Genetic analysis of the fear-potentiation of startle response in mice.

摘要

Anxiety and fear related disorders affect close to 19 million people in America annually. These disorders have complex causes, and may have a significant genetic component. Fear-potentiation of startle (FPS) was employed in mice to investigate the genetic contribution to fear and anxiety like traits. FPS uses conditioned fear and the acoustic startle reflex to gauge differences in fear induced arousal. It shows face, construct and predictive validity with analogous paradigms in man. In this study, basic parameters for the FPS behavioral assay were developed and the process of genetic dissection begun using quantitative trait loci (QTL) analysis methods in a multistep, multi-disciplinary approach to locate fear, and emotionality related genetic loci.;In the first stage the basic parametrics for generating FPS in mice were examined in two polymorphic mouse strains. These experiments were expanded to examine FPS acquisition and extinction in ten additional, genetically diverse inbred strains. The DBA/2J strain proved to possess the best FPS response.;The BXD/Ty recombinant inbred series was used to detect putative FPS QTL based on relationships between genotype strain distribution profiles and strain phenotypic means. Because of the potentially high number of false positive results, a population of B6D2F2 hybrids were generated to confirm identified QTL and detect additional QTL through a genome wide scan. Several BXD quantitative trait loci were confirmed on chromosomes 3, 5, 7, 8, and 16. In addition, the genome wide scan revealed a significant FPS QTL on chromosome 11 and suggestive QTL on chromosomes 1, 2, 4, 10, 14, 16 and 19.;The final stage examined changes in allelic frequency in selectively bred lines of high and low FPS responder mice. This technique was used as a further confirmation of putative BXD and BDF2 QTL. It confirmed previously identified loci on 1, 2, 5, 7, 16, 19, and X. Many of these regions contain genes for neurotransmitters believed to influence behavior and emotionality.