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Dr Neil Hardingham
(e/fe)
Darlithydd
Trosolwyg
Mae gen i ddiddordeb mewn trosglwyddo synaptig a hefyd mewn morffoleg niwronau a circuitry yn y cortex cerebral. Mae'r cortex yn chwarae rhan allweddol wrth brosesu mewnbynnau synhwyraidd a hefyd swyddogaethau lefel uwch o lawer fel gwneud penderfyniadau a rheolaeth weithredol. Gall deall y prosesau hyn a sut maent yn cael eu haddasu gan ddatblygiad neu blastigrwydd synaptig ein helpu i ddatblygu triniaethau ar gyfer anhwylderau niwrolegol lle mae morffoleg niwronaidd, trosglwyddiad synaptig a phlastigrwydd synaptig yn cael eu peryglu.
Cyhoeddiad
2023
- Pandey, A. et al. 2023. Interdependence of primary and secondary somatosensory cortices for plasticity and texture discrimination learning. [Online]. BioXiv. (10.1101/2023.04.25.538217v1) Available at: https://www.biorxiv.org/content/10.1101/2023.04.25.538217v1
2022
- Pandey, A., Hardingham, N. and Fox, K. 2022. Differentiation of Hebbian and homeostatic plasticity mechanisms within layer 5 visual cortex neurons. Cell Reports 39(9), article number: 110892. (10.1016/j.celrep.2022.110892)
2021
- Bonneau, M. et al. 2021. Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness. Translational Psychiatry 11(1), article number: 135. (10.1038/s41398-021-01256-3)
2018
- Tropea, D., Hardingham, N. R., Millar, K. and Fox, K. D. 2018. Mechanisms underlying the role of DISC1 in synaptic plasticity. Journal of Physiology 596(14), pp. 2747-2771. (10.1113/JP274330)
2017
- Papale, A. et al. 2017. Severe intellectual disability and enhanced gamma-aminobutyric acidergic synaptogenesis in a novel model of rare RASopathies. Biological Psychiatry 81(3), pp. 179-192. (10.1016/j.biopsych.2016.06.016)
2015
- Greenhill, S. D., Juczewski, K., de Haan, A. M., Seaton, G., Fox, K. and Hardingham, N. R. 2015. Adult cortical plasticity depends on an early postnatal critical period. Science 349(6246), pp. 424-237. (10.1126/science.aaa8481)
- Cerovic, M. et al. 2015. Derangement of Ras-guanine nucleotide-releasing Factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia. Biological Psychiatry 77(2), pp. 106-115. (10.1016/j.biopsych.2014.04.002)
2013
- Hardingham, N. R., Dachtler, J. and Fox, K. D. 2013. The role of nitric oxide in pre-synaptic plasticity and homeostasis. Frontiers in Cellular Neuroscience 7, article number: 190. (10.3389/fncel.2013.00190)
2012
- Dachtler, J., Hardingham, N. R. and Fox, K. D. 2012. The role of nitric oxide synthase in cortical plasticity is sex specific. Journal of Neuroscience 32(43), pp. 14994-14999. (10.1523/JNEUROSCI.3189-12.2012)
2011
- Hardingham, N. R., Gould, T. M. and Fox, K. D. 2011. Anatomical and sensory experiential determinants of synaptic plasticity in layer 2/3 pyramidal neurons of mouse barrel cortex. The Journal of Comparative Neurology 519(11), pp. 2090-2124. (10.1002/cne.22583)
- Dachtler, J., Hardingham, N. R., Glazewski, S., Wright, N. F., Blain, E. J. and Fox, K. D. 2011. Experience-dependent plasticity acts via GluR1 and a novel neuronal nitric oxide synthase-dependent synaptic mechanism in adult cortex. Journal of Neuroscience 31(31), pp. 11220-11230. (10.1523/JNEUROSCI.1590-11.2011)
