Consequences of chronic stress in females in dependence on their reproductive status
Final Report Abstract
According to the overall aim of the DFG project, the results generated in the funding period substantially increased our understanding of peripartum-associated adaptations under both basal and chronic stress conditions. We could reveal that pregnancy stress leads to changes in maternal behaviour, attenuates lactationinduced anxiolysis and alters the behavioural effect of acute imipramine administration in forced swim test behaviour. This changes were associated with alterations in oxytocin (OXT) mRNA expression within the hypothalamic paraventricular nucleus. However, when animals bred for high- and low-anxiety-related behaviour (HAB and LAB, respectively), the behavioural consequences of pregnancy stress exposure were not observed. This may be to a floor effect in HAB rats regarding anxiety-related behaviour and a low level of nursing in LAB rats to begin with. We could further show that basal MAPK pathway activity is altered in lactation within this nucleus and that it mediates, at least in part, the anxiolysis observed at this time. Moreover, after revealing sex-differences in both basal- and repeated restraint stress-induced hippocampal neurogenesis, we could extent the knowledge regarding lactation-associated changes in this process. In detail, while confirming the lactation-associated decrease in cell proliferation, we demonstrated that, contrary to expectations, repeated restraint stress exposure reversed this decrease and also decreased neuronal differentiation compared with non-stressed controls. While we attempted to determine whether these changes could be reversed via chronic antidepressant administration, the addition of medication on top of the stress procedure was not tolerated by pregnant rats, therefore, we decided to extend our understanding of alterations in HPA axis activity across the peripartum period. We demonstrated for the first time that all adrenal gland cholesterol delivery pathways undergo peripartum plasticity, which we hypothesized to be due, at least in part, to the increase in circulating cholesterol at this time. These changes, as opposed to the repeated speculation that the adrenal gland may have altered sensitivity to ACTH, are likely to mediate both the elevation in basal corticosterone in late pregnancy and early to mid-lactation. Moreover, we revealed that high-fat diet intake prevented all but one of the peripartum-associated changes in adrenal gland plasticity that we assessed and also abolished the basal hypercorticosterone levels and stress-hyporesponsiveness. While not identical, we finally could show that the mouse adrenal glands undergo similar peripartum-associated changes, which supports the idea that such changes may be conserved across species. In summary, these data complement our knowledge on peripartum-associated adaptations, extending them to the level of the adrenal gland for the first time and providing novel insight into changes in complex aspects of hippocampal neurogenesis. Moreover, they reveal that exposure to stress in the peripartum period leads to the abolishment of the majority of such adaptations and, thus, that such changes may be essential for maternal mental health.
Publications
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(2011) Exposure to chronic pregnancy stress reverses peripartum-associated adaptations: Implications for postpartum anxiety and mood disorders. Endocrinology 152: 3930-40
Hillerer, K., Reber, S.O., Neumann, I.D., Slattery, D.A.
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(2012) Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats. PLoS ONE 7: art. no. e37060
Jurek, B., Slattery, D.A., Maloumby, R., Hillerer, K., Koszinowski, S., Neumann, I.D., van den Burg, E.H.
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(2012)- From stress to postpartum mood disorders: How chronic peripartum stress can impair maternal adaptations. Neuroendocrinology 95: 22-38
Hillerer, K., Neumann, I.D., & Slattery, D.A.
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(2013) Sex-dependent regulation of hippocampal neurogenesis under basal and chronic stress conditions in rats. Hippocampus 23: 476-487
Hillerer, K.M., Neumann, I.D., Couillard-Despres, S., Aigner, L. & Slattery, D.A.
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(2014) Hippocampal plasticity during the peripartum period: Influence of sex steroids, stress and ageing. Journal of Neuroendocrinology 26: 641-8
Galea, L.A.M., Leuner, B. & Slattery, D.A.
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(2014) Lactationinduced reduction in hippocampal neurogenesis is reversed by repeated stress exposure. Hippocampus 24: 673-83
Hillerer, K.M., Neumann, I.D., Couillard-Despres, S., Aigner, L. & Slattery, D.A.
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(2014) The ups and downs of modelling mood disorders in rodents. ILAR Journal 55: 297-309
Slattery, D.A. & Cryan, J.F.
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(2014) Using animal models to study postpartum psychiatric disorders. British Journal of Pharmacology 171: 4539-55
Perani, C.V. & Slattery, D.A.
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(2015) High-fat diet prevents adaptive peripartum-associated adrenal gland plasticity and anxiolysis. Scientific Reports. 5: 14821
Perani, C.V., Neumann, I.D., Reber, S.O. & Slattery, D.A.
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(2015) Oxytocin in general anxiety and social fear: A translational approach. Biological Psychiatry pii: S0006-3223(15)00478-3
Neumann, I.D & Slattery, D.A.
