Extrasynaptic γ-aminobutyric acid type A(GABAA)receptors are a class of inhibitory neurotransmitter receptors that are distributed in non-synaptic structures such as cell bodies and dendrites.Extrasynaptic GABAA receptors are heteropentamers usually containing δ-subunit.Changes of δ-subunit expressions can be observed in model animals of postpartum depression and premenstrual syndrome,and δ-/-or δ+/-mice exhibit behavioral phenotypes of postpartum depression,suggesting that extrasynaptic GABAA receptors are involved in the pathogenesis of related diseases.The present review is concerned with the relationship between extrasynaptic GABAA receptors and postpartum depression as well as premenstrual syndrome in general,and the advances in research on drugs targeting extrasynaptic GABAA receptors for the treatment of these two conditions in particular.The article highlights the value of extrasynaptic GABAA receptors as a therapeutic target for female mood disor-ders,and may provide a reference for the development and application of related drugs.

OBJECTIVE To investigate the role of δ-subunit-containing extrasynaptic γ-aminobutyric acid type A receptor(GABAAR)in sleep-promoting effects of zolpidem(ZPD).METHODS ①C57BL/6J mice were implanted with skull electrodes and allowed postoperative recovery of seven days.Groups of mice were intraperitoneally(ip)administered with ZPD at 0(vehicle control),2.5,5 and 10 mg·kg-1.Cortical electroencephalography(EEG)was recorded to analyze latencies of non-rapid eye movement(NREM)and rapid eye movement(REM)sleep,the percentage of wakefulness,NREM and REM sleep,sleep architecture(the proportion of NREM and REM sleep in sleep,number of times and mean duration of NREM and REM sleep,microarousals and short awakenings),EEG power density and slow-wave activity(SWA,0.5-4 Hz)during NREM sleep.② Wild-type(WT)and δ-subunit knockout(δ-KO)mice were ip administered with vehicle or ZPD 10 mg·kg-1 before cortical EEG parameters were ana-lyzed to compare ZPD effects between genotypes.RESULTS ①Compared with the vehicle,ZPD 2.5,5 and 10 mg·kg-1 significantly shortened NREM sleep latency.ZPD 5 and 10 mg·kg-1 markedly reduced wakefulness and increased NREM sleep time.ZPD 2.5 and 10 mg·kg-1 increased NREM sleep episode frequency while ZPD 10 mg·kg-1 elevated brief awakening frequency.REM sleep remained unchanged.②In δ-KO mice,ZPD 10 mg·kg-1 significantly shortened NREM sleep latency compared with WT mice,but its effects on increasing short awakenings and suppressing SWA were abolished.Zolpidem showed no significant differences in the proportion of each sleep phase,the average duration of NREM sleep,and the frequency of REM sleep in KO mice compared to its effects on WT mice.CONCLUSION ZPD-induced sleep fragmentation and reduced sleep depth are mediated by δ-subunit-containing extra-synaptic GABAAR,whereas its shortening of NREM sleep latency is independent of this receptor subtype.

The paper reviews the evolution of the theory related to meridians and zangfu organs during the Warring States, Qin and Han dynasties, so as to reveal the rules and value of its development. By analyzing historical documents, especially Zubi Shiyimai Jiujing (Moxibustion Classics of Eleven Meridians of Legs and Arms), Yinyang Shiyimai Jiujing (Moxibustion Classic on Eleven Yin and Yang Meridians), Laoguanshan bamboo medical slips of Han Dynasty and lacquer figure of meridian points, the evolutionary stages, i.e. the germination, development, and maturity of meridian-zangfu theory, are explored. In the time of the Warring States, Qin and Han dynasties, the meridian-zangfu related theory was developed from the germination to the maturity. In the classics of the early time, Zubi Shiyimai Jiujing and Yinyang Shiyimai Jiujing demonstrated the preliminary relationship between meridians and zangfu organs, focusing on the physiological connection and pathogenesis of three yin meridians of foot and zangfu organs. In the literature of Laoguanshan bamboo medical slips of Han Dynasty and lacquer figure of meridian points, the physiological connection between the yin meridians of hand and foot, and five zang organs, as well as the related diseases were further clarified; additionally, the meridian-zangfu theory had been developed in the field of diagnosis and treatment. In the era of Chapter of Meridians in Lingshu (Miraculous Pivot), there were up to 31 descriptions relevant with the connection of meridian distribution and zangfu physiological functions. It marks the construction of the "circular" flow of meridians and the interior-exterior communication of zang and fu organs; and enriches the knowledge in diseases, diagnosis and treatment with meridians and zangfu organs involved. The review on the evolution of the meridian-zangfu theory is conductive to supplementing and improving the development history of this theory of early time, and further recognizing its development rules and value. The maturity of this theoretical system not only links the meridians with the five zang and six fu organs, but also provides an important theoretical basis for the diagnosis and treatment of traditional Chinese medicine.
Meridians ; Humans ; History, Ancient ; China ; History, Medieval ; History, 19th Century ; History, 20th Century ; History, 18th Century ; History, 17th Century ; History, 16th Century ; Medicine, Chinese Traditional/history*

