Nerve cells are connected into neuronal networks which constitute the cellular basis of brain function. Within these network, long thin cellular protrusions called axons convey neuronal messages and pass them on at synapses to other neurons, muscles or gland cells. The growth of axons is therefore a key process during brain development and regeneration. The molecular machinery underlying axonal growth provides key drug targets for the treatment of stroke or paralysis patients, or of impaired nerve regeneration in diseases (e.g. diabetes). This project aims to decipher the molecular mechanisms of this machinery, thus addressing a key challenge to modern neurobiology.
Extracellular signalling factors line the path of growing axons and guide them towards their target areas in the brain. But the actual growth of axons is executed by the cytoskeleton, composed of actin and microtubules. You will investigate the molecular mechanisms mediating between signalling factors and cytoskeleton. To this end you will use unique strategies available for the genetic model organism Drosophila, based on a neuronal cell culture system established in our group. In this system, regulatory mechanisms of axonal growth can be dissected with an unparalleled repertoire of genetic and pharmacological means. Given the universal requirements of cytoskeletal dynamics for most cell functions, your work will have further implications in other relevant areas of investigation, such as cancer biology, neurodegenerative diseases (e.g. Alzheimer's) or pathologies, such as mental retardation.
During this project you will gain excellent training in biotechnology. You will generate cell cultures from neural embryonic stem cells or dissociated brains, use sophisticated genetic strategies and molecular biology techniques, generate transgenic animals, employ drugs for pharmacological manipulations, and use advanced microscopy including live imaging. The postgraduate training programme of Manchester's Faculty of Life Sciences will enable you to prepare for all aspects of your future career.
 

• Lowery & van Vactor, 2009, Nat Rev Mol Cell Biol 10, 332ff.
• Sánchez-Soriano et al., 2007, Neural Develop 2, 9ff.
• Sánchez-Soriano et al., 2010, Dev. Neurobiol. 70, 58ff.
• Sánchez-Soriano et al., 2009, J Cell Sci 122, 2534ff. 

• Animal Biology
• Biomolecular Sciences
• Cell Biology
• Developmental Biology
• Genetics
• Molecular and Cellular Neuroscience
• Molecular Biology
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The physiological impact of Alzheimer’s Disease (AD) on the brain is poorly understood and there is a clear need for in vivo electrophysiological recordings to provide a better understanding of synaptic failure in AD. This project will use the 3xTgAD mouse (Oddo et al., 2003) to investigate hippocampal dysfunction in an AD model in vivo. This behavioural deficits and pathological levels of A?42 and tau pathology expressed in this model are comparable to human AD. The student will determine how and when synaptic changes occur in the hippocampal formation, specifically the CA1 connection to subiculum (structures that are early pathological foci in both human AD and the 3xTg model). Experiments will record subicular responses after activation of CA1 inputs using both traditional stimulus patterns and stimulus trains that match the activity of CA1 neurons in behaving animals (Tunstall et al., 2010). The latter are important as they provide a means by which our novel, quantitative computational analyses (Montemurro et al., 2008) can provide a more sophisticated measure of neural circuit function than can be obtained with traditional stimulus patterns alone. This project will, for the first time, correlate the development of synaptic deficits in AD in vivo to both cognitive decline and pathological state. This will provide vital insights into how aberrant amyloid accumulation impacts the function of hippocampal circuits in AD. The student will receive full training in electrophysiological methods for recording brain activity in AD model mice using multiple electrodes and the computational approached required to analyze these large data sets.

• Oddo et al. (2003). Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39: p409-21.
• Montemurro, Rasch, Murayama, Logothetis and Panzeri (2008). Phase-of-firing coding of natural visual stimuli in primary visual cortex. Current Biology. 18: p375-80.

• Integrative Neurobiology & Behaviour
• Neuroscience
• Systems Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Background and aims
Aluminium is ubiquitous in the environment, is bioavailable at neutral pH (Desouky et al., 2002) and is highly neurotoxic to freshwater invertebrates (Campbell et al., 2000). Aqueous Al is toxic to the crayfish via damage to the gills resulting in behavioural toxicity within 10 days of exposure (Alexopoulos et al., 2003). Recent unpublished work has shown that Al in the food is also bioavailable and is accumulated in certain tissues. The hypotheses are that Al is toxic to the crayfish, specifically the nervous system, and that this is due to accumulation in the tissues. The aims are to:
1. Examine partitioning of Al in the tissues (including haemolymph) with time.
2. Monitor potential sublethal toxicity of Al to the crayfish by examination of changes in behaviour (using standard behaviour measures plus additional methods to be developed during the course of the study)
3. Examination of electrophysiological properties of central neurones following in vivo exposure to Al, and in vitro.
Methods
• Metal analysis of tissues and water using inductively-coupled plasma optical emission spectroscopy (ICPOES).
• Behavioural monitoring
• Intracellular electrophysiological techniques to examine membrane conductances underlying electrical activity patterns (action potentials)
 

• Desouky, M, Jugdaohsingh, R, McCrohan, C R, White, K N & Powell, J J (2002) Aluminium-dependent regulation of intracellular silicon in the aquatic invertebrate Lymnaea stagnalis. Proc. Nat Acad. Sci. US, 99, 3394-3399.

• Campbell, M M, Jugdaohsingh, R, White, K N, Powell, J J & McCrohan, C R (2000) Aluminium toxicity in a molluscan neuron: effects of counterions. J. Toxicol. Environ. Health, Part A 59, 253-270.

• Alexopoulos, E, McCrohan, C.R., Powell, J.J. Jugdaohsingh, R. & White, K.N. (2003) Bioavailability and toxicity of freshly neutralised aluminium to the freshwater crayfish Pacifastacus leniusculus. Arch. Environ. Contam. Toxicol., 45, 509-514.

• Adaptive Organismal Biology
• Animal Biology
• Environmental Biology
• Integrative Neurobiology & Behaviour
• Physiology
• Toxicology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Over the past 14 years we have established that cerebrospinal fluid has a vital role in the control of the function of neural stem cells in the developing nervous system. As well as changes in fluid volume output, fluid pathway and composition changes, we have identified a critical change in folate handling associated with the development of the cerebral cortex. Problems in fluid output, flow or drainage seem to result in fluid composition changes that result in cerebral folate deficiencies.
This project will investigate cerebrospinal fluid taken from new born babies with a range of neurological conditions as well as fluid taken from adults with dementia and associated conditions. Fluid will be analysed using proteomic and metabolomic techniques as well as tissue culture. Analysis of human samples will be compared with certain animal models of similar conditions. Information from this analysis may expose powerful new therapeutic targets for prevention or treatment of such conditions.
 

