黄志力
下丘脑睡眠觉醒调节机制;失眠动物模型和失眠机制;生理性睡眠药物开发;携带式脑电图仪及分析软件开发
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- 姓名:黄志力
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学术头衔:
博士生导师, 国家杰出青年科学基金获得者
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学科领域:
神经生物学
- 研究兴趣:下丘脑睡眠觉醒调节机制;失眠动物模型和失眠机制;生理性睡眠药物开发;携带式脑电图仪及分析软件开发
黄志力,复旦大学特聘教授、博士生导师,2006 年获国家杰出青年基金。1985年毕业于皖南医学院临床医学系,1988年获药理学硕士学位。1992、1997年二次获笹川医学奖学金赴日本留学,1999年获得博士学位。1999年起任日本学术振兴会博士后、大阪生命科学研究所研究员,研究副部长,2005年起加盟复旦大学医学神经生物学国家重点实验室。现任上海医学院药理学系主任,中国睡眠研究会副理事长、中国药理学会麻醉药理学专业委员会副主任委员、上海市药理学会副理事长、日本睡眠学会外国人评议员。
研究兴趣:下丘脑睡眠觉醒调节机制;失眠动物模型和失眠机制;生理性睡眠药物开发;携带式脑电图仪及分析软件开发;建立中国人脑电数据库。近五年来,从基因到行为系统地阐明了组胺能神经睡眠觉醒调节网络;发现了有效调控组胺能神经的内源性物质与作用机制;提出了下丘脑睡眠觉醒调节的跷跷板模型;纠正了睡眠界长期认为咖啡因促觉醒作用由腺苷A1受体介导的错误观点,发现A2A受体是睡眠觉醒调节的重要受体。
曾主持或参与日本文部省基盘研究基金、脑科学研究基金等7项科研项目,累计经费达550万美元。现承担国家"新药创制重大专项"、国家基础研究重大项目973、国家杰出青年基金、国家自然基金创新群体、上海市科委基础重点、重点攻关及优秀学科带头人等国家及上海市科研项目。用中、英、日三种文字发表研究论文与综述84篇,其中SCI论文33篇,包括Nature Neuroscience, PNAS (6篇),Journal of Neuroscience(3篇)等,论文被SCI杂志引用800多次。应邀为Progress in Neurobiology、Current Opinion in Pharmacology、Curr Topics in Medical Chemistry等杂志撰写综述,为PNAS,Journal of Neuroscience, Neuropharmacology、J Neurosci Res等20个SCI杂志审稿。多次应邀赴美国、日本、法国、乌拉圭、新加坡、印度、泰国、澳大利亚、韩国等国家作学术报告。
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黄志力, Wei-Min Qu, Xin-Hong Xu, Ming-Ming Yan, Yi-Qun Wang, Yoshihiro Urade, and Zhi-Li Huang
The Journal of Neuroscience, March 24, 2010, 30(12): 4382-4389,-0001,():
-1年11月30日
Dopamine (DA) and its D2 receptor (R) are involved in cognition, reward processing, and drug addiction. However, their roles in sleep-wake regulation remain unclear. Herein we investigated the role of D2R in sleep wake regulation by using D2R knock-out (KO) mice and pharmacological manipulation. Compared with WT mice, D2R KO mice exhibited a significant decrease in wakefulness, with a concomitant increase in non-rapid eye movement (non-REM, NREM) andREMsleep and a drastic decrease in the low-frequency (0.75-2 Hz) electroencephalogram delta power of NREM sleep, especially during the first 4 h after lights off. The KO mice had decreased mean episode duration and increased episode numbers of wake andNREMsleep, many stage transitions between wakefulness andNREMsleep during the dark period, suggesting the instability of the wake stage in these D2R KO mice. When the KO mice were subjected to a cage change or an intraperitoneal saline injection, the latency to sleep in the KO mice decreased to half of the level for WT mice. The D2R antagonist raclopride mimicked these effects inWTmice. When GBR12909, a dopamine transport inhibitor, was administered intraperitoneally, it induced wakefulness inWTmice in a dose-dependent manner, but its arousal effect was attenuated to one-third in theD2RKO mice. However, these 2 genotypes showed an identical response in terms of sleep rebound after 2, 4, and 6 h of sleep deprivation. These results indicate that D2R plays an essential role in the maintenance of akefulness, but not in homeostatic regulation of NREM sleep.
