進階搜尋


 
系統識別號 U0026-0812200913480397
論文名稱(中文) 探討新生分離作用對於海馬廻CA1區域的長期抑制現象誘發之影響
論文名稱(英文) The effect of neonatal isolation on the developmental downregulation of long term depression in hippocampal CA1 region
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 95
學期 2
出版年 96
研究生(中文) 顧曉耘
研究生(英文) Hsiao-yun Ku
電子信箱 s2694409@mail.ncku.edu.tw
學號 s2694409
學位類別 碩士
語文別 中文
論文頁數 82頁
口試委員 指導教授-許桂森
口試委員-黃阿敏
口試委員-郭余民
中文關鍵字 長期抑制現象  新生分離模式 
英文關鍵字 Neonatal isolation  Long term depression 
學科別分類
中文摘要 神經突觸活性改變所引起的持續性修飾作用,被廣泛地認為參與神經發育過程中神經元間連結的精密化及在成熟大腦學習與記憶表現之分子機制。而持續性神經突觸修飾包含突觸間的傳遞功能的改變或連結結構之改變。在突觸神經塑性的研究中,給予重複短暫或連續的電刺激可以快速地引起神經突觸間傳遞強度的持久性改變意即長期增益現象(long-term potentiation;LTP)以及長期抑制現象(long-term depression;LTD) 。
研究顯示新生鼠的生理狀態及其發育的情形與母鼠之間的互動情形有關。研究證據指出母性的照顧在小鼠出生後的一個星期對於小鼠的海馬廻的發育和功能上具有意義深遠且持久的影響。先前我們實驗室發現,輕度的新生鼠與母鼠分離模式,會影響海馬迴 CA1區域長期增益現象誘發機制的改變。
而在本次實驗中,我們發現經由連續低頻電刺激所誘發的長期抑制現象會隨著年齡的增加而其表現逐漸減少的情形。當給予新生鼠進行新生短暫分離的處理,此種隨發育漸減的情形會被延遲。意即在原本不會誘發長期抑制現象的年齡之海馬廻中仍然可以成功地誘發長期抑制現象,此外,我們也發現這種現象係經由改變NMDA受體的表現量與組成所引起的。更者,此種現象係經由活化促皮質素釋放因子(corticotrophin-releasing factor,CRF)的系統,進一步活化CRF第一型受體所產生。此外,改變NMDA受體的表現量可能是經由調控其基因的轉錄作用所產生。
另外,我們也利用恐懼的空間制約性學習動物模式(fear-contexual conditioning test),發現新生鼠分離會影響其後此等制約性學習記憶的表現(memory aquizition)和記憶的消退(memory extinction)。因此,新生鼠與母鼠分離在其成長後除了造成會造成突觸神經塑性改變外亦會造成學習記憶行為上的改變。
英文摘要 Activity-dependent persistent synaptic modifications are generally thought to be the cellular mechanisms underlying the refinement of neuronal connection in developing nervous systems and for learning and memory in the mature brain. Persistent synaptic modifications can involve alterations in both the function of synaptic transmission and the structure of neuronal connections. Studies of synaptic plasticity have shown that repetitive
electrical activity can rapidly induce persistent changes in the strength of synaptic transmission, known as long-term potentiation (LTP) and long-term depression (LTD). Neonatal physiology and development are regulated by the
ongoing mother-infant interactions. Maternal care during the first week of postnatal life has been shown to have profound and enduring impacts on hippocampal development and function. We have previously showed that a mild maternal separation paradigm (once per day for 1 h from postnatal days 1-7, P1-P7) can accelerates the developmental switch in the signaling cascades for hippocampal CA1 LTP induction from a cyclic AMP-dependent
protein kinase (PKA)- to a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pattern and that the developmental expression profile of CaMKIIα is highly correlated with the LTP dependence on CaMKII signaling
pathway. Here we confirm that the amount of LTD induced by LFS (1 Hz for 15 min) protocol correlates negatively with developmental age and show that mild neonatal isolation may delays this developmental downregulation of hippocampal CA1 LTD induction through chaning the composition of NMDA receptor via corticotrophin-releasing factor (CRF) system. In addition, we VII have demonstrated that this maternal separation model has a profound
influence on conditional fear memory aquizition and extinction.
論文目次 中文摘要 II
英文摘要 V
目錄 VIII
圖目錄 IX
縮寫檢索 XI
第一章 緒論 01
第二章 材料及方法 11
一、 實驗動物和新生分離動物模式
二、 海馬迴腦薄片的製備
三、 電氣生理學紀錄法
四、 西方點墨法
五、 腦室內注射
六、 恐懼的空間制約性學習動物模式
七、 實時聚合脢連鎖反應
八、 統計分析

第三章 實驗結果 31
第四章 討論 46
第五章 圖表 54
第六章 參考文獻 73
自述 82
參考文獻 Avishai-Eliner S, Yi SJ, Baram TZ: Developmental profile of messenger RNA for the corticotropin-releasing hormone receptor in the rat limbic system. Dev. Brain. Res. 91:159-163, 1996.
