Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom and King's College London and MRC National Institute for Medical Research, London NW7 1AA, United Kingdom.
J Neurosci. 2014 Mar 5;34(10):3607-21. doi: 10.1523/JNEUROSCI.3388-13.2014.
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.
昼夜节律和稳态神经回路组织生理和行为的时间结构，但它们之间的相互作用的知识并不完善。例如，含有神经肽食欲素的神经元在稳态上控制觉醒和食欲状态，而视交叉上核（SCN）中的神经元则作为大脑的主生物钟。SCN 调节食欲素神经元，使其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相互调节 SCN 时钟。在这里，我们在小鼠 SCN 中显示了食欲素能神经支配和编码食欲素受体（OX1 和 OX2）的基因表达，其中 OX1 在黄昏时上调。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 Period1（Per1）-EGFP 表达的时钟细胞。这些抑制作用的机制在昼夜周期中有所不同，从白天抑制性 GABA 能信号的突触前调制到夜间直接激活渗漏 K(+)电流。食欲素还增强了另一种觉醒神经化学相关物神经肽 Y（NPY）对 SCN 时钟重置的作用，并增强了 NPY 对 SCN Per1-EGFP 细胞的抑制作用。这些结果建立在新兴文献的基础上，这些文献挑战了食欲素信号仅为兴奋性的广泛观点，并为避免大脑中昼夜节律信号和稳态线索之间的冲突提供了新的机制。
