Thyrotropin-Releasing Hormone Increases Behavioral Arousal through Modulation of Hypocretin/Orexin Neurons
Thyrotropin-Releasing Hormone Increases Behavioral Arousal through Modulation of Hypocretin/Orexin Neurons
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DOI：
10.1523/jneurosci.0431-09.2009
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发表时间：
2009-03-25
影响因子：
5.3
通讯作者：
Kilduff, Thomas S.
中科院分区：
文献类型：
--
作者：
Hara, Junko;Gerashchenko, Dmitry;Kilduff, Thomas S.
促甲状腺激素释放激素(TRH)此前已被证明可以促进觉醒并诱导从冬眠中唤醒。TRH-R1(TRH受体1)在结节和下丘脑外侧区(LHA)表达丰富，下丘脑下丘脑区是下丘脑区(LHA)和下丘脑下丘脑外侧区(LHA)下丘脑下丘脑(LHA)、下丘脑下丘脑外侧区(LHA)、下丘脑外侧区(LHA)和下丘脑外侧区(LHA)表达TRH-R1(TRH受体1)。因为Hcrt系统与睡眠/觉醒控制有关，所以我们假设TRH为Hcrt细胞提供调制输入。体外电生理研究表明，应用TRH可引起Hcrt神经元的浓度依赖性膜去极化，降低输入电阻，增加放电频率。在河豚毒素存在的情况下，TRH诱发内向电流，这种内向电流与微小突触后电流(PSCs)的频率降低有关，但与幅度无关。离子替代实验表明，TRH诱导的内向电流部分是由钙离子内流介导的。尽管TRH对自发兴奋性PSCs的频率和幅度没有显著影响，但TRH(100 NM)使自发抑制性PSCs的频率增加一倍，而不影响这些事件的幅度，表明突触前GABA在Hcrt神经元上释放增加。相反，TRH显著降低微型兴奋性PSC的频率，但不影响微型抑制性PSC的频率或幅度，这表明TRH还降低了谷氨酸释放到Hcrt神经元的可能性。当TRH注射到LHA中时，TRH增加了野生型小鼠的运动活动，但对出生后Hcrt神经元退化的增食欲素/ataxin-3小鼠却没有。总之，这些结果与TRH部分通过HCRT系统调节行为唤醒的假设是一致的。
Thyrotropin-releasing hormone (TRH) has previously been shown to promote wakefulness and to induce arousal from hibernation. Expression of TRH-R1 (TRH receptor 1) is enriched in the tuberal and lateral hypothalamic area (LHA), brain regions in which the hypocretin/orexin (Hcrt) cells are located. Because the Hcrt system is implicated in sleep/wake control, we hypothesized that TRH provides modulatory input to the Hcrt cells. In vitro electrophysiological studies showed that bath application of TRH caused concentration-dependent membrane depolarization, decreased input resistance, and increased firing rate of identified Hcrt neurons. In the presence of tetrodotoxin, TRH induced inward currents that were associated with a decrease in frequency, but not amplitude, of miniature postsynaptic currents (PSCs). Ion substitution experiments suggested that the TRH-induced inward current was mediated in part by Ca2+ influx. Although TRH did not significantly alter either the frequency or amplitude of spontaneous excitatory PSCs, TRH(100 nM) increased the frequency of spontaneous inhibitory PSCs by twofold without affecting the amplitude of these events, indicating increased presynaptic GABA release onto Hcrt neurons. In contrast, TRH significantly reduced the frequency, but not amplitude, of miniature excitatory PSCs without affecting miniature inhibitory PSC frequency or amplitude, indicating that TRH also reduces the probability of glutamate release onto Hcrt neurons. When injected into the LHA, TRH increased locomotor activity in wild-type mice but not in orexin/ataxin-3 mice in which the Hcrt neurons degenerate postnatally. Together, these results are consistent with the hypothesis that TRH modulates behavioral arousal, in part, through the Hcrt system.