Dr Dave Furness

Reader (CNS Group leader)

Current Research

• Transduction by hair cells

• Neurotransmission by hair cells

• Efferent control of hair cells

• Damage and repair of hair cell epithelia

• Glutamate uptake mechanisms and homoestasis in CNS and cochlea

Confocal image of the organ of Corti (labelled green for a cytoskeletal marker protein) and the supporting cells containing glutamate transporter protein (labelled red).

An electron microscopic immunogold labeled image showing uptake of a glutamate analogue (large particles) into nerve terminals in the hippocampus.  

For more images of cochlea and cell structure please visit the EM unit galleries

Recent Publications

Löwenheim H, Furness DN, Kil J, Zinn C, Gültig K, Fero ML, Frost D, Gummer AW, Roberts JMW, Rubel EW, Hackney CM and Zenner HP (1999) Gene disruption of p27Kip1 allows cell proliferation in the organ of Corti.  PNAS USA Vol. 96, pp. 4084-4088.

Lawton DM, Furness DN, Lindemann B, Hackney CM (2000) Localization of the glutamate-aspartate transporter, GLAST, in rat taste buds. Eur J Neurosci 12: 163-171.

Furness DN, Hulme JA, Lawton DM, Hackney CM. (2002) Distribution of the glutamate/aspartate transporter GLAST in relation to the afferent synapses of outer hair cells in the guinea pig cochlea. J Assoc Res Otolaryngol 3: 234-247.

Schulte CC, Meyer J, Furness DN, Hackney CM, Kleyman TR, Gummer AW (2002) Functional effects of a monoclonal antibody on mechanoelectrical transduction in outer hair cells. Hear Res 164:190-205.

Furness DN, Karkanevatos A, West B, Hackney CM (2002) An immunogold investigation of the distribution of calmodulin in the apex of cochlear hair cells. Hear Res 173:10-20.

Furness DN (2002) The Vestibular System. In: Signals and Perception (Roberts, D, Ed).  The Open University; Palgrave Macmillan, Chapter 7 (pages 77-87).

Furness DN, Lawton DM  (2003) Comparative distribution of glutamate transporters and receptors in relation to afferent innervation density in the mammalian cochlea. J Neurosci 23(36):11296-11304.

Dr Douglas R Corfield

Reader

Current Research

• Neural control of respiration in humans

• Neural basis of breathlessness

• Control of the cerebral circulation during sleep

• Changes in brain morphology and function associated with hypoxia
  

Images of the brain taken using FMRI  (adapted from Evans et al., 2002)

Recent Publications

Evans KC, Banzett RB, Adams L, McKay  L, Frackowiak RS,  Corfield DR (2002) BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 88: 500-1511.

Deichmann R, Josephs O, Hutton C, Corfield DR, Turner R (2001) Compensation of susceptibility -induced BOLD sensitivity losses in echo-planar fMRI imaging. Neuroimage 15:120-135.

Corfield DR, Murphy K, Josephs O, Adams L, Turner R (2001) Does hypercapnia-induced cerebral vasodilation modulate the hemodynamic response to neural activation?  Neuroimage 13: 1207-1211.

Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ (2000) Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans.  J Physiol 523:259-270.

Corfield DR, Roberts CA, Griffiths MJ, Adams L (1999) Sleep-related changes in the human 'neuromuscular' ventilatory response to hypoxia. Respir Physiol 117: 109-120.

Dr Nigel Cooper

Senior Lecturer

Current Research

Laser interferometric investigations of the cochlea: different regions respond to different components of a sound

• Sound encoding in the inner ear – the cochlear response to components of sound
  
  

Cellular detail of the cochlear partition: sound-evoked responses vary with position, and may indicate how the sounds are amplified in normal hearing.

• Mechanical basis of the cochlear amplifier – how do hair cells deflect the basilar membranes
  
  

Neuronal control of outer hair cell function modulates the cochlea’s mechanics.

·         Olivocochlear efferent feedback mechanisms – what do the medial olivocochlear efferents do to the cochlea’s mechanics, and how do they do it?

·         Otoacoustic emissions from the cochlea – where do sounds emitted from the cochlea come from, and how do they get back out of the cochlea?

·         Laser interferometry – can we make a device to measure sub-microscopic vibrations of almost transparent sub-cellular structures at both infra- and super-sonic frequencies?