- Hardingham, N. R., Gould, T. M. and Fox, K. D. 2011. Erratum: Anatomical and sensory experiential determinants of synaptic plasticity in layer 2/3 pyramidal neurons of mouse barrel cortex. The Journal of Comparative Neurology 519(13), pp. 2711. (10.1002/cne.22712)
2010
- Hardingham, N. R., Read, J. C. A., Trevelyan, A. J., Nelson, J. C., Jack, J. J. B. and Bannister, N. J. 2010. Quantal Analysis Reveals a Functional Correlation between Presynaptic and Postsynaptic Efficacy in Excitatory Connections from Rat Neocortex. The Journal of Neuroscience 30(4), pp. 1441-1451. (10.1523/JNEUROSCI.3244-09.2010)
2008
- Phillips, K. G., Hardingham, N. R. and Fox, K. D. 2008. Post-synaptic action potentials are required for nitric oxide-dependent LTP in CA1 neurons of adult GluR1 knockout and wild-type mice. Journal of Neuroscience 28(52), pp. 14031-14041. (10.1523/JNEUROSCI.3984-08.2008)
- Hardingham, N. R., Wright, N. F., Dachtler, J. and Fox, K. D. 2008. Sensory deprivation unmasks a PKA-dependent synaptic plasticity that operates in parallel with CaMKII. Neuron 60(5), pp. 861-874. (10.1016/j.neuron.2008.10.018)
- Wright, N. F., Glazewski, S., Hardingham, N. R., Phillips, K., Pervolaraki, E. and Fox, K. D. 2008. Laminar analysis of the role of GluR1 in experience-dependent and synaptic depression in barrel cortex. Nature Neuroscience 11(10), pp. 1140-1142. (10.1038/nn.2188)
2007
- Hardingham, N. R., Hardingham, G. E., Fox, K. D. and Jack, J. J. B. 2007. Presynaptic efficacy directs normalization of synaptic strength in layer 2/3 rat neocortex after paired activity. Journal of Neurophysiology 97(4), pp. 2965-2975. (10.1152/jn.01352.2006)
2006
- Hardingham, N. R. and Fox, K. D. 2006. The Role of Nitric Oxide and GluR1 in Presynaptic and Postsynaptic Components of Neocortical Potentiation.. Journal of Neuroscience Vol 26(Issue), pp. 7395-7404. (10.1523/JNEUROSCI.0652-06.2006)
- Soriano, F. X., Papadia, S., Hofmann, F., Hardingham, N. R., Bading, H. and Hardingham, G. E. 2006. Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability. Journal of Neuroscience 26(17), pp. 4509-4518. (10.1523/JNEUROSCI.0455-06.2006)
- Hardingham, N. R., Bannister, N. J., Read, J. C. A., Fox, K. D., Hardingham, G. E. and Jack, J. J. B. 2006. Extracellular calcium regulates postsynaptic efficacy through group 1 metabotropic glutamate receptors. Journal of Neuroscience 26(23), pp. 6337-6345. (10.1523/JNEUROSCI.5128-05.2006)
2005
- Papadia, S., Stevenson, P., Hardingham, N. R., Bading, H. and Hardingham, G. E. 2005. Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. Journal of Neuroscience 25(17), pp. 4279-4287. (10.1523/JNEUROSCI.5019-04.2005)
2003
- Hardingham, N. R., Glazewski, S., Pakhotin, P., Mizuno, K., Chapman, P. F. J., Giese, K. P. and Fox, K. D. 2003. Neocortical long-term potentiation and experience-dependent synaptic plasticity require alpha-calcium/calmodulin-dependent protein kinase II autophosphorylation. Journal of Neuroscience 23(11), pp. 4428-4436.
