Prenatal ethanol exposure & neocortex, functional org. & gene expression

University Of California Riverside, Riverside CA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Children diagnosed with Fetal Alcohol Spectrum Disorder (FASD) exhibit a range of physical, perceptual, cognitive, emotional and behavioral deficits that result from underlying neurobiological damage following prenatal alcohol exposure. The human neocortex, the part of the brain responsible for many of these functions, is a likely location of ethanol-induced alterations to the developing nervous system. To investigate the impact of prenatal ethanol exposure (PrEE) on functional anatomy of the neocortex, we created an FASD mouse model in the CD-1 strain. In our preliminary studies, we found disrupted targeting of motor and sensory intraneocortical connections (INCs) in newborn PrEE mice. Sensory and motor INCs represent a complex neural circuit that regulates behavior, attention and integrates sensori-motor processing. The aberrant developmental targeting of INCs in neocortex may reflect a disorganized circuit or altered cortical area boundaries, as we observed abnormal anatomical connections between the frontal and occipital lobes on the day of birth. In this two-year research proposal, we begin an in-depth analysis of the phenotype throughout the lifespan of our murine model. We plan to first examine potential mechanisms underlying the abnormal INC development. As cortical gene expression has been shown to regulate INC development (Huffman et al., 2004, Dye et al., 2011a, 2011b) we will identify early patterning of 7 genes, including RZR-ss, Id2, Cad8, Ephrin A5, Eph A7, COUP-TFI and Lhx2, in the neocortex of the PrEE mice. Next, we will extend our analyses of INCs, gene expression and anatomical staining to determine whether the phenotype persists in postnatal ages (including postnatal day (P) 0, 6, 10, 20, 50, 90 and 365). Finally, we will conduct multi-unit electrophysiological recording experiments in the neocortex of PrEE mice aged from P50 to P365 to determine the location of functional boundaries and internal features of sensory (Visual, Somatosensory and Auditory) and motor cortical areas. All data obtained in PrEE mice will be compared to age matched controls. We believe that the profoundly abnormal neocortical wiring observed in ethanol-exposed newborn mice may represent an underlying substrate for many perceptual, cognitive, emotional and behavioral deficits observed in children with FASD. Thus, the mechanisms underlying this phenotype must be explored, and the long-term postnatal impact on the anatomy and physiology in the brain of the animal must be determined.