Paternal transmission of stress-induced pathologies

Abstract

Background: There has been recent interest in the possibility that epigenetic mechanisms might contribute to the transgenerational transmission of stress-induced vulnerability. Here, we focused on possible paternal transmission with the social defeat stress paradigm.

Methods: Adult male mice exposed to chronic social defeat stress or control nondefeated mice were bred with normal female mice, and their offspring were assessed behaviorally for depressive- and anxiety-like measures. Plasma levels of corticosterone and vascular endothelial growth factor were also assayed. To directly assess the role of epigenetic mechanisms, we used in vitro fertilization (IVF); behavioral assessments were conducted on offspring of mice from IVF-control and IVF-defeated fathers.

Results: We show that both male and female offspring from defeated fathers exhibit increased measures of several depression- and anxiety-like behaviors. The male offspring of defeated fathers also display increased baseline plasma levels of corticosterone and decreased levels of vascular endothelial growth factor. However, most of these behavioral changes were not observed when offspring were generated through IVF.

Conclusions: These results suggest that, although behavioral adaptations that occur after chronic social defeat stress can be transmitted from the father to his male and female F1 progeny, only very subtle changes might be transmitted epigenetically under the conditions tested.

Figure 1. Paternal transmission of stress-induced depression- and anxiety-like behaviors via natural breeding

(A) Chronic social defeat induced robust social avoidance in male C57Bl6/J mice compared to control non-defeated mice (*p<0.05). Experimental time line of how these mice were then bred with normal females for behavioral analysis of the offspring. (B) Offspring of socially defeated mice displayed robust social avoidance when exposed to a submaximal defeat paradigm (*p<0.05), which produced no such social avoidance in the offspring of control mice. (C-F) Comparisons of offspring of control mice and offspring from fathers both before undergoing social defeat (pre-defeat) and after undergoing social defeat (post-defeat). (C) Male and female offspring of post-defeat offspring only showed an anxiogenic-like phenotype as measured by an increase in time spent in the open arms of the elevated plus maze (*p<0.05). (D) Only the post-defeat male offspring showed an increase in locomotor behavior in a novel environment (*p<0.05). (E) Likewise, in the sucrose preference test, only the post-defeat male offspring exhibited a trend toward a reduction in sucrose preference (#p<0.07). (F) Both male and female post-defeat offspring showed a decrease in latency to become immobile in the forced swim test (*p<0.05), compared to control and pre-defeat offspring. All values represent means ± standard error of the mean. All (*s) are comparisons of pre- and post-defeat offspring.

Figure 2. Paternal transmission of stress-induced depression- and anxiety-like behaviors via IVF

(A) Chronic social defeat stress induced robust social avoidance in male C57Bl6/J mice compared to control non-defeated mice (*p<0.05). Experimental time line including IVF and subsequent behavioral experiments. (B) Offspring derived from defeated or control fathers using IVF showed no social avoidance following a sub-maximal defeat paradigm. (C) IVF defeated male and female offspring did not differ in time spent in the open arms of the elevated plus maze compared to IVF control offspring. (D) There was a trend for increased locomotor activity in a novel environment in female IVF defeated offspring compared to female IVF control offspring (p=0.06), but no difference in males. (E) There was no difference in sucrose preference in either male or female IVF defeated offspring compared to IVF control offspring. (F) In comparison to IVF control offspring, both male and female IVF defeated offspring showed a small but significant decrease in latency to become immobile in the forced swim test (*p<0.05). All values represent means ± standard error of the mean.