Roles of orexin-producing neurons in awakening from anesthesia : Analyses using various genetically-modified mice

我们分析了在食欲素神经元中缺乏GABA_<B1>基因的小鼠（GABA_<B1>^<flox/flox>； orexin- cre小鼠）的体内和体外表型，并证明了食欲素神经元上的GABA_B受体在稳定和巩固睡眠/觉醒状态中至关重要。在GABA_<B1>^<flox/flox>；我们发现，GABA_B受体的缺失降低了食欲素神经元对兴奋性和抑制性输入的敏感性，这是由于gaba_a介导的抑制增强，增加了这些神经元的膜电导并分流突触后电流。gaba_a介导的抑制性张力的增加显然是由于OX1食欲素受体介导的局部gaba能中间神经元的激活，该神经元投射回食欲素神经元。GABA_ < B1 > ^ <液氧/液氧>;orexin-Cre小鼠在光照期和黑暗期都表现出严重的睡眠/清醒状态碎片化，但没有表现出总睡眠时间的异常或猝倒的迹象。因此，食欲素神经元上的GABA_B受体在睡眠/清醒状态下适当控制食欲素张力，从而稳定状态转换机制中起着至关重要的作用。我们还制造了在食欲素神经元中特异性缺乏5HT1a基因的小鼠，并分析了它们的表型。

We analyze the in vivo and in vitro phenotype of mice lacking the GABA_<B1> gene specifically in orexin neurons (GABA_<B1>^<flox/flox> ; orexin-Cre mice), and demonstrate that GABA_B receptors on orexin neurons are essential in stabilizing and consolidating sleep/wake states. In GABA_<B1>^<flox/flox> ; orexin-Cre brain slices, we show that the absence of GABA_B receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs, due to an augmented GABA_A-mediated inhibition that increases the membrane conductance and shunts postsynaptic currents in these neurons. This increase in GABA_A-mediated inhibitory tone is apparently due to an OX1 orexin receptor-mediated activation of local GABAergic interneurons that project back onto orexin neurons. GABA_<B1>^<flox/flox> ; orexin-Cre mice exhibit severe fragmentation of sleep/wake states during both the light and dark periods, without showing an abnormality in total sleep time or signs of cataplexy. Thus, GABA_B receptors on orexin neurons are crucial in the appropriate control of the orexinergic tone through sleep/wake states, thereby stabilizing the state switching mechanisms. We also made mice lacking the 5HT1a gene specifically in orexin neurons, and are anlyzing their phenotypes.