑内c-Fos蛋白的表达。结果:条件恐惧使大鼠的僵立比逐渐升高,达到87.22%;而消退训练则使僵立比逐渐降低,在消退训练末期时降至30.53%。在消退记忆提取时,大鼠的僵直比维持在较低水平。条件恐惧引起双侧杏仁核的[18F]FDG摄取增加,而引起双侧第二运动皮层(secondary motor cortex,M2)、左侧第一躯体感觉皮层(primary somatosensory cortex,S1)和左侧丘脑腹后内侧核(ventroposterior medial nucleus,VPM)的[18F]FDG摄取降低(P0.001)。在消退记忆提取时,右侧视觉皮层(primary visualcortex)和右侧岛叶(insularcortex)的[18F]FDG摄取增高,而右侧眶额皮层(orbital cortex)、侧膈(lateral septum)和双侧终纹床核(bed nucleus of the stria terminalis,BNST)的[18F]FDG摄取降低CP0.001)。免疫组化染结果显示,在消退记忆提取时,右侧岛叶的c-Fos蛋白表达明显增加(P0.01)。结论:我们的研究结果表明,杏仁核在条件恐惧记忆形成过程中起着重要作用,而岛叶在提取消退记忆时起着至关重要的作用。microPET可以来用研究精神疾病引起的大鼠脑内葡萄糖代谢的改变情况。进一步研究岛叶与其他脑区之间的功能联系,以及它们在消退记忆中的作用,有助于我们了解PTSD的发病机制。第二部分场景恐惧记忆的PET分子影像研究目的:为了研究焦虑的神经机制,本研究利用microPET检测大鼠在场景恐惧形成和场景恐惧记忆提取时,脑内[18F]FDG摄取的变化。方法:大鼠进行为期三天的场景恐惧训练:第一天,将大鼠放入恐惧训练箱中,自由探索周围环境30min;第二天,进行场景恐惧训练,给予10次电击刺激;第三天,将大鼠放入训练箱中30min,检测场景恐惧记忆。大鼠在每次行为学训练结束后,进行[18F]FDG microPET扫描。结果:场景恐惧训练使大鼠的僵立比升高,达到67.2%,表明电击刺激引起大鼠产生恐惧和焦虑行为。在场景恐惧记忆提取时,大鼠的平均僵立比为77.46%,表明大鼠对训练箱产生恐惧和焦虑。场景恐惧训练引起双侧腹侧海马(ventral hippocampus,vHPC)、前扣带皮层(anterior cingulate cortex,ACC)和嗅球的[18F]FDG摄取增加,而引起双侧第一运动皮层(primary motor cortex,M1)、右侧S1、小脑和右侧视皮层的[18F]FDG摄取降低(P0.001)。场景恐惧记忆提取引起双侧vHPC、左侧杏仁核、ACC和嗅球的[18F]FDG摄取增加,而双侧S1、右侧第二躯体感觉皮层(secondary somatosensory cortex,S2)、小脑单小叶和双侧丘脑后核团的[18F]FDG摄取降低(P0.001)。结论:vHPC和ACC共同参与调控场景恐惧形成和场景恐惧记忆提取过程中大鼠焦虑行为的表达,vHPC-ACC神经环路可能参与编码动物处于焦虑状态时的空间场景。在场景恐惧记忆提取时,还伴有杏仁核的激活,提示杏仁核参与调节疼痛刺激引起的焦虑和恐惧行为。当个体处于引起焦虑的环境时,vHPC、ACC和杏仁核共同参与调节机体的焦虑状态。进一步研究三个脑区之间的功能联系,以及它们在引起焦虑行为时的相互作用,有助于我们了解焦虑的神经机制,为临床治疗焦虑相关疾病提供实验依据和理论基础
[Abstract]:In recent years, with the continuous deterioration of the natural environment, the increasing disharmony between human and nature makes the global natural disasters frequent and the sudden disaster events are difficult to avoid. The disaster not only engulfed a large number of life, but also caused great trauma and pain to the body and mind of the survivors. The fear response and psychological trauma, the light person belongs to a physiological defense response, the symptoms are mild and short, and can be gradually relieved; the stress related diseases such as post traumatic stress disorder (post-traumatic stress disorder, PTSD) and anxiety disorder (anxiety disorders) may occur if the weight is not intervened in time. At present, it is used in the treatment of PTSD in clinical. Drugs and anxiety disorders do not completely relieve the symptoms of the patients and have limited treatment. More and more studies have shown that cognitive behavioral therapy (cognitive behavioral therapy) has a better effect on PTSD than drug treatment, but its neural mechanism is not fully elucidated. The study mechanism, we envisage that using the high sensitivity of the small animal PET (microPET), the quantitative and direct transformation of clinical advantages, the neural mechanism of rat fear memory acquisition and regression is studied from the neuroimaging method, that is, the use of 18F labeled fluorodeoxyglucose (2-deoxy-2-[18F]fuoro-d-glucose, [18F]FDG) as a PET imaging agent The living body tests the changes in glucose metabolism in the brain when the fear memory is acquired and subsided, and studies the nervous mechanism of fear formation and retreat in combination with immunohistochemical technique. In addition, in order to study the nervous mechanism of anxiety, we use microPET to detect the [18F]FDG uptake in the brain when the rat's horror formation and the scene fear memory are extracted. PET molecular imaging study of the formation and fading of conditional fear memory. Purpose: To study the pathogenesis of PTSD and the neural mechanism of exposure therapy, this study used microPET to detect the alteration of [18F]FDG uptake in the brain during the formation and decline of conditioned fear. Methods: rats were subjected to 5 days of conditional fear. And retreat training: on the first day, only sound was given (as control); sound and shock stimulation were given on the second day, conditioned fear was established, retreat training was performed on the third and fourth days, and the formation of receding memory was detected on the fifth day. The [18F]FDGmicroPET scan was performed after the