蓝斑核谷氨酸能神经元参与调节小鼠体重

Glutamatergic Neurons in Locus Ceruleus Mediated in the Regulation of Body Weight in Mice

下丘脑是参与进食调控的重要脑区,具有复杂的环路调控机制。然而,是否存在下丘脑以外同样发挥体重调节功能的神经核团尚不清楚。本试验利用神经环路示踪技术,鉴定向背肩胛棕色脂肪组织(interscapular brown adipose tissue, IBAT)发送神经元投射的神经元类型和分布,探究中枢神经元及神经环路调节能量稳态的形态学基础。首先通过报告基因和逆行示踪识别囊泡型谷氨酸转运体2(vesicular glutamate transporter 2, VGlut2)和细胞外调节蛋白激酶(extracellular regulated protein kinase, ERK)神经元,顺行示踪试验拓展VGlut2神经元发送神经支配的大脑区域。化学遗传技术验证VGlut2免疫阳性神经元的体重和采食调控作用。结果显示:LC^(VGlut2::ERK)神经元向IBAT发送密集的神经支配信号。ERK免疫阳性神经元富集表达在LC,可作为LC特异性标记物。LC^(VGlut2)神经元向纹状体(neurons project to the striatum, CPu)、第二运动皮层(secondary motor cortex, M2)、下丘脑腹内侧核(ventromedial hypothalamic nucleus, VMH)和迷走神经背核(dorsal motor nucleus of the vagus, DMV)发送神经元投射。化学遗传激活LC^(VGlut2)神经元显著降低小鼠体重(P=0.016 5)和采食(P=0.029 0)。综上,LC^(VGlut2)神经元参与小鼠的体重调节过程。鉴定除下丘脑室旁核(paraventricular nucleus of hypothalamus, PVN)以外的谷氨酸能神经元及调节体重的下游神经环路,将进一步加深对于摄食行为和摄食过程中神经调控机制的了解,为研究和干预肥胖相关的疾病提供新思路。

Hypothalamus is an important brain area involved in the regulation of food intake,which has a complex circuit regulation mechanism.However,it is not clear whether there are nuclei that also play a role in weight regulation outside the hypothalamus.Therefore,in this study,the neural circuit tracer technique was used to identify the distribution and projection pattern of neurons in the locus coeruleus(LC)projecting to the interscapular brown adipose tissue(IBAT),and to explore the morphological basis of central neurons and neural circuits regulating energy homeostasis.The reporter gene and retrograde tracing were used to identify the localization of vesicular glutamate transporter 2(VGlut2)and extracellular regulated protein kinase(ERK)neurons in the brain,and the anterograde tracing experiment expanded the brain area where VGlut2 neurons sent innervation.The body weight and feeding regulation of VGlut2 immunoreactive neurons were verified by chemical genetics.The results showed that LC VGlut2::ERK neurons sent dense innervation signals to IBAT.ERK immunoreactive neurons are enriched and expressed in LC and can be used as specific markers of LC.LC^(VGlut2) neurons project to the striatum(CPu),secondary motor cortex(M2),ventromedial hypothalamic nucleus(VMH)and dorsal motor nucleus of the vagus(DMV).Chemical genetic activation of LC^(VGlut2) neurons significantly decreased body weight(P=0.0165)and feed intake(P=0.0290).These results suggesting that LC^(VGlut2) neurons were involved in the process of body weight regulation in mice.Identification of glutamatergic neurons other than paraventricular nucleus of hypothalamus(PVN)and downstream neural circuits regulating body weight will further understand the feeding mechanism and provide some inspiration for the development of obesity drugs.