Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY: A critical function of the nervous system is to rapidly process sensory information and initiate appropriate behavioral responses. Defects in sensory processing and behavior selection are commonly observed in neuro-psychiatric conditions including anxiety, autism (ASD), and schizophrenia (SZ). Despite the biological and clinical relevance, our understanding of the cellular and molecular mechanisms regulating these processes is limited, in part due to the intricate and dynamic circuitry involved in complex human decision-making. The etiology of sensory processing disorders remains equivocal; however, it is hypothesized that intrinsic/genetic, extrinsic/environmental and the interactions of intrinsic and extrinsic factors can play fundamental roles. Understanding the genetic components of environmental triggered response is critical in understanding the overall impact of the environment on organisms, including humans. Many environmental changes show differential response within populations of individuals due to genetic differences in the affected pathways. In parallel, many environmental pollutants have a range of adverse neuro-health outcomes and despite increasing recognition of the importance of evaluating neurotoxicity in safety assessment, tens of thousands of commercial chemicals in current use, have not been evaluated. In this R21 proposal we investigate how gene by environmental interactions (GxE) impact developmental neurotoxicity linked to sensory processing deficits and neuro-psychiatric conditions later in life. We utilize the Medaka Inbred Kiyosu-Karlsruhe (MIKK) Panel to test the hypothesis that there are common pathways of environmental contaminant response across vertebrates, and that the majority of these pathways have segregating genetic variation contributing to polygenic GxE effects of contaminant responses. The MIKK panel consists of 80 near- isogenic inbred lines, currently inbred for 22 generations, with fully sequenced genomes and transcriptome. Both molecular and organismal phenotypes are distinguishable, and molecular traits can be mapped to specific loci. We propose that the MIKK panel will provide unique insights into GxE components of developmental neurotoxicity and sensory processing behaviors related to neuropsychiatric conditions. Advances in developmental toxicity studies using zebrafish and medaka, key biomedical model species, have provided insights using larval behavioral studies. The high relative fecundity of teleost models, as compared to mice, as well as the regulatory advantages to using an earlier-diverging vertebrate (reducing the use of animals in research) provides additional incentives to developing these methods. The MIKK panel provides a key resource with the isogenic strains necessary to characterize the genomic contributions to environmental effects with important implications for sensitive human populations.
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