臺灣博碩士論文加值系統

記憶形成牽涉到神經塑性（synaptic plasticity）的改變，其中長期增益現象（long-term potentiation，LTP）被認為可能是學習記憶的分子機轉。Brain-derived neurotrophic factor（BDNF）已被發現廣泛參與突觸塑性的調節，並牽涉到一些記憶形成的過程。
本論文探討大腦杏仁核（amygdala）BDNF調控恐懼記憶形成的分子機轉。在大鼠杏仁核區，恐懼制約學習後1小時內，鈣離子經由NR2B-NMDA receptor及L-type voltage-dependent calcium channel（L-VDCC）進入細胞，活化PKA及CaMKIV，此二訊息蛋白繼而進入細胞核，將CREB的ser-133磷酸化。pCREB結合到BDNF promoter I及III，啟動BDNF轉錄製出BDNF exon I-及III-containing transcript。經由轉譯製造出proBDNF，最後蛋白酶plasmin將其裁切成mature BDNF，進而結合到TrkB receptor tyrosine kinase使之活化。活化之TrkB receptor與其adaptor蛋白質Shc、Shc與Ras產生結合，繼而活化Ras及PI3K，最後共同活化MAPK。
在本研究亦發現訓練後12小時杏仁核BDNF蛋白質增加，於是進一步探討兩次增加的BDNF對恐懼記憶形成的影響。恐懼訓練前抑制杏仁核BDNF訊息，會減弱老鼠訓練後一及七天記憶的表現。反之，抑制訓練後12小時BDNF的訊息，只降低訓練後七天、但不影響訓練後一天的記憶。此外，growth-associated protein 43（GAP-43，為軸突新生的一個標記）在訓練後七天依賴BDNF訊息而增加，此時興奮性神經元的spine數目、樹突複雜程度及AMPA/NMDA ratio亦上升。這些證據指出，早期上升的BDNF影響記憶初期固化；延遲的BDNF負責記憶後期固化及表現，並引發神經微細網絡重塑（synaptic remodeling），媒介長期記憶的表現。
總括以上研究，我們探討恐懼記憶早期形成固化時，調控BDNF生合成及其下游訊息傳遞路徑，更發現後期上升的BDNF造成神經網絡重塑，最後維持了長期記憶表現。由於恐懼制約學習模式是探討創傷後壓力症候群（post-traumatic stress disorder）的理想工具，這些研究將提供治療藥物發展之根基。

Long-term potentiation (LTP), a form of synaptic plasticity, is a putative cellular mechanism for learning and memory. Brain-derived neurotrophic factor (BDNF) is widely identified that it modulates synaptic plasticity and learning and memory.
This thesis mainly describes the molecular mechanisms underlying the regulation of amygdala-dependent fear memory formation by BDNF. Our data reveal that calcium influx through NR2B-containing NMDA receptor and L-type voltage-dependent calcium channel (L-VDCC) activated PKA and CaMKIV to phosphorylate CREB at ser-133. Activated CREB bound to BDNF promoter region of exon I and III to initiate BDNF expression. Moreover, BDNF arose from precursor pro-BDNF, which was proteolytically cleaved to mature BDNF by plasmin, and bound to TrkB receptor tyrosine kinase. Activated TrkB receptor associated with its adaptor protein, Shc, and, thus, Shc recruited Ras and PI3K to activate MAPK.
Fear conditioning induced BDNF expression not only 1 h but also 12 h after training. We try to find out the functional role of early- and late-expressed BDNF in regulating fear memory formation. Our results indicate that pre-training blockade of BDNF signaling impaired fear memory in a test carried out 1 or 7 days after training. By contrast, interfering BDNF signaling 9 h after fear conditioning, which did not affect memory retention measured 1 day after training, impaired memory when the rats were tested 7 days after training. Furthermore, we found a BDNF-dependent expression of growth-associated protein 43 (GAP-43), a marker of newly formed synapses, in the amygdala 7 days after fear training. In parallel, conditioned rats had more number of spines and branches, and higher AMPA/NMDA ratio in pyramidal cells. These data suggest early-expressed BDNF processes the consolidation of newly acquired memory and late-expressed BDNF is required for the persistence of fear memory.
In summary, these results demonstrate candidate signaling pathways regulated BDNF expression and coupled to TrkB receptor activation. BDNF-mediated structural modifications of synaptic connections in the amygdala are required in the persistence of long-term fear memory. Thus, BDNF may become an avenue of therapeutic intervention for the treatment of fear-related mental disorders, like post-traumatic stress disorders.

