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

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

A Lifespan Analysis of Intraneocortical Connections and Gene Expression in the Mouse II

The mammalian neocortex contains an intricate processing network of multiple sensory and motor areas that allows the animal to engage in complex behaviors. These anatomically and functionally unique areas and their distinct connections arise during early development, through a process termed arealization. Both intrinsic, activity-independent and extrinsic, activity-dependent mechanisms drive arealization, much of which occurs during the areal patterning period (APP) from late embryogenesis to early postnatal life. How areal boundaries and their connections develop and change from infancy to adulthood is not known. Additionally, the adult patterns of sensory and motor ipsilateral intraneocortical connections (INCs) have not been thoroughly characterized in the mouse. In this report and its companion (I), we present the first lifespan analysis of ipsilateral INCs among multiple sensory and motor regions in mouse. We describe the neocortical expression patterns of several developmentally regulated genes that are of central importance to studies investigating the molecular regulation of arealization, from postnatal day (P) 6 to P50. In this study, we correlate the boundaries of gene expression patterns with developing areal boundaries across a lifespan, in order to better understand the nature of gene–areal relationships from early postnatal life to adulthood