Abstract

Background Cognitive impairment affects prognosis and quality of life in patients with trigeminal neuralgia (TN). Modulating hippocampal microglial activation is a promising approach for addressing TN-related cognitive deficits. Nuclear receptor subfamily 4 group A member 1 ( Nr4a1 ) is involved in hippocampal-dependent cognition and microglial homeostasis. However, its role in trigeminal neuralgia-associated cognitive dysfunction remains unclear. We aimed to investigate the role of Nr4a1 in regulating neuroinflammation mediated by microglial hyperactivation, and to establish the relationship between the resulting synaptic plasticity impairment and cognitive dysfunction. Methods A TN rat model was established using chronic constriction injury of the distal infraorbital nerve. Cognitive function and hippocampal microglial activation were evaluated over time. Transcriptomic sequencing was performed to identify differentially expressed genes related to microglial activation. Nr4a1 was overexpressed in hippocampal microglia using adeno-associated virus and lentivirus in TN rats and BV2 cells, respectively. Multi-omics analyses, co-immunoprecipitation, and mass spectrometry were used for mechanistic assessments. Results Here, we observed that TN rats exhibited time-dependent cognitive impairment accompanied by excessive activation of hippocampal microglia and significant downregulation of Nr4a1 expression. Nr4a1 overexpression suppresses excessive activation of microglia and the neuroinflammation they mediate. These effects correlate with restored neuronal autophagy, enhanced synaptic plasticity, and improved cognitive function in TN rats. Mechanistically, we first revealed aberrant alterations in the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway through multi-omics sequencing. Furthermore, we identified Nr4a1 primarily targeting Akt2 among the Akt isoforms in the rat hippocampus. Restoring Nr4a1 expression reversed PI3K/Akt2 signal