恐懼制約對於神經可塑性的影響涉及到AMPA receptor與NMDA receptor的調控，其中在fear conditioning的刺激之下會造成NMDA receptor的downregulation及current的降低以對於conditioning後所造成的神經高度興奮狀態產生一種保護的機制。另外，extinction後所產生的extinction learning與NMDA receptor調控也有某種程度的關聯，在先前的研究證據下指出，NMDA receptor antagonist的使用之下可以干擾這種extinction learning。
　　因此本論文的研究目的，就在於探討恐懼制約及其消除模式的這兩種調控方式對於AMPA 及NMDA receptor在surface expression方面所產生的影響。研究的內容主要分為古典恐懼制約(classical fear conditioning)與恐懼記憶消除模式(extinction protocol)兩方面的動物模式進行探討，另外在最後也建立了一套旁側抑制(lateral inhibition)的動物模式，以這幾種模式評估受體層面的變化與記憶之間的相關聯性。由於AMPA與NMDA receptor各個subunit在fear memory及extinction learning中之receptor trafficking之詳細機轉尚屬未知，因此希望藉由surface expression 的偵測做為一個初步的了解，以期更進一步釐清AMPA與NMDA receptor在中樞神經系統中所調控的的真正生理功能。
　　由實驗結果顯示，恐懼制約及其消除模式的確造成AMPA 及NMDA receptor其中的GluR1及NR2A subunit產生突觸表面表現量的變化情形，而若分別以不同藥物與抑制劑進行杏仁核區腦內給藥，則可觀察到不同的逆轉現象，顯示受體於突觸表面的表現涉及到不同的訊息傳遞路徑。而接著將影響受體表現層面的藥物應用在動物恐懼記憶形成及消除的實際評估上，的確可觀察到兩者之間的平行現象，進一步的證實受體表現及其所經由的訊息傳遞路徑對於學習與記憶的影響。其中蛋白質的生成、PI-3 kinase及NMDA receptor的活化影響了恐懼狀況後受體突觸表現量，也參與了恐懼記憶形成的機制。而MAP kinase與NMDA receptor則影響了恐懼記憶消除後的受體突觸表現量及其記憶消除機制。最後在旁側抑制的模式評估下，不會有受體表現量的變化產生，同時在恐懼驚嚇指數方面也觀察到降低的情形。綜合以上，顯示記憶的形成與消除的確涉及到受體的消長，而這些消長則是分別透過不同的訊息路徑所產生。

　　Fear conditioning induces associative long-term potentiation in the amygdala, and is a powerful regulator of long-term synaptic plasticity which involved in protein and kinase phosphorylation. Previous study indicated that NMDA currents and receptor protein are downregulated in the amygdala during maintenance of fear memory. This may protect against excitotoxicity of unchecked NMDA receptor recruitment during induction and consolidation of fear memories. NMDA receptors also are involved in fear memory extinction, and infusions into the amygdala of either NMDA receptor antagonists or inhibitors of the NMDA receptor-linked mitogen activated protein kinase cascade block extinction learning.
　　Here we show that fear conditioning and its extinction protocol cause different AMPA and NMDA receptor synaptic membrane expression, especially GluR1 and NR2A subunit. We apply different chemical and inhibitors for intra-amygdala injection to prove that protein synthesis inhibitor, PI-3 kinase inhibitor and NMDA receptor antagonist inhibit GluR1 expression after fear conditioning. MAP kinase inhibitor and NMDA receptor antagonist inhibit GluR1 and NR2A expression after extinction protocol. These inhibitors also interfere with fear memory and extinction memory formation.
　　Finally, receptor membrane expression was unaltered in the model of lateral inhibition. These data suggest that receptor trafficking participate in fear memory formation and extinction, and this phenomenon is through different signaling pathway.

Applegate C.D., Frysinger R.C., Kapp B.S., Gallagher M. ( 1982 ) Multiple unit activity recorded from amygdala central nucleus during Pavlovian heart rate conditioning in rabbit. Brain Research, 238: 457–462.
