Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and.
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
J Neurosci. 2020 Mar 18;40(12):2573-2588. doi: 10.1523/JNEUROSCI.2887-19.2020. Epub 2020 Feb 20.
Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPO neurons). To investigate the identity of MnPO neurons, we first used hybridization to show coexpression of EP3R and the VGluT2 transporter in MnPO neurons. Retrograde tracing showed extensive direct projections from MnPO but few from MnPO neurons to a key site for fever production, the raphe pallidus. Ablation of MnPO but not MnPO neurons abolished fever responses but not changes in Tb induced by behavioral stress or thermal challenges. Finally, we crossed EP3R conditional knock-out mice with either VGluT2-IRES-cre or Vgat-IRES-cre mice and used both male and female mice to confirm that the neurons that express EP3R and mediate fever are glutamatergic, not GABAergic. This finding will require rethinking current concepts concerning the central thermoregulatory pathways based on the MnPO neurons being GABAergic. Body temperature is regulated by the CNS. The rise of the body temperature, or fever, is an important brain-orchestrated mechanism for fighting against infectious or inflammatory disease, and is tightly regulated by the neurons located in the median preoptic nucleus (MnPO). Here we demonstrate that excitatory MnPO neurons mediate fever and examine a potential central circuit underlying the development of fever responses.
发热是感染或炎症状态下的常见现象。这种对炎症刺激的体温（Tb）的典型升高是由前列腺素 E2 作用于中前脑核（MnPO 神经元）中表达的 EP3 受体引发的自主反应的结果。为了研究 MnPO 神经元的特性，我们首先使用杂交技术显示 EP3R 和 VGluT2 转运体在 MnPO 神经元中的共表达。逆行追踪显示 MnPO 神经元与发热产生的关键部位苍白球之间有广泛的直接投射，但 MnPO 神经元的投射很少。MnPO 神经元的消融消除了发热反应，但对行为应激或热挑战引起的 Tb 变化没有影响。最后，我们将 EP3R 条件敲除小鼠与 VGluT2-IRES-cre 或 Vgat-IRES-cre 小鼠杂交，并使用雄性和雌性小鼠来证实表达 EP3R 并介导发热的神经元是谷氨酸能的，而不是 GABA 能的。这一发现将需要重新思考当前基于 MnPO 神经元是 GABA 能的中枢体温调节途径的概念。体温受中枢神经系统调节。体温升高，即发热，是对抗感染或炎症性疾病的重要大脑协调机制，由位于中前脑核（MnPO）的神经元紧密调节。在这里，我们证明兴奋性 MnPO 神经元介导发热，并研究了发热反应发展的潜在中枢回路。
