THE UNIVERSITY OF EDINBURGH COLLEGE OF MEDICINE AND VETERINARY MEDICINE EDINBURGH NEUROSCIENCE

CENTRE FORINTEGRATIVE PHYSIOLOGY

Director: Professor Michael J. Shipston, BSc, PhD,Professor of Physiology

CENTRE FOR

INTEGRATIVE PHCCNS WAS

ESTABLISHED IN2005 TO PROMOTERESEARCH IN THE

GENERAL AREA OFCOGNITION, AS IT APPLIED TO

MEDICINE,INFORMATICS

AND NEUROSCIENCE

The Centre was formally established in 2004 from three existingInterdisciplinary Research Groups with additional investigators acrossEdinburgh. It moved into the refurbished Hugh Robson Buildingbuilding in 2007.

THE UNIVERSITY OF EDINBURGH COLLEGE OF MEDICINE AND VETERINARY MEDICINE EDINBURGH NEUROSCIENCE

TO DEVELOP AND PROMOTE INTERNATIONAL

EXCELLENCE IN RESEARCH AND

TRAINING IN INTEGRATIVEPHYSIOLOGY RELEVANT TOHUMAN AND MAMMALIAN

PHYSIOLOGY,DEVELOPMENT AND

DISEASE

YSIOLOGYRESEARCH PROFILE

The CIP aims to foster supportive, outward-looking and cohesive

multi-disciplinary programmes of research into fundamental

physiological mechanisms and pathways relevant to human function

and disease. CIP investigators exploit rapid advances in the enabling

technologies available from genomics, proteomics, imaging and

informatics to allow development of predictive modelling and in vivo

analysis to understand the function of gene products at the cell,

organ and whole animal level. Importantly CIP investigators exploit

the most appropriate model organisms/systems to investigate the

key physiological question being posed – a delicate balance

between high biomedical relevance (e.g., human, mouse, rat) and

high genetic power (lower organisms such as drosophila and fish).

The research activities of the CIP are thus focused around the ‘four

cornerstones’ of the Integrative Physiology approach with

investigators working across these domains: i). manipulation &

regulation of genes & their products; ii). molecular imaging and

quantitation; iii) complex systems function & behaviour; iv). predictive

modelling of complex systems.

By exploiting these approaches investigators are addressing

fundamental regulatory mechanisms in the control of body

development and homeostasis and how defects in these processes

lead to disease. Our work thus underpins major human disorders

including: the neuroendocrine control of feeding and obesity; mental

retardation syndromes (such as Fragile X); stress and affective

disorders; neurodegenerative disorders; epilepsy and reproductive

function.

Research is informally grouped into the research themes of

Membrane Biology, Neural Control Systems, and Genes and

Development. Within these groupings, current research activity

extends over the breadth of modern bioscience, including:

• Systems-and cellular-level physiological studies of neuronal

networks, neuroendocrine regulation and adaptive plasticity

• Cellular molecular and behavioural level studies of ion channels,

membrane receptors, adaptor proteins and vesicle trafficking

• Molecular-, cellular-, tissue-, and organismal-level studies of

neural, kidney and ovary development and function, particularly

with regard to gene regulatory networks.

UNIQUE EXPERTISE:

1) In vivo and in vitro electrophysiology: facilities span from analysis

of single ion channels to analysis of ion channel function in vivo

and roles in behaviour

2) Cellular fluorescent imaging: expertise in confocal, multiphoton,

FLIM/FRET and TIRF microscopy within dedicated imaging facility

(IMPACT).

Tian NM, Pratt T & Price DJ (2008) Foxg1 regulates retinal axonpathfinding by repressing an ipsilateral program in nasal retina and by causing optic chiasm cells to exert a net axonal growth-promoting activity. Development 135:4081-4089

Brunton PJ, Meddle SL, Ma S, Ochedalski T, Douglas AJ,Russell JA (2005) Endogenous opioids and reduced neuroendocrine stress responses to immune challenge in pregnantrats. Journal of Neuroscience 25: 5117-5126

McCartney CE, McClafferty H, Huibant J-M, Rowan EG,Shipston MJ, Rowe ICM (2005) A cysteine rich motif confershypoxia sensitivity to mammalian BK channel alpha-subunits. Proc Natl Acad Sci USA 102: 17870-17876

