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Title: Hypothalamic mechanisms mediating inhibition of prolactin secretion following stress in early pregnant mice
Author: Parker, Victoria Joanne
ISNI:       0000 0004 2726 636X
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2012
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In early pregnancy prolonged exposure to stress is known to have profound adverse effects on reproduction and is associated with suppressed progesterone secretion and consequent disturbance of the pregnancy-protective cytokine milieu, thus threatening early pregnancy maintenance. Maternal neuroendocrine responses to stress in early pregnancy are poorly understood. Therefore, we designed experiments to (1) study the hypothalamo-pituitary-adrenal (HPA) axis responses to stress in early pregnant mice, to discover whether and how responses change and (2) to determine the effect of stress in early gestation on pregnancy hormones, with a particular focus on the secretion and regulation of prolactin. To establish the effects of stress in early pregnancy (day 5.5) two different ethologically relevant stressors were used: lipopolysaccharide (LPS) or 24h fast stress, to mimic situations that may potentially arise during pregnancy in women: infection or hunger. HPA axis secretory responses to immune stress in early-mid pregnancy were robust and comparable to that in virgins. Vasopressin rather than the usual CRH neurone responses play a key role in maintaining this. However, the mode of action of glucocorticoids in mediating pregnancy complications is not yet established. Prolactin, and its hypothalamic control mechanisms, is a key candidate to mediate brain-to-body responses to stress. Prolactin has important roles in progesterone secretion, pregnancy establishment and immune regulation. We hypothesised that stress would negatively affect prolactin and its neuroendocrine control systems. Prolactin is mainly under the inhibitory control of dopamine, released predominantly from the tuberoinfundibular dopamine (TIDA) neurones. Prolactin also negatively feeds back on itself via prolactin receptors on the TIDA neurones and janus kinase (JAK)2/signal transducer and activator of transcription (STAT)5 signalling. Both immune and fasting stressors strongly inhibited basal prolactin secretion in early pregnancy, accompanied by a mild increase in activation of TIDA as shown by elevated Fos expression, compared to virgins. In addition, pregnancy attenuated LPS-induced recruitment of parvocellular paraventricular nucleus neurones and increased activation of brainstem noradrenergic nuclei which could potentially contribute to altered control of the dopamine-prolactin system. Following either immune or fast stress in early pregnancy ovine prolactin was able to drive enhanced expression of phosphorylated (p)STAT5. However, stress alone did not alter pSTAT5 implying it is not exclusively responsible for the stress-reduced prolactin observed in early pregnancy and another stress-induced stimulus must be activating TIDA neurones in these mice. LPS did not alter dopamine activity the median eminence (DOPAC: dopamine ratio) suggesting dopamine does not underlie stress-reduced prolactin secretion and other mechanisms must be considered. Direct effects of LPS, or its associated cytokines, on pituitary lactotrophs to inhibit prolactin secretion is a possible candidate. To investigate the effect of proinflammatory cytokines on the prolactin system in early pregnancy, d5.5 mice were administered TNF-alpha (a) or interleukin (IL)-6. Both cytokines increased TIDA activation, however, only TNF-a decreased plasma prolactin and progesterone, suggesting additional TNF-alpha action at the pituitary. As prolactin is anxiolytic we further proposed that stress would have a more profound effect on elevated plus maze performance in pregnant mice. However, early pregnant mice were generally more anxious vs. virgins regardless of LPS treatment. Taken together data show that stress in early pregnancy reduces prolactin and progesterone secretion, contributing to pregnancy complications/failure, but the neuroendocrine stress-related mechanism behind this suppression is yet to be determined.
Supervisor: Douglas, Alison. ; Leng, Gareth. Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: stress ; pregnancy ; prolactin