Berg W.K., Davis M. ( 1985 ) Associative learning modifies startle reflexes at the lateral lemniscus. Behavior Neuroscience, 99 : 191–199.
Berman D.E., Dudai Y.（2001）Memory extinction, learning anew, and learning the new :Dissociations in the molecular machinery of learning in cortex. Science, 291: 2417-2419.
Bredt D.S., Nicoll R.A.（2003）AMPA receptor trafficking at excitatory synapses. Neuron, 40: 361–379.
Carroll R.C. and Zukin R.S.（2002） NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends in Neurosciences, 25: (11) 571-577.
Davis M. (2002) Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eurpean Journal of Neuroscience, 16: pp. 395-398.
Esser L., Wang C.R., Hosaka M., Smagula C.S., Sudhof T.C., Deisenhofer J. (1998) Synapsin I is structurally similar to ATP-utilizing enzymes. EMBO Journal, 17： 977-984.
Falls, W.A., Miserendino, M.J.D.,Davis M. (1992) Extinction of fear potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. The Journal of Neuroscience, 12: 854-863.
Fendt M.（2001）Injections of the NMDA receptor antagonist aminophosphonopentanoic acid into the lateral nucleus of the amygdala block the expression of fear-potentiated startle and freezing. The Journal of Neuroscience, 21: 4111–4115.
Fischer A., Sananbenesi F., Schrick C., Spiess J., Radulovic J.（2002） Cyclin-dependent kinase 5 is required for associative learning. The Journal of Neuroscience, 22: 3700-3707.
Hartline H.K., Wagner H.G., Ratliff F.（1956） Inhibition in the eye of Limulus. Journal of General Physiology, 39: 651-673.
Johnson M.W., Chotiner J.K.,. Watson J.B. （1997）Isolation and characterization of synaptoneurosomes from single rat hippocampal slices. Journal of Neuroscience Methods, 77: 151–156.
Jovanovic J.N., Sihra T.S., Nairn A.C., Hemmings H.C. Jr, Greengard P., Czernik A.J. ( 2001 ) Opposing changes in phosphorylation of specific sites in synapsin I during Ca2+-dependent glutamate release in isolated nerve terminals. The Journal of Neuroscience, 21: 7944-7953.
Kennedy M.B., McGuinness T., Greengard P. (1983) A calcium/calmodulin-dependent protein kinase from mammalian brain that phosphorylates Synapsin I: partial purification and characterization. The Journal of Neuroscience, 3: 818-831.
Lamprecht R., LeDoux J.：Structural plasticity and memory. （2004）Nature Review Neuroscience, 5: 45-54.
Lee H.J., Choi J.S., Brown T.H., Kim J.J.（2001） Amygdalar NMDA receptors are critical for the expression of multiple conditioned fear responses. The Journal of Neuroscience, 21: 4116–4124.
Lin CH, Yeh SH, Lin CH, Lu KT, Leu TH, Chang WC, Gean PW（2001）A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron, 31: 841-851.
Lin CH, Yeh SH, Lu HY, Gean PW（2003）The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory. The Journal of Neuroscience, 23: 8310-8317.
Lissek S., Gunturkun O.（2003）Dissociation of extinction and behavioral disinhibition: the role of NMDA receptors in the pigeon associative forebrain during extinction. The Journal of Neuroscience, 23: 8119-8124.
Lu K.T., Walker D.L., Davis M. (2001) Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. The Journal of Neuroscience, 21: RC162.
Mandelkow EM, Biernat J, Drewes G, Gustke N, Trinczek B, Mandelkow E (1995) Tau domains, phosphorylation, and interactions with microtubules. Neurobiology Aging, 16: 355-362; discussion 362-353.
Maren S., Poremba A., Gabriel M. (1991 ) Basolateral amygdaloid multi-unit neuronal correlates of discriminative avoidance conditioning in rabbits. Brain Research, 549: 311–316.
