实验室丨药理学系张永鹤课题组
北京大学基础医学院主要从事生物医学领域的基础及应用基础研究，拥有雄厚的科学研究综合实力以及一批具备国际先进水平的科研基地和实验技术平台。接下来基础研会将为大家依次介绍北医基础医学院各大实验室，让大家对学院的科研状况能有更为深入的了解。本期将进行基础医学院药理学系实验室推送，一起走进张永鹤课题组！
药理学系张永鹤实验室
先通过一则小视频来了解一下药理学系张永鹤课题组吧！
张永鹤实验室成立于2001年，主要研究睡眠和行为障碍（包括抑郁、焦虑和创伤后应激障碍等）的神经网络和分子机制；建立伴发睡眠障碍的神经精神性疾病动物模型，如焦虑、抑郁、创伤后应激障碍、神经退行性病变等；筛查天然产物和安神中药的活性物质基础，并探讨天然产物调控睡眠及对异常行为的影响机制，目前实验室成员包括3名老师和5名学生。
01
导师简介
张永鹤教授，博士，博士生导师，现任北京大学医学部睡眠医学中心副主任、基础医学院药理学系副主任。兼任中国药理学会秘书长；中国药理学会教学与科普专业委员会主任委员；中国睡眠研究会睡眠生理与药理专业委员会副主任；中国民族医药学会药理与毒理学分会执行会长；国家科技进步奖评审专家；科技部863项目评审专家；科技部科技型中小企业技术创新基金评审专家；国家自然科学基金评审专家；Biomolecules & Therapeutics(SCIE)编委；《药理学通报》编委；北京市科学技术奖励评审专家。自2001年回国工作以来，先后主持了国家自然科学基金、“重大新药创制”科技重大专项“十一五”、“十三五”候选药及临床前研究项目、教育部基金、美国中华医学基金——人才奖、北京大学“十五”211和985工程项目等科研项目。自1983年以来，分别从事天然药物化学，神经药理和心血管药理的研究工作。已在国内外杂志上发表论文100余篇，其中SCI收录论文80余篇，参编出版著作10本，获美国专利授权1项。
02
实验室研究领域
睡眠及神经精神药物药理学
(1)伴发睡眠障碍疾病（包括抑郁、焦虑和创伤后应激障碍等）的神经网络和分子机制；
(2)睡眠障碍的表型，例如焦虑、抑郁、创伤后应激障碍相关的动物模型的建立以及天然产物；
(3)筛查安神中药的活性物质基础，并探讨天然产物调控睡眠及对异常行为的影响机制。
03
实验室团队及培养
1、人员组成
实验室地址：北京大学医学部生理楼2层
本实验室现有教职工3名，八年制学生2名，直博生1名，统招博士生2名。
2. 培养模式
周一上午组会，主要内容包括：(1)汇报课题进展，集思广益，及时解决课题中遇到的问题；(2)文献学习，精讲文献内容，学习前沿发展，深入探讨课题思路及新技术，开阔视野。
3. 实验室氛围
实验室的氛围极度融洽。实验室内部老师和学生之间以及学生内部（包括已毕业学生）在课题研究和学习生活等各方面都关系紧密，互相关心，相互帮助。
与其他国内知名实验室密切合作：如协和药物研究所，军科院等。
张老师注重每位学生综合能力的培养，不仅鼓励学生在科研中发散思维，更关心学生的全面发展，对学生进行全面的培养和教育。
近些年实验室发表文章数量和水平都比较可观，在按时毕业的前提下学生们都进行了相当有原创性和建设性的工作。
实验室会定期进行团建活动，学期初、学期末、迎新、毕业、节假日等实验室都会进行聚餐，且每年还会举办春游或秋游。工作时间比较灵活，可根据实验自行安排。
今年实验室师兄师姐取得不错的成绩，获得北京市三好学生。组内的同学们各有所长，在科研之外也有丰富的生活经历。
04
主要发现
(1) 在国际上首次建立心理性创伤后应激障碍动物模型，并揭示激发和调取心理性创伤相关记忆的神经环路；
(2) 首次提出蓝斑核中黑色素聚积激素受体（MCHR1）可能是抑郁症治疗的重要靶标；
(3) 阐明中缝背核的钙通道参与睡眠-觉醒调控机制；
(4) 成功建立阿尔茨海默病、抑郁、创伤后应激障碍、精神分裂症、高血压伴发睡眠障碍的动物模型，并揭示相关的睡眠障碍表型特征；
(5) 阐明了酸枣仁、人参、灵芝、五味子、远志等传统安神中药催眠活性成分及其作用机制。
05
实验室已发表文章
1) Cui, S. Y., Huang, Y. L., Cui, X. Y., Zhao, H. L., Hu, X., Liu, Y. T., . . . Zhang, Y. H. (2020). A common neuronal mechanism of hypertension and sleep disturbances in spontaneously hypertensive rats: Role of orexinergic neurons. Prog Neuropsychopharmacol Biol Psychiatry, 100, 109902. doi:10.1016/j.pnpbp.2020.10990
2) Xu, Y. P., Cui, X. Y., Liu, Y. T., Cui, S. Y., & Zhang, Y. H. (2019). Ginsenoside Rg1 promotes sleep in rats by modulating the noradrenergic system in the locus coeruleus and serotonergic system in the dorsal raphe nucleus. Biomed Pharmacother, 116, 109009. doi:10.1016/j.biopha.2019.10900
