學習與記憶為生物體生存的必要能力，亦為生物體發展的動力；然而，錯誤的恐懼經驗往往會造成焦慮等負面的結果。焦慮症狀的產生，乃生物體對於恐懼經驗的過度學習與記憶所導致，以此情緒表現所衍生的精神疾病更是目前人類所處環境的一大危害及負擔。因此，恐懼記憶形成機制的探討，實為解決焦慮症狀最直接而明顯的途徑。

　　大腦杏仁核體對於恐懼記憶的表現及誘發扮演著重要角色。在研究恐懼記憶形成機制多以杏仁核體的腦神經細胞為主體。其研究成果除了對於腦部運作的基本功能有所了解外，也可以應用在一些精神官能疾病，神經損傷，神經退行性病變中。神經細胞中有幾種物質參與記憶的形成，包括N-Methyl-D-aspartic Acid (NMDA) receptor，protein kinase A (PKA)，mitogen-activated protein kinase (MAPK)，cAMP response element binding protein (CREB)等等，而它們的相關訊息傳遞路逕也有些了解。除了前述物質之外，目前發現NF-kB的活化與一些神經損傷及與記憶有關。本研究首先探討NF-kB在恐懼記憶模式中活化的程度，以及相關活化的因子。結果發現，在高頻電刺激(TS)及直接活化PKA等離體刺激下，或是恐懼學習後的活體模式中，都可以造成IKK的酵素活性快速上升，IkB-a的表現量快速減少。在此同時，NF-kB p50次體進入細胞核，NF-kB的DNA binding activity也顯著的增加，經由supershift assay也發現此時活化的NF-kB複合體主要為 p50/p65異合體型式。我們也發現細胞外訊息主要經由NMDA receptor，PKA，PI-3 kinase等訊息傳遞路徑造成IKK活化，IkB-a被分解，最後促使NF-kB在細胞質活化。這些NF-kB相關的訊號傳遞只局限於杏仁核體(amygdala)內，在其他腦區如海馬迴(hippocampus)及小腦區(cerebellum)則不改變，顯示此一現象只發生在與恐懼記憶有關的腦區中。此外，由非配對對照組(unpair control group)中觀察，給予不經由配對的光及電擊刺激，並不能促使NF-kB的DNA binding activity上升，顯示NF-kB與制約條件的學習有密切的正相關性。

　　在大鼠腦內杏仁核注射NF-kB活化抑制劑，如TPCK，TLCK或是kB decoy DNA後，可明顯抑制恐懼記憶的形成，顯示NF-kB的活化與記憶的形成有密切的關聯性。另外，我們也發現細胞核中CREB與NF-kB似乎有交互作用的產生，此現象可能促進CREB及NF-kB與相關DNA binding sequence的結合能力，並導致相關基因調控的改變。

　　NF-kB的活性可被其乙醯化(acetylation)程度所調控，此現象主要決定於HAT (histone acetyltransferase)及HDAC (histone deacetylase)的活性變化，這種調控會因不同的細胞模式而有所改變。接下來我們的研究發現，恐懼學習能夠促使HAT (histone acetyltransferase)活性增加，NF-kB p65和CBP的交互作用增強，以及促使p65乙醯化程度增加，而此現象僅見於杏仁核體。另一方面，抑制HDAC3的酵素活性會降低p65與HDAC3的交互作用，進而增強p65乙醯化的程度，增加NF-kB 的DNA binding activity，並且增強大鼠的恐懼反應，以及離體模式中LTP (long-term potentiation)的表現。若只單獨給予HDAC抑制劑，而不合併處理活體恐懼學習或是離體活化PKA等刺激，上述增強情形則消失，而且此現象可被kB decoy DNA干擾，顯示HDAC抑制劑的效果確實是直接經由特異性的調控NF-B的功能所致。最後，由非配對對照組(unpair control group)中觀察，給予不經由配對的光及電擊刺激，並不能促使p65乙醯化的表現增加。綜合以上，在杏仁核體中，由HDAC所媒介的去乙醯化功能影響NF-kB在細胞核中的活性變化。

