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Teratology v2.0: Building a path forward
Neurotoxicology and Teratology 43 (2014) 76–97
Contents lists available at ScienceDirect
Neurotoxicology and Teratology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / n e u t e r a
Platform presentations NBTS 01 Teratology v2.0: Building a path forward T.B. Knudsen US EPA, Research Triangle Park, NC, United States Unraveling the complex relationships between environmental factors and early life susceptibility in assessing the risk for adverse pregnancy outcomes requires advanced knowledge of biological systems. Large datasets and deep data-mining tools are emerging resources for predictive modeling that can be broadly applied to the analysis of developmental pathways, processes, and toxicities. For the teratologist, does this “big data” stream represent a new solution for traditional problems, or new problems for traditional solutions? Reducing a complex embryological system into simpler components on one hand may facilitate analysis, but on the other hand disrupts precisely the combination of qualities and features that makes the system complex in the first place. Multi-cellular interactions ultimately determine the resolution of molecular impairment(s) into critical effects that ultimately determine a developmental defect or disability. This lecture will focus on challenges and opportunities associated with utilizing complex data for predictive and mechanistic understanding of teratogenesis, strategies to interact big-data with principles of teratology for hypothesis generation and adverse outcome pathway elucidation, and spatio-temporal prediction utilizing the major organizing principles of dosimetry, criticality, and susceptibility. This abstract does not reflect US EPA policy. doi:10.1016/j.ntt.2014.04.004
NBTS 02 Amphetamine exposure during adolescent development induces long lasting changes in cognition that are associated with prefrontal cortex dysfunction J. Gulley University of Illinois, Champaign IL, USA As individuals age from adolescence into adulthood, the brain undergoes significant changes in structure and function that may contribute to age-dependent differences in behavior. Research in both humans and laboratory animals has shown that this normal developmental process may be perturbed by exposure to drugs of abuse. Moreover, drug exposure during this time may have adverse consequences on behavior that persist into adulthood. Thus, it is important to determine if the mechanisms of drug-induced plasticity differ in adolescents compared to adults and how this contributes to behavioral dysfunction. In my presentation, I will discuss our studies using rats that are exposed to amphetamine during adolescence or
adulthood and then later given tests of cognitive performance and brain function. We have observed disruptions in working memory and inhibitory control that persist as long as three months after drug exposure ceases, with some of these changes being more significant following adolescent compared to adult exposure. A potential mechanism for these cognitive changes is amphetamine-induced adaptation of prefrontal cortex function, including reductions in dopaminemediated inhibitory control of layer V pyramidal neurons. Overall, these changes in cognitive function and neurophysiology, which appear to result from drug-induced changes in the normal trajectory of adolescent development, may contribute to the numerous complications associated with adolescent-onset substance abuse.
doi:10.1016/j.ntt.2014.04.005
NBTS 03 Neurobiological and neuropsychological consequences of substance abuse in adolescents M. Silveri Department of Psychiatry, Harvard Medical School, Boston, MA, USA McLean Hospital Imaging Center, Belmont, MA, USA Recent advances in neuroimaging are providing new opportunities to non-invasively characterize the development of the adolescent brain. In particular, studies utilizing magnetic resonance (MR) technologies have helped identify important neurobiological milestones in brain development that, when examined in the context of cognitive and emotional maturation, ultimately allow for behavioral transitions from dependence to independence. The frontal lobe is the last region of the brain to undergo major remodeling, a process that occurs late in adolescence and extends into the early twenties, the period referred to as emerging adulthood. Frontal lobe refinement, along with maturation of the gamma-amino-butyric-acid (GABA) inhibitory neural system, permits necessary developmental improvements in cognitive control and reduced impulsivity. This critical period of neurobiological development therefore confers heightened vulnerability to the initiation and escalation of substance use that often accompanies the second decade of life. Thus, developmental investigations are necessary to provide important insights regarding the consequences of early substance use on adolescent brain maturation and cognitive development, which may also help reveal potential risk factors for the later manifestation of addictive disorders and the onset of psychiatric illnesses.
