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研究方向及研究室特色：
學習與記憶是神經系統中最複雜的活動，大腦如何將單純的事件經由學習建立關聯，並將之轉換成
為記憶儲存，自古以來一直是神經生物學家們想要瞭解的重要課題。人類的大腦估計超過一千億顆
神經細胞，小鼠的大腦由 大約七千五百萬顆神經細胞所組成，其神經網路的分工相對複雜 。因此
我們的研究工作主要利用果蠅(Drosophila melanogaster)為模式動物，去瞭解大腦細胞內記憶形成
過程基本的分子機制及相對應之神經網路，果蠅大腦只有約十萬顆神經細胞，但這十萬顆神經細胞
卻負責控制果蠅的所有複雜的生物行為，包含其先天擁有的生存技能和後天的學習與記憶能力。雖
然果蠅與人類在大腦的型態上以及神經結構上有所不同，但是兩者的記憶形成卻必需透過類似的基
因網絡與調控機制來達成。我們過去的研究工作發現了果蠅腦中也存在著原來被認為只存在於哺乳
類動物的麩胺酸受器(N-methyl-D-aspartate, NMDA receptors)。利用遺傳學方式破壞果蠅腦內正
常功能的麩胺酸受器，同時影響果蠅的學習與記憶。代表果蠅腦內學習記憶的分子機制，很可能和
哺乳類動物甚至人類是相似的。此外，果蠅與人類的疾病相關基因有高達六至七成的相似度。在人
類，許多神經退化性疾病例如帕金森氏症、阿茲海默症也都出現記憶能力衰退的現象。因此，以果
蠅研究腦神經相關的疾病或運作機制，將是切入人腦研究前最迅速方式之一。
我們利用果蠅大腦組織免疫染色搭配共軛焦顯微鏡技術觀察果蠅大腦內神經分子的變化情
形。另外利用動物行為學分析，觀察特定基因突變或特定神經細胞的神經活性改變是否影響果蠅
學習與記憶能力。我們先給予果蠅聞某一特定的氣味A並同時給予電擊，之後再給予果蠅第二種氣味
B但不給電擊，此過程稱之為訓練。正常的果蠅能夠將第一種氣味與電擊事件產生關連性學習，之後
在行為測試的時候，同時給予果蠅兩種氣味但不給任何電擊，有記憶能力的果蠅便會毫不猶豫的躲
避氣味 A，選擇氣味 B，在過去的研究發現，果蠅腦中一個稱為蕈狀體 (mushroom body) 的神經結
構負責學習與記憶，蕈狀體是一個果蠅腦內的對稱結構，每半邊大腦由大約2500顆左右的Kenyon
cells 所組成，Kenyon cells 將他們的神經纖維延伸出去形成各種不同的蕈杯(Lobes) 結構，我
們可以根據蕈杯的結構，將其分成 α、α'、β、β' 及 γ等五個區域。之前的研究也顯示氣味與
電極的神經訊號最後接匯集至蕈狀體，另外，阻斷蕈狀體的神經傳導物質輸出會破壞果蠅的中期記
憶(Intermediate-Term Memory, ITM)，其包含了昏迷敏感性記憶(Anesthesia-Sensitive Memory,
ASM)以及抗昏迷記憶(Anesthesia-Resistant Memory, ARM)。
我們最近的研究成果發現兩對特殊的蕈狀體外源神經細胞Anterior Paired Lateral (APL
neurons)及Dorsal Paired Medial (DPM neurons)存在著縫隙連接(Gap junctions)，利用遺傳學
方式阻斷此縫隙連接的形成會破壞昏迷敏感性記憶但絲毫不影響學習能力以及抗昏迷記憶，然而，
到目前為止神經生物學家對於抗昏迷記憶的形成機制以及其相對應神經網路的研究仍然不清楚。我
們的研究結果顯示，當阻斷 APL neurons的神經傳導物質，在果蠅嗅覺學習之後的記憶固化階段，
會造成抗昏迷記憶的缺損。另一方面，利用RNA 干擾技術(RNA interference)去抑制APL的奧克巴胺
(Octopamine)[結構類似於人類的正腎上腺素(Norepinephrine)]的合成也同樣會破壞抗昏迷記憶。
由於APL的軸突(Axon)進入果蠅腦中蕈狀體α'β'區域，因此我們推測會有特定種類的奧克巴胺接受
器在蕈狀體α'β'區域內扮演著接收 APL 釋放的奧克巴胺分子。我們也進一步發現當破壞蕈狀體內
特定的奧克巴胺接受器(Octβ2R)，則果蠅抗昏迷記憶便會產生缺陷。由於抗昏迷記憶是一種可以長
時間存在的固化型記憶(Consolidated memory)，我們實驗室目前的工作是進一步去研究果蠅抗昏迷
記憶的形成分子機制以及負責抗昏迷記憶的神經迴路。
圖說:果蠅大腦內APL、DPM及蕈狀體(mushroom body)結構。(A)及(B)，利用遺傳操作方式分別表現
綠色螢光蛋白在果蠅腦中單一顆APL神經細胞(圖A)及DPM神經細胞(圖B)，雖然APL及DPM的神經元位
在蕈狀體外，但其神經纖維伸入並且分佈在整個蕈狀體結構。(C) 果蠅半邊大腦之蕈狀體結構，由
大約2500顆Kenyon cells所組成，Kenyon cells的神經元分布於Calyx周圍並且將神經纖維延伸出去
形成Peduncle，最終匯集成各種不同的蕈杯(lobes)結構。我們可以根據蕈杯的結構及分布，將其分
成α、α'、β、β' 及γ 等五個區域。蕈狀體為果蠅大腦學習與記憶中樞，過往的研究已證實許
多與果蠅學習與記憶相關分子均表現在蕈狀體內。Scale bar 20μm。
RESEARCH INTERESTS:
My research interest is to understand the neural circuits and molecular mechanisms
contribute to memory. Drosophila melanogaster has contributed to this insight, fly can
be taught to associate an odor, conditioned stimulus (CS), with a punitive foot shock,
unconditioned stimulus (US). Fly memory can be genetically and behaviorally dissected into
