|Alternative Title||Effects on Classical Fear Conditioning by Corticosterone Injected within Post-training Peri-traumatic Period and the Mechanisms of Dopamine|
|Place of Conferral||北京|
|Keyword||创伤后应激障碍 条件性恐惧 记忆巩固 围创伤期 早期干预 皮质酮 多巴胺|
|Abstract||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。创伤时所形成的恐惧记忆是 PTSD 症状发作的关键因素，因此消除已经巩固的恐惧记忆是治疗 PTSD 的一个重要目标。但相关研究证明一旦恐惧记忆被巩固就不可能被消除。因此许多临床心理学家试图从二级预防的角度专门针对高危人群给予干预以减少 PTSD 的发病率。临床上的相关研究证明早期干预能够降低 PTSD的发病率。前临床对动物的条件性恐惧研究也发现，条件性恐惧训练后立即进行干预以破坏已经获得的条件性恐惧记忆的巩固，恐惧记忆才不能复发。因此应激后围创伤期阻断恐惧记忆的巩固可能是预防PTSD发病的最有效途径。|
糖皮质激素（glucocorticoids，GCs）是预防 PTSD的一种良好选择，如临床上已发现为了抵抗炎症而给予经历过严重创伤的 ICU 病人氢化可的松就能够降低 PTSD 形成的概率，但目前这种效应起效的机制还不清楚。研究者认为甾体类药物之所以能够预防PTSD的形成可能是因为GCs阻断了恐惧记忆的巩固或提取。但是，大量的研究还证明 GCs 促进记忆的巩固。这种矛盾的结论与 GCs给药的剂量和时间点有密切关系，即低剂量或高剂量GCs 无效或破坏记忆巩固，而中等剂量 GCs 促进记忆巩固；记忆获得后立即给予应激会促进记忆的巩固，而获得后间隔一定的时间给予应激则破坏记忆的巩固。但这个假设主要依据海马依赖的非情绪性记忆的研究结论，它是否在声音条件性恐惧记忆中成立也没有相应。
另外，个体的急性应激反应是影响 GCs 效应的另外一个重要因素，这也是预防或治疗应激相关障碍必须要考虑的因素。急性应激反应主要表现在动物在条件性恐惧训练时获得的恐惧水平的高低，训练时恐惧水平高的动物（HF）为应激反应较强的动物，而训练时恐惧水平低的动物（LF）为应激反应较弱的动物其分类标准为训练时 CS2-CS5 的恐惧水平均值是否高于 60%或 50%。在机制上，由于 GCs 可能会首先作用于多巴胺（dopamine，DA）系统而调控人类的精神障碍，且边缘-皮层 DA 系统是参与应激后恐惧记忆巩固的重要通路，因此我们探索内侧前额皮层多巴胺活动对皮质酮调控恐惧记忆的影响。我们的实验主要是探索糖皮质激素是否能够破坏动物条件性恐惧记忆的巩固，以及糖皮质激素对恐惧记忆巩固的影响是否在急性应激反应不同的个体间是不同，并在机制上上探索内侧前额皮层多巴胺的作用。
我们给予动物 5 次声音（CS，30s，80d0B，4000Hz）-电击（US，1s，1.0mA）的匹配训练，在训练后的不同时间点给予不同剂量的皮质酮并测试动物的恐惧记忆表达水平，我们发现：
2. 动物训练时的恐惧水平与恐惧记忆的较短时程的表达（训练后 48h）及其长时程表达（训练后 22d）之间均不存在显著的相关。并且，LF 与 HF 在恐惧记忆的表达上也不存在显著的差异。
3. 低剂量皮质酮（5mg/kg，i.p）对恐惧记忆没有显著的影响，但围创伤期内不同时间点给予高剂量皮质酮（25mg/kg，i.p）对恐惧记忆具有不同的影响：在围创伤期的应激状态（训练后0h）给予高剂量皮质酮能够增强训练后 9d的恐惧记忆表达，而在围创伤期的非应激状态（训练后 1h）给予高剂量皮质酮却降低了训练后 48h和训练后 1w 的恐惧记忆表达；并且围创伤期非应激状态不给药模型组（VEH 组）的恐惧记忆能够得到良好的重建，而皮质酮组（CORT 组）的恐惧记忆难以重建。
5. 皮质酮并不是对所有动物的恐惧记忆都具有调节的作用，训练后0h给予皮质酮能够增强 HF动物恐惧记忆的巩固，对 LF无影响；但训练后 1h给予皮质酮则削弱 LF动物恐惧记忆的巩固，对 HF动物无影响。
6. 在训练后 1h 给予皮质酮前先 mPFC 内给予多巴胺 D2 受体拮抗剂依替必利，则单纯皮质酮和依替必利均不能调控动物恐惧记忆的巩固，而皮质酮协同较高剂量（1μg/μl/侧）的依替必利则显著的削弱了HF 动物恐惧记忆的巩固，且有逆转皮质酮对LF动物恐惧记忆破坏作用的趋势。这说明 mPFC内 DA系统参与了皮质酮对恐惧记忆的调控。
我们的研究说说明在不干预的情况下，无论 LF 与 HF 均能够保持长久牢固的恐惧记忆，而皮质酮能够破坏动物恐惧记忆的巩固以降低其表达和重建。但这种效应只对应激反应较弱的动物有效，说明此类动物才能够从早期干预中获益。
总之，我们的研究结论提供了一个有力的证据，即 GCs 类药物可能可以用于预防 PTSD 的形成、防止 PTSD 复发。对于难以干预的应激反应较强的个体，探索应激后HPA轴活动与DA系统的协同作用将会非常有意义。
|Other Abstract||Posttraumatic stress disorder (PTSD) is developed after individuals suffering from life-threatening trauma. Consolidated fear memory induced by trauma is the key maintaining factor of the symptoms of PTSD. Therefore, the most conventional and desirable method to treat PTSD is to erase fear memory. But researches showed that it is impossible to erase a consolidated memory. Many clinical psychologists began to find methods to prevent the development of PTSD after trauma. Clinical studies have proved that early prevention could decrease the incidence rate of PTSD. Moreover, pre-clinical studies also found that early intervention immediately after fear conditioning could block the consolidation of fear memory. This maybe mean that early prevention, which is conducted in the time window of fear memory consolidation (peri-traumatic period), might is an effective way to decrease the damage of traumatic stress.|
It is supposed that glucocorticoids (GCs) maybe a good choice to prevent the development of PTSD. For example, a series of clinical researches found that when short-term high doses hydrocortisone used to treat acute attack of cardiac surgery and septic shock, it will be protective with regard to the later development of PTSD. But the mechanism of this effect is still not clear. It was assumed that the anti-anxiety effects of steroids hormone might be achieved by disrupting fear memory consolidation or by impairing fear memory retrieval.