• Cains et al. (2009) Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus. J.Neuropathol.Exp.Neurol. 68(4): 404-16
• Miyan et al. (2006) Cerebrospinal fluid supports viability and proliferation of cortical cells in vitro, mirroring in vivo development. Cerebrospinal Fluid Research 3:2
• Miyan et al. (2003) Development of the brain: a vital role for cerebrospinal fluid. Can.J.Physiol.Pharmacol. 81(4): 317-28
• Owen-Lynch et al. (2003) Defective cell cycle control underlies abnormal cortical development in the hydrocephalic Texas rat. Brain 126(3): 623-31
• Mashayekhi et al. (2002) Deficient cortical development in the hydrocephalic Texas (H-Tx) rat: a role for CSF. Brain 125(8): 1859-74
   

• Biochemistry
• Cell Biology
• Developmental Biology
• Molecular & Cellular Neuroscience
• Neuroscience
• Physiology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive function, associated cell loss throughout the forebrain. However, in its early stages, there is a specific impairment of short-term memory. Given that the temporal lobes (TLs - including entorhinal cortex and hippocampus) have a crucial role in this mnemonic function, the early signs of disease imply that the TLs are first to manifest pathological change. Indeed, the view is supported by animal models of AD, which show such early disease-related changes in the same brain regions. There is additional cell loss in the cholinergic neuromodulatory system of the forebrain (nucleus basalis of Meynert) in both human AD and animal models. Nicotinic and muscarinic cholinergic receptors are regulators of the synaptic and cellular functions believed to underpin memory formation and recall in the temporal lobes. Therefore, this aspect of the AD aetiology probably explains the effectiveness of current therapies for the early stages of disease that target the cholinergic neuromodulatory systems to increase its effectiveness. However, in spite of this, little is know about these underlying changes in the temporal lobe circuitry and the direct impact of this cholinergic input on this system during AD development. This needs to be rectified, as a more specific understanding will highlight the effectiveness of current treatment and could facilitate better targeted therapy and potentially lead to developments in treatments.
The project will focus on the electrophysiological activity of entorhinal cortex and hippocampus and its modulation by cholinergic nicotinic and muscarinic receptor activation. This work will be carried out using extracellular recording and intracellular sharp and whole-cell patch electrode recording from mouse brain slices maintained in vitro. By comparing observations using tissue from normal and a transgenic model of AD (3xTgAD), new insights in to the issues highlighted above will be revealed.
 

• Nakauchi et al. (2007). Nicotine gates long-term potentiation in the hippocampal CA1 region via the activation of α2* nicotinic ACh receptors. Eur J Neurosci 25:2666-81.
• Oddo et al. (2003). Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409-21.
• Wang et al. (2009). Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices. Neurobiol Aging 30:1061-8.

• Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Circadian clocks are the internal timing system that generates endogenous 24 hour cycles, governing nearly all aspects of mammalian physiology and behaviour. Most body organs harbour self-sustained circadian oscillators, which orchestrate local rhythmic output in order to anticipate the cyclic light/dark environment. Within the cardiovascular system, many physiological parameters (such as heart rate) and adverse events (including myocardial infarction and sudden cardiac death) show clear circadian rhythms. However, the tissue-specific functions of the cardiovascular clocks are not well understood. This project will utilize transgenic mouse models in which cardiovascular clocks have been eliminated to gain novel insights into the clock driven cardiovascular physiology and pathology. Circadian control of key cardiovascular pathways (such as PAI-1, AKT, GSK3beta and ERK5) will also be addressed. In collaboration with Pfizer and GSK, we have previously identified new pharmacological tools to manipulate clock function in living cells and tissues. These compounds will be used to explore the therapeutic potential of targeting local clocks in order to alleviate cardiovascular pathologies.

1. Meng Q-J, et al. PNAS, 2010; 107 (34), 15240.
2. Meng Q-J, et al. J Cell Sci, 2008; 121 (21), 3629.
3. Meng Q-J, et al. Neuron, 2008; 58(1), 78.
 

• Animal Biology
• Biochemistry
• Cell Biology
• Gene Expression 
• Molecular Biology
• Pharmacology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Local Field Potentials (LFP) correspond to the lower frequency range of the extracellular signal captured by a low impedance microelectrode located sufficiently away from any individual neuron. It is believed that LFP reflect mostly the summed dendritic activity of neurons in local neural networks that lie within a sphere of radius 50-300µm centred at the tip of the electrode. At variance with spikes, which reflect the output of a given area, LFP are thought to be more correlated with the input to it.
In most models of cortical computation it is assumed that information is mainly encoded in the action potentials fired by neurons. However, there is increasing evidence that oscillations in the extracellular electric fields (LFP) may have an important role in the encoding of information about external stimuli. For instance, LFP may encode different information to that carried by spikes, or they may provide a local time frame that can facilitate the decoding of the information carried by spikes. The main goal of this project is to understand the mechanisms of information processing and transmission by action and Local Field Potentials, using models of cortical activity and advanced data analysis.
The project will involve the development of novel data analysis methods, their application to real and simulated data, and the design of large computer simulations of networks of neurons with different degrees of biophysical realism. The project is highly interdisciplinary and will draw on methods and techniques from Computational Neuroscience, Neuroinformatics, Information Theory, and Biophysics. In addition to excellent programming skills (C / Fortran and Matlab), the candidate should have good Physics / Mathematics background. Previous experience in Neuroscience is not essential.
 

1. Montemurro MA, Rasch MJ, Murayama Y, Logothetis NK, Panzeri S (2008) Phase-of-firing coding of natural visual stimuli in primary visual cortex. Current Biology 18(5): 375-380.
2. Montemurro MA., Senatore R and Panzeri S (2007) Tight data-robust bounds to mutual information combining shuffling and model selection techniques. Neural Computation 19(11): 2913-2957.
3. Logothetis NK, (2003). The Underpinnings of the BOLD Functional Magnetic Resonance Imaging Signal. J. Neurosci. 23, 3963-3971
 

• Neuroscience
• Physiology
• Systems Neuroscience

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The HIV pandemic is one of the greatest challenges facing healthcare providers across the globe today. Worldwide 33.2 million people were HIV positive at the end of 2007 with 2.5 million new cases reported that year. Highly active antiretroviral therapy (HAART), is the current treatment for HIV, however HAART does not cure HIV infection and also has several disadvantages including severe, unpleasant side effects as well as the emergence of resistance. Prevention of HIV transmission would therefore be a better approach and requires a vaccination or microbicide approach. Attempts to develop an HIV vaccine have so far been unsuccessful. New microbicides may therefore represent the best opportunity to prevent transmission of HIV, and thereby lessen the pandemic.

One source of such microbicides may be antimicrobial peptides. Dr Dobson’s group have previously developed a range of peptides based on a cationic sequence within apolipoprotein E and apolipoprotein B with broad antiviral activity, including activity against HIV, both blocking viral entry into cells and selectively disrupting the viral envelope. The peptides inhibit all strains of HIV tested, and herpesviruses. The peptides would be suitable for development as microbicides for topical application to prevent HIV transmission. This project will focus on the further development of these peptides as microbicides against HIV and HSV2.

Specifically the study will identify more potent peptides and features associated with potency whilst retaining biocompatibility. A small a library of peptides will be screened primarily against HSV2, and ultimately against HIV, benchmarking against existing candidate microbicides. Activity will be correlated with a range of structural properties of the peptides, assessed using state of the art biophysical techniques. Additionally, the impact of formulation in standard microbicidal gels will be assessed as will the influence of physiological fluids on activity.
 

• Kelly, B.A., Harrison, I., McKnight, A. & Dobson, C.B (2010). Anti-infective activity of apolipoprotein domain derived peptides in vitro: identification of novel antimicrobial peptides related to apolipoprotein B with anti-HIV activity. BMC Immunology, 11, 13.

• Kelly BA, Neil SJ, McKnight A, Santos JM, Sinnis P, Jack ER, Middleton DA, Dobson CB. (2007). Apolipoprotein E-derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity. FEBS Journal, 274, 4511-4525.

• Dobson CB, Sales SD, Hoggard P, Wozniak MA, Crutcher KA. (2006). The receptor-binding region of human apolipoprotein E has direct anti-infective activity. J Infec Dis, 193(3), 442-450.

