Objective

Histaminergic 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.

Methods

We utilized Hdc-Cre mice in combination with whole-cell patch-clamp electrophysiology and in vivo chemogenetic techniques to determine whether HDC neurons receive metabolically relevant information via the melanocortin system.

Results

We 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 vivo chemogenetic 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.

Conclusions

These 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.

中文翻译：

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黑色素皮质素通过下丘脑外侧下丘脑黑色素皮质素4受体调节组胺能神经元。

目的

结核母核（TMN）的组胺能神经元促进唤醒，并有助于调节能量稳态。有证据表明，黑色素皮质素4受体（MC4R）在TMN中表达。但是，黑皮质素系统是否影响表达组氨酸合成所需的组氨酸脱羧酶（HDC）的TMN神经元的活性和功能，目前尚不确定。

方法

我们利用Hdc -Cre小鼠与全细胞膜片钳电生理学和体内化学发生技术相结合，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。

结果

我们发现，表达HDC的神经元的子集被melanotan II（MTII）（一种非选择性的melanocortin受体激动剂）所兴奋。使用黑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，AP5）表明该作用是由MC4Rs介导的，并且涉及谷氨酸能依赖性突触前机制。MTII增强了诱发电的刺激下丘脑外侧下丘脑区（PeFLH）诱发的突触后兴奋性电流（EPSC），支持黑皮质素对谷氨酸能PeFLH投射到TMN的作用。最后，体内 HDC神经元的化学发生抑制作用显着增强了MTII的脑室内给药的厌食作用，这表明组胺能神经元的MC4R激活可能抑制了黑皮质素系统激活的厌食作用。

结论

这些实验确定了黑皮质素和组胺能系统之间的功能相互作用，并表明HDC神经元自然发挥作用来抑制黑皮质素系统激活的厌食作用。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，这两个过程均发生变化。