非联想性应激诱发恐惧复发的相关脑区及 HPA 轴  相关功能分子的作用研究

PSYCH OpenIR > 健康与遗传心理学研究室

	非联想性应激诱发恐惧复发的相关脑区及 HPA 轴相关功能分子的作用研究
其他题名	Fear return evoked by non-associative acute stress in rats: roles of distinct brain regions and HPA axis-related molecules
	邢小莉
	2014-05
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了长期持续的精神障碍。临床上基于条件性恐惧消退原理的暴露疗法（exposure therapy）对创伤后应激障碍的治疗发挥了重要作用，但仍有一大部分经过消退的 PTSD 患者难以治愈，复发可能是 PTSD 难以治愈的重要原因。已有研究表明恐惧复发易受到情境、时间和应激等因素的影响，但这些因素引起的复发特点及神经机制并不相同，复发的这种异质性可能是复发难以干预的重要原因。传统研究中应激诱发的恐惧复发主要指重建，重建刺激通常与创伤刺激相同，最近的研究还关注了高台应激（elevated platform stress，EP）这种急性应激引起的恐惧复发，它与最初的创伤刺激性质完全不同，本研究称之为非联想性应激，至目前为止我们对这种非联想性应激诱发的恐惧复发知之甚少，因此本研究主要关注了这一复发的影响因素及干预。首先，本研究建立了高台应激诱发的大鼠条件性恐惧复发模型。研究发现消退后给予高台应激的确再次诱发了大鼠对声音的恐惧反应，并且这种急性应激引起的恐惧复发具有时间依赖性。高台应激结束后的恢复时间影响了恐惧复发水平，在应激结束后的较短时间内（少于1小时）复发效应并不明显，而相对较长的恢复时间（2 小时到6小时）则引起了较明显的条件恐惧反应。其次，恐惧复发是消退记忆与恐惧记忆相互竞争的结果，大量的研究表明应激调控了海马中糖皮质激素的两种受体盐皮质激素盐皮质激素受体（mineralocorticoid receptor，MR）和糖皮质激素受体（glucocorticoids receptor，GR）的变化，同时这两种受体都参与了条件性恐惧不同阶段的记忆加工。基于背侧和腹侧海马在线索性条件性恐惧中的不同，本研究测量了消退和高台应激复发引起的背侧和腹侧海马中 MR/GR 水平，结果发现条件性恐惧消退选择性地增加了腹侧海马中的 MR 蛋白表达，而高台应激诱发的恐惧复发组大鼠VH的MR 水平显著低于单纯消退组，但与对照组无应激大鼠 VH的MR 水平无差异。这一结果提示腹侧海马中的MR 蛋白水平增加可能是暴露疗法改善焦虑障碍的一个重要神经机制，而高台应激可能干扰了 VH的MR 活动影响了消退记忆的提取，从而引起了恐惧记忆复发，但也可能VH的MR活动并不参与高台应激引起的恐惧复发，VH以及其MR 活动在高台应激复发中的作用还需要进一步的验证。再者，与情境改变引起的续新复发不同，高台应激与最初的创伤事件毫无相关，失活调控续新的三个相关脑区边缘前皮层（prelimbic cortex，PL）、背侧海马（dorsal hippocampus，DH）和腹侧海马（ventral hippocampus，VH）发现，PL失活显著抑制了高台应激的失活，而 DH 和 VH 失活并没有抑制高台应激诱发的恐惧复发。这提示 PL是调控高台应激诱发的恐惧复发的重要区域，而海马对高台应激复发的调控相对较小。结合VH的MR 在恐惧消退和高台应激复发中的作用，本实验支持了VH 的MR 活动不参与高台应激复发的可能性，同时也进一步表明了不同复发模型具有不同的神经机制，为复发机制的差异性研究提供了证据。最后，研究关注了高剂量糖皮质激素对高台应激复发干预的效应。研究发现高剂量糖皮质激素对高台应激复发的干预具有时间依赖性，只有在条件性恐惧训练后 1小时给予25mg/kg的糖皮质激素才能有效抑制高台应激的复发。早期高剂量糖皮质激素可能提高了HPA轴对应激的敏感性，进而抑制了急性应激的恐惧复发。
其他摘要	Posttraumatic stress disorder (PTSD) is a stress-related mental disorder that is caused by a traumatic experience. Fear extinction decreases conditioned fear responses that normally occur when a conditioned stimulus (CS) is repeatedly presented in the absence of an aversive unconditioned stimulus (US), which is the behavioral basis of exposure therapy for PTSD. However，extinction does not erase the original fear memory but inhibits its expression. The extinguished conditioned fear response can spontaneously recover with the passage of time, they can be reinstated by the reinforcer alone, and they can also be renewed in a context-depedent manner. Therefore, fear return evoked by different stimuli may be an important factor for the treatment of PTSD. Many investigations have indicated that the underlying mechanisms governing the return of fear appear to be different. The present study was to investigate the impact factors and prevention of fear return induced by elevated platform (EP) stress. For reinstatement, the stress event was typically the shock US similar to conditioning training. Similar to reinstatement, EP stress-induced fear return also belonged to the category of stress-induced relapse, but the characteristics of stress events were different apparently. In this study, the EP stress was called as non-associative stress relative to original unconditioned stimuli. First, we