Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors.
Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors.
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DOI：
10.1016/j.bbrc.2018.01.145
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发表时间：
2018-02
影响因子：
3.1
通讯作者：
Yukari Suda;N. Kuzumaki;Michiko Narita;Yusuke Hamada;M. Shibasaki;Kenichi Tanaka;H. Tamura;T. Kawamura;T. Kondo;A. Yamanaka;M. Narita
中科院分区：
文献类型：
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作者：
Yukari Suda;N. Kuzumaki;Michiko Narita;Yusuke Hamada;M. Shibasaki;Kenichi Tanaka;H. Tamura;T. Kawamura;T. Kondo;A. Yamanaka;M. Narita
Ghrelin通过激活生长激素促分泌素受体（GHSR）在广泛的中枢功能中发挥作用。最近在黑质（substantia nigra，SN）中发现了这种受体，其控制多巴胺（dopamine，DA）相关的生理功能。在SN的多巴胺神经元的调节异常（SNc）和随之而来的纹状体DA的耗竭是已知的基础上观察到的帕金森病（PD）的运动缺陷。在本研究中，我们进一步研究了在立体定向注射AAV-CMV-FLEX-白喉毒素A（DTA）到多巴胺转运蛋白（DAT）-Cre（DATSN：：DTA）小鼠的SN中以清除SNc的DA神经元的情况下，SN-ghrelin系统在运动功能中的作用。首先，我们证实了显性表达的GHSR 1a，这是一个功能性的GHSR，在酪氨酸羟化酶（TH）阳性DA神经元在SNc的对照小鼠。在DATSN：：DTA小鼠中，我们使用几种行为测试清楚地观察到运动功能障碍。免疫组织化学研究显示，TH阳性DA神经元的SNc和DAT标记的轴突末梢在纹状体中的显着损失，并没有TH和DAT的mRNA在SN的DATSN：：DTA小鼠。GHSR 1a的mRNA水平在这些小鼠的SN中急剧下降。正常小鼠黑质网状部（SNr）GABA能神经元内也有GHSR 1a mRNA表达。在这些条件下，向SN中单次注射生长素释放肽未能改善使用DATSN：：DTA小鼠的黑质纹状体DA网络消融引起的运动缺陷，而SN内注射生长素释放肽抑制了氟哌啶醇给药引起的运动功能障碍，这与DA传递的短暂抑制有关。这些研究结果表明，SNc-ghrelin系统的阶段性激活可以改善与PD的初始阶段有关的黑质纹状体DA传递的失调，但不能改善黑质纹状体DA耗竭下的运动缺陷。虽然在SNr的非DA细胞中发现了GHSRs，但SNc中DA神经元上的GHSRs可能在运动功能中起着至关重要的作用。
Ghrelin plays roles in a wide range of central functions by activating the growth hormone secretagogue receptor (GHSR). This receptor has recently been found in the substantia nigra (SN) to control dopamine (DA)-related physiological functions. The dysregulation of DA neurons in the SN pars compacta (SNc) and the consequent depletion of striatal DA are known to underlie the motor deficits observed in Parkinson's disease (PD). In the present study, we further investigated the role of the SN-ghrelin system in motor function under the stereotaxic injection of AAV-CMV-FLEX-diphtheria toxin A (DTA) into the SN of dopamine transporter (DAT)-Cre (DATSN::DTA) mice to expunge DA neurons of the SNc. First, we confirmed the dominant expression of GHSR1a, which is a functional GHSR, in tyrosine hydroxylase (TH)-positive DA neurons in the SNc of control mice. In DATSN::DTA mice, we clearly observed motor dysfunction using several behavioral tests. An immunohistochemical study revealed a dramatic loss of TH-positive DA neurons in the SNc and DAT-labeled axon terminals in the striatum, and an absence of mRNAs for TH and DAT in the SN of DATSN::DTA mice. The mRNA level of GHSR1a was drastically decreased in the SN of these mice. In normal mice, we also found the mRNA expression of GHSR1a within GABAergic neurons in the SN pars reticulata (SNr). Under these conditions, a single injection of ghrelin into the SN failed to improve the motor deficits caused by ablation of the nigrostriatal DA network using DATSN::DTA mice, whereas intra-SN injection of ghrelin suppressed the motor dysfunction caused by the administration of haloperidol, which is associated with the transient inhibition of DA transmission. These findings suggest that phasic activation of the SNc-ghrelin system could improve the dysregulation of nigrostriatal DA transmission related to the initial stage of PD, but not the motor deficits under the depletion of nigrostriatal DA. Although GHSRs are found in non-DA cells of the SNr, GHSRs on DA neurons in the SNc may play a crucial role in motor function.