Hippocampal neural progenitor cells play a distinct role in fear memory retrieval in male and female CIE rats

Adult male and female GFAP-TK transgenic rats experienced six weeks of chronic intermittent ethanol vapor inhalation (CIE). During the last week of CIE, a subset of male and female TK rats were fed with Valcyte to ablate neural progenitor cells (NPCs). Seventy-two hours after CIE cessation, all CIE and age-matched ethanol naïve controls experienced auditory trace fear conditioning (TFC). Twenty-four hours later all animals were tested for cue-mediated retrieval in the fear context. Adult male CIE rats showed a significant burst in NPCs paralleled by reduction in fear retrieval compared to naïve controls and Valcyte treated CIE rats. Adult female CIE rats did not show a burst in NPCs and showed similar fear retrieval compared to naïve controls and Valcyte treated CIE rats, indicating that CIE-mediated impairment in fear memory and its regulation by NPCs was sex dependent. Valcyte significantly reduced Ki-67 and NeuroD labeled cells in the dentate gyrus (DG) in both sexes, demonstrating a role for NPCs in reduced fear retrieval in males. Valcyte prevented adaptations in GluN2A receptor expression and synaptoporin density in the DG in males, indicating that NPCs contributed to alterations in plasticity-related proteins and mossy fiber projections that were associated with reduced fear retrieval. These data suggest that DG NPCs born during withdrawal and early abstinence from CIE are aberrant, and could play a role in weakening long-term memory consolidation dependent on the hippocampus.