• Dobson C.B., Wozniak M.A. and Itzhaki R.F. (2003). Do infectious agents play a role in dementia? Trends in Microbiology, 7: 312-317.
 

• Biochemistry
• Biomolecular Sciences
• Biotechnology
• Cell Biology
• Immunology
• Microbiology
• Pharmacology
• Structural Biology

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Parkinson’s disease is a neurodegenerative disorder caused by the loss of dopaminergic cells in the substantia nigra. These neurones normally project to mid- and fore-brain targets in the basal ganglia and ventral thalamus. Together with the neocortex, these brain areas form the cortical-basal ganglia-thalamic loop, which is crucial to the integration of sensory and motor function, and hence the initiation and control of movement. Dopaminergic cell loss is believed to result in reduced dopamine levels in the basal ganglia and ventral thalamus, which gives rise to the impairment of movement characteristic of Parkinson’s disease.
While much is now understood about the role played by dopamine in the regulation of basal ganglia function, little is know about its role in the thalamus. This needs to be rectified, as thalamus is not only the target of basal ganglia output, it is the principle source of input for most of the neocortex. Therefore, an understanding how dopamine regulates thalamic function will provide new insights into the role of the dopaminergic neuromodulatory system outside the basal ganglia. This knowledge could help explain further not only the impact of dopaminergic cell loss on motor function, but also some of the other non-motor cognitive dysfunction associated with Parkinson’s disease.
The project will involve evaluating the impact of dopamine receptor activation on the biophysical properties of thalamic neurones and their responses to activation of input pathways. This will be achieved using the electrophysiological techniques of sharp and whole-cell patch electrode recording from rodent brain slices maintained in vitro. Pharmacological agents and post hoc immunocytochemistry with dopamine receptor subtype specific antibodies will be used to identify the receptor subtypes involved in mediating these effects. By comparing observations using tissue from normal and Parkinson’s disease models animals, new insights into the changes that underlie this disorder will be revealed.
 

• Florán et al. (2004). Activation of dopamine D4 receptors modulates [3H]GABA release in slices of the rat thalamic reticular nucleus. Neuropharmacology 46:497–503.
• Freeman et al. (2001). Nigrostriatal collaterals to thalamus degenerate in parkinsonian animal models. Ann. Neurol. 50:321-9.
• Govindaiah & Cox (2005). Excitatory actions of dopamine via D1-like receptors in the rat lateral geniculate nucleus. J Neurophysiol 94: 3708–18.
• Huang et al. (1992). Immunohistochemical localization of the D1 dopamine receptor in rat brain reveals its axonal transport, pre- and postsynaptic localization, and prevalence in the basal ganglia, limbic system, and thalamic reticular nucleus. Proc. Natl. Acad. Sci. USA 89:11988-92.

• Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Acute brain injuries, such as stroke, sub-arachnoid haemorrhage, and brain trauma, are leading causes of mortality and severe disability worldwide. These conditions are characterised by a primary damage to the brain, followed by the development of an acute neuroinflammatory response driven by the pro-inflammatory cytokine interleukin-1 leading to neurotoxicity. Neurones express very high levels of chemokines (CXCL-1, CCL2 and CXCL-10) in response to IL-1, but the role of IL-1-induced neuronal chemokine production on glial activation and neuronal injury in cerebral ischaemia is unknown. The aim of this project will be to test the hypothesis that neuronal chemokines produced in response to IL-1 are key mediators of glial activation, inflammation and subsequent neuronal injury. The project will use a varied combination of endothelial, neutrophils and glial-neuronal cultures, and discoveries will be validated using organotypic cultures, and experimental cerebral ischaemia in vivo.

• Tsakiri N, Kimber I, Rothwell NJ, Pinteaux E. (2008) Differential effects of interleukin-1 alpha and beta on interleukin-6 and chemokine synthesis in neurones. Mol Cell Neurosci. 38:259-65.
• Tsakiri N, Kimber I, Rothwell NJ, Pinteaux E. (2008) Mechanisms of interleukin-6 synthesis and release induced by interleukin-1 and cell depolarisation in neurones. Mol Cell Neurosci. 37:110-8.
   

• Immunology
• Molecular and Cellular Neuroscience
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Early life experiences have a critical effect on the developing nervous system, and the consequences of a disrupted environment are carried on for the rest of life.

The aim of this project is to identify the key steps in the development of the master biological clock in the brain, and how these are modified by postnatal environment.

This project will utilise an integrated tools package, including behavioural analysis, tissue culture, histology and molecular biology techniques. This multiple approach will provide training in various skills and allow the student to learn a wide range of laboratory methods.
 

• M.M. Canal, N.M. Mohammed, J.J. Rodriguez. Early programming of astrocyte organisation in the mouse suprachiasmatic nuclei by light. Chronobiol. Int. 26:1545-1558, 2009.
• L. Smith, M.M. Canal. Expression of circadian neuropeptides in the hypothalamus of adult mice is affected by postnatal light experience. J. Neuroendocrinol. 21:946-953, 2009.
• M.M. Canal-Corretger et al. Functioning of the rat circadian system is modified by light applied in critical postnatal days. Am. J. Physiol. 280:R1023-R1030, 2001.
   

• Animal Biology
• Developmental Biology
• Integrative Neurobiology & Behaviour
• Neuroscience
• Physiology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Self-sustaining daily or circadian rhythms in physiology and behaviour such as metabolism or the sleep-wake cycle arise because a neuronal network in our brain functions as an intrinsic body clock. This daily clock is localized to cells in the suprachiasmatic nuclei (SCN) of the hypothalamus. Here some (but not all) neurons contain the intracellular molecular clock and so function as autonomous cellular oscillators. These individual clock neurons synchronize together and regulate brain centres controlling cognition, motivation, arousal, thermoregulation, and hormone release as well as influencing peripheral physiology. In turn, the SCN are responsive to a variety of brain chemicals and environmental sensory signals and it is through these inputs that the SCN itself is synchronized to the external world. Very recently it was shown that endogenous cannabinoids, molecules that resemble the psychoactive constituents of cannabis, could influence the activity of cells in SCN. Exactly how these endogenous cannabinoids regulate SCN neuronal activity and the intracellular clock is unknown. Using experimental compounds that are selective for cannabinoid receptors, this project will employ state of the art electrophysiological and bioimaging approaches to directly determine how activation and blockade of cannabinoid signalling pathways alters SCN neuronal and molecular clock activities. Through this PhD, the student will receive training in patch-clamp electrophysiology and analysis of bioluminescence and fluorescent reporter constructs.

•  Acuna-Goycolea C, Obrietan K, and van den Pol A (2010) Cannabinoids excite circadian clock neurons. Journal of Neuroscience 30: 10061-10066.
• Belle MDC, Diekman C, Forger D, and Piggins HD (2009) Daily electrical silencing in the mammalian circadian clock. Science 326: 281-284.
• Brown TM and Piggins HD (2007) Electrophysiology of the suprachiasmatic circadian clock. Progress in Neurobiology 82: 229-255.
• Guilding C, Hughes ATL, and Piggins HD (2010) Circadian oscillators in the epithalamus. Neuroscience 169: 1630-1639.
• Hughes ATL, Guilding C, Lennox L, Samuels RE, McMahon DG, and Piggins HD (2008) Live imaging of altered period1 expression in the suprachiasmatic nuclei of Vipr2-/- mice (2008) Journal of Neurochemistry 106: 1646-1657.

