Microglial Engulfment of Spines in the Ventral Zona Incerta Regulates Anxiety-Like Behaviors in a Mouse Model of Acute Pain

Although activation of microglial cells is critical in developing brain disorders, their role in anxiety-like behaviors in pain is still vague. This study indicates that alteration of microglia's neuronal spine engulfment capacity in ventral zona incerta (ZI(V)) leads to significant pain and anxiety-like behaviors in mice 1-day post-injection of Complete Freud's Adjuvant (CFA1D). Performing whole-cell patch-clamp recordings in GABAergic neurons in the ZI(V) (ZI(V)(GABA)) in brain slices, we observed decreased activity in ZIv(GABA) and reduced frequency of the miniature excitatory postsynaptic currents (mEPSCs) in ZI(V)(GABA) of CFA1D mice compared with the saline1D mice. Besides, chemogenetic activation of ZI(V)(GABA) significantly relieved pain and anxiety-like behaviors in CFA1D mice. Conversely, in naive mice, chemogenetic inhibition of ZI(V)(GABA) induced pain and anxiety-like behaviors. Interestingly, we found changes in the density and morphology of ZI(V)(Microglia) and increased microglial engulfment of spines in ZI(V) of CFA1D mice. Furthermore, pain sensitization and anxiety-like behaviors were reversed when the ZI(V)(Microglia) of CFA1D-treated mice were chemically inhibited by intra-ZI(V) minocycline injection, accompanied by the recovery of decreased ZI(V)(GABA) excitability. Conclusively, our results provide novel insights that dysregulation of microglial engulfment capacity encodes maladaptation of ZI(V)(GABA), thus promoting the development of anxiety-like behaviors in acute pain.

Automated summary

This study suggests that microglial cells play a critical role in anxiety-like behaviors induced by pain. Changes in microglial engulfment capacity of neuronal spines were found to be associated with pain and anxiety-like behaviors in mice. Activation or inhibition of specific neurons in the brain region called ventral zona incerta (ZI(V)) could alleviate or induce pain and anxiety-like behaviors. Furthermore, inhibition of microglial engulfment capacity reversed pain sensitization and anxiety-like behaviors.