下丘脑弓状核—外侧隔核ghrelin通路构成及对胃运动调控研究
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摘要
目的：
Ghrelin是生长激素促分泌素受体(GHS-R)的内源性配体,具有多种生物学活性,如促进生长激素(GH)分泌、摄食及胃肠运动等。Ghrelin及其受体在中枢神经系统特别是与摄食和食欲调控相关中枢广泛分布。本实验将定位于下丘脑弓状核(ARC)和外侧隔核：①观察外侧隔核ghrelin及其受体GHSR-la的表达；研究下丘脑ARC_外侧隔核ghrelin神经通路的构成；②探讨ghrelin对外侧隔核胃扩张(GD)敏感神经元放电活动的影响,以及下丘脑ARC对其调控作用,阐明下丘脑ARC-外侧隔核ghrelin功能通路的构成；③探讨下丘脑ARC-外侧隔核ghrelin通路对胃运动的调控作用,补充和完善胃运动调控的中枢机制。
方法：
1.采用聚合酶链反应(PCR)、 Western blot和荧光免疫组化研究,观察ghrelin及其受体GHSR-1a在外侧隔核的定位和定性表达；采用荧光金(FG)逆行追踪结合荧光免疫组化技术,观察下丘脑ARC→外侧隔核ghrelin神经通路的构成。
2.采用核团微量注射、核团电刺激、细胞外放电记录方法,观察ghrelin及其受体拮抗剂[D-Lys-3]-GHRP-6,以及电刺激ARC对外侧隔核GD敏感神经元放电活动的影响。
3.采用核团电刺激、核团电损毁、在体胃运动等方法,观察外侧隔核微量注射ghrelin、电刺激ARC以及电损毁外侧隔核对清醒大鼠胃运动的影响；采用实时荧光定量PCR (Real-time PCR)和Western blot方法,观察电刺激/IRC对外侧隔核ghrelin及其受体GHSR-1a mRN A和蛋白表达水平的影响。
结果：
1.大鼠外侧隔核有ghrelin及其受体GHSR-1a的表达；ghrelin免疫阳性神经元主要分布于外侧隔核的背侧区和中间区,而GHSR-1a免疫阳性神经元分布于外侧隔核的背侧区、中间区和腹侧区。
2.下丘脑ARC发出纤维投射至外侧隔核,并呈同侧投射优势；下丘脑ARC有ghrelin免疫阳性神经元向外侧隔核的投射。
3.外侧隔核共记录到123个GD敏感神经元,其中59个(47.97%)为GD兴奋神经元(GD-E),64个(52.03%)为GD抑制神经元(GD-I),提示外侧隔核可接受来自胃肠道的传入信息。
4.外侧隔核给予ghrelin后,71.19%的GD-E神经元兴奋,放电频率从5.82±1.22Hz升高到8.20±1.68Hz(P<0.01);75.56%的GD-Ⅰ神经元兴奋,放电频率从5.30±1.61Hz升高到7.27±1.95Hz (P<0.01).这一兴奋作用可被外侧隔核预先给予ghrelin受体拮抗齐[D-Lys-3]-GHRP-6完全阻断(P<0.01)。电刺激ARC,外侧隔核对ghrelin有反应的神经元中,66.67%的GD-E神经元兴奋,放电频率从4.88±1.32Hz升高到7.69±2.48Hz (P<0.01);65.31%的GD-Ⅰ神经元被激活,放电频率从5.04±1.74Hz增加到7.08±1.15Hz (P<0.01).电刺激ARC的这一兴奋作用可被外侧隔核预先给予[D-Lys-3]-GHRP-6部分阻断(P<0.05)。外侧隔核单独给予[D-Lys-3]-GHRP-6或NS则无显著影响(P>0.05)。
5.外侧隔核微量注射ghrelin,大约5min后胃收缩幅度和频率显著增加,并呈现剂量依赖关系(P<0.05-0.01);外侧隔核给予ghrelin及其受体拮抗剂[D-Lys-3]-GHRP-6混合液,ghrelin促进胃运动的兴奋作用消失(P<0.05-0.01)。电刺激ARC,3-23min期间胃收缩幅度和频率显著增加(P<0.05-0.01)；外侧隔核预先给予ghrelin受体拮抗剂[D-Lys-3]-GHRP-6,电刺激ARC的这一兴奋作用显著减弱(P<0.05-0.01)。外侧隔核单独给予[D-Lys-3]-GHRP-6或NS对胃运动则无显著影响(P>0.05)。
6.电损毁外侧隔核,胃收缩强度为26.85±9.76g,与假损毁组(40.66±10.03g)比较显著下降(P<0.05)；电损毁外侧隔核,再电刺激ARC,胃收缩幅度和频率与假损毁+假电刺激组比较显著升高(P<0.05-0.01),但与假损毁+电刺激组比较则有所下降,但无统计学意义(P>0.05)。
7.电刺激ARC,外侧隔核ghrelin表达显著增加(P<0.05)；但ghrelin mRNA, GHSR-1a mRNA及其蛋白表达均无显著改变(P>0.05)。
结论：
1.外侧隔核有ghrelin及其受体GHSR-la的表达。
2.下丘脑ARC ghrelin免疫阳性神经元可发出纤维投向外侧隔核。
3.外侧隔核可接受胃传入信息并参与胃运动的调控。
4. Ghrelin在外侧隔核可兴奋GD-E和GD-Ⅰ神经元,并可促进胃运动,下丘脑ARC参与该过程调控。
5. Ghrelin参与下丘脑ARC-外侧隔核信息传递及胃运动的调控。
Objective
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). It has been known as a multifunctional hormone, such as increasing secretion of growth hormone (GH), food intake and gastric motility. Ghrelin and its receptor distribute widely in the central nervous system especially those related with feeding and appetite. The study focuses on the hypothalamic arcuate nucleus (ARC) and the lateral septum:①to observe the expression of ghrelin and its receptor GHSR-la in the lateral septum; to study the constitute of ghrelin neuronal pathway from the ARC to the lateral septum;②to explore the effects of ghrelin on the discharge activities of gastric distension (GD) responsive neurons in the lateral septum and the regulation by the ARC; to illustrate the constitute of ghrelin functional pathway from the ARC to the lateral septum;③to explore the regulation of ghrelin pathway from the ARC to the lateral septum on the gastric motility so as to supplement and complete the central mechanisms of gastric motility regulation.
