UCLA

Memories made early in life are rapidly forgotten, but those made later in life can last a lifetime. Recent work shows that early-formed memories leave a lasting trace in the brain, but why they fail to be retrieved remains poorly understood. Here, we performed a brain-wide screen to identify developmental changes in fear memory networks that align with the emergence of persistent memory. We used TRAP2 mice (Targeted Recombination in Active Populations) in combination with brain clearing and light sheet fluorescence microscopy to compare neuronal populations and networks activated by recent (1 day) fear memory retrieval at infant (P17), juvenile (P25) or adult (P60) stages. While adults had more functional connectivity with the thalamus and hypothalamus, infants had more functional connectivity within the cortex and olfactory areas at 1 day memory retrieval. Network analyses revealed that the functional organization of memory networks was also developmentally regulated. Infant memory network was highly interconnected across the entire brain, while the juvenile network was sparser. The adult fear memory network was sparse and more clustered, with most connections between cortical regions, hippocampal formation, amygdala, and striatum. Of these regions, the retrosplenial cortex (RSP), a key memory center, had activation patterns highly corresponding to successful memory retrieval at all ages. To further examine how RSP memory functions change with age, we examined the extent to which neurons activated during recent memory retrieval (1d) are reactivated during later memory retrieval (7d) at different ages. Adults had higher reactivation rates in RSP compared to younger groups, suggesting ensemble stability contributes to memory persistence. We next tested whether chemogenetic reactivation of tagged RSP ensembles could enhance memory. Chemogenetic RSP reactivation a week after learning enhanced memory retrieval in adults, but not in infants. In contrast, reactivating infant-tagged RSP ensembles a month later recovered forgotten memories. Together these data reveal specific changes in the activity and functional connectivity of brain regions and circuits that coincide with the developmental transition from amnesic to persistent memories. Particularly the RSP, which stores latent infant memories and continues to functionally mature with age, may contribute to the developmental emergence of persistent memories.