Perinatal Brain Group

Lead: Professor Gennadij Raivich

Main Aims

Our research goals are to improve understanding of the mechanisms underlying perinatal brain injury, to define its consequences and to design effective preventative and therapeutic strategies with the long- term aim of reducing the number of children who have neurological impairment or die as a result of brain injury around the time of birth.

Background

Perinatal brain injury is a common cause of cerebral palsy and other neurodisability that affects 1-2 per 1000 live births in the UK. Globally, it has been estimated that such injury results in 1 million neonatal deaths annually. In addition to the devastating impact on individuals and families, the economic cost of caring for affected children is enormous, amounting to hundreds of millions of pounds per annum.

There are 2 main forms of hypoxic ischemic (HI) encephalopathy. The frequently periventricular subcortical white matter damage, also known as periventricular leukomalacia, is a form more common in very immature babies, and may involve primary axonal or glial damage. Term infants show more frequent damage to their grey matter, in the cerebral cortex, basal ganglia and thalamus, with maternal and/or fetal infection predisposing to an adverse outcome.

Despite many years of research into this area the rates of cerebral palsy and other neurodisability have not fallen, and the precise causes and mechanisms of injury to the newborn brain have yet to be fully explained. To better understand these complex issues requires the coordinated expertise of individuals from across scientific and clinical fields. In this, we are strongly collaborating with the other two research groups that are a part of the Centre for Perinatal Brain Protection and Repair (Lead Prof Donald Peebles), the Neonatology Neuroscience group led by Dr Nikki Robertson and the Neonatal Medicine group (Prof Neil Marlow), who share facilities and have common meetings, and work in close collaboration.

Our own main region of interest centers on identifying the molecules involved in mediating the detrimental outcome following hypoxic ischemic (HI) insult to the immature white and grey matter. Current studies in our group focus on the role of Mitogen-Activated Protein kinase cascade, particularly that of Extracellular signal Regulated Kinase (ERK), and activated microglia in mediating HI-axonal damage, with a second line of research centering on the involvement of infectious stimuli, inflammation-associated cytokines, transcription factors and ion transporters in grey matter injury. In addition to these projects, many of which involve transgenic animals, we are have extended interest in broader experimental neuropathology, to define molecular mechanisms acting in neurodegenerative diseases (e.g. amyotrophic lateral sclerosis), and those that promote repair following central and peripheral nerve injury.

Current Projects

Hypoxic Ischemic Encephalopathy Focus:

Extracellular signal Regulated Kinase in Neonatal Subcortical Axonal Damage
Microglial Activation and Axonal Degeneration in Normal Development and following HI Insult
AP1 Transcription Factor c-Jun and its role in HI Grey Matter Injury
Regulation and Changes Na/H Transporters and in intracellular brain pH
Infection-associated Signals and Tumour Necrosis Factor Family of Cytokines

Extended Experimental Neuropathology Interest

Ras Signalling Cascade in Repair following Central and Peripheral Nerve Injury
AP1 Transcription Factor c-Jun in animal models of Amyotrophic Lateral Sclerosis

Main Achievements, Funding and Publications

Publications - since 2004 – 22 papers and 8 reviews, including papers in Nat Med, Neuron, Trends Neurosci, Proc Nat Acad Sci USA, Annals Neurology, J Neurosci, J Clin Invest and J Cerebr Blood Flow Metab. According to the Institute of Scientific Information (Thomson Inc, USA), these papers since 2004, have, so far, been cited over 600 times. Grant Funding - current funding of £850,000, including funding from BBSRC (£450,000), SPARKS (£200,000), Int Spinal Research Trust (£120,000), Motoneuron Disease (£79,000), and via Industry (Glaxo-Smith-Kline).

