Publications
18 results found
Alonso AM, Cork SC, Phuah P, et al., 2024, The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake, Molecular Metabolism, Vol: 81, ISSN: 2212-8778
Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.
Doggett T, Warr H, Johnson J-A, et al., 2024, Response to: "ChatGPT for assessment writing"., Med Teach
Cork SC, 2023, A Model for Online Delivery of Multiple Mini Interviews, JOURNAL OF MEDICAL EDUCATION AND CURRICULAR DEVELOPMENT, Vol: 10, ISSN: 2382-1205
Wildner K, Mirza KB, De La Franier B, et al., 2020, Iridium oxide based potassium sensitive microprobe with anti-fouling properties, IEEE Sensors Journal, Vol: 20, Pages: 12610-12619, ISSN: 1530-437X
Here, we present a new type of potassium sensor which possesses a combination of potassium sensing and anti-biofouling properties. Two major advancements were required to be developed with respect to the current technology; Firstly, design of surface linkers for this type of coating that would allow deposition of the potassiumselective coating on Iridium (Ir) wire or micro-spike surface for chronic monitoring for the first time. As this has never been done before, even for flat Ir surfaces, the material’s small dimensions and surface area render this challenging. Secondly, the task of transformation of the coated wire into a sensor. Here we develop and bench-test the electrode sensitivity to potassium and determine its specificity to potassium versus sodium interference. For this purpose we also present a novel characterisation platform which enables dynamic characterization of the sensor including step and sinusoidal response to analyte changes. The developed sensor shows good sensitivity (<1 mM concentrations of K+ ions) and selectivity (up to approximately 10 times more sensitive to K+ than Na+ concentration changes, depending on concentrations and ionic environment). In addition, the sensor displays very good mechanical properties for the small diameter involved (sub 150 μm), which in combination with anti-biofouling properties, renders it an excellent potential tool for the chemical monitoring of neural and other physiological activities using implantable devices.
Lubba CH, Le Guen Y, Jarvis S, et al., 2019, Correction to: PyPNS: Multiscale Simulation of a Peripheral Nerve in Python., Neuroinformatics
The original version of this article unfortunately contained a mistake. The following text: "This project has received funding from European Research Council (ERC) Synergy Grant no. 319818." is missing in the Acknowledgments.
Lubba CT, Le Guen Y, Jarvis S, et al., 2019, PyPNS: multiscale simulation of a peripheral nerve in Python, Neuroinformatics, Vol: 17, Pages: 63-81, ISSN: 1539-2791
Bioelectronic Medicines that modulate the activity patterns on peripheral nerves have promise as a new way of treating diverse medical conditions from epilepsy to rheumatism. Progress in the field builds upon time consuming and expensive experiments in living organisms. To reduce experimentation load and allow for a faster, more detailed analysis of peripheral nerve stimulation and recording, computational models incorporating experimental insights will be of great help.We present a peripheral nerve simulator that combines biophysical axon models and numerically solved and idealised extracellular space models in one environment. We modeled the extracellular space as a three-dimensional resistive continuum governed by the electro-quasistatic approximation of the Maxwell equations. Potential distributions were precomputed in finite element models for different media (homogeneous, nerve in saline, nerve in cuff) and imported into our simulator. Axons, on the other hand, were modeled more abstractly as one-dimensional chains of compartments. Unmyelinated fibres were based on the Hodgkin- Huxley model; for myelinated fibres, we adapted the model proposed by McIntyre et al. in 2002 to smaller diameters. To obtain realistic axon shapes, an iterative algorithm positioned fibres along the nerve with a variable tortuosity fit to imaged trajectories. We validated our model with data from the stimulated rat vagus nerve. Simulation results predicted that tortuosity alters recorded signal shapes and increases stimulation thresholds. The model we developed can easily be adapted to different nerves, and may be of use for Bioelectronic Medicine research in the future.
Cork SC, 2018, The role of the vagus nerve in appetite control: implications for the pathogenesis of obesity, Journal of Neuroendocrinology, Vol: 30, ISSN: 0953-8194
The communication between the gut and the brain is important for the control of energy homeostasis. In response to food intake, enteroendocrine cells secrete gut hormones which ultimately suppress appetite through centrally-mediated processes. Increasing evidence implicates the vagus nerve as an important conduit in transmitting these signals from the gastrointestinal tract to the brain. Studies have demonstrated that many of the gut hormones secreted from enteroendocrine cells signal through the vagus nerve, and the sensitivity of the vagus to these signals is regulated by feeding status. Furthermore, evidence suggests that a reduction in the ability of the vagus nerve to respond to the switch between a "fasted" and "fed" state, retaining sensitivity to orexigenic signals when fed or a reduced ability to respond to satiety hormones, may contribute to obesity. This article is protected by copyright. All rights reserved.