Methods
1. The expressions of ghrelin and its receptor GHSR-1a in the lateral septum were detected by polymerase chain reaction (PCR), western blot and fluo-immunohistochemistry staining techniques respectively. The constitute of ghrelin neuronal pathway from the ARC to the lateral septum were observed by retrograde tracer deposits of Fluoro-Gold (FG) and fluo-immunohistochemistry staining.
2. Nuclei microinjection, electrical stimulation and extracellular discharge recording methods were employed to observe the effects of ghrelin and its receptor antagonist [D-Lys-3]-GHRP-6and electrical stimulating the ARC on the discharge activities of GD neurons in the lateral septum.
3. Electrical stimulation/lesion and gastric motility recording methods were employed to observe the effects of ghrelin administration into the lateral septum, electrical stimulating the ARC and electrical lesion of the lateral septum on the gastric motility in the conscious rats. The effects of electrical stimulating ARC on the mRNA and protein expression of ghrelin and its receptor GHSR-1a in the lateral septum were observed by Real-time PCR and western blot ananlysis.
Results
1. Ghrelin and its receptor GHSR-1a were expressed in the lateral septum. Ghrelin-immonoreactive (IR) neurons mainly located in the dorsal and intermedial part of the lateral septum, while GHSR-1a-IR neurons were widely distributed in the dorsal, intermedial and ventral part of the lateral septum.
2. Hypothalamic ARC sent axons projecting to the lateral septum, and was ipsilateral projection advantages. There were ghrelin-IR neurons arised from the hypothalamic ARC projecting to the lateral septum.
3. One hundred and twenty-three GD neurons were recorded in the lateral septum. Out of them there were59(47.97%) identified as GD-excitatory (GD-E) neurons and64(52.03%) were GD-inhibited (GD-I) neurons, indicating that the lateral septum could receive the afferent information from the gastrointestinal tract.
4. After administration of ghrelin in the lateral septum,71.19%GD-E were activated with firing frequency increased from5.82±1.22Hz to8.20±1.68Hz (P<0.01), and75.56%GD-I were activated with firing frequency increased from5.30±1.61Hz to7.27±1.95Hz (P<0.01). The excitatory effects induced by ghrelin could be completely abolished by pretreatment with ghrelin receptor antagonist [D-Lys-3]-GHRP-6(P<0.01). After electrical stimulating the ARC,66.67%GD-E neurons excited by ghrelin in the lateral septum were activated with firing frequency increased from4.88±1.32Hz to7.69±2.48Hz (P<0.01), and65.31%GD-I neurons were excited with firing frequency increased from5.04±1.74Hz to7.08±1.15Hz (P<0.01). The effects induced by electrical stimulating the ARC were partially blocked by pretreatment with ghrelin receptor antagonist [D-Lys-3]-GHRP-6to the lateral septum (P<0.05).[D-Lys-3]-GHRP-6or NS administration singly to the lateral septum had no significant effect on the GD neurons in the lateral septum (P>0.05).