• Animal Biology
• Biochemistry
• Channels & Transporters
• Integrative Neurobiology & Behaviour
• Molecular & Cellular Neuroscience
• Neuroscience
• Pharmacology
• Physiology
• Systems Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The degeneration of sensory axons in the skin, and subsequent failure of nerve regeneration is a key pathological feature of diabetic neuropathy. The cause of the regenerative deficit in diabetes is complex – a combination of oxidative stress, reduced growth factors, impaired synthesis and axonal transport of cytoskeletal components, and associated biochemical changes including formation of advanced glycation endproducts (AGEs). The extracellular matrix (ECM) not only provides important physical structure and support for cells and tissue, but also has a crucial role in regulating cell behaviour via specific cell adhesion receptors such as the integrins. We have recently shown that AGEs accumulate in ECM proteins of peripheral nerve in experimental diabetes, and that glycation of the ECM proteins laminin and fibronectin, increases AGE residue content of these proteins and dramatically impairs regeneration of sensory neurons in vitro. This project aims to elucidate the mechanisms underlying this failure in regeneration, and to identify therapeutic strategies for treating diabetic neuropathy. The project will utilise a number of techniques including primary neuronal cultures, experimental models of diabetes, molecular biology and immunocytochemistry. 

• Duran-Jimenez B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, Tomlinson DR, Gardiner NJ (2009). Advanced Glycation Endproducts in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes. [Epub ahead of print]
• Tomlinson DR, Gardiner NJ. (2008) Glucose neurotoxicity. Nat Rev Neurosci. 9(1):36-45.
• Karamoysoyli E, Burnand RC, Tomlinson DR, Gardiner NJ. (2008) Neuritin mediates nerve growth factor-induced axonal regeneration and is deficient in experimental diabetic neuropathy. Diabetes. 57(1):181-9
• Gardiner NJ, Moffatt S, Fernyhough P, Humphries MJ, Streuli CH, Tomlinson DR. (2007) Preconditioning injury-induced neurite outgrowth of adult rat sensory neurons on fibronectin is mediated by mobilisation of axonal alpha5 integrin. Mol Cell Neurosci. 35(2):249-60
 

• Cell Matrix Research
• Integrative Neurobiology & Behaviour
• Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

It is now clearly established that Alzheimer’s disease (AD) is a multi-factorial, complex disease. Several abnormalities, such as elevated levels of Aβ40-42) leading to β-amyloid plaques formation, neurofibrillary tangles (NFT), alteration of the cholinergic system, brain atrophy, decreased brain metabolism, have all been extensively documented as characteristic features of the disease. In parallel, neuroinflammation has emerged over the recent years as an important component in many neurodegenerative diseases. Microglial activation and elevated cytokine expression profiles have been demonstrated in vivo and in post-mortem human tissues, whilst it has been demonstrated in vitro that Aβ induces cytokine release from brain cells. However, the temporal cytokine expression profile and the contribution of neuroinflammation to AD pathology remain unknown. Whether neuroinflammation is purely an epiphenomenon of the disease or contributes to the disease processes is an open debate, although increasing evidence suggests that inflammation and neuroinflammation are active contributors.

This PhD project will take place in the framework of the EU FP7 INMiND project (http://www.uni-muenster.de/InMind/). The project includes in vitro techniques looking at the role of Damage Associated Molecular Patterns (DAMPs) on microglial activation and in vivo work in animal model of AD to follow neuroinflammation through the use of molecular imaging (PET) by using existing radiotracers, developing new ones towards new targets.

The overall aims are to understand the contribution of neuroinflammation in AD, identify biomarkers of neuroinflammation and more specifically of the microglial phenotype and identify new potential therapeutic targets.
 

This project is jointly supervised by Dr Stuart Allan, Dr Herve Boutin, Dr Emmanuel Pinteaux

1. H. Boutin, F. Chauveau, C. Thominiaux, M.C. Gregoire, M.L. James, R. Trebossen, P. Hantraye, F. Dolle, B. Tavitian, and M. Kassiou. (2007) 11C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J. Nucl. Med. 48:573-581.

• Immunology
• Integrative Neurobiology & Behaviour
• Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Lead Supervisor: Rasmus Petersen

Thalamo-cortical circuitry is the essential organ for all higher brain function. It underpins a remarkable variety of functions from sensory processing, to motor control and cognition. However, underlying this diversity is remarkable unity at the level of neural circuitry. There is a thalamo-cortical ‘canonical microcircuit’ that is common, not only to different areas of the cerebral cortex, but also to different species. The rodent whisker-barrel system is an ideal preparation for studying thalamo-cortical function, since neurons with a common function (processing sensory input from a given whisker) cluster together in discrete, histochemically identifiable modules. This project will address two key questions: (1) how do multiple neurons in the thalamo-cortical whisker system cooperate to process sensory information; (2) how does the circuit process the complex sensory signals that animals encounter in their natural environment? It will do so using a cross-disciplinary systems approach involving the combination of neurophysiological experiments and computational modelling. You will have the opportunity (1) to work with state-of-the-art multi-channel electrophysiology to record the activity of neurons and (2) to learn cutting edge computational modelling techniques to interpret the data.

• Bioinformatics
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Impaired sensory nerve regeneration in trauma or disease can lead to sensory loss. Sensory nerve injuries are commonly encountered in trauma surgery, yet despite major technical advances in repair techniques, recovery is poor. The most common cause of sensory loss due to disease is diabetic sensory polyneuropathy, which affects approximately 1.5 million people in the UK. There is no treatment or cure for this, or indeed other types of sensory neuropathy. Thus, an improved understanding of the mechanisms underlying sensory nerve outgrowth and regeneration is crucial for development of novel therapeutic strategies to improve patient outcome after sensory loss.

In response to neurotrophins and other growth factors, regenerating neurons interact with extracellular matrix (ECM) molecules (laminin, LM and fibronectin, FN) to navigate away from regions of injury in an attempt to re-innervate their target tissue. Increasing intracellular calcium modulates signal transduction in the growth cone and neurite outgrowth. In culture models of regeneration, neurite outgrowth from sensory neurons has been found to be dependent on the presence of both ECM and neurotrophic factors. Signals from the ECM are transduced to the cell interior via heteromeric integrin receptors. In addition, voltage-gated calcium channels (Cav) are also important mediators of neurite outgrowth, and evidence in various cell types, including neurons, suggests that crosstalk exists between integrin and Cav signalling.

This project aims to define the functional crosstalk between Cav and integrin receptors, which we hypothesize is essential for neurotrophic factor-mediated signal transduction and subsequent regeneration of sensory neurons. Using state of the art facilities and expertise available within The University of Manchester, the student will use biochemistry, cell biology, imaging and electrophysiology to conduct studies in cultured sensory neurons.
 

Bolsover, S. R. Calcium signalling in growth cone migration. Cell Calcium 37, 395-402 (2005).

Woodall, A.J. et al. (2008) Growth factors differentially regulate Cav channels via ERK-dependent signalling in rat sensory neurones. Cell Calcium, 43, 562-575.

Gardiner, N. J. et al. (2007) Pre-conditioning injury-induced neurite outgrowth of adult rat sensory neurons on fibronectin is mediated by mobilisation of axonal alpha5 integrin. Mol. Cell Neurosci. 35, 249-260.
 