Recent Publications

Homer M, Champneys A, Hunt G, Cooper NP (2004). Mathematical modeling of the radial profile of basilar membrane vibrations in the inner ear. J Acoust Soc Am 116: 1025-1034.

Cooper NP, Guinan JJ, Jr. (2003). Separate mechanical processes underlie fast and slow effects of medial olivocochlear efferent activity. J Physiol (Lond) 548: 307-312.

Guinan JJ, Jr., Cooper NP (2005). Medial olivocochlear efferent inhibition of basilar membrane click responses. In Assoc Res Otolaryngol: 28, New Orleans.

Cooper N, Shera C (2004). Reverse traveling waves in the cochlea? Comparing basilar membrane vibrations and otoacoustic emissions from individual guinea-pig ears. In Assoc Res Otolaryngol  27, Daytona Beach, FL.

Guinan JJ, Jr., Cooper NP (2003). Medial olivocochlear efferent fast effects on basilar membrane motion in guinea-pigs. In Assoc Res Otolaryngol 26, Daytona Beach, FL.

Cooper NP (2002). Mechanical pre-processing of sound in the base and apex of the cochlea. In Assoc Res Otolaryngol 25, Clearwater Beach, FL.

Cooper NP (2003). Compression in the peripheral auditory system. In Compression: from cochlea to cochlear implants, 17. ed. Bacon, S., Fay, R. R., Popper, A. N., pp. 18-61. Springer-Verlag, New York
.

Cooper NP, Dong W (2003). Baseline position shifts and mechanical compression in the apical turns of the cochlea. In The Biophysics of the Cochlea: Molecules to Models. ed. Gummer, A. W., pp. 261-270. World Scientific, Singapore.

Guinan JJ, Jr., Cooper NP (2003). Fast effects of efferent stimulation on basilar membrane motion. In The Biophysics of the Cochlea: Molecules to Models. ed. Gummer, A. W., pp. 245-251. World Scientific, Singapore.

Dr Michael G. Evans

Lecturer

Current Research

I am investigating the following aspects of hair cell function using a combination of whole cell recording and imaging of fluorescent dyes:

• Efferent control of outer hair cells over both fast and slow time scales

• The mechanism of transduction in hair cells
  

Measurements of fluorescence indicating changes in concentration of calcium at different points in a hair cell following stimulus with carbachol, an acetylcholine receptor agonist (see Evans et al., 2000). 

Recent Publications

Evans MG (1996) Acetylcholine activates two currents in guinea-pig outer hair cells. J. Physiol.  491: 563-578.

Evans MG, Kiln J and Pinch D (1996) No evidence for functional GABA receptors in outer hair cells isolated from the apical half of the guinea-pig cochlea. Hear Res 101: 1-6.

Chan E and Evans MG (1998) Kinetics of activation of a Ca2+-dependent K+ current induced by flash photolysis of caged carbachol in isolated guinea-pig outer hair cells. Neurosci Lett 254: 45-48.

Evans MG, Lagostena L, Darbon P and Mammano F (2000) Cholinergic control of membrane conductance and intracellular free Ca2+ in outer hair cells of the guinea pig cochlea. Cell Calcium 28: 195-203.

Kennedy HJ, Evans MG, Crawford AC, Fettiplace R. (2003) Fast adaptation of mechanoelectrical transducer channels in mammalian cochlear hair cells. Nat Neurosci 6(8): 832-836

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Professor Robert Fettiplace (FRS)

Visiting Professor

Current Research

My research is on the the physiology of inner ear hair cells, using patch clamp recording and optical imaging. This has provided descriptions of the mechanosensory transduction mechanism, membrane channels involved in frequency tuning and regulatory roles of intracellular calcium. Current interest lies with molecular variations in the Ca2+-activated K+ channels which cause hair cells at different cochlear locations to be tuned to different frequencies.

Confocal images of an isolated auditory hair cell before (left) and during (right) a depolarization to open calcium channels.

Recent Publications

Ricci, AJ, Crawford AC and Fettiplace R (2000) Active hair bundle motion linked to fast transducer adaptation in auditory hair cells. J Neurosci 20: 7131-7142.

Fettiplace R, Ricci AJ and Hackney CM (2001) Clues to the cochlear amplifier from the turtle ear. Trends Neurosci 24: 169-175.

Ricci AJ, Crawford AC, Fettiplace R. (2003) Tonotopic variation in the conductance of the hair cell mechanotransducer channel. Neuron 40: 983-990.