several different phases depending on the training protocols. In our prior studies, we
have identified the NMDA receptors play the exclusive roles for different types of memory
consolidation in Drosophila (Xia S et al., 2005 Current Biology, Wu CL et al., 2007 Nature
Neuroscience, Wu CL et al., 2008, Journal of Neurogenetics).
In our recent studies, we have revealed the gap junctions involved in specific type of
intermediate-term memory formation. Gap junctions are important for normal brain functions
but their contribution to memory has not been well characterized. We showed two modulatory
neurons, i.e. the anterior paired lateral (APL) and dorsal paired medial (DPM) neurons,
form gap-junctional communication in the mushroom body (MB), the learning and memory center
in the Drosophila brain. Following disruption of such gap junctions with RNAi-mediated
knockdowns of inx7 and inx6 in the APL and DPM neurons, respectively, we found that flies
showed normal olfactory associative learning and intact Anesthesia-Resistant Memory (ARM)
but could not form three-hour Anesthesia-Sensitive Memory (ASM). Our results indicate
the heterotypic gap junctions between the APL and DPM neurons are an essential part of the
MB circuitry for ASM, suggesting that a recurrent neural circuit, consisting of APL, DPM
and MB neurons, may stabilize ASM inside the MB (Wu CL et al., 2011 Current Biology).
More interestingly, we also found that chemical neurotransmission from the APL neuron
is necessary for ARM consolidation rather than ASM. We identified the APL neurons are
tyramine, Tβh, and octopamine immunopositive. Octopamine is the counterpart of human
norepinephrine and may also play the role for memory formation. With an adult-stage-specific
RNAi knockdown of Tβh in the APL neurons or Octβ2R octopamine receptors in the MB α’/β’
Kenyon cells (KCs) impaired ARM. Our data imply octopamine released from the APL neurons
acts on MB α’/β’ KCs via Octβ2R receptor to modulate Drosophila ARM formation. Together
with previous findings suggest that two parallel ARM pathways, serotoninergic DPM-MB α/β
KCs and octopaminergic APL-MB α’/β’ KCs, exist in the Drosophila brain (Wu CL et al.,
2013 Current Biology).
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發表論文：
Peer-review journal:
- Hsu CY, Yeh JY, Chen CY, Wu HY, Chiang MH, Wu CL, Lin HJ, Chiu CH, Lai CH. (2021). Helicobacter pylori cholesterol-α-glucosyltransferase manipulates cholesterol for bacterial adherence to gastric epithelial cells. Dec;12(1):2341-2351.
