Igfbp2 Downregulation in PVT-CeA Glutamatergic Circuits Drives Neonatal Anesthesia-Induced Fear Memory Deficits

Abstract

Repeated neonatal general anesthesia results in long-term cognitive dysfunction; however, the underlying mechanisms remain unclear. This study finds that repeated neonatal anesthesia impaired fear memory in adolescent mice of both sexes, along with hypoactivated glutamatergic neurons in the paraventricular thalamus (PVT). Optogenetic activation of PVT glutamatergic neurons rescued fear memory deficits in anesthesia-treated mice, whereas optogenetic inhibition of these neurons recapitulated memory deficits in control mice. Specifically, repeated neonatal anesthesia reduced insulin-like growth factor-binding protein 2 (Igbp2) expression and dendritic spine density in PVT glutamatergic neurons in both males and females. Selectively manipulating PVT glutamatergic Igfbp2 mediated anesthesia-induced fear memory deficits through modulating neuron excitability and spine density. Notably, optogenetic activation or restoring Igfbp2 expression in glutamatergic projections from the PVT to the central amygdala (CeA) blocked anesthesia-induced memory impairment, whereas optogenetic inhibition or knocking down of Igfbp2 expression in these projections is sufficient to engender similar memory impairment in control mice. The findings demonstrate that Igfbp2 in glutamatergic neurons in the PVT afferents to the CeA mediates fear memory deficits caused by repeated neonatal anesthesia in mice of both sexes, highlighting Igfbp2 as a potential therapeutic target for repeated anesthesia-induced cognitive impairment.

Keywords: Insulin‐like growth factor‐binding protein 2; anesthesia; central amygdala; fear memory; paraventricular thalamus.