Fettiplace R, Ricci AJ. (2003) Adaptation in auditory hair cells.Curr Opin Neurobiol 13:446-451..

Kennedy HJ, Evans MG, Crawford AC, Fettiplace R. (2003) Fast adaptation of mechanoelectrical transducer channels in mammalian cochlear hair cells. Nat Neurosci 6: 832-836.

Hackney CM, Mahendrasingam S, Jones EM, Fettiplace R. (2003) The distribution of calcium buffering proteins in the turtle cochlea. J Neurosci 23: 4577-4589.

Kennedy HJ, Crawford AC, Fettiplace R. (2005) Force generation by mammalian hair bundles supports a role in cochlear amplification. Nature 433:880-883.

Dr Rosemary Fricker-Gates

Lecturer

Current Research

My group’s current work focuses on the characterisation of immature stem/progenitor cells and their ability for neuronal differentiation and axonal growth, both in vitro and in vivo. We work mainly with neural stem cells from both embryonic and adult tissue, and our research aims to discover both intrinsic and extrinsic factors that govern neuronal differentiation.

We are investigating the growth factor requirements of stem cell populations, and the genetic basis of their potential to differentiate into specific types of neurons. Using cell culture and targeted transplantation studies, we hope to tease out to what extent external signals in the environment drive neuronal differentiation.

A transplanted cell (green) with a neuronal morphology, expressing TH (red), a marker for dopamine neurons.

Cells grafted to the developing brain form neuronal phenotypes specific to the site of integration.

Recent Publications

Hughes AC, Errington RJ, Fricker-Gates RA and Jones L (2004) Endophilin A3 forms filamentous structures which colocalise with microtubules but not actin filaments. Mol Brain Res (In Press).

Fricker-Gates RA, Muir JL and Dunnett SB (2004) Transplanted hNT cells (‘LBS neurons’) in a rat model of Huntington’s Disease: good survival, incomplete differentiation and limited functional recovery. Cell Transplantation 13(2).

Gates MA, Coupe VM, Torres EM, Fricker-Gates RA and Dunnett SB (2004) Spatially- and temporally-restricted chemoattractive and chemorepulsive cues direct the formation of the nigrostriatal circuit. Eur J Neurosci 19: 831-844.

Fricker-Gates RA, White A, Gates MA and Dunnett SB (2004) Striatal neurons in striatal grafts are derived from both post-mitotic cells and dividing progenitors. Eur J Neurosci19: 513-520.

Smith R, Bagga V and Fricker-Gates RA (2003) Embryonic neural progenitor cells: The effects of species, region, and culture conditions on cell proliferation and neuronal differentiation. J Hemat Stem Cell Res12: 713-725. 

Fricker-Gates RA., Smith R, Muhith J and Dunnett SB (2003) The role of pretraining on skilled forelimb use in an animal model of Huntington’s Disease. Cell Transplantation 12: 257-264.

Dr Monte Gates

Lecturer

Research Interests:

I have a long standing interest in understanding the cellular and molecular mechanisms that facilitate the development of circuits in the mammalian central nervous system (CNS), particularly those circuits which (in the adult) can undergo neurodegenerative episodes (e.g., Parkinson's disease) or are disrupted/destroyed by common traumatic injuries (e.g., spinal cord injury).  If we can identify cells, genes or gene products that facilitate and guide the growth of specific neural circuits during development we might be able to exploit these factors to improve the integration, connectivity and functioning of stem/primary/neural stem cell transplants to the adult CNS, or facilitate the regenerative capacity of neurons remaining in the afflicted system.

Recently, I have begun highlighting tissues/cells in the developing CNS which attract (or repel) nigro-striatal axonal growth via a novel culture explant system which allows me establish a segement of the dopaminergic circuit in vitro.  The advantage of this system is that I am able to manipulate axonal growth in vitro and determine the spatial and temporal localization of chemoattractive and chemorepulsive cues that guide nigro-striatal axons during circuitry formation.  Currently I am using gene arrays to discern the particular genes involved in these effects and hope to identify constituents which may be exploited to manipulate circuitry formation in vivo, or increase connectivity of cell transplants to the adult brain.