However, it is also well known that GCs enhance memory consolidation for emotionally aversive experiences in both animals and healthy humans. Maybe that the enhancement and impairment effects on memory of GCs largely depend on drug doses and treatment time. It is that midrange doses enhancing but very high or low doses having no effects or impairing memory, and immediately stress after learning enhances memory consolidation but delayed stress disrupts it. The impairment effects on memory of posttraining high doses corticosterone or stress have been observed in tasks depending on hippocampus. However, the effects of corticosterone on cued fear conditioning, a PTSD model which depend on amygdala, are still not clear.
The effects of GCs on conditioned fear memory also depend on the acute stress reaction （ASR）. Animals with low level freezing (LF) behaviors in fear conditioning session are seen as strong response ones who adopt active coping style; whereas rats with high level freezing (HF) behaviors are seen as weak responders who adopt passive coping strategies. The separating criterion of LF and HF was according to that whether the mean freezing scores of CS2-CS5 obtained from fear conditioning session are higher than 60% or 50%. Meanwhile, based on the finding that GCs ameliorate symptoms of mental disorders firstly by affecting the activity of dopamine, we concerned the modulating activity of mPFC dopamine on corticosterone effects. Therefore, we mainly concern whether the fear memory consolidation could be impaired by GCs treated after fear conditioning in our research. We also concern whether the effects of GCs were modulated by ASR and it’s mechanism about mPFC dopamine activity.
Rats received five pairings of an auditory stimulus (30s, 80dB, 4000Hz) and an intensive footshock (1s, 1.0mA), then we treated rats at peritraumatic period with different doses of corticosterone and test the long term fear memory. We found that:
1. The fear conditioning of rats present a trend of bimodal distribution. This proved that the stress responses of rats are bipolar.
2. There was no significant correlation between fear conditioning and fear expression. Moreover, there was no significant difference of fear expression between LF and HF rats.
3. Low dose corticosterone (5mg/kg) exerted no effect on fear memory when high dose corticosterone (25mg/kg) significantly enhanced or disrupt memory expression. The contradictory effects of high dose corticosterone were caused by the administration time after fear conditioning. It was showed that: when corticosterone administrated at the stressed state (0h after fear conditioning), the fear memory, which was tested 48 h and 9 d after conditioning, was enhanced; whereas when corticosterone administrated at the rest state (1h after fear conditioning), the fear memory, which was tested 48 h and 1 w after conditioning, was disrupted. Moreover, 1 h administration of high dose corticosterone impaired the reinstatement of fear memory.
4. Corticosterone administrated outside the peri-traumatic period (24h after fear conditioning) did not affect fear memory expression.
5. Corticosterone did not present the same modulating effect for all rats. The fear memory of HF but not LF was enhanced by 0h corticosterone administration, but 1h corticosterone administration only impaired the fear memory of LF but not HF rats.
6. When eticlopride, a D2 receptor antagonist, or saline was microinjected into mPFC before 1h corticosteron (25mg/kg) administration, the fear memory consolidation of HF rats was significant impaired; and moreover, the impairment effect of corticosterone on memory consolidation of LF was blockaded by eticlopride. But corticosterone or eticlopride alone present no effect on fear expression compared with each corresponding vehicle rats. This indicates that the DA activity in mPFC is involved in the modulating effects of corticosterone on fear memory consolidation.
Our research indicated that, whether in LF or HF rats, the conditioned fear memory will maintain for a long term without intervention. When corticosterone administrated with peritraumatic period, corticosterone disrupt the expression and reinstatement of fear memory. But these effects only present in LF rats.
This implies that the fear memory of weak stress reaction individuals is easy to be enhanced. All in all, our results provided evidences that modulating the activity of HPA axis might be one way to prevent the development and relapse of PTSD. For the stress susceptible individuals who are difficult to intervention, to explore the post-stress interaction between HPA axis and DA system might be very meaningful.
|安献丽. 围创伤期皮质酮对恐惧记忆巩固的影响及其前额叶皮层多巴胺机制[D]. 北京. 中国科学院研究生院,2011.|
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