在過去許多的動物實驗及臨床的觀察研究中，已經發現到壓力對於中樞系統學習記憶的表現有很大的影響，其影響的程度隨著壓力的強度及個體的差異有著兩極化(biphasic)的現象；例如短暫且輕度的壓力會促進記憶的形成，但是過度及長期的壓力反而會造成神經元的損傷，而破壞了學習記憶的表現。然而，雖然已經有許多的研究指出過度的壓力會造成了一種“learned helplessness”的現象；截至目前為止，我們對於壓力究竟如何去影響到學習記憶的表現，仍然是不清楚的。在先前的研究中，我們發現藉由將老鼠放入窄小的圓筒中並搭配一個小時之尾巴電刺激，可以觀察到老鼠海馬迴CA1 區域的LTP(長期增益現象)的表現是被抑制的，相反的其LTD(長期抑制現象)卻是被促進的，而此現象主要是藉由活化皮質激素接受體而造成Erk1/2 高度磷酸化進而影響神經可塑性的表現所造成的；因而我們可以藉由皮下注射皮質激素接受體的拮抗劑或是直接在海馬迴中投予一些訊息傳遞的抑制劑如：MEK1/2 (U0126), protein kinase C (Bis-I), tyrosine kinase (K252a), and BDNF antisense oligonucleotides 而抑制壓力對於神經塑性的影響。此外，我們發現到壓力可以明顯地降低海馬迴中glutamate transporter 的活性因而造成glutamate 的大量堆積而跑到突觸間隙以外而活化了分布於那邊的NMDA 接受體而導致了長期抑制現象的過度表現。進ㄧ步的實驗，我們發現藉由一些方式去調節動物海馬迴區域的神經活性(例:麻醉會抑制，而新奇事物刺激則可增加神經活性)，分別會造成壓力影響學習記憶的作用時間被延長或縮短，所以證實了神經活性可藉調節腦中磷酸化及去磷酸化酵素的活性衡，而決定壓力作用消除的速率。此外，我們同時觀察到amygdala 的不同核區：BLA 及CEA 在壓力作用的形成及消除過程中，分別扮演著不同的角色。因而如果我們事先在杏仁核的BLA 中投予Erk1/2 的抑制劑(U0126)或是NMDA 接受體的拮抗劑(APV)可以有效地抑制壓力所造成神經塑性的影響，但是投予在CEA 中則沒有效果。另一方面，新奇事物刺激加速壓力作用消除的現象則會被事先於CEA 中投予U0126 或是APV 所抑制，但是反過來投予在BLA 中則沒有效果。此外如果長時間反覆地回憶起這些負面壓力相關記憶的話可能會容易導致一些精神疾病的產生，所以在我們最後一部分的實驗中，思考如何有效地移除這些負面相關的記憶及其機轉成了我們研究的重點。我們發現藉由重複接觸負面記憶相關的特定提示號(cue)只能消除一小部分的恐懼記憶，但是對於其他與此恐懼記憶相關提示訊號完全沒有任何幫助，而這種現象就算我們給予D-cycloserine 來輔助也不能改善，因而暗示了臨床上運用此方式來進行恐懼記憶的消除可能會遇到一些挫折。然而另一方面，藉由一些分生的方式去干擾動物體內CREB-CBP 訊息傳遞路徑可以藉由影響記憶再固化的過程，而使得所有與負面記憶相關提示訊號的連結全部被破壞而抑制了恐懼記憶的表現。同時，我們發現比較老舊的記憶進行再固化破壞較不容易，進而提供了一些可以干擾比較老舊的記憶再固化的方法。在此，藉由這些實驗發現，我們已經對於壓力影響學習記憶及
神經可塑性之分子機制及調控方式有更深入的研究探討，希望這些發現將有助於未來改善壓力負面影響之藥物開發及臨床治療。

Extensive evidences from animal and human studies showing that psychological stress has a biphasic influence on cognitive function depend on the severity and context. Brief periods of stress can potentiate memory formation, where as more severe or prolonged stressors may cause neuron degeneration or synaptic plasticity blockade and exhibit marked deficits in various learning and memory tasks. However, the underlying cellular and molecular mechanisms by which stress exerts its effects on learning and memory remain unclear.
By using unpredictable and inescapable restraint tail-shock, we found that animals experienced behavioral stress show marked impairment of long term potentiation (LTP), however enhancement of long term depression expression. Meanwhile, the effects of stress on synaptic plasticity may originate from the corticosterone-induced sustained activation of Erk1/2 signaling cascades. As the changes of synaptic functions can be inhibited by intraperitoneal injection of glucocorticoid receptor antagonist before the stress, and also can be blocked by intrahippocampal injection of specific inhibitors of MEK1/2 (U0126), protein kinase C (Bis-I), tyrosine kinase (K252a), and BDNF antisense oligonucleotides. Besides, we found a significant reduction in the glutamate transporter activity after stress which may contribute to a temporal summation of glutamate and then spillover to activate the NMDA receptors at the extra-synaptic sites that in turn result in the enhanced expression of long term depression in the stressed animals. Furthermore, we found that manipulations which could modulate neuronal activity, such as reduced in anesthetized rats or increased after novelty stimulation, may prolong or shorten the duration of stress effects on synaptic plasticity. We also provide certain evidences showing that fluctuations in neuronal activity may control the tempo of extinguishing the stress effects through modulating the balance between kinases and phosphatases activity. Moreover, we found that different subnuclei of the amygdala (BLA and CEA) may exhibit different roles in mediating the formation and elimination of stress effects. As the administration of ERK1/2 inhibitor (U0126) or NMDA receptor antagonist (APV) into the BLA, but not the CEA, blocked the stress effects on the hippocampal synaptic functioning. In other hand, novelty exploration-induced reversal of stress effects was prevented when animals were injected U0126 or APV into the CEA, but not the BLA, before subjected to the novel environment. Because of the repetitive replaying of stressful experiences precipitates the incidence of many psychiatric disorders; in the last part of our work, we are interested in studying the mechanisms involved in the removing of distressing bad memories linked to the stress events. As we found that extinction therapy with a single paired cue result in a “cue-specific” extinction effect, but left all other cues untouched. The invalidity of extinction therapy persisted even we combined the treatment with the extinction enhancer: D-cycloserine, which these results may reveal the existing of certain handicaps for clinical explosure therapy. In the other hand, targeting memory reconsolidation processing by an in vivo inducible transgenic manipluations of CREB-CBP signaling can remove all the cues and fear memory connections comprehensively. Also we provide novel directions that could extend the accessible time windows for the disrupting of elder bad memories. Here by series of experiments, we understand more about the mechanisms involved in stress on the regulation of brain functioning, and hope that we could ultimately develop new therapeutic strategies or effective pharmacological management in treatment of individuals with defeated learning performances following distressing events.

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