Recent publications

Gates MA, Lanier LM (co-first authors), Witke W, Menzies AS, Wehman AM, Macklis JD, Kwiatkowski D, Soriano P and Gertler FB (1999)  Mena is required for neurulation and commissure formation.  Neuron 22:313-325

Fricker RA, Carpenter MK, Winkler C, Greco C, Gates MA and Bjorklund A (1999) Site- specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain.  J Neurosci  19:5990-6005

Eriksson C, Ericson C, Gates MA, Wictorin K (2000) Long-term, EGF-stimulated cultures of attached GFAP-positive cells derived from the embryonic mouse lateral ganglionic eminence: in vitro and transplantation studies. Exp Neurol 164:184-199

Gates MA, Tai CC and Macklis JD (2000) Abnormal differentiation and process elongation by TrkB deficient neocortical neurons in vitro and in vivo.  Neurosci  98:437-447

Gates MA, Coupe VM, Torres EM, Fricker-Gates RA, Dunnett (2004) Spatially-and temporally- restricted chemoattractive and chemorepulsive cues direct the formation of the nigro- striatal circuit.  Eur J Neurosci 19:831-844

Fricker-Gates RA, White A Gates MA and Dunnett SB (2004) Striatal neurons in striatal grafts are derived from both post-mitotic cells and dividing progenitors. Eur J Neurosci 19:513-520.

Dr Stanislav Glazewski

Lecturer

Current Research

• The role of inhibition in experience-dependent plasticity in neocortex.

• Stabilisation of neuronal transmission during early development of neocortex.

• The role of GluR1 receptors in neocortical experience-dependent plasticity.

• The effects of genetic loss of CaMKK on experience -dependent plasticity in neocortex.

• The origin of surround receptive fields in neocortical layer IV.

•  Effects of point mutation at T286 of CaMKII on synaptic plasticity in neocortex.

•  Frequency dependence of plasticity

•  Barrel cortex of the mouse stained for cytochrome oxidase.
  

Recent Publications

Glazewski S, Giese K-P, Silva A, Fox K. (2000) The role of the alpha-CaMKII switch in neocortical experience-dependent plasticity. Nature Neurosci 3: 911-918.

Barth A, McKenna M, Glazewski S, Hill P, Impey S, Storm D, Fox K. (2000) Upregulation of CRE-mediated gene expression during experience-dependent plasticity in adult neocortex. J Neurosci 20: 4206-4216.

Skibinska A,Glazewski S, Fox K, Kossut M (2000) Age-dependent response of the mouse barrel cortex to sensory deprivation: a 2-deoxyglucose study. Exp Brain Res 132: 138-143.

Wallace H, Glazewski S, Liming K, Fox K (2001) The role of cortical activity in experience-dependent potentiation and depression of sensory responses in rat barrel cortex. J Neurosci 21: 3881-3894.

Glazewski S, Bejar M, Mayford M, Fox K (2001) The effect of autonomous alpha CamKII expression on sensory responses and experience-dependent plasticity in mouse barrel cortex. Neuropharmacology, 41: 771-778.

Fox K, Wallace H and Glazewski S (2002) Is there a thalamic component to experience dependent cortical plasticity? Phil Trans Biol Sci 357: 1709-1715.

Fox K, Wright N, Wallace H, Glazewski S (2003) The origin of cortical surround receptive fields studied in the barrel cortex. J Neurosci 23: 8380-8391.

Hardingham N, Glazewski S, Pakhotin P, Mizuno K, Chapman PF, Giese KP, Fox K (2003) Neocortical long-term potentiation and experience-dependent synaptic plasticity require alpha-calcium/calmodulin-dependent protein kinase II autophosphorylation. J Neurosci 23: 4428-4436.

Professor Carole M. Hackney
 

Professor of Auditory Neuroscience  

(and Science Learning Centre West Midlands facilitator)

Current Research

• transduction by hair cells

• calcium buffering  in hair cells

• neurotransmitters and transporters of the cochlea

• neurotansmitters of the auditory brainstem

• repair and regeneration in the inner ear

Double immunogold labelling of glycine neurotransmitter (large particles) and GABA transporter small particles arrowed) in a cochlear nucleus nerve terminal.

Scanning electron micrographs showing a sensory hair cell and a hair bundle.

Recent Publications

Fettiplace R, Ricci AJ, Hackney CM. (2001) Clues to the cochlear amplifier from the turtle ear. Trends Neurosci 24:169-175.

