Androgen receptor signaling in the medial amygdala is necessary for stress resilience in dominant Syrian hamsters
J. Alex Grizzell1,2, Catie T. Clinard1, Brooke N. Dulka1, Samuel G. Adler1, Matthew A. Cooper1
1 - Department of Psychology, NeuroNET Research Center, The University of Tennessee, Knoxville
2 – Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder (current address)
1 - Department of Psychology, NeuroNET Research Center, The University of Tennessee, Knoxville
2 – Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder (current address)
Overarching hypothesis:
Androgen receptor (AR) signaling in the medial amygdala (MeA) is necessary for development of social stress resilience in dominant male Syrian hamsters
Take Home Findings:
Androgen receptor (AR) signaling during formation & maintenance of dominant status is necessary for expression of resilience to social defeat
Systemic AR blockade halts dominance-driven AR upregulation in MeA
AR signaling in MeA confers resilience during acquisition (but not expression) of “conditioned defeat” (CD)
Systemic AR blockade halts dominance-driven AR upregulation in MeA
AR signaling in MeA confers resilience during acquisition (but not expression) of “conditioned defeat” (CD)
Introduction
•The medial amygdala (MeA) is a key node of the social behavior network with roles in stress, fear, sexual behavior, and aggression, among others.
•MeA activity has been linked with the “conditioned defeat” response in Syrian hamsters, though it is likely that learned responses associated with acute stress do not involve neural plasticity within the MeA.
•Stress resilience associated with ”the winner effect” implicates testosterone-dependent signaling via androgen receptors (AR) and upregulated AR expression brain-wide
•The MeA contains an abundance of gonadal steroid receptors & stress resilience/winning have been readily associated with a surge in testosterone signaling and AR expression in MeA, including in male Syrian hamsters.
•Dominant hamsters (who have maintained their status for 2 weeks) display less social avoidance & increased c-Fos expression in MeA after social defeat stress - implicating AR-dependent MeA activity in social stress resilience.
•MeA activity has been linked with the “conditioned defeat” response in Syrian hamsters, though it is likely that learned responses associated with acute stress do not involve neural plasticity within the MeA.
•Stress resilience associated with ”the winner effect” implicates testosterone-dependent signaling via androgen receptors (AR) and upregulated AR expression brain-wide
•The MeA contains an abundance of gonadal steroid receptors & stress resilience/winning have been readily associated with a surge in testosterone signaling and AR expression in MeA, including in male Syrian hamsters.
•Dominant hamsters (who have maintained their status for 2 weeks) display less social avoidance & increased c-Fos expression in MeA after social defeat stress - implicating AR-dependent MeA activity in social stress resilience.
Methods
General Methodology
1.Subjects: Adult, male, Syrian Hamsters (Mesocricetus auratus)
2.Dominance Establishment and Maintenance: Following territorial establishment (7d of solo housing), subjects were weight matched into dyads for 14d of daily 5-min agonistic encounters.
3.Acute Social Defeat: Following dyadic encounters, (day 15), subjects were exposed to three, 5-min aggressive encounters in home cages of three, larger, aggressive hamsters. Encounters occurred at 5-min intervals.
4.Conditioned Defeat (CD) Testing: 24-h after defeat stress, a non-aggressive intruder was placed in the home cage of each subject for 5-mins to assay the durations of defeat-induced changes in submissive, defensive, aggressive, social and nonsocial behavior.
Experiment 1
•Aim: To determine the effects of systemic blockade of ARs during dominance status formation and maintenance on the behavioral responses to defeat stress and the expression of ARs in MeA and lateral septum
•Approach: The AR antagonist, flutamide (Sigma-Aldrich; 5% DMSO in sesame oil) was systemically injected (15mg/kg s.c.) one hour prior to dyadic encounters daily for 14d, but not prior to social defeat or CD tests.
Experiment 2
•Aim: To determine the effects of AR blockade within the MeA in the acquisition of defeat-induced social avoidance (i.e. CD)
•Approach: Flutamide (Sigma-Aldrich; 5% DMSO in sterile PBS; 600ng/300nL) was injected directly into MeA via cannulae (surgically implanted 21 days prior) two hours prior to social defeat testing which occurred 24-h following dyadic encounters and 24-h prior to CD testing.
Experiment 3
•Aim: To determine the effects of AR blockade within the MeA in the expression of defeat-induced social avoidance (i.e. CD)
•Approach: Flutamide (Sigma-Aldrich; 5% DMSO in sterile PBS; 600ng/300nL) was injected directly into MeA via cannulae (surgically implanted 22 days prior) two hours prior to CD testing which occurred
48-h following dyadic encounters and 24-h following CD testing.
Results
Conclusions
•Flutamide treatment, which blocks AR activity, attenuates the dominance-dependent resistance to social defeat stress as assayed in the conditioned defeat test.
•Flutamide treatment, if occurring during daily maintenance of social status, blocks AR upregulation associated with winning agonistic encounters in dominants. Importantly, dominants display surges in plasma testosterone (T) after winning. This implicates T in winning-induced upregulation of ARs, which is necessary for resilience.
•Flutamide treatment directly in the MeA attenuates dominance-dependent resistance to social defeat if injected just before social defeat stress, but not prior to conditioned defeat testing.
•Overall, these findings suggest that the maintenance of a dominant social status drives AR-dependent neural plasticity in the MeA. Further, AR activity in MeA during social defeat promotes resilience
in dominant male Syrian hamsters.
•Flutamide treatment, if occurring during daily maintenance of social status, blocks AR upregulation associated with winning agonistic encounters in dominants. Importantly, dominants display surges in plasma testosterone (T) after winning. This implicates T in winning-induced upregulation of ARs, which is necessary for resilience.
•Flutamide treatment directly in the MeA attenuates dominance-dependent resistance to social defeat if injected just before social defeat stress, but not prior to conditioned defeat testing.
•Overall, these findings suggest that the maintenance of a dominant social status drives AR-dependent neural plasticity in the MeA. Further, AR activity in MeA during social defeat promotes resilience
in dominant male Syrian hamsters.
Acknowledgements
We would like to thank the many Cooper Lab members who’ve helped with these experiments. This project was supported by the NIH R15 grant MH107007 to MC.