1998
- Hardingham, N. R. and Larkman, A. U. 1998. The reliability of excitatory synaptic transmission in slices of rat visual cortex in vitro is temperature dependent. The Journal of Physiology 507(1), pp. 249-256. (10.1111/j.1469-7793.1998.249bu.x)
Articles
- Pandey, A., Hardingham, N. and Fox, K. 2022. Differentiation of Hebbian and homeostatic plasticity mechanisms within layer 5 visual cortex neurons. Cell Reports 39(9), article number: 110892. (10.1016/j.celrep.2022.110892)
- Bonneau, M. et al. 2021. Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness. Translational Psychiatry 11(1), article number: 135. (10.1038/s41398-021-01256-3)
- Tropea, D., Hardingham, N. R., Millar, K. and Fox, K. D. 2018. Mechanisms underlying the role of DISC1 in synaptic plasticity. Journal of Physiology 596(14), pp. 2747-2771. (10.1113/JP274330)
- Papale, A. et al. 2017. Severe intellectual disability and enhanced gamma-aminobutyric acidergic synaptogenesis in a novel model of rare RASopathies. Biological Psychiatry 81(3), pp. 179-192. (10.1016/j.biopsych.2016.06.016)
- Greenhill, S. D., Juczewski, K., de Haan, A. M., Seaton, G., Fox, K. and Hardingham, N. R. 2015. Adult cortical plasticity depends on an early postnatal critical period. Science 349(6246), pp. 424-237. (10.1126/science.aaa8481)
- Cerovic, M. et al. 2015. Derangement of Ras-guanine nucleotide-releasing Factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia. Biological Psychiatry 77(2), pp. 106-115. (10.1016/j.biopsych.2014.04.002)
- Hardingham, N. R., Dachtler, J. and Fox, K. D. 2013. The role of nitric oxide in pre-synaptic plasticity and homeostasis. Frontiers in Cellular Neuroscience 7, article number: 190. (10.3389/fncel.2013.00190)
- Dachtler, J., Hardingham, N. R. and Fox, K. D. 2012. The role of nitric oxide synthase in cortical plasticity is sex specific. Journal of Neuroscience 32(43), pp. 14994-14999. (10.1523/JNEUROSCI.3189-12.2012)
- Hardingham, N. R., Gould, T. M. and Fox, K. D. 2011. Anatomical and sensory experiential determinants of synaptic plasticity in layer 2/3 pyramidal neurons of mouse barrel cortex. The Journal of Comparative Neurology 519(11), pp. 2090-2124. (10.1002/cne.22583)
- Dachtler, J., Hardingham, N. R., Glazewski, S., Wright, N. F., Blain, E. J. and Fox, K. D. 2011. Experience-dependent plasticity acts via GluR1 and a novel neuronal nitric oxide synthase-dependent synaptic mechanism in adult cortex. Journal of Neuroscience 31(31), pp. 11220-11230. (10.1523/JNEUROSCI.1590-11.2011)
- Hardingham, N. R., Gould, T. M. and Fox, K. D. 2011. Erratum: Anatomical and sensory experiential determinants of synaptic plasticity in layer 2/3 pyramidal neurons of mouse barrel cortex. The Journal of Comparative Neurology 519(13), pp. 2711. (10.1002/cne.22712)
- Hardingham, N. R., Read, J. C. A., Trevelyan, A. J., Nelson, J. C., Jack, J. J. B. and Bannister, N. J. 2010. Quantal Analysis Reveals a Functional Correlation between Presynaptic and Postsynaptic Efficacy in Excitatory Connections from Rat Neocortex. The Journal of Neuroscience 30(4), pp. 1441-1451. (10.1523/JNEUROSCI.3244-09.2010)
- Phillips, K. G., Hardingham, N. R. and Fox, K. D. 2008. Post-synaptic action potentials are required for nitric oxide-dependent LTP in CA1 neurons of adult GluR1 knockout and wild-type mice. Journal of Neuroscience 28(52), pp. 14031-14041. (10.1523/JNEUROSCI.3984-08.2008)
- Hardingham, N. R., Wright, N. F., Dachtler, J. and Fox, K. D. 2008. Sensory deprivation unmasks a PKA-dependent synaptic plasticity that operates in parallel with CaMKII. Neuron 60(5), pp. 861-874. (10.1016/j.neuron.2008.10.018)
- Wright, N. F., Glazewski, S., Hardingham, N. R., Phillips, K., Pervolaraki, E. and Fox, K. D. 2008. Laminar analysis of the role of GluR1 in experience-dependent and synaptic depression in barrel cortex. Nature Neuroscience 11(10), pp. 1140-1142. (10.1038/nn.2188)
- Hardingham, N. R., Hardingham, G. E., Fox, K. D. and Jack, J. J. B. 2007. Presynaptic efficacy directs normalization of synaptic strength in layer 2/3 rat neocortex after paired activity. Journal of Neurophysiology 97(4), pp. 2965-2975. (10.1152/jn.01352.2006)