• Biomolecular Sciences
• Cell Biology
• Cell Matrix Research
• Channels & Transports
• Molecular & Cellular Neuroscience
• Neuroscience
• Pharmacology
• Physiology

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Synapses are the points of contact where neurons transmit signals to other neurons, glands or muscles. They are key regulators of information flow in the nervous system, acting to filter and modify the information passing through them. For this reason the precise control of synapse formation and function crucially underlies cognitive abilities, such as learning and memory. Aberrant control of synapse development has been implicated in causing neurological disorders including autism, mental retardation, schizophrenia and epilepsy. Understanding how synapses develop remains a prime challenge in modern neurobiology.
The cytoskeleton, composed of actin and microtubules, is a key component for the formation of synapses. However, the mechanisms regulating the synaptic cytoskeleton remain little understood. To decipher these mechanisms, we have established unique strategies in the genetic model organism Drosophila. These strategies are based on a novel primary neuronal cell culture system, which is amenable to systematic genetic and pharmacological manipulations. Using this system, you will carry out pioneering work on cytoskeletal regulation of synapses, within a laboratory specialised in cytoskeletal regulators and with a long standing expertise on synapse formation. Given the universal requirements of cytoskeletal dynamics for almost every cell function, your work will have further implications in other relevant areas of investigation, ranging from Alzheimer's research to cancer biology.
During this project you will gain excellent training in biotechnology. You will generate cell cultures from neural embryonic stem cells or dissociated brains. You will also use sophisticated genetic strategies, molecular biology techniques, generate transgenic animals, employ drugs for pharmacological manipulations, and use advanced microscopy including live imaging. The postgraduate training programme of Manchester's Faculty of Life Sciences will enable you to prepare for all aspects of your future career.
 

• Dillon & Goda, 2005, Annu Rev Neurosci 28, 25ff.
• Sánchez-Soriano et al., 2010, Dev. Neurobiol. 70, 58ff.
• Küppers-Munther et al., 2004, Dev. Biol. 269, 459ff.
• Prokop & Meinertzhagen, 2006, Semin Cell Dev Biol 17, 20ff.

• Animal Biology
• Biomolecular Science
• Cell Biology
• Developmental Biology
• Genetics
• Molecular & Cellular Neuroscience
• Molecular Biology
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

This project will address how the circadian clockwork of the lung regulates inflammatory responses which underpin disease. The student will study the role of broncho-epithelial (BE) cells in this process as these cells are strongly implicated in the pulmonary inflammatory response and our previous studies have shown that these same cells are strongly circadian rhythmic in nature. Previous studies also reveal that BE cells act as local stem cells, regenerating local tissue following injury or external insult. Our current studies of the circadian clock have revealed a potentially important role for a clock driven nuclear hormone receptor – RevErb alpha – and loss of this gene in mice strongly pre-disposes animals to exaggerated inflammatory responses. RevErb alpha has recently been shown to employ heme as a ligand, and thus this receptor provides a sensitive read out of the redox state of the cell. As such, it links clocks to cellular energy metabolism, and as altered cellular energetics are now considered to underpin many diseases states, now offers insight into how clocks, metabolism and disease may be linked. In collaboration with a pharmaceutical company GlaxoSmithKline (GSK), we are using novel ligands of RevErb alpha which are potent at suppressing in macrophage cells inflammatory responses.
The project will involve the use of transgenic animal models in which key clock genes are suppressed in specific tissues responsible for generating local inflammatory responses, access to novel ligands via collaboration with GSK, and use of cellular and tissue reporter assays. By manipulating activity of RevErb and other associated nuclear hormones, the student will develop novel insight into how a clock driven receptor, acting within local stem cells of the lung may control the severity of pulmonary inflammation. Lung inflammatory diseases are major causes of mortality world-wide, and the research project may also extend to use of human cells and tissues and involve collaborations with clinical colleagues involved in treatment of inflammatory lung diseases.
 

• Gibbs JE, Beesley S, Plumb J, Singh D, Farrow S, Ray DW, Loudon AS. 2009 Circadian timing in the lung; a specific role for bronchiolar epithelial cells. Endocrinology.150(1):268-76.
• Meng QJ, McMaster A, Beesley S, Lu WQ, Gibbs J, Parks D, Collins J, Farrow S, Donn R, Ray D, Loudon A. 2008 Ligand modulation of REV-ERBalpha function resets the peripheral circadian clock in a phasic manner. J Cell Sci. 121:3629-35.
• Bechtold DA, Gibbs JE, Loudon AS. Circadian dysfunction in disease. Trends Pharmacol Sci. 31(5):191-8.
• McMaster A, Chambers T, Meng QJ, Grundy S, Loudon AS, Donn R, Ray DW. 2008 Real-time analysis of gene regulation by glucocorticoid hormones. J Endocrinol. 197(2):205-11.
• Meng QJ, …..Hastings MH, Loudon AS. 2008Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron. 58(1):78-88. 

• Adaptive Organismal Biology
• Animal Biology
• Biochemistry
• Developmental Biology
• Environmental Biology
• Gene Expression
• Integrative Neurobiology & Behaviour
• Molecular & Cellular Neuroscience
• Neuroscience
• Physiology
• Systems Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The neocortex of mammals is organised in a layered fashion. Each of the layers fulfils a different function in the communication with other cortical areas. Intrinsic functional brain imaging techniques like functional magnetic resonance imaging (fMRI) are important research tools in cognitive neurosciences research. However, the underlying mechanisms that relate the recorded signal to brain activity are not fully understood and no conclusions can be made about which layers of the cortex contribute the signal. A more direct intrinsic signal that is related to neural activity is the change in tissue scattering during activation. Optical coherence tomography can detect these scattering changes in a depth resolved manner with high spatial and temporal resolution.
Imaging the layer specific responses in the somato-sensory cortex using optical coherence tomography will allow us to answer a question of fundamental importance:
How is the intrinsic signal linked to the corresponding functional brain response? 

 

• Neuroscience
• Physiology
• Systems Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

In the early stages of the sensory system, external information is converted into neuronal activity in the form of trains of action potentials or spikes. A fundamental problem in neuroscience is to understand how biologically relevant stimulus features are encoded in these spike sequences.
However, not all spikes represent the same basic information-carrying symbol. In particular, many neurons can fire spikes in two basic modes: tonic and bursting. Tonic firing consists of sequences of isolated spikes and is the normal mode of firing of regular and fast spiking neurons. During bursting mode, compact groups of 2 to 15 high frequency spikes are fired within a 5 to 60 millisecond window. Recently, the understanding of the role of tonic firing in the processing of sensory information has progressed rapidly. The role of bursting in neural coding, however, still remains unclear. Although there is consensus that bursting is a meaningful signaling mode in neuron communication, there is no unified understanding of the computational role of the different types of bursting, and its relation to the underlying burst-triggering mechanisms.
In this project we will use methods and ideas from Computational Neuroscience, Information Theory, and Dynamical Systems to understand the coding functions of bursting in neurons, both at the level of single cells and their role in neural networks. The work will involve the design of computer simulations of neural models with different degrees of biophysical detail, and the application of advanced data analysis methods to real and simulated data. In addition to good programming skills (C / Fortran and Matlab), the candidate should have basic knowledge of Neuroscience and good mathematical background.
 

• Bioinformatics
• Molecular & Cellular Neuroscience
• Neuroscience
• Physiology
• Systems Neuroscience

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Each human brain contains more neurons than there are people on the planet. Everything that we experience or do involves large groups of neurons operating in concert. However, although we now know a tremendous amount about the biology of single neurons, we still know surprisingly little about how groups of neurons work together.