Extrasynaptic γ-aminobutyric acid type A(GABAA)receptors are a class of inhibitory neurotransmitter receptors that are distributed in non-synaptic structures such as cell bodies and dendrites.Extrasynaptic GABAA receptors are heteropentamers usually containing δ-subunit.Changes of δ-subunit expressions can be observed in model animals of postpartum depression and premenstrual syndrome,and δ-/-or δ+/-mice exhibit behavioral phenotypes of postpartum depression,suggesting that extrasynaptic GABAA receptors are involved in the pathogenesis of related diseases.The present review is concerned with the relationship between extrasynaptic GABAA receptors and postpartum depression as well as premenstrual syndrome in general,and the advances in research on drugs targeting extrasynaptic GABAA receptors for the treatment of these two conditions in particular.The article highlights the value of extrasynaptic GABAA receptors as a therapeutic target for female mood disor-ders,and may provide a reference for the development and application of related drugs.

OBJECTIVE To investigate the role of δ-subunit-containing extrasynaptic γ-aminobutyric acid type A receptor(GABAAR)in sleep-promoting effects of zolpidem(ZPD).METHODS ①C57BL/6J mice were implanted with skull electrodes and allowed postoperative recovery of seven days.Groups of mice were intraperitoneally(ip)administered with ZPD at 0(vehicle control),2.5,5 and 10 mg·kg-1.Cortical electroencephalography(EEG)was recorded to analyze latencies of non-rapid eye movement(NREM)and rapid eye movement(REM)sleep,the percentage of wakefulness,NREM and REM sleep,sleep architecture(the proportion of NREM and REM sleep in sleep,number of times and mean duration of NREM and REM sleep,microarousals and short awakenings),EEG power density and slow-wave activity(SWA,0.5-4 Hz)during NREM sleep.② Wild-type(WT)and δ-subunit knockout(δ-KO)mice were ip administered with vehicle or ZPD 10 mg·kg-1 before cortical EEG parameters were ana-lyzed to compare ZPD effects between genotypes.RESULTS ①Compared with the vehicle,ZPD 2.5,5 and 10 mg·kg-1 significantly shortened NREM sleep latency.ZPD 5 and 10 mg·kg-1 markedly reduced wakefulness and increased NREM sleep time.ZPD 2.5 and 10 mg·kg-1 increased NREM sleep episode frequency while ZPD 10 mg·kg-1 elevated brief awakening frequency.REM sleep remained unchanged.②In δ-KO mice,ZPD 10 mg·kg-1 significantly shortened NREM sleep latency compared with WT mice,but its effects on increasing short awakenings and suppressing SWA were abolished.Zolpidem showed no significant differences in the proportion of each sleep phase,the average duration of NREM sleep,and the frequency of REM sleep in KO mice compared to its effects on WT mice.CONCLUSION ZPD-induced sleep fragmentation and reduced sleep depth are mediated by δ-subunit-containing extra-synaptic GABAAR,whereas its shortening of NREM sleep latency is independent of this receptor subtype.

