Issue 67 - British Neuroscience Association

special issue! BNA2013: Festival of NeuroscienceBNA BulletinThe Voice of British NeuroScience todayIssue No. 67Spring 2013Rhythm of lifeLight and the body clockHair cell to hearingThe genetics of deafnessPlus:Stem cells forneurodegenerationNeuroscience inthe courtroomErasing memoriesCognitive ageingAnt navigation

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ContentsNews05Message fromthe President06Secretary’s report05–11BNA2013: Festival ofNeuroscienceBNA updatesEventsNeuroscience summitFunding and fellowshipsAnalysis12Whitherneuroscience?What does the futurehold in store for UKneuroscience?14Wonderful lifePublic events linked toBNA2013: Festival ofNeuroscience16Neuroscience inthe courtroomIs neuroscience poised tohave a major impact inthe UK courtroom?19Stem cell therapy:Will it work?What is the future ofstem cell research inneurodegeneration?22Memories aremade of thisWill it be possibleto selectively eraseunwanted memories?Research24Bright sparksBoosting maths skillswith brain stimulation25Bilingual lessonsHow the braindeals with differentlanguages26How an ant getsfrom A to BAn ant’s-eye view ofnavigation27Seeing the lightLight control of bodyclocks has importantmedical implications,says Russell Foster30Stress the positiveHans Reul hasdiscovered epigeneticlinks between stressand memory32The ups and downsof systems biologyOscillating systemsmay be central to cellfunction, says MichaelWhite34Cognitive ageingin the heart ofMidlothianUnique cohorts studiedby Ian Deary areshedding light on brainchanges in old age36A happy accidentA chance event ledKaren Steel intoauditory researchEt cetera38Obituaries:Alan CoweyRita Levi-Montalcini39-41Neurological conditionsand artSporting prowessCover: Neurons derived fromcultured stem cells (courtesyRoberta Cagnetta, Livesey Lab,Gurdon Institute).BNA executiveActing Chief Executive:Ian Varndell(ian.varndell@bna.org.uk)Chief Operating Officer:Elaine Snell(elaine.snell@bna.org.uk)Executive Officer:Louise Tratt(office@bna.org.uk)BNA BulletinEditor:Ian Jones, Jinja Publishing LtdDesign and production:Tess WoodPrinting:Sustainably printed byBurleighPortishead usingvegetable oil-based inks andcarbon-balanced paper.Advertising in the BNA Bulletin:Contact Louise Tratt(office@bna.org.uk) foradvertising rates andsubmission criteria.Copyright: © The BritishNeuroscience Association.Extracts may be reproduced onlywith permission of the BNA.ISSN: 1475-8679British Neuroscience AssociationDana Centre165 Queen’s GateSouth KensingtonLondon SW7 5HETel: +44 (0) 208 166 8713Web: www.bna.org.ukThe British NeuroscienceAssociation is a registeredcharity (1103852) and aregistered company (4307833)limited by guarantee.CBP00013040210120510www.bna.org.uk Spring 2013 BNA Bulletin 03

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NewsMessage from the PresidentDearBNA Members2013 is a very exciting year for the BNA. Our ambitiousplans for the BNA 2013: Festival of Neuroscience areabout to come to life! It will be held at one of Europe’sleading arts venues, the Barbican in Central London. Some1500 people from 30 different countries have registered.Our plenary lecturers are world-renowned in their fields.There will be 56 symposia and workshops, 240 speakersand over 900 abstracts have been submitted. As well asthe scientific sessions, there will be a big trade exhibitiontoo. If you haven’t registered yet, it’s not too late!An arts venue may seem an unusual choice but,in parallel with the BNA’s academic conference, theWellcome Trust has teamed up with the Barbican tohost an astonishing programme of public events(www.bna2013.com/211561). ‘Wonder: Art and Scienceon the Brain’ will feature Ruby Wax talking about herdepression, while mathematician Marcus du Sautoy andDJ James Holden will explore consciousness throughan audiovisual spectacular. There will be a theatricalrecreation of a 19th-century Parisian debating salon,performances, demonstrations, films and even ‘I’m aneuroscientist – get me out of here’. Do ask your friends,relatives and colleagues to come along.Immediately after the Festival, on 11 April there willbe a special Neuroscience Summit at the Royal Societyin London (see page 6). At a time when more than one inthree people have at least one brain disorder costing anestimated €780 billion each year – and rising – it is timelyto discuss neuroscience policy in the UK and Europe.Leading academics and representatives from industry,charities, brain organisations and the Research Councilswill present their views and contribute to a discussionwhich will help gain investment in and direct the brainresearch we need to meet the challenges we all face.Members of the BNA are welcome to attend.David Nutt, Presidentwww.bna.org.uk Spring 2013 BNA Bulletin 05