中文摘要………………………...……………………...……….………..…..……..1
英文摘要………………………………………………….........…..………..………3
縮寫檢索表…………………..…………………………………….............………5

第一章 緒論………………………………………………..………………...……..7
1.1研究動機…………………..…………………………………………….....8
1.2創傷後壓力症候群（post-traumatic stress disorder，PTSD）……………....8
1.3中樞杏仁核（amygdala）與恐懼記憶（fear memory）………………...……9
1.4恐懼制約學習動物模式（fear conditioning）…………………………...…9
1.5 Brain-derived neurotrophic factor與恐懼制約學習……………………..10
1.6研究目的…………………....................................................................….12

第二章 研究方法及材料………...………………..……………………...….........15
2.1實驗動物（Animals）………………………………………………….…..16
2.2 恐懼訓練模式（Fear conditioning）……………………………………...16
2.2.1 環境適應（Acclimation）……………………………..………………16
2.2.2 配對（Match）…………………………………………………………16
2.2.3 訓練（Training）……………………………………………………….. 16
2.2.4 測試（Testing）…………………………………………………………16
2.2.5 評估老鼠的恐懼訓練成果（Assessments of potentiated acoustic startle）
…………………………………………………………………………17
2.3 腦切片之製作（Slice preparation）………………………………………17
2.4 全細胞萃取液（Whole cell lysate preparation）…………………………18
2.5 BDNF酵素連結免疫吸附（BDNF enzyme-linked immunosorbent assay）
…………………………………………………………………………18
2.6 免疫螢光染色（Immunofluorescence）…………………………………. 19
2.7 西方點墨法（Western blotting）………………………………………….20
2.8 半定量反轉錄及聚合酵素鏈鎖反應（Semi-quantitative reverse
transcription-coupled polymerase chain reaction，RT-PCR）….………21
2.9 立體定位手術（Stereotaxic surgery）………………………………….22
2.10 DNA親和力沉降試驗（DNA affinity precipitation assay）……………24
2.11 染色質沉降試驗（Chromatin immunoprecipitation assay）……………25
2.12 免疫沉降法（Immunoprecipitation）……………………………………26
2.13 Ras活性試驗（Ras activation assay）…………………………………26
2.14 全細胞膜鉗制紀錄（Whole-cell patch-clamp recording）…………….27
2.15 Biocytin標記細胞及形態學分析（Biocytin labeling and morphological
Analysis）…..………………………………………………..…………28
2.16 統計分析（Statistic analysis）………………………………………...…29

第三章 結果……………………………………………………….........................30
3.1老鼠經過恐懼制約學習後1及12小時，杏仁核BDNF蛋白質表現量明顯上升。…………………………………………………………………31
3.2老鼠經過恐懼學習後1及12小時，免疫螢光染色證實在杏仁核原位BDNF蛋白質表現量明顯上升。………...……………………………..32
3.3 恐懼訓練增加的BDNF會經由proBDNF轉變成mature BDNF。……32
3.4 恐懼制約學習後4小時內，BDNF mRNA在杏仁核明顯上升。訓練之前於杏仁核注入轉錄及轉譯抑制劑，會抑制因恐懼訓練而增加的BDNF。………………………………………………………..…………33
3.5 大鼠杏仁核區注入NMDA receptor及L-VDCC抑制劑，會干擾恐懼訓練後1小時增加的BDNF。…………………………………………..…34
3.6 降低杏仁核區域PKA、CaMKIV的活性，會抑制恐懼訓練後1小時
BDNF的增加。……..……………………………………………………36
3.7恐懼訓練之後30分鐘，p-CREB活化並結合到BDNF promoter I/III，但NF-κB對BDNF promoter的結合活性沒有改變。………………37
3.8 NMDA receptor、L-VDCC、PKA及CaMKIV抑制劑會減弱恐懼訓練後30分鐘增加的p-CREB結合到BDNF promoter I/III的活性。….….38
3.9 在老鼠杏仁核注射BDNF promoter I及III CRE decoy DNA，明顯降低老鼠於恐懼訓練後1天的記憶表現。…………………………………39
3.10 恐懼制約學習後1小時，plasmin將proBDNF轉變成mature BDNF的過程為恐懼記憶形成所必需。………..……………………………39
3.11 恐懼學習後1小時增加的BDNF會活化下TrkB receptor。........……..40
3.12 恐懼學習後2小時內，在杏仁核區域Shc與TrkB及Ras之結合上升，而且Ras、MAPK會被活化。………………………………….……41
3.13 杏仁核切片施予BDNF造成Ras活化，而此現象被K252a抑制。…42
3.14 杏仁核切片施與BDNF活化TrkB之後，再活化Ras造成MAPK磷酸化增加。………………………………………..……………………43
3.15 杏仁核切片施予BDNF造成Akt活化，而FTI277及U0126則不影響此表徵。…………………………………………..…………………44
3.16 訓練前30分鐘及訓練後9小時，在老鼠杏仁核注射注TrkB-IgG及K252a抑制TrkB receptor，對老鼠恐懼記憶有不同的影響。………..45
3.17 恐懼訓練之後12小時，Zif268在杏仁核腦區神經細胞表現量上升，顯示此時神經活性上升。……………………………………………46
3.18 恐懼訓練後七天，GAP-43在杏仁核腦區神經細胞表現量上升，顯示此時神經細胞經歷了微細結構上的改變。…………………………..48
