Cheung Clement C, Krause William C, Edwards Robert H, Yang Cindy F, Shah Nirao M, Hnasko Thomas S, Ingraham Holly A
Department of Cellular and Molecular Pharmacology, Mission Bay Campus, University of California, San Francisco 94143, United States.
Department of Physiology and Neurology, Mission Bay Campus, University of California, San Francisco 94143, United States.
Mol Metab. 2015 Sep 11;4(11):857-66. doi: 10.1016/j.molmet.2015.09.001. eCollection 2015 Nov.
The ventromedial hypothalamic nucleus (VMH) regulates energy homeostasis as well as social and emotional behaviors. Nearly all VMH neurons, including those in the sexually dimorphic ventrolateral VMH (VMHvl) subregion, release the excitatory neurotransmitter glutamate and use the vesicular glutamate transporter 2 (Vglut2). Here, we asked how glutamatergic signaling contributes to the collective metabolic and behavioral responses attributed to the VMH and VMHvl.
Using Sf1-Cre and a Vglut2 floxed allele, Vglut2 was knocked-out in SF-1 VMH neurons (Vglut2 (Sf1-Cre) ). Metabolic and neurobehavioral assays were carried out initially on Vglut2 (fl/fl) and Vglut2 (Sf1-Cre) mice in a mixed, and then in the C57BL/6 genetic background, which is prone to hyperglycemia and diet induced obesity (DIO).
Several phenotypes observed in Vglut2 (Sf1-Cre) mice were largely unexpected based on prior studies that have perturbed VMH development or VMH glutamate signaling. In our hands, Vglut2 (Sf1-Cre) mice failed to exhibit the anticipated increase in body weight after high fat diet (HFD) or the impaired glucose homeostasis after fasting. Instead, there was a significant sex-dependent attenuation of DIO in Vglut2 (Sf1-Cre) females. Vglut2 (Sf1-Cre) males also display a sex-specific loss of conditioned-fear responses and aggression accompanied by more novelty-associated locomotion. Finally, unlike the higher anxiety noted in Sf1 (Nestin-Cre) mice that lack a fully formed VMH, both male and female Vglut2 (Sf1-Cre) mice were less anxious.
Loss of VMH glutamatergic signaling sharply decreased DIO in females, attenuated aggression and learned fear in males, and was anxiolytic in males and females. Collectively, our findings demonstrate that while glutamatergic output from the VMH appears largely dispensable for counter regulatory responses to hypoglycemia, it drives sex-dependent differences in metabolism and social behaviors and is essential for adaptive responses to anxiety-provoking stimuli in both sexes.
腹内侧下丘脑核（VMH）调节能量平衡以及社交和情绪行为。几乎所有VMH神经元，包括性二态性腹外侧VMH（VMHvl）亚区的神经元，都释放兴奋性神经递质谷氨酸，并使用囊泡谷氨酸转运体2（Vglut2）。在此，我们探讨了谷氨酸能信号传导如何促成归因于VMH和VMHvl的集体代谢和行为反应。
利用Sf1-Cre和一个Vglut2条件性敲除等位基因，在SF-1 VMH神经元中敲除Vglut2（Vglut2（Sf1-Cre））。最初在混合背景下，然后在C57BL/6遗传背景（易患高血糖和饮食诱导肥胖（DIO））中，对Vglut2（fl/fl）和Vglut2（Sf1-Cre）小鼠进行代谢和神经行为分析。
基于先前干扰VMH发育或VMH谷氨酸信号传导的研究，Vglut2（Sf1-Cre）小鼠中观察到的几种表型在很大程度上出乎意料。在我们的研究中，Vglut2（Sf1-Cre）小鼠在高脂饮食（HFD）后未表现出预期的体重增加，在禁食后也未出现葡萄糖稳态受损。相反，Vglut2（Sf1-Cre）雌性小鼠的DIO有显著的性别依赖性减弱。Vglut2（Sf1-Cre）雄性小鼠还表现出条件性恐惧反应和攻击性的性别特异性丧失，同时伴有更多与新奇相关的运动。最后，与缺乏完全形成的VMH的Sf1（Nestin-Cre）小鼠中观察到的更高焦虑不同，雄性和雌性Vglut2（Sf1-Cre）小鼠的焦虑程度均较低。
VMH谷氨酸能信号的缺失显著降低了雌性小鼠的DIO，减弱了雄性小鼠的攻击性和习得性恐惧，并且对雄性和雌性小鼠均具有抗焦虑作用。总体而言，我们的研究结果表明，虽然VMH的谷氨酸能输出对于低血糖的反调节反应似乎在很大程度上是可有可无的，但它驱动了代谢和社交行为中的性别依赖性差异，并且对于两性对焦虑诱发刺激的适应性反应至关重要。