NewsSecretary’s ReportDearColleaguesWith the ground-breaking BNA2013: Festival ofNeuroscience only a short time away, the past fewmonths have been especially hectic for your BNA.We hosted the very successful Christmas Symposiumon the neuroscience of navigation at the Royal Society,where awards were given to Steven Rose (OutstandingContribution to Neuroscience), Claudia Hammond(Public Understanding of Neuroscience), FlorenceFricker (Postgraduate Prize) and Lewis Hou(Undergraduate Prize).The day before, the BNA Local Group Representatives(LGRs) assembled for a discussion session at our HQ atthe Science Museum’s Dana Centre in South Kensington.The meeting, the second in a series that we hope tocontinue on an annual basis, was organised and chairedby Local Groups’ Coordinator, Trevor Bushell, and wasa valuable opportunity to hear from our LGRs as tohow we can best drive the BNA forward to truly reflectthe aspirations of our members around the UK, andneuroscience in general. Many good points were madeand we are actively following up suggestions, which wewill report on in due course. Since LGRs have a strongvoice within BNA, you may wish to contact your LGR tohave your views communicated directly to BNA HeadOffice. A full list of LGRs can be found on the BNA website.Telling the public about brain research is so important.The annual Brain Awareness Week (11–17 March 2013)enables you to reach people in your area and be part ofa global event. In the past BNA members have been veryresourceful and creative in staging a range of activitiesfrom demonstrations and displays to talks and visits. Youcan find details for this year’s Brain Awareness Week onthe BNA website.The BNA2013: Festival of Neuroscience will be thebiggest BNA meeting ever. Along with the WellcomeTrust’s and Barbican’s public events, the Festival will bea fantastic window on neuroscience.Bruno Frenguelli, SecretaryNeuroscience SummitThe BNA is holding a special one-day Neuroscience Summit onThursday 11 April 2013, at the Royal Society in London, bringingtogether those who can influence policy and generate new initiativesfor research into, and treatment for, disorders of the brain.Mental health and neurological conditions are a priorityfor our nation and the economy. It follows, therefore, thatneuroscience must aim to deliver a better understanding of thebrain and brain disorders in order to develop better diagnosis andnew treatments.The purpose of the Neuroscience Summit is to discuss withleaders in neuroscience and related fields what needs to bedone to meet the societal challenge of brain disorders in the UK,Europe and beyond, and how this can be achieved. A report will beproduced after the meeting.This meeting is being organised by the BNA, in associationwith the European College of Neuropsychopharmacology and theEuropean Brain Council.The morning session, ‘Current status, future challengesand funding’, will feature contributions from Russell Foster(BNA; chair), Hugh Perry (MRC), Monica di Luca (European BrainCouncil), John Williams (Wellcome Trust), Mark Trickelbank (LillyUK), Melanie Welham (BBSRC) and Richard Morris (Edinburgh).The afternoon session, ‘Working with other organisationsto maximise developments’, will include comment fromMary Baker (European Brain Council; chair), Jackie Hunter(OI Pharma Partners), Arlene Wilkie (Neurological Alliance),Colin Blakemore (Oxford), David Nutt (European College ofNeuropsychopharmacology) and Russell Foster (BNA).Talks will be followed by discussions led by Quentin Cooper,presenter of BBC Radio 4’s Material World. Places are available, freeof charge. If you would like to attend please contact Elaine Snell(elaine.snell@bna.org.uk). Full details can be found at bit.ly/YgGLzTNew Year’s HonoursCongratulations to the following who were recognised in the NewYear’s Honours List 2013:• Simon Wessely: KnighthoodInstitute of Psychiatry, King’s College London. For services tomilitary healthcare and to psychological medicine.• David M Clark: CBEUniversity of Oxford. For services to mental health.• Les Iversen: CBEChair, Advisory Council on the Misuse of Drugs. For services topharmacology.• David Porteous: OBEUniversity of Edinburgh. For services to science.Congratulations also to Richard Morris and Tim Bliss who, alongwith Yadin Dudai of the Weizmann Institute, Israel, were awardedthis year’s Fondation Ipsen Prize for Neuronal Plasticity for theirresearch into the ‘mechanisms of memory’.06 BNA Bulletin Spring 2013www.bna.org.uk

NewsBNA2013:Festival ofNeuroscienceThe BNA2013: Festival of Neuroscience is almostupon us! Two years of planning, and now we arecounting the days. There has been nothing like thisbefore. More than 1500 delegates from 30 differentcountries will be converging on the Barbican inLondon on 7–10 April 2013.Karen Steel from King’s College London willgive the first plenary lecture, ‘Understanding thegenetics of deafness using mouse mutants’ (seepage 36 for our special feature on her work). Ourother renowned plenary speakers are AndersBjörklund (Sweden), Yves Agid (France), TimBliss, Uta Frith, Michael White (see page 32),Irene Tracey and David Attwell (all UK) and KarlDeisseroth (USA).There will be 56 scientific symposia spanningeight themes: development; molecular, cellularand synaptic mechanisms; sensory and motorsystems; cognition, circadian, homeostatic andneuroendocrine systems; nervous system disorders,methods and techniques; and public awareness andsocietal impacts. Many of these sessions have beensponsored by our partners, 18 organisations with aninterest in brain research.When you are not at the talks, you can explorethe posters and trade exhibition. Join us for ourreception on Sunday evening featuring MarcAbrahams of Ig Nobel Award fame.As we are in one of Europe’s leading arts andentertainment venues, the Wellcome Trust and theBarbican are hosting ‘Wonder: Art and science onthe brain’ (see page 14). Why not take advantage ofthe delegate discount?And looking more broadly at brain research, thereare sessions on the influence of sensory neuroscienceon the arts, humanities and even the food and drinksindustry; on cognitive enhancers; animal research;and public engagement. There really is somethingfor everyone.As if there is not enough to do and see inLondon, BrainStorm is the party night for Festivaldelegates with food, cocktails and dancing: Mondaynight, 8 April at the Grand Union in Farringdon.The Festival is a fabulous opportunity tonetwork, see old friends, make new friends,as well as discover the latest in brain research.Details of all this and everything else that willmake up the Festival are on our websitewww.bna2013.comBNA UpdatesBNA President David Nutt with (from left to right) Lewis Hou, Florence Fricker and Claudia Hammond.PrizesCongratulations to thefollowing who wereawarded prizes at the2012 BNA ChristmasSymposium:Lewis Hou (Edinburgh)won the UndergraduatePrize for his research intolanguage and auditoryprocessing. His researchhas implications for theearly detection ofmental illness.Florence Fricker (King’sCollege London) wonthe Postgraduate Awardfor demonstrating forthe first time that aneuregulin (NRG-1) isdispensable for peripheralnerve maintenancebut essential forremyelination and axonregeneration followingnerve injury.The prize for the ‘PublicUnderstanding ofNeuroscience’ went toClaudia Hammond, bestknown for presentingBBC Radio 4’s All inthe Mind. Claudia is aterrific advocate forneuroscience, bringingthe excitement andpromise of brain researchto ever-increasingand enthusiasticpublic audiences.Steven Rose receivedthe ‘OutstandingContribution toNeuroscience’ award –not least for playingan important role inestablishing the BNA.Steven is EmeritusProfessor of Biology atthe Open University,where he establishedand directed the Brainand Behaviour ResearchGroup. He is bestknown academicallyfor his research intothe processes involvedin memory formationand treatments forAlzheimer’s disease. Hehas published more than300 research papers andreviews and his workhas won him numerousmedals and prizes.Animal researchThe BNA has joinedleading charities,universities andpharmaceuticalcompanies in signing aDeclaration of Opennesson animal research.Signatories to thedeclaration “…commit towork together toestablish a Concordatthat will develop principlesof openness, practicalsteps and measurableobjectives which willunderpin a moretransparent approach toanimal research”. A copyof the declaration can befound at bit.ly/WHLZlmSteven Rose speaking at the BNA Christmas Symposium.www.bna.org.uk Spring 2013 BNA Bulletin 07

