We have explored the changes in neuroendicrine mechanisms in pregnancy leading to suppressed stress responses: reduced activation of the hypothalamo-pituitary-adrenal (HPA) axis and oxytocin neurones.
Recently, we explored the changes in neuroendocrine mechanisms in pregnancy (in rats, mice and pigs) that lead to suppressed responses to stress: reduced activation of the hypothalamo-pituitary-adrenal (HPA) axis and oxytocin neurones.
Our integrative approach measures hormone secretion in vivo, and behaviour, coupled with electrophysiological recording of single neurones, and measurement of neurotransmitter release in vivo, and molecular ex vivo analysis of gene expression in functionally characterised neurones.
We have tested a core hypothesis that HPA axis responses are strongly attenuated in pregnancy, that responses are reduced to all types of stress (emotional and physical, e.g. exposure to peptides that signal energy shortage or infection), and that this adaptation extends to the control of oxytocin secretion (a store of which is needed for birth).
This hypothesis has survived critical testing. Recently we have tested the further hypothesis that an inhibitory opioid system in the brain is activated in pregnancy, suppressing stress responses, and that this is induced by a neuroactive metabolite of progesterone, the hormone signalling pregnancy.
Figure 1 is situa hybridisation autoradiographs of the hypothalamic paraventricular nuclei (PVN), showing corticotropin releasing factor (CRF) mRNA after intravenous injection of interleukin-1beta (a cytokine, simulating infection). The left is a virgin rat, the right a pregnant rat. Note lack of CRF mRNA signal in late pregnancy, indicating absent response to infection stress.
Results show that this hypothesis is correct. Why is it important?
Neuroendocrinology exemplifies integrative physiology: it is about understanding the co-ordination of neural and endocrine systems that regulate essential body processes, including reproduction, metabolism and stress responses, with impact on harmonising bodily and higher level brain functions.
Derangement of neuroendocrine stress mechanisms leads to physical ill-health, mental illness and shorter life.
Of great current interest is adverse programming of health in later life by exposure to stress or adversity early in life (pre-or post-natal), and the role of consequent setting of neuroendocrine stress response mechanisms to be more sensitive to stress.
Our research relates to prenatal stress in two respects: we showed HPA axis responses to stress are normally suppressed in pregnancy, and have revealed the mechanism, which also prevents premature oxytocin secretion.
The findings explain how the developing fetus is normally given some protection from being exposed to programming by stress hormones, and how premature oxytocin release and preterm birth (a major obstetric problem) may be prevented, and indicate how these protective mechanisms may fail.
The main thrust now is to exploit the above discoveries, supported by a major 5 year BBSRC grant (£2.66M, with S Fleetwood-Walker, JR Seckl, A Lawrence at SAC, A Nolan, Glasgow Vet School), with my group taking forward stress studies in rats to investigate the extent to which suppressed stress responses in pregnancy protect against adverse fetal programming by social stress in pregnancy.
Having found that this type of stress can lead to adverse programming of neuroendocrine and behavioural responses to stress in the offspring, we are investigating the long-term consequences and ways in which such programming may be over-written.
Brunton PJ, Russell JA (2008) The expectant brain: neurobiological adaptations for motherhood. Nature Neuroscience Reviews 9: 11-25.
Brunton P.J., Sausbier M, Wietzorrek G, Sausbier U, Knaus H-G, Russell JA, Ruth P, Shipston MJ (2007) Hypothalamic-pituitaryadrenal axis hyporesponsiveness to restraint stress in mice deficient for large conductance voltage- and calcium- activated potassium (BK) channels. Endocrinology. 148 5496-5506.
Brunton PJ, Bales J, and Russell JA (2006) Neuroendocrine stress but not feeding responses to centrally administered neuropeptide Y are suppressed in pregnant rats. Endocrinology 147 (8): 3737-3745.
Brunton PJ, Sabatier N, Leng G, and Russell JA (2006) Suppressed oxytocin neurone response to immune challenge in pregnant rats: a role for endogenous opioids. European Journal of Neuroscience 23 (5): 1241-1247.
Neural Control Systems Group