Tian L, Coghill LS, McClafferty H, MacDonald SH-F, AntoniFA, Ruth P, Knaus H-G, Shipston MJ (2004) Distinct stoichiometry of BKCa channel tetramer phosphorylation specifieschannel activation and inhibition by cAMP-dependent proteinkinase. Proc Natl Acad Sci USA 101: 11897-11902

zur Lage PI, Powell LM, Prentice DRA, Jarman AP (2004) EGFreceptor signalling triggers recruitment of Drosophila sense organprecursors by stimulating proneural gene autoregulation.Developmental Cell 5: 687-696

Duncan RR, Greaves J, Wiegand UK, Matskovich I,Bodammer G, Apps DK, Shipston MJ, Chow RH (2003)Functional and spatial segregation of secretory vesicle poolsaccording to vesicle age. Nature 422: 176-180

Tan TC, Valova VA, Malladi CS, Graham ME, Berven LA, JuppOJ, Hansra G, McClure SJ, Sarcevic B, Boadle RA, LarsenMR, Cousin MA Robinson PJ (2003) Cdk5 is essential forsynaptic vesicle endocytosis. Nature Cell Biology 5: 701-710

Kind PC, Mitchell DE, Ahmed B, Blakemore C, Bonhoeffer T,Sengpiel F (2002) Correlated binocular activity guides recoveryfrom monocular deprivation. Nature 416: 430-433

Ludwig M, Sabatier N, Bull PM, Landgraf R, Dayanithi G Leng G (2002) Intracellular calcium stores regulate activity-dependent neuropeptide release from dendrites. Nature 418: 85-89

Hannan AJ, Blakemore C, Katsnelson A, Vitalis T, Huber KM,Bear M, Roder J, Kim D, Shin HS, Kind PC (2001) PLC-beta 1,activated via mGluRs, mediates activity-dependent differentiationin cerebral cortex. Nature Neuroscience 4: 282-288

Kirby RJ, Hamilton GM, Finnegan DJ, Johnson KJ, JarmanAP (2001) Drosophila homolog of the myotonic dystrophy-associated gene, SIX5, is required for muscle and gonad development. Current Biology 11: 1044-1049

Mitchell DE, Gingras G, Kind PC (2001) Initial recovery of visionafter early monocular deprivation in kittens is faster when botheyes are open. Proc Natl Acad Sci USA 98: 11662-11667

MAJOR RESEARCH SUCCESSES

Manuel M, Georgala PA, Carr CB, Chanas S, Kleinjan DA,Martynoga B, Mason JO, Molinek M, Pinson J, Pratt T, QuinnJC, Simpson TI, Tyas DA, van Heyningen V, West JD, Price DJ(2007) Controlled overexpression of Pax6 in vivo negatively auto-regulates the Pax6 locus, causing cell-autonomous defects oflate cortical progenitor proliferation with little effect on cortical arealization. Development 134:545-555

Harlow EG, Till SM, Russell TA, Wijetunge LS, Kind P &Contractor A (2010) Critical Period Plasticity Is Disrupted in theBarrel Cortex of Fmr1 Knockout Mice. Neuron: 65:385-398

Tobin VA, Hirofumi H, Wacker DW, Takayanagi Y, Langnaese K,Caquineau C, Noack J, Landgraf R, Onaka T, Leng G, MeddleSL, Engelmann M, Ludwig M. An intrinsic vasopressin system inthe olfactory bulb is involved in social recognition. Nature 2010 (inpress).

Anggono V, Smillie KJ, Graham ME, Valova VA, Cousin MA,Robinson PJ (2006) Syndapin I is the phosphorylation-regulateddynamin I partner in synaptic vesicle endocytosis. NatureNeuroscience 9: 752-760

Gillingwater TH, Wishart TM, Chen PE, Haley JE, Robertson K,MacDonald SHF, Middleton S, Wawrowski K, Shipston MJ,Melmed S, Wyllie DJA, Skehel PA, Coleman MP, Ribchester RR(2006) The neuroprotective Wld(S) gene regulates expression ofPTTG1 and erythroid differentiation regulator 1-like gene in mice andhuman cells. Human Molecular Genetics 15:625-635

Johnstone LE, Fong TM, Leng G (2006) Neuronal activation in thehypothalamus and brainstem during feeding in rats. Cell Metabolism4:313-321

Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X,Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C,Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, GalioneA, Zhu MX. (2009) NAADP mobilizes calcium from acidic organellesthrough two-pore channels. Nature. 459:596-600.

