Engrams, Neurogenesis, and Forgetting

In this thesis, three projects are described that add to our understanding of how forgetting is represented in the brain. In project 1, age-dependent changes in forgetting of spatial information is characterized in mice. Infant mice displayed significant forgetting when tested one month following training (i.e., infantile amnesia). Overtraining infant mice did not overcome the forgetting phenotype, indicating that the observed forgetting is not due to a deficit in memory encoding. Presentation of an environmental reminder one month following training led to memory recovery, suggesting that infantile forgetting is caused, at least in part, by a deficit in memory retrieval. Given the evidence that infantile amnesia is a deficit in memory retrieval, project 2 asked whether infantile forgetting can be overcome via a dentate gyrus engram ‘tag-and-activate’ strategy. Optogenetic stimulation of dentate gyrus encoding neural ensembles recovered ‘lost’ infant memories even 90 days following the initial learning event. In a process akin to pattern completion, memory recovery was associated with reinstatement of both hippocampal and cortical engram neurons. Recent work from our lab has shown that hippocampal neurogenesis promotes forgetting in both infants and adults. In project 3, the mechanism underlying neurogenesis-mediated forgetting was explored. Multiple transgenic mouse lines were used that granted bidirectionally control over the extent to which adult-generated dentate gyrus neurons remodel surrounding neural circuitry. Using this strategy, we found evidence that newborn neurons promote forgetting by reconfiguring the circuitry within which hippocampal memories are embedded. Importantly, neurogenesis-induced forgetting was negatively correlated with engram reinstatement in the hippocampus. Together, this thesis adds to the growing literature on the neural basis of forgetting.Ph.D