NewsEventsEdinburghNeuroscience DayThe 2013 EdinburghNeuroscience Day willbe held on 20 March2013 at the RoyalCollege of Physiciansof Edinburgh. TheAnnual DistinguishedLecture will be givenby Tobias Bonhoeffer(Max Planck Institutefor Neurobiology,Germany). In addition tothe annual PhD studentposter competition(supported by Takeda),the day will alsoinclude an Art–Sciencecompetition showcasingcollaborative workbetween EdinburghNeuroscienceresearchers andstudents at EdinburghCollege of Art.CambridgeNeuroscienceThe CambridgeNeuroscience Seminarwill be held on 26 March2013 at the BabbageLecture Theatre. Thisyear’s theme is ‘Fromsensation to action’.Plenary lectures will begiven by Johan Bolhuis(Utrecht) and Silvia Arber(Basel), while José del RMillán will deliver a publicplenary lecture. The BNAis sponsoring the GabrielHorn Memorial Lecture.More details at bit.ly/VPXRFyIon channelsymposiumCambridge Neuroscienceis also organisinga special two-daysymposium, ‘IonChannels in Health andDisease’, to celebratethe 50th anniversaryof the award of theNobel Prize to AlanHodgkin and AndrewHuxley. The symposiumwill take place on 16–17September 2013 in theWest Road Concert Hallin Cambridge. Furtherdetails can be foundat www.neuroscience.cam.ac.uk/events/ orcontact Dervila Glynn(dg248@cam.ac.uk) formore information.CannabinoidresearchThe 6th EuropeanWorkshop onCannabinoid Researchwill be held at TrinityCollege Dublin in theRepublic of Irelandon 18–20 April 2013.Organised by the BritishPharmacological Society,the meeting will featurean international line-upof speakers workingon cannabinoids andendocannabinoids inhealth and disease.Full details at bit.ly/UnMCnpFENS FeaturedRegional Meeting2013The FENS FeaturedRegional Meeting2013 will be held on11–14 September 2013, inPrague, Czech Republic.The deadline for earlyregistration and abstractsubmission is 31 March2013. The meetingwebsite includes themeeting schedule,details of symposia andspecial interest sessions,information abouttravel stipends, as wellas summaries of threetraining schools thatwill be held in Praguebefore the meeting, on9–11 September 2013.A satellite symposiumon neuroinflammationwill be held on8–11 September2013. See www.fensrmprague2013.com/ for more details.Maria Fitzgerald (centre), Kamini Vashist (left) and Stephanie McGarrity (right).Neuroscience@NottinghamOn Wednesday 12 December 2012, Nottinghamneuroscientists gathered for the annualNeuroscience@Nottingham Poster and LectureDay. There were 50 poster presentations ofneuroscience research from Nottingham andthe guest speaker, Maria Fitzgerald (UCL), gavea fascinating overview of her research on thedevelopment of touch and pain sensation in rodentmodels and humans.Kamini Vashist and Stephanie McGarrity wereawarded the two postgraduate poster prizes,for their excellent research and presentations on‘Blood–brain barrier breakdown after ischaemicstroke’ and ‘Schizophrenia-related neurobehaviouraleffects of hippocampal disinhibition –attentional deficits’, respectively.Neuroscience IrelandThe 7th Annual Meeting of Neuroscience Ireland was held on 5–6 September2012 at the Royal College of Surgeons of Ireland, Dublin.This year’s meeting featured a strong programme of invited speakers, aswell as talks by locally based and early-stage researchers. Some 167 participantsheard talks from 13 international and 23 national speakers.The two-day meeting was held in conjunction with the ‘Neurons underStress’ conference. It covered a number of new topics, including epigeneticsand non-coding RNA in neuronal function and dysfunction, and cell deathand survival pathways. The Distinguished Investigator Award was made toJohn J Foxe (Albert Einstein College of Medicine, USA) for his contributionsto cognitive neurophysiology. Tobias Engel (Royal College of Surgeons inIreland) received the Early Career Investigator Award for his work on apoptosisassociatedsignalling pathways in epilepsy.A Neuroscience Advocacy workshop, funded by FENS and the Societyfor Neuroscience, was held the day before the Annual Meeting. Organised byRichard Roche (National University of Ireland Maynooth, NUIM), the workshopheard talks by Audrey Craven (President of the European Federation ofNeurological Associations), Duncan Banks (BNA) and Andrew Coogan (NUIM).The afternoon session yielded lively group discussions on how to improve publicoutreach and political engagement.08 BNA Bulletin Spring 2013www.bna.org.uk

