Prelimbic cortex to zona incerta pathway mediates recognition memory recovery delay through down-regulating astrocytic GAT-3

GABAergic signaling of the zona incerta (ZI) is involved in neural circuits and negative complications caused by surgery. Here, we aim to investigate the circuit mechanisms underlying the memory impairment induced by surgery. The prefrontal cortex and ZI were systematically investigated through behavioral tests, patch-clamp recordings, genetic approaches, and the laparotomy surgery model. The surgical mice showed significant impairment in recognition memory. Immunostaining revealed that the prelimbic cortex (PL)→ZI projecting neurons were deactivated. Optogenetic activation of the PL→ZI pathway, rather than the infralimbic cortex→ZI pathway, alleviated surgery-induced recognition memory deficits. Short-term activation of PL→ZI pathway could up-regulate GABA transporter 3 (GAT-3). Furthermore, continuous activation of PL→ZI projections enhanced GAT-3 expression, thereby promoting recovery from recognition memory dysfunction. These results revealed that PL→ZI-related astrocyte GAT-3 is a key signal regulatory factor for preventing postoperative cognitive dysfunction.