缰核在视交叉上核—松果体昼夜节律控制系统中的作用研究
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摘要
昼夜节律是生物的基本生命特征之一,它的稳定是机体正常生理功能进行的基础。许多资料证明:外界光照可通过下丘脑视交叉上核(SCN)和松果体(PG)来调节昼夜节律,并使内源性昼夜节律和环境的24小时昼夜节律同步,提示SCN和PG在机体昼夜节律的调节中起重要作用,缰核(Hb)密切联系这两个结构,并且Hb本身也有视网膜纤维投射,因此,Hb可能介导SCN—PG昼夜节律的信息传递,与SCN和PG等结构共同组成中枢昼夜节律控制系统。
本实验首先应用电生理学方法,观察电刺激或化学刺激兴奋SCN及化学阻断SCN,对外侧缰核(LHb)和内侧缰核(MHb)神经元自发放电的影响,从细胞水平弄清SCN与Hb间的功能联系。进一步应用逆转录聚合酶链法(RT-PCR),在海人酸(KA)损毁LHb2周后,检测SCN和PG在六个不同时间点的时钟基因Per2、Bmal1和Clock mRNA的表达水平,以及褪黑素(MT)合成限速酶N-乙酰转移酶(NAT)及其受体MT1和MT2 mRNA的表达水平。探讨SCN和PG的昼夜节律相关基因和物质的表达是否需要有Hb的存在,从另一角度明确Hb的作用。
实验结果显示:50%Hb神经元对SCN刺激有反应,且不同部位的Hb神经元对SCN刺激的电生理反应不同,即MHb主要表现为抑制,而LHb则没有明显趋势,但SCN被阻断后对LHb起抑制效应;LHb损毁后PG和SCN内NAT以及MT1、MT2 mRNA在不同时间点的表达多下调,但其表达的周期没有改变;SCN和PG中时钟基因Per2、Bmal1和Clock的昼夜表达水平,在损毁组也多显著下降,但其周期也无变化。以上结果提示LHb与SCN和PG之间具有密切的功能联系,LHb可通过影响PG活动进而影响SCN的功能,同时LHb也接受SCN和PG的调控。LHb可能通过影响PG内褪黑素的合成及其受体的表达,进而影响时钟基因的表达,参与中枢昼夜节律调节,成为中枢昼夜节律调控系统组构中的重要成分。
Biological rhythm is one of the characteristics of life. In the occurrence and biological evolution, the organism formed the endogenous rhythm which sychronous with seasonal changes of the natural environment in order to adapt to the changes of the environment. But it is different from the rhythm of the natural environment in the time features. As the result of organisms living in the light-dark cycle of day and night environment, many activities of lives have shown 24h cycle of biological rhythm—the circadian rhythm. Cirdadian rhythm is the strongest biological rhythm of the body. Many physiological and biochemical parameters of body are changed following the circadian rhythm.
In mammals, the circadian rhythm exists widespreadly on the level of cells, tissues and organs. There is a complex control system to regulate it. The suprachiasmatic nucleus (SCN) of hypothalamus is the circadian pacemaker of mammalian. The oscillation of variety of circadian clock gene of the SCN is the basis of circadian rhythm. Pineal gland (PG) is an important target of SCN integration. The melatonin (MT) is produced by PG. As the most important zeitgeber of the body, MT could act on SCN to induce the changes of circadian rhythm and this effect has phase-dependence. The SCN-PG as the most important control system of circadian rhythm controls the input, oscillation and output process of circadian rhythm.
The habenular nucleus (Hb) which located behind the hypothalamus is the major relay station between forebrain and midbrain. The vasopressin nerve fibers relationship between the Hb and the SCN had been proved. And the Hb also could get indirect relationship with the SCN via preoptic area and rapheal nuclei. The Hb has a close relationship with the PG both morphologically and functionally. The stimulation of the Hb can influence the firing rate of PG neurons. The Hb, especially the medial part of lateral Hb contains abundant of MT receptors. It suggests that the Hb is an important target of PG. The Hb could project to PG. And the Hb also can get relationship with the SCN via PG to regulate the circadian rhythm.
In this study, we observed the changes of spontaneous firing rate of LHb and MHb neurons after elctric stimulating or microinjection of Glu/Lid into the SCN by extracellular recording. We observed the mRNA expression of Per2, Clock and Bmal1 in SCN and PG by RT-polymerase chain reaction (RT-PCR) after chemical destroied LHb by kainic acid (KA). And the expression level changes of melatonin synthesis limited enzyme—NAT, and its receptors MT1, MT2 at 8:00, 12:00, 16:00, 20:00, 24:00 and 4:00. The results are as followed:
1. The firing rate of 46 neurons were recorded when electric stimulate SCN. Among them 8 neurons were excited in LHb, 7 neurons were inhibited in LHb, 3 neurons were excited in MHb and 4 neurons were inhibited in MHb. There are no significant difference between LHb and MHb (P>0.05).
2. The firing rate of 105 neurons were recorded after microinjection of Glu into SCN. 13 of these neurons were excited and 15 of them were inhibited in LHb after micrinjection. 7 of these neurons were excited and 26 of these neurons were inhibited in MHb after microinjection. Excited SCN could inhibit the activities of MHb (P<0.05).
3. The firing rate of 49 neurons were recorded after microinjection of Lid into SCN. In LHb, 3 of them were exctied and 7 of them were inhibited. In MHb, 11 of neurons were excited and 4 of them were inhibited. Inhibition of SCN could excite the MHb and inhibit the LHb (P<0.05).
4. The day and night oscillate rhythm of clock gene Per2, Bmall and Clock in SCN were not changed . But the mRNA of Per2 were decreased at all of six points. The mRNA of Bmall were decreased at 8:00, 16:00, 20:00 and 4:00. The mRNA of Clock were decreased at 8:00, 12:00, 16:00, 20:00 and 4:00.(P<0.05)
5. The circadian rhythm of clock gene Per2, Bmall and Clock in PG were not changed. But the mRNA of Per2 were decreased at 8:00, 12:00, 24:00. The mRNA of Bmall were decreased at 12:00, 16:00, 20:00 and 4:00. The mRNA of Clock were decreased at all of six points (8:00, 12:00, 16:00, 20:00, 24:00 and 4:00).(P<0.05)
6. The expression of MT related gene NAT, MT1 and MT2 in SCN were decreased in lesion groups at all of six points, but the day and night oscillate rhythm was not changed. The decrease of NAT was occurred at all of six points. The decrease of MT1 occurred at 8:00, 12:00, 20:00, 24:00 and 4:00. The decrease of MT2 was occurred at 12:00, 16:00, 20:00, 24:00 and 4:00. (P<0.05)
7. In PG, the expression of MT related gene NAT, MT1 and MT2 were decreased in lesion groups. But the circadian rhythm of them were not changed. The points of change of NAT are 8:00, 16:00, 20:00, 24:00. The changed points of MT1 are 8:00, 12:00 and 4:00. The changed point of MT2 is 24:00. (P<0.05)
We have confirmed that there is a functional relationship between the Hb and SCN by elctrophysiological methods. Coupled with the results of RT-PCR, we further prove that chemical lesions of the LHb can decrease the expression of clock genes in SCN and PG, but can not change their circadian rhythm. The mechanism is implicated in the effect of the LHb on the synthesis of melatonin in the PG which may further induceof the change of clock genes expression in the SCN. Thus, the LHb can affect the function of the SCN through the effect of the LHb on the activities of the PG; in turn, the Hb is also controlled by the SCN and PG. These studies suggest that the LHb is an important component of the central circadian rhythm control system and the Hb participates in the circadian rhythm regulation through the functional interaction with the SCN and PG.
本实验首先应用电生理学方法,观察电刺激或化学刺激兴奋SCN及化学阻断SCN,对外侧缰核(LHb)和内侧缰核(MHb)神经元自发放电的影响,从细胞水平弄清SCN与Hb间的功能联系。进一步应用逆转录聚合酶链法(RT-PCR),在海人酸(KA)损毁LHb2周后,检测SCN和PG在六个不同时间点的时钟基因Per2、Bmal1和Clock mRNA的表达水平,以及褪黑素(MT)合成限速酶N-乙酰转移酶(NAT)及其受体MT1和MT2 mRNA的表达水平。探讨SCN和PG的昼夜节律相关基因和物质的表达是否需要有Hb的存在,从另一角度明确Hb的作用。
实验结果显示:50%Hb神经元对SCN刺激有反应,且不同部位的Hb神经元对SCN刺激的电生理反应不同,即MHb主要表现为抑制,而LHb则没有明显趋势,但SCN被阻断后对LHb起抑制效应;LHb损毁后PG和SCN内NAT以及MT1、MT2 mRNA在不同时间点的表达多下调,但其表达的周期没有改变;SCN和PG中时钟基因Per2、Bmal1和Clock的昼夜表达水平,在损毁组也多显著下降,但其周期也无变化。以上结果提示LHb与SCN和PG之间具有密切的功能联系,LHb可通过影响PG活动进而影响SCN的功能,同时LHb也接受SCN和PG的调控。LHb可能通过影响PG内褪黑素的合成及其受体的表达,进而影响时钟基因的表达,参与中枢昼夜节律调节,成为中枢昼夜节律调控系统组构中的重要成分。
Biological rhythm is one of the characteristics of life. In the occurrence and biological evolution, the organism formed the endogenous rhythm which sychronous with seasonal changes of the natural environment in order to adapt to the changes of the environment. But it is different from the rhythm of the natural environment in the time features. As the result of organisms living in the light-dark cycle of day and night environment, many activities of lives have shown 24h cycle of biological rhythm—the circadian rhythm. Cirdadian rhythm is the strongest biological rhythm of the body. Many physiological and biochemical parameters of body are changed following the circadian rhythm.