3.19 在恐懼制約訓練後七天，杏仁核腦區spine數目及樹突複雜程度增加。……………………………………………………………………49
3.20 在恐懼訓練後七天，皮質區至杏仁核區（cortico-amygdala synapses）興奮性神經傳訊增加。………………………………………………50

第四章 討論………………………………...……………..………………............52
4.1 恐懼制約學習後，早期上升的BDNF是否會調控後期BDNF的表現。.………………………………………………………………………53
4.2 經由NMDA receptor與L-VDCC進入的鈣離子，共同調控制約學習後1小時BDNF蛋白質表現。…………………………………………...…53
4.3 恐懼制約學習後1小時，調控BDNF表現的訊息傳遞路徑。……..…55
4.4 PKA與CaMKIV調控制約學習後1小時BDNF表現的上下游關係。.55
4.5 恐懼制約訓練後調控BDNF exon I/III-containing transcripts的表現。..56
4.6 Mature BDNF和恐懼制約學習的關係。………………………………58
4.7 BDNF與恐懼制約學習的關聯性。…...………………………………58
4.8 制約學習後1小時BDNF的下游訊息傳遞路徑。………...……………59
4.9 生理時鐘是否調控杏仁核BDNF而影響恐懼記憶。…………..………60
4.10長期記憶的維持牽涉到續發性固化。……………...…………………61
4.11 恐懼學習後增加的spine數目，是否會經由BDNF調控，並提供更多
平台讓AMPA receptor運送（trafficking）到突觸膜表面。……………61

第五章 結論………………………………………..……………….............……..65
參考文獻…………………..………………………………………………...….….68
圖表…………………..……………………………………………………...….….83
圖表索引…………………………………………………….………..…………115
個人簡歷及發表文章…………………………………………….………………118

Ackermann M and Matus A (2003) Activity-induced targeting of profilin and stabilization of dendritic spine morphology. Nat Neurosci 6(11):1194-1200.
Adolphs R, Tranel D, Damasio H and Damasio A (1994) Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 372(6507):669-672.
Aid T, Kazantseva A, Piirsoo M, Palm K and Timmusk T (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 85(3):525-535.
Alder J, Thakker-Varia S, Bangasser DA, Kuroiwa M, Plummer MR, Shors TJ and Black IB (2003) Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J Neurosci 23(34):10800-10808.
Aliaga E, Arancibia S, Givalois L and Tapia-Arancibia L (2002) Osmotic stress increases brain-derived neurotrophic factor messenger RNA expression in the hypothalamic supraoptic nucleus with differential regulation of its transcripts. Relation to arginine-vasopressin content. Neuroscience 112(4):841-850.
Allen PB, Ouimet CC and Greengard P (1997) Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc Natl Acad Sci U S A 94(18):9956-9961.
Alonso M, Medina JH and Pozzo-Miller L (2004) ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 11(2):172-178.
An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F, Torre ER, Jones KR, Feng Y, Lu B and Xu B (2008) Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134(1):175-187.
Bailey DJ, Kim JJ, Sun W, Thompson RF and Helmstetter FJ (1999) Acquisition of fear conditioning in rats requires the synthesis of mRNA in the amygdala. Behav Neurosci 113(2):276-282.
Bauer EP, Schafe GE and LeDoux JE (2002) NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J Neurosci 22(12):5239-5249.
Baumgartel K, Genoux D, Welzl H, Tweedie-Cullen RY, Koshibu K, Livingstone-Zatchej M, Mamie C and Mansuy IM (2008) Control of the establishment of aversive memory by calcineurin and Zif268. Nat Neurosci 11(5):572-578.
Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I and Medina JH (2007) Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron 53(2):261-277.
Bellone C and Luscher C (2006) Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci 9(5):636-641.
Benowitz LI and Routtenberg A (1997) GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci 20(2):84-91.
