Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output.
Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output.
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DOI：
10.1016/j.molmet.2015.09.001
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发表时间：
2015-11
影响因子：
8.1
通讯作者：
Ingraham HA
中科院分区：
文献类型：
--
作者：
Cheung CC;Krause WC;Edwards RH;Yang CF;Shah NM;Hnasko TS;Ingraham HA
下丘脑腹内侧核（VMH）调节能量稳态以及社会和情感行为。几乎所有的VMH神经元，包括那些在性二形VMH腹外侧（VMHvl）亚区，释放兴奋性神经递质谷氨酸和使用囊泡谷氨酸转运蛋白2（VEGF 2）。在这里，我们询问了VMH和VMHvl引起的代谢和行为反应是如何影响的。使用Sf 1-Cre和Vf 12 floxed等位基因，在SF-1 VMH神经元中敲除Vf 12（Vf 12 Sf 1-Cre）。代谢和神经行为测定首先在混合的V57 BL/6小鼠和V57 BL 2fl/fl和V57 BL 2Sf 1-Cre小鼠上进行，然后在C57 BL/6遗传背景下进行，其易于高血糖症和饮食诱导的肥胖（DIO）。基于先前干扰VMH发育或VMH谷氨酸信号传导的研究，在VEGF 2Sf 1-Cre小鼠中观察到的几种表型在很大程度上是出乎意料的。在我们的手中，VEGF 2Sf 1-Cre小鼠在高脂饮食（HFD）后未能表现出预期的体重增加或禁食后葡萄糖稳态受损。相反，在VEGF 2Sf 1-Cre雌性中，DIO存在显著的性别依赖性衰减。VAP 2Sf 1-Cre男性还显示出特定性别的条件性恐惧反应和侵略的损失，伴随着更多的新奇相关的运动。最后，与缺乏完全形成的VMH的Sf 1 Nestin-Cre小鼠中观察到的较高焦虑不同，雄性和雌性Vf 2 Sf 1-Cre小鼠都不那么焦虑。VMH神经元能信号的丢失急剧降低了女性的DIO，减弱了男性的攻击性和学习性恐惧，并且在男性和女性中具有抗焦虑作用。总的来说，我们的研究结果表明，虽然从VMH的embramatergic输出似乎在很大程度上抑制了对低血糖的反调节反应，但它驱动了代谢和社会行为的性别依赖性差异，并且对于两性对焦虑刺激的适应性反应至关重要。兴奋性VMH输出控制性别依赖的代谢和行为表型。VEGF 2Sf 1-Cre小鼠不容易发生饮食诱导的肥胖或葡萄糖失调。VMH神经元信号的丢失导致女性的负能量状态。缺乏VMH兴奋性输出的男性的攻击性和习得性恐惧较低。VMH神经元能信号驱动两性的正常焦虑反应。
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 (Vglut2Sf1-Cre). Metabolic and neurobehavioral assays were carried out initially on Vglut2fl/fl and Vglut2Sf1-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 Vglut2Sf1-Cre mice were largely unexpected based on prior studies that have perturbed VMH development or VMH glutamate signaling. In our hands, Vglut2Sf1-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 Vglut2Sf1-Cre females. Vglut2Sf1-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 Sf1Nestin-Cre mice that lack a fully formed VMH, both male and female Vglut2Sf1-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. Excitatory VMH output controls sex-dependent metabolic and behavioral phenotypes. Vglut2Sf1-Cre mice are not prone to diet-induced obesity or glucose misregulation. Loss of VMH glutamatergic signaling leads to negative energy state in females. Aggression and learned fear are lower in males lacking VMH excitatory output. VMH glutamatergic signaling drives normal anxiety responses in both sexes.