Acute Suppressive and Long-Term Phase Modulation Actions of Orexin on the Mammalian Circadian Clock
Acute Suppressive and Long-Term Phase Modulation Actions of Orexin on the Mammalian Circadian Clock
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DOI：
10.1523/jneurosci.3388-13.2014
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发表时间：
2014-03-05
影响因子：
5.3
通讯作者：
Piggins, Hugh D.
中科院分区：
文献类型：
--
作者：
Belle, Mino D. C.;Hughes, Alun T. L.;Piggins, Hugh D.
昼夜节律和自我平衡的神经回路组织生理和行为的时间结构，但他们的相互作用的知识是不完善的。例如，含有神经肽食欲素的神经元稳态地控制唤醒和食欲状态，而视交叉上核（SCN）中的神经元则充当大脑的主生物钟。SCN调节食欲素神经元，使它们在昼夜节律的夜晚比昼夜节律的白天更活跃，但尚不清楚食欲素神经元是否间接调节SCN时钟。在这里，我们显示食欲素能神经支配和编码食欲素受体（OX 1和OX 2）的基因在小鼠SCN的表达，与OX 1在黄昏上调。值得注意的是，我们通过体外生理记录发现，食欲素主要抑制小鼠SCN Period 1（Per 1）-EGFP表达的时钟细胞。支持这些抑制的机制在昼夜节律周期中各不相同，从白天抑制性GABA能信号的突触前调节到夜间直接激活漏K（+）电流。食欲素还增强了神经肽Y（NPY）（觉醒的另一种神经化学相关物）的SCN时钟重置作用，并增强了NPY对SCN Per 1-EGFP细胞的抑制作用。这些结果建立在新兴文献的基础上，这些文献挑战了广泛持有的观点，即食欲素信号传导完全是兴奋性的，并提出了避免昼夜节律钟信号和大脑内稳态线索之间冲突的新机制。
Circadian and homeostatic neural circuits organize the temporal architecture of physiology and behavior, but knowledge of their interactions is imperfect. For example, neurons containing the neuropeptide orexin homeostatically control arousal and appetitive states, while neurons in the suprachiasmatic nuclei (SCN) function as the brain's master circadian clock. The SCN regulates orexin neurons so that they are much more active during the circadian night than the circadian day, but it is unclear whether the orexin neurons reciprocally regulate the SCN clock. Here we show both orexinergic innervation and expression of genes encoding orexin receptors (OX1 and OX2) in the mouse SCN, with OX1 being upregulated at dusk. Remarkably, we find through in vitro physiological recordings that orexin predominantly suppresses mouse SCN Period1 (Per1)-EGFP-expressing clock cells. The mechanisms underpinning these suppressions vary across the circadian cycle, from presynaptic modulation of inhibitory GABAergic signaling during the day to directly activating leak K (+) currents at night. Orexin also augments the SCN clock-resetting effects of neuropeptide Y (NPY), another neurochemical correlate of arousal, and potentiates NPY's inhibition of SCN Per1-EGFP cells. These results build on emerging literature that challenge the widely held view that orexin signaling is exclusively excitatory and suggest new mechanisms for avoiding conflicts between circadian clock signals and homeostatic cues in the brain.