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

Papers by Siobhán Kirk

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor... more Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS. Here, using the SOD1 G93A mouse model of ALS, 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 ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.

Prolactin Signalling in the Median Eminence in the Mouse

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

Lipids play an important role in the central nervous system (CNS). They contribute to the structu... more Lipids play an important role in the central nervous system (CNS). They contribute to the structural integrity and physical characteristics of cell and organelle membranes, act as bioactive signalling molecules, and are utilised as fuel sources for mitochondrial metabolism. The intricate homeostatic mechanisms underpinning lipid handling and metabolism across two major CNS cell types; neurons and astrocytes, are integral for cellular health and maintenance. Here, we explore the various roles of lipids in these two cell types. Given that changes in lipid metabolism have been identified in a number of neurodegenerative diseases, we also discuss changes in lipid handling and utilisation in the context of amyotrophic lateral sclerosis (ALS), in order to identify key cellular processes affected by the disease, and inform future areas of research.

Frontiers in Neurology, Mar 18, 2019

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterior... more Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterioration of motor neurons. However, this complex disease extends beyond the boundaries of the central nervous system, with metabolic alterations being observed at the systemic and cellular level. While the number of studies that assess the role and impact of metabolic perturbations in ALS is rapidly increasing, the use of metabolism biomarkers in ALS remains largely underinvestigated. In this review, we discuss current and potential metabolism biomarkers in the context of ALS. Of those for which data does exist, there is limited insight provided by individual markers, with specificity for disease, and lack of reproducibility and efficacy in informing prognosis being the largest drawbacks. However, given the array of metabolic markers available, the potential exists for a panel of metabolism biomarkers, which may complement other current biomarkers (including neurophysiology, imaging, as well as CSF, blood and urine markers) to overturn these limitations and give rise to new diagnostic and prognostic indicators.

Zenodo (CERN European Organization for Nuclear Research), Sep 24, 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 superoxide dismutase 1, glycine to alanine substitution at amino acid 93 (SOD1 G93A ) 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 expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, within the patient cohort, there was considerable heterogeneity in whole-body metabolism and fuel oxidation profiles. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis.

Journal of Neuroendocrinology, May 26, 2019

In addition to its established lactational roles prolactin acts on multiple target tissues and it... more In addition to its established lactational roles prolactin acts on multiple target tissues and its circulating levels are responsive to a range of physiological stimuli. This investigation has used immunohistochemistry to demonstrate that systemic administration of prolactin activates target cells in the arcuate nucleus and median eminence of the male mouse. Prolactin receptor stimulation results in the phosphorylation and thus activation of signal transducer and activator of transcription (STAT)5. Interestingly, while in the arcuate nucleus this response was localized to cell nuclei, the median eminence displayed both nuclear and diffuse, non-nuclear, phospho-STAT5 (pSTAT5) staining. Dual-label immunostaining demonstrated that while the majority of nuclear pSTAT5 within the median eminence was located within vimentin-positive tanycytes, the non-nuclear staining occurred primarily in neuronal (βIII tubulin immunoreactive) elements. This conclusion was supported by the marked reduction of this signal in prolactintreated mice lacking neuronal prolactin receptors. A smaller reduction was also seen in animals lacking prolactin receptors on GABAergic, but not glutamatergic, neurons. These findings identify a new prolactin target tissue, and in doing so support the proposal that the median eminence has a sensory role in addition to its established secretory function. The physiological significance of this prolactin response is unknown although its rapidity (maximum within 2 min of intraperitoneal injection) suggests it may provide early detection of an increase in circulating prolactin. It is also possibility is that non-nuclear prolactin-generated pSTAT5 in the median eminence may have a local, non-transcriptional, action. To this end we used Evan Blue dye to demonstrate that elevated prolactin appears to reduce median eminence permeability and that this effect is lost in animals lacking neuronal prolactin receptors.

Brain Communications, 2020

Plasticity of Hypothalamic Dopamine Neurons during Lactation Results in Dissociation of Electrical Activity and Release

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...

Journal of Neuroendocrinology, Jun 1, 2017

Prolactin is a pleiotropic peptide hormone produced by the lactotrophs in the anterior pituitary.... more Prolactin is a pleiotropic peptide hormone produced by the lactotrophs in the anterior pituitary. Its rate of secretion is primarily regulated by a negative feedback mechanism whereby prolactin stimulates the activity of the tuberoinfundibular dopaminergic (TIDA) neurons, increasing their release of dopamine which accesses the pituitary via the median eminence to suppress further prolactin secretion. In addition to its well established role in lactation, circulating prolactin is secreted in response to stress, although the mechanism by which this is achieved or its cellular targets are unknown. In this study we show that a 15 min period of restraint stress causes an approximately 7-fold increase in circulating prolactin concentration in male This article is protected by copyright. All rights reserved. mice. Monitoring prolactin receptor activation, using immunohistochemistry to determine the level and distribution of tyrosine phosphorylated signal transducer and activator of transcription 5 (pSTAT5), we show that this stress-induced increase in prolactin interacts with both central and peripheral targets. A 15 min period of restraint stress significantly increased pSTAT5 staining in the arcuate nucleus, median eminence and the zona fasciculata of the adrenal cortex. In each case this response was prevented by pretreating the animals with bromocriptine to block prolactin secretion from the pituitary. Interestingly, in contrast to many cells in the arcuate nucleus, stress reduced pSTAT5 staining of the TIDA neurons (identified by dual-labelling for tyrosine hydroxylase). This suggests reduced prolactin signalling in these cells and thus potentially a decline in their inhibitory influence on prolactin secretion. These results provide evidence that prolactin secreted in response to acute stress is sufficient to activate prolactin receptors in selected target tissues which are known to be involved in the physiological adaptation to stress.