The Petersen lab has state-of-the-art equipment that enables the activity of many neurons to be recorded at the same time, using silicon-bases polytrodes. The lab also has a strong track record in using advanced computational methods for analysing and modelling such data. The aim of this project is to use this technology to record simultaneously from as many neurons as possible from the somatosensory cortex. The rat whisker-barrel system is an ideal preparation for addressing this general question, since neurons with a common function (processing sensory input from a given whisker) cluster together in discrete, histochemically identifiable modules.

This approach will lead to important insights into the critical question of how the collective activity of neurons achieves useful information processing. The project is inter-disciplinary and the successful student will be working as part of a cross-disciplinary team, incorporating skills in both biological experimentation and computer/mathematical modelling. There is the opportunity for the student, depending on their interests, to train in experimental methods, theoretical methods or both. The project could therefore suit applicants from either a biomedical or physical sciences background.
 

•  Petersen R.S., Panzeri S., Diamond M.E. (2001) Population coding of stimulus location in rat somatosensory cortex. Neuron 32:503-514.
• Petersen R.S., Brambilla M., Bale M.R., Alenda A., Panzeri S., Montemurro M.A., Maravall M. (2008) Diverse and temporally precise kinetic feature selectivity  in the VPm thalamic nucleus. Neuron 60: 890-903.
 

• Integrative Neurobiology & Behaviour
• Neuroscience
• Systems Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

This project will use behavioural, electrophysiological and molecular techniques to study the chemosensory behaviour of adult Drosophila. Responses to both taste (salt, sugar, amino-acids) and pheromonal stimuli will be studied. Electrical response patterns of individual sensory neurons, extracted from multi-unit recordings using spike analysis software, will be characterised. The aim is to develop neurophysiological coding correlates of well-known behavioural responses, using mutant lines affecting peripheral chemosensory coding. Investigating neuronal activity following stimulation with both artificial and extracted cuticular hydrocarbon pheromones will be a central part of the project, testing hypotheses about the role of the components of the fruitfly's pheromone bouquet. Combining the genetic flexibility of Drosophila with the neurobiological challenge of chemoreception, this project is appropriate for a student wishing to obtain unique skills in one of the most fast-moving fields of neuroscience.

• Svetec N, Cobb M, Ferveur JF (2005) Current Biology 15:R790-R792.
• Hoare D, McCrohan CR and Cobb M (2008) Precise and fuzzy coding by olfactory sensory neurons. J.Neurosci. 28, 9710-9722.

• Adaptive Organismal Biology
• Animal Biology
• Genetics
• Integrative Neurobiology & Behaviour
• Molecular & Cellular Neuroscience
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The olfactory system of Drosophila larvae provides a simple model system in a highly manipulable organism. The organisation of the olfactory system is essentially identical to that in higher vertebrates, with the exception of its scale: the larva has only 21 olfactory sensory neurons (OSNs), whereas the mouse has 2 million.
Behavioural studies have shown that olfactory responses are plastic; following prolonged stimulation, some odours cease to elicit a response, whereas other odours change from being attractive to being repulsive. Furthermore, we have demonstrated that there are peripheral changes in the electrophysiological response of the OSNs following prolonged odour stimulation.
We hypothesise that the behavioural effects are due in part to local interactions between the activity of peripheral OSNs, in addition to changes in the action of central pathways. The project will combine electrophysiological recording, molecular genetics and behavioural studies. The power of Drosophila neurogenetics will be applied to create larvae with only one functional OSN, lacking a particular OSN and with altered central structures. This will enable us to address the key problem of plasticity in olfactory responses, which occurs in all organisms.
 

• Hoare D, McCrohan CR and Cobb M (2008) Precise and fuzzy coding by olfactory sensory neurons. J.Neurosci. 28, 9710-9722.

• Adaptive Organismal Biology
• Animal Biology
• Genetics
• Integrative Neurobiology & Behaviour
• Molecular & Cellular Neuroscience
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Epilepsy is a common syndrome that affects ~1% of the global population. Although anti-epileptic drugs (AEDs) are available, roughly one-third of sufferers are insensitive. Even for those that respond, drug treatment is only palliative. There is, therefore, a critical need for new drugs, based on novel targets, with the ultimate aim of providing a cure for those individuals that exhibit idiopathic epilepsies (i.e. heritable forms). The fruitfly Drosophila offers tractable genetics and genotypes that readily and reliably display reduced seizure thresholds. Seizures in these so-called ‘bang-sensitive’ mutants exhibit sufficient parallels with human epilepsy to implicate the underlying neuronal abnormalities are highly similar. We have recently completed a first detailed study of neuron signalling in bang-sensitive mutants and, remarkably, have shown that treatment of mated females with the AED phenytoin fully prevents seizure in their larval progeny. This result provides a first real indication that at least some forms of epilepsy arise as a consequence of incorrect neural development. Moreover, our results suggest that early drug intervention, during embryonic development, may represent a highly effective method to control (and perhaps even eliminate) epilepsy in humans. The available project will fully test this hypothesis by attempting to both reduce and induce seizures in wild type and bang-sensitive mutants through manipulation of embryonic neural development. You will join a large and active group and will receive training in a wide range of techniques, including but not limited to: Drosophila genetics, electrophysiology (whole cell patch clamp), confocal microscopy and analysis of seizure-behaviour. Further information can be found at:

http://personalpages.manchester.ac.uk/staff/Richard.Baines/default
 

Reynolds, E.R., et al., (2004) Treatment with the antiepileptic drugs phenytoin and gabapentin ameliorates seizure and paralysis of Drosophila bang-sensitive mutants. J Neurobiol, 58(4): p. 503-13.

Song, J. and M.A. Tanouye. (2008) From bench to drug: human seizure modeling using Drosophila. Prog Neurobiol, 84(2): p. 182-91.

Muraro NI, Baines RA. (2008) Drosophila melanogaster in the study of epilepsy. SEB Exp Biol Ser 60:141-160.
 

Animal Biology
Channels & Transporters
Genetics
Integrative Neurobiology & Behaviour
Molecular & Cellular Neuroscience
Neuroscience
Pharmacology
Physiology
Systems Neuroscience
 

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The prevalence of obesity leads to ever-increasing diabetes and cardiovascular disease, which puts added pressure on health service resources. The high-energy fuels in our bloodstream (glucose) and storage depots (fat) are regulated ultimately by small regions of the brain, notably the hypothalamus and brainstem, which respond to signals from the gut, the pancreas and fat tissue. For example, by acting on the hypothalamus, the fat-derived hormone, leptin, supports a reduction in appetite and an increase in energy expenditure. Lack of leptin or its receptor leads to obesity in animal models and in some humans. Thus, to manipulate the brain’s involvement, and to discover potential new therapies for the treatment of obesity and other eating disorders, we need to understand the appetite-regulating pathways in the brain. We have discovered that blocking the actions of signalling messengers in the hypothalamus and brainstem, e.g. PACAP and PrRP, reduces leptin’s effects on eating and metabolism. In addition, these homeostatic mechanism interact with parts of the brain, such as the prefrontal cortex and nucleus accumbens, that mediate the reward value of food. These pathways are heavily modified by other transmitters, such as the endogenous opioids and cannabinoids. In fact, we have recently described the actions of the first-ever peptide to act through central cannabinoid receptor to reduce food intake without causing deleterious side effects. Our studies will include the use of naturally-occurring mutants and transgenic mice to investigate individual pathways and complex interactions in the brain. Our laboratory uses a number of cutting-edge technologies to carry out such research. This will help us to understand circuitry of the brain that controls appetite, metabolism and glucose balance, and to provide new avenues of research to develop drugs to treat obesity.