Baram TZ, Yi S, Avishai-Eliner S, Schultz L: Development neurobiology of the stress response: multilevel regulation of corticotropin-releasing hormone function. Ann. N. Y. Acad. Sci. 814:252-265, 1997.
Bear MF, Abraham WC: Long-term depression in hippocampus. Annu. Rev. Neurosci.19:437-462, 1996.
Bliss TV, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361: 31-39, 1993.
Bliss TV, Lomo T: Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232:331-356, 1973.
Bredy TW, Grant RJ, Champagne DL, Meaney MJ: Maternal care influences neuronal survival in the hippocampus of the rat. Eur. J. Neurosci. 18:2903-2909, 2003.
Burgees N, Maguire EA, O’Keefe J: The human hippocampus and spatial and episodic memory. Neuron 35:625-641, 2002.
Chen Y, Bender RA, Frotscher M, Baram TZ: Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J. Neurosci. 21:7171-7181, 2001.
Chen Y, Bender RA, Brunson KL, Pomper JK, Grigoriadis DE, Wurst W, Baram TZ: Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus. Proc. Natl. Acad. Sci. USA 101:15782-15787, 2004.
Chen S, Diamond JS: Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina. J. Neurosci. 22:2165-2173, 2002.
Clancy B, Darlington RB, Finlay BL: Translating developmental time across mammalian species. Neuroscience 105(1):7-17, 2001.
Collingridge GL, John Isaac TR, Wang YT: Receptor trafficking and synaptic plasticity. Nature review neuroscience 5:952-962, 2004.
De Souza EB: Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology 20:789-819, 1995.
Dudek SM, Bear MF: Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc. Natl. Acad. Sci. USA 89:4363-4367, 1992.
Dumas TC: Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning. Prog. Neurobiol. 76:189-211, 2005.
Fox CJ, Russell KI, Wang YT, Christie BR: Contribution of NR2A and NR2B NMDA Subunits to Bidirectional Synaptic Plasticity in the Hippocampus In Vivo. Hippocampus 16:907-915, 2006.
Francis DD, Meaney MJ: Maternal care and the development of stress responses. Curr Opin. Neurobiol. 9:128-134, 1999.
Han BH, Holtzman DM: BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J. Neurosci. 20:5775-5781, 2000.
Hendricson AW, Miao CL, Lippmann MJ, Morrisett RA: Ifenprodil and ethanol enhance NMDA receptordependent long-term depression. J. Pharmacol. Exp. Ther. 301:938–944, 2002.
Hrabetova S, Sacktor TC: Long-term potentiation and long-term depression are induced through pharmacologically distinct NMDA receptors. Neurosci. Lett. 226:107–110, 1997.
Hrabetova S, Serrano P, Blace N, Tse HW, Skifter DA, Jane DE, Monaghan DT, Sacktor TC: Distinct NMDA receptor subpopulations contribute to long-term potentiation and long-term depression induction. J. Neurosci. 20: RC81, 2000.
Huot RL, Plotsky PM, Lenox RH, McNamara RK: Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats. Brain. Res. 950:52-63, 2002.
Huang CC, Chou PH, Yang CH, Hsu KS: Neonatal isolation accelerates the developmental switch in the signalling cascades for long-term potentiation induction. J. Physiol. 569:789-799, 2005.
Kutsuwada T, Sakimura K, Manabe T, Takayama C, Katakura N, Kushiya E, Natsume R, Watanabe M, Inoue Y, Yagi T, Aizawa S, Arakawa M, Takahashi T, Nakamura Y, Mori H, Mishina M: Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor 2 subunit mutant mice. Neuron 16:333–344, 1996.
Kaufman J, Plotsky PM, Nemeroff CB, Charney DS: Effects of early adverse experiences on brain structure and function: clinical implications. Biol. Psychiatry 48:778–790, 2000.
Katz LC, Shatz CJ: Synaptic activity and the construction of cortical circuits. Science 274:1133-118, 1996.
Kemp A and Manahan-Vaughan D: Hippocampal long-term depression and long-term potentiation encode different aspects of novelty acquisition. Proc. Natl. Acad. Sci. U. S. A. 101: 8192–8197, 2004.
Kemp N, Bashir ZI: NMDA receptor-dependent and -independent long-term depression in the CA1 region of the adult rat hippocampus in vitro. Neuropharmacology 36:397-399, 1997.
Kemp N, Bashir ZI: Long-term depression: a cascade of induction and expression mechanisms. Prog. Neurobiol. 65:339-365, 2001.
Kemp N, McQueen J, Faulkes S, Bashir ZI: Different forms of LTD in the CA1 region of the hippocampus: role of age and stimulus protocol.
Eur. J. Neurosci. 12:360-366, 2000.
Kim JJ, Yoon KS: Stress: metaplastic effects in the hippocampus. Trends. Neurosci. 21: 505–509, 1998.
Lisman, J: A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc. Natl. Acad. Sci. U.S.A. 86: 9574–9578, 1989.