- Cheng KC, Chen YH, Wu CL, Lee WP, Cheung CHA, Chiang HC. (2021).Rac1 and Akt Exhibit Distinct Roles in Mediating Aβ-Induced Memory Damage and Learning Impairment. Molecular Neurobiology, Jul 17. doi: 10.1007/s12035-021-02471-1.
- Lee WP, Chiang MH, Chang LY, Lee JY, Tsai YL, Chiu TH, Chiang HC, Fu TF, Wu T, Wu CL*. (2020). Mushroom body subsets encode CREB2-dependent water-reward long-term memory in Drosophila. PLOS Genetics, 16(8): e1008963. (*corresponding author).
- Lien WY, Chen YT, Li YJ, Wu JK, Huang KL, Lin JR, Lin SC, Hou CC, Wang HD, Wu CL, Huang SY, Chan CC*. (2020). Lifespan regulation in α/β posterior neurons of the fly mushroom bodies by Rab27. Aging Cell, 19(8): e13179.
- Shyu WH, Lee WP, Chiang MH, Chang CC, Fu TF, Chiang HC, Wu T, Wu CL* (2019). Electrical synapses between mushroom body neurons are critical for consolidated memory retrieval in Drosophila. PLOS Genetics, 15(5): e1008153. (*corresponding author).
- Sneapati B, Tsao CH, Juan YA, Chiu TH, Wu CL, Waddell S, Lin S*. (2019). A neural mechanism for deprivation state-specific expression of relevant memories in Drosophila. Nature Neuroscience, 22(12): 2029-2039.
- Chen YR, Li YH, Hsieh TC, Wang CM, Cheng KC, Wang L, Lin TY, Cheung CHA, Wu CL, Chiang H* (2019). Aging-induced Akt activation involves in aging-related pathologies and Aβ-induced toxicity. Aging Cell, 18(4) e12989.
- Chi KC, Tsai WC, Wu CL, Lin TY, Hueng DY (2019). An adult Drosophila glioma model for studying pathometabolic pathways of gliomagenesis. Molecular Neurobiology, 56(6): 4589-4599.
- Lien HM, Wu HY, Hung CL, Chen CJ, Wu CL, Chen KW, Huang CL, Chang SJ, Chen CC, Lin HJ, Lai CH* (2019). Antibacterial activity of ovatodiolide isolated from Anisomeles indica against Helicobacter pylori. Scientific Reports, (9)1: 4205. doi: 10.1038/s41598-019-40735-y.
- Wu CL*, Chang CC, Wu JK, Chiang MH, Yang CH, Chiang HC (2018). Mushroom body glycolysis is required for olfactory memory in Drosophila. Neurobiology of Learning and Memory, 150: 13-19 (*corresponding author).
- Chen YA, Tzeng D TW, Huang YP, Lin CJ, Lo UG, Wu CL, Lin H, Hsieh JT, Tang CH, Lai CH*. Antrocin sensitizes prostate cancer cells to radiotherapy through inhibiting PI3K/AKT and MAPK signaling pathways. Cancers, 11(1): 34. doi 10.3390/cancers11010034.
- Chen YA, Shih HW, Lin YC, Hsu HY, Wu TF, Tsai CH, Wu CL, Wu HY, Hsieh JT, Tang CH, Lai CH* (2018). Simvastatin sensitizes radioresistant prostate cancer cells by compromising DNA double-strand break repair. Frontiers in Pharmacology, 9: 600.
- Ji XR, Cheng KC, Chen YR, Lin TY, Cheung CHA, Wu CL, Chiang HC* (2018). Dysfunction of different cellular degeneration pathways contributes to specific β-amyloid42-induced pathologies. FASEB Journal, 32(3): 1375-1387.
- Yang CN, Wu MF, Liu CC, Jung WH, Chang YC, Lee WP, Shiao YJ, Wu CL, Liou HH, Lin SK, Chan CC* (2017) Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia. Human Molecular Genetics, 26(20): 3909-3921.
- Shyu WH, Chiu TH, Chiang MH, Cheng YC, Tsai YL, Fu TF, Wu T, Wu CL* (2017). Neural circuits for long-term water-reward memory processing in thirsty Drosophila. Nature Communications, 8: 15230; doi: 10.1038/ncomms15230 (*corresponding author).