Mahendrasingam S, Wallam CA, Hackney CM. (2000) An immunogold investigation of the relationship between the amino acids GABA and glycine and their transporters in terminals in the guinea-pig anteroventral cochlear nucleus. Brain Res 887: 477-481.

Lawton DM, Furness DN, Lindemann B, Hackney CM.  (2000) Localization of the glutamate-aspartate transporter, GLAST, in rat taste buds. Eur J Neurosci 12: 163-171.

Furness DN, Hulme JA, Lawton DM, Hackney CM. Distribution of the glutamate/aspartate transporter GLAST in relation to the afferent synapses of outer hair cells in the guinea pig cochlea. (2002)  J Assoc Res Otolaryngol 3: 234-247.

Schulte CC, Meyer J, Furness DN, Hackney CM, Kleyman TR, Gummer AW. (2002) Functional effects of a monoclonal antibody on mechanoelectrical transduction in outer hair cells. Hear Res 164:190-205.

Furness DN, Karkanevatos A, West B, Hackney CM. (2002) An immunogold investigation of the disribution of calmodulin in the apex of cochlear hair cells. Hear Res 173:10-20.

Hackney CM, Mahendrasingam S, Jones EM, Fettiplace R. (2003) The distribution of calcium buffering proteins in the turtle cochlea. J Neurosci 23:4577-4589.

Mahendrasingam S, Wallam CA, Hackney CM. (2003) Two approaches to double post-embedding immunogold labeling of freeze-substituted tissue embedded in low temperature Lowicryl HM20 resin. Brain Res Brain Res Protoc 11:134-141.

Mahendrasingam S, Wallam CA, Polwart A, Hackney CM (2004) An immunogold investigation of the distribution of GABA and glycine in nerve terminals on the somata of spherical bushy cells in the anteroventral cochlear nucleus of guinea pig. Eur J Neurosci 19:993-1004.

Dr Mary Palmer

MRC Research Fellow

Current research

I study various aspects of retinal synaptic function by recording from bipolar cell terminals, amacrine cells and ganglion cells in intact, functional retinal tissue. These include:

• Presynaptic and postsynaptic properties underlying the conversion from tonic to phasic signal transmission.

• The modulation of bipolar cell output by negative feedback mechanisms:

i. GABA_A / GABA_C receptor activation by reciprocal amacrine cell synapses.

ii. Glutamate transporter-mediated Cl^- current activation.

iii. Inhibition of Ca²⁺ channels by protons released from synaptic vesicles.

The results will improve our understanding of how visual signals are processed in the retina and may reveal mechanisms of synaptic function that are relevant to synapses throughout the nervous system.

Figure - Upper: DIC image of a bipolar cell in a fish retinal slice. The presynaptic terminal, which is ~10 mm long, is visible in the top right corner. Lower: Fluorescence image of a different retinal slice bipolar cell filled with fluorescent dye via a patch pipette on the terminal.

With colleagues at Bristol University, I have also been studying synaptic plasticity in the hippocampal CA1 region of the brain. I initially characterised a form of long-term depression (LTD) which is induced by the transient activation of metabotropic glutamate receptors, and more recently I have been studying long-term potentiation (LTP) at very young CA1 synapses. I am currently testing the hypothesis that presynaptic increases in glutamate release contribute to the potentiation at this developmental stage. Increased knowledge of the mechanisms by which synaptic connections between neurons are modified is fundamental to our understanding of how the brain processes and stores information, and will benefit the search for treatments for major neurological diseases.

Recent publications

Palmer MJ, Isaac JTR & Collingridge GL (2004) Multiple, developmentally regulated expression mechanisms of long-term potentiation at CA1 synapses. J Neurosci 24:4903-4911

Palmer MJ, Hull C, Vigh J & von Gersdorff H (2003) Synaptic cleft acidification and modulation of short-term depression by exocytosed protons in retinal bipolar cells. J Neurosci 23:11332-11341

Palmer MJ, Taschenberger H, Hull C, Tremere L & von Gersdorff H (2003) Synaptic activation of presynaptic glutamate transporter currents in nerve terminals. J Neurosci 23:4831-4841

Palmer MJ, Fitzjohn SM, May JER, Neeson A, Morris SAC & Collingridge GL (2001) A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro. J Physiol 537:421-430

Palmer M.J., Irving A.J., Seabrook G.R., Jane D.E. & Collingridge G.L. (1997) The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus.  Neuropharmacol 36: 1517-1532