NewsDid you go homefor Christmas?If you did, how did you get there? How do humansand animals find their way? More than 200 peoplecame along to the BNA Christmas symposium‘Going Home for Christmas?’ on 19 December 2012,enjoying fascinating insights into the neuroscienceof navigation.Paul Graham (Sussex) described how insects –expert navigators despite their tiny brains – findtheir way around. Some of the mechanisms used byinsects, he suggested, might be relevant to visuallyguided navigation in larger-brained animals. DoraBiro (Oxford) talked about flock navigation and therules followed by birds when responding to othersin the air, producing aerial displays that are amongnature’s most visually arresting scenes.Emma Wood’s research at the University ofEdinburgh examines the activity of hippocampalplace cells in rats navigating through mazes. Spatialnetworks contain head direction, place, boundaryand grid cells. One outstanding question FrancescaCacucci (UCL) asks is how these spatial networks arewired to produce such exquisitely tuned responses.And on to the human brain. Carlo De Lillo(Leicester) discussed his research investigating thetrade-off between working memory capacity andsearch organisation in humans and other species,arguing that the ability to offload memory mayhelp the characterisation of the idiosyncrasiesof human cognitive sophistication. Jan Wiener(Bournemouth) described some of the effects ofcognitive ageing on the selection and adoption ofnavigation strategies.Finally, John O’Keefe (UCL), who discoveredplace cells and proposed that the hippocampuscontains a spatial map, revisited early days of thecognitive map theory in the early 1970s. Bringingus bang up to date, he also predicted where newtechnologies might take our understanding of thehippocampal cognitive map and its relationship toother brain areas.MRC–AZpartnershipThe MRC recently announced £7m funding for15 research projects through its partnership withAstraZeneca, which is providing access to22 chemical compounds to academic researchers.The compounds will be used in projects focusingon a range of conditions including Alzheimer’sdisease, motor neurone disease and musculardystrophies. Eight of the projects will involveclinical trials of potential new therapies, andseven will focus on earlier work in laboratory andanimal models.AstraZeneca had conducted early trials of the22 compounds and validated their use for futureresearch, but had put them on hold for furtherdevelopment.Launch symposiumThe Anne Rowling Regenerative Neurology Clinicin Edinburgh has launched a new website and isorganising a symposium to celebrate its opening.The ‘Clinical Science of Regenerative Neurology’symposium, featuring leading speakers fromthe worlds of stem cell biology and regenerativemedicine, will take place on 30–31 May 2013 at OurDynamic Earth in central Edinburgh.http://annerowlingclinic.com/home.htmlScience blog awardsNeuroscientists fared well at the first UK ScienceBlog Prize awards, organised by Good Thinking.At an event held in association with SohoSkeptics, judges including Ben Goldacre and SimonSingh awarded prizes to David Colquhoun’s DC’sImprobable Science and Suzi Gage’s Sifting theEvidence. Other short-listed blogs included DorothyBishop’s BishopBlog (runner up), Neuroskeptic’seponymous blog, Andre Tomlin’s The Mental Elfand Dean Burnett’s Brain Flapping.AddendumThe list of new Fellows of the Academy of MedicalSciences featured in the last issue of the BNABulletin should also have included Anthony Turner(University of Leeds).News in BriefEdinburghlectures onlineThe EdinburghNeuroscience PublicChristmas Lecture,‘Madness, Geniusand the Origin of theBrain’ by Seth Grant(Edinburgh), can beviewed online at bit.ly/V1BOdl. Meanwhile,Colin Blakemore’sBurns Nightpresentation, ‘But och!I backward castmy e’e’, can be enjoyedat bit.ly/13s8Llt.EnhancementreportThe Academy of MedicalSciences, the BritishAcademy, the RoyalAcademy of Engineeringand the Royal Societyhave published areport highlightinghow technologiesthat enhance humanfunctions such asmemory, hearingand mobility coulddramatically changehow people work.‘Human Enhancementand the Future of Work’can be downloaded atbit.ly/RX7u55A bit of nakedneuroscienceHot topics inneuroscience werethe focus of a recentNaked Scientistsshow, with HannahCritchlow speakingwith CambridgeNeuroscience’s BarbaraSahakian, John Rogersand David Weston.A podcast of the showis available at bit.ly/13IfwkZwww.bna.org.uk Spring 2013 BNA Bulletin 09

