Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Eur J Neurosci. 2012 May;35(9):1426-32. doi: 10.1111/j.1460-9568.2012.08057.x. Epub 2012 Apr 16.
Orexin/hypocretin (orx/hcrt) neurons are thought to ensure that reward-seeking is accompanied by alertness, but the underlying circuit organization is unclear. Reports of differential regulation of lateral versus medial orx/hcrt cells produced a hypothesis of 'efferent dichotomy', in which lateral orx/hcrt cells innervate the ventral tegmental area (VTA) and control reward, while medial orx/hcrt cells innervate locus coeruleus (LC) and control arousal. Two distinct types of orx/hcrt cells also emerged from analysis of intrinsic and input-driven single-cell electrical activity. To examine the projections of these emerging orx/hcrt subtypes to LC and VTA, we injected retrograde tracer into these regions in the mouse brain in vivo, and then examined the properties of tracer-containing orx/hcrt cells in hypothalamic slices. VTA- and LC-projecting orx/hcrt cells were found across the entire orx/hcrt field, including the zona incerta, perifornical area, dorsomedial/anterior and lateral hypothalamus. Within these areas, orx/hcrt cells had similar probabilities of projecting to VTA or LC. Examination of lateral versus medial sections revealed that VTA and LC received inputs from both lateral and medial orx/hcrt cells, but, unexpectedly, lateral orx/hcrt cells were more likely to project to LC than medial orx/hcrt cells. Finally, patch-clamp recordings revealed that VTA and LC received projections from both electrical classes of orx/hcrt cells, which had similar likelihoods of projecting to VTA or LC. Contrary to previous predictions, our data suggest that medial and lateral orx/hcrt cells, and the different electrical and morphological subclasses of orx/hcrt cells identified to date, send projections to both LC and VTA.
食欲素/下丘脑分泌素（orexin/hypocretin，orx/hcrt）神经元被认为可确保觅药行为伴随着觉醒，但相关的环路组织尚不清楚。外侧与内侧 orx/hcrt 神经元的差异调控报告产生了“传出二分法”假说，即外侧 orx/hcrt 神经元支配腹侧被盖区（ventral tegmental area，VTA）并控制奖励，而内侧 orx/hcrt 神经元支配蓝斑核（locus coeruleus，LC）并控制觉醒。内在和输入驱动的单细胞电活动分析也揭示了两种不同类型的 orx/hcrt 细胞。为了研究这些新兴的 orx/hcrt 亚型投射到 LC 和 VTA 的情况，我们在活体小鼠大脑中向这些区域注射逆行示踪剂，然后在下丘脑切片中检查含有示踪剂的 orx/hcrt 细胞的特性。发现 VTA 和 LC 投射型 orx/hcrt 细胞分布于整个 orx/hcrt 区，包括未定带、peri-PVN 区、下丘脑背内侧/前区和外侧区。在这些区域中，orx/hcrt 细胞投射到 VTA 或 LC 的概率相似。对外侧与内侧切片的检查表明，VTA 和 LC 接收来自外侧和内侧 orx/hcrt 细胞的输入，但出乎意料的是，外侧 orx/hcrt 细胞比内侧 orx/hcrt 细胞更有可能投射到 LC。最后，膜片钳记录显示，VTA 和 LC 接收来自 orx/hcrt 细胞的两种电类型的投射，它们投射到 VTA 或 LC 的可能性相似。与先前的预测相反，我们的数据表明，内侧和外侧 orx/hcrt 细胞以及迄今为止鉴定出的不同电和形态亚类的 orx/hcrt 细胞，向 LC 和 VTA 都有投射。
