Melanocortin regulation of histaminergic neurons via perifornical lateral hypothalamic melanocortin 4 receptors.
Melanocortin regulation of histaminergic neurons via perifornical lateral hypothalamic melanocortin 4 receptors.
复制标题
黑皮质素通过下丘脑外侧黑皮质素 4 受体对组胺能神经元的调节。
DOI：
10.1016/j.molmet.2020.01.020
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发表时间：
2020
影响因子：
8.1
通讯作者：
Elmquist,JoelK
中科院分区：
文献类型：
--
作者：
Michael,NatalieJ;Caron,Alexandre;Lee,CharlotteE;Castorena,CarlosM;Lee,Syann;Zigman,JeffreyM;Williams,KevinW;Elmquist,JoelK
结节乳头核（TMN）的组胺能神经元具有唤醒促进作用，并有助于调节能量稳态。有证据表明黑皮质素4受体（MC 4 R）在TMN内表达。然而，黑皮质素系统是否影响表达组胺合成所需的组氨酸脱羧酶（HDC）的TMN神经元的活性和功能，方法我们利用Hdc-Cre小鼠结合全细胞膜片钳电生理学和体内化学发生技术来确定HDC神经元是否通过黑皮质素系统接收代谢相关信息。表达神经元被melanotan II（MTII）（一种非选择性黑皮质素受体激动剂）兴奋。黑素皮质素受体选择性激动剂（THIQ，[D-Trp 8]-γ-MSH）和突触传递抑制剂（TTX，CNQX，AP 5）的应用表明，这种作用是由MC 4 Rs特异性介导的，并涉及一种神经递质依赖的突触前机制。MTII增强诱发兴奋性突触后电流（EPSC）起源于穹窿周围外侧下丘脑区（PeFLH）的电刺激，支持黑皮质素对丘脑能PeFLH投射到TMN的影响。最后，HDC神经元的体内化学发生抑制显著增强了侧脑室给予MTII的致凋亡作用，结论HDC神经元在抑制黑素皮质素系统的促凋亡作用中起着重要的作用，黑素皮质素系统的促凋亡作用可能与HDC神经元的MC 4 R激活有关activation.这些发现可能对唤醒和代谢稳态的控制有影响，特别是在肥胖的情况下，这两个过程都受到改变。
ObjectiveHistaminergic neurons of the tuberomammillary nucleus (TMN) are wake-promoting and contribute to the regulation of energy homeostasis. Evidence indicates that melanocortin 4 receptors (MC4R) are expressed within the TMN. However, whether the melanocortin system influences the activity and function of TMN neurons expressing histidine decarboxylase (HDC), the enzyme required for histamine synthesis, remains undefined.MethodsWe utilizedHdc-Cre mice in combination with whole-cell patch-clamp electrophysiology andin vivochemogenetic techniques to determine whether HDC neurons receive metabolically relevant information via the melanocortin system.ResultsWe found that subsets of HDC-expressing neurons were excited by melanotan II (MTII), a non-selective melanocortin receptor agonist. Use of melanocortin receptor selective agonists (THIQ, [D-Trp8]-γ-MSH) and inhibitors of synaptic transmission (TTX, CNQX, AP5) indicated that the effect was mediated specifically by MC4Rs and involved a glutamatergic dependent presynaptic mechanism. MTII enhanced evoked excitatory post-synaptic currents (EPSCs) originating from electrical stimulation of the perifornical lateral hypothalamic area (PeFLH), supportive of melanocortin effects on the glutamatergic PeFLH projection to the TMN. Finally,in vivochemogenetic inhibition of HDC neurons strikingly enhanced the anorexigenic effects of intracerebroventricular administration of MTII, suggesting that MC4R activation of histaminergic neurons may restrain the anorexigenic effects of melanocortin system activation.ConclusionsThese experiments identify a functional interaction between the melanocortin and histaminergic systems and suggest that HDC neurons act naturally to restrain the anorexigenic effect of melanocortin system activation. These findings may have implications for the control of arousal and metabolic homeostasis, especially in the context of obesity, in which both processes are subjected to alterations.