Asymmetric activation of microglia in the hippocampus drives anxiodepressive consequences of trigeminal neuralgia

Patients suffering from trigeminal neuralgia (TN) are often accompanied by anxiety and depression. Whether and how microglia are involved in TN-induced anxiodepressive remains unclear. Here, we unconventionally report that TN activates ipsilateral but not contralateral hippocampal microglia, upregulates ipsilateral hippocampal ATP and interleukin1β (IL-1β) levels, impairs ipsilateral hippocampal long-term potentiation (LTP), and induces anxiodepressive-like behaviors in a time-dependent manner in rodents. Specifically, activation of ipsilateral hippocampal microglia is necessary for TN-induced anxiodepressive-like behaviors; and unilateral activating hippocampal microglia is sufficient to elicit an anxiodepressive state and impair LTP. Knockdown of ipsilateral hippocampal P2X7 receptor prevented TN-induced microglial activation and anxiodepressive-like behaviors. Furthermore, we demonstrate that microglia-derived IL-1β mediates microglial activation-induced anxiodepressive-like behaviors and LTP impairment. Together, these findings suggest that priming of microglia with ATP/P2X7R in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviors via IL-1β. Our results also reveal an asymmetric role of the bilateral hippocampus in TN-induced anxiety and depression.