NewsBiomedical Catalyst fundingJamie Loan and Rory Piper, organisers of the ‘Neuroscience to Neurology’ conference.Neuroscience to NeurologyOn 26 January 2013, the Edinburgh Undergraduate Neurological Societyhosted the 1st Neuroscience to Neurology conference, supported by EdinburghNeuroscience and the BNA.Some 100 students attended the event, from 18 universities andrepresenting both science and medical disciplines. The multidisciplinarycomponent of the conference spurred the theme of the day – ‘Neuroscience toNeurology’, or ‘translation neuroscience’ as it is better known. This theme waschosen to allow students to consider how their work relates to this process.Students had the opportunity to present their research through oral orposter presentations. Josh King-Robson (Barts and The London) won the prizefor the best poster presentation and Luke Sansom (Leeds) won the prize for thebest oral presentation. Veny Lukito (Edinburgh) received the ‘Neuroscience toNeurology’ prize for a presentation that best captured the conference theme.Delegates received lectures from nationally renowned academics inneuroscience, neurology and neurosurgery, including Richard Morris andCharles ffrench-Constant (Edinburgh), Sam Eljamel (Dundee) and JohnPickard (Cambridge).In addition, interactive workshops offered attendees the chance to developtheir academic and clinical skills. The workshops included guidance in writingmanuscripts for publication, giving a presentation, becoming a neurologist orneurosurgeon and dealing with cases of neuro-trauma.Faster diagnosis of dementia is one possibleoutcome of £39m funding awarded throughBiomedical Catalyst, a partnership between theTechnology Strategy Board and the Medical ResearchCouncil (MRC), to 32 projects led by small andmedium-sized enterprises (SMEs) and universities.London-based company IXICO Ltd and itspartners, including Cambridge Cognition andacademic partners, received funding for acollaborative project to develop a novel digitalhealthcare system that will enable faster, earlierand more cost-effective dementia diagnosis. Itsaim is to shorten the time to diagnosis from anaverage of 18 months to three months.In the latest round of awards, grants totalling£29.6m were made for 22 SME-led projects, whileten projects worth £9.5m are being led by academicinstitutions. Further awards in the £180m initiativewill be made in 2013. See bit.ly/11wQMxp formore details.Sir Henry Dale FellowsTwo neuroscientists are among those awarded SirHenry Dale Fellowships, in a new joint initiativebetween the Royal Society and the Wellcome Trust.Ten fellowships were awarded, with recipientsincluding Tiago Branco (UCL; Dendritic integrationin the ventromedial nucleus of the hypothalamus)and Jennifer K Bizley (UCL; Listening in a noisyworld: the role of visual activity in auditory cortexfor sound perception).The fellowships, named after Sir Henry Dale(1875–1968), a Nobel Prize winner and formerChairman of the Wellcome Trust and Presidentof the Royal Society, provide funding to enableresearchers to establish their independent researchcareers. For more details, see bit.ly/ZT8k1zPrincipal’s MedalCongratulations to Jane Haley, Scientific Manager for Edinburgh Neuroscience,who has been awarded the 2012 Principal’s Medal for Outstanding Service fromthe University of Edinburgh. This award rewards staff members who havemade a major contribution to the University community. Jane won this year’saward in recognition of her leadership at Edinburgh Neuroscience, where shehas been fostering communication, collaboration and community spirit amongneuroscientists since 2006.Jane received her Principal’s Medal at a postgraduate Graduation Ceremonyon 30 November 2012, which was streamed live and also took place virtually onSecond Life. The occasion was made particularly special as Jane wore her PhDgrown from the University of London for the first time – she missed her ownPhD graduation, having already started work in the USA.Jane Haley (right) with Edinburgh’s Vice-Principal, Mary Bownes.10 BNA Bulletin Spring 2013www.bna.org.uk

Newswww.bna.org.uk Spring 2013 BNA Bulletin 011

AnalysisWhitherneuroscience?We asked a selection of notablefigures in neuroscience abouttheir hopes for the future. Hereare some of their thoughts…Opportunitiesabound…Richard Morris“The Festival is an incredible opportunityfor people from all branches of theneurosciences, basic and clinical, andall different levels of analysis, to cometogether and see the immense scope ofthe subject.This is a very exciting time for youngpeople in neuroscience. All manner ofnew technologies are becoming availablethat were never dreamt of before. Wenow have the opportunity to do confocalmicroscopy in living animals, record frommultiple cells in behaving animals, interactin a causal way using optogenetics – thesetechniques all give a new technologicalstimulus to time-honoured questions inneuroscience, in development, cognition,motor control, all manner of fields. I hopeyounger scientists coming to the meetingwill participate not only by presenting theirown work, but will also learn about thenew technologies, and hopefully go backand think about how to use them in theirown research.As a community, we also need to thinkvery carefully, and very positively, aboutthe ways in which basic neurosciencecan be applied in all kinds of settings– clinically, but also in areas such aseducation. We’re sitting on discoveriesthat have the potential to make all kindsof changes. We shouldn’t be frightenedof those opportunities. While doingtranslational work can sometimes be a bitmessy, it’s a fantastic opportunity for us tothink about the impact that neuroscienceis making beyond the academic domain.I hope this is something we spend sometime thinking about at the Festival.”Reasons to becheerful…Ruth McKernan“The pharmaceutical industry is goingthrough some dramatic changes. We’reseeing moves towards smaller, moreentrepreneurial research units in areasof biotech and academic innovation.Opportunities still exist – in our companyat least, we’re still committedto neuroscience.We’re definitely moving towardsan era of ‘precision medicine’, with newopportunities being provided by greaterunderstanding of the impact of geneticbackground. For ion channel-basedtherapies, a better understanding ofgenetic variability may allow us to developmore precise drugs tailored to the cause ofyour pain or your epilepsy.Use of stem cells is also opening upnew opportunities. We can use iPS cells[induced pluripotent stem cells] and EScells [embryonic stem cells] and turn theminto sensory neurons for studies of pain.We can look at how well drugs work indifferentiated cells – we’ve found themvery useful. A European repository is nowbeing set up, through the EU InnovativeMedicines Initiative.Access to tissue has always madeit exceptionally difficult to work inneuroscience. Now we have better accessto cells that more closely recapitulate thebiology that drives a patient’s phenotype.”Ruth McKernan is Chief Scientific Officer of Pfizer’sNeusentis Unit in Cambridge.Richard Morris is Professor of Neuroscience at the Universityof Edinburgh.12 BNA Bulletin Spring 2013www.bna.org.uk