Medina J.F., Repa J.C., .Mauk M.D. LeDoux J.E. （2002）Parallels between cerebellum and amygdala -dependent conditioning. Nature Review Neuroscience, 3: 122-131.
Miserendino M.J.D., Sananes C.B., Melia K.R., Davis M. (1990) Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature, 345: 716-718.
Myers K.M., Davis M.（2002）Behavioral and neural analysis of extinction. Neuron, 36: 567–584.
Pantev C., Okamoto H., Ross B., Stoll W., Ciurlia-Guy E., Kakigi R., Kubo T. (2004) Lateral inhibition and habituation of the human auditory cortex. European Journal of Neuroscience, 19: 2337-2344.
Rodrigues S.M., Schafe G.E., LeDoux J.E.（2001）Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. The Journal of Neuroscience, 21: 6889–6896.
Rogan M.T.,. Sta¨ ubli U.V., LeDoux J.E. (1997) Fear conditioning induces associative long-term potentiation in the amygdala . Nature, 390: 604–607.
Royer S. Pare D.（2002）bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses. Neuroscience, 115: 455-462.
Sananes C.B., Davis M. (1992) N-Methyl-D-aspartate lesions of the lateral and basolateral nuclei of the amygdala block fear-potentiated startle and shock sensitization of startle. Behavioral Neuroscience , 106: 72-80.
Schafe G.E., Nader K., Blair H.T., LeDoux J.E.（2001）Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. TRENDS in Neurosciences, 24: 540-546.
Schoepp D.D. ( 1994 ) Novel functions for subtypes of metabotropic glutamate receptors. Neurochemistry International, 24: 439-449.
Sheng M., Lee S.H. (2003) AMPA receptor trafficking and synaptic plasticity: major unanswered questions. Neuroscience Research, 46: 127-134.
Shi S.H., Hayashi Y., Petralia R.S., Zaman S.H., Wenthold R.J., Svoboda K., Malinow R. (1999). Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science, 284: 1811–1816.
Shi S., Hayashi Y., Esteban J.A., Malinow R. (2001). Subunit specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell, 105: 331–343.
Song I., and Huganir R.L. (2002) Regulation of AMPA receptors during synaptic plasticity. Trends in Neuroscience, 25: 578–588.
Sutton M.A., Schmidt E.F., Choi K.H., Schad C.A., Whisler K., Simmons D., Karanian D.A., Monteggia L.M., Neve R.L., Self D.W. (2003) Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature, 421: 70-75.
Vignes M., Clarke V.R., Davies C.H., Chambers A., Jane D.E., Watkns J.C., Collingride G.L. ( 1995 ) Pharmacological evidence for an involvement of group II and group III mGluRs in the presynaptic regulation of excitatory synaptic responses in the CA1 region of rat hippocampal slices. Neuropharmacology, 34 : 973-982.
Walker DL, Davis M (2000) Involvement of NMDA receptors within the amygdala in short- versus long-term memory for fear conditioning as assessed with fear-potentiated startle. Behavioral Neuroscience, 114: 1019–1033.
Walker D.L., Davis M. (2002) The role of amygdala glutamate receptors in fear learning, fear-potentiated startle and extinction. Pharmacology, Biochemistry and Behavior, 71: 379– 392.
Walker D.L., Ressler K.J., Lu K.T., Davis M. (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. The Journal of Neuroscience, 22: 2343-2351.
Yeh SH, Lin CH, Lee CF, Gean PW (2002) A requirement of nuclear factor-kappaB activation in fear-potentiated startle. The Journal of Biological chemistry, 277: 46720-46729.
Zinebi F., Xie J., Liu J., Russell R.T. Gallagher, Margaret J.P., McKernan G., Shinnick-Gallagher P. (2003) NMDA currents and receptor protein are downregulated in the amygdala during maintenance of fear memory. The Journal of Neuroscience, 23: 10283–10291.