The CRHR1→PN→PVI Pathway in Medial Prefrontal Cortex Mediates Early-life Stress-induced Cognitive Deficits in Adolescent Mice

Abstract

Abstract Cognitive impairment, one core symptom of psychiatric disorders, is frequently observed in adolescents exposed to early-life stress (ES). However, the underlying neural mechanisms are unclear and the therapeutic efficacy is limited. Targeting at parvalbumin-expressing interneurons (PVIs) in the medial prefrontal cortex (mPFC), we report that mPFC PVI activity was reduced by ES and causally mediated ES-induced cognitive deficits in adolescent mice through chemogenetic or optogenetic experiments. We then demonstrate that ES reduced the excitatory inputs onto PVIs and pyramidal neuron (PN) activity and that ES negative effects were reversed by the knockout of corticotropin-releasing hormone receptor 1 (CRHR1, mainly expressed in PNs) in mouse mPFC, supporting the prefrontal CRHR1→PN→PVI pathway in mediating ES-induced cognitive deficits. Finally, antalarmin (a CRHR1 antagonist) treatment and environmental enrichment successfully restored PVI activity and cognitive deficits induced by ES. These findings highlight the critical role of PVIs in mediating and preventing ES-induced cognitive deficits in adolescent mice.