記憶形成的機制牽涉到神經塑性 (synaptic plasticity) 的改變，其中長期增益現象 (long-term potentiation:LTP) 被認為是學習記憶的分子機轉。以往glutamate系統在調節突觸塑性中被廣泛研究，近年來則發現一些neurotrophic factor也參與調節突觸塑性，它們經由影響一些神經調節因子 (neuromodulator) 的表現，進而間接調控神經調節因子的釋放；或是釋放到突觸中，使它們可以調節突觸前神經傳遞物質的釋放或突觸後神經細胞的功能。在這些neurotrophic factor中，brain-derived neurotrophic factor (BDNF) 廣泛參與在突觸塑性的調節，並牽涉到一些記憶的形成，例如空間記憶。

　　本論文主要在研究恐懼記憶與BDNF之間的關係。實驗發現，老鼠經由驚嚇恐懼訓練之後，杏仁核 (amygdala : 大腦主管情緒記憶的腦區，對於恐懼記憶的表現扮演著重要角色) 中BDNF的量會上升，同時BDNF的接受體 (TrkB receptor tyrosine kinase) 有明顯的活化，其下游訊息傳遞路徑中的Ras-ERK、PI3K-Akt、phospholipaseC1也有活化的情形。此外，經由intra-amygdala投與K252a ( TrK receptor tyrosine kinase inhibitor ) 、TrkB-IgG (其結構與TrkB receptor相似，無tyrosine kinase activity，和內生性TrkB receptor競爭與BDNF的binding以減弱BDNF的作用) 以及Ras、MEK、PI3K、PLC inhibitor則減弱了老鼠的驚嚇反應；反之，投與BDNF會增強老鼠的驚嚇反應，而且此現象被Ras、MEK、PI3K、PLC inhibitor阻斷。在in vitro的實驗探討BDNF下游訊息路徑，發現Ras位於ERK及PI3K上游，而PI3K位於ERK上游。

　　此外，cell surface GluR1這種activity-dependent表現在細胞膜上的AMPA receptor subunit，在fear training之後24小時有上升的現象，這是一種LTP的表現，與記憶形成相關。Intra-amygdala打入K252a及TrkB-IgG之後則抑制了這個現象，顯示BDNF可能經由增加細胞膜上的AMPA receptor，增強突觸傳訊，最後媒介fear memory的形成。

　　以上結果顯示，BDNF所媒介的訊息路徑可能直接參與在恐懼記憶形成的過程當中，但更詳細的機制仍需探討。

　　Brain-derived neurotropic factor (BDNF) and its receptor tyrosine kinase (TrkB) play important roles in neural plasticity, long-term potentiation and memory formation. One of the best-characterized neurotrophin-activated signal transduction pathways is the extracellular -regulated kinase / mitogen-activated protein kinase (ERK / MAPK) cascade. We have previously reported that fear conditioning led to the phosphorylation of ERK. The purpose of this study is to investigate whether BDNF and its downstream pathways are involved in the consolidation of fear memory measured with fear-potentiated startle paradigm.

　　Neuronal tissues taken from the lateral and basolateral amygdala of the conditioned rats showed an increase in the BDNF protein expression as compared with the control. Fear training also led to an increase in the phosphorylation of TrkB receptor, ERK, Akt, PLCγ1 and the activation of Ras. In behavioral tests, rats given intra-amygdala infusion of Trk, MEK, PI3K and Ras inhibitor had impaired memory.Direct application of BDNF to the amygdala enhanced the startle potentiation and the enhancememt is abolished by pre-treatment of Trk, MEK, PI3K and Ras inhibitor.

　　Treatment of amygdala slices with BDNF increased the levels of p- ERK, Akt and PLCγ1. Pretreatment of amygdala slices with Ras and PI3K inhibitor blocked the activation of ERK induced by BDNF.PI3K activation induced by BDNF was blocked by Ras inhibitor.

　　On the other hand, fear conditioning caused a Trk-dependent increase of cell surface expression of GluR1 in the amygdala.

　　Taken together, these results demonstrate a functional role of BDNF in fear learning and provide candidate signaling pathways coupled to TrkB receptor activation.

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