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Elevated aggressive behavior in male mice with thyroid-specific Prkar1a and global Epac1 gene deletion.

ABSTRACT: 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.

SUBMITTER: Russart KLG

PROVIDER: S-EPMC5828986 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Elevated aggressive behavior in male mice with thyroid-specific Prkar1a and global Epac1 gene deletion.

Russart Kathryn L G KLG Huk Danielle D Nelson Randy J RJ Kirschner Lawrence S LS

Hormones and behavior 20180103

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;Prkar1a<sup>flox/flox</sup>;Epac1<sup>-/-</sup> (R1A-Epac1KO) mice, originally bred to investigate the role of exchange protein directly activated by cAMP (Epac1) in follicular thyroid cancer, displayed self-mutilati ...[more]

PMID: 29289659

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Project description:Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC.The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC.We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors.The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals.Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases.There were no interventions.Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression.Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement.These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.

Dataset Information

Elevated aggressive behavior in male mice with thyroid-specific Prkar1a and global Epac1 gene deletion.

Publications

Elevated aggressive behavior in male mice with thyroid-specific Prkar1a and global Epac1 gene deletion.

Similar Datasets

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