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

Abstract

Background and Purpose Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia‐mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia‐induced anxiodepression remains unclear. Experimental Approach Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive‐like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia. Key Results Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up‐regulated ipsilateral hippocampal ATP and interleukin‐1β (IL‐1β) levels, impaired ipsilateral hippocampal long‐term potentiation (LTP) and induced anxiodepressive‐like behaviours in a time‐dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia‐induced anxiodepressive‐like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia‐induced microglial activation and anxiodepressive‐like behaviours. Furthermore, we demonstrated that microglia‐derived IL‐1β mediated microglial activation‐induced anxiodepressive‐like behaviours and LTP impairment. Conclusion and Implications These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain‐related anxiodepressive‐like behaviours via IL‐1β. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia‐induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia‐related anxiety and depressive disorder.

Corticotropin-releasing hormone neurons control trigeminal neuralgia-induced anxiodepression via a hippocampus-to-prefrontal circuit

“…We previously showed that TN mice exhibit obvious anxiodepressive-like behaviors by 14 days but not 4 day after chronic constriction injury of the infraorbital nerve (CION), indicating that anxiodepressive-like behaviors caused by neuropathic pain were time dependent ( 21 ). In this study, we investigated whether TN altered the excitability and synaptic transmission of mPFC neurons accompanying the anxiodepressive-like behaviors.…”

“…S4, A to G). Our previous study showed that inhibition of microglia in the ipsilateral but not the contralateral dorsal hippocampus (dHPC) blocked CION-induced anxiodepressive-like behaviors, suggesting an asymmetric role of dHPC ( 21 ). However, unlike manipulating dHPC microglia, there was no significant difference in the anti-anxiodepressive effects of silencing ipsilateral and contralateral vHPC CaMK2A + neurons (fig.…”

“…In TN mice, sustained trigeminal pain leads to enhanced activity of CaMK2A + vHPC neurons, which in turn produced increased excitatory inputs to the CRH + subset of GABAergic neurons in the mPFC, causing a feed-forward inhibition of layer V mPFC pyramidal neurons. Notably, this enhanced feed-forward inhibition occurs after 14 days of TN, coinciding with the time window of the development of anxiodepressive-like consequences ( 21 ). Consistently, inactivation and activation of the vHPC CaMK2A -mPFC CRH circuits can sufficiently suppress and produce anxiodepressive-like consequences in TN and naïve mice, respectively.…”

“…It has been previously demonstrated that the anxiodepressive-like consequences of neuropathic pain evolve in a time-dependent manner ( 19 , 20 ). Our recent study has also demonstrated that mechanical hypersensitivity occurs immediately following trigeminal neuralgia (TN), whereas anxiodepressive-like behaviors are observed 14 days (14d) later ( 21 ). The delayed development of anxiodepressive-like emotions may be attributed to the retrieval and consolidation of negative emotional memories related to pain episodes evoked by daily activities such as eating, drinking, and licking.…”

Electroacupuncture treatment ameliorates depressive-like behavior and cognitive dysfunction via CB1R dependent mitochondria biogenesis after experimental global cerebral ischemic stroke

“…In line with previous studies, in this research, the injury of hippocampal structure and function exhibited depressive-like behaviors, as evidenced SPT, TST, and NSFT tests. Additionally, the deficiency in hippocampal activity is required for anxiety-like behaviors ( Chen et al, 2022 ; Scholl et al, 2022 ). Some studies reported by other groups have indicated that anxiety-like behaviors could be generated through ischemic/reperfusion injury ( Jin et al, 2017 ).…”