Enhanced Fear Memory in Adult Male C57BL/6 Mice Following Low‐Dose Isoflurane Exposure During Juvenile Development

Objective To elucidate the neural mechanisms through which neonatal exposure to low‐dose anesthetic isoflurane (ISO) enhances adult fear memory, specifically examining neural oscillations and activation patterns in the mediodorsal thalamus (MDL), dentate gyrus (DG), anterior cingulate cortex (ACC), and medial entorhinal cortex (MEC). Methods Male C57BL/6 mice received 0.75% ISO or saline injections at postnatal day 7 (P7). At 6 months, contextual fear‐memory testing was conducted (Saline + Air: n = 14; Saline + ISO: n = 13). Neural correlates were assessed via in vivo electrophysiology during behavioral tasks and c‐Fos immunohistochemistry in the MDL, DG, ACC, and MEC. Results ISO‐exposed mice exhibited significantly enhanced fear memory, with >75% displaying freezing as the dominant conditional response (vs. controls). This was accompanied by increased c‐Fos+ cell density in the MDL and altered slow gamma oscillation power in fear‐processing circuits. Non‐freezing responses (e.g., jumping/darting) were reduced in the Saline + ISO group. Interpretation Early low‐dose ISO intervention in neonatal mice enhances adult fear memory, potentially through MDL activation and slow gamma oscillation modulation. These findings indicate that low‐dose ISO may improve cognitive function by optimizing fear memory consolidation, contrasting with known detrimental effects of high‐dose anesthetics on neurodevelopment.