快速眼球运动睡眠剥夺及γ-氨基丁酸能药物干预对大鼠认知功能的影响
쾌속안구운동수면박탈급γ-안기정산능약물간예대대서인지공능적영향
Effects of rapid eye movement sleep deprivation and GABAergic drug intervention on cognition in rats
  • 万方数据
    中华神经科杂志 중화신경과잡지
    Chinese Journal of Neurology
    2011年 8期 538-543 ,共6页

    李振%赵忠新%黄流清%向正华%张琳%张鹏%李雁鹏%吴惠涓%庄建华%王文昭%贺斌

    리진%조충신%황류청%향정화%장림%장붕%리안붕%오혜연%장건화%왕문소%하빈

    睡眠剥夺%认知%γ氨基丁酸%神经肽类%细胞内信号肽和蛋白质类%大鼠 睡眠剝奪%認知%γ氨基丁痠%神經肽類%細胞內信號肽和蛋白質類%大鼠
    수면박탈%인지%γ안기정산%신경태류%세포내신호태화단백질류%대서
    Sleep deprivation%Cognition%Gamma-aminobutyric acid%Neuropeptides%Intracellular signaling peptides and proteins%Rats
    目的 建立快速眼球运动(REM)睡眠剥夺和下丘脑穹隆周围核微量渗析大鼠模型,研究不同程度REM睡眠剥夺和恢复对SD大鼠认知功能、下丘脑泌素(Hcrt)能系统和γ-氨基丁酸(GABA)能系统的影响及其可能机制.方法 将雄性SD大鼠随机分为对照组和REM睡眠剥夺组,REM睡眠剥夺组又分非手术对照组(nonOP)、假手术对照组(Sham)、GABAA受体拈抗剂SR-95531组(SR)和GABA再摄取抑制剂NO-711组(NO).采用改良多平台水环境法(MMPM)建立REM睡眠剥夺SD大鼠模型,利用Morris水迷宫测定大鼠在不同程度REM睡眠剥夺对认知功能的影响变化,采用免疫荧光技术检测下丘脑Hcrt神经元数量形态和原癌基因(Fos)表达、下丘脑GABA的A型受体α1(GABAA Rα1)亚单位表达累积吸光度值;采用高效液相色谱仪(HPLC)测定下丘脑GABA和谷氨酸(Glu)含量.建立穹隆周围核微量渗析SD大鼠模型,观察GABAA受体拈抗剂SR-95531和GABA再摄取抑制剂NO-711对上述指标的影响.结果 REM睡眠剥夺导致nonOP组和Sham组SD大鼠认知功能下降、下丘脑外侧区Fos阳性细胞总数和Fos-Hcrt双阳性细胞(F+&H+)数量增加、下丘脑GABA含量和GABAA Rα1表达增加,且变化程度均与REM睡眠剥夺时间长短呈正相关.但上述指标的变化都能够在不同程度睡眠恢复后得以修正.NO组与对照组比较,睡眠剥夺期间认知功能下降、下丘脑外侧区Fos阳性细胞总数和F+&H+数量增加(F=9.56、12.14、10.12,P＜0.05),且增加程度均与REM睡眠剥夺时间长短呈正相关;但睡眠恢复后差异无统计学意义.SR组与对照组比较,睡眠剥夺期间差异无统计学意义,但睡眠恢复期间认知功能下降、下丘脑外侧区Fos阳性细胞总数和F+&H+数量增加(F=12.03、11.38、8.36,均P＜0.05).SR组GABA含量和GABAA Rα1表达在全部5个时间点均明显增加(F=11.36、14.67,均P＜0.05),而NO组仅在SD 5d的GABAA Rα1表达明显增加(F=12.06,P＜0.05).结论 在REM睡眠剥夺和恢复过程中,GABA能系统存在自身调节机制,但无论是其再摄取抑制剂NO-711还是受体竞争剂SR-95531,均对认知功能下降产生不利影响,因此GABA能系统并不是治疗失眠的最理想靶点.Hcrt能神经元系统和GABA能系统之间存在相互抑制的作用,可以通过降低Hcrt神经元激活来改善睡眠的效果.并据此推断,Hcrt能系统可能是诱导睡眠和治疗失眠的潜在理想靶点.
    목적 건립쾌속안구운동(REM)수면박탈화하구뇌궁륭주위핵미량삼석대서모형,연구불동정도REM수면박탈화회복대SD대서인지공능、하구뇌비소(Hcrt)능계통화γ-안기정산(GABA)능계통적영향급기가능궤제.방법 장웅성SD대서수궤분위대조조화REM수면박탈조,REM수면박탈조우분비수술대조조(nonOP)、가수술대조조(Sham)、GABAA수체념항제SR-95531조(SR)화GABA재섭취억제제NO-711조(NO).채용개량다평태수배경법(MMPM)건립REM수면박탈SD대서모형,이용Morris수미궁측정대서재불동정도REM수면박탈대인지공능적영향변화,채용면역형광기술검측하구뇌Hcrt신경원수량형태화원암기인(Fos)표체、하구뇌GABA적A형수체α1(GABAA Rα1)아단위표체루적흡광도치;채용고효액상색보의(HPLC)측정하구뇌GABA화곡안산(Glu)함량.건립궁륭주위핵미량삼석SD대서모형,관찰GABAA수체념항제SR-95531화GABA재섭취억제제NO-711대상술지표적영향.결과 REM수면박탈도치nonOP조화Sham조SD대서인지공능하강、하구뇌외측구Fos양성세포총수화Fos-Hcrt쌍양성세포(F+&H+)수량증가、하구뇌GABA함량화GABAA Rα1표체증가,차변화정도균여REM수면박탈시간장단정정상관.단상술지표적변화도능구재불동정도수면회복후득이수정.NO조여대조조비교,수면박탈기간인지공능하강、하구뇌외측구Fos양성세포총수화F+&H+수량증가(F=9.56、12.14、10.12,P＜0.05),차증가정도균여REM수면박탈시간장단정정상관;단수면회복후차이무통계학의의.SR조여대조조비교,수면박탈기간차이무통계학의의,단수면회복기간인지공능하강、하구뇌외측구Fos양성세포총수화F+&H+수량증가(F=12.03、11.38、8.36,균P＜0.05).SR조GABA함량화GABAA Rα1표체재전부5개시간점균명현증가(F=11.36、14.67,균P＜0.05),이NO조부재SD 5d적GABAA Rα1표체명현증가(F=12.06,P＜0.05).결론 재REM수면박탈화회복과정중,GABA능계통존재자신조절궤제,단무론시기재섭취억제제NO-711환시수체경쟁제SR-95531,균대인지공능하강산생불리영향,인차GABA능계통병불시치료실면적최이상파점.Hcrt능신경원계통화GABA능계통지간존재상호억제적작용,가이통과강저Hcrt신경원격활래개선수면적효과.병거차추단,Hcrt능계통가능시유도수면화치료실면적잠재이상파점.
