Susceptibility or resilience? Prenatal stress predisposes male rats to social subordination, but facilitates adaptation to subordinate status
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.
Section snippets
Animals
All animal procedures were approved by the University of Cincinnati Institutional Animal Care and Use Committee and were performed in accordance with guidelines established by the NIH Guide for the Care and Use of Laboratory Animals. Timed pregnant female Long-Evans rats (Harlan, Indianapolis, IN) arrived at the University of Cincinnati animal facility on gestational day 2 (GD 2). The females were singly housed in conventional cages (18 × 24.5 × 18 cm) within a temperature- and humidity- controlled
Maternal and litter data
Prenatal stress had no effect on maternal body weight (Fig. 2A) or daily food intake (Fig. 2B) through the duration of gestation. As expected, no difference in maternal basal CORT was detected prior to treatment exposure (GD 14). On D 21, NS CORT levels were not significantly higher than basal levels assessed on GD). CORT levels of PCVS dams were significantly higher on GD 21 than on GD 14 (p < 0.001), and significantly higher than either day for NS dams (p < 0.001) (Fig. 2C).
Litter size ranged
Discussion
Over the years of using the VBS model, our lab and others have tried, but have been unable to predict which animals will become subordinate. Social status has not been predicted by body weight, composition, plasma testosterone, or plasma corticosterone [43], [53]. In these studies we tested the hypothesis that early life adversity would increase vulnerability to social subordination in adulthood. This part of the hypothesis was supported, as prenatally stressed males were significantly more
Funding
This research was supported by NIH grants MH088230 (KAS) and DK068273 (RRS).
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Present address: APC Microbiome Institute, University College Cork, Cork, Ireland.