AnalysisGeraint Rees Jenni Harvey Russell FosterInside interactingminds…“There’s been growing interest in socialcognitive neuroscience, and that’s goingto continue. We’ve traditionally studiedpeople in isolation, prodded and probedthem in the lab, but of course that’s nothow we live our lives. We’re constantlysocially interacting. So what are the brainmechanisms and adaptations responsiblefor our social abilities?What’s particularly exciting is thatthese traits are, if not unique to humans,certainly special to humans. Why do wehave such strong social networks, andfriendships with people who we’re notgenetically related to? Why is it onlyhumans have LinkedIn and Facebook? It’snot just because other species don’t havecomputers – it says something profoundabout our nature.It also gets to the heart of some reallyimportant questions. Why do we live incities? How do we make (or lose) friends?Why do we end up lonely without them?We also need to know more aboutwhat happens when two brains interact.That’s technically challenging but withmore portable technologies we canmonitor brain activity while peopleinteract in, say, economic games. Thisbrings us much closer to everyday humanactivities, and ultimately that’s what I’minterested in.”Geraint Rees is Director of the UCL Institute of CognitiveNeuroscience.Light at the endof the tunnel…“It’s a dynamic and interesting time inmy area of research, cognitive decline inold age. With an ageing population, this isgoing to be a growing problem. Everyoneis soon going to know someone withAlzheimer’s disease and overallit’s going to pose a huge burden onhealthcare services.There aren’t enough agents to treatpeople, but there are encouraging signs ofprogress. It’s proving possible to identifyearly brain changes which may lead toearlier diagnosis. A better understandingof the genetics of disease should enableus to identify people more likely to benefitfrom drugs.There are still too many possibletreatments that look promising inlaboratory studies but do not proveeffective in humans. Hopefully a betterunderstanding of disease mechanismsmay improve the translation process.”Jenni Harvey is a Senior Lecturer in the Division ofNeuroscience, University of Dundee, and a member of theBNA National Committee.“We’re sitting on discoveriesthat have the potential tomake all kinds of changes.We shouldn’t be frightenedof those opportunities.”The future isinterdisciplinary…“One of the exciting things now is theability to work across multiple levels ofanalysis, all the way from patterns ofgene expression to behaviour, then clinicaltranslation. Increasingly this means thatas a researcher you have to ‘de-silo’.There’s been incredible technologicaldevelopment we can draw upon –cellular imaging, brain imaging, RNAiknockdown, optogenetics, reporting frommultiple neurons in freely living animalssimultaneously to address specific setsof questions. That’s both an excitementand a barrier. How do you actually organiselarge multidisciplinary teams?One of the problems is that the REF[Research Excellence Framework] isnot a good way of acknowledging thealmost equal input of multiple individualsaddressing a particular biological question.The physicists have done it – all the peopleon CERN are just listed alphabetically. Inour discipline we haven’t got that right.But in biomedicine the REF only gives fullcredit to first and last authors. That’s areal problem.”Russell Foster is Professor of Circadian Neuroscience andHead of the Department of Ophthalmology at the Universityof Oxford, a Fellow of the Royal Society and President-Electof the BNA.Have your say...Agree? Disagree? What else shouldwe neuroscientists be thinking about?Let us know your thoughts for inclusionin future issues of the BNA Bulletin –email office@bna.org.ukwww.bna.org.ukSpring 2013 BNA Bulletin 13

AnalysisWonderful lifeIn partnership with the Wellcome Trust, the Barbican is hosting anexciting programme of public events in association with the BNA’sFestival of Neuroscience.The mysteries of the human brain formthe focus of a major partnership betweenthe Barbican and the Wellcome Trustthis spring. Through March and April2013, ‘Wonder: Art and science on thebrain’ will feature thought-provoking andimaginative talks, shows, performancesand other entertainments to inspire andenthuse, including a special ‘Street Fair’at BNA2013: Festival of Neuroscience.‘Headline acts’ include Marcus duSautoy, Simonyi Professor for the PublicUnderstanding of Science and Professorof Mathematics at the University ofOxford, who on 2 March 2013 will leadingan audiovisual extravaganza exploringconsciousness. As well as leading figuresfrom the world of neuroscience, theevening will also feature a speciallycommissioned soundtrack from electronicmusic artist and DJ James Holden, whilevisuals have been provided by theSoho-based studio One of Us.On 8 April 2013, comedian andactress Ruby Wax will talk about herdecision to return to education to studyneuroscience, and the impact it has hadon her perceptions of her mental healthproblems. Alongside her successful workin television and theatre, Ruby’s shows‘Losing It’ and ‘Out of Her Mind’ havedrawn upon her experience of depressionand mental illness.The Barbican will also be hostingits version of the ‘Packed Lunch’ talkspopularised by Wellcome Collection.Lunchtime talks and discussion will covereverything from body clocks to howworking in the City affects the brain (andvice versa). There will also be opportunitiesRuby Wax.to join Robert Kingham on a walkingtour through ‘The Grey Soul of London’.Finsbury, adjacent to the Barbican, wasa fascination of writer Arthur Machen(1863–1947) – ‘a district both devious andNC3RsWellcome ImagesThe location of functions in the human brain according to the principles of phrenology.14 BNA Bulletin Spring 2013www.bna.org.uk

