Abnormal Ontogeny and Cortical Function in a Mouse ModelEarly stress experience is regarded as powerfully contributing factor in the etiology of mental healthdisorders such as schizophrenia and mood disorders. Early stress experience leads to permanentalterations in the adreno-cortical-hypothalamic [HPA] response in later life. In rodent models, long-term,early postnatal maternal separation [MS] (3-24 hours) leads to profound HPA hyper-responsiveness to stressin later life, along with increased anxiety and impaired cognition. However, early, short term 'handling' ofpups (10-15 minutes) results in long-term stress hypo-responsiveness, decreased anxiety and improvedcognition, apparently as result of increased maternal grooming of the handled pups upon their return. Overthe current funding period, we have developed a neonatal MS separation paradigm in mouse, based on asplit-litter design. Stressed male mice [STR] from these liters develop cognitive impairments, increasedanxiety and aggression by adulthood, and, altered cortical width, that is modifiable by experience.Surprisingly, non-stressed litter-mate males [LMC] also develop cortical changes and cognitive andemotional impairments, albeit at somewhat lower levels, compared to age matched control [AMC] mice fromlitters without any stress exposure. Preliminary data suggest decreased maternal grooming of LMCcompared to STR pups. This proposal aims to test the hypotheses that 1) maternal grooming of the STRand LMC pups induces graded effects on early HPA axes responsiveness that subsequently, differentiallyalter the monoaminergic innervation to cortex and hippocampus. Furthermore, based on effects of neonatalserotonin [5-HT] and dopamine [DA] depletions on cortical morphogenesis and plasticity, we hypothesizethat 2) cortical morphological differences in both STR and LMC, compared to AMC mice, are the result ofimpaired cortical morphogenesis and plasticity resulting from altered 5-HT and/or DA innervation; suchmorphological changes, in turn, may precipitate altered behavior. The long-term goal of this competitiverenewal application is to understand, on the level of cellular neurobiology, how developmental interactionsbetween environmental triggers and genetic vulnerabilities can induce altered cognitive function akin to thoseseen in a variety of mental health disorders.
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