Molecular mechanisms of infantile learning and memory

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Project Summary Behavioral studies have shown that early life experience significantly shapes the development of brain abilities. Accordingly, if early experiences are highly unbalanced, e.g. if they occur under the influence of chronic challenges or stresses, the individual's personality will develop specific traits, including some that are associated with severe psychopathologies. Despite these extensive behavioral characterizations, very little is known about the biological mechanisms underlying learning and memory in early life, with the exception of the effects of trauma and stress. Understanding the mechanisms underlying learning and memory in early development is key for comprehending how the learning and memory systems are built and function throughout life, as well as to better elucidate the deficits associated to neurodevelopmental disabilities. One of the most important systems operating in the brain is the medial temporal lobe-dependent memory system, which processes information about episodic, spatial, contextual and social experiences. Until recently it was believed that this memory system does not function in infancy because it is developmentally immature, and only begins to be involved late in development. However, recent studies in rodent models, including our own, showed that episodic and spatial forms of learning require the function of biological mechanisms in the dorsal hippocampus (dHC), a main region, together with the medial prefrontal cortex (mPFC), of the medial temporal lobe memory system. Despite this recent progress, knowledge of the biological and system-level mechanisms of infantile, hippocampus-dependent learning and memory is lacking. To fill this knowledge gap we propose to employ rodent models of episodic and spatial learning, genetically engineered mouse models, molecular imaging technology, spatial transcriptomics and RiboTag mouse technology combined with omic analyses to pursue the following specific aims: (1) To map the distribution at a system level (dHC and mPFC) of the cellular networks activated in response to episodic learning in infancy and in memory recovery following reminders at later ages, and to test the malleability and roles of recovered infantile memories in adult behavior. (2) To comprehensively profile in situ dHC and mPFC gene expression at the level of the whole transcriptome, as well as obtain a comprehensive translatome specifically regulated in excitatory and inhibitory neurons, in response to learning in both infant and adult brains. These experiments will provide an unprecedented amount of novel information regarding the biological and system-level mechanisms underlying infantile learning and memory, as well as an invaluable source of knowledge for generating novel hypotheses regarding neurodevelopmental and adult cognitive disorders.