Cork SC, Eftekhar A, Mirza KB, et al., 2018, Extracellular pH monitoring for use in closed-loop vagus nerve stimulation, Journal of Neural Engineering, Vol: 15, Pages: 1-11, ISSN: 1741-2552
Objective: Vagal nerve stimulation (VNS) has shown potential benefits for obesity treatment; however, current devices lack physiological feedback, which limit their efficacy. Changes in extracellular pH (pHe) have shown to be correlated with neural activity, but have traditionally been measured with glass microelectrodes, which limit their in vivo applicability. Approach. Iridium oxide has previously been shown to be sensitive to fluctuations in pH and is biocompatible. Iridium oxide microelectrodes were inserted into the subdiaphragmatic vagus nerve of anaesthetised rats. Introduction of the gut hormone cholecystokinin (CCK) or distension of the stomach was used to elicit vagal nerve activity. Main results. Iridium oxide microelectrodes have sufficient pH sensitivity to readily detect changes in pHe associated with both CCK and gastric distension. Furthermore, a custom-made Matlab script was able to use these changes in pHe to automatically trigger an implanted VNS device. Significance. This is the first study to show pHe changes in peripheral nerves in vivo. In addition, the demonstration that iridium oxide microelectrodes are sufficiently pH sensitive as to measure changes in pHe associated with physiological stimuli means they have the potential to be integrated into closed-loop neurostimulating devices.
Mirza KB, Wildner K, Kulasekeram N, et al., 2017, Live Demo: Platform for Closed Loop Neuromodulation Based on Dual Mode Biosignals, IEEE Biomedical Circuits and Systems Conference (BioCAS), Publisher: IEEE, ISSN: 2163-4025
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- Citations: 2
Cork SC, Chazot PL, Pyner S, 2016, Altered GABAA α5 subunit expression in the hypothalamic paraventricular nucleus of hypertensive and pregnant rats, Neuroscience Letters, Vol: 620, Pages: 148-153, ISSN: 1872-7972
A characteristic of both hypertension and pregnancy is increased sympathetic nerve activity. The level of sympathetic activation is determined, in part, by a tonic GABAergic inhibition arising from the hypothalamic paraventricular nucleus (PVN). In hypertension, decreases in GABAergic inhibition and increases in glutamatergic excitation within the PVN contribute to this sympatho-excitation. In late-term pregnancy however, the sympatho-excitation appears to be mediated by decreases in GABAergic inhibition only. This study examined whether changes in subunit expression for GABAA receptors in the PVN could provide a molecular basis for the sympatho-excitation characteristic of hypertension and pregnancy. Hypertension and pregnancy were accompanied by significant decrease in the GABAA receptor α5 subunit in the PVN. We suggest that decreases in the α5 subunit of the GABAA receptor may be important in mediating the sympatho-excitation observed in both hypertension and pregnancy.
Richards JE, Cork SC, Holt MK, et al., 2015, Role of Incretins in the Brain, Incretin Biology - A Practical Guide: Glp-1 and Gip Physiology, Editors: Rutter, Zac-Varghese, Publisher: Imperial College Press, Pages: 99-130, ISBN: 9781783267361
This is one of the fastest areas of growth within diabetes research, and over the past decade, increasing numbers of novel diabetes drugs — many based on incretin action — have been added to the therapeutic armoury.Following an ...