　　與NF-kB有關的訊息傳遞路徑到底如何改變神經塑性?近期研究指出，GluR (glutamate receptor)是快速突觸傳導及突觸間信號傳遞的主要媒介。而其中的AMPA receptor則在神經細胞突觸的動態平衡，與突觸間神經電生理信號的增強或減弱有非常密切的相關性。包含有GluR1/2次體的AMPA receptor在神經細胞膜上的表現與突觸活性有密切相關性。我們利用細胞膜蛋白質標定法及粹取突觸神經體(synaptoneurosome)，發現大鼠經過恐懼訓練之後，杏仁核體細胞膜及突觸中GluR1次體的表現有明顯增加的趨勢。而NMDA receptor拮抗劑(D-APV)，PI-3 kinase抑制劑(wortmannin)，MEK抑制劑(U0126)，蛋白質合成抑制劑(anisomycin)皆可以消減GluR1的表現。另一方面，投予HDAC抑制劑(Tricostastin A)會增強細胞膜上GluR1的表現，但此現象會被NF-kB抑制劑(helenalin)及anisomycin所阻斷。在恐懼訓練後給予一連串制約性刺激(conditional stimulation)，即消減記憶(memory extinction)步驟，也可以壓抑GluR1次體增加。而此現象也被D-APV及anisomycin所反轉。在離體實驗中，高頻電刺激(TS)能增加杏仁核體腦薄片中細胞膜上的GluR1次體，合併處理低頻電刺激(LFS)則消除此現象。總合以上結果，大鼠恐懼記憶的表現及神經細胞突觸塑性的變化，與細胞膜上GluR1的表現呈現高度相關性。而與GluR1在細胞膜上表現有關的蛋白質，則很可能是參與恐懼記憶的基因表現之一。

　　Learning and memory is the basis for the survival and development of creatures, however, aversive experience of fear leads to anxiety. With the changes of the society, anxious complications happen commonly in the modern life. Therefore, the problems of anxiety can be solved by an understanding of emotional fear in terms of its underlying cellular and molecular mechanisms.

　　NF-kB, originally identified as a regulator of immunoglobulin k light chain gene expression, is a DNA-binding factor that functions as a dimer. Recent studies indicate that NF-kB played an important role in the synaptic plasticity. Therefore, we used fear-potentiated startle paradigm to identify the role of NF-kB signaling pathway in memory formation. The results show that p50 and p65 subunits of NF-kB were selectively activated in the amygdala following fear conditioning through the signal-induced activation of PI-3 kinase, IKK and subsequent proteolytic degradation of IkB-a in the cytoplasm. This allows NF-kB to translocate into the nucleus where it binds to specifickB DNA consensus sequences in the enhancer region ofB-responsive genes. Pharmacological blockade of NF-kB impairs fear memory in a dose-dependent manner. In in vitro slice preparation, bath application of kB decoy DNA attenuates tetanus-induced L-LTP in the amygdala. Therefore, a novel role of NF-kB in fear conditioning and synaptic plasticity has been demonstrated here.

　　CBP/p300 contains histone acetyltransferase that has been implicated in the regulation of gene expression. Recent studies show that the action of NF-kB is regulated by reversible acetylation. We found that the expression of acetyl-p65 subunit was selectively increased in the amygdala following fear conditioning through the increase associated with CBP (CREB binding protein). Pharmacological blockade of histone deacetylase further increase DNA binding activity of NF-kB and fear memory in a dose-dependent manner. In in vitro slice preparation, bath application of histone deacetylase inhibitor increases the degree of forskolin-induced L-LTP in the amygdala. Therefore, a novel role of NF-kB in fear conditioning and synaptic plasticity has been demonstrated. These results suggest that HDAC-mediated deacetylation functions as an intranuclear molecular switch culminating in the termination of NF-kB transcriptional response.

　　AMPA receptors mediate the majority of the fast excitatory synaptic transmission. One recently identified mechanism contributing to synaptic plasticity is the regulated trafficking of AMPA receptors in and out of synapses. Receptors with long cytoplasmic tails (GluR4/2 and GluR1/2) are driven into synapses in an activity-dependent manner. Our results show that synaptoneurosome membrane expression of GluR1 was selectively increased in the amygdala following fear conditioning through the signal-induced activation of PI-3 kinase, NMDA receptor and NF-kB. Pharmacological blockade of histone deacetylase further increases conditioning-induced membrane expression of GluR1 in NF-kB-dependent manner. Furthermore, fear training-induced increase in GluR1 was reversed when animal was exposed to the memory extinction protocol. The reversal of GluR1 increase was also blocked by D-APV and anisomycin treatment. The similar pattern of changes in GluR1 was observed in the amygdala slices after delivery of high-frequency stimulation (HFS) or HFS followed by low-frequency stimulation (LFS) that elicited long-term potentiation (LTP) and depotentiation respectively. These results suggest that long-term synaptic plasticity and memory formation are correlated with the changes in modification of GluR1 expression, and surface expression of GluR1 is a potential effector that contributes at least in part to the expression of fear memory.

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