Enrichment-induced forgetting is associated with white matter microstructure in mice

Memories are stored in brain circuits, sometimes referred to as engrams. Forgetting happens when these neural activity patterns fail to be reactivated by retrieval cues. Neuroplasticity can destabilize existing memory circuits by altering the fidelity of neural signals and contribute to forgetting. Existing research has described plasticity in grey matter that contributes to forgetting; however, plasticity within white matter has not been explored. Here, brain plasticity was induced after contextual fear conditioning by housing mice in environmentally-enriched multilevel cages (EE) for four weeks. EE mice demonstrated forgetting as measured by reduced time spent freezing during the fear conditioning test compared to mice housed in standard cages (SE) (EE<SE β=-52.2 %, p = 1.1 ×10^-11). Ex vivo brain diffusion-weighted MRI was used to assess enrichment-induced plasticity in white matter and revealed that fractional anisotropy (FA) was increased in the anterior commissure, cerebral peduncle, corpus callosum, cortical spinal tract, and fimbria, in EE mice compared to SE mice (10 % FDR). In EE mice, increased FA in the corpus callosum and fimbria predicted reduced freezing (p < 0.05), suggesting that in these tracts, white matter changes induced by enrichment may contribute to forgetting. Consistent with the above, administering clemastine fumarate, a pro-myelinating drug, induced forgetting in male mice (β=-23.5 %, p = 0.009). Neurogenesis, an established mechanism that contributes to forgetting, indexed by the volume of the granule cell layer of the dentate gyrus, independently predicted forgetting (β=-13.6 %, p = 0.036). These findings indicate that myelin-related plasticity in white matter tracts that support contextual fear memory may play a role in enrichment-induced forgetting.