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Department of Biochemistry and Molecular Biology

Department of Biochemistry and Molecular Biology
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吳嘉霖老師

Chia-Lin Wu

JobTitle： Director of the Pre-Medical Program, Department of Medicine, Chang Gung University

CurrentJob： Chang Chung University

E-mail： clwu@mail.cgu.edu.tw

Phone： 5159

Education： Tsinghua University PhD

Expertise： Neuroscience

Website： https://clwu88.wixsite.com/chialinwu-lab

Research Directions and Laboratory Features


Learning and memory are among the most complex activities of the nervous system. How the brain establishes associations between simple events through learning and converts them into stored memories has long been an important question that neurobiologists have sought to understand. The human brain is estimated to contain more than 100 billion neurons, while the mouse brain is composed of approximately 75 million neurons, making the functional organization of their neural networks relatively complex.

Therefore, our research mainly uses the fruit fly, Drosophila melanogaster, as a model organism to understand the basic molecular mechanisms underlying memory formation in brain cells and the corresponding neural circuits. The fruit fly brain contains only about 100,000 neurons, yet these neurons control all of the fly’s complex biological behaviors, including innate survival skills as well as acquired learning and memory abilities.

Although fruit flies and humans differ in brain morphology and neural structure, memory formation in both organisms must be achieved through similar genetic networks and regulatory mechanisms. Our previous research found that glutamate receptors known as N-methyl-D-aspartate receptors, or NMDA receptors, which were originally thought to exist only in mammals, are also present in the fruit fly brain. Using genetic approaches to disrupt the normal function of NMDA receptors in the fruit fly brain affects both learning and memory in fruit flies. This suggests that the molecular mechanisms of learning and memory in the fruit fly brain are likely similar to those in mammals and even humans.

In addition, 60% to 70% of disease-related genes in fruit flies are similar to those in humans. In humans, many neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, are accompanied by memory decline. Therefore, using fruit flies to study brain-related diseases or neural mechanisms is one of the fastest approaches before moving into human brain research.

We use immunostaining of fruit fly brain tissue combined with confocal microscopy to observe changes in neural molecules in the fruit fly brain. In addition, we use animal behavioral analysis to examine whether mutations in specific genes or changes in the neural activity of specific neurons affect learning and memory ability in fruit flies.

In our behavioral experiments, fruit flies are first exposed to a specific odor, odor A, together with an electric shock. They are then exposed to a second odor, odor B, without an electric shock. This process is called training. Normal fruit flies are able to form an associative memory between the first odor and the electric shock. Later, during the behavioral test, the flies are exposed to both odors without any electric shock. Flies with memory will immediately avoid odor A and choose odor B.

Previous studies have found that a neural structure in the fruit fly brain called the mushroom body is responsible for learning and memory. The mushroom body is a symmetric structure in the fruit fly brain. Each hemisphere contains approximately 2,500 Kenyon cells. These Kenyon cells extend their neural fibers to form different lobe structures. Based on the structure of these lobes, the mushroom body can be divided into five regions: α, α’, β, β’, and γ.

Previous research has also shown that neural signals related to odor and electric shock eventually converge in the mushroom body. In addition, blocking neurotransmitter output from the mushroom body disrupts intermediate-term memory, or ITM, in fruit flies. ITM includes anesthesia-sensitive memory, or ASM, and anesthesia-resistant memory, or ARM.

Our recent research findings revealed that two pairs of special mushroom body extrinsic neurons, the anterior paired lateral neurons, or APL neurons, and the dorsal paired medial neurons, or DPM neurons, form gap junctions. Using genetic approaches to block the formation of these gap junctions disrupts anesthesia-sensitive memory, while leaving learning ability and anesthesia-resistant memory completely unaffected. However, to date, the mechanisms underlying the formation of anesthesia-resistant memory and its corresponding neural circuits remain unclear to neurobiologists.

Our research results show that blocking neurotransmission from APL neurons during the memory consolidation stage after olfactory learning in fruit flies causes defects in anesthesia-resistant memory. On the other hand, using RNA interference to suppress the synthesis of octopamine in APL neurons also disrupts anesthesia-resistant memory. Octopamine is structurally similar to norepinephrine in humans.

Because the axons of APL neurons enter the α’β’ region of the mushroom body in the fruit fly brain, we hypothesize that specific types of octopamine receptors in the α’β’ region of the mushroom body receive octopamine molecules released by APL neurons. We further found that disrupting a specific octopamine receptor, Octβ2R, in the mushroom body causes defects in anesthesia-resistant memory in fruit flies.

Since anesthesia-resistant memory is a type of consolidated memory that can persist for a long period of time, our laboratory is currently working to further investigate the molecular mechanisms underlying the formation of anesthesia-resistant memory in fruit flies, as well as the neural circuits responsible for this type of memory.



吳家

Figure Legend: Structure of APL neurons, DPM neurons, and the mushroom body in the fruit fly brain.

(A) and (B) Through genetic manipulation, green fluorescent protein (GFP) was expressed in a single APL neuron in the fruit fly brain (A) and in a DPM neuron (B), respectively. Although the cell bodies of APL and DPM neurons are located outside the mushroom body, their neural fibers extend into and are distributed throughout the entire mushroom body structure.

(C) The mushroom body structure in one hemisphere of the fruit fly brain is composed of approximately 2,500 Kenyon cells. The cell bodies of Kenyon cells are distributed around the calyx, and their neural fibers extend outward to form the peduncle, eventually converging into different lobe structures. Based on the structure and distribution of these lobes, the mushroom body can be divided into five regions: α, α’, β, β’, and γ.


Publication

Peer-review journal:

  1. 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.
  2. 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.
  3. 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).
  4. 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.
  5. 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).
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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).
  11. 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.
  12. 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.
  13. 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. 
  14. 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.
  15. 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).
  16. 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.
  17. 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).
  18. 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).    
  19. 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).
  20. 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).
  21. 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).
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. Wu CL, Chiang AS* (2008). Genes and circuits for olfactory-associated long-term memory in Drosophila. Journal of Neurogenetics, 22: 257-284.
  29. 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.
  30. 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:

  1. Shih MFM, Wu CL* (2017) Network functions and Plasticity—Gap Junction Underlying Labile Memory. Book Chapter, ELSEVIER (*corresponding author).