Tian L, Jeffries OJ, McClafferty H, Molyvdas A, Rowe ICM,Saleem F, Chen L, Greaves J, Chamberlain LH, Knaus HG, RuthP, Shipston MJ (2008) Palmitoylation gates phosphorylation-dependent regulation of BK potassium channels. Proc Natl Acad SciUSA 105:21006-21011

Garden DLF, Dodson PD, O’Donnell C, White MD, Nolan MF(2008) Tuning of Synaptic Integration in the Medial Entorhinal Cortexto the Organization of Grid Cell Firing Fields. Neuron 60:875-889

Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, HansenHH, Kaindl A, Sifringer M, Fowler J, Stefovska V, McKenzie G,Craigon M, Corriveau R, Ghazal P, Horsburgh K, Yankner BA,Wyllie DJA, Ikonomidou C, Hardingham GE (2008) SynapticNMDA receptor activity boosts intrinsic antioxidant defenses. NatureNeuroscience 11:476-487

Rossoni E, Feng JF, Tirozzi B, Brown D, Leng G & Moos F(2008) Emergent Synchronous Bursting of Oxytocin NeuronalNetwork. PLoS Computational Biology 4

RESEARCH GROUPS

GENES & DEVELOPMENT (G&D): aims “to understand fundamental

developmental processes, including neural fate specification,

neuronal targeting and pre- and post-natal brain development”,

exploiting a range of transgenic model organisms, including mice

and flies, using molecular, cellular and bioinformatics analyses.

MEMBRANE BIOLOGY GROUP (MBG): aims “to understand how

molecular traffic across membranes (via either ion channels,

transporters or vesicles) is co-ordinated in space and time and

how perturbations of these may lead to disease”, exploiting a

variety of real time imaging, electrophysiological, cell/molecular

biochemical and behavioural approaches.

NEURAL CONTROL SYSTEMS GROUP (NCS): aims to “understand how

specific neuronal and neuroendocrine networks generate and

control physiological behaviour and how disruption of these

networks underlies major human and animal disorders” using a

multi-disciplinary approach integrating molecular genetics,

molecular and functional neuroanatomy, microdialysis, in vivo and

in vitro electrophysiology, functional and behavioural studies and

computational modelling.

CENTRE FOR INTEGRATIVE PHYSIOLOGYTHE UNIVERSITY OF EDINBURGH COLLEGE OF MEDICINE AND VETERINARY MEDICINE EDINBURGH NEUROSCIENCE

VALUE ADDED

• increased critical mass and cohesion of an interactive community of basic science researchers in Integrative Physiology

• providing a clear focus of basic science research and training in the central area in close proximity to the strengths in Informatics

• greater added value and multi-disciplinarity across colleges

• improved research interactions, profile and productivity for RAE and external funding initiatives

• establishing a key node in a network of ‘Centres’ developing complementary expertise and training

• consolidation of 3 CMVM IDG’s (Membrane Biology, NeuralControl systems, Genes & Development)

• optimisation of personnel and infrastructure resources

• development of novel Fellowship and postgraduate training

• Focus of ion channel and in vitro/in vivo electrophysiology in Edinburgh

MAJOR SOURCES OF FUNDING

• Wellcome Trust (includes 3 programmes, 2 University awards, 1 RCDF)

• BBSRC (includes grant and doctoral training grant, BBSRC Welfare Initiative programme grant)

• MRC (includes programme, Senior non-Clinical Fellowship and Career Development Fellowship)

• EU (includes FP7’Integrated neurobiology of food intake, addition & stress’, FP6 Diabesity and FP6 Euregene) programmes

MAJOR FACILITIES/EQUIPMENT

• In vivo physiological and behavioural studies, including multiple and single unit recording in rodent brain

• In vivo and electrophysiology and neuropharmacology, from single ion channels to neural networks

• A variety of molecular biology techniques, including real time qPCR.

• Model organism technology – in particular Drosophila and mouse, including genetics, transgenesis, and associated techniques. (The main building houses a newly refurbished rodent barrier facility with integrated procedure, behavioural and experimental rooms.)