established a model of the return of fear induced by EP stress and found that acute stress after extinction evoked the return of conditioned fear. The interval time between EP stress and retrieval test affected the levels of freezing. The shorter recovery time (less than 1 h) after EP stress did not exhibit obvious freezing behavior, but the longer recovery time (from 2 h to 6 h) induced higher fear response to tone. Second, the presnt study investigated changes in the protein expression of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the dorsal and ventral hippocampus, induced by extinction and return of conditioned fear responses to an auditory signal. The return of fear after exinction was the compensation between extinction memory and fear memory. The previous study has indicated that stress regulated the protein expression of MR/GR in hippocampus, and the dorsal and ventral hippocampus had different functions in extinction and the return of fear conditioning. However, the effects of extinction and the return of fear on GR and MR expression levels remain largely unclear. Therefore, the protein expression of MR/GR in the dorsal and ventral hippocampus was examined by Western blot analysis. We found that extinction after stress selectively increased the protein expression of MRs in the VH, which was reversed by EP stress. The extinction memoy might be suppressed by EP stress through preventing the activation of MR in VH, resulting in the reemergence of fear again after extinction. Another possibility is that the activation of MR in VH did not involve in the return of fear evoked by EP stress because of the equal protein expression of MR in VH between the extinguished rats evoked by EP stress and the ones without any stress. Further research should be needed to clarify this issue. Third, the different roles of prelimbic cortex (PL), ventral hippocampus (DH) and dorsal hippocampus (VH) were assessed between renewal and the return of fear induced by EP stress. We used small doses of the GABAA muscimol to selectively inactivate PL, VH or DH prior to the retrieval test. Inactivation of VH and DH had no effect on the return of fear evoked by EP stress, but impaired the renewal. Both renewal and fear return induced by EP stress were suppressed by lesion of PL. The dissociable roles of hippocampus further indicated different mechanisms existed in the two models of the fear return. And the EP-induced return of fear was little dependent on hippocampus. This results support Last, the preventive effects of high-dose corticosterone on fear return by EP stress were assessed. The present study found that the drug-induced suppression of fear return seemed fragile. Only the administration 1 h after fear conditioning acquisition suppressed the return of fear by EP stress.
学科领域	医学心理学
关键词	创伤后应激障碍高台应激糖皮质激素阈下二次条件化
学位类型	博士
语种	中文
学位专业	心理学
学位授予单位	中国科学院研究生院
学位授予地点	北京
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/19731
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	邢小莉. 非联想性应激诱发恐惧复发的相关脑区及 HPA 轴相关功能分子的作用研究[D]. 北京. 中国科学院研究生院,2014.

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