Trapp S, Cork SC, 2015, PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation, AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, Vol: 309, Pages: R795-R804, ISSN: 0363-6119
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- Citations: 52
Cork SC, Richards JE, Holt MK, et al., 2015, Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain., Molecular Metabolism, Vol: 4, Pages: 718-731, ISSN: 2212-8778
OBJECTIVE: Although Glucagon-like peptide 1 is a key regulator of energy metabolism and food intake, the precise location of GLP-1 receptors and the physiological relevance of certain populations is debatable. This study investigated the novel GLP-1R-Cre mouse as a functional tool to address this question. METHODS: Mice expressing Cre-recombinase under the Glp1r promoter were crossed with either a ROSA26 eYFP or tdRFP reporter strain to identify GLP-1R expressing cells. Patch-clamp recordings were performed on tdRFP-positive neurons in acute coronal brain slices from adult mice and selective targeting of GLP-1R cells in vivo was achieved using viral gene delivery. RESULTS: Large numbers of eYFP or tdRFP immunoreactive cells were found in the circumventricular organs, amygdala, hypothalamic nuclei and the ventrolateral medulla. Smaller numbers were observed in the nucleus of the solitary tract and the thalamic paraventricular nucleus. However, tdRFP positive neurons were also found in areas without preproglucagon-neuronal projections like hippocampus and cortex. GLP-1R cells were not immunoreactive for GFAP or parvalbumin although some were catecholaminergic. GLP-1R expression was confirmed in whole-cell recordings from BNST, hippocampus and PVN, where 100 nM GLP-1 elicited a reversible inward current or depolarisation. Additionally, a unilateral stereotaxic injection of a cre-dependent AAV into the PVN demonstrated that tdRFP-positive cells express cre-recombinase facilitating virally-mediated eYFP expression. CONCLUSIONS: This study is a comprehensive description and phenotypic analysis of GLP-1R expression in the mouse CNS. We demonstrate the power of combining the GLP-1R-CRE mouse with a virus to generate a selective molecular handle enabling future in vivo investigation as to their physiological importance.
Wells JA, Christie IN, Hosford PS, et al., 2015, A Critical Role for Purinergic Signalling in the Mechanisms Underlying Generation of BOLD fMRI Responses, JOURNAL OF NEUROSCIENCE, Vol: 35, Pages: 5284-5292, ISSN: 0270-6474
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- Citations: 42
Rutter GA, Broichhagen J, Schönberger M, et al., 2014, Optical control of insulin release using a photoswitchable sulfonylurea, Nature Communications, Vol: 5, ISSN: 2041-1723
Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (KATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardiovascular disease, both potentially fatal complications. Here, we describe the design and development of a photoswitchable sulfonylurea, JB253, which reversibly and repeatedly blocks KATP channel activity following exposure to violet-blue light. Using in situ imaging and hormone assays, we further show that JB253 bestows light sensitivity upon rodent and human pancreatic beta cell function. Thus, JB253 enables the optical control of insulin release and may offer a valuable research tool for the interrogation of KATP channel function in health and T2DM.
Richards P, Parker HE, Adriaenssens AE, et al., 2014, Identification and Characterization of GLP-1 Receptor-Expressing Cells Using a New Transgenic Mouse Model, DIABETES, Vol: 63, Pages: 1224-1233, ISSN: 0012-1797
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- Citations: 308
Cork SC, Chazot P, Pyner S, 2011, NMDA Receptor Subunit Expression in the Paraventricular Nucleus of the Spontaneously Hypertensive and Pregnant Rat, Experimental Biology Meeting 2011, Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638
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- Citations: 1
Watkins ND, Cork SC, Pyner S, 2009, An immunohistochemical investigation of the relationship between neuronal nitric oxide synthase, GABA and presympathetic paraventricular neurons in the hypothalamus., Neuroscience, Vol: 159, Pages: 1079-1088
Functional studies suggest that nitric oxide (NO) modulates sympathetic outflow by enhancing synaptic GABAergic function. Furthermore, the paraventricular nucleus of the hypothalamus (PVN), an important site for autonomic and endocrine homeostasis constitutes an important center mediating NO actions on sympathetic outflow. However, the exact anatomical organization of GABA and NO releasing neurons with the PVN neurons that regulate autonomic activity is poorly understood. The present study addressed this by identifying PVN-presympathetic neurons in the rat with the retrograde tracer Fluorogold injected into T2 segment of the spinal cord or herpes simplex virus injected into the adrenal medulla (AM). GABAergic or nitric oxide cell bodies were identified by antibodies directed towards GABA or glutamate decarboxylase (GAD67) enzyme or neuronal nitric oxide synthase. This revealed a population of GABAergic neurons to be synaptically associated with a chain of pre-sympathetic neurons targeting the AM. Furthermore, this GABAergic population is not a cellular source of NO. Within the PVN, the majority of cellular nitric oxide was localized to non-spinally projecting neurons while for the PVN-spinally projecting neuronal pool only a minority of neuron were immunopositive for neuronal nitric oxide synthase. In summary, nitrergic and GABAergic neurons are associated with a hierarchical chain of neurons that regulate autonomic outflow. This anatomical arrangement supports the known function role of a NO-GABA modulation of sympathetic outflow.
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