3) Cui, S. Y., Yang, M. X., Zhang, Y. H., Zheng, V., Zhang, H. T., Gurney, M. E., . . . O'Donnell, J. M. (2019). Protection from Amyloid β Peptide-Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor. J Pharmacol Exp Ther, 371(2),250-259.
doi:10.1124/jpet.119.259986
4) Cui, S. Y., Huang, Y. L., Cui, X. Y., Zhao, H. L., Hu, X., Liu, Y. T., & Zhang, Y. H. (2019). Serotonergic system may be involved in alterations of sleep homeostasis in spontaneously hypertensive rats. J Sleep Res, e12947. doi:10.1111/jsr.12947
5) Ye, H., Cui, X. Y., Ding, H., Cui, S. Y., Hu, X., Liu, Y. T., . . . Zhang, Y. H. (2018). Melanin-Concentrating Hormone (MCH) and MCH-R1 in the Locus Coeruleus May Be Involved in the Regulation of Depressive-Like Behavior. Int J Neuropsychopharmacol, 21(12), 1128-1137. doi:10.1093/ijnp/pyy088
6) Song, J. Z., Cui, S. Y., Cui, X. Y., Hu, X., Ma, Y. N., Ding, H., . . . Zhang, Y. H. (2018). Dysfunction of GABAergic neurons in the parafacial zone mediates sleep disturbances in a streptozotocin-induced rat model of sporadic Alzheimer's disease. Metab Brain Dis, 33(1), 127-137. doi:10.1007/s11011-017-0125-y
7) Ding, H., Cui, X. Y., Cui, S. Y., Ye, H., Hu, X., Zhao, H. L., . . . Zhang, Y. H. (2018). Depression-like behaviors induced by chronic corticosterone exposure via drinking water: Time-course analysis. Neurosci Lett, 687, 202-206. doi:10.1016/j.neulet.2018.09.059
8) Cui, X. Y., Yang, G., Cui, S. Y., Cao, Q., Huang, Y. L., Ding, H., . . . Zhang, Y. H. (2018). Sleep patterns deteriorate over time in chronic corticosterone-treated rats. Neurosci Lett, 682, 74-78. doi:10.1016/j.neulet.2018.06.017
9) Cui, S. Y., Song, J. Z., Cui, X. Y., Hu, X., Ma, Y. N., Shi, Y. T., . . . Zhang, Y. H.(2018). Intracerebroventricular streptozotocin-induced Alzheimer's disease-like sleep disorders in rats: Role of the GABAergic system in the parabrachial complex. CNS Neurosci Ther, 24(12), 1241-1252. doi:10.1111/cns.13032
10) Yu, B., Cui, S. Y., Zhang, X. Q., Cui, X. Y., Li, S. J., Sheng, Z. F., . . . Zhang, Y. H. (2016). Mechanisms Underlying Footshock and Psychological Stress-Induced Abrupt Awakening From Posttraumatic "Nightmares". Int J Neuropsychopharmacol, 19(4). doi:10.1093/ijnp/pyv113
11) Huang, Y. L., Cui, S. Y., Cui, X. Y., Cao, Q., Ding, H., Song, J. Z., . . . Zhang, Y. H. (2016). Tetrandrine, an alkaloid from S. tetrandra exhibits anti-hypertensive and sleep-enhancing effects in SHR via different mechanisms. Phytomedicine, 23(14), 1821-1829. doi:10.1016/j.phymed.2016.10.021
