Social dominance predicts hippocampal glucocorticoid receptor recruitment and resilience to prenatal adversity

Abstract

The developing fetus is highly sensitive to prenatal stress, which may alter Hypothalamic-Pituitary-Adrenal (HPA) axis programming and increase the risk of behavioral disorders. There is high variability among the human population, wherein many offspring of stressed pregnancies display resilience to adversity, while the remainder displays vulnerability. In order to identify biological substrates mediating between resilience or vulnerability to prenatal adversity, we exposed stress-resistant Dominant (Dom) and stress-sensitive Submissive (Sub) mice to mild prenatal restraint stress (PRS, 45 min on gestational days (GD) 15, 16 and 17). We hypothesized that PRS would differentially alter prenatal programming of limbic regions regulating the HPA axis and affect among Dom and Sub offspring. Indeed, PRS increased Sub offspring’s serum corticosterone, and exaggerated their anxiety- and depressive-like behavior, while Dom offspring remained resilient to the hormonal and behavioral consequences of PRS. Moreover, PRS exposure markedly facilitated glucocorticoid receptor (GR) recruitment to the hippocampus among Dom mice in response to restraint stress, which may be responsible for their resilience to stressful challenge. These findings suggest proclivity to adaptive or maladaptive prenatal programming of hippocampal GR recruitment to be inheritable and predictable by social dominance or submissiveness.

Innate sensitivity to stress facilitates inflammation, alters metabolism and shortens lifespan in a mouse model of social hierarchy

“…We have previously shown that Sub mice are characterized by a high sensitivity to various stressogenic triggers, including acute [14], chronic mild (CMS) [10], social [15, 16] and prenatal [17, 18] stresses. At physiological and biochemical levels, this stress sensitivity is underlined by the hyper-activation of the HPA axis, resulting in elevated levels of stress- induced corticosterone and in the decreased expression of glucocorticoid receptor (GR), leading to an altered negative feedback regulation of the HPA axis activity [18].…”

Animal Models of Depression: What Can They Teach Us about the Human Disease?

“…Paroxetine showed dose dependent anti-depressive-like effect in Sub mice and caused a paradoxical effect in Dom mice. Sub mice serve as an animal model of depression demonstrating depressive-like behavior and are susceptible to stressful stimuli, whereas Dom mice exhibit strong characteristics of manic-like behavior and show pronounced stress resilience [180,183]. The altered monoamine content in brain areas referring to emotionality and social hierarchy underly the behavioral phenotype in Sub and Dom mice.…”

Gut microbiota determines the social behavior of mice and induces metabolic and inflammatory changes in their adipose tissue

“…Using comprehensive behavioral and pharmacological approaches 29 , 32 , we previously demonstrated that dominant (Dom) and submissive (Sub) mice differentially respond to psychotropic agents 29 and stressogenic 30 , possess different life spans 33 , distinct brain neurochemistry 34 , and cognitive and learning capabilities 35 . More specifically, while Dom mice are relatively stress resilient, Sub mice exhibit strong sensitivity to stress 30 , alongside depressive-like and anti-social 30 characteristics 36 , as well as systematic inflammation, demonstrated by higher interleukin (IL)-6 and IL-1b serum levels 33 . The multi-aspect differences between Dom and Sub animals led us to hypothesize that these mice possess different gut microbiome compositions, which may play a crucial role in shaping their social behavior by inducing inflammation leading to alterations in adipose tissue physiological homeostasis.…”