Analysis“The Street Fair will bringto life the very latest inneuroscience researchand some of the creativeinterpretations inspiredby it.”Gayle Chong Kwan, ‘Memory Trace’, 2012.obscure’. The tour will explore some ofthe most notable sites and how an urbanlandscape can have such a deep impact onthe psyche.In Wonder on Film, a programme ofmainstream and arthouse works at theBarbican will illustrate some of the waysthe human mind has been portrayed onscreen. With debates and Q&A sessions,it will also explore how film has addressedabnormalities of mind and mental illness –including a special event in which filmmakers,film theorists, psychiatrists andneuroscientists will discuss the role of filmin conveying the internal experience ofthose with psychosis.Over the weekend of 2–3 March 3012,the Brain Waves Barbican Weekenderwill feature a dynamic mix of dance,theatre, music, art and science. Theweekend will be the last chance for visitorsto experience Random International’sacclaimed ‘Rain Room’.During 4–14 April 2013, audiences willhave the chance to dress up in periodcostume and enter the world of a 19thcenturyParisian salon, as part of UntitledProjects’ ‘The Salon Project’. Guests willenjoy an evening of stimulating discussionwith leading figures from the arts,sciences, politics and technology, includingexperts in neuroscience.Each year the Barbican runs a ‘BarbicanBox’ project – an actual box filled withstimulus materials to provoke thoughtand discussion in young people. This year,www.bna.org.ukComplicité are the Barbican Box’s artisticpartners. Their box is a battered suitcase,containing clues to the life and work of amystery neuroscientist. The stimulatingtheatrical work will be enjoyed by some500 young people from schools and youthgroups across north and east London.During the Festival of Neuroscienceitself, on 7–9 April 2013, the corridors andfoyers of the Barbican will come alivewith the Wonder Street Fair. Scores ofscientists, artists and performers willbe organising a fascinating programmeof hands-on activities, performances,interactive exhibits and demonstrations.The Street Fair will bring to life the verylatest in neuroscience research and some ofthe creative interpretations inspired by it.On Tuesday 9 April, the Barbicanis hosting the final of a special ‘I’ma neuroscientist, get me out ofhere’ competition. A group of braveneuroscientists will attempt to answerquestions from the floor, to win theultimate accolade and a donation to thecharity of their choice.The Wellcome Trust has also produceda special issue of its schools publication,Big Picture. ‘Inside the Brain’ examinessome of the imaging technologies beingused to explore brain function, alongsideuseful animations, teaching suggestionsand personal stories.It has also launched a new blog, ThInk(http://thinkneuroscience.wordpress.com), dedicated to the brain and thescience, art and innovation associated withit. Contributors include Doug Turnbull fromthe University of Newcastle, historianJen Wallis from Queen Mary, Universityof London, and researchers from theWellcome Trust Centre for Neuroimagingat UCL. Inspired by the Festival, the blogalso aims to encourage interdisciplinarythinking, spanning arts, sciences andthe humanities. Initial posts cover topicssuch as the neuroscience of rewards, byRobb Rutledge, a global perspective onmental health by Vikram Patel, the historyof psychiatry by Jennifer Wallis and theFestival of Neuroscience by the BNA’sChief Executive, Ian Varndell.More details of the Wonder programme can be found at:www.barbican.org.uk/wonderJoin the BNAWe’re growing fast, so why not join us?In addition to discounted journals andbooks and other occasional ‘specialoffers’, the benefits of membershipnow include reduced registration feesor free admission to BNA events,regular news updates, prizes,bursaries and more.£40 for students, £75 for full membersSee www.bna.org.uk/about/benefitsof-membership.htmlSpring 2013 BNA Bulletin 15

