Susceptibility or resilience? Prenatal stress predisposes male rats to social subordination, but facilitates adaptation to subordinate status

Highlights

• Prenatally stressed (PCVS) males were significantly more likely to become subordinate (SUB) upon exposure to the visible burrow (VBS).

• Prenatally stressed subordinate males did not develop an exaggerated depressive-like phenotype, but rather appeared better able to cope in the VBS

• Exposure to prenatal stress may impart resilience upon exposure to a stressful environment in adulthood.

Abstract

Mood disorders such as major depressive disorder (MDD) affect a significant proportion of the population. Although progress has been made in the development of therapeutics, a large number of individuals do not attain full remission of symptoms and adverse side effects affect treatment compliance for some. In order to develop new therapies, there is a push for new models that better reflect the multiple risk factors that likely contribute to the development of depressive illness. We hypothesized that early life stress would exacerbate the depressive-like phenotype that we have previously observed in socially subordinate (SUB) adult male rats in the visible burrow system (VBS), a semi-natural, ethologically relevant environment in which males in a colony form a dominance hierarchy. Dams were exposed to chronic variable stress (CVS) during the last week of gestation, resulting in a robust and non-habituating glucocorticoid response that did not alter maternal food intake, body weight or litter size and weight. As adults, one prenatal CVS (PCVS) and one non-stressed (NS) male were housed in the VBS with adult females. Although there were no overt differences between PCVS and NS male offspring prior to VBS housing, a greater percentage of PCVS males became SUB. However, the depressive-like phenotype of SUB males was not exacerbated in PCVS males; rather, they appeared to better cope with SUB status than NS SUB males. They had lower basal plasma corticosterone than NS SUB males at the end of VBS housing. In situ hybridization for CRH in the PVN and CeA did not reveal any prenatal treatment or status effects, while NPY expression was higher within the MeA of dominant and subordinate males exposed to the VBS in comparison with controls, but with no effect of prenatal treatment. These data suggest that prenatal chronic variable stress may confer resilience to offspring when exposed to social stress in adulthood.

Introduction

Mood disorders affect a significant segment of society, reducing the quality of life and placing a significant burden on the workforce, economy and health care systems [25], [28], [64]. The etiology of affective disorders are largely unknown, and characterized by symptoms that can vary greatly by individual. Altered serotonergic transmission and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity are the most widely accepted hallmarks of Major Depressive Disorder (MDD), but these findings are far from universal [15], [30], [39], [42]. The majority of available pharmacological therapies target the serotonergic system, and while these help many, it is estimated that up to one third of individuals fail to achieve full remission of symptoms [2], [23], [36], [44]. It is clear that much more research is required to tackle this problem, and some investigators have turned their focus to more nuanced models of depression in laboratory animals. Since preexisting risk factors are thought to underlie stress-sensitivity and the susceptibility to mood disorders, some question the validity of previously utilized paradigms that often used naïve, or “normal,” rodents to model aspects of human illness and have proposed that more “sophisticated” models are necessary to tease out the mechanistic underpinnings of depressive disorders [10], [13], [14], [58]. The general consensus in the field is that there is no single cause of affective disorders, and no “silver bullet” for treatment. One's susceptibility likely arises through the interaction of multiple genetic and/or environmental factors, and chronic stress exposure may act as a particularly robust trigger. Indeed, certain stressful experiences are thought to engender a vulnerability to depressive illness and stress is frequently reported to precede or exacerbate depressive episodes [18], [24], [50].

In social animals (including humans), some of the most common and salient stressors encountered are social in nature [7], [22], [62]. In their natural environment, rats form “societies” and social interactions can be a significant source of stress, which can be utilized to study chronic social stress [5], [6], [27], [62]. A seminatural social environment can be recreated in the laboratory using the visible burrow system (VBS), a housing system with a large open surface area connected to a series of tunnels and chambers. Male rats housed with females in the VBS quickly establish a dominance hierarchy, and socially subordinate males (SUBs) develop a behavioral, neurochemical and neuroendocrine profile that resembles some symptoms similar to MDD [8], [9], [33]. The “standard” VBS colony consists of 4 males and 2 females housed over a period of 2 weeks. Typically, the dominance hierarchy is established during the first day or two, with one male becoming and remaining dominant throughout the period of housing. Previous VBS studies have demonstrated that SUB males have enhanced HPA axis activity and that this corresponds with elevated CRH mRNA expression within the paraventricular nucleus of the hypothalamus (PVN) and the central nucleus of the amygdala (CeA). Occasionally, one subordinate male will be the main recipient of attacks in the burrow, and is referred to as the OMEGA; OMEGA males incur more wounds, more severe weight loss and exhibit depressive-like behaviors at the end of the 2 wk. VBS housing period [40].

A female-biased VBS design can also be used, with 4 females and 2 males housed in the VBS. In our experience, the subordinate phenotype is further enhanced when two males are housed with four females, perhaps because there is only one male recipient of the dominant male's aggression [61]. These males often resemble the OMEGA male of a traditional VBS, and experience increased wounding and more severe weight loss, although depressive-like behaviors have not been assessed in these males.

Other environmental conditions also contribute to adult stress reactivity, and early life is a particularly sensitive period that can shape the health, coping style and physiological responses across the lifespan [12], [16], [17], [34], [49]. To this end, we designed a study to assess whether early life stress would alter adult stress responses and behaviors within the VBS. Our hypothesis was that prenatal stress would increase the likelihood of becoming socially subordinate. We also assessed the combined and individual effects of prenatal stress and adult social stress, and hypothesized that the behavioral and physiological characteristics of SUB would be exaggerated by prenatal stress exposure. Finally, we hypothesized that changes in neurotransmission and CRH and NPY expression within limbic structures may mediate these effects.