本文選題：正電子發(fā)射斷層顯像 + 創(chuàng)傷后應(yīng)激障礙��； 參考：《浙江大學(xué)》2017年博士論文

【摘要】：近年來,隨著自然環(huán)境持續(xù)惡化,人與自然之間的不和諧因素增多,使得全球自然災(zāi)害頻發(fā),突發(fā)性災(zāi)害性事件難以避免。災(zāi)難不僅吞噬了大量生命,也對幸存者的身心造成了重大創(chuàng)傷和痛苦。大部分的人面對重大災(zāi)難時會產(chǎn)生程度不等的恐懼反應(yīng)與心理創(chuàng)傷,輕者屬于一種生理防御反應(yīng),癥狀輕微而短暫,能逐漸緩解;重者若不及時干預(yù)可能會出現(xiàn)應(yīng)激相關(guān)的疾病,如創(chuàng)傷后應(yīng)激障礙(post-traumatic stress disorder,PTSD)和焦慮障礙(anxiety disorders)等。目前,臨床上用于治療PTSD和焦慮障礙的藥物并不能完全緩解患者的癥狀,治療效果有限。越來越多的研究顯示認(rèn)知行為療法(cognitive behavioral therapy)對PTSD的療效要優(yōu)于藥物治療,但其神經(jīng)機(jī)制并未完全闡明。暴露療法與動物恐懼記憶的消退具有相似的神經(jīng)生物學(xué)機(jī)制,我們設(shè)想,利用小動物PET(microPET)的靈敏度高,可定量以及可直接轉(zhuǎn)化臨床的優(yōu)點,從神經(jīng)影像方法入手,研究大鼠恐懼記憶獲得與消退的神經(jīng)機(jī)制;即利用18F標(biāo)記的氟代脫氧葡萄糖(2-deoxy-2-[18F]fuoro-d-glucose,[18F]FDG)作為 PET 顯像劑,活體檢測恐懼記憶獲得與消退時腦內(nèi)葡萄糖代謝的變化,并結(jié)合免疫組化技術(shù)深入研究恐懼形成和消退的神經(jīng)機(jī)制。另外,為了研究焦慮的神經(jīng)機(jī)制,我們利用microPET檢測大鼠在場景恐懼形成和場景恐懼記憶提取時,腦內(nèi)[18F]FDG攝取的變化。第一部分條件恐懼記憶形成和消退的PET分子影像研究目的:為了研究PTSD的發(fā)病機(jī)制以及暴露療法的神經(jīng)機(jī)制,本研究利用microPET檢測大鼠在條件恐懼形成和消退過程中,腦內(nèi)[18F]FDG攝取的變化。方法:大鼠進(jìn)行為期5天的條件恐懼和消退訓(xùn)練:第一天只給予聲音(作為對照);第二天給予聲音和電擊刺激,建立條件恐懼;第三天和第四天進(jìn)行消退訓(xùn)練;第五天檢測消退記憶的形成。分別在第一、第二和第五天大鼠訓(xùn)練結(jié)束后,進(jìn)行[18F]FDGmicroPET掃描。同時,用免疫組化技術(shù)檢測腦內(nèi)c-Fos蛋白的表達(dá)。結(jié)果:條件恐懼使大鼠的僵立比逐漸升高,達(dá)到87.22%;而消退訓(xùn)練則使僵立比逐漸降低,在消退訓(xùn)練末期時降至30.53%。在消退記憶提取時,大鼠的僵直比維持在較低水平。條件恐懼引起雙側(cè)杏仁核的[18F]FDG攝取增加,而引起雙側(cè)第二運動皮層(secondary motor cortex,M2)、左側(cè)第一軀體感覺皮層(primary somatosensory cortex,S1)和左側(cè)丘腦腹后內(nèi)側(cè)核(ventroposterior medial nucleus,VPM)的[18F]FDG攝取降低(P0.001)。