first, second and fifth days of training of rats. At the same time, the immunization technique was used. Results: the expression of c-Fos protein in the brain was detected. Results: condition fear increased the stiffness ratio of rats to 87.22%, while the regression training reduced the deadlock ratio gradually. At the end of the retreat training, the stiffness ratio of the rat was lower than that of 30.53%. when the receding memory was extracted. The condition fear caused the [18F]FDG uptake of the bilateral amygdala. The increased intake of the bilateral second motor cortex (secondary motor cortex, M2), the left first somatosensory cortex (primary somatosensory cortex, S1) and the left posterior ventral nucleus of the left thalamus (ventroposterior medial nucleus, VPM) decreased. The [18F]FDG uptake of the right Island leaf (insularcortex) increased, while the right orbital frontal cortex (orbital cortex), the lateral diaphragm (lateral septum) and the bilateral terminated bed nucleus (bed nucleus of the stria terminalis) decreased. Increase (P0.01). Conclusion: Our results show that the amygdala plays an important role in the formation of conditioned memory memory, while the island leaves play a vital role in extracting receding memory..microPET can be used to study the changes in glucose metabolism in the brain of rats induced by mental illness. The functional connections between the regions and their role in receding memory help us to understand the pathogenesis of PTSD. Second the purpose of the PET molecular imaging study of the scene of the fear memory is to study the nervous mechanism of anxiety. This study uses microPET to detect the [18F] in the rat in the scene of the scene fear formation and the scene fear memory extraction. FDG intake changes. Methods: rats were trained for three days of scene fear training. On the first day, the rats were placed in a fear training box, free to explore the surrounding environment 30min; the second day, scene fear training, 10 electric shock stimulation; third days, the rats were put into the training box, 30min, to detect the scene fear memory. Rats in each behavior learning. After the training, the [18F]FDG microPET scan was performed. Results: the scene fear training made the rat's deadlock ratio rise to 67.2%, indicating that the electric shock stimulated the rats to produce fear and anxiety. The average deadlock ratio of the rat was 77.46% when the scene fear memory was extracted, indicating that the rat had fear and anxiety for the training box. Bilateral ventral hippocampal (ventral hippocampus, vHPC), the anterior cingulate cortex (anterior cingulate cortex, ACC) and the olfactory ball [18F]FDG uptake increased, and the bilateral first motor cortex (primary motor cortex, M1), the right side, the cerebellum and the right visual cortex decreased. The uptake of [18F]FDG in the lateral amygdala, ACC and olfactory bulb increased, while bilateral S1, the right second somatosensory cortex (secondary somatosensory cortex, S2), the [18F]FDG uptake of the cerebellar single lobule and the bilateral posterior nucleus of the thalamus decreased (P0.001). Conclusion: vHPC and ACC are involved in regulating the anxiety of the scene and the fear memory extraction of the scene. The expression of behavior, the vHPC-ACC nerve loop may participate in the space scene that encodes an animal in the state of anxiety. When the scene of fear is extracted, it is accompanied by amygdala activation, suggesting that the amygdala participates in the anxiety and fear behavior caused by pain stimulation. When the individual is in an environment that causes anxiety, vHPC, ACC, and the amygdala join together. Regulating the state of anxiety in the body. Further study of the functional connections between the three brain regions and their interaction in the cause of anxiety can help us to understand the nervous mechanism of anxiety and provide experimental and theoretical basis for the clinical treatment of anxiety related diseases.

【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R817;R749

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