Bernabeu R, Bevilaqua L, Ardenghi P, Bromberg E, Schmitz P, Bianchin M, Izquierdo I and Medina JH (1997) Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats. Proc Natl Acad Sci U S A 94 (13):7041-7046.
Black IB (1999) Trophic regulation of synaptic plasticity. J Neurobiol 41(1):108-118.
Brambilla R, Gnesutta N, Minichiello L, White G, Roylance AJ, Herron CE, Ramsey M, Wolfer DP, Cestari V, Rossi-Arnaud C, Grant SG, Chapman PF, Lipp HP, Sturani E and Klein R (1997) A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390(6657):281-286.
Bramham CR (2008) Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol 18(5):524-531.
Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE and Barad M (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14(4):268-276.
Campeau S and Davis M (1995) Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J Neurosci 15(3 Pt 2):2301-2311.
Cassella JV and Davis M (1986) The design and calibration of a startle measurement system. Physiol Behav 36(2):377-383.
Chaudhury D and Colwell CS (2002) Circadian modulation of learning and memory in fear-conditioned mice. Behav Brain Res 133(1):95-108.
Chen X, Ye H, Kuruvilla R, Ramanan N, Scangos KW, Zhang C, Johnson NM, England PM, Shokat KM and Ginty DD (2005) A chemical-genetic approach to studying neurotrophin signaling. Neuron 46(1):13-21.
Cho-Chung YS, Park YG, Nesterova M, Lee YN and Cho YS (2000) CRE-decoy oligonucleotide-inhibition of gene expression and tumor growth. Mol Cell Biochem 212(1-2):29-34.
Clem RL and Barth A (2006) Pathway-specific trafficking of native AMPARs by in vivo experience. Neuron 49(5):663-670.
Davis M (1997) Neurobiology of fear responses: the role of the amygdala. J Neuropsychiatry Clin Neurosci 9(3):382-402.
de Rooij J and Bos JL (1997) Minimal Ras-binding domain of Raf1 can be used as an activation-specific probe for Ras. Oncogene 14(5):623-625.
Devan BD, Goad EH, Petri HL, Antoniadis EA, Hong NS, Ko CH, Leblanc L, Lebovic SS, Lo Q, Ralph MR and McDonald RJ (2001) Circadian phase -shifted rats show normal acquisition but impaired long-term retention of place information in the water task. Neurobiol Learn Mem 75(1):51-62.
Dias BG, Banerjee SB, Duman RS and Vaidya VA (2003) Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology 45(4):553-563.
Du J, Creson TK, Wu LJ, Ren M, Gray NA, Falke C, Wei Y, Wang Y, Blumenthal R, Machado-Vieira R, Yuan P, Chen G, Zhuo M and Manji HK (2008) The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior. J Neurosci 28(1):68-79.
Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS and Storm DR (2008) Circadian oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nat Neurosci 11(9):1074-1082.
Ernfors P and Bramham CR (2003) The coupling of a trkB tyrosine residue to LTP. Trends Neurosci 26(4):171-173.
Fan GH, Wang LZ, Qiu HC, Ma L and Pei G (1999) Inhibition of calcium/calmodulin -dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence. Mol Pharmacol 56(1):39-45.
Fernandez RI, Lyons LC, Levenson J, Khabour O and Eskin A (2003) Circadian modulation of long-term sensitization in Aplysia. Proc Natl Acad Sci U S A 100(24):14415-14420.
Folkard S, Wever RA and Wildgruber CM (1983) Multi-oscillatory control of circadian rhythms in human performance. Nature 305(5931):223-226.
Gromeier M, Bossert B, Arita M, Nomoto A and Wimmer E (1999) Dual stem loops within the poliovirus internal ribosomal entry site control neurovirulence. J Virol 73(2):958-964.
Hall J, Thomas KL and Everitt BJ (2000) Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 3(6):533-535.
Han JH, Kushner SA, Yiu AP, Cole CJ, Matynia A, Brown RA, Neve RL, Guzowski JF, Silva AJ and Josselyn SA (2007) Neuronal competition and selection during memory formation. Science 316(5823):457-460.
Hao J, Janssen WG, Tang Y, Roberts JA, McKay H, Lasley B, Allen PB, Greengard P, Rapp PR, Kordower JH, Hof PR and Morrison JH (2003) Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys. J Comp Neurol 465(4):540-550.
Hauber W and Bareiss A (2001) Facilitative effects of an adenosine A1/A2 receptor blockade on spatial memory performance of rats: selective enhancement of reference memory retention during the light period. Behav Brain Res 118(1):43-52.