- Chen SL, Chen YH, Wang CC, Yu YW, Tsai YC, Hsu HW, Wu CL, Wang PY, Chen LC, Lan TH*, Fu TF* (2017). Active and passive sexual roles that arise in Drosophila male-male courtship are modulated by dopamine levels in PPL2ab neurons. Scientific Reports, 7:44595/doi:10.1038/srep44595.
- Yang CH, Shih MF M, Chang CC, Chiang MH, Shih HW, Tsai YL, Chiang AS, Fu TF, Wu CL* (2016). Additive expression of consolidated memory through Drosophila mushroom body subsets. PLOS Genetics, 12(5): e1006061 (*corresponding author).
- Wu CL*, Fu TF, Chiang MH, Chang YW, Her JL, Wu T (2016). Magnetoreception regulates male courtship activity in Drosophila. PLOS One, 11(5): e0155942 (*corresponding author).
- Shih HW#, Wu CL#*, Chang SW, Liu TH, Lai SY, Fu TF, Fu CC, Chiang AS* (2015). Parallel circuits control temperature preference in Drosophila during ageing. Nature Communications, 6: 7775; doi: 10.1038/ncomms8775 (#co-first authors; *co-corresponding authors).
- Kuo SY#, Wu CL#, Hsieh MY, Lin CT, Wen RK, Chen LC, Chen YH, Yu YW, Wang HD, Su YJ, Lin CJ, Yang CY, Guan HY, Wang PY, Lan TH, Fu TF* (2015). PPL2ab neurons restore sexual responses in aged Drosophila males through dopamine. Nature Communications, 6: 7490; doi: 10.1038/ncomms8490 (#co-first authors).
- Wu CL*, Fu TF, Chou YY, Yeh SR (2015). A single pair of neurons modulates egg-laying decisions in Drosophila. PLOS One, 10(3): e0121335 (*corresponding author).
- Wu CL, Shih MF M, Lee PT, Chiang AS* (2013). An octopamine-mushroom body circuit modulates the formation of anesthesia-resistant memory in Drosophila. Current Biology, 23: 2346-2354.
- Wu TH, Lu YN, Chuang CL, Wu CL, Chiang AS, Krantz DE, Chang HY*. (2013). Loss of vesicular dopamine release precedes tauopathy in degenerative dopaminergic neurons in a Drosophila model expressing human tau. ACTA NEUROPATHOLOGICA, 125(5): 711-725.
- Kuo SY, Tu CH, Hsu YT, Wang HD, Wen RK, Lin CT, Wu CL, Huang YT, Huang GS, Lan TH, Fu TF* (2012). A hormone receptor-based transactivator bridges different binary systems to precisely control spatial-temporal gene expression in Drosophila. PLOS One, 7(12): e50855.
- Chen CC, Wu JK, Lin HW, Pai TP, Fu TF, Wu CL, Tully T, Chiang AS* (2012). Visualizing long-term memory formation in two neurons of Drosophila brain. Science, 335: 678-685.
- Wu CL, Shih MF M, Lai J SY, Yang HT, Turner CG, Chen L, Chiang AS* (2011). Heterotypic gap junctions between two neurons in the Drosophila brain are critical for memory. Current Biology, 21: 848-854.
- Chang YC, Hung WZ, Chang YC, Chang HC, Wu CL, Chiang AS, Jackson GR, Sang TK* (2011). Pathogenic VCP/TER94 alleles are dominant actives and contribute to neurodegeneration by altering cellular ATP level in a Drosophila IBMPFD model. PLOS Genetics, 7(2): e1001288.
- Wu CL, Chiang AS* (2008). Genes and circuits for olfactory-associated long-term memory in Drosophila. Journal of Neurogenetics, 22: 257-284.
- Wu CL, Xia S, Fu TF, Wang H, Chen YH, Leong D, Chiang AS*, Tully T* (2007). Specific requirement of NMDA receptors for long-term memory consolidation in Drosophila ellipsoid body. Nature Neuroscience, 10(12): 1578-1586.
- Xia S, Miyashita T, Fu TF, Lin WY, Wu CL, Pyzocha L, Lin IR, Saitoe M, Tully T, Chiang AS* (2005). NMDA receptors mediate olfactory learning and memory in Drosophila. Current Biology, 15: 603-615.
Book chapter:
- Shih MFM, Wu CL* (2017) Network functions and Plasticity—Gap Junction Underlying Labile Memory. Book Chapter, ELSEVIER (*corresponding author).
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