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;Prkar1a;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;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.

EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury

“…Previous studies have reported that EPAC1 −/− mice are protected against inflammatory (Eijkelkamp et al, 2013, Singhmar et al, 2016, Wang et al, 2013) and neuropathic pain (Eijkelkamp et al, 2013, Singhmar et al, 2018), but possible roles for EPAC2 are unknown. We show that EPAC2 −/− mice do not differ from their wild-type counterparts for general behavioral functions as found previously for EPAC1 −/− mice (Russart et al, 2018). While our results are in accord with previous publications (Lee et al, 2015, Srivastava et al, 2012), another study reported that EPAC2 −/− mice exhibit signs of anxiety (Zhou et al, 2016).…”

“…As previously shown for EPAC1 −/− mice (Russart et al, 2018), we first confirmed that EPAC2 −/− mice did not exhibit major differences from wild-type mice in general behavioral functions (Lee et al, 2015, Srivastava et al, 2012) but see also (Zhou et al, 2016): anxiety, as tested by time spent in the open arms of the elevated plus maze (EPM); motor coordination, as tested by latency to fall off the rotarod; and general activity level, as tested by average velocity within an activity box (Table 1). In addition, von Frey mechanical sensitivity tests and Hargreaves heat sensitivity tests were used to assess basal mechanical and thermal sensitivity, respectively.…”