Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry.
Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry.
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DOI：
10.1016/j.mcn.2014.08.001
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Routh VH
中科院分区：
文献类型：
--
作者：
Sheng Z;Santiago AM;Thomas MP;Routh VH
下丘脑外侧区(LHA)食欲素神经元通过激活腹侧被盖区(VTA)多巴胺(DA)神经元来调节基于奖赏的摄食。我们假设，外周能量状态的信号通过调节LHA增食欲素葡萄糖抑制(GI)神经元的葡萄糖敏感性来影响基于奖励的喂养。对4-6周龄雄性小鼠脑片LHA增食欲素GI神经元的电生理记录验证了这一假设，这些脑片上的增食欲素神经元表达绿色荧光蛋白(GFP)或C57BL/6小鼠可能的VTA-DA神经元。在全细胞和细胞贴壁记录中，低糖直接激活约60%的LHA增食欲素-GFP神经元。Leptin间接抑制和Ghrelin直接增强葡萄糖对下丘脑增食欲素-Gi神经元的激活作用分别为53±12%(n=16，P<0.001)和41±24%(n=8，P<0.05)。GABA或神经降压素受体阻断可阻止瘦素对葡萄糖敏感性的影响。禁食可以通过降低血糖来增加LHA增食欲素-胃肠神经元的激活，正如这些激素效应所预测的那样。我们还在一种新的含有LHA和VTA的水平切片中评估了推测的VTA-DA神经元。降糖使45%(9/20)的VTA DA神经元的自发兴奋性突触后电流(sEPSCs；125±40%，n=9，P<；0.05)和动作电位(n=9；P<；0.05)频率增加。AMPA和NMDA谷氨酸受体拮抗剂(CNQX2 0μM，n=4；APV2 0μM，n=4)可完全阻断sEPSCs，表明这些sEPSCs是由谷氨酸能传递到VTA DA神经元介导的。SB334867(10μM；n=9)和TCS-OX2-29(2μM；n=5)分别拮抗增食欲素-1受体，但不能拮抗2受体拮抗剂SB334867(n=9)和TCS-OX2-29(n=5)拮抗降糖对VTA DA神经元的作用。因此，葡萄糖减少增加了VTA DA神经元上依赖食欲素的兴奋性谷氨酸神经传递。这些数据表明，LHA食欲素胃肠神经元对葡萄糖的敏感性将代谢状态和基于奖励的喂养联系在一起。
Lateral hypothalamic area (LHA) orexin neurons modulate reward-based feeding by activating ventral tegmental area (VTA) dopamine (DA) neurons. We hypothesize that signals of peripheral energy status influence rewardbased feeding by modulating the glucose sensitivity of LHA orexin glucose-inhibited (GI) neurons. This hypothesis was tested using electrophysiological recordings of LHA orexin-GI neurons in brain slices from 4 to 6 week old male mice whose orexin neurons express green fluorescent protein (GFP) or putative VTA-DA neurons from C57Bl/6 mice. Low glucose directly activated ~60% of LHA orexin-GFP neurons in both whole cell and cell attached recordings. Leptin indirectly reduced and ghrelin directly enhanced the activation of LHA orexin-GI neurons by glucose decreases from 2.5 to 0.1 mM by 53 ± 12% (n = 16, P < 0.001) and 41 ± 24% (n = 8, P <0.05), respectively. GABA or neurotensin receptor blockade prevented leptin’s effect on glucose sensitivity. Fasting increased activation of LHA orexin-GI neurons by decreased glucose, as would be predicted by these hormonal effects. We also evaluated putative VTA-DA neurons in a novel horizontal slice preparation containing the LHA and VTA. Decreased glucose increased the frequency of spontaneous excitatory post-synaptic currents (sEPSCs; 125 ± 40%, n = 9, P < 0.05) and action potentials (n = 9; P < 0.05) in 45% (9/20) of VTA DA neurons. sEPSCs were completely blocked by AMPA and NMDA glutamate receptor antagonists (CNQX 20 μM, n = 4; APV 20 μM, n = 4; respectively), demonstrating that these sEPSCs were mediated by glutamatergic transmission onto VTA DA neurons. Orexin-1 but not 2 receptor antagonism with SB334867 (10 μM; n = 9) and TCS-OX2–29 (2 μM; n = 5), respectively, blocks the effects of decreased glucose on VTA DA neurons. Thus, decreased glucose increases orexin-dependent excitatory glutamate neurotransmission onto VTA DA neurons. These data suggest that the glucose sensitivity of LHA orexin-GI neurons links metabolic state and reward-based feeding.
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