Department of Neurology, Beth Israel Deaconess Medical Center and Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts 02215.
Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan, and.
J Neurosci. 2019 Nov 6;39(45):8929-8939. doi: 10.1523/JNEUROSCI.1032-19.2019. Epub 2019 Sep 23.
The histaminergic neurons of the tuberomammillary nucleus (TMN) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMN neurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMN neurons on sleep-wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMN neurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep-wake quantities, perhaps because very few TMN neurons coexpressed VGAT. Acute chemogenetic activation of TMN neurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMN neurons in arousal control. Further, if TMN neurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMN neurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions. The histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMN) have long been thought to promote arousal. Additionally, TMN neurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMN neurons does not impact sleep-wake amounts and that few TMN neurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMN neurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMN neurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.
下丘脑后部的结节乳头核 (TMN) 的组胺能神经元长期以来一直被认为可促进觉醒。最近，TMN 神经元的 GABA 能信号传递在觉醒控制中的作用也被提出。在这里，我们研究了选择性慢性破坏 TMN 神经元中的 GABA 合成（通过遗传缺失 GABA 合成酶谷氨酸脱羧酶 67）或 GABA 能传递（通过遗传缺失囊泡 GABA 转运体（VGAT））对雄性小鼠睡眠-觉醒的影响。我们还研究了急性化学遗传激活和 TMN 神经元的光遗传抑制对雄性小鼠觉醒的影响。出乎意料的是，我们发现，GABA 合成的破坏或 GABA 能传递的破坏都没有改变每小时的睡眠-觉醒量，这可能是因为很少有 TMN 神经元共表达 VGAT。TMN 神经元的急性化学遗传激活并没有使觉醒水平高于基线，但当老鼠暴露于行为笼改变挑战时，确实增强了警觉性。同样，急性光遗传抑制对基线觉醒水平几乎没有影响。总之，我们无法确定 TMN 神经元释放 GABA 在觉醒控制中的作用。此外，如果 TMN 神经元确实释放 GABA，则其释放机制仍不清楚。我们的研究结果支持 TMN 神经元在某些条件下（如暴露于新环境）增强觉醒的观点，但在基线条件下，TMN 神经元在行为和 EEG 觉醒中仅起次要作用。下丘脑 TMN 中的组胺能神经元长期以来被认为可促进觉醒。此外，TMN 神经元可能通过共释放抑制性神经递质 GABA 来拮抗组胺的促醒作用。在这里，我们表明，破坏 TMN 神经元的 GABA 信号传递不会影响睡眠-觉醒量，并且很少有 TMN 神经元包含囊泡 GABA 转运体，这可能是释放 GABA 所必需的。我们进一步表明，TMN 神经元的急性激活或抑制对基线觉醒水平的影响有限，而激活在行为挑战期间增强警觉性。与普遍看法相反，我们的研究结果支持 TMN 神经元在基线条件下既不是觉醒启动和维持所必需的，也不是充分的观点。
