Differential actions of orexin receptors in brainstem cholinergic and monoaminergic neurons revealed by receptor knockouts: implications for orexinergic signaling in arousal and narcolepsy.
Differential actions of orexin receptors in brainstem cholinergic and monoaminergic neurons revealed by receptor knockouts: implications for orexinergic signaling in arousal and narcolepsy.
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DOI：
10.3389/fnins.2013.00246
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发表时间：
2013
影响因子：
4.3
通讯作者：
Leonard CS
中科院分区：
文献类型：
--
作者：
Kohlmeier KA;Tyler CJ;Kalogiannis M;Ishibashi M;Kristensen MP;Gumenchuk I;Chemelli RM;Kisanuki YY;Yanagisawa M;Leonard CS
食欲素神经肽影响多种稳态功能，并在正常睡眠-觉醒行为的表达中发挥重要作用。虽然它们的两种已知受体（OX1 和 OX2）是新型药物治疗的靶点，但每种受体介导的作用在很大程度上仍未被探索。利用本质上缺乏任一受体的小鼠的脑切片，我们使用全细胞和 Ca2+ 成像方法来描绘胆碱能 [背侧被盖核 (LDT)] 和单胺能 [中缝背侧 (DR) 和蓝斑 (LC)] 脑干核中每种受体的细胞作用，其中食欲素促进唤醒并抑制快速眼动睡眠。在 OX−/−2 小鼠的切片中，食欲素-A (300 nM) 在 LDT、DR 和 LC 神经元中引发野生型反应，包括去极化电流和增强的电压依赖性 Ca2+ 瞬变。在 OX−/−1 小鼠切片中，LDT 和 LC 神经元中不存在去极化电流，而 DR 神经元中去极化电流减弱，尽管 Ca2+ 瞬变仍然增强。由于食欲素-A在缺乏这两种受体的切片中均不产生这些作用，我们的研究结果表明，食欲素介导的去极化是由DR中的两种受体介导的，但在LDT和LC神经元中仅由OX1介导，即使OX2存在并且OX2 mRNA在OX−/−1小鼠的脑干中似乎升高。考虑到已发表的行为数据，这些发现支持了一种模型，其中食欲素介导的中脑桥胆碱能和单胺能神经元的兴奋对稳定自发觉醒和睡眠发作几乎没有贡献，但在上下文依赖性唤醒中发挥作用，并有助于将肌肉无力限制为快速眼动睡眠。两种受体产生的增强的 Ca2+ 瞬变似乎是通过 L 型 Ca2+ 通道的流入介导的，这通常与转录信号传导有关。这可以提供适应性信号来补偿受体损失或长期拮抗作用，并可能有助于降低单受体敲除小鼠的发作性睡病的严重程度。
Orexin neuropeptides influence multiple homeostatic functions and play an essential role in the expression of normal sleep-wake behavior. While their two known receptors (OX1 and OX2) are targets for novel pharmacotherapeutics, the actions mediated by each receptor remain largely unexplored. Using brain slices from mice constitutively lacking either receptor, we used whole-cell and Ca2+ imaging methods to delineate the cellular actions of each receptor within cholinergic [laterodorsal tegmental nucleus (LDT)] and monoaminergic [dorsal raphe (DR) and locus coeruleus (LC)] brainstem nuclei—where orexins promote arousal and suppress REM sleep. In slices from OX−/−2 mice, orexin-A (300 nM) elicited wild-type responses in LDT, DR, and LC neurons consisting of a depolarizing current and augmented voltage-dependent Ca2+ transients. In slices from OX−/−1 mice, the depolarizing current was absent in LDT and LC neurons and was attenuated in DR neurons, although Ca2+-transients were still augmented. Since orexin-A produced neither of these actions in slices lacking both receptors, our findings suggest that orexin-mediated depolarization is mediated by both receptors in DR, but is exclusively mediated by OX1 in LDT and LC neurons, even though OX2 is present and OX2 mRNA appears elevated in brainstems from OX−/−1 mice. Considering published behavioral data, these findings support a model in which orexin-mediated excitation of mesopontine cholinergic and monoaminergic neurons contributes little to stabilizing spontaneous waking and sleep bouts, but functions in context-dependent arousal and helps restrict muscle atonia to REM sleep. The augmented Ca2+ transients produced by both receptors appeared mediated by influx via L-type Ca2+ channels, which is often linked to transcriptional signaling. This could provide an adaptive signal to compensate for receptor loss or prolonged antagonism and may contribute to the reduced severity of narcolepsy in single receptor knockout mice.
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DOI：
10.1007/978-1-59745-471-1_23
发表时间：
2009
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Doetschman, Thomas
通讯作者：
Doetschman, Thomas
影响因子：
3.7
作者：
del Cid-Pellitero, Esther;Garzon, Miguel
通讯作者：
Garzon, Miguel
DOI：
10.1073/pnas.1202526109
发表时间：
2012-09-25
影响因子：
11.1
作者：
Carter, Matthew E.;Brill, Julia;de Lecea, Luis
通讯作者：
de Lecea, Luis
DOI：
10.1073/pnas.0507480102
发表时间：
2005-12-27
影响因子：
11.1
作者：
Boutrel, B;Kenny, PJ;de Lecea, L
通讯作者：
de Lecea, L
影响因子：
16.2
作者：
Borgland, SL;Taha, SA;Bonci, A
通讯作者：
Bonci, A