Hering H and Sheng M (2001) Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2(12):880-888.
Holloway FA and Wansley RA (1973) Multiple retention deficits at periodic intervals after active and passive avoidance learning. Behav Biol 9(1):1-14.
Huang EJ and Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609-642.
Huang F, Chotiner JK and Steward O (2007) Actin polymerization and ERK phosphorylation are required for Arc/Arg3.1 mRNA targeting to activated synaptic sites on dendrites. J Neurosci 27(34):9054-9067.
Huang YY and Kandel ER (1998) Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala. Neuron 21(1):169-178.
Huang YY, Martin KC and Kandel ER (2000) Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation. J Neurosci 20(17):6317-6325.
Iida N, Namikawa K, Kiyama H, Ueno H, Nakamura S and Hattori S (2001) Requirement of Ras for the activation of mitogen-activated protein kinase by calcium influx, cAMP, and neurotrophin in hippocampal neurons. J Neurosci 21(17):6459-6466.
Jopling CL and Willis AE (2001) N-myc translation is initiated via an internal ribosome entry segment that displays enhanced activity in neuronal cells. Oncogene 20(21):2664-2670.
Kang H and Schuman EM (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267 (5204):1658-1662.
Kapp BS, Supple WF, Jr. and Whalen PJ (1994) Effects of electrical stimulation of the amygdaloid central nucleus on neocortical arousal in the rabbit. Behav Neurosci 108(1):81-93.
Katoh-Semba R, Tsuzuki M, Miyazaki N, Matsuda M, Nakagawa C, Ichisaka S, Sudo K, Kitajima S, Hamatake M, Hata Y and Nagata K (2008) A phase advance of the light-dark cycle stimulates production of BDNF, but not of other neurotrophins, in the adult rat cerebral cortex: association with the activation of CREB. J Neurochem 106(5):2131-2142.
Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, Shelton DB, McMahon SB and Thompson SW (1999) Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci 19(12):5138-5148.
Korte M, Carroll P, Wolf E, Brem G, Thoenen H and Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92(19):8856-8860.
Kourrich S, Rothwell PE, Klug JR and Thomas MJ (2007) Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J Neurosci 27(30):7921-7928.
Kroll J (2003) Posttraumatic symptoms and the complexity of responses to trauma. JAMA 290(5):667-670.
Lamprecht R, Farb CR, Rodrigues SM and LeDoux JE (2006) Fear conditioning drives profilin into amygdala dendritic spines. Nat Neurosci 9(4):481-483.
Lamprecht R and LeDoux J (2004) Structural plasticity and memory. Nat Rev Neurosci 5(1):45-54.
LeDoux JE, Iwata J, Cicchetti P and Reis DJ (1988) Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci 8(7):2517-2529.
Lee HJ, Choi JS, Brown TH and Kim JJ (2001a) Amygdalar nmda receptors are critical for the expression of multiple conditioned fear responses. J Neurosci 21(11):4116-4124.
Lee R, Kermani P, Teng KK and Hempstead BL (2001b) Regulation of cell survival by secreted proneurotrophins. Science 294(5548):1945-1948.
Lee YN, Park YG, Choi YH, Cho YS and Cho-Chung YS (2000) CRE-transcription factor decoy oligonucleotide inhibition of MCF-7 breast cancer cells: cross-talk with p53 signaling pathway. Biochemistry 39(16):4863-4868.
Leirer VO, Tanke ED and Morrow DG (1994) Time of day and naturalistic prospective memory. Exp Aging Res 20(2):127-134.
Li HS, Xu XZ and Montell C (1999) Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron 24(1):261-273.
Liang FQ, Walline R and Earnest DJ (1998) Circadian rhythm of brain-derived neurotrophic factor in the rat suprachiasmatic nucleus. Neurosci Lett 242(2):89-92.
Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, Koeppe RA and Fig LM (1999) Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 45(7):817-826.
Lin CH, Yeh SH, Lu HY and Gean PW (2003) The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory. J Neurosci 23(23):8310-8317.
Lin CH, Yeh SH, Lu KT, Leu TH, Chang WC and Gean PW (2001) A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31(5):841-851.
Lin HC, Wang SJ, Luo MZ and Gean PW (2000) Activation of group II metabotropic glutamate receptors induces long-term depression of synaptic transmission in the rat amygdala. J Neurosci 20(24):9017-9024.
Lindvall O, Ernfors P, Bengzon J, Kokaia Z, Smith ML, Siesjo BK and Persson H (1992) Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc Natl Acad Sci U S A 89(2):648-652.