• Bechtold, D.A. and Luckman, S.M., 2006, Prolactin-releasing peptide mediates CCK-induced satiety in mice. Endocrinology 147: 4723-4729
• Dodd, G.T., Stark, J.A., McKie, S., Williams, S.R. and Luckman, S.M., 2009, Central cannabinoid signaling mediating food intake: a pharmacological-challenge MRI and functional histology study in rat. Neuroscience 163: 1192-1200
• Hawke, Z., Ivanov, T.R., Bechtold, D.A., Dhillon, H., Lowell, B.B. and Luckman, S.M., 2009, PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling. J. Neurosci. 29: 14828-14835
• Dodd, G.T., Mancini, G., Lutz, B., Luckman, S.M., 2010, The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. J. Neurosci. 30:7369-7376.
 

• Adaptive Organismal Biology
• Animal Biology
• Integrative Neurobiology & Behaviour
• Molecular & Cellular Neuroscience
• Neuroscience
• Pharmacology
• Physiology

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Obesity is associated with an increased risk of several diseases, such as diabetes and some cardiovascular conditions. However, recent data also suggest that obesity is a risk factor for several neurodegenerative conditions, such as stroke and Alzheimer’s disease. Furthermore, obese mice suffer worse outcome after experimental stroke. The mechanisms underlying the effects of obesity and changes in energy balance on brain diseases are unknown, but may be related to changes in inflammation. This project will study the role of inflammation in the effect of obesity on neurodegeneration, and can either focus on stroke or Alzheimer’s disease.

A combination of techniques will be employed such as experimental surgery, in vivo behavioural analysis, histology and immunohistochemistry.
 

• Knight, E.M., Luckman S.M., Verkhratsky A., Allan, S.M. and Lawrence C.B. (2010) Hypermetabolism in a triple transgenic mouse model of Alzheimer’s disease. Neurobiology of aging March 30, Epub.
• McColl B., Rose N., Robson F., Rothwell N.J. and Lawrence C.B. (2010) Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. JCBFM 30(2):267-72. (Epub 2009 Oct 14).
• Bruce-Keller et al (2009) Obesity and vulnerability of the CNS. Biochim Biophys Acta 1792, 395-400.
• Naderali et al (2009) Obesity and Alzheimer’s disease: A link between body weight and cognitive function in old age. Am J Alzeimer’s Disease & other dementias Oct 2 (Epub ahead of print).
   

• Immunology
• Integrative Neurobiology & Behaviour
• Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Glaucoma is a progressive optic neuropathy that affects many millions of people worldwide. Recent research has suggested that altered blood flow plays an important role in both the development and progression of glaucomatous optic neuropathy (GON). While there is no one standard method for monitoring blood flow within the retina, laser doppler flow and optical coherence tomography are commonly used in research laboratories and specialist clinical labs. These are quite technical procedures requiring expensive equipment and specialist knowledge and are also limited in the area that is probed in each scan.
Optical imaging is a technique for indirectly recording neural activity using light. Historically this technique has been employed to monitor the response properties of groups of cells in the neocortex of living animals. Our group in Manchester has been at the forefront of the development of this technique and its associated analysis software. Over the years we have built a number of imaging systems for recording activity from the brains of rodents and primates.
A recent intriguing report has suggested that optical imaging can be used to directly measure blood flow from the surface vessels of the human retina. This account presented data demonstrating flow impairment in the retinae of patients with a variety of eye disorders. Given current thinking that altered blood flow may significantly contribute to the development and be indicative of the prognosis of GON we have recently developed a new retinal imaging system based on a combination of an existing fundus camera and a high-resolution optical imaging camera. This project will make use of our new imaging system to monitor blood flow in retinae of diseased and normal retinae and correlate these findings with standard optometric measurements such as visual field maps.
 

• Neuroscience
• Ophthalmology
• Optometry
• Physiology
• Systems Neuroscience

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Small cell lung cancer (SCLC) is characterised by an aggressive clinical course, with typical survival of less than one year from diagnosis. SCLC is initially exquisitely sensitive to chemotherapy but invariably relapses. A major goal is to identify blood-borne biomarkers that can underpin design of optimal treatment for this disease. Pro-opiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), is one of the most prevalent neuropeptides secreted by SCLC tumours1 and can ultimately cause ectopic ACTH syndrome2. Therefore plasma POMC may have pharmacodynamic value as well as prognostic value as a biomarker for SCLC.

This project will utilise an extensive panel of SCLC cell lines 3,4,5 to study the association of POMC secretion with other SCLC biomarkers. This will be achieved by using RT-PCR and quantitative expression analysis to compare differences in biomarker expression which will be confirmed by analysis of protein expression using ELISA and western blotting. Epigenetic changes associated with variations in biomarker profile will be examined by the investigation of the methylation status of the gene using both methylation enrichment PCR and quantitative analysis by pyrosequencing. These data will be used to identify cell lines with different biomarker expression profiles which can then be used as tools to examine whether dose-response profiles to anti-cancer treatments vary depending on the biomarkers expressed by the cell line. Overall this project will generate in vitro models to assess the value of POMC as a biomarker.
 

1.Clark, AJL Stewart, MF Lavender, PM Farrell, WE, Crosby SR, Rees LH & White A (1990) Defective glucocorticoid regulation of pro-opiomelanocortin gene expression and peptide secretion in a small cell lung cancer cell line. J Clinical Endocrinology and Metabolism 70, (2) 485-490

2. Oliver RL, Davis JRE and White A (2003) Characterisation of ACTH related peptides in ectopic Cushing’s Syndrome. Pituitary, 6, (3), 119-126
 

• Molecular Biology
• Molecular Cancer Studies

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Inflammation is now recognised as a key contributor to neuronal injury in both acute and chronic neurodegenerative disease. Many studies in this area have focussed on the post-injury inflammatory response and in particular on the role of specific cytokines in the central nervous system. A key mediator, identified from both experimental and clinical studies, is interleukin-1 and this has been the focus of much of our research for the last few years. However, increasing interest has now been focussed on the peripheral response to injury and also on the inflammatory status before injury. This is particularly true for acute conditions, such as stroke, where preceding infection is a major risk factor. Recent data also indicate that peripheral inflammation has an important role in chronic conditions, such as epilepsy and Alzheimer’s disease.

This project will therefore assess the contribution of peripheral inflammation both before and after injury, using appropriate experimental paradigms.
 

• Denes A, Thornton P, Rothwell NJ & Allan SM (2010) Inflammation and brain injury: Acute cerebral ischaemia, peripheral and central inflammation. Brain Behav. Immun. 24:708-23
• Esiri MM (2007) The interplay between inflammation and neurodegeneration in CNS disease. J. Neuroimmunol. 184:4-16
   

• Immunology
• Integrative Neurobiology & Behaviour
• Neuroscience

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Nanotechnologies have experienced a huge expansion in recent years, with clear socio-economic benefits. The number of consumer products incorporating nanoparticles, for example, has grown by >350% in three years However, studies of their long term impact on the environment have not kept pace with these developments. The most common nano-materials used in consumer products are nono-metals such as silver. The latter is bactericidal and is found in an extensive range of products such as clothing, medical dressings, air and water purifiers. Our knowledge of the potential environmental impact of nano-metals in freshwaters is extremely limited and largely confined to fish. Current work has also examined responses at concentrations much higher than are predicted to occur in the aquatic environment. The project will compare and contrast the bioavailability and toxicity of two nano particles, aluminium and silver, to the freshwater crayfish. This ubiquitous and ecologically important organism is common throughout the world. We have shown that crayfish responds to metal particulates both following ingestion and, externally via interaction with the gills. However, nothing is known of the response of crayfish to nanoparticles.
The project will examine the kinetics of uptake of the two nanoparticles in the crayfish, their distribution in the tissues and rate of excretion using bulk analysis and sub-cellular X-ray microprobe examination at environmentally relevant concentrations. Parallel experiments will examine the interaction of the nanometals with the gills, by conventional and atomic force microscopy. Toxicity will be assessed by behavioural changes, cell morphology and oxidative stress. Blood ion composition will also be examined as an indicator of respiratory stress in the case of external (exogenous) toxicity.
 

