Peripheral inflammation triggering central anxiety through the hippocampal glutamate metabolized receptor 1

Abstract Aims This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. Methods Anxiety‐like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open‐field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll‐like receptor 4 (TLR4) inhibitor TAK‐242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. Results DSS‐induced colitis increased anxiety‐like behaviors, which was reduced by TAK‐242. Spatial transcriptome analysis of the hippocampus showed an excitatory‐inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. Conclusion Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over‐excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety‐like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC‐associated anxiety.