Lipsky RH, Xu K, Zhu D, Kelly C, Terhakopian A, Novelli A and Marini AM (2001) Nuclear factor kappaB is a critical determinant in N-methyl-D-aspartate receptor-mediated neuroprotection. J Neurochem 78(2):254-264.
Lu B, Pang PT and Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6(8):603-614.
Lu L, Dempsey J, Liu SY, Bossert JM and Shaham Y (2004) A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J Neurosci 24(7):1604-1611.
Lubin FD, Roth TL and Sweatt JD (2008) Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci 28(42):10576-10586.
Malcangio M and Lessmann V (2003) A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors. Trends Pharmacol Sci 24(3):116-121.
Malkani S, Wallace KJ, Donley MP and Rosen JB (2004) An egr-1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning. Learn Mem 11(5):617-624.
Mann MJ and Dzau VJ (2000) Therapeutic applications of transcription factor decoy oligonucleotides. J Clin Invest 106(9):1071-1075.
Maren S (1999) Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci 22(12):561-567.
Maren S, Aharonov G, Stote DL and Fanselow MS (1996) N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats. Behav Neurosci 110(6):1365-1374.
Maury P and Queinnec Y (1992) Influence of time of 24-hour day on depth of processing in recall memory. Br J Psychol 83 ( Pt 2):249-260.
Maviel T, Durkin TP, Menzaghi F and Bontempi B (2004) Sites of neocortical reorganization critical for remote spatial memory. Science 305(5680):96-99.
Mealer ML, Shelton A, Berg B, Rothbaum B and Moss M (2007) Increased prevalence of post-traumatic stress disorder symptoms in critical care nurses. Am J Respir Crit Care Med 175(7):693-697.
Messaoudi E, Kanhema T, Soule J, Tiron A, Dagyte G, da Silva B and Bramham CR (2007) Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci 27(39):10445-10455.
Messaoudi E, Ying SW, Kanhema T, Croll SD and Bramham CR (2002) Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo. J Neurosci 22(17):7453-7461.
Miserendino MJ, Sananes CB, Melia KR and Davis M (1990) Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 345(6277):716-718.
Misra K and Pandey SC (2006) The decreased cyclic-AMP dependent-protein kinase A function in the nucleus accumbens: a role in alcohol drinking but not in anxiety-like behaviors in rats. Neuropsychopharmacology 31(7):1406-1419.
Mizuno M, Yamada K, Olariu A, Nawa H and Nabeshima T (2000) Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci 20(18):7116-7121.
Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, Meuth S, Nagy A, Greene RW and Nestler EJ (2004) Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A 101(29):10827-10832.
Mowla SJ, Pareek S, Farhadi HF, Petrecca K, Fawcett JP, Seidah NG, Morris SJ, Sossin WS and Murphy RA (1999) Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J Neurosci 19(6):2069-2080.
Nagerl UV, Eberhorn N, Cambridge SB and Bonhoeffer T (2004) Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron 44(5):759-767.
Nakata H and Nakamura S (2007) Brain-derived neurotrophic factor regulates AMPA receptor trafficking to post-synaptic densities via IP3R and TRPC calcium signaling. FEBS Lett 581(10):2047-2054.
Narisawa-Saito M, Iwakura Y, Kawamura M, Araki K, Kozaki S, Takei N and Nawa H (2002) Brain-derived neurotrophic factor regulates surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors by enhancing the N-ethylmaleimide-sensitive factor/GluR2 interaction in developing neocortical neurons. J Biol Chem 277(43):40901-40910.
Neuhoff H, Sassoe-Pognetto M, Panzanelli P, Maas C, Witke W and Kneussel M (2005) The actin-binding protein profilin I is localized at synaptic sites in an activity-regulated manner. Eur J Neurosci 21(1):15-25.
Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A, Yoshikawa H and Noguchi K (2004) Contribution of degeneration of motor and sensory fibers to pain behavior and the changes in neurotrophic factors in rat dorsal root ganglion. Exp Neurol 188(1):149-160.
Oliff HS, Berchtold NC, Isackson P and Cotman CW (1998) Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus. Brain Res Mol Brain Res 61(1-2):147-153.
Pandey SC, Zhang H, Roy A and Xu T (2005) Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest 115(10):2762-2773.
Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL and Lu B (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306(5695):487-491.
Park YG, Nesterova M, Agrawal S and Cho-Chung YS (1999) Dual blockade of cyclic AMP response element- (CRE) and AP-1-directed transcription by CRE-transcription factor decoy oligonucleotide. gene-specific inhibition of tumor growth. J Biol Chem 274(3):1573-1580.
Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C and Kandel ER (2001) Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 32(1):123-140.
Paxinos G, Watson C (1986): The rat brain in stereotaxic coordinates. Academic Press; New York.
Pinkstaff JK, Chappell SA, Mauro VP, Edelman GM and Krushel LA (2001) Internal initiation of translation of five dendritically localized neuronal mRNAs. Proc Natl Acad Sci U S A 98(5):2770-2775.
Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2(1):24-32.
Radley JJ, Johnson LR, Janssen WG, Martino J, Lamprecht R, Hof PR, LeDoux JE and Morrison JH (2006) Associative Pavlovian conditioning leads to an increase in spinophilin-immunoreactive dendritic spines in the lateral amygdala. Eur J Neurosci 24(3):876-884.
Rattiner LM, Davis M, French CT and Ressler KJ (2004a) Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. J Neurosci 24(20):4796-4806.
Rattiner LM, Davis M and Ressler KJ (2004b) Differential regulation of brain-derived neurotrophic factor transcripts during the consolidation of fear learning. Learn Mem 11(6):727-731.
Ressler KJ, Paschall G, Zhou XL and Davis M (2002) Regulation of synaptic plasticity genes during consolidation of fear conditioning. J Neurosci 22(18):7892-7902.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM and Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27(11):3017-3029.
Rodrigues SM, Farb CR, Bauer EP, LeDoux JE and Schafe GE (2004) Pavlovian fear conditioning regulates Thr286 autophosphorylation of Ca2+/calmodulin -dependent protein kinase II at lateral amygdala synapses. J Neurosci 24(13):3281-3288.
Rodrigues SM, Schafe GE and LeDoux JE (2001) Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. J Neurosci 21(17):6889-6896.
Rosch H, Schweigreiter R, Bonhoeffer T, Barde YA and Korte M (2005) The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc Natl Acad Sci U S A 102(20):7362-7367.
Rosen JB, Fanselow MS, Young SL, Sitcoske M and Maren S (1998) Immediate-early gene expression in the amygdala following footshock stress and contextual fear conditioning. Brain Res 796(1-2):132-142.
Routtenberg A, Cantallops I, Zaffuto S, Serrano P and Namgung U (2000) Enhanced learning after genetic overexpression of a brain growth protein. Proc Natl Acad Sci U S A 97(13):7657-7662.
Saarelainen T, Vaittinen S and Castren E (2001) trkB-receptor activation contributes to the kainate-induced increase in BDNF mRNA synthesis. Cell Mol Neurobiol 21(4):429-435.
Salter MW (2001) LTP gets culture. Trends Neurosci 24(10):560-561.
Sananes CB and 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. Behav Neurosci 106(1):72-80.
Sansom AJ, Smith PF, Darlington CL and Laverty R (2000) The effects of protein kinase C and calmodulin kinase II inhibitors on vestibular compensation in the guinea pig. Brain Res 882(1-2):45-54.
Saxon AJ, Davis TM, Sloan KL, McKnight KM, McFall ME and Kivlahan DR (2001) Trauma, symptoms of posttraumatic stress disorder, and associated problems among incarcerated veterans. Psychiatr Serv 52(7):959-964.
Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD and LeDoux JE (2000) Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J Neurosci 20(21):8177-8187.
Schafe GE and LeDoux JE (2000) Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci 20(18):RC96.
Schmidt-Hieber C, Jonas P and Bischofberger J (2007) Subthreshold dendritic signal processing and coincidence detection in dentate gyrus granule cells. J Neurosci 27(31):8430-8441.
Sei H, Fujihara H, Ueta Y, Morita K, Kitahama K and Morita Y (2003) Single eight-hour shift of light-dark cycle increases brain-derived neurotrophic factor protein levels in the rat hippocampus. Life Sci 73(1):53-59.
Shimizu E, Tang YP, Rampon C and Tsien JZ (2000) NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290(5494):1170-1174.
Siebenlist U, Franzoso G and Brown K (1994) Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 10:405-455.
Song I and Huganir RL (2002) Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci 25(11):578-588.
Steiger JL, Bandyopadhyay S, Farb DH and Russek SJ (2004) cAMP response element-binding protein, activating transcription factor-4, and upstream stimulatory factor differentially control hippocampal GABABR1a and GABABR1b subunit gene expression through alternative promoters. J Neurosci 24(27):6115-6126.
Stephan FK and Kovacevic NS (1978) Multiple retention deficit in passive avoidance in rats is eliminated by suprachiasmatic lesions. Behav Biol 22(4):456-462.
Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76(1):1-10.
