Abstract：
Regulated neural-metabolic-inflammatory responses are essential for maintaining physiological homeostasis. However, the molecular machinery that coordinates neural, metabolic, and inflammatory responses is largely unknown. Here, we show that semaphorin 6D (SEMA6D) coordinates anxiogenic, metabolic, and inflammatory outputs from the amygdala by maintaining synaptic homeostasis. Using genome-wide approaches, we identify SEMA6D as a pleiotropic gene for both psychiatric and metabolic traits in human. Sema6d deficiency increases anxiety in mice. When fed a high-fat diet, Sema6d-/- mice display attenuated obesity and enhanced myelopoiesis compared with control mice due to higher sympathetic activity via the β3-adrenergic receptor. Genetic manipulation and spatial and single-nucleus transcriptomics reveal that SEMA6D in amygdalar interneurons is responsible for regulating anxiogenic and autonomic responses. Mechanistically, SEMA6D is required for synaptic maturation and γ-aminobutyric acid transmission. These results demonstrate that SEMA6D is important for the normal functioning of the neural circuits in the amygdala, coupling emotional, metabolic, and inflammatory responses.
摘要：
调节的神经代谢炎症反应对于维持生理稳态至关重要。然而,协调神经的分子机制，新陈代谢，炎症反应在很大程度上是未知的。这里,我们表明，信号蛋白6D（SEMA6D）协调抗焦虑，新陈代谢，通过维持突触稳态，杏仁核的炎症输出。使用全基因组方法，我们确定SEMA6D是人类精神和代谢性状的多效性基因。Sema6d缺乏增加小鼠的焦虑。当喂高脂肪饮食时，与对照小鼠相比，Sema6d-/-小鼠表现出减轻的肥胖和增强的骨髓生成，这是由于通过β3-肾上腺素能受体具有更高的交感神经活性。遗传操作以及空间和单核转录组学表明，杏仁核中间神经元中的SEMA6D负责调节抗焦虑和自主神经反应。机械上,SEMA6D是突触成熟和γ-氨基丁酸传递所必需的。这些结果表明，SEMA6D对杏仁核神经回路的正常功能很重要，耦合情感，新陈代谢，和炎症反应。
