Early-life stress has persistent effects on amygdala function and development in mice and humans

Abstract

Relatively little is known about neurobiological changes attributable to early-life stressors (e.g., orphanage rearing), even though they have been associated with a heightened risk for later psychopathology. Human neuroimaging and animal studies provide complementary insights into the neural basis of problem behaviors following stress, but too often are limited by dissimilar experimental designs. The current mouse study manipulates the type and timing of a stressor to parallel the early-life stress experience of orphanage rearing, controlling for genetic and environmental confounds inherent in human studies. The results provide evidence of both early and persistent alterations in amygdala circuitry and function following early-life stress. These effects are not reversed when the stressor is removed nor diminished with the development of prefrontal regulation regions. These neural and behavioral findings are similar to our human findings in children adopted from orphanages abroad in that even following removal from the orphanage, the ability to suppress attention toward potentially threatening information in favor of goal-directed behavior was diminished relative to never-institutionalized children. Together, these findings highlight how early-life stress can lead to altered brain circuitry and emotion dysregulation that may increase the risk for psychopathology.

Keywords: anxiety; c-fos; cross-species; emotion regulation; infralimbic cortex.

Fig. 1.

Behavioral paradigm and results. (A) Human paradigm. Subjects were instructed to detect frequently presented neutral targets embedded among rare threat nontarget cues. (B) Mouse paradigm. Mice were trained where to obtain sweetened milk in their home cage for 3 consecutive days, and then latency to approach the milk was measured in the home cage on the fourth day and in an odorless, brightly lit novel cage on the fifth day. (C) Behavioral results. The difference in time that control and stressed mice take across development to approach a cue in a novel cage compared with their home cage (F = 3.40; P < 0.01; n_c = 49; n_els = 43). Data are z-scored and expressed as means ± SEM.

Fig. 2.

c-Fos activity by group and age. (A) The density of c-Fos protein in the amygdala following exposure to the threatening context (i.e., novel cage) was elevated in ELS mice across development, similar to adolescent controls. The age by experimental group interaction [F = 2.132; P < 0.05; n = 5–8 mice per experimental group (10–15 slices per animal)] shows the most robust differences were between the preadolescent ELS and control groups (t = 4.71; P < 0.001). Data are expressed as means ± SEM. (B) The density of c-Fos protein in the IL increases with age [F = 2.466; P < 0.05; n = 3–8 mice per experimental group (10–15 slices per animal)]. All data expressed as means ± SEM.

Fig. 3.

Greater amygdala activity in humans and mice following ELS. (A) Stressed preadolescent humans take longer than their standard reared counterparts to detect frequently presented neutral targets embedded among rare threat nontarget cues that they were instructed to ignore (t = 2.08; P < 0.05; n_c = 10; n_els = 16). Data are z-scored and expressed as means ± SEM. (B) Parameter estimates of amygdala activity in response to the threat cue (i.e., fearful face) were greater in stressed preadolescent humans than their standard-reared counterparts (F = 4.43; P < 0.05; n_c = 10; n_els = 16). (C) Bilateral region of the amygdala identified as more reactive to threat (i.e., fear face stimuli) in stressed preadolescent humans than their standard reared counterparts. (D) The difference in time that control and stressed preadolescent mice take to approach a cue in a novel cage compared with their home cage (F = 2.06; P < 0.05; n_c = 18; n_els = 14). Data are z-scored and expressed as means ± SEM. (E) The density of c-Fos protein in the amygdala following exposure to the threatening context (i.e., novel cage) was greater in stressed preadolescent mice than their standard-reared counterparts [t = 4.71; P < 0.001; n_c = 6; n_els = 5 (10–15 slices per animal)]. Data are z-scored and expressed as means ± SEM. (F) An individual slice cut through the amygdala taken from each mouse was stained for c-Fos (red) and PVA (green) and used for quantification of c-Fos following exposure to the threatening context, clustered by experimental group and at 10x magnification.