Tabuchi A, Nakaoka R, Amano K, Yukimine M, Andoh T, Kuraishi Y and Tsuda M (2000) Differential activation of brain-derived neurotrophic factor gene promoters I and III by Ca2+ signals evoked via L-type voltage-dependent and N-methyl-D-aspartate receptor Ca2+ channels. J Biol Chem 275 (23):17269-17275.
Tabuchi A, Sakaya H, Kisukeda T, Fushiki H and Tsuda M (2002) Involvement of an upstream stimulatory factor as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem 277(39):35920-35931.
Takehara-Nishiuchi K, Nakao K, Kawahara S, Matsuki N and Kirino Y (2006) Systems consolidation requires postlearning activation of NMDA receptors in the medial prefrontal cortex in trace eyeblink conditioning. J Neurosci 26(19):5049-5058.
Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC and Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319(5870):1683-1687.
Tang Y, Janssen WG, Hao J, Roberts JA, McKay H, Lasley B, Allen PB, Greengard P, Rapp PR, Kordower JH, Hof PR and Morrison JH (2004) Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys. Cereb Cortex 14(2):215-223.
Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ and Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor- dependent mechanism. Neuron 20(4):709-726.
Tapp WN and Holloway FA (1981) Phase shifting circadian rhythms produces retrograde amnesia. Science 211(4486):1056-1058.
Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A and Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25(22):5455-5463.
Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M and Persson H (1993) Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10(3):475-489.
Tischkau SA, Mitchell JW, Tyan SH, Buchanan GF and Gillette MU (2003) Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J Biol Chem 278(2):718-723.
Tojima T and Ito E (2004) Signal transduction cascades underlying de novo protein synthesis required for neuronal morphogenesis in differentiating neurons. Prog Neurobiol 72(3):183-193.
Tongiorgi E (2008) Activity-dependent expression of brain-derived neurotrophic factor in dendrites: facts and open questions. Neurosci Res 61(4):335-346.
Tongiorgi E, Domenici L and Simonato M (2006) What is the biological significance of BDNF mRNA targeting in the dendrites? Clues from epilepsy and cortical development. Mol Neurobiol 33(1):17-32.
Tsankova N, Renthal W, Kumar A and Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8(5):355-367.
Tsukahara T, Iihara K, Hashimoto N, Nishijima T and Taniguchi T (1998) Increases in levels of brain-derived neurotrophic factor mRNA and its promoters after transient forebrain ischemia in the rat brain. Neurochem Int 33(2):201-207.
Tsvetkov E, Carlezon WA, Benes FM, Kandel ER and Bolshakov VY (2002) Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Neuron 34(2):289-300.
Ungless MA, Whistler JL, Malenka RC and Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411(6837):583-587.
Vaynman S, Ying Z and Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20 (10):2580-2590.
Walker DL and Davis M (2002) The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol Biochem Behav 71(3):379-392.
Walker DL and Davis M (2008) Amygdala infusions of an NR2B-selective or an NR2A-preferring NMDA receptor antagonist differentially influence fear conditioning and expression in the fear-potentiated startle test. Learn Mem 15(2):67-74.
Weisskopf MG, Bauer EP and LeDoux JE (1999) L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala. J Neurosci 19(23):10512-10519.
West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, Takasu MA, Tao X and Greenberg ME (2001) Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A 98(20):11024-11031.
Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, Jia YH, Shum FW, Zerbinatti CV, Bu G, Wei F, Xu TL, Muglia LJ, Chen ZF, Auberson YP, Kaang BK and Zhuo M (2005) Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 25(48):11107-11116.
Yeh SH, Lin CH and Gean PW (2004) Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory. Mol Pharmacol 65(5):1286-1292.
Yeh SH, Lin CH, Lee CF and Gean PW (2002) A requirement of nuclear factor-kappaB activation in fear-potentiated startle. J Biol Chem 277 (48):46720-46729.
Yeh SH, Mao SC, Lin HC and Gean PW (2006) Synaptic expression of glutamate receptor after encoding of fear memory in the rat amygdala. Mol Pharmacol 69(1):299-308.
Yehuda R (2002) Post-traumatic stress disorder. N Engl J Med 346(2):108-114.
Zafra F, Hengerer B, Leibrock J, Thoenen H and Lindholm D (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 9(11):3545-3550.
Zhang W and Davidson JR (2007) Post-traumatic stress disorder: an evaluation of existing pharmacotherapies and new strategies. Expert Opin Pharmacother 8(12):1861-1870.
Zaitsev, E. and Lu, B. 2003. Cap-independent translation of BDNF: IRES activity of two BDNF RNA transcripts. Soc Neurosci Abstr Program No. 334.5.