Yu Weonjin, Xiao Yixin, Jayaraman Anusha, Yen Yi-Chun, Lee Hae Ung, Pettersson Sven, Je H Shawn
Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
ASEAN Microbiome Nutrition Centre, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.
EMBO Mol Med. 2025 Feb;17(2):249-264. doi: 10.1038/s44321-024-00179-y. Epub 2025 Feb 5.
Changes in gut microbiota composition have been linked to anxiety behavior in rodents. However, the underlying neural circuitry linking microbiota and their metabolites to anxiety behavior remains unknown. Using male C57BL/6J germ-free (GF) mice, not exposed to live microbes, increased anxiety-related behavior was observed correlating with a significant increase in the immediate early c-Fos gene in the basolateral amygdala (BLA). This phenomenon coincided with increased intrinsic excitability and spontaneous synaptic activity of BLA pyramidal neurons associated with reduced small conductance calcium-activated potassium (SK) channel currents. Importantly, colonizing GF mice to live microbes or the microbial-derived metabolite indoles reverted SK channel activities in BLA pyramidal neurons and reduced the anxiety behavioral phenotype. These results are consistent with a molecular mechanism by which microbes and or microbial-derived indoles, regulate functional changes in the BLA neurons. Moreover, this microbe metabolite regulation of anxiety links these results to ancient evolutionarily conserved defense mechanisms associated with anxiety-related behaviors in mammals.
肠道微生物群组成的变化与啮齿动物的焦虑行为有关。然而，将微生物群及其代谢产物与焦虑行为联系起来的潜在神经回路仍然未知。使用未接触过活微生物的雄性C57BL/6J无菌（GF）小鼠，观察到与焦虑相关的行为增加，这与基底外侧杏仁核（BLA）中即刻早期c-Fos基因的显著增加相关。这一现象与BLA锥体神经元内在兴奋性和自发突触活动增加同时出现，这与小电导钙激活钾（SK）通道电流减少有关。重要的是，将GF小鼠定殖为活微生物或微生物衍生的代谢产物吲哚可恢复BLA锥体神经元中的SK通道活性，并减少焦虑行为表型。这些结果与一种分子机制一致，即微生物和/或微生物衍生的吲哚调节BLA神经元的功能变化。此外，这种微生物代谢产物对焦虑的调节将这些结果与哺乳动物中与焦虑相关行为相关的古老进化保守防御机制联系起来。
