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海马-腹内侧前额叶边缘前皮层通路在阈下二次 条件化诱发的大鼠恐惧复发中的作用
其他题名The role of hippocampal - prelimbic area of ventromedial prefrontal cortex pathway in the fear return evoked by a sub-conditioning procedure in rats
付娟
学位类型博士
导师郑希耕
2016-05
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业心理学
关键词恐惧复发 阈下二次条件化 海马 前额叶
摘要创伤后应激障碍(posttraumatic stress disorder,PTSD)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。条件性恐惧是研究创伤后应激障碍的典型动物模型,根据巴甫洛夫恐惧条件化理论,一个中性刺激与一个伤害性刺激(非条件化刺激,US)重复配对呈现后,中性刺激将转变为条件化刺激(CS)进而能够单独引起机体的恐惧反应(条件化反应)。条件化恐惧建立之后,如果仅CS重复呈现而不呈现US,则CS引起机体条件化恐惧反应的能力将逐渐减弱乃至丧失,该过程即为恐惧消退。临床上常用的暴露疗法就是基于消退原理,但经过治疗的患者遇到某些刺激因素后创伤症状会再度恶化,即复发,这提示抑制复发可能是治疗创伤后应激障碍的关键问题。生活中的刺激多种多样,复发也具有异质性。临床研究发现个体经历创伤事件后,再次暴露很小的刺激便能诱发PTSD症状,而在正常个体中不会发生。阈下二次条件化诱发的恐惧复发模型很好的模拟了这一现象:在条件性恐惧消退后给予很弱的阈下刺激,个体会再次恢复对条件化刺激的恐惧反应。 以往很多研究表明海马与前额叶是恐惧消退和复发的关键脑区,近期研究也提示海马和前额叶参与了阈下二次条件化诱发的恐惧复发,但是各亚区及通路的功能并不清楚。因此,我们提出以下假设:腹内侧前额叶的PL(Prelimbic cortex)区域、海马是阈下二次条件化诱发的恐惧复发的关键脑区,为了明确各亚区的作用,我们把目标脑区定在海马的三个位点:背侧海马(dorsal hippocampus,DH)的CA1区,腹侧海马(ventral hippocampus,VH)的齿状回区(dentate gyrus,DG)和CA1区,如果假设成立,即PL、DH、vDG与vCA1确实参与了阈下二次条件化诱发的恐惧复发,那么DH与PL、vDG与PL及vCA1与PL之间的投射是怎样的?这三条通路在阈下二次条件化诱发的恐惧复发中有无差异性调控?这是本研究拟回答的问题。 研究方案分为两大部分: 1.研究四个独立脑区在阈下二次条件化诱发的大鼠恐惧复发中的作用。
此部分包括四个实验:分别失活PL、DH、vDG、vCA1脑区检测其对阈下二次条件化诱发的恐惧复发的影响。
2.研究DH-PL、vDG-PL及vCA1-PL三条通路在阈下二次条件化诱发的恐惧复发中的作用。 此部分包括三个实验:采用药理学方法分别交叉失活DH与PL、vDG与PL及vCA1与PL脑区,检测每条通路在恐惧复发中的作用。 研究结果与结论: 1.失活PL降低了阈下二次条件化诱发的恐惧复发水平。前人的研究结果发现:失活PL会降低恐惧的表达,续新复发时,PL脑区的c-Fos呈高表达;支持了我们的实验结果。 2.很多研究提示DH和VH作为海马的两个亚区,其功能存在差异性。我们的结果显示分别失活DH、vDG、vCA1都降低了阈下二次条件化诱发的复发,但是只有失活vDG影响了消退的提取过程。实验室前期研究表明DH与VH并不参与高台应激诱发的复发,这也进一步说明了复发的异质性。 3.DH-PL、vDG-PL及vCA1-PL这三条通路中,只有交叉失活vCA1-PL通路显著降低了阈下二次条件化诱发的恐惧复发,而其他两条通路并没有显著作用,说明vCA1-PL这条通路参与介导了阈下二次条件化诱发的恐惧复发,同时也验证了海马与PL直接的投射主要集中在vCA1区域,只有很少投射在vDG区域,而到DH区域的投射几乎没有。
其他摘要 Posttraumatic stress disorder (PTSD) is a mental disorder due to persistent symptoms caused by the individual experience of life threatening or severe trauma. Fear conditioning is a typical animal model of posttraumatic stress disorder. According to Pavlov fear conditioning, after repeated pairing of a neutral stimulus and a noxious stimulus (non conditioned stimulus, US), neutral stimuli convert to be conditioned stimuli (CS), that is, it comes to elicit conditioned fear responses (conditioned reaction). Conditioned fear responses can be extinguished by repeatedly presenting the CS without the US, this process is called fear extinction. Exposure therapy that is commonly used in clinical practice is based on fear extinction. Symptoms will deteriorate again after treatment when patients encounter some stimulus, that is, fear return. It suggests that inhibition of fear return may be the key problem in the treatment of post-traumatic stress disorder. There is a variety of stimuli in the life, and the fear return is heterogeneous. The clinical study found that the individual who has experienced traumatic events would once again display PTSD symptoms when exposed to a small stimulus, but it will not occur in normal individuals. Fear return evoked by a sub-conditioning procedure is a good simulation of this phenomenon: the individual will show fear response again when exposed to a sub-threshold stimulation after fear extinction.