doi:10.1016/j.ntt.2014.04.006
Contents lists available at ScienceDirect
Neurotoxicology and Teratology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / n e u t e r a
Platform presentations NBTS 01 Teratology v2.0: Building a path forward T.B. Knudsen US EPA, Research Triangle Park, NC, United States Unraveling the complex relationships between environmental factors and early life susceptibility in assessing the risk for adverse pregnancy outcomes requires advanced knowledge of biological systems. Large datasets and deep data-mining tools are emerging resources for predictive modeling that can be broadly applied to the analysis of developmental pathways, processes, and toxicities. For the teratologist, does this “big data” stream represent a new solution for traditional problems, or new problems for traditional solutions? Reducing a complex embryological system into simpler components on one hand may facilitate analysis, but on the other hand disrupts precisely the combination of qualities and features that makes the system complex in the first place. Multi-cellular interactions ultimately determine the resolution of molecular impairment(s) into critical effects that ultimately determine a developmental defect or disability. This lecture will focus on challenges and opportunities associated with utilizing complex data for predictive and mechanistic understanding of teratogenesis, strategies to interact big-data with principles of teratology for hypothesis generation and adverse outcome pathway elucidation, and spatio-temporal prediction utilizing the major organizing principles of dosimetry, criticality, and susceptibility. This abstract does not reflect US EPA policy. doi:10.1016/j.ntt.2014.04.004
NBTS 02 Amphetamine exposure during adolescent development induces long lasting changes in cognition that are associated with prefrontal cortex dysfunction J. Gulley University of Illinois, Champaign IL, USA As individuals age from adolescence into adulthood, the brain undergoes significant changes in structure and function that may contribute to age-dependent differences in behavior. Research in both humans and laboratory animals has shown that this normal developmental process may be perturbed by exposure to drugs of abuse. Moreover, drug exposure during this time may have adverse consequences on behavior that persist into adulthood. Thus, it is important to determine if the mechanisms of drug-induced plasticity differ in adolescents compared to adults and how this contributes to behavioral dysfunction. In my presentation, I will discuss our studies using rats that are exposed to amphetamine during adolescence or
adulthood and then later given tests of cognitive performance and brain function. We have observed disruptions in working memory and inhibitory control that persist as long as three months after drug exposure ceases, with some of these changes being more significant following adolescent compared to adult exposure. A potential mechanism for these cognitive changes is amphetamine-induced adaptation of prefrontal cortex function, including reductions in dopaminemediated inhibitory control of layer V pyramidal neurons. Overall, these changes in cognitive function and neurophysiology, which appear to result from drug-induced changes in the normal trajectory of adolescent development, may contribute to the numerous complications associated with adolescent-onset substance abuse.
doi:10.1016/j.ntt.2014.04.005
NBTS 03 Neurobiological and neuropsychological consequences of substance abuse in adolescents M. Silveri Department of Psychiatry, Harvard Medical School, Boston, MA, USA McLean Hospital Imaging Center, Belmont, MA, USA Recent advances in neuroimaging are providing new opportunities to non-invasively characterize the development of the adolescent brain. In particular, studies utilizing magnetic resonance (MR) technologies have helped identify important neurobiological milestones in brain development that, when examined in the context of cognitive and emotional maturation, ultimately allow for behavioral transitions from dependence to independence. The frontal lobe is the last region of the brain to undergo major remodeling, a process that occurs late in adolescence and extends into the early twenties, the period referred to as emerging adulthood. Frontal lobe refinement, along with maturation of the gamma-amino-butyric-acid (GABA) inhibitory neural system, permits necessary developmental improvements in cognitive control and reduced impulsivity. This critical period of neurobiological development therefore confers heightened vulnerability to the initiation and escalation of substance use that often accompanies the second decade of life. Thus, developmental investigations are necessary to provide important insights regarding the consequences of early substance use on adolescent brain maturation and cognitive development, which may also help reveal potential risk factors for the later manifestation of addictive disorders and the onset of psychiatric illnesses.
doi:10.1016/j.ntt.2014.04.006