OBJECTIVE To study the sedative and hypnotic effects of zolpidem and the content of amino acid neurotransmitters in the thalamus and hypothalamus after treatment with zolpidem.METHODS Experiments on the loss of righting reflex(LORR)induced by the upper-threshold dose pentobarbital sodium(50 mg·kg-1,ip)were conducted to establish a hypoxic insomnia model in mice by simulating an altitude of 5500 m.Based on this model,the synergistic effect of zolpidem(0.33,1,3,9 and 27 mg·kg-1,ip)and the subthreshold(20 mg·kg-1,ip)and upper-threshold pentobarbital sodium,as well as the sedative hypnotic effect of zolpidem(10,13,17,20,23,30 and 40 mg·kg-1,ip)were evaluated via the LORR in normoxic and hypoxic environments.One hour after ip given zolpidem,the levels of glutamic acid(Glu)and γ-aminobutyric acid(GABA)in the thalamus and hypothalamus of mice in either environment were determined by the high-performance liquid chromatography(HPLC)with fluorescence detection.RESULTS One-day treatment with hypoxia significantly shortened the duration of LORR induced by the upper-threshold dose pentobarbital sodium.Compared with normoxia vehicle and hypoxia induced insomnia vehicle groups,zolpidem 9 and 27 mg·kg-1 significantly shortened the latency to LORR(P<0.01,P<0.05)and prolonged duration of LORR induced by subthreshold and upper-threshold pentobarbital sodi-um(P<0.01,P<0.05).The median effective dose(ED50)of LORR induced by zolpidem was 16.21 and 20.55 mg·kg-1 in normoxic and hypoxic environments,respectively.The results of neurotransmitter level detection showed that Glu contents in the thalamus and hypothalamus and the ratio of Glu/GABA in the hypothalamus were decreased after treatment with zolpidem 40 mg·kg-1 in a normoxic environment(P<0.01,P<0.05).Compared with the normoxia control group,Glu content and the ratio of Glu/GABA in the hypothalamus were significantly increased after treatment with hypoxia(P<0.01,P<0.05),and zolpidem 40 mg·kg-1 could reverse their elevation.CONCLUSION The sedative-hypnotic effect of zolpidem is weakened in a hypoxic environment,and the effect of zolpidem on the levels of Glu and GABA in the hypothalamus may play an important role in the sedative-hypnotic effect of zolpidem.

OBJECTIVE To evaluate the psychological dependence of the extrasynaptic GABAA receptor(GABAAR)agonist gaboxadol and compare it with the synaptic GABAAR modulator midazolam in the two-bottle free-choice model of mice.METHODS ① Male C57BL/6J mice were ig administered with vehicle,midazolam(59.0,73.7,92.2,115.2,144.0 and 180.0 mg·kg-1)or gaboxadol(8.4,10.5,13.1,16.4,20.5,25.6 and 32.0 mg·kg-1),and the loss of righting reflex was observed.The median effective dose(ED50)was obtained from the dose-response curve.② A two-bottle free-choice model was used to find out whether gaboxadol and midazolam induced preference behavior in mice.The mice were divided into normal control,gaboxadol or midazolam groups.During the habituation stage(the first day to the third day,D1-D3),both test and vehicle bottles contained water.During the trail stage(D4-D5),4%sucrose solution was provided in both bottles.During the test stage(D6-D15),test bottles contained vehicle,gaboxadol(3.9×10-6 mol·L-1)or midazolam(1.4×10-5 mol·L-1)in sucrose solu-tions,while other bottles contained the corresponding vehicle in sucrose solutions.Bottles were placed on the two sides of the home cage,to which mice had free access,and their consumption from each bottle was recorded daily.Total consumption,accumulated daily consumption,relative consumption,and accumulated relative consumption during the test stage were calculated.The weight of the mice was also recorded.RESULTS ① Midazolam and gaboxadol dose-dependently increased the rate of loss of right reflex in mice,with ED50 of 105.3 mg·kg-1(95%CI:96.4-115.2 mg·kg-1,R2=0.9796),13.7 mg·kg-1(95%CI:12.6-15.0 mg·kg-1,R2=0.9773),respectively.② Compared with the normal control group,there was no significant difference in the total consumption in the gaboxadol and midazolam groups.Compared to the vehicle bottles,the daily consumption from test bottles in the midazolam group increased significantly on D11-D15 of the test stage(P<0.05),while daily consumption from gaboxadol test bottles was significantly higher than that of vehicle bottles(P<0.01).Compared with the normal control group,the daily relative consumption in the gaboxadol group was significantly increased on D9(P<0.05),and the accumulative relative consumption was significantly higher than in the normal control group(P<0.01).There was no significant change in body weight across the groups over the test stage.CONCLU-SION Like midazolam,gaboxadol exhibits psychological dependence potential in a two-bottle free-choice model.