12) Cui, S. Y., Li, S. J., Cui, X. Y., Zhang, X. Q., Yu, B., Huang, Y. L., . . . Zhang, Y. H. (2016). Ca(2+) in the dorsal raphe nucleus promotes wakefulness via endogenous sleep-wake regulating pathway in the rats. Mol Brain, 9(1), 71. doi:10.1186/s13041-016-0252-0
13) Cui, S. Y., Li, S. J., Cui, X. Y., Zhang, X. Q., Yu, B., Sheng, Z. F., . . . Zhang, Y. H. (2016). Phosphorylation of CaMKII in the rat dorsal raphe nucleus plays an important role in sleep-wake regulation. J Neurochem, 136(3), 609-619. doi:10.1111/jnc.13431
14) Cao, Q., Jiang, Y., Cui, S. Y., Tu, P. F., Chen, Y. M., Ma, X. L., . . . Zhang, Y. H. (2016). Tenuifolin, a saponin derived from Radix Polygalae, exhibits sleep-enhancing effects in mice. Phytomedicine, 23(14), 1797-1805. doi:10.1016/j.phymed.2016.10.015
15) Yu, B., Cui, S. Y., Zhang, X. Q., Cui, X. Y., Li, S. J., Sheng, Z. F., . . . Zhang, Y. H. (2015). Different neural circuitry is involved in physiological and psychological stress-induced PTSD-like "nightmares" in rats. Sci Rep, 5, 15976. doi:10.1038/srep15976
16) Wang, Z. J., Zhang, X. Q., Cui, X. Y., Cui, S. Y., Yu, B., Sheng, Z. F., . . . Zhang, Y. H. (2015). Glucocorticoid receptors in the locus coeruleus mediate sleep disorders caused by repeated corticosterone treatment. Sci Rep, 5, 9442. doi:10.1038/srep09442
17) Sheng, Z. F., Cui, X. Y., Cui, S. Y., Yu, B., Zhang, X. Q., Li, S. J., . . . Zhang, Y. H. (2015). Involvement of adrenoceptors, dopamine receptors and AMPA receptors in antidepressant-like action of 7-O-ethylfangchinoline in mice. Acta Pharmacol Sin, 36(8), 949-956. doi:10.1038/aps.2015.57
18) Liu, R., Sheng, Z. F., Cai, B., Zhang, Y. H., & Fan, D. S. (2015). Increased orexin expression promotes sleep/wake disturbances in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Chin Med J (Engl), 128(2), 239-244. doi:10.4103/0366-6999.149214
19) Li, S. J., Cui, S. Y., Zhang, X. Q., Yu, B., Sheng, Z. F., Huang, Y. L., . . . Zhang, Y. H. (2015). PKC in rat dorsal raphe nucleus plays a key role in sleep-wake regulation. Prog Neuropsychopharmacol Biol Psychiatry, 63, 47-53. doi:10.1016/j.pnpbp.2015.05.005
20) Zhang, J., Yu, B., Zhang, X. Q., Sheng, Z. F., Li, S. J., Wang, Z. J., . . . Zhang, Y. H. (2014). Tetrandrine, an antihypertensive alkaloid, improves the sleep state of spontaneously hypertensive rats (SHRs). J Ethnopharmacol, 151(1), 729-732. doi:10.1016/j.jep.2013.09.054
21) Wang, L. E., Zhang, X. Q., Yin, Y. Q., & Zhang, Y. H. (2012). Augmentative effect of spinosin on pentobarbital-induced loss of righting reflex in mice associated with presynaptic 5-HT1A receptor. J Pharm Pharmacol, 64(2), 277-282. doi:10.1111/j.2042-7158.2011.01400.x
22) Cui, X. Y., Cui, S. Y., Zhang, J., Wang, Z. J., Yu, B., Sheng, Z. F., . . . Zhang, Y. H. (2012). Extract of Ganoderma lucidum prolongs sleep time in rats. J Ethnopharmacol, 139(3), 796-800. doi:10.1016/j.jep.2011.12.020
23) Cui SY, Cui XY, Zhang J, Wang ZJ, Yu B, Sheng ZF, Zhang XQ, Shi XL, Zhang YH.* Diltiazem potentiates pentobarbital-induced hypnosis via 5-HT(1A) and 5-HT(2A/2C) receptors: Role for dorsal raphe nucleus. Pharmacol Biochem Behav 2011;99:566-72.
24) Ca(2+) modulation in dorsal raphe plays an important role in NREM and REM sleep regulation during pentobarbital hypnosis. Brain Res 2011;1403:12-8.
25) Jie-Xin Cao, Qing-Ying Zhang, Su-Ying Cui, Xiang-Yu Cui, Juan Zhang, Yong-He Zhang, Yan-Jing Bai, Yu-Ying Zhao. Hypnotic effect of jujubosides from Semen Ziziphi Spinosae. Journal of Ethnopharmacology. 2010, 130:163–166.
26) Wang LE, Cui XY, Cui SY, Cao JX, Zhang J, Zhang YH*, Zhang QY, Bai YJ, Zhao YY. Potentiating effectofspinosin, a C-glycosideflavonoidof semen Ziziphi spinosae, onpentobarbital-inducedsleepmayberelatedtopostsynaptic 5-HT1A receptors. Phytomedicine 2010, 17: 404–409.
27) Xin Zhao, Xiang-Yu Cui, Li-En Wang, Yong-He Zhang*. Potentiating effect of diltiazem on pentobarbital-induced hypnosis is augmented by serotonergic system: The TMN and VLPO as key elements in the pathway. Neuropharmacology 2009, 56, 937–943.
28) Wang Li-En, Bai Yan-Jing, Shi Xiao-Rong, Cui Xiang-Yu, Cui Su-Ying, Zhang Fan, Zhang Qing-Ying, Zhao Yu-Ying, Zhang Yong-He*. Spinosin, a C-glycoside flavonoid from semen Zizhiphi Spinozae, potentiated pentobarbital-induced sleep via the serotonergic system, Pharmacology Biochemistry and Behavior 2008, 90(3): 399-403.
29) 师晓荣，王黎恩，崔素颖，崔翔宇，杜楠，张帆，张永鹤*. 氟桂利嗪对戊巴比妥钠睡眠的增强作用. 中国药理学通报. 2009，25（3）：335-340。
30) Nan Du, Li-En Wang, Xiao-Rong Shi, Xiang-Yu Cui, Su-Ying Cui, Fan Zhang and Yong-He Zhang*.Journal of Chinese Pharmaceutical Sciences. 2008, 17, 192-196.
31) Qing-Ping Chu, Li-En Wang, Xiang-Yu Cui, Hong-Zheng Fu, Zhi-Bin Lin, Shu-Qian Lin, Yong-He Zhang*. Extract of Ganoderma lucidum potentiates pentobarbital-induced sleep via a GABAergic mechanism. Pharmacol Biochem and Beh 2007, 86 (4): 693-698.