- Hardingham, N. R. and Fox, K. D. 2006. The Role of Nitric Oxide and GluR1 in Presynaptic and Postsynaptic Components of Neocortical Potentiation.. Journal of Neuroscience Vol 26(Issue), pp. 7395-7404. (10.1523/JNEUROSCI.0652-06.2006)
- Soriano, F. X., Papadia, S., Hofmann, F., Hardingham, N. R., Bading, H. and Hardingham, G. E. 2006. Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability. Journal of Neuroscience 26(17), pp. 4509-4518. (10.1523/JNEUROSCI.0455-06.2006)
- Hardingham, N. R., Bannister, N. J., Read, J. C. A., Fox, K. D., Hardingham, G. E. and Jack, J. J. B. 2006. Extracellular calcium regulates postsynaptic efficacy through group 1 metabotropic glutamate receptors. Journal of Neuroscience 26(23), pp. 6337-6345. (10.1523/JNEUROSCI.5128-05.2006)
- Papadia, S., Stevenson, P., Hardingham, N. R., Bading, H. and Hardingham, G. E. 2005. Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. Journal of Neuroscience 25(17), pp. 4279-4287. (10.1523/JNEUROSCI.5019-04.2005)
- Hardingham, N. R., Glazewski, S., Pakhotin, P., Mizuno, K., Chapman, P. F. J., Giese, K. P. and Fox, K. D. 2003. Neocortical long-term potentiation and experience-dependent synaptic plasticity require alpha-calcium/calmodulin-dependent protein kinase II autophosphorylation. Journal of Neuroscience 23(11), pp. 4428-4436.
- Hardingham, N. R. and Larkman, A. U. 1998. The reliability of excitatory synaptic transmission in slices of rat visual cortex in vitro is temperature dependent. The Journal of Physiology 507(1), pp. 249-256. (10.1111/j.1469-7793.1998.249bu.x)
Websites
- Pandey, A. et al. 2023. Interdependence of primary and secondary somatosensory cortices for plasticity and texture discrimination learning. [Online]. BioXiv. (10.1101/2023.04.25.538217v1) Available at: https://www.biorxiv.org/content/10.1101/2023.04.25.538217v1
Ymchwil
Diddordebau Ymchwil Hardingham
Mae'r cortex cerebrol yn cyflawni llawer o swyddogaethau mwy cymhleth yr ymennydd, yn enwedig mewn primatiaid uwch; Felly, os ydym am ddeall sut mae'r ymennydd yn gweithio, mae angen i ni ddeall y cortex. Mae datblygiad cortigol yn cael ei gysylltu'n gynyddol ag anhwylderau niwrolegol fel sgitsoffrenia, syndrom Fragile X, Retardation Meddyliol a chlefyd Alzheimer ac mae diffygion strwythurol a swyddogaethol yn y cortecs bellach yn cael eu cysylltu â'r anhwylderau seicolegol hyn. Mae angen i ni ddeall yr anhwylderau hyn er mwyn darparu triniaethau yn y dyfodol. Mae modelau llygoden cyflyrau niwrolegol wedi dechrau helpu i ddatrys sail fiolegol y cyflyrau hyn trwy ddangos diffygion naill ai mewn ceryntau synaptig, arborizations dendritig, dwysedd asgwrn cefn neu gysylltedd niwronaidd. Mae ymchwil yn labordy Fox lle bûm yn gweithio yng Nghaerdydd wedi dangos bod tarfu ar signalau DISC-1 yn P7, ar ôl i fewnfudo celloedd gael ei gwblhau yn cynhyrchu diffygion mewn plastigrwydd mewn cortex aeddfed, ond nid yw sefydlu DISC-1 mutant yn P28 yn cael unrhyw effaith (Greenhill et al, Science, 2015). Mae fy ymchwil wedi bod yn edrych ar ddatblygiad arferol dros y cyfnod hwn (P7-P28) a sut mae tarfu DISC1 yn effeithio arno ac mae wedi dangos bod datblygiad dendritig yn cael ei leihau'n sylweddol dros y cyfnod tyngedfennol hwn o'i gymharu â mathau gwyllt (Greenhill et al 2015). At hynny, mae priodweddau aeddfedu synaptig hefyd yn gwanhau o'u cymharu â mathau gwyllt ac effeithir ar ddwysedd asgwrn cefn ar orchmynion penodol o dendrites. Rwyf wedi datblygu methodoleg gadarn i allu ymchwilio i briodweddau synaptig niwronau a hefyd mesur morffoleg niwronau ar y lefel dendritig i fesur ei ddatblygiad a hefyd i fesur dwysedd asgwrn cefn a morffoleg asgwrn cefn yn fanwl a chydberthyn hyn â swyddogaeth (Greenhill et al 2015). Yn ogystal, rwyf wedi cael mutant DISC1 cyfansoddol (Der1) sy'n atgynhyrchu'r trawsleoliad gwreiddiol yn gywir ac rwy'n ymchwilio i ddiffygion yn y llygoden hon, gan gymharu effeithiau aflonyddwch DISC1 cronig i dros dro.