Objective To explore the effects of different acupoints,different target organs,and different interventions on acupoint efficacy based on ACU&MOX-DATA platform;To illustrate and visualize whether the above factors have the characteristics of"specific effect"or"common effect"of acupoint efficacy.Methods The multi-source heterogeneous data were integrated from the original omics data and public omics data.After standardization,differential gene analysis,disease pathology network analysis,and enrichment analysis were performed using Batch Search and Stimulation Mode modules in ACU&MOX-DATA platform under the conditions of different acupoints,different target organs,and different interventions.Results Under the same disease state and the same intervention,there were differences in effects among different acupoints;under the same disease state,the same acupoint and intervention,the responses produced by different target organs were not completely consistent;under the same disease state and acupoint,there were differences in effects among different intervention measures.Conclusion Based on the analysis of ACU&MOX-DATA platform,it is preliminary clear that acupoints,target organs,and interventions are the key factors affecting acupoint efficacy.Meanwhile,the above results have indicated that there are specific or common regulatory characteristics of acupoint efficacy.Applying ACU&MOX-DATA platform to analyze and visualize the critical scientific problems in the field of acupuncture and moxibustion can provide references for deepening acupoint cognition,guiding clinical acupoint selection,and improving clinical efficacy.

Objective This study aims to compare the accuracy of self-developed universal implant guide(SDG),3D printed digital guide(DG),and free hand(FH)simulated implantation in the posterior tooth area of dental models.Methods Ten junior dentists were selected to place three implants in the 35,37,and 46 tooth sites of the mandibular models(35,36,37,and 46 missing teeth)by using SDG,DG,and FH,and the process was repeated again to take the av-erage value.Cone beam computed tomography(CBCT)was used to evaluate the global coronal deviation,global apical deviation,depth deviation,and angular deviation between the actual position and preoperative planned position.Re-sults The coronal deviation and apical deviation of the three implant sites in the SDG group were not significantly dif-ferent from those in the two other groups(P>0.05).The depth deviation and angular deviation in the SDG group were smaller than those in the DG group(P<0.05)and FH group(P<0.05),respectively.All deviations at site 37 in the SDG group were not different from those at site 35(P>0.05),while the depth and angular deviation at site 37 in the DG group were higher than those at site 35(P<0.05).Conclusion The precision of the self-developed universal dental im-plant guide can meet the requirements of clinical posteri-or implantation.

Objective To observe the intervention effect of acupuncture at"Zusanli"(ST36)or"Neiguan"(PC6)on the ulcerative colitis(UC)model mice.And to analyze the similarities and differences of gene transcription expression between the diseased colon and the non-diseased heart after acupuncture intervention by using transcriptomics,to explore whether there are efficacy differences between the two acupoints.Methods The UC mouse model was established by inducing dextran sulfate sodium salt(DSS).After successful modeling,the mice were randomly divided into model group,Zusanli group,and Neiguan group,with 9 mice in each group.Zusanli group and Neiguan group intervened with acupuncture at"Zusanli"and"Neiguan",respectively,30 min each time,once a day,for 5 consecutive days.The control and model groups were only bound without acupuncture.Observe the general situation of mice in each group,calculate the disease activity index(DAI),observe the morphological changes of colon tissue by HE staining.Use transcriptome sequencing technology to sequence and biologically analyze the colon tissue of mice in each group,and compare and study whether the two acupoints have differences in acupoint efficacy from the perspective of diseased tissue.At the same time,take the heart tissues of each group for comparative analysis,and discuss whether the effects of the two acupoints are different from the perspective of non-diseased tissue.Results Compared with control group,the DAI score of the model group increased significantly(P<0.001),and HE staining results showed significant pathological damage;after acupuncture at Zusanli or Neiguan,the DAI scores of UC mice were reduced considerably(P<0.05),and the pathological damage was significantly improved.The results of transcriptome sequencing and bioinformatics analysis showed that the effects of acupuncture at Zusanli or Neiguan on the colon of diseased tissue involved multiple genes,and 825 differential genes with similar changes(co-DEGs)were mainly enriched in white blood cells and chemokine pathways;there were 168 differentially expressed genes(ST36 only-DEGs)affected only by Zusanli,which were enriched to gastric acid secretion and other pathways;there were 325 differentially expressed genes(PC6 only-DEGs)only affected by Neiguan,which were enriched in cytokine-cytokine receptor interaction and other pathways.There were 95 co-DEGs in the heart of non-diseased tissue,which were mainly enriched in positive regulation of defense response and response to interleukin-1;there were 28 ST36 only-DEGs;there were114 PC6 only-DEGs,which were enriched in cardiovascular diseases and other pathways.Conclusion Acupuncture of"Zusanli"and"Neiguan"could improve UC mice's symptoms and pathological colon changes.However,through transcriptomic analysis,it was found that the two acupoints had differences in gene transcription effects on the colon of diseased tissue and the heart of non-diseased tissue,suggesting that acupoints with different distribution positions had some similarities in macro efficacy.Still,there were some differences at a micro level.