Siobhán Kirk - Academia.edu (original) (raw)

Papers by Siobhán Kirk

The median eminence represents the interface between the hypothalamus and the portal blood, allow... more The median eminence represents the interface between the hypothalamus and the portal blood, allowing access to the anterior pituitary and thus regulation of its secretion. The structure of the blood brain barrier at the median eminence is highly modified in order to allow the passage of these hypophysiotrophic factors from nerve terminals into the blood. These modifications also permit blood borne hormones to access the median eminence thus potentially modulating its function. This thesis will examine the potential activity of one such hormone, prolactin, at the level of the median eminence. Prolactin is a multifunctional peptide hormone produced in the anterior pituitary gland. Its secretion is primarily regulated by an inhibitory input by dopamine released into the median eminence by the tuberoinfundibular dopaminergic (TIDA) neurons of the hypothalamus and transported to the pituitary. Prolactin secretion is elevated during a number of physiological events including pregnancy, lactation, stress and sexual activity. Following its secretion, prolactin targets many different cell-types around the body to perform a wide variety of functions. Immunohistochemical observations in this thesis demonstrated that treatment of adult male mice with ovine prolactin resulted in the rapid phosphorylation (phospho-) of Signal Transducer and Activator of Transcription (STAT)5 in the median eminence thus indicating prolactin receptor activation in this tissue. Phospho-STAT5 labelling within the median eminence was present in two forms: nuclear and non-nuclear. Phospho-STAT5, being a transcription factor, typically translocates to the nucleus to regulate gene expression. Observations of non-nuclear phospho-STAT5 have rarely been described and its function remains unknown. The expression of non-nuclear phospho-STAT5 was confirmed through a number of validation experiments which utilised various antibodies, labelling methods and a STAT5b knockout mouse. Immunohistochemistry utilised dual-labelling and an array of knockout mice to investigate the cellular location of prolactin-induced phospho-STAT5 within the median eminence. These experiments revealed nuclear phospho-STAT5 was predominantly within a tanycytes, and that the non-nuclear phospho-STAT5 was present primarily within neuronal processes. The nature of these neuronal processes has remained elusive but they do not appear to be TIDA, CRH, oxytocin or glutamatergic neurons or indeed, based on fluorogold studies, other neuroendocrine neurons, suggesting that they were non-neuroendocrine neurons. The physiological relevance of prolactin actions in the median eminence was investigated using restraint stress, which is known to elevate circulating prolactin levels. These results demonstrated that this elevation of prolactin caused a similar phospho-STAT5 response in the median eminence as that observed following exogenous prolactin stimulation. The effect of prolactin on the permeability of the median eminence was evaluated using Evans Blue. It was found that 1 h treatment with prolactin reduced the permeability of the median eminence. This suggested that during periods of elevated prolactin, the permeability of the median eminence may be modulated. This action of prolactin may have downstream effects on the activity of the median eminence and the regulation of the pituitary. This thesis has identified the median eminence as a novel target of prolactin signalling and in doing so has demonstrated that the median eminence has both secretory and sensory roles

Seminars in Cell & Developmental Biology, Apr 1, 2021

Frontiers in Neurology, Mar 18, 2019

Zenodo (CERN European Organization for Nuclear Research), Sep 24, 2020

Journal of Neuroendocrinology, May 26, 2019

Brain Communications, 2020

Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neuro... more Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the SOD1G93A mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expend...

The Journal of Neuroscience, 2013

Tuberoinfundibular dopamine (TIDA) neurons are the central regulators of prolactin (PRL) secretio... more Tuberoinfundibular dopamine (TIDA) neurons are the central regulators of prolactin (PRL) secretion. Their extensive functional plasticity allows a change from low PRL secretion in the non-pregnant state to the condition of hyperprolactinemia that characterizes lactation. To allow this rise in PRL, TIDA neurons are thought to become unresponsive to PRL at lactation and functionally silenced. Here we show that, contrary to expectations, the electrical properties of the system were not modified during lactation and that the neurons remained electrically responsive to a PRL stimulus, with PRL inducing an acute increase in their firing rate during lactation that was identical to that seen in non-pregnant mice. Furthermore, we show a long-term organization of TIDA neuron electrical activity with an harmonization of their firing rates, which remains intact during lactation. However, PRL-induced secretion of dopamine (DA) at the median eminence was strongly blunted during lactation, at leas...