Details of positions available will be posted as and when the arise. We also welcome enquiries for fellowships and postdoctoral positions to work in any of the research areas that are encompassed by the MRC Centre. Please contact individual PIs for to discuss opportunities that may be available to work in their laboratories.
We welcome enquiries and applications in any of the research areas encompassed by the MRC Centre. Individual PI's may be contacted to discuss opportunities for postgraduate work in their laboratories. Listed below are details of studentships that are currently available for start in October 2010. For further information and application forms please contact: Elaine Sparey . Tel: 0117 3311904, e-mail Elaine Sparey (Elaine.Sparey@bristol.ac.uk). Closing date for applications is 1st February 2010.
Most postgraduate research projects have funding attached and are available only to UK citizens or those who have been resident in the UK for a period of 3 years or more. Some projects, which are funded by charities or by the universities themselves may have more stringent restrictions'.
Non-UK Students: In most cases if you have the correct qualifications and access to your own funding, either from your home country or your own finances, your application to work with this supervisor will be considered.
This is an opportunity to work in a 5** rated department. State-of-the-art equipment is available to tackle some of the most fascinating questions in neuroscience.
Regulation synaptic function in health and disease
Supervisor: Prof Jeremy Henley
Investigation of dynamic microtubules in mediating synaptic plasticity: implications for Alzheimer’s disease.
Supervisors: Kei Cho, Jihoon Jo, Graham Collingridge
Novel signalling molecules involved in synaptic plasticity in the hippocampus
Supervisors: Prof Graham Collingridge, Dr Celine Nicolas, Prof Kei Cho
A multilevel analysis of associational recognition memory
Supervisors: Dr Clea Warburton, Prof Zafar Bashir and Prof Malcolm Brown
Investigation of the molecular organisation and distribution of native ionotropic glutamate receptors: A novel affinity reagent-based approach
Supervisors: Profs. Elek Molnar and David Jane
The consolidation of memory during sleep by synaptic plasticity
Supervisors: Dr Jack Mellor and Dr Matt Jones
Effect of anaesthetic agents on NMDA receptors
Supervisors: Professor Zafar Bashir, Dr Stephen Fitzjohn
Jet-lag or memory: The role of circadian rhythms in synaptic plasticity
Supervisors: Professors Stafford Lightman, Kei Cho, Graham Collingridge
Age-dependent alterations in the mechanisms involved in synaptic plasticity in the hippocampus
Z.A Bortolotto & G.L. Collingridge
There is flexibility in the exact nature of the project but it will focus on novel aspects of research projects currently underway in the lab. In general these are 1) the mechanisms underlying AMPA or kainate receptor trafficking to and from synapses or 2) the roles of protein SUMOylation on synaptic function. In both cases studies will include work on normal and stressed (e.g. ischaemia, disease models etc) tissue. Techniques and training will include, molecular biology, biochemistry, viral transduction technology, live and fixed cell confocal microscopy of native and fluorophore-tagged proteins, primary neuronal, stem cell and hippocampal slice culture.
References S. Martin, A. Nishimune, J. Mellor and J.M. Henley (2007) SUMOylation regulates kainate receptor mediated synaptic transmission. Nature. 447, 321-5 F.
Jaskolski and J.M. Henley (2008) Synaptic Protein trafficking in synapses: the horizontal point of view. Neuroscience doi:10.1016/j.neuroscience.2008.01.075
In the brain, activity dependent changes in the strength on synapses, termed synaptic plasticity, are mediated by glutamate receptors and dendritic spine morphogenesis. Recent studies have shown that dynamic microtubules play a role in synaptic structure (Schlager and Hoogenraad, 2009, Molecular Brain 2:25; Selkoe, 2002, Science 298, 789-791). Microtubules deliver essential protein molecules from the cell body to dendritic spines. The project will investigate whether oligomeric amyloid-beta 1-42 (Ab1-42), a characteristic peptide of Alzheimer’s disease (AD), regulates dynamic microtubules. Many previous studies have shown that oligomeric Ab induces neurotoxic effects and these resulted in synaptic failure, including glutamate receptor internalisation and synaptic atrophy. Furthermore, Aβ regulates phosphorylated-tau formation that impacts on the trafficking of microtubules in the dendrites. Dynamic microtubules therefore are a good candidate molecule to investigate in the examination of AD pathology.
Using a combination of molecular biology (western-blot, gene-transfection), electrophysiology (extracellular and/or whole-cell patch-clamp recording) and imaging (as appropriate), the project will investigate the protein-protein interaction and synaptic plasticity mechanisms in rat hippocampal tissue in vitro.
Two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), are believed to underlie most forms of learning and memory. Dysfunction of these systems can lead to devastating disorders such as Alzheimer's disease, schizophrenia and depression. We have recently identified an enzyme, glycogen synthase kinase (GSK-3), that is required for one form of synaptic plasticity, N-methyl-D-aspartate (NMDA) receptor-dependent LTD in the hippocampus (Peineau et al, 2007 Neuron 53, 703-717). This enzyme holds the key to how dysfunction of synaptic plasticity can lead to these terrible diseases. In an attempt to understand how GSK-3 is involved in this form of LTD we have systematically investigated the role of other protein kinases (Peineau et al, 2009 Molecular Brain 2, 22-) and have recently identified a new signalling cascade (unpublished). The aim of this project will be to investigate how this new signal cascade is involved in hippocampal LTD.
The project will involve electrophysiology (extracellular and/or whole-cell patch-clamp recording), biochemistry and imaging (as appropriate) to investigate synaptic plasticity mechanisms in rat hippocampal tissue in vitro.