在消退記憶提取時,右側(cè)視覺皮層(primary visualcortex)和右側(cè)島葉(insularcortex)的[18F]FDG攝取增高,而右側(cè)眶額皮層(orbital cortex)、側(cè)膈(lateral septum)和雙側(cè)終紋床核(bed nucleus of the stria terminalis,BNST)的[18F]FDG攝取降低CP0.001)。免疫組化染結(jié)果顯示,在消退記憶提取時,右側(cè)島葉的c-Fos蛋白表達(dá)明顯增加(P0.01)。結(jié)論:我們的研究結(jié)果表明,杏仁核在條件恐懼記憶形成過程中起著重要作用,而島葉在提取消退記憶時起著至關(guān)重要的作用。microPET可以來用研究精神疾病引起的大鼠腦內(nèi)葡萄糖代謝的改變情況。進(jìn)一步研究島葉與其他腦區(qū)之間的功能聯(lián)系,以及它們在消退記憶中的作用,有助于我們了解PTSD的發(fā)病機(jī)制。第二部分場景恐懼記憶的PET分子影像研究目的:為了研究焦慮的神經(jīng)機(jī)制,本研究利用microPET檢測大鼠在場景恐懼形成和場景恐懼記憶提取時,腦內(nèi)[18F]FDG攝取的變化。方法:大鼠進(jìn)行為期三天的場景恐懼訓(xùn)練:第一天,將大鼠放入恐懼訓(xùn)練箱中,自由探索周圍環(huán)境30min;第二天,進(jìn)行場景恐懼訓(xùn)練,給予10次電擊刺激;第三天,將大鼠放入訓(xùn)練箱中30min,檢測場景恐懼記憶。大鼠在每次行為學(xué)訓(xùn)練結(jié)束后,進(jìn)行[18F]FDG microPET掃描。結(jié)果:場景恐懼訓(xùn)練使大鼠的僵立比升高,達(dá)到67.2%,表明電擊刺激引起大鼠產(chǎn)生恐懼和焦慮行為。在場景恐懼記憶提取時,大鼠的平均僵立比為77.46%,表明大鼠對訓(xùn)練箱產(chǎn)生恐懼和焦慮。場景恐懼訓(xùn)練引起雙側(cè)腹側(cè)海馬(ventral hippocampus,vHPC)、前扣帶皮層(anterior cingulate cortex,ACC)和嗅球的[18F]FDG攝取增加,而引起雙側(cè)第一運動皮層(primary motor cortex,M1)、右側(cè)S1、小腦和右側(cè)視皮層的[18F]FDG攝取降低(P0.001)。場景恐懼記憶提取引起雙側(cè)vHPC、左側(cè)杏仁核、ACC和嗅球的[18F]FDG攝取增加,而雙側(cè)S1、右側(cè)第二軀體感覺皮層(secondary somatosensory cortex,S2)、小腦單小葉和雙側(cè)丘腦后核團(tuán)的[18F]FDG攝取降低(P0.001)。結(jié)論:vHPC和ACC共同參與調(diào)控場景恐懼形成和場景恐懼記憶提取過程中大鼠焦慮行為的表達(dá),vHPC-ACC神經(jīng)環(huán)路可能參與編碼動物處于焦慮狀態(tài)時的空間場景。在場景恐懼記憶提取時,還伴有杏仁核的激活,提示杏仁核參與調(diào)節(jié)疼痛刺激引起的焦慮和恐懼行為。當(dāng)個體處于引起焦慮的環(huán)境時,vHPC、ACC和杏仁核共同參與調(diào)節(jié)機(jī)體的焦慮狀態(tài)。進(jìn)一步研究三個腦區(qū)之間的功能聯(lián)系,以及它們在引起焦慮行為時的相互作用,有助于我們了解焦慮的神經(jīng)機(jī)制,為臨床治療焦慮相關(guān)疾病提供實驗依據(jù)和理論基礎(chǔ)
[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.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R817;R749

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