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

Kathryn L G Russart; Danielle Huk; Randy J Nelson; Lawrence S Kirschner

doi:10.1016/j.yhbeh.2017.12.012

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

Horm Behav. 2018 Feb:98:121-129. doi: 10.1016/j.yhbeh.2017.12.012. Epub 2018 Jan 3.

Authors

Kathryn L G Russart¹, Danielle Huk², Randy J Nelson³, Lawrence S Kirschner⁴

Affiliations

¹ Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address: kathryn.russart@osumc.edu.
² Department of Cancer Biology and Genetics, Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
³ Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
⁴ Department of Cancer Biology and Genetics, Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

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;Prkar1a^flox/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;Prkar1a^flox/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.

Keywords: Aggression; Behavioral phenotyping; Epac1; Hyperthyroidism; Prkar1a.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aggression / physiology*
Animals
Anxiety / genetics
Behavior, Animal / physiology*
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics*
Gene Deletion
Genotype
Guanine Nucleotide Exchange Factors / genetics*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Organ Specificity / genetics
Signal Transduction / genetics
Thyroid Gland / metabolism*

Substances

Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
Epac protein, mouse
Guanine Nucleotide Exchange Factors
Prkar1a protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding