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Alterations in circulating thyroid hormone concentrations are associated with several psychological and behavioral disorders. In humans, behavioral disorders such as anxiety, depression, and attention-deficit hyperactivity disorder can be associated with thyroid disease. The Tpo-Cre;Prkar1aflox/flox;Epac1−/− (R1A-Epac1KO) mice, originally bred to investigate the role of exchange protein directly activated by cAMP (Epac1) in follicular thyroid cancer, displayed self-mutilating and aggressive behaviors during casual observation. To assess these atypical responses, behavioral testing was conducted with the R1A-Epac1KO mice, as well as their single knockout counterparts, the thyroid-specific Prkar1a−/− and global Epac1−/− mice. Mice of all three genotypes demonstrated increased aggressive behavior against an intruder mouse. In addition, Epac1−/− mice increased response to an auditory stimulus, and the Prkar1a−/− and R1A-Epac1KO mice increased swimming behavior in the Porsolt forced swim test. Both Prkar1a−/− mice and R1A-Epac1KO mice have increased circulating thyroxine and corticosterone concentrations. Although hyperthyroidism has not been previously associated with aggression, increased thyroid hormone signaling might contribute to the increased aggressive response to the intruder mouse, as well as the increased swimming response. Mice with a genetic background of Tpo-Cre;Prkar1aflox/flox;Epac1−/− are aggressive, and both the thyroid-specific knockout of Prkar1a and global knockout of Epac1 likely contribute to this aggressive behavior. This study supports the hypothesis that altered thyroid signaling and aggressive behavior are linked.Thyroid-specific knockout of Prkar1a and global Epac1 knockout induce aggression.Prkar1a knockout causes hyperthyroidism, leading to hyper-responsiveness to stimuli.Epac1−/− also causes hyper-responsiveness, likely due to sensorimotor gating deficits.Both mutations contribute to aggression in Tpo-Cre;Prkar1aflox/flox;Epac1−/− mice.