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dc.contributor.advisorBunn, Stephen J.
dc.contributor.advisorGrattan, David R.
dc.contributor.authorYip, Siew Hoong
dc.date.available2013-03-19T19:45:30Z
dc.date.copyright2013
dc.identifier.citationYip, S. H. (2013). The Mechanisms Underlying Prolactin-induced Enkephalin Expression in Tuberoinfundibular Dopaminergic Neurons in the Mouse (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/3779en
dc.identifier.urihttp://hdl.handle.net/10523/3779
dc.description.abstractProlactin is a physiologically important hormone with multiple actions. Its secretion from the anterior pituitary is regulated by dopamine secretion from the tuberoinfundibular dopaminergic (TIDA) neurons located in the arcuate nucleus of the hypothalamus. Prolactin acts via a short-loop negative feedback mechanism to increase this dopamine secretion and thus inhibit further prolactin release. This feedback response undergoes a remarkable adaptation during lactation when prolactin levels must rise. During this time the TIDA neurons secrete less dopamine and start to express enkephalin. The mechanism(s) responsible for this adaptation are unknown. This thesis focuses on investigating these mechanisms in the lactating mouse and addresses the overarching hypothesis that these are prolactin-mediated events. Initial immunohistochemical investigations demonstrated that while the number of tyrosine- hydroxylase-positive cells in the arcuate nucleus did not change during lactation, the percentage co-expressing enkephalin increased. This increase in enkephalin expression was dependent on prolactin in that it was lost following bromocriptine treatment. Despite the constant number of tyrosine hydroxylase-positive cells there was a lactation-associated decline in the level of Ser-40 phosphorylated (active) form of the enzyme in the external zone of median eminence. This observation is consistent with reduced dopamine secretion during lactation and thus elevated prolactin levels. The data also indicate that during lactation prolactin may be responsible for enkephalin expression in the TIDA neurons. There are two of many prolactin-signalling pathways mediated by signal transducer and activator of transcription factor 5 (STAT5) and extracellular signal-regulated kinases 1/2 (Erk1/2), respectively. A combination of immunohistochemistry and Western blotting demonstrated that both these pathways were activated in TIDA neurons during lactation. The number of TIDA neurons during lactation showing STAT5 phosphorylation (and thus activation) in response to exogenous prolactin was however lower than that seen in the diestrous animal. Exogenous prolactin also increased Erk activation during diestrous but was without a significant effect during lactation. These results indicate that the balance of intracellular signalling activated by prolactin is altered during lactation perhaps leading to a more STAT5 dominated response. There are two STAT5 isoforms, namely STAT5a and STAT5b but it is not known which isoform is activated in hypothalamus by prolactin. This issue was investigated using STAT5b- deficient mice. When stimulated with prolactin, phosphorylated STAT5 was observed in hypothalamus of wild-type but not STAT5b-deficient mice, suggesting it is the major and perhaps exclusive STAT-mediator in this tissue. In addition, mice lacking STAT5b had a significantly reduced number of enkephalin-positive TIDA neurons compared to wild-type controls, suggesting that STAT5b is required for this prolactin-induced enkephalin expression in TIDA neurons. In summary, these findings indicated that prolactin signalling in TIDA neurons is altered during lactation. Not only is dopamine synthesis reduced (as indicated by the phosphorylation status of tyrosine hydroxylase activity) but enkephalin expression is increased. This latter response is dependent on prolactin and probably arises from an alteration in the balance between intracellular signalling pathways. This thesis concludes with a discussion of the possible physiological significance of this neuronal plasticity, particularly how it may aim in maintaining elevated levels essential for lactation and material behaviour.
dc.language.isoen
dc.publisherUniversity of Otago
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dc.titleThe Mechanisms Underlying Prolactin-induced Enkephalin Expression in Tuberoinfundibular Dopaminergic Neurons in the Mouse
dc.typeThesis
dc.date.updated2013-03-19T02:44:39Z
dc.language.rfc3066en
thesis.degree.disciplineDepartment of Anatomy
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.interloanno
otago.openaccessAbstract Only
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