• Alexopoulos, E, McCrohan, C.R., Powell, J.J. Jugdaohsingh, R. & White, K.N. (2003) Bioavailability and toxicity of freshly neutralised aluminium to the freshwater crayfish Pacifastacus leniusculus. Arch. Environ. Contam. Toxicol., 45, 509-514.
• Baun, A., N. B. Hartmann, et al. (2008). Ecotoxicity of engineered nanoparticles to aquatic invertebrates: a brief review and recommendations for future toxicity testing. Ecotoxicol. 17: 387-395.

• Adaptive Organismal Biology
• Animal Biology
• Biochemistry
• Physiology
• Toxicology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

In excitable cells, such as neurons and muscle, physiological responses depend upon the density of ion channels at the cell surface. The factors which control the numbers and distributions of such channels are poorly understood, but, if manipulated could lead to new therapies to correct diseases such as epilepsy and sleep disorders. 

Work in this laboratory is aimed at identifying the mechanisms which control the trafficking and distributions of voltage-gated calcium and potassium channels. One such channel - the N-type voltage-gated calcium channel (Cav2.2) – is a multi-subunit complex, intimately involved in synaptic transmission and dendritic integration. This project aims to test the hypothesis that the surface expression and distribution of Cav2.2 channels is controlled by an orchestrated intersection of discrete physiological signals and trafficking mechanisms acting upon different task-specific subunit components. To test this hypothesis our goal is to define the kinetics, and regulation of Cav2.2 expression, in response to cell stimuli e.g. growth factors and electrical activity, using novel cell biological strategies that permit the visualisation of Cav2.2 assembly, trafficking and distribution in live cells.

This project lies at the interface of several disciplines including cell and molecular biology, pharmacology, physiology and neurobiology and would be suitable for students with a background in any of the above fields. 

 

• Jones, V., Rodriguez, J., Verkhratsky, A., Jones, O. (2009) A lentivirally-delivered photoactivatable GFP to assess continuity in the endoplasmic reticulum of neurones and glia. Pflugers Archiv-European Journal of Physiology (In Press, ePUb March 19th)
• Mckeown L, Burnham MP, Hodson C, Jones OT. (2008) Identification of an evolutionarily conserved extracellular threonine residue critical for surface expression and its potential coupling of adjacent voltage-sensing and gating domains in voltage-gated potassium channels. J. Biol. Chem. 283:30421-304332.
• Jones, V.C., McKeown, L., Verkhratsky, A., Jones, O.T., (2008) LV-pIN-KDEL: a novel lentiviral vector for probing the dynamics and morphology of the endoplasmic reticulum in live neurones. BMC Neuroscience, 9:10. 
• Bernstein, G.M., Jones, O.T. (2006) Kinetics of Internalization and Degradation of N-type Voltage-Gated Calcium Channels: Role of the alpha2/delta Subunit. Cell calcium, 41, 27-40.
• McKeown, L., Robinson, P., Greenwood, S.M., Hu, W., Jones, O.T. (2006) PIN-G - A novel reporter for imaging and defining the effects of trafficking signals in membrane proteins. BMC Biotechnology, 6:15.

• Biotechnology
• Cell Biology
• Channels & Transporters
• Integrative Neurobiology & Behaviour
• Membrane Trafficking
• Molecular & Cellular Neuroscience
• Neuroscience
• Systems Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

While a simple, nocturnal animal, the rat brain contains the same basic pattern of neural connections in its visual system that higher mammals use. I am investigating the relationship between thalamus and cortex using a combination of visual neurophysiology, single unit recording, pharmacology and anatomy to extract information about how the cerebral cortex modulates or modifies its own input from thalamus. I am therefore asking how the network of feed-forward and feed-back connections interact in a precise and timely manner to produce seamless “vision”. Students should expect to learn how to record single cell activity, programme data recording equipment and create novel visual stimuli, along with the basic but important skills involved in whole animal neuroscience experimentation (anaesthesia, surgery etc). This laboratory can provide a full training in the neurophysiology of vision to interested students from a wide variety of backgrounds - I would welcome students from biology - but also students of mathematics and physics or even electronics, who may wish to consider a more biological approach to their science.

• Grieve KL (2005) Binocular responses in cells of the rat dLGN JPhysiol 566:119-124

• Animal Biology
• Neuroscience
• Physiology
• Systems Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Among the most surprising recent discoveries in sensory biology is that photoreception in the mammalian retina is not restricted to rods and cones. Instead, a small proportion of the retina’s projection neurons (so-called retinal ganglion cells, whose axons form the optic nerve) are intrinsically photosensitive. These ganglion cell photoreceptors absorb light using a specialist protein called melanopsin. They do not contribute directly to visual perception, but drive many sub-conscious visual responses including synchronisation of internal biological clocks to local time of day, improvements in mood and alertness, changes in gross physiology (e.g. body temperature and heart rate), and constriction of the pupil in our eye. Because these responses are not required for us to ‘see’ its easy to overlook their important contribution to human health and well-being. In fact, these new photoreceptors are unsung heroes in helping us avoid insomnia and depression and keeping us alert and productive.

I am happy to consider PhD candidates who are interested in studying this new and important sensory modality in either of the following ways:
1.) Determine how these ganglion cell photoreceptors support sub-conscious vision by recording neural activity in the brain of mice.
2.) Determine how melanopsin makes ganglion cells photoreceptive using molecular biology and cell culture techniques.
 

• Lall GS, Revell VL, Momiji M, al Enezi J, Altimus CM, Güler AD, Aguilar C, Cameron MA, Allender A, Hankins MW, Hattar S and Lucas RJ (2010). Distinct contributions of rod, cone and melanopsin photoreceptors to encoding irradiance. Neuron 66:417-28
• Güler AD, Ecker JL, Lall GS, Haq S, Altimus CM, Liao H-W, Barnard AR, Cahill H, Badea TC, Zhao H, Hankins MW, Berson DM, Lucas RJ, Yau K-W and Hattar S. (2008) Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision. Nature 453:102-105
• Bellingham J, Chaurasia SS, Melyan Z, Liu C, Cameron MA, Tarttelin EE, Iuvone PM, Hankins MW, Tossini G, Lucas RJ (2006) Evolution of melanopsin photoreceptors: Discovery and characterization of a new melanopsin gene in non-mammalian vertebrates PLoS Biology 4(8):e254
• Melyan Z, Tarttelin EE, Bellingham J, Lucas RJ, Hankins MW (2005). Addition of human melanopsin renders mammalian cells photoresponsive. Nature 433:741-5
• Lucas RJ, Hattar S, Takao M, Berson DM, Foster RG, Yau K-W (2003) Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299:245-247. 

• Adaptive Organismal Biology
• Animal Biology
• Integrative Neurobiology and Behaviour
• Molecular and Cellular Neuroscience
• Neuroscience
• Opthalmology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.