Current Group Members

Gena Raivich – Professor, Lead for Perinatal Neuroscience
Donald Peebles – Professor, Lead, Obstetrics and Gynaecology
Giles S Kendall – Academic Clinical Lecturer, Neonatology
Mariya Hristova – HEFCE funded Postdoctoral Research Fellow
Roman Gonitel – Postdoctoral Fellow (BBSRC)
Milan Makwana – PhD, Med Student at UCL
Crystal Ruff – PhD Student (UCL Overseas Research Studentship)
Alejandro Acosta-Saltos – MB/PhD Student (MotoNeuron Disease Association)
Laura Thei – PhD Student (SPARKS)
Carolina Acosta-Saltos – PhD Student (International Spinal Research Trust)

Future Plans

We plan to to consolidate existing collaborations within the Institute for Women’s Health, particularly by accessing facilities for high throughput genomic and proteomic research. This collaboration will be further strengthened by incorporating research activities in Women’s Health into a single, purpose built building on the Chenies Mews site.

Publications Since 2004

Original Studies

Bohatschek M, Kloss CUA, Pfeffer K, Labow M, RAIVICH G (2004) Cytokine regulation of microglial MHC1 in the axotomized facial motor nucleus: role of TNF receptors TNFR1 and TNFR2. J Comp Neurol 470:382-99
RAIVICH G, Bohatschek M, Clive DaCosta C, Iwata O, Galiano M, Hristova M, Wolfer DP, Lipp HP, Aguzzi A, Wagner EF, Behrens A (2004) Essential role of the AP-1 transcription factor c-jun in axonal regeneration. Neuron 43:57-67
Bohatschek M, Kloss CUA, Pfeffer K, Bluethmann H, RAIVICH G (2004) B7.2 on activated and phagocytic microglia in the facial axotomy model: regulation by interleukin-1 receptor type 1, tumor necrosis factor receptors 1 and 2 and endotoxin. J Neuroimmunol 156:132– 145
Werner C, RAIVICH G, Cowen M, Sillaber I, Spanagel R, Hofmann F (2004) Importance of NO/cGMP signaling via cGMP-dependent protein kinase II for controlling emotionality and neurobehavioural effects of alcohol. Eur J Neurosci 20:3498-506
Brecht S, Kirchhof R, Chromik A, Willesen M, Nicolaus T, RAIVICH G, Wessig J, Waetzig V, Goetz M, Claussen M, Pearse D, Kuan CY, Vaudano E, Behrens A, Wagner E, Flavell RA, Davis RJ, Herdegen T (2005) Specific pathophysiological functions of JNK isoforms in the brain. Eur J Neurosci. 21:363-77
Heppner FL, Greter M, Marino D, Falsig J, RAIVICH G, Hövelmeyer N, Waisman A, Rülicke T, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146-52
Liu ZQ, Bohatschek M, Pfeffer K, Bluethmann H, RAIVICH G (2005) Major histocompatibility complex (MHC2+) perivascular macrophages in the axotomized facial motor nucleus are regulated by receptors for interferon-gamma (IFNgamma) and tumor necrosis factor (TNF). Neuroscience 131:283-92
Iwata O, Thornton JS, Sellwood MW, Iwata S, Sakata Y, Noone MA, O'Brien FE, Bainbridge A, De Vita E, RAIVICH G, Peebles D, Scaravilli F, Cady EB, Ordidge R, Wyatt JS, Robertson NJ (2005) Depth of delayed cooling alters neuroprotection pattern after hypoxia-ischemia. Ann Neurol. 58:75-87
Friedrichsen S, Heuer H, Christ S, Cuthill D, Bauer K, RAIVICH G (2005) Gene expression of connective tissue growth factor in adult mouse. Growth Factors 23:43 – 53
Kendall G, Robertson NJ, Peebles DM, RAIVICH G (2006) N-methyl-isobutyl-amiloride ameliorates brain injury when commenced prior to hypoxia ichemia in neonatal mice. Ped Res 59:227-31
Guo C, Willem M, Werner A, RAIVICH G, Emerson M, Neyses L, Mayer U (2006) Absence of {alpha}7 integrin in dystrophin-deficient mice causes a myopathy similar to Duchenne muscular dystrophy. Hum Mol Genet 15:989-98 4
Rhodes KE, Raivich G, Fawcett JW (2006) The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience. 140:87-100