AnalysisNeuroscience in the courtroomIs neuroscience poised to have a major impact on UK court proceedings?The man who developed paedophilictendencies because of a brain tumour.A killer who claimed his geneticinheritance and upbringing conspiredto excuse a brutal murder. The imagingstudies suggesting that psychopathshave distinctively abnormal brains.The existence or otherwise of free will.Potentially, neuroscience would seem tobe raising multiple issues for the legalsystem – perhaps even threateningits very foundations.In the USA, Duke University’s NitaFarahany has documented rapidly growingdiscussion of neuroscientific evidence in thecourtroom. Is this trend likely to be seen inthe UK? And what impact will neurosciencehave on the foundations of law, such as theprinciple of criminal responsibility?Central to the US situation, suggestsNikolas Rose, Professor of Sociology atKing’s College London, is its use of thedeath penalty: “There are lots of defenseattorneys, especially in capital cases,where they are obliged to do everythingthey can to get their clients off or get thesentence mitigated.”Will neuroscientific evidence play a greater role inviolent crime?The extent to which neuroscience isinfiltrating UK courts is actually hard tojudge, points out Lisa Claydon, AssociateProfessor of Criminal Responsibility at theUniversity of the West of England. “Not allcases are reported, and not all the evidencethat is heard is reported.” Nevertheless, shesuggests, there is increasing reference toneuroscientific evidence in court, particularlyto establish severity of injury and withrespect to mental condition defences.Ashley Cooper, Visuals Unlimited/SPLTaking responsibilityAs well as proof of an unlawful act, thelegal system also requires that actionsbe voluntary. In extreme cases, peoplecan escape punishment if they weremanifestly not in control of their actions atthe time of a crime – as in the sad case ofBrian Thomas, who in 2008 strangled hiswife during a night terror.‘Automatism’, or complete loss ofcontrol for one’s actions, is extremely rare.A decision may be made not to prosecute,accepting that in conditions such as‘homicidal sleepwalking’ or night terrors,the perpetrators of crimes are whollyunaware of their actions.Culpability can also be abolishedby way of a plea of insanity, so itmight be expected that psychiatry andneuroscience would hold considerablesway. However, as Nigel Eastman,Emeritus Professor of Law and Ethicsin Psychiatry, points out, the impactis not as direct as might be expected.Law and science, he stresses, are quitedistinct domains, following differentsets of ‘rules’ and with different waysof operating. The two disciplines askdifferent questions in different ways.And while science can illuminate certainaspects of human behaviour, this isnot necessarily going to influence howthe legal system responds. “You mightsay there are constructs within sciencethat might reasonably be relevant tomoral constructs like responsibility orculpability but ultimately there’s not adirect translation. That is, ultimately thelaw controls what shall amount to itsown constructs, and therefore ultimatelycontrols the potential relevance ofscientific evidence to those constructs.”A striking example of this lack ofcongruity is the defence of insanity.This is very tightly defined legally, andharks back to the M’Naghten case ofthe 19th century. The defence dependson ‘a defect of reason’ resulting from‘disease of the mind’, such that eitherthe defendant ‘did not know the natureor quality of his actions’, or ‘did notknow that they were wrong’. What evenamounts to a ‘disease of the mind’,however, is determined by legal authorityrather than science or medicine. “Thelaw looks towards a justice solutionand defines its constructs accordingly.Hence it will not necessarily acknowledgescientific constructs.”Notably, the legal system also setsthe bar very high for a finding of insanity.“Many people with severe schizophreniawho kill or seriously injure people don’tsatisfy the legal criteria for insanity,”points out Professor Eastman.Nevertheless, the Law Commissionhas recognised the need to reflectmore up-to-date concepts in line withcurrent medical thinking, providingupdated guidance. It has recommendeda capacity basis for determining bothinsanity and diminished responsibility,the latter enacted in 2009. However, itis debatable whether the definitionalchanges have been fully reflected yetin significant changes in practice: “Thatwas an attempt to make the law moreresponsive to how medicine thinks, butin practice it looks as though the courtsare not as restricted by this new medicalapproach as it was predicted they mightbe, mainly by adherence to the principleof the primacy of the jury over expertevidence.”A case for mitigation?The existence of mitigating circumstancesother than ‘insanity’ ultimately led to theintroduction of ‘diminished responsibility’.Evidence may also be introduced toprovide a ‘partial defence’, to mitigatepunishments. Here, there may well bescope for input from neuroscience.Julian Savulescu, a bioethicist at theUniversity of Oxford, highlights a US casewhere legal criteria made little scientificsense. A woman from Virginia was foundguilty of murder. One thing that couldhave saved her from the death penaltywas a defence of intellectual disability.“They tested her and she had an IQ of72. The cut off for intellectual disabilityis 70. So she was said to be healthyand ‘normal’. But there’s no functional16 BNA Bulletin Spring 2013www.bna.org.uk

Analysisdifference between someone with anIQ of 69 and 72.” She was executedon the basis of an arbitrary statisticalrule. “That’s an entirely inappropriatebiological fact to ground attributions ofresponsibility. In this kind of case youneed more sophisticated functionaltests of things that are relevantto responsibility.”More generally, a growingneurobiological understanding ofbehaviour may point to situations inwhich, it could be argued, people haveless control over their actions than iscommonly assumed. “I think we’remuch less free than we believe we are,”argues Professor Savulescu. “A lot ofenvironmental, biological, psychologicalinfluences profoundly shape our choices,even apparently rational choices.”One of the most commonly citedexamples concerns the monoamineoxidase A (MAOA) system, where itis now reasonably well establishedthat inheritance of a risk allele of theMAOA gene combined with an abusiveupbringing increases the likelihood ofviolent behaviour. In Italy, this defence wassuccessfully used to mitigate a murdersentence, though the decision has provenhighly controversial.Professor Savulescu suggests that,when the science is well established, thiskind of evidence should feed into legalconsiderations: “It is reasonable to saythese people have diminished free will,”he suggests. “It’s harder with peoplewith that mutation and that relevanthistory of abuse as a child to controltheir behaviour.”Nevertheless, he also argues that thecase is less strong in other situations.“Just showing that there are differences inbrain activity in psychopaths is not enoughto say they are less responsible. I thinkyou have to tell a story about how thoseabnormalities somehow threaten whatwe take to be essential for responsibility,something like reason responsiveness. It’snot enough to show there is a structuralor physiological difference, that differencehas to be implicated in the right way.”A good example is the case of anAmerican accountant who developedpaedophilic tendencies in his 40s. Hewas later diagnosed with a tumouraffecting areas of the brain implicatedwww.bna.org.ukEvidence from brain imaging is increasingly being used in US courtrooms.in social decision making. After removalof the tumour, his behaviour returned tonormal. Later, his paedophilic behaviourre-emerged – and his tumour was foundto have recurred. After further surgery,his behaviour again returned to normal.In this case, therefore, the evidence wassufficiently strong that the tumour wasresponsible for the errant behaviour.But in most cases, the evidencefor causality is weaker. Professor Rosehighlights a notable case from the 1970s,in which it was argued that premenstrualsyndrome was a justifiable defence forwomen. The case went all the way to theHouse of Lords before being rejected.“What the courts argued there was that inrelation to an individual, probabilities arenot enough.”The case, he suggests, illustrates ageneral principle; “What you have to showis a causal pathway that shows that this“The law will look towardsa