In mammals, the circadian rhythm exists widespreadly on the level of cells, tissues and organs. There is a complex control system to regulate it. The suprachiasmatic nucleus (SCN) of hypothalamus is the circadian pacemaker of mammalian. The oscillation of variety of circadian clock gene of the SCN is the basis of circadian rhythm. Pineal gland (PG) is an important target of SCN integration. The melatonin (MT) is produced by PG. As the most important zeitgeber of the body, MT could act on SCN to induce the changes of circadian rhythm and this effect has phase-dependence. The SCN-PG as the most important control system of circadian rhythm controls the input, oscillation and output process of circadian rhythm.
The habenular nucleus (Hb) which located behind the hypothalamus is the major relay station between forebrain and midbrain. The vasopressin nerve fibers relationship between the Hb and the SCN had been proved. And the Hb also could get indirect relationship with the SCN via preoptic area and rapheal nuclei. The Hb has a close relationship with the PG both morphologically and functionally. The stimulation of the Hb can influence the firing rate of PG neurons. The Hb, especially the medial part of lateral Hb contains abundant of MT receptors. It suggests that the Hb is an important target of PG. The Hb could project to PG. And the Hb also can get relationship with the SCN via PG to regulate the circadian rhythm.
In this study, we observed the changes of spontaneous firing rate of LHb and MHb neurons after elctric stimulating or microinjection of Glu/Lid into the SCN by extracellular recording. We observed the mRNA expression of Per2, Clock and Bmal1 in SCN and PG by RT-polymerase chain reaction (RT-PCR) after chemical destroied LHb by kainic acid (KA). And the expression level changes of melatonin synthesis limited enzyme—NAT, and its receptors MT1, MT2 at 8:00, 12:00, 16:00, 20:00, 24:00 and 4:00. The results are as followed:
1. The firing rate of 46 neurons were recorded when electric stimulate SCN. Among them 8 neurons were excited in LHb, 7 neurons were inhibited in LHb, 3 neurons were excited in MHb and 4 neurons were inhibited in MHb. There are no significant difference between LHb and MHb (P>0.05).
2. The firing rate of 105 neurons were recorded after microinjection of Glu into SCN. 13 of these neurons were excited and 15 of them were inhibited in LHb after micrinjection. 7 of these neurons were excited and 26 of these neurons were inhibited in MHb after microinjection. Excited SCN could inhibit the activities of MHb (P<0.05).
3. The firing rate of 49 neurons were recorded after microinjection of Lid into SCN. In LHb, 3 of them were exctied and 7 of them were inhibited. In MHb, 11 of neurons were excited and 4 of them were inhibited. Inhibition of SCN could excite the MHb and inhibit the LHb (P<0.05).
4. The day and night oscillate rhythm of clock gene Per2, Bmall and Clock in SCN were not changed . But the mRNA of Per2 were decreased at all of six points. The mRNA of Bmall were decreased at 8:00, 16:00, 20:00 and 4:00. The mRNA of Clock were decreased at 8:00, 12:00, 16:00, 20:00 and 4:00.(P<0.05)
5. The circadian rhythm of clock gene Per2, Bmall and Clock in PG were not changed. But the mRNA of Per2 were decreased at 8:00, 12:00, 24:00. The mRNA of Bmall were decreased at 12:00, 16:00, 20:00 and 4:00. The mRNA of Clock were decreased at all of six points (8:00, 12:00, 16:00, 20:00, 24:00 and 4:00).(P<0.05)
6. The expression of MT related gene NAT, MT1 and MT2 in SCN were decreased in lesion groups at all of six points, but the day and night oscillate rhythm was not changed. The decrease of NAT was occurred at all of six points. The decrease of MT1 occurred at 8:00, 12:00, 20:00, 24:00 and 4:00. The decrease of MT2 was occurred at 12:00, 16:00, 20:00, 24:00 and 4:00. (P<0.05)
7. In PG, the expression of MT related gene NAT, MT1 and MT2 were decreased in lesion groups. But the circadian rhythm of them were not changed. The points of change of NAT are 8:00, 16:00, 20:00, 24:00. The changed points of MT1 are 8:00, 12:00 and 4:00. The changed point of MT2 is 24:00. (P<0.05)
We have confirmed that there is a functional relationship between the Hb and SCN by elctrophysiological methods. Coupled with the results of RT-PCR, we further prove that chemical lesions of the LHb can decrease the expression of clock genes in SCN and PG, but can not change their circadian rhythm. The mechanism is implicated in the effect of the LHb on the synthesis of melatonin in the PG which may further induceof the change of clock genes expression in the SCN. Thus, the LHb can affect the function of the SCN through the effect of the LHb on the activities of the PG; in turn, the Hb is also controlled by the SCN and PG. These studies suggest that the LHb is an important component of the central circadian rhythm control system and the Hb participates in the circadian rhythm regulation through the functional interaction with the SCN and PG.
引文
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