Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
Center for Brain Science, Harvard University, Cambridge, MA, USA.
Nature. 2022 Jun;606(7916):937-944. doi: 10.1038/s41586-022-04793-z. Epub 2022 Jun 8.
During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPO) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPO neurons. Finally, we show that VMPO neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPO neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.
在感染过程中，动物会表现出生理和行为上的适应性变化，以提高生存能力。尽管存在许多感染的原因，但它们会引发类似的刻板症状，如发热、寻求温暖、食欲不振和疲劳。然而，神经系统如何改变体温并引发疾病行为以协调对感染的反应仍然未知。在这里，我们确定了下丘脑腹内侧视前区（VMPO）中以前未被描述的神经元群体，这些神经元在脂多糖（LPS）或聚肌苷酸：聚胞苷酸引起的疾病后被激活。这些神经元对于产生发热反应和其他疾病症状，如寻求温暖和食欲不振至关重要。单细胞 RNA 测序和多重抗误差荧光原位杂交揭示了 LPS 激活的 VMPO（VMPO）神经元和非神经元细胞的身份和分布。基因表达和电生理测量表明，在感染过程中非神经元细胞释放免疫信号的旁分泌机制激活了附近的 VMPO 神经元。最后，我们表明 VMPO 神经元对与行为和体内平衡功能相关的大脑区域的活动产生广泛影响，并且与控制体温和食欲的回路节点进行突触和功能连接。总之，这些结果揭示了 VMPO 神经元作为一个控制中枢，整合免疫信号以协调感染时的多种疾病症状。