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黄志力, Mei-Hong Qiu a, b, Wei-Min Qu a, *, Xin-Hong Xu a, Ming-Ming Yan a, Yoshihiro Urade c, Zhi-Li Huang a, c
Pharmacology, Biochemistry and Behavior 94(2009)16-23,-0001,():
-1年11月30日
L-stepholidine, an active ingredient of the Chinese herb Stephonia, is the first compound known to havemixed dopamine D1 receptor agonist/D2 antagonist properties and to be a potential treatment medication forschizophrenia. In schizophrenic patients insomnia is a common symptom and could be partly related to thepresumed over-activity of the dopaminergic system. To elucidate whether stepholidine modulates sleepbehaviors, we observed its effects on sleep–wake profiles in mice. The results showed that stepholidineadministered i.p. at doses of 20, 40 or 80 mg/kg significantly shortened the sleep latency to non-rapid eyemovement (non-REM, NREM) sleep, increased the amount of NREM sleep, and prolonged the duration ofNREM sleep episodes, with a concomitant reduction in the amount of wakefulness. Stepholidine at doses of40 and 80 mg/kg increased the number of state transitions from wakefulness to NREM sleep andsubsequently from NREM sleep to wakefulness. However, stepholidine had no effect on either the amount ofREM sleep or electroencephalogram power density of either NREM or REM sleep. Immunohistochemistrystudy showed that stepholidine dose-dependently increased c-Fos expression in neurons of the ventrolateralpreoptic area, a sleep center in the anterior hypothalamus, as compared with the vehicle control. Theseresults indicate that stepholidine initiates and maintains NREM sleep with activation of the sleep center inmice, suggesting its potential application for the treatment of insomnia.
Dopamine receptor L-stepholidine Mice Sleep
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黄志力, Yo Oishia, b, Zhi-Li Huanga, c, , Bertil B. Fredholmd, Yoshihiro Uradea, and Osamu Hayaishia
19992-19997, PNAS, December 16, 2008, vol. 105, no.50,-0001,():
-1年11月30日
Adenosine has been proposed to promote sleep through A1 receptors(A1R’s) and/or A2A receptors in the brain. We previouslyreported that A2A receptors mediate the sleep-promoting effect ofprostaglandin D2, an endogenous sleep-inducing substance, andthat activation of these receptors induces sleep and blockade ofthem by caffeine results in wakefulness. On the other hand, A1Rhas been suggested to increase sleep by inhibition of the cholinergicregion of the basal forebrain. However, the role and targetsites of A1R in sleep–wake regulation remained controversial. Inthis study, immunohistochemistry revealed that A1R was expressedin histaminergic neurons of the rat tuberomammillarynucleus (TMN). In vivo microdialysis showed that the histaminerelease in the frontal cortex was decreased by microinjection intothe TMN of N6-cyclopentyladenosine (CPA), an A1R agonist, adenosineor coformycin, an inhibitor of adenosine deaminase, whichcatabolizes adenosine to inosine. Bilateral injection of CPA into therat TMN significantly increased the amount and the delta powerdensity of non-rapid eye movement (non-REM; NREM) sleep butdid not affect REM sleep. CPA-promoted sleep was observed in WTmice but not in KO mice for A1R or histamine H1 receptor, indicatingthat the NREM sleep promoted by A1R-specific agonist dependedon the histaminergic system. Furthermore, the bilateral injection ofadenosine or coformycin into the rat TMN increased NREM sleep,which was completely abolished by coadministration of 1,3-dimethyl-8-cyclopenthylxanthine, a selective A1R antagonist.These results indicate that endogenous adenosine in the TMNsuppresses the histaminergic system via A1R to promote NREMsleep.