    Objective To establish an animal model of rapid eye movement (REM) sleep deprivation (SD) and an animal model for perifornical nucleus microdialysis and investigate the change of cognition, hypocretinergic system and GABAergic system in rats' hypothalamus after various degrees of REM sleep deprivation and sleep revival and two GABAergic drugs intervention. Methods The modified multiple platform method (MMPM)was used to establish sleep deprivation model and the cognitive function was assessed by Morris' water maze. Immunofluorescence technique was used to analyze the number of Hypocretin (Hcrt) immunoreactive neurons, total Fos immunoreactive neurons, Hcrt and Fos colabeled neurons, and the integrated optical density ( IA ) of GABAA Rαl immunoreactive area in rats' hypothalamus.High performance liquid chromatograph (HPLC) was used to quantitatively analyze the level of GABA and Gluin in the rats' hypothalamus. Two GABAergic drugs, a selective GABAA R antagonist, SR-95531, and a selective blocker of type 1 GABA transporter (uptake blocker), NO-711, were used for perifornical nucleus microdialysis. Results There was no statistically significant difference in tests between CC and TC ( Define CC and TC). There was a significant decrease (P ＜ 0. 05 ) of cognitive function measured by Morris maze test in SD 3 d, SD 5 d and RS 6 h of SD groups compared with CC and TC groups. Number of Fos immunoreactive, F+ &H+ immunoreactive neuronsand IA of GABAA Rαl immunoreactive area were all significantly increased ( P ＜ 0. 05 ). Content of GABA measured by HPLC was also increased ( P ＜ 0. 05 ). However, all these changes were partly reversed by sleep revival SR-95531 and NO-711 had different effect on these changes. Conclusions Sleep deprivation, no matter mild or severe, has adverse effects on cognitive function. Activities of both GABAergic and Hcrtergic system are increased during REMSD. These two neurons system could be regulated by each other and the relationship between them is positive correlation. GABAergic system also had self-regulation during REMSD, but microdialysision of either SR-95531 or NO-711 acquired adverse effects on cognitive function of rats. So GABAergic system is not an optimal therapeutic target. Because GABAergic and Hcrtergic system has inhibitory effect on each other,suppressing activity of Hcrtergic system might be a promising therapeutic target.
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