| Chronic early-life stress affects a majority of the world's children and is associated with deficits in hippocampus-dependent cognitive function during adulthood. Studies in humans cannot establish with certainty whether early-life stress causes cognitive dysfunction because other influences, including differences in genes and in environment, cannot be controlled. Therefore, we created a novel mouse model of chronic early-life stress to take advantage of the power of genetically modified mice to elucidate the molecular mechanisms and roles of specific genes responsible for the consequences of early-life stress on hippocampal function and dendritic structure.;The chronic early-life stress paradigm involved altering the cage environment during the first week of life, which led to fragmentation of maternal care, in turn resulting in stress in the pups. Stress early in life was manifest in hormonal and molecular changes in the hypothalamus, and led to persistent impairment of hippocampus-dependent learning and memory in adult mice in the absence of anxiety-like or depression-like behaviors. Enrichment of the environment after the early-life stress period could not reverse the cognitive deficits provoked by the stress.;Taking advantage of genetically engineered mice expressing yellow-fluorescent protein in hippocampal neurons, we examined the neuroanatomical basis of the cognitive defects provoked by stress. Whereas we did not confirm dendritic loss after early-life stress, we found that loss of dendritic spines, even in the absence of dendritic atrophy, was associated with profound memory defects in adult mice subjected to short, multi-modal stress.;In summary, this dissertation developed mouse models for stress, and employed these models to study fundamental processes related to stress-provoked losses of hippocampus-dependent learning and memory throughout life. |