Recognition memory, our ability to judge if we have seen something before, is essential to normal everyday life. Recent research in my laboratory has shown that three brain regions, the hippocampus, prefrontal and perirhinal cortices interact during recognition memory. However there are multiple routes through which these brain regions can interact. When and how these distinct neural regions co-operate is a fundamental question that this PhD project will attempt to address. Specifically the project will investigatethe contributions of hippocampal subfields, DG, CA3 and CA1 to associative recognition memory and investigate the role of plasticity within these hippocampal subfields.in the formation of associative recognition memories.
An integrative approach will be taken to investigate these questions, which will combine three techniques in parallel. 1) Selective excitotoxic lesions, 2) Measurements of neuronal activation. These measurements will be made using immunohistochemical imaging of the protein products (Fos) of the immediate early gene c-fos to determine the functional dependencies of neural regions following the lesions; 3) The application of selective neurotransmitter antagonists. The antagonists will be administered into specific brain regions to allow an examination of the role of specific neurotransmitter systems in recognition memory. By combining both behavioural and cellular techniques within this programme of research a greater understanding of the functional neuroanatomy of recognition memory in the rat will be achieved.
The student will receive training in whole animal physiology, cognitive neuroscience, behavioural pharmacology and immunohistochemical techniques.
Barker, G.R.I. and Warburton, E.C. (2008) NMDA receptor plasticity in the perirhinal and prefrontal cortices is crucial for the acquisition of long-term object-in-place associative memory. Journal of Neuroscience 28: 2837 – 2844.[Medline]
The amino acid glutamate is the major excitatory neurotransmitter in the mammalian brain, and it exerts its physiological effects by binding to different ionotropic (ligand gated ion channels) and metabotropic (G protein coupled) glutamate receptors. There are three main types of ionotropic glutamate receptors identified by their differential sensitivity to the agonists NMDA, AMPA and kainate. Although the roles of ionotropic glutamate receptors in synaptic plasticity and neurological diseases are well documented [1], the molecular organisation, subunit composition and interactions of the native receptor complexes are not well understood, largely due to the lack of selective drugs and affinity reagents.
The general aim of this project is to obtain information about the subunit composition and distribution of native ionotropic glutamate receptors in the central nervous system. Through the modification of previously characterised high affinity ligands [2] we have recently developed new biotin-conjugated compounds for the tagging, retrieval or localisation of native kainate receptors. The purpose of this project is to exploit exciting new opportunities created by the availability of these affinity reagents for the analysis of the subunit composition, protein-protein interactions and distribution of native kainate receptors. A combination of molecular, pharmacological, biochemical and cell imaging approaches will be applied in close collaboration with chemists and electrophysiologists. The better understanding of the molecular composition, distribution and targeting of native glutamate receptors is crucial to understand their involvement in synaptic transmission, neuronal plasticity, development and neurological disorders.
Jane DE, Lodge D, Collingridge GL (2009) Kainate receptors: pharmacology, function and therapeutic potential. Neuropharmacology 56:90-113. [Medline]
Electrophysiology will be combined with pharmacological manipulations in order to model hippocampal network dynamics during REM and non-REM sleep stages, with the ultimate aim of establishing the synaptic basis of sleep-associated memory consolidation. These phenomena may also be studied in rodent models of psychiatric disease, many of which are associated with sleep abnormalities. The student will be exposed to a wide range of in vitro and in vivo systems neuroscience techniques spanning the two labs, plus a number of national and international collaborations with academia and industry.
Lee AK & Wilson MA (2002) Memory of sequential experience in the hippocampus during slow wave sleep. Neuron 36: 1183-94 [Medline]
Walker MP & Stickgold R (2004) Sleep-dependent learning and memory consolidation. Neuron 44: 121-33. [Medline]
The dominant circadian oscillator in the mammalian brain, the hypothalamic suprachiasmatic nucleus (SCN) coordinates molecular, cellular, physiological and behavioural rhythms. Experimental interference with SCN activity disrupts cognitive function but there is little information as to how the SCN communicates phase information to extrahypothalamic structures. The hypothesis to be investigated in this proposal is that changes in circadian activity entrain core circadian clock genes within the hippocampus with consequent changes in synaptic plasticity and behaviour. Studies in the Lightman laboratory have already shown that ultradian pulses of the stress hormone glucocorticoid, which is known to be released in a circadian manner, are important in hippocampal physiology and probably cognitive function. In this project we propose to follow on from these studies at both in vivo and in vitro levels to determine the importance of the pattern of glucocorticoid presentation on the hippocampus.
Rats will be kept under normal or reversed lighting schedules to allow studies in both the active and rest phases of their circadian cycles. Electrophysiology, extracellular field and whole-cell patch clamp recording, will be performed to compare synaptic transition in both the normal and reversed lighting groups, comparing LTP and LTD in the CA1-Schaffer collateral synapses. Finally, siRNA technology will be used to knock down per 1 and per 2 in the hippocampus to allow us to determine the causal effect of these genes in the regulation of synaptic plasticity.
In this project we aim to rectify this situation by investigating LTP and LTD mechanisms in slices of adult rats and mice, using pharmacological agents and knockout techniques to explore the roles of glutamate receptor subtypes and signalling molecules, such as protein kinases. A key aspect of this work will be to establish how the signalling mechanisms that are involved in LTP and LTD alter during the life-span of the animal. This is important if we are to understand how cognitive processes alter during ageing.
The student will learn electrophysiological techniques such as extracellular and patch-clamp recordings in the slice prepartion, and a combination of patch-clamp and 2-photon excitation microscopy technique will be available as the project develops.