Previous studies have suggested that the hippocampus and prefrontal cortex are the key brain regions of fear extinction and fear return. Recent studies have suggested that the hippocampus and prefrontal cortex are involved in the fear return evoked by a sub-conditioning procedure, but the function of the sub-regions and pathways is not clear. We therefore propose the following hypothesis: the prelimbic cortex and hippocampus are the key brain regions in the fear return evoked by a sub-conditioning procedure. In order to identify the function of the sub-regions, we focus on three sites of the hippocampus [CA1 area of dorsal hippocampus, DG (dentate gyrus) and CA1 region of ventral hippocampus]. If this were the case, that is, the prelimbic cortex (PL), dorsal hippocampus (DH), vDG and vCA1 do participate in the fear return evoked by a sub-conditioning procedure, what is the projection between DH and PL, vDG and PL, or vCA1 and PL? Is there any siginificant difference among roles of these three pathways in this fear return? This is issues to be clarified in this study. The research is divided into two parts: 1. Effects of four independent brain regions on the fear return evoked by a sub-conditioning procedure. This part includes four experiments: inactivating PL, DH, vDG or vCA1 respectively to examine region-specific role in this model. 2. To examine the role of pathway (DH-PL, vDG-PL or vCA1-PL) in the sub-conditioning procedure induced fear return. This part includes three experiments: using pharmacological methods to disconnect the DH-PL, vDG-PL or vCA1-PL pathway, respectively, to detect the role of each pathway in the fear return. Research results and conclusions: 1. Our results showing that inactivation of the PL area impaired fear return using the sub-conditioning paradigm. Previous studies found that inactivation of PL reduced expression of conditioned fear and the expression of c-Fos in PL brain region was highly expressed in renewal, which support our results. 2. Many studies have suggested that the two subregions of the hippocampus: DH and VH, have different functions. Our results showed that inactivation of DH, vDG, and vCA1, reduced fear return evoked by a sub-conditioning procedure respectively. Moreover, inactivation of vDG affected the extinction process. Our previous study showed that DH and VH are not involved in fear return evoked by elevated platform stress. It further illustrats the heterogeneity of fear return.
3. Among these three pathways (DH-PL, vDG-PL or vCA1-PL), only inactivation of vCA1-PL significantly reduced the fear return whereas other two pathways have no significant effect on it, indicating that vCA1-PL pathway is involved in mediated the fear return evoked by a sub-conditioning procedure. Results also verified that the direct projection between hippocampal and PL is mainly concentrated in the area of vCA1, only few projection located in the region of vDG, and almost no projection located in DH area.
学科领域医学心理学
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/19830
专题健康与遗传心理学研究室
作者单位中国科学院心理研究所
推荐引用方式
GB/T 7714
付娟. 海马-腹内侧前额叶边缘前皮层通路在阈下二次 条件化诱发的大鼠恐惧复发中的作用[D]. 北京. 中国科学院研究生院,2016.
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