Trajkovic M, Visser TJ, Mittag J, Horn S, Lukas J, RAIVICH G, Bauer K, Heuer H (2007) Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. J Clin Invest 117:627-35
Makwana M, Jones LL, Cuthill D, Heuer H, Bohatschek M, Hristova M, Friedrichsen S, Ormsby I, Bueringer D, Koppius A, Bauer K, Doetschman T, RAIVICH G (2007) Endogenous transforming growth factor beta1 suppresses inflammation and promotes survival in adult CNS. J Neurosci. 27:11201-13
Nateri AS, RAIVICH G, Vreugdenhil M, Milan Makwana M, Brandner S, Adams RH, Jefferys JGR, Kann O, Behrens (2007) A ERK activation causes epilepsy by stimulating NMDA receptor activity through transcriptional and translational mechanisms. EMBO J 26:4891-901
Wang XL, Carmichael DW, Cady EB, Oliver Gearing, Bainbridge A, Ordidge RJ, RAIVICH G, Peebles DM (2008) Greater hypoxia-induced cell death in prenatal brain following bacterial-endotoxin pre-treatment is not due to enhanced cerebral energy depletion: a chicken embryo model of the intrapartum response to hypoxia and infection. J Cerebr Blood Flow Metab, 28:948-60
Mills C, Makwana M, Wallace A, Benn S, Schmidt H, Tegeder I, Costigan M, Brown RH Jr, RAIVICH G, Woolf CJ (2008) Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats. Eur J Neurosci. 27:937-46
Tebar LA, Géranton SM, Parsons-Perez C, Fisher AS, Bayne R, Smith AJ, Turmaine M, Perez-Luz S, Sheasby A, De Felipe C, Ruff C, RAIVICH G, Hunt SP (2008) Deletion of the mouse RegIIIbeta (Reg2) gene disrupts ciliary neurotrophic factor signaling and delays myelination of mouse cranial motor neurons. Proc Natl Acad Sci USA 105:11400-5
Makwana M, Serchov T, Hristova M, Bohatschek M, Gschwendtner A, Kalla R, Liu ZQ, Heumann R, RAIVICH G (2009) Regulation and function of neuronal GTP-Ras in facial motor nerve regeneration J Neurochem 108:1453-63
Rahim AA, Wong AMS, Howe SJ, Buckley SMK, Acosta-Saltos AD, Elston KE, Ward NJ, Philpott NJ, Cooper JD, Anderson PN, Waddington SN, Thrasher AJ, RAIVICH G (2009) Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors. Gene Therapy 16:509-20
Laufer J, Zhang E, RAIVICH G, Beard P (2009) Three dimensional non invasive imaging of the vasculature in the mouse brain using a high resolution photoacoustic scanner. Appl Optics 48:D299-306
Hristova M, Cuthill D, Zbarsky V, Acosta-Saltos A, Wallace AS, Blight K, Buckley SM, Peebles DM, Heuer H, Waddington SN, RAIVICH G (2009) Activation and deactivation of periventricular white matter phagocytes during postnatal mouse development. GLIA, in press

Reviews

RAIVICH G, Banati RB (2004) Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease. Brain Res Rev 46:261-281
Makwana M, RAIVICH G (2005) Molecular mechanisms in successful peripheral regeneration FEBS J 272:2628-2638
Raivich G (2005) Like cops on the beat: the active role of resting microglia. Trends Neurosci, 28:571-3
RAIVICH G, Behrens A (2006) Role of the AP-1 transcription factor c-Jun in developing, adult and injured brain. Prog Neurobiol, 78(6):347-63
RAIVICH G, Makwana M (2007) The making of successful axonal regeneration: genes, molecules and signal transduction pathways. Brain Res Rev 53: 287-311
RAIVICH G (2008) c-Jun expression, activation and function in neural cell death, inflammation and repair. J Neurochem 107:898-906
Raivich G (2008) Axonal Injury: Neuronal Response. Encyclopedia of Neuroscience, Elsevier.
RAIVICH G, Peebles DM (2008) Infection, Inflammation and Damage to Fetal and Perinatal Brain. In The Newborn Brain (Lagercrantz et al., eds), 2nd edition, in press