Sleep, NMDA Receptor Subunits, and the Compensatory Pathway: Understanding Contextual Fear Conditioning in the Absence of the Dorsal Hippocampus

Abstract The loss of the dorsal hippocampus (DH) results in profound deficits in contextual fear-conditioned (CxFC) memory. Nonetheless, CxFC memories can still form without the DH, specifically with multiple trials at three-day intervals. The infralimbic cortex (IL) is pivotal in initiating this compensatory process post-DH loss, but the precise factors remain elusive. Our study aims to delineate key factors of compensatory CxFC in DH absence by investigating the effects of sleep deprivation (SD) and NMDA receptor subunits NR2A and NR2B. Using a DH-lesioned rat model, we conducted two conditioning trials separated by three days and assessed fear response during the subsequent test. We observed that DH-lesioned animals exhibited to SD (DHL-SD) did not elicit a compensatory CxFC response, displaying significantly impaired freezing during the second test. Conversely, DH-lesioned non-sleep-deprived animals (DHL-NSD) compensated for DH loss and exhibited robust CxFC responses during the second test. Moreover, inhibiting NR2B subunits in the IL during initial CxFC training disrupted the formation of compensatory fear memory in DH-lesioned animals, while NR2A subunit blockade showed no significant effect. These emphasize the adverse impact of SD on compensatory memory and the critical role of NR2B subunits in facilitating compensatory CxFC memory formation following DH loss. Competing Interest Statement The authors have declared no competing interest.