32) Cui XY, Zhao X, Chu QP, Chen BQ, Zhang YH*.Influence of diltiazem on the behavior of zolpidem-treated mice in the elevated-plus maze test. J Neural Transm. 2007, 114 (2): 155-160.
33) Yong-Ri Jin, Xiang-Hua Han, Yong-He Zhang, Jung-Jin Lee, Yong Lim, Tack-Joong Kim, Hwan-Soo Yoo, Yeo-Pyo Yun. Hesperetin, a bioflavonoid, inhibits rat aortic vascular smooth muscle cells proliferation by arresting cell cycle. J Cell Biochem 2009, 104: 1-14.
34) Yong-Ri Jin, Xiang-Hua Han, Yong-He Zhang, Jung-Jin Lee, Yong Lim, Jin-Ho Chung and Yeo-Pyo. YunAntiplatelet activity of hesperetin, a bioflavonoid, is mainly mediated by inhibition of PLC-gamma2 phosphorylation and cyclooxygenase-1 activity. Atherosclerosis 2007, 194 (1): 144-152.
35) Zhao X, Cui XY, Chu QP, Chen BQ, Wang XM, Lin ZB, Li XJ, Ku BS, Zhang YH*. Potentiating effects of L-type Ca2+ channel blockers on pentobarbital-induced hypnosis are influenced by serotonergic system. J Neural Transm. 2006, 113 (10): 1395-1402.
36) Bao-Qiong Chen, Xiang-Yu Cui, Xin Zhao, Hui-Shan Piao, Jin-Hwa Kim, Bum-Chun Lee, Hyeong-Bae Pyo, Yeo-Pyo Yun, Yong-He Zhang*. Antioxidative and acute antiinflammatory effects of Torreya grandis Fort. Fitoterapia 2006, 77 (4): 262-267.
37) Xiang-Yu Cui, Jin-Hwa Kim, Xin Zhao, Bao-Qiong Chen, Bum-Chun Lee, Hyeong-Bae Pyo, Yeo-Pyo Yun, Yong-He Zhang*. Antioxidative and acute antiinflammatory effects of Campsis grandiflora. J Ethnopharmacol 2006, 103(2): 223-228.
38) Ying Xu, Bao-Shan Ku, Hai-Yan Yao, Yan-Hua Lin, Xing Ma, Yong-He Zhang, Xue-Jun Li. The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 2005, 518, 40- 46.
39) Ying Xu, Bao-Shan Ku, Hai-Yan Yao, Yan-Hua Lin, Xing Ma, Yong-He Zhang, Xue-Jun Li. Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem and Beh 2005, 82, 200-206.
40) Lian-Hua Fang, Yong-He Zhang*, Bao-Shan Ku. Fangchinoline inhibited the antinociceptive effect of morphine in mice. Phytomedicine 2005, 12(3): 183-188.
41) Lian-Hua Fang, Yong-He Zhang*, Jing-Jie Ma, Guan-Hua Du, Bao-Shan Ku, Hai-Yan Yao, Yeo-Pyo Yun, TJ Kim. Inhibitory Effects of Tetrandrine on the Serum- and Platelet Derived Growth Factor-BB-induced Proliferation of Rat Aortic Smooth Muscle Cells through Inhibition of Cell Cycle Progression, DNA Synthesis, ERK1/2 Activation and c-fos Expression. Atherosclerosis 2004, 174(2): 215-223.
42) Xin Zhao, Xiang-Yu Cui, Bao-Qiong Chen, Qing-Ping Chu, Hai-Yan Yao, Bao-Shan Ku, Yong-He Zhang*. Tetrandrine, a bisbenzylisoquinoline alkaloid from Chinese herb Radix, augmented the hypnotic effect of pentobarbital through serotonergic system. Eur J Pharmacol 2004, 506, 101-105.
06
联系方式
张永鹤
北京大学医学部药理学系
Email: zhyh@hsc.pku.edu.cn
电话：01082801112
图文：张永鹤
课题组
编辑：高浩萌
审核：索利苹