Cynigion Ymchwil y Dyfodol
Mae gan lawer, os nad pob anhwylder niwroseiciatrig ddiffygion gwybyddol sy'n gyson â chyfranogiad y cortex rhagflaenol, sy'n ymwneud â llawer o swyddogaethau gwybyddol trefn uchel, felly dyma lle rwyf bellach yn canolbwyntio fy sylw. Rwy'n gweithio ar mutant DISC1 (y Der-1) sef y cyntaf sy'n dynwared yn gywir y trawsleoliad gwreiddiol a welwyd mewn bodau dynol a oedd yn ffactor risg potensial uchel ar gyfer nifer o anhwylderau niwroseiciatrig, gan gynnwys sgitsoffrenia. Rwyf eisoes wedi dod o hyd i ddiffygion mewn niwronau prefrontal ar y dendrite ac ar y lefel asgwrn cefn, ond yn ddiddorol mae'r diffygion yn dendrite penodol, gyda diffygion yn benodol i dendritau sylfaenol. Hoffwn ymestyn fy ymchwil i fodelau llygoden eraill o anhwylderau niwrolegol a gobeithio nodi cyffredinrwydd rhwng mecanweithiau clefydau.
Mae sgitsoffrenia wedi cael ei gynnig ers amser maith i gael ei achosi gan ddiffygion mewn cysylltedd rhwng gwahanol ranbarthau'r ymennydd tra bod y cortex rhagarweiniol yn derbyn mewnbynnau o lawer o wahanol rannau o'r ymennydd gan gynnwys hippocampus, amygdala a'r thalamws. Gan ddefnyddio dulliau optogenetig gallaf ysgogi a nodweddu mewnbynnau unigol i'r cortex blaen a safleoedd mewnbwn map ar goed dendritig penodol a phenderfynu a yw gwahanol fewnbynnau wedi'u lleoli'n wahanol ar dendrites a hefyd a ydynt yn cael eu newid yn y llygod mwtant yn dibynnu ar eu lleoliad. Yna gellid dilyn yr arbrofion hyn gan brofion ymddygiadol sy'n benodol i'r mewnbynnau yr effeithir arnynt fwyaf yn y mutants.
Addysgu
Rwy'n addysgu mewn amrywiaeth o feysydd niwrowyddoniaeth, yn darlithio ac yn dysgu seiliedig ar ymarferol ac mae gennyf ddiddordeb mewn gweithredu ystod o dechnegau dysgu i ennyn diddordeb myfyrwyr ymhellach yn y gweithgareddau dysgu a'u cyfrannu. Mae gen i gymrodoriaeth mewn Addysg Uwch ym Mhrifysgol Cardff (FHEA).
Rwy'n ymwneud â threfnu modiwlau ar sawl lefel, fi yw arweinydd asesu (BI2432), arweinydd arholiadau (BI1002) a swyddog cyswllt arholiadau ail flwyddyn. Rwy'n rhedeg wythnos ymarferol a hefyd yn rhedeg gradd Meistr 3 wythnos estynedig yn ymarferol.
Contact Details
+44 29208 76276
Adeilad Syr Martin Evans, Rhodfa'r Amgueddfa, Caerdydd, CF10 3AX