• Bioinformatics – including a well equipped bioinformatics laboratory (the Wolfson laboratory)

• Tissue and explant culture

• IMPACTfacility: Cellular imaging & analysis. This includes high power bright field microscopy with colour ccd image capture, epifluorescence microscopy, multichannel confocal microscopy, multiphoton confocal microscopy, FRET (fluorescence resonance energy transfer) and FLIM (fluorescence lifetime imaging) technologies. Also associated computer hardware, software and technical expertise in live cell and live organism imaging. Imaging equipment is housed in centrally accessible facilities which are serviced by excellent technical support. (www.bms.ed.ac.uk/services/impact/)

KEY EXTERNAL LINKS/COLLABORATIONS

• Numerous major research Centres in USA, Europe, Japan, Australia

FUTURE PLANS AND DIRECTIONSDirections/themes for the three groupings outlined include:1) G&D Development of physiological systems: The CIP has amajor strength in developmental neurobiology, exploiting modelsystems such as mouse and Drosophila using transgenic, cell biological, physiological and informatics approaches. There is considerable added value from interactions with investigatorsanalysing fundamental mechanisms of development in other systems such as the renal, cardiovascular and reproductive systems. Much of the work relates to specific human congenitaldiseases such as Greig’s cephalopolysyndactyly and congenitialaniridia, developmental causes of mental illness such as schizophrenia and fragile X-mental retardation, and developmentof novel methods for the treatment of renal failure and reproductivedisorders using stem cells. A central issue for these developmentalsystems is understanding and controlling developmental cues andmorphogenic gradients for specification of cell migration /cell interaction and the appropriate spatiotemporal regulation of geneand protein expression to allow correct assembly of organs.

2) MBG: Dynamics of cellular communication: The CIP hasextensive expertise in the analysis of molecular traffic and communication across membranes (via either channels, transporters or vesicles). A central issue is understanding the spatiotemporal dynamics and regulation of signalling systems withparticular focus on two major thematic areas underpinning cellularcommunication and related disorders: i) dynamics of secretoryvesicle trafficking in particular the exploitation of state of the artreal-time, quantitative imaging tools, in concert with geneticallyencoded reporters to understand the role of protein and lipid complexes and posttranslational modifications in the control ofvesicle trafficking; ii) pre-and post transcriptional control mechanisms of ion channel/transporter regulation, their assemblyinto signalling complexes and the functional consequence of thesemechanisms from the single channel to systems and organismlevel behaviour. Together, these themes are interrogating intra-and inter-cellular traffic from the single molecule to systems andorganism level, providing key information on the integration of cellular communication in both the nervous, vascular andendocrine systems. Thus these studies underpin fundamentalphysiological mechanisms and disease processes ranging fromepilepsy to neurodegeneration, pain and stress.

3) NCS: Controlling body homeostasis and behaviours: TheCIP has a major strength in the functional analysis of neuronal andneuroendocrine networks using a variety of in vivo electrophysiological, computational and behavioural analyses. A significant new area for considerable synergy and added valueof CIP activities will be to exploit the expertise relevant to the control of body homeostasis, including energy balance, and themechanisms of dysregulation. For example, the interplay of short- and long term afferent signals to the neuroendocrine brainfrom the periphery in regulating energy intake and expenditure, the hormonal milieu, reproduction, growth, early life experienceand development represents a major integrative physiology challenge with significant healthcare implications. Furthermore,linking peptidergic control of neural network activity to behavioursincluding social, feeding and reproductive behaviours provides anadditional avenue for cross Centre integration.

ADDITIONAL INFORMATION• Coordination of Cellular imaging technique workshops in CMVM

• Focussed Workshop programmes coordinated by all groupings

• Biannual Junior Academics meeting: exocytosis & endocytosis

• Regular externally hosted seminar/symposia programmes

POSTGRADUATE CONTACT DETAILSProfessor Andrew Jarman: Andrew.Jarman@ed.ac.ukTel: 0131 6503737 www.cip.ed.ac.uk/postgraduate/index.htm

CONTACT DETAILS

Centre for Integrative PhysiologyHugh Robson BuildingGeorge Square Edinburgh EH8 9XD

Contact tel. +44 131 650 1692 Sarah Matheson Email cip@ed.ac.ukWebsite: www.cip.ed.ac.uk