New knockout model confirms a role for androgen receptors in regulating anxiety-like behaviors and HPA response in mice - PubMed (original) (raw)
New knockout model confirms a role for androgen receptors in regulating anxiety-like behaviors and HPA response in mice
Chieh V Chen et al. Horm Behav. 2014 Mar.
Abstract
Men are less likely than women to suffer from anxiety disorders. Because gonadal hormones play a crucial role in many behavioral sex differences, they may underlie sex differences in human anxiety. In rodents, testosterone (T) exerts anxiolytic effects via the androgen receptor (AR): we found that male mice with a naturally-occurring mutation rendering the AR dysfunctional, referred to as spontaneous testicular feminization mutation (sTfm), showed more anxiety-like behaviors than wildtype (WT) males. Here, we used Cre-lox recombination technology to create another dysfunctional allele for AR. These induced Tfm (iTfm) animals also displayed more anxiety-like behaviors than WTs. We further found that AR-modulation of these behaviors interacts with circadian phase. When tested in the resting phase, iTfms appeared more anxious than WTs in the open field, novel object and elevated plus maze tests, but not the light/dark box. However, when tested during the active phase (lights off), iTfms showed more anxiety-related behavior than WTs in all four tests. Finally, we confirmed a role of T acting via AR in regulating HPA axis activity, as WT males with T showed a lower baseline and overall corticosterone response, and a faster return to baseline following mild stress than did WT males without T or iTfms. These findings demonstrate that this recombined AR allele is a valuable model for studying androgenic modulation of anxiety, that the anxiolytic effects of AR in mice are more prominent in the active phase, and that HPA axis modulation by T is AR dependent.
Keywords: Androgen insensitivity; Androgen receptor; Anxiety; Corticosterone; Cre–lox technology; HPA axis; Photoperiod; Testosterone.
Copyright © 2014 Elsevier Inc. All rights reserved.
Figures
Figure 1
The external phenotype of _i_Tfm males is feminine. AGD: anogenital distance. Compared to WT males, iTfm males have a visibly shorter anogenital distance (A vs. B) and have much smaller and undescended testis (arrow in C vs. D). _i_Tfm males also have external nipples (arrows in A) typical of WT females but not WT males (B).
Figure 2
Brain AR immunoreactivity confirms full AR KO in _i_Tfm animals. Robust nuclear AR immunoreactivity is present in the amygdala (A) and hippocampus (C) of WT males, while absent in the amygdala and hippocampus (B and D, respectively) of iTfm males. Black scale bar: 200µm; white scale bar: 40µm.
Figure 3
ARs are necessary to alleviate anxiety-related behavior in mice tested during the resting phase (lights on). Number of rears in the open field (OF) test (A) and the novel object (NO) test (B) both show a main effect of genotype only, with testosterone (T)-treated _i_Tfms showing fewer rears than T-treated WTs. Latency to visit the object in the NO test (C) and total time spent in the open arms of the elevated plus maze (EPM; D) were affected by T treatment only in WT males. WT males given T made more open arm entries than _i_Tfms given T (E). For OF, NO and EPM tests, T treatment has anxiolytic effects only in WT males, not _i_Tfm males, indicating these effects of T are normally mediated through AR. There was no effect of T treatment or genotype in the light dark box (LD) when tested during the resting phase (F, G). These results replicate our previous findings of anxiolytic effects of T in _s_Tfm mice, validating the _i_Tfm model. *p<.05.
Figure 4
Anxiety-related behavior is also heightened in intact _i_Tfm male mice compared to intact WT males tested during their active phase (lights off). With one exception (latency to visit object in the novel object test, C), _i_Tfm males show significantly increased levels of anxiety-like behavior compared to WT males based on performance in the open field (A), novel object (B), elevated plus maze (D), and light/dark box (E, F) tests. These results further support the idea that AR plays a role in the modulation of anxiety. Testing during the active phase reveals group differences in the light dark box that were not observed during the resting phase (see Figure 3). *p<.05.
Figure 5
Functional AR is required for T to regulate basal levels of CORT as well as CORT response to an anxiety-provoking stimulus (light dark box). Basal levels of CORT (time point 0) are highest in _i_Tfm males given T and lowest in WT castrates given T, with control-treated WT males intermediate, indicating that T exposure in adulthood normally reduces basal CORT levels by activating ARs. Additionally, despite equivalent T treatment, _i_Tfm males show an even more elevated response and a hastened CORT return to baseline compared to WT males after exposure to an anxiety-provoking situation. *indicates significantly different from _i_Tfm+T males, p<.05.
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