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【期刊论文】Dopaminergic D1 and D2 Receptors Are Essential for theArousal Effect of Modafinil
黄志力, Wei-Min Qu, Zhi-Li Huang, , Xin-Hong Xu, Naomi Matsumoto, and Yoshihiro Urade
The Journal of Neuroscience, August 20, 2008, 28 (34): 8462-8469,-0001,():
-1年11月30日
Modafinil is a wake-promoting compound with low abuse potential used in the treatment of narcolepsy. Although the compound isreported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine,however, the molecular mechanism by which modafinil increases wakefulness is debated. Herein we used dopamine (DA) D2 receptor(D2R)-deficient mice combined with D1R- and D2R-specific antagonists to clarify the role of DA receptors in the arousal effects ofmodafinil. In wild-type mice, intraperitoneal modafinil induced wakefulness in a dose-dependent manner. Pretreatment with eitherD1Rantagonist SCH23390 [R-(_)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] at 30 _g/kg or D2R antagonistraclopride at 2 mg/kg blocked the arousal effects of low-dose modafinil at 22.5 and 45 mg/kg. When modafinil was given at 90 and180 mg/kg, pretreatment of D1R antagonist did not affect the wakefulness at all, whereas D2R antagonist significantly attenuated thewakefulness to the half level compared with vehicle control. Similarly,D2R knock-out (KO) mice exhibited attenuated modafinil-inducedwakefulness. However, pretreatment of D2R KO mice with D1R antagonist completely abolished arousal effects of modafinil. Thesefindings strongly indicate that dopaminergic D1R and D2R are essential for the wakefulness induced by modafinil.
dopamine receptor, EEG, knock-out mice, modafinil, sleep, wakefulness
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黄志力, Wei-Min Qua, Zhi-Li Huanga, b, ?, Naomi Matsumotoa, Xin-Hong Xua, Yoshihiro Uradea
Journal of Neuroscience Methods 175(2008)58-63,-0001,():
-1年11月30日
To avoid the stress encountered during oral drug administration, we implanted chronically a catheterinto the stomach, and recorded electroencephalogram (EEG) and electromyogram, in freely moving ratsto evaluate their sleep–wake pattern. Rats with catheters in their stomach did not exhibit any changesin sleep–wake profiles in terms of sleep amount, number of episodes and EEG power spectra. Whenadministered through the catheter, caffeine (6 mg/kg) statistically increased wakefulness, as comparedwith the vehicle control. However, when given orally by hand restraint and gavage, it caused no increasein wakefulness, owing to the masking effect of this method, which caused increased wakefulness whensaline was used by handling animals. These results indicate that oral administration through a chronicstomach catheter is a useful way for evaluating wake-promoting components.
Caffeine Gavage Hand restraint Stomach catheter Sleep Stress
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【期刊论文】Gene expression in the rat brain during prostaglandin D2 andadenosinergically-induced sleep
黄志力, Akira Terao, *, , Zhi-Li Huang, ?, Jonathan P. Wisor, * Takatoshi Mochizuki, Dmitry Gerashchenko, * Yoshihiro Urade? and T. S. Kilduff*
JOURNAL OF NEUROCHEMISTRY|2008|105|1480-1498,-0001,():
-1年11月30日
Previous studies have supported the hypothesis that macromolecularsynthesis occurs in the brain during sleep as a responseto prior waking activities and that prostaglandin D2(PGD2) is an endogenous sleep substance whose effects aredependent on adenosine A2a receptor-mediated signaling. Wecompared gene expression in the cerebral cortex, basalforebrain, and hypothalamus during PGD2-induced and adenosinergically-induced sleep to results from our previouslypublished study of recovery sleep (RS) after sleep deprivation(SD). Immediate early gene expression in the cortex duringsleep induced by PGD2- or by the selective adenosine A2aagonist CGS21680 showed limited similarity to that observedduring RS while, in the basal forebrain and hypothalamus,widespread activation of immediate early genes not seenduring RS occurred. In all three brain regions, PGD2 andCGS21680 reduced the expression of arc, a transcript whoseexpression is elevated during SD. Using GeneChips_, themajority of genes induced by either PGD2 or CGS21680 wereinduced by both, suggesting activation of the same pathways.However, gene expression induced in the brain after PGD2 orCGS21680 treatment was distinct from that described duringRS after SD and apparently involves glial cell gene activationand signaling pathways in neural-immune interactions.
