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Open Access Publications from the University of California

An Analysis of the Murine Neocortex: Normal Development and the Impact of Prenatal Ethanol Exposure on Connectivity, Gene Expression, and Behavior

  • Author(s): El Shawa, Hani
  • Advisor(s): Huffman, Kelly
  • et al.
Abstract

A hallmark of mammalian evolution is the structural and functional complexity of the cerebral cortex. Within the cerebral cortex, the neocortex is a complexly organized structure that is comprised of multiple interconnected sensory and motor areas. These areas and their precise patterns of connections arise during development, through a process termed arealization. Intrinsic, activity-independent and extrinsic, activity-dependent mechanisms are involved in the development of neocortical areas and their connections. This dissertation presents a lifespan analysis of ipsilateral intra-neocortical connections (INCs) among multiple sensory and motor regions as well as a summary of neocortical expression patterns of several developmentally regulated genes that are of central importance to investigating the control of arealization, from the embryonic period to adulthood in the mouse. In this analysis, we utilize novel methods to correlate the boundaries of gene expression with intra-neocortical connections and developing areal boundaries, in order to better understand the nature of gene-arealization relationships during development. Additionally, we investigated if prenatal exposure to toxins, such as ethanol, could alter the normal development of the neocortex. Children diagnosed with Fetal Alcohol Spectrum Disorder (FASD) exhibit a range of cognitive, emotional and behavioral deficits that are presumed to result from underlying developmental brain damage from prenatal alcohol exposure. We investigated the anatomical development of INCs of primary sensory areas in a prenatal ethanol-exposed (PrEE) mouse model through a detailed analysis of the complex circuitry that, in humans, integrates sensori-motor processing and behavior. The mouse model was generated through systematic per oral administration in pregnant CD-1 mice during the entire 19-day gestational period. Despite being regulated by genetic influences, INC development can be altered by exposure to ethanol via maternal consumption during pregnancy. Observed changes in brain anatomy that occur may be related to the neocortically-mediated cognitive, emotional and behavioral characteristics of FASD in humans. We then investigated behavioral features associated with anxiety, motor coordination, balance and sensorimotor disintegration (SSD) in adolescent control and PrEE mice. In mammals, INCs integrate sensori-motor processing, emotion, cognition and behavior. The PrEE induced changes in behavior in a FASD mouse model may stem from abnormal cortical connectivity seen at birth and possibly mimic neocortically-mediated behavioral characteristics of human FASD.

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