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

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.

Figure 1

Schematic of the visible burrow system (VBS). The chambers and surface area contained standard chow and water. Chambers and tunnels were kept under constant darkness, whereas the open surface area was under a 12:12 light cycle.

Figure 2

Effects of prenatal stress paradigm on maternal body weight, food intake and plasma corticosterone (n= 8 NS, 9 PCVS). Prenatal stress treatment began on gestation day (GD) 14. (A) Prenatal treatment did not significantly affect maternal body weight during gestation, nor did it affect food intake (B). (C) There was no difference in plasma corticosterone (CORT) before onset of PCVS treatment on GD 14. PCVS CORT was significantly higher on GD 21 than GD 14, and significantly higher than NS dams on GD 14 and GD 21. Data are expressed as mean +/− SEM. **p <0.01.

Figure 3

Percentage of males that became SUB (n= 18 VBS colonies). Significantly more PCVS males became SUB; Of 18 burrows, 14 PCVS males and 4 NS males were SUB (X² analysis). ** p <0.01.

Figure 4

Percentage of time spent in the SFC area. DOM (n=18) spent significantly more time in the SFC area than SUB (n=18) on D2, but there was no effect of, or interaction with prenatal treatment. Data are expressed as mean +/− SEM. **p <0.01.

Figure 5

Plasma corticosterone and testosterone at the end of VBS or control housing. (A) There was a main effect of social status; a main effect of prenatal stress approached, but did not reach statistical significance (p= 0.059). Post hoc comparison of prenatal stress treatment and SUB status by t-test indicated a significantly higher basal CORT in NS-SUB males (n=4) compared to PCVS-SUBs (n=14). (B) There was no main effect of prenatal treatment or housing/social status on plasma testosterone, although a t-test indicated a significant difference between plasma testosterone of NS-DOM and PCVS-SUB males. Data are expressed as mean +/− SEM. *p <0.05, **p <0.01, ***p <0.001.

Figure 6

Body weights during VBS housing expressed as percentage of starting weight. A. DOM males weighed significantly more than SUB males on days 9, 11, 13 and 14 of the VBS. B. Body weights of DOM and SUB during VBS housing by prenatal treatment. There was a significant difference in percentage body weight change between NS-DOM and PCVS-SUB on days 9,11,13 and 14, but no difference between PCVS-DOM and NS-SUB. Data are expressed as mean +/− SEM. *p <0.05, **p <0.01, ***p <0.001, ****p <0.0001.

Figure 7

Adrenal and thymus weights at the end of VBS or control housing. (A) Adrenal weights are adjusted to BW (mg/kg) at the end of VBS housing. DOM and SUB adrenal weights were significantly higher than CON adrenal weight. PCVS-DOM (n=4) adrenal weight was heavier than PCVS-CON. (C) Thymus weights are adjusted to BW (mg/kg) at the end of VBS housing. Thymus weight of DOM (n=18) and SUB (n=18) was significantly less than that of CON after 14 days of social stress in the VBS. Data are expressed as mean +/− SEM. *p <0.05.

Figure 8

CRH and NPY mRNA expression within brain after 14 days social stress. (A) There was no effect of prenatal treatment or adult status on CRH mRNA expression within the PVN, and no interactions between the two. (B) There was no main effect of prenatal or adult status on CRH mRNA expression within the CeA, and no interactions between the two. (C) NPY mRNA expression was significantly higher in DOM and SUB compared to CON with no effect of prenatal condition. For all graphs, NS-CON is set to 100%. Data are expressed as mean +/− SEM. *p <0.05.