Lee HJ, Kim JW, Yim SV, Kim MJ, Kim SA, Kim YJ, Kim CJ, Chung JH: Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats. Mol. Psychiatry 6:725-728, 2001.
Liu D, Diorio J, Day JC, Francis DD, Meaney MJ: Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat. Neurosci. 3: 799-806, 2000.
Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng M, Auberson YP, Wang YT: Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304:1021–1024, 2004.
Lui PW, Suen KC, Chan YS, Yung WH, Yung KK.: Striatal neurons but not nigral dopaminergic neurons in neonatal primary cell culture express endogenous functional N-methyl-D-aspartate receptors. Brain Res. Mol. Brain Res. 12: 9-21, 2003.
Lynch GS, Dunwiddie T, Gribkoff V: Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature 266: 737-739, 1977.
MacDonald JF, Nowak LM: Mechanisms of blockade of excitatory amino acid receptor channels. Trends Pharmacol. Sci. 11:167-172, 1990.
Malenka RC, Bear MF: LTP and LTD: an embarrassment of riches. Neuron 44:5-21, 2004.
Manahan-Vaughan D, Braunewell KH: Novelty acquisition is associated with induction of hippocampal long-term depression. Proc. Natl. Acad. Sci. U. S. A. 96:8739–8744, 1999.
Martin SJ, Grimwood PD, Morris RG: Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23:649-711, 2000.
Massey PV, Bashir ZI: Long-term depression: multiple forms and implications for brain function. Trends Neurosci. 30:176-84., 2007.
Massey PV, Johnson BE, Moult PR, Auberson YP, Brown MW, Molnar E, Collingridge GL, Bashir ZI: Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J. Neurosci. 24:7821-7828, 2004.
Mayford M, Wang J. Kandel ER, O’Dell T: CaMKIl regulates the asociativity function of hipocampal synapses for the production of both LTD and LTP. Cell 81:891-899, 1995.
Meaney MJ (2001): Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24:1161-1192.
Meaney MJ, Aitken DH, Bhatnagar S, Berkel CV, Sapolsky RM: Postnatal handling attenuates neuroendocrine, anatomical, and cognitive impairments related to the aged hippocampus. Science 238:766 –768, 1988.
Meaney MJ, Szyf M : Maternal care as a model for experience-dependent chromatin plasticity? Trends Neurosci. 28:456-63, 2005.
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH: Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529-540, 1994.
Mulkey RM, Malenka RC: Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron 9:967-975, 1992.
Myers SJ, Dingledine R, Borges K: Genetic regulation of glutamate receptor ion channels. Annu. Rev. Pharmacol. Toxicol. 39:221-241, 1999.
Naassila M, Daoust M: Effect of prenatal and postnatal ethanol exposure on the developmental profile of mRNAs encoding NMDA receptor subunits in rat hippocampus. J. Neurochem. 80:850-860, 2002.
Paupard MC, Friedman LK, Zukin RS: Status epilepticus-induced alterations in metabotropic glutamate receptor expression in young and adult rats. J. Neurosci. 17:8588-8595, 1997.
Pérez-Otaño I, Ehlers MD: Homeostatic plasticity and NMDA receptor trafficking. Trends Neurisci. 28:229-238, 2005.
Pickering C, Gustafsson L, Cebere A, Nylander I, Liljequist S.: Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex. Brain Res.12: 101-108, 2006.
Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA: Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol. Psychiatry 7:609-616, 2002.
Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, Yagi T, Aizawa S, Inoue Y, Sugiyama H: Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit. Nature 373:151–155, 1995.
Schilström B, Yaka R, Argilli E, Suvarna N, Schumann J, Chen BT, Carman M, Singh V, Mailliard WS, Ron D, Bonci A: Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors. J Neurosci. 26:8549-8558, 2001.
Seeburg PH: The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 16:359-365, 1993.
Sjostrom PJ, Turrigiano GG, Nelson SB: Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 39:641–654, 2003.
Squire LR: Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99:195-231, 1992.
Stocca G, Vicini S: Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons. J. Physiol. 507:13-24, 1998.
Tang YP, Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ: Genetic enhancement of learning and memory in mice. Nature 401:63–69, 1999.
Tovar KR, Westbrook GL: The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19:4180-4188, 1999.
Xu L, Anwyl R , Rowan MJ: Spatial exploration induces a persistent reversal of long-term potentiation in rat hippocampus. Nature 394:891–894, 1998.
Yang CH, Huang CC, Hsu KS: Behavioral stress enhances hippocampal CA1 long-term depression through the blockade of the glutamate uptake. J. Neurosci. 25:4288-4293, 2005.
Yoshimura Y, Ohmura T, Komatsu Y: Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex. J. Neurosci. 23:6557–6566, 2003.
Zhang LI, Poo MM: Electrical activity and development of neural circuits. Nat. Neurosci. 4:1207-1214, 2001.
Zhou Q, Homma KJ, Poo MM: Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44:749-757, 2004.
Zundert BV, Yoshii A, Constantine-Paton M: Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal. Trends Neurosci. 27:428-437, 2004.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2009-07-26起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2012-07-26起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw