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研究生: 馮冠霖
Feng, Kuan-Lin
論文名稱: 去抑制機制在果蠅長期記憶固化之角色
A disinhibition mechanism of long-term memory consolidation in Drosophila
指導教授: 江安世
Chiang, Ann-Shyn
口試委員: 連正章
Lien, Cheng-Chang
桑自剛
Sang, Tzu-Kang
吳嘉霖
Wu, Chia-Lin
林書葦
Lin, Sue-Wei
學位類別: 博士
Doctor
系所名稱: 生命科學暨醫學院 - 生物科技研究所
Biotechnology
論文出版年: 2021
畢業學年度: 109
語文別: 英文
論文頁數: 81
中文關鍵詞: 記憶固化神經肽多巴胺神經
外文關鍵詞: memory, consolidation, neuropeptide F, dopaminergic neurons
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  • 長期記憶的生成仰賴固化的歷程以克服干擾訊號對記憶的損耗。果蠅的嗅覺記憶透過由投射細胞(projection neuron)傳遞的嗅覺訊號以及由多巴胺神經(dopaminergic neuron)傳遞的電擊訊號匯集至蕈狀體(mushroom body)而生成。然而,訓練後多巴胺的神經活動如何持續地影響記憶的固化歷程依然未知。我們藉由基因操作搭配行為學及電生理來回答這個問題。我們的研究發現: 一、在訓練後,後側腦多巴胺神經(posterior lateral protocerebrum, PPL1)的神經活動會干擾長期記憶的生成。二、神經肽 F (neuropeptide F)會在間格訓練後阻斷來自PPL1-α2α'2和PPL1-α3多巴胺神經的干擾訊號,而允許長期記憶生成。三、我們進一步發現,訓練誘發的神經肽F訊號來自兩顆背前側(dorsal-anterior-lateral)神經DAL2,而從這兩顆神經釋放出的神經肽F及其神經傳導物質是長期記憶生成所必需的。總體來說,我們發現DAL2傳遞神經肽F訊號至特定PPL1多巴胺神經以移除防止長期記憶生成的剎車,藉此機制來確保反覆出現的事件可以被固化成長期記憶。


    Long-term memory (LTM) formation requires consolidation processes to overcome interfering signals that erode memory formation. Olfactory memory in Drosophila involves convergent projection neuron (PN; odor) and dopaminergic neuron (DAN; reinforcement) input to the mushroom body (MB). How post-training DAN activity in the posterior lateral protocerebrum (PPL1) continues to regulate memory consolidation remains unknown. Here we address this question using targeted transgenes in behavior and electrophysiology experiments to show that (1) persistent post-training activity of PPL1 DANs interferes with aversive LTM formation; (2) neuropeptide F (NPF) signaling blocks this interference in PPL1-α2α'2 and PPL1-α3 DANs after spaced training to enable LTM formation; and (3) training-induced NPF release and neurotransmission from two upstream dorsal-anterior-lateral (DAL2) neurons are required to form LTM. Thus, NPF signals from DAL2 neurons to specific PPL1 DANs disinhibit the memory circuit, ensuring that periodic events are remembered as consolidated LTM.

    中文摘要----------------------------------------------------------------------------1 Abstract -----------------------------------------------------------------------------2 1. Introduction -------------------------------------------------------------------3 2. Materials and Methods ------------------------------------------------------5   3. Results ------------------------------------------------------------------------10 4. Discussion --------------------------------------------------------------------16 5. Figures-------------------------------------------------------------------------22 6. Tables--------------------------------------------------------------------------38 7. References --------------------------------------------------------------------76

    Nairne, J.S., Thompson, S.R., and Pandeirada, J.N. (2007). Adaptive memory: survival processing enhances retention. J Exp Psychol Learn Mem Cogn 33, 263-273. 10.1037/0278-7393.33.2.263.
    2. McGaugh, J.L. (1966). Time-dependent processes in memory storage. Science 153, 1351-1358. 10.1126/science.153.3742.1351.
    3. Tonegawa, S., Morrissey, M.D., and Kitamura, T. (2018). The role of engram cells in the systems consolidation of memory. Nat Rev Neurosci 19, 485-498. 10.1038/s41583-018-0031-2.
    4. Davis, R.L., and Zhong, Y. (2017). The biology of forgetting-a perspective. Neuron 95, 490-503. 10.1016/j.neuron.2017.05.039.
    5. Aso, Y., Herb, A., Ogueta, M., Siwanowicz, I., Templier, T., Friedrich, A.B., Ito, K., Scholz, H., and Tanimoto, H. (2012). Three dopamine pathways induce aversive odor memories with different stability. PLoS Genet 8, e1002768. 10.1371/journal.pgen.1002768.
    6. Qin, H., Cressy, M., Li, W., Coravos, J.S., Izzi, S.A., and Dubnau, J. (2012). Gamma neurons mediate dopaminergic input during aversive olfactory memory formation in Drosophila. Curr Biol 22, 608-614. 10.1016/j.cub.2012.02.014.
    7. Aso, Y., and Rubin, G.M. (2016). Dopaminergic neurons write and update memories with cell-type-specific rules. Elife 5. 10.7554/eLife.16135.
    8. Berry, J.A., Cervantes-Sandoval, I., Nicholas, E.P., and Davis, R.L. (2012). Dopamine is required for learning and forgetting in Drosophila. Neuron 74, 530-542. 10.1016/j.neuron.2012.04.007.
    9. Tully, T., Preat, T., Boynton, S.C., and Del Vecchio, M. (1994). Genetic dissection of consolidated memory in Drosophila. Cell 79, 35-47. 10.1016/0092-8674(94)90398-0.
    10. Krashes, M.J., and Waddell, S. (2008). Rapid consolidation to a radish and protein synthesis-dependent long-term memory after single-session appetitive olfactory conditioning in Drosophila. J Neurosci 28, 3103-3113. 10.1523/JNEUROSCI.5333-07.2008.
    11. Schwaerzel, M., Monastirioti, M., Scholz, H., Friggi-Grelin, F., Birman, S., and Heisenberg, M. (2003). Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila. J Neurosci 23, 10495-10502.
    12. Séjourné, J., Plaçais, P.Y., Aso, Y., Siwanowicz, I., Trannoy, S., Thoma, V., Tedjakumala, S.R., Rubin, G.M., Tchenio, P., Ito, K., et al. (2011). Mushroom body efferent neurons responsible for aversive olfactory memory retrieval in Drosophila. Nat Neurosci 14, 903-910. 10.1038/nn.2846.
    13. Hige, T., Aso, Y., Modi, M.N., Rubin, G.M., and Turner, G.C. (2015). Heterosynaptic plasticity underlies aversive olfactory learning in Drosophila. Neuron 88, 985-998. 10.1016/j.neuron.2015.11.003.
    14. Perisse, E., Owald, D., Barnstedt, O., Talbot, C.B., Huetteroth, W., and Waddell, S. (2016). Aversive learning and appetitive motivation toggle feed-forward inhibition in the Drosophila mushroom body. Neuron 90, 1086-1099. 10.1016/j.neuron.2016.04.034.
    15. Handler, A., Graham, T.G.W., Cohn, R., Morantte, I., Siliciano, A.F., Zeng, J., Li, Y., and Ruta, V. (2019). Distinct dopamine receptor pathways underlie the temporal sensitivity of associative learning. Cell 178, 60-75 e19. 10.1016/j.cell.2019.05.040.
    16. Plaçais, P.Y., Trannoy, S., Isabel, G., Aso, Y., Siwanowicz, I., Belliart-Guerin, G., Vernier, P., Birman, S., Tanimoto, H., and Preat, T. (2012). Slow oscillations in two pairs of dopaminergic neurons gate long-term memory formation in Drosophila. Nat Neurosci 15, 592-599. 10.1038/nn.3055.
    17. Ichinose, T., Aso, Y., Yamagata, N., Abe, A., Rubin, G.M., and Tanimoto, H. (2015). Reward signal in a recurrent circuit drives appetitive long-term memory formation. Elife 4, e10719. 10.7554/eLife.10719.
    18. Berry, J.A., Cervantes-Sandoval, I., Chakraborty, M., and Davis, R.L. (2015). Sleep facilitates memory by blocking dopamine neuron-mediated forgetting. Cell 161, 1656-1667. 10.1016/j.cell.2015.05.027.
    19. Cervantes-Sandoval, I., Chakraborty, M., MacMullen, C., and Davis, R.L. (2016). Scribble scaffolds a signalosome for active forgetting. Neuron 90, 1230-1242. 10.1016/j.neuron.2016.05.010.
    20. Himmelreich, S., Masuho, I., Berry, J.A., MacMullen, C., Skamangas, N.K., Martemyanov, K.A., and Davis, R.L. (2017). Dopamine receptor DAMB signals via Gq to mediate forgetting in Drosophila. Cell Rep 21, 2074-2081. 10.1016/j.celrep.2017.10.108.
    21. Cervantes-Sandoval, I., Davis, R.L., and Berry, J.A. (2020). Rac1 Impairs Forgetting-induced cellular plasticity in mushroom body output neurons. Front Cell Neurosci 14, 258. 10.3389/fncel.2020.00258.
    22. Shuai, Y., Lu, B., Hu, Y., Wang, L., Sun, K., and Zhong, Y. (2010). Forgetting is regulated through Rac activity in Drosophila. Cell 140, 579-589. 10.1016/j.cell.2009.12.044.
    23. Berry, J.A., Phan, A., and Davis, R.L. (2018). Dopamine neurons mediate learning and forgetting through bidirectional modulation of a memory trace. Cell Rep 25, 651-662 e655. 10.1016/j.celrep.2018.09.051.
    24. Brown, M.R., Crim, J.W., Arata, R.C., Cai, H.N., Chun, C., and Shen, P. (1999). Identification of a Drosophila brain-gut peptide related to the neuropeptide Y family. Peptides 20, 1035-1042. 10.1016/s0196-9781(99)00097-2.
    25. Krashes, M.J., DasGupta, S., Vreede, A., White, B., Armstrong, J.D., and Waddell, S. (2009). A neural circuit mechanism integrating motivational state with memory expression in Drosophila. Cell 139, 416-427. 10.1016/j.cell.2009.08.035.
    26. Donlea, J.M., Thimgan, M.S., Suzuki, Y., Gottschalk, L., and Shaw, P.J. (2011). Inducing sleep by remote control facilitates memory consolidation in Drosophila. Science 332, 1571-1576. 10.1126/science.1202249.
    27. Chung, B.Y., Ro, J., Hutter, S.A., Miller, K.M., Guduguntla, L.S., Kondo, S., and Pletcher, S.D. (2017). Drosophila neuropeptide F signaling independently regulates feeding and sleep-wake behavior. Cell Rep 19, 2441-2450. 10.1016/j.celrep.2017.05.085.
    28. Plaçais, P.Y., de Tredern, E., Scheunemann, L., Trannoy, S., Goguel, V., Han, K.A., Isabel, G., and Preat, T. (2017). Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory. Nat Commun 8, 15510. 10.1038/ncomms15510.
    29. Dag, U., Lei, Z., Le, J.Q., Wong, A., Bushey, D., and Keleman, K. (2019). Neuronal reactivation during post-learning sleep consolidates long-term memory in Drosophila. Elife 8. 10.7554/eLife.42786.
    30. Chouhan, N.S., Griffith, L.C., Haynes, P., and Sehgal, A. (2021). Availability of food determines the need for sleep in memory consolidation. Nature 589, 582-585. 10.1038/s41586-020-2997-y.
    31. Tsao, C.H., Chen, C.C., Lin, C.H., Yang, H.Y., and Lin, S. (2018). Drosophila mushroom bodies integrate hunger and satiety signals to control innate food-seeking behavior. Elife 7. 10.7554/eLife.35264.
    32. Lin, S., Senapati, B., and Tsao, C.H. (2019). Neural basis of hunger-driven behaviour in Drosophila. Open Biol 9, 180259. 10.1098/rsob.180259.
    33. Chen, C.C., Wu, J.K., Lin, H.W., Pai, T.P., Fu, T.F., Wu, C.L., Tully, T., and Chiang, A.S. (2012). Visualizing long-term memory formation in two neurons of the Drosophila brain. Science 335, 678-685. 10.1126/science.1212735.
    34. Lin, H.-W., Chen, C.-C., de Belle, J.S., Tully, T., and Chiang, A.-S. (2021). CREBA and CREBB in two identified neurons gate long-term memory formation in Drosophila. Proc Natl Acad Sci U S A 118, e2100624118. 10.1073/pnas.2100624118 %J
    35. Dubnau, J., Grady, L., Kitamoto, T., and Tully, T. (2001). Disruption of neurotransmission in Drosophila mushroom body blocks retrieval but not acquisition of memory. Nature 411, 476-480. 10.1038/35078077.
    36. Viswanath, V., Story, G.M., Peier, A.M., Petrus, M.J., Lee, V.M., Hwang, S.W., Patapoutian, A., and Jegla, T. (2003). Opposite thermosensor in fruitfly and mouse. Nature 423, 822-823. 10.1038/423822a.
    37. Reale, V., Chatwin, H.M., and Evans, P.D. (2004). The activation of G-protein gated inwardly rectifying K+ channels by a cloned Drosophila melanogaster neuropeptide F-like receptor. Eur J Neurosci 19, 570-576. 10.1111/j.0953-816x.2003.03141.x.
    38. McGuire, S.E., Le, P.T., Osborn, A.J., Matsumoto, K., and Davis, R.L. (2003). Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302, 1765-1768. 10.1126/science.1089035.
    39. Scheffer, L.K., Xu, C.S., Januszewski, M., Lu, Z., Takemura, S.Y., Hayworth, K.J., Huang, G.B., Shinomiya, K., Maitlin-Shepard, J., Berg, S., et al. (2020). A connectome and analysis of the adult Drosophila central brain. Elife 9. 10.7554/eLife.57443.
    40. Klapoetke, N.C., Murata, Y., Kim, S.S., Pulver, S.R., Birdsey-Benson, A., Cho, Y.K., Morimoto, T.K., Chuong, A.S., Carpenter, E.J., Tian, Z., et al. (2014). Independent optical excitation of distinct neural populations. Nat Methods 11, 338-346. 10.1038/nmeth.2836.
    41. Rao, S., Lang, C., Levitan, E.S., and Deitcher, D.L. (2001). Visualization of neuropeptide expression, transport, and exocytosis in Drosophila melanogaster. J Neurobiol 49, 159-172. 10.1002/neu.1072.
    42. Carew, T.J., Pinsker, H.M., and Kandel, E.R. (1972). Long-term habituation of a defensive withdrawal reflex in aplysia. Science 175, 451-454. 10.1126/science.175.4020.451.
    43. Ebbinghaus, H. (2013). Memory: a contribution to experimental psychology. Ann Neurosci 20, 155-156. 10.5214/ans.0972.7531.200408.
    44. Pagani, M.R., Oishi, K., Gelb, B.D., and Zhong, Y. (2009). The phosphatase SHP2 regulates the spacing effect for long-term memory induction. Cell 139, 186-198. 10.1016/j.cell.2009.08.033.
    45. Waddell, S. (2013). Reinforcement signalling in Drosophila; dopamine does it all after all. Curr Opin Neurobiol 23, 324-329. 10.1016/j.conb.2013.01.005.
    46. Pavlowsky, A., Schor, J., Plaçais, P.Y., and Preat, T. (2018). A GABAergic feedback shapes dopaminergic input on the Drosophila mushroom body to promote appetitive long-term memory. Curr Biol 28, 1783-1793 e1784. 10.1016/j.cub.2018.04.040.
    47. Scaplen, K.M., Talay, M., Fisher, J.D., Cohn, R., Sorkac, A., Aso, Y., Barnea, G., and Kaun, K.R. (2021). Transsynaptic mapping of Drosophila mushroom body output neurons. Elife 10. 10.7554/eLife.63379.
    48. Vaccaro, A., Issa, A.R., Seugnet, L., Birman, S., and Klarsfeld, A. (2017). Drosophila clock is required in brain pacemaker neurons to prevent premature locomotor aging independently of its circadian function. PLoS Genet 13, e1006507. 10.1371/journal.pgen.1006507.
    49. Postman, L., and Underwood, B.J. (1973). Critical issues in interference theory. Mem Cognit 1, 19-40. 10.3758/BF03198064.
    50. Sabandal, J.M., Berry, J.A., and Davis, R.L. (2021). Dopamine-based mechanism for transient forgetting. Nature 591, 426-430. 10.1038/s41586-020-03154-y.
    51. Dubnau, J., and Chiang, A.S. (2013). Systems memory consolidation in Drosophila. Curr Opin Neurobiol 23, 84-91. 10.1016/j.conb.2012.09.006.
    52. Huang, C., Zheng, X., Zhao, H., Li, M., Wang, P., Xie, Z., Wang, L., and Zhong, Y. (2012). A permissive role of mushroom body alpha/beta core neurons in long-term memory consolidation in Drosophila. Curr Biol 22, 1981-1989. 10.1016/j.cub.2012.08.048.
    53. Cervantes-Sandoval, I., Martin-Peña, A., Berry, J.A., and Davis, R.L. (2013). System-like consolidation of olfactory memories in Drosophila. J Neurosci 33, 9846-9854. 10.1523/JNEUROSCI.0451-13.2013.
    54. Lee, P.T., Lin, G., Lin, W.W., Diao, F., White, B.H., and Bellen, H.J. (2018). A kinase-dependent feedforward loop affects CREBB stability and long term memory formation. Elife 7. 10.7554/eLife.33007.
    55. Miyashita, T., Kikuchi, E., Horiuchi, J., and Saitoe, M. (2018). Long-term memory engram cells are established by c-Fos/CREB transcriptional cycling. Cell Rep 25, 2716-2728 e2713. 10.1016/j.celrep.2018.11.022.
    56. Pai, T.P., Chen, C.C., Lin, H.H., Chin, A.L., Lai, J.S., Lee, P.T., Tully, T., and Chiang, A.S. (2013). Drosophila ORB protein in two mushroom body output neurons is necessary for long-term memory formation. Proc Natl Acad Sci U S A 110, 7898-7903. 10.1073/pnas.1216336110.
    57. Bouzaiane, E., Trannoy, S., Scheunemann, L., Plaçais, P.Y., and Preat, T. (2015). Two independent mushroom body output circuits retrieve the six discrete components of Drosophila aversive memory. Cell Rep 11, 1280-1292. 10.1016/j.celrep.2015.04.044.
    58. Wu, J.K., Tai, C.Y., Feng, K.L., Chen, S.L., Chen, C.C., and Chiang, A.S. (2017). Long-term memory requires sequential protein synthesis in three subsets of mushroom body output neurons in Drosophila. Sci Rep 7, 7112. 10.1038/s41598-017-07600-2.
    59. Scheunemann, L., Plaçais, P.Y., Dromard, Y., Schwarzel, M., and Preat, T. (2018). Dunce phosphodiesterase acts as a checkpoint for Drosophila long-term memory in a pair of serotonergic neurons. Neuron 98, 350-365 e355. 10.1016/j.neuron.2018.03.032.
    60. Wong, M.Y., Cavolo, S.L., and Levitan, E.S. (2015). Synaptic neuropeptide release by dynamin-dependent partial release from circulating vesicles. Mol Biol Cell 26, 2466-2474. 10.1091/mbc.E15-01-0002.
    61. Williams, M.J., Akram, M., Barkauskaite, D., Patil, S., Kotsidou, E., Kheder, S., Vitale, G., Filaferro, M., Blemings, S.W., Maestri, G., et al. (2020). CCAP regulates feeding behavior via the NPF pathway in Drosophila adults. Proc Natl Acad Sci U S A 117, 7401-7408. 10.1073/pnas.1914037117.
    62. Hirano, Y., Masuda, T., Naganos, S., Matsuno, M., Ueno, K., Miyashita, T., Horiuchi, J., and Saitoe, M. (2013). Fasting launches CRTC to facilitate long-term memory formation in Drosophila. Science 339, 443-446. 10.1126/science.1227170.
    63. van den Pol, A.N. (2012). Neuropeptide transmission in brain circuits. Neuron 76, 98-115. 10.1016/j.neuron.2012.09.014.
    64. Aso, Y., Ray, R.P., Long, X., Bushey, D., Cichewicz, K., Ngo, T.T., Sharp, B., Christoforou, C., Hu, A., Lemire, A.L., et al. (2019). Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics. Elife 8. 10.7554/eLife.49257.
    65. Kondo, S., Takahashi, T., Yamagata, N., Imanishi, Y., Katow, H., Hiramatsu, S., Lynn, K., Abe, A., Kumaraswamy, A., and Tanimoto, H. (2020). Neurochemical organization of the Drosophila brain visualized by endogenously tagged neurotransmitter receptors. Cell Rep 30, 284-297 e285. 10.1016/j.celrep.2019.12.018.
    66. Perkins, K.L. (2006). Cell-attached voltage-clamp and current-clamp recording and stimulation techniques in brain slices. J Neurosci Methods 154, 1-18. 10.1016/j.jneumeth.2006.02.010.

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