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

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.