5. The frequency and amplitude of the gastric contraction were significantly increased from5min after administration of ghrelin in the lateral septum with a dose dependent manner (P<0.05-0.01). The promotion effects of ghrelin on the gastric motility disappeared when ghrelin and its receptor antagonist [D-Lys-3]-GHRP-6mixture were administrated to the lateral septum (P<0.05-0.01). The frequency and amplitude of gastric contraction were significantly increased during3-23min period after electrical stimulating the ARC (P<0.05-0.01). The excitatory effects induced by electrical stimulating the ARC were significantly diminished by pretreatment with [D-Lys-3]-GHRP-6to the lateral septum (P<0.05).[D-Lys-3]-GHRP-6or NS administration singly to the lateral septum had no effect on the gastric motility (P>0.05).
6. The gastric contraction intensity in the electrical lesion of the lateral septum significantly decreased compared with the sham lesion group (P<0.0.5,26.85±9.76g versus40.66±10.03g). Electrical stimulating the ARC after electrical lesion of the lateral septum resulted in the increasement of the amplitude and frequency of gastric contraction compared with the sham electrical lesion+sham electrical stimulaton group (P<0.05-0.01). When compared with the sham electrical lesion+electrical stimulation group, the amplitude and frequency of the gastric contraction decreased but had no statistical significance (P>0.05).
7. Electrical stimulating the ARC significantly increased the expression of ghrelin in the lateral septum (P<0.05), while the expression of ghrelin mRNA, GHSR-1a mRNA and protein had no significant change (P>0.05).
Conclusions
1. Ghrelin and its receptor GHSR-la were expressed in the lateral septum.
2. Ghrelin-IR neurons in the hypothalamic ARC could send axons to the lateral septum.
3. The lateral septum could accept the afferent information from the stomach and participate in the regulation of the gastric motility.
4. Ghrelin in the lateral septum could excite the GD-E and GD-I neurons and promote the gastric motility, which could be regulated by the hypothalamic ARC.
5. Ghrelin may involve in the information transduction and regulation of the gastric motility by the hypothalamic ARC to the lateral septum pathway.
Ghrelin是生长激素促分泌素受体(GHS-R)的内源性配体,具有多种生物学活性,如促进生长激素(GH)分泌、摄食及胃肠运动等。Ghrelin及其受体在中枢神经系统特别是与摄食和食欲调控相关中枢广泛分布。本实验将定位于下丘脑弓状核(ARC)和外侧隔核：①观察外侧隔核ghrelin及其受体GHSR-la的表达；研究下丘脑ARC_外侧隔核ghrelin神经通路的构成；②探讨ghrelin对外侧隔核胃扩张(GD)敏感神经元放电活动的影响,以及下丘脑ARC对其调控作用,阐明下丘脑ARC-外侧隔核ghrelin功能通路的构成；③探讨下丘脑ARC-外侧隔核ghrelin通路对胃运动的调控作用,补充和完善胃运动调控的中枢机制。
方法：
1.采用聚合酶链反应(PCR)、 Western blot和荧光免疫组化研究,观察ghrelin及其受体GHSR-1a在外侧隔核的定位和定性表达；采用荧光金(FG)逆行追踪结合荧光免疫组化技术,观察下丘脑ARC→外侧隔核ghrelin神经通路的构成。
2.采用核团微量注射、核团电刺激、细胞外放电记录方法,观察ghrelin及其受体拮抗剂[D-Lys-3]-GHRP-6,以及电刺激ARC对外侧隔核GD敏感神经元放电活动的影响。
3.采用核团电刺激、核团电损毁、在体胃运动等方法,观察外侧隔核微量注射ghrelin、电刺激ARC以及电损毁外侧隔核对清醒大鼠胃运动的影响；采用实时荧光定量PCR (Real-time PCR)和Western blot方法,观察电刺激/IRC对外侧隔核ghrelin及其受体GHSR-1a mRN A和蛋白表达水平的影响。
结果：
1.大鼠外侧隔核有ghrelin及其受体GHSR-1a的表达；ghrelin免疫阳性神经元主要分布于外侧隔核的背侧区和中间区,而GHSR-1a免疫阳性神经元分布于外侧隔核的背侧区、中间区和腹侧区。