adenosine,, cytokines,, GeneChip*, ,, neural-immune,, quantitative PCR,, TaqMan*, analysis.,
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【期刊论文】Prostaglandins and adenosine in the regulation of sleep andwakefulness
黄志力, Zhi-Li Huang, , Yoshihiro Urade and Osamu Hayaishi
Current Opinion in Pharmacology 2007, 7: 33-38,-0001,():
-1年11月30日
Prostaglandin (PG) D2 and adenosine are potent humoralsleep-inducing factors that accumulate in the brain duringprolonged wakefulness. PGD2 is produced in the brain bylipocalin-type PGD synthase, which is localized mainly in theleptomeninges, choroid plexus and oligodendrocytes, andcirculates in the cerebrospinal fluid as a sleep hormone. Itstimulates DP1 receptors on leptomeningeal cells of the basalforebrain to release adenosine as a paracrine signalingmolecule to promote sleep. Adenosine activates adenosine A2Areceptor-expressing sleep-active neurons in the basalforebrain and the ventrolateral preoptic area. Sleep-promotingneurons in the ventrolateral preoptic area send inhibitorysignals to suppress the histaminergic neurons in thetuberomammillary nucleus, which contribute to arousal throughhistamine H1 receptors. Increased knowledge of the molecularmechanisms by which PGD2 induces sleep through activationof adenosine A2A receptors and inhibition of the histaminergicarousal system will be useful both for a better understanding ofsleep/wake regulation and for the development of novel typesof sleeping pills or anti-doze drugs.
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黄志力, Namiko Nishida a, b, , Zhi-Li Huang b, c, *, Nobuhiro Mikuni a, Yoshiki Miura d, Yoshihiro Urade b, Nobuo Hashimoto a
Experimental Neurology 205(2007)132-144,-0001,():
-1年11月30日
Deep brain stimulation (DBS) is a promising therapy for intractable epilepsy, yet the optimum target and underlying mechanism remaincontroversial. We used the rat pentylenetetrazol (PTZ) seizure model to evaluate the effectiveness of DBS to three targets: two known to be criticalfor arousal, the histaminergic tuberomammillary nucleus (TMN) and the orexin/hypocretinergic perifornical area (PFN), and the anterior thalamicnuclei (ATH) now in clinical trial. TMN stimulation provided the strong protection against the seizure, and PFN stimulation elicited a moderateeffect yet accompanying abnormal behavior in 25% subjects, while ATH stimulation aggravated the seizure. Power density analysis showed EEGdesynchronization after DBS on TMN and PFN, while DBS on ATH caused no effect with the same stimulation intensity. EEG desynchronizationafter TMN stimulation was inhibited in a dose-dependent manner by pyrilamine, a histamine H1 receptor selective antagonist, while the effect ofPFN stimulation was inhibited even at a low dose. In parallel, in vivo microdialysis revealed a prominent increase of histamine release in thefrontal cortex after TMN stimulation, a moderate level with PFN and none with ATH. Furthermore, antiepileptic effect of DBS to TMN was alsoblocked by an H1 receptor antagonist. This study clearly indicates that EEG desynchronization and the activation of the histaminergic systemcontributed to the antiepileptic effects caused by DBS to the posterior hypothalamus.
Anterior thalamic nuclei, EEG desynchronization, Epilepsy, Histamine, Perifornical area, Pyrilamine, Tuberomammillary nucleus
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黄志力, C.R. Chen a, W.M. Qu c, M.H. Qiu b, X.H. Xu a, c, M.H. Yao a, Y. Urade c, Z.L. Huang b, *
Neuropharmacology 53(2007)534-541,-0001,():
-1年11月30日
Epilepsy is characterized by neuronal hyperexcitability and hypersynchronization. Disruption of electroencephalographically (EEG) synchronizedepileptiform discharges may be a possible therapy for epilepsy. In the present study, to clarify the role of EEG desynchronization onepilepsy, we investigated the effect of modafinil, a potent wake-promoting substance with EEG desynchronization activity, on epilepsy inmice and clarified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) kindlingmodels. Modafinil given at 22.5, 45, and 90 mg/kg, i.p. significantly decreased the incidence of tonic hindleg extension in MES seizuremodels, and protected against PTZ-induced convulsive behaviors in a dose-dependent manner. In addition, modafinil at 180 mg/kg exerted anantiepileptic effect in the MES model; however, at the same dosage it increased the seizure stage in the PTZ-kindling model. The antiepilepticeffect in both MES and PTZ models was antagonized by the adrenergic a1 receptor antagonist terazosin, but not by the adrenergic a2 receptorantagonist yohimbine or by dopaminergic receptor antagonists, SCH-23390 (for D1 receptors) and haloperidol (for D2 ones). Pyrilamine, a histaminergicH1 receptor antagonist, counteracted the antiepileptic action of modafinil in the PTZ induced-kindling model, but not in the MESseizure model. Taken together, the present findings indicate that modafinil exerted its antiepileptic effect via adrenergic a1 and histaminergicH1 receptors, and might be of potential use in the treatment of epilepsy.
Maximal electroshock, Pentylenetetrazol, Pyrilamine, Seizure, Terazosin
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黄志力, Wei-Min Qu*, Zhi-Li Huang*?, Xin-Hong Xu*?, Kosuke Aritake*, Naomi Eguchi*, Fumio Nambu?, Shu Narumiya§, Yoshihiro Urade*, and Osamu Hayaishi*?
PNAS, November 21, 2006, vol. 103, no.47, 17949-17954,-0001,():
-1年11月30日
Prostaglandin (PG) D2 has been proposed to be essential for theinitiation and maintenance of the physiological sleep of ratsbecause intracerebroventricular administration of selenium tetrachloride(SeCl4), a selective inhibitor of PGD synthase (PGDS), wasshown to reduce promptly and effectively the amounts of sleepduring the period of infusion. However, gene knockout (KO) miceof PGDS and prostaglandin D receptor (DP1R) showed essentiallythe same circadian profiles and daily amounts of sleep as wild-type(WT) mice, raising questions about the involvement of PGD2 inregulating physiological sleep. Here we examined the effect ofSeCl4 on the sleep of WT and KO mice for PGDS and DP1R and thatof a DP1R antagonist, ONO-4127Na, on the sleep of rats. The i.p.injection of SeCl4 into WT mice decreased the PGD2 content in thebrain without affecting the amounts of PGE2 and PGF2_. It inhibitedsleep dose-dependently and immediately after the administrationduring the light period when mice normally sleep, increasing thewake time; and the treatment with this compound resulted in adistinct sleep rebound during the following dark period. TheSeCl4-induced insomnia was observed in hematopoietic PGDS KOmice but not at all in lipocalin-type PGDS KO, hematopoietic andlipocalin-type PGDS double KO or DP1R KO mice. Furthermore, theDP1R antagonist ONO-4127Na reduced sleep of rats by 30% duringinfusion into the subarachnoid space under the rostral basalforebrain at 200 pmol_min. These results clearly show that thelipocalin-type PGDS_PGD2_DP1R system plays pivotal roles in theregulation of physiological sleep.
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