The central hypothesis is that prenatal exposure to ethanol induces developmental defects that lead to permanent imbalances in the brain. These imbalances include opposing neurotransmitter systems and ligand-receptor relations. Corollary hypotheses are that the outcomes of ethanol-induced defects are focal hyper-development and mismatches between afferents and their targets. These defects can result from mistiming of developmental events. That is, proper establishment of neural structure is requisite for proper neural function, e.g., behavior and cognition. Prenatal ethanol exposure causes profound deficits in learning and behavior. Indeed, alcohol-related neurodevelopmental disorder (ARND) affects as many as two of every 100 live births. Human studies point to particular targets of ethanol teratogenicity, however, they are confounded by factors such as the timing, duration and amount of the alcohol exposure, poly-drug use, and nutrition during the pregnancy. A non-human primate model allows us to avoid these confounds and to assess the effects of in utero ethanol exposure per se. The proposed studies will use the brains of monkeys that were exposed to ethanol episodically. Preliminary data show that episodic prenatal exposure to ethanol can produce two kinds of anatomical changes- decreases and increases. We will perform five studies of the effects of prenatal exposure to ethanol on the structure of the brains of adolescent non-human primates. The proposed studies will examine structures (1) that are increased in size or (2) that are poorly matched with afferent and efferent nuclei following prenatal exposure to ethanol. The effects of ethanol on interactive, overlapping systems that define neuronal communication will be determined. These systems include (3) glutamatergic (excitatory) and GABAergic (inhibitory) neurons key to cortical circuitry and (4) neurotrophins (and their receptors) that support cortical neurons and apparently underlie the subtle plasticity involved in learning and memory. (5) We will examine the effect of timing and duration of the ethanol exposure on outcomes. These will focus on brainstem nuclei with different developmental origins and sequences of gene expression. The five studies will rely on rigorous stereological analyses of light and electron immunohistochemical microscopic preparations. As a unit, they will provide insight into the etiology and outcomes of ethanol teratogenicity and an anatomical basis for ARND.
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