2.下丘脑ARC发出纤维投射至外侧隔核,并呈同侧投射优势；下丘脑ARC有ghrelin免疫阳性神经元向外侧隔核的投射。
3.外侧隔核共记录到123个GD敏感神经元,其中59个(47.97%)为GD兴奋神经元(GD-E),64个(52.03%)为GD抑制神经元(GD-I),提示外侧隔核可接受来自胃肠道的传入信息。
4.外侧隔核给予ghrelin后,71.19%的GD-E神经元兴奋,放电频率从5.82±1.22Hz升高到8.20±1.68Hz(P<0.01);75.56%的GD-Ⅰ神经元兴奋,放电频率从5.30±1.61Hz升高到7.27±1.95Hz (P<0.01).这一兴奋作用可被外侧隔核预先给予ghrelin受体拮抗齐[D-Lys-3]-GHRP-6完全阻断(P<0.01)。电刺激ARC,外侧隔核对ghrelin有反应的神经元中,66.67%的GD-E神经元兴奋,放电频率从4.88±1.32Hz升高到7.69±2.48Hz (P<0.01);65.31%的GD-Ⅰ神经元被激活,放电频率从5.04±1.74Hz增加到7.08±1.15Hz (P<0.01).电刺激ARC的这一兴奋作用可被外侧隔核预先给予[D-Lys-3]-GHRP-6部分阻断(P<0.05)。外侧隔核单独给予[D-Lys-3]-GHRP-6或NS则无显著影响(P>0.05)。
5.外侧隔核微量注射ghrelin,大约5min后胃收缩幅度和频率显著增加,并呈现剂量依赖关系(P<0.05-0.01);外侧隔核给予ghrelin及其受体拮抗剂[D-Lys-3]-GHRP-6混合液,ghrelin促进胃运动的兴奋作用消失(P<0.05-0.01)。电刺激ARC,3-23min期间胃收缩幅度和频率显著增加(P<0.05-0.01)；外侧隔核预先给予ghrelin受体拮抗剂[D-Lys-3]-GHRP-6,电刺激ARC的这一兴奋作用显著减弱(P<0.05-0.01)。外侧隔核单独给予[D-Lys-3]-GHRP-6或NS对胃运动则无显著影响(P>0.05)。
6.电损毁外侧隔核,胃收缩强度为26.85±9.76g,与假损毁组(40.66±10.03g)比较显著下降(P<0.05)；电损毁外侧隔核,再电刺激ARC,胃收缩幅度和频率与假损毁+假电刺激组比较显著升高(P<0.05-0.01),但与假损毁+电刺激组比较则有所下降,但无统计学意义(P>0.05)。
7.电刺激ARC,外侧隔核ghrelin表达显著增加(P<0.05)；但ghrelin mRNA, GHSR-1a mRNA及其蛋白表达均无显著改变(P>0.05)。
结论：
1.外侧隔核有ghrelin及其受体GHSR-la的表达。
2.下丘脑ARC ghrelin免疫阳性神经元可发出纤维投向外侧隔核。
3.外侧隔核可接受胃传入信息并参与胃运动的调控。
4. Ghrelin在外侧隔核可兴奋GD-E和GD-Ⅰ神经元,并可促进胃运动,下丘脑ARC参与该过程调控。
5. Ghrelin参与下丘脑ARC-外侧隔核信息传递及胃运动的调控。
Objective
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). It has been known as a multifunctional hormone, such as increasing secretion of growth hormone (GH), food intake and gastric motility. Ghrelin and its receptor distribute widely in the central nervous system especially those related with feeding and appetite. The study focuses on the hypothalamic arcuate nucleus (ARC) and the lateral septum:①to observe the expression of ghrelin and its receptor GHSR-la in the lateral septum; to study the constitute of ghrelin neuronal pathway from the ARC to the lateral septum;②to explore the effects of ghrelin on the discharge activities of gastric distension (GD) responsive neurons in the lateral septum and the regulation by the ARC; to illustrate the constitute of ghrelin functional pathway from the ARC to the lateral septum;③to explore the regulation of ghrelin pathway from the ARC to the lateral septum on the gastric motility so as to supplement and complete the central mechanisms of gastric motility regulation.
Methods
1. The expressions of ghrelin and its receptor GHSR-1a in the lateral septum were detected by polymerase chain reaction (PCR), western blot and fluo-immunohistochemistry staining techniques respectively. The constitute of ghrelin neuronal pathway from the ARC to the lateral septum were observed by retrograde tracer deposits of Fluoro-Gold (FG) and fluo-immunohistochemistry staining.
2. Nuclei microinjection, electrical stimulation and extracellular discharge recording methods were employed to observe the effects of ghrelin and its receptor antagonist [D-Lys-3]-GHRP-6and electrical stimulating the ARC on the discharge activities of GD neurons in the lateral septum.
