COCAINE INDUCED DISTURBANCES OF MOUSE BRAIN DEVELOPMENT

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Between 5-15% of infants born in urban America today have been exposed to cocaine in utero. There is a spectrum of outcomes for "crack kids", with prenatal and postnatal factors influencing the expression of transplacental cocaine effects. Clinical studies have suggested that the single best marker for prenatal cocaine effects, including the postnatal developmental compromise seen in a subset of affected children, is impairment of fetal and postnatal brain growth. We have developed an animal model, in mice, of prenatal cocaine exposure which has allowed us to dissociate the direct effects of cocaine in altering fetal brain development, from the indirect effects associated with cocaine-induced malnutrition. We find that transplacental cocaine exposure independently impairs fetal brain and body growth, results in transient as well as permanent behavioral disturbances in exposed offspring, and results in permanent alterations in neocortical cytoarchitecture. We have proposed experiments to investigate the determinants, correlates and mechanisms underlying these growth, behavioral, and neuropathologic changes. We will use these measures to determine whether cocaine administered during a more restricted gestational period, or at a lower dose, is sufficient to produce alterations in fetal growth and postnatal behavior, and to see whether these features can be dissociated. We propose experiments to identify and quantitate alterations in neocortical structure: a quantitative cytoarchitectonic analysis of the "barrel field" of somatosensory cortex, including measures of cortical thickness, cell density as well as characterization of anatomic markers which reflect alterations in the maturation and precision of anatomic organization of this neocortical region consequent to transplacental cocaine exposure. We propose a series of experiments to map neuronal activation to identify those brain structures and neural systems which are altered in cocaine exposed mice as adults, and which correlate with specific behavioral impairments evident in blocking of second-order aversive conditioning. Information gained from these animal studies should lead to clinical insights regarding gestational exposure to cocaine in humans, fostering improved diagnostics, treatment and prevention of one of the escalating causes of developmental disability in our society.