Investigating the Mechanisms of Memory Engram Plasticity in Infantile Amnesia

Abstract

Infantile amnesia describes the inability to recall memories formed during a critical period of development in infancy and early childhood. While significant advancements have been made in characterizing this phenomenon in both humans and rodents, the neurobiological mechanisms remain poorly understood. This thesis focuses on gaining a better mechanistic understanding of infantile amnesia. Research in rodents has demonstrated that memories formed prior to the onset of infantile amnesia are not completely lost but rather maintained across the lifespan in a latent and inaccessible state. Furthermore, our previous work has shown that a gestational immune challenge, maternal immune activation (MIA), prevents infantile amnesia in male offspring suggesting an important role of immune signalling pathways in the neurobiology of this phenomenon. Here, we characterised the mechanistic relationship between immune signalling, infantile amnesia and infant engram plasticity with a focus on microglial cells. Microglia, the resident immune cells of the brain, are known to play an important role in synaptic refinement during postnatal development and are also perturbed by MIA. We found that inhibition of microglial activity during a specific postnatal window prevents infantile amnesia for a contextual fear memory. Using activity-dependent ensemble labelling, we labelled infant memory engram cells and through histological analysis we have explored changes in engram activity and microglia-engram interactions following microglial manipulation. We explored the overlap between MIA, microglia activity and infantile amnesia and revealed a key role for microglia in MIA-induced changes in infant memory retention. Lastly, we focused on developing translational behavioural paradigms to study infantile amnesia and with the hope of furthering cross-species research approaches. This body of work aims to further our understanding of the biological mechanisms of memory formation and forgetting across development.