3. Electrical stimulation/lesion and gastric motility recording methods were employed to observe the effects of ghrelin administration into the lateral septum, electrical stimulating the ARC and electrical lesion of the lateral septum on the gastric motility in the conscious rats. The effects of electrical stimulating ARC on the mRNA and protein expression of ghrelin and its receptor GHSR-1a in the lateral septum were observed by Real-time PCR and western blot ananlysis.
Results
1. Ghrelin and its receptor GHSR-1a were expressed in the lateral septum. Ghrelin-immonoreactive (IR) neurons mainly located in the dorsal and intermedial part of the lateral septum, while GHSR-1a-IR neurons were widely distributed in the dorsal, intermedial and ventral part of the lateral septum.
2. Hypothalamic ARC sent axons projecting to the lateral septum, and was ipsilateral projection advantages. There were ghrelin-IR neurons arised from the hypothalamic ARC projecting to the lateral septum.
3. One hundred and twenty-three GD neurons were recorded in the lateral septum. Out of them there were59(47.97%) identified as GD-excitatory (GD-E) neurons and64(52.03%) were GD-inhibited (GD-I) neurons, indicating that the lateral septum could receive the afferent information from the gastrointestinal tract.
4. After administration of ghrelin in the lateral septum,71.19%GD-E were activated with firing frequency increased from5.82±1.22Hz to8.20±1.68Hz (P<0.01), and75.56%GD-I were activated with firing frequency increased from5.30±1.61Hz to7.27±1.95Hz (P<0.01). The excitatory effects induced by ghrelin could be completely abolished by pretreatment with ghrelin receptor antagonist [D-Lys-3]-GHRP-6(P<0.01). After electrical stimulating the ARC,66.67%GD-E neurons excited by ghrelin in the lateral septum were activated with firing frequency increased from4.88±1.32Hz to7.69±2.48Hz (P<0.01), and65.31%GD-I neurons were excited with firing frequency increased from5.04±1.74Hz to7.08±1.15Hz (P<0.01). The effects induced by electrical stimulating the ARC were partially blocked by pretreatment with ghrelin receptor antagonist [D-Lys-3]-GHRP-6to the lateral septum (P<0.05).[D-Lys-3]-GHRP-6or NS administration singly to the lateral septum had no significant effect on the GD neurons in the lateral septum (P>0.05).
5. The frequency and amplitude of the gastric contraction were significantly increased from5min after administration of ghrelin in the lateral septum with a dose dependent manner (P<0.05-0.01). The promotion effects of ghrelin on the gastric motility disappeared when ghrelin and its receptor antagonist [D-Lys-3]-GHRP-6mixture were administrated to the lateral septum (P<0.05-0.01). The frequency and amplitude of gastric contraction were significantly increased during3-23min period after electrical stimulating the ARC (P<0.05-0.01). The excitatory effects induced by electrical stimulating the ARC were significantly diminished by pretreatment with [D-Lys-3]-GHRP-6to the lateral septum (P<0.05).[D-Lys-3]-GHRP-6or NS administration singly to the lateral septum had no effect on the gastric motility (P>0.05).
6. The gastric contraction intensity in the electrical lesion of the lateral septum significantly decreased compared with the sham lesion group (P<0.0.5,26.85±9.76g versus40.66±10.03g). Electrical stimulating the ARC after electrical lesion of the lateral septum resulted in the increasement of the amplitude and frequency of gastric contraction compared with the sham electrical lesion+sham electrical stimulaton group (P<0.05-0.01). When compared with the sham electrical lesion+electrical stimulation group, the amplitude and frequency of the gastric contraction decreased but had no statistical significance (P>0.05).
7. Electrical stimulating the ARC significantly increased the expression of ghrelin in the lateral septum (P<0.05), while the expression of ghrelin mRNA, GHSR-1a mRNA and protein had no significant change (P>0.05).
Conclusions
1. Ghrelin and its receptor GHSR-la were expressed in the lateral septum.
2. Ghrelin-IR neurons in the hypothalamic ARC could send axons to the lateral septum.
3. The lateral septum could accept the afferent information from the stomach and participate in the regulation of the gastric motility.
4. Ghrelin in the lateral septum could excite the GD-E and GD-I neurons and promote the gastric motility, which could be regulated by the hypothalamic ARC.
5. Ghrelin may involve in the information transduction and regulation of the gastric motility by the hypothalamic ARC to the lateral septum pathway.
引文
1. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach[J]. Nature(Lond),1999,402 (6762):656-660.
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