Fujita Akie, Bonnavion Patricia, Wilson Miryam H, Mickelsen Laura E, Bloit Julien, de Lecea Luis, Jackson Alexander C
Departments of Physiology and Neurobiology and.
Biomedical Engineering, and.
J Neurosci. 2017 Sep 27;37(39):9574-9592. doi: 10.1523/JNEUROSCI.0580-17.2017. Epub 2017 Sep 5.
Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons (-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal.
组胺能（HA）神经元位于下丘脑后结节乳头体核（TMN），其纤维延伸至整个大脑，并对众多生理系统发挥调节作用。尽管缺乏直接的因果证据表明其在清醒期间维持觉醒的必要性，但多条证据表明HA神经元的活动在警觉性调节中很重要。鉴于HA神经元兴奋性与行为觉醒之间的强相关性，我们研究了脑片中HA神经元的电生理多样性以及它们在雄性小鼠中急性沉默的影响。为此，我们首先验证了一种在表达组氨酸脱羧酶的神经元中表达cre重组酶的转基因小鼠品系（-Cre），随后对腹侧TMN（TMNv）区域的HA和非HA神经元的膜特性进行了系统普查。通过无监督层次聚类分析，我们发现TMNv HA和非HA神经元之间以及HA神经元之间存在电生理多样性。为了直接确定HA神经元活动的急性停止对清醒和行为小鼠睡眠-觉醒状态的影响，我们研究了TMNv HA神经元光遗传学沉默的效果。我们发现，在低睡眠压力期间，清醒时HA神经元的急性沉默会促进慢波睡眠，但不会促进快速眼动睡眠。总之，这些数据表明HA神经元的紧张性放电是维持清醒所必需 的，它们的沉默不仅会损害觉醒，而且足以迅速且选择性地诱导慢波睡眠。调节睡眠和觉醒的单胺能系统和回路的功能在许多神经精神疾病的病理生理学中常常受到破坏。其中一个这样的回路是下丘脑后部组胺（HA）系统，它与支持觉醒和高级脑功能有关，但由于该区域的细胞异质性，一直难以进行选择性操纵。在这里，我们使用转基因小鼠来研究HA神经元的特征性放电特性及其在维持觉醒中的特定作用。我们的结果表明，清醒时HA神经元的急性、细胞类型特异性沉默不仅足以损害觉醒，而且足以迅速且选择性地诱导慢波睡眠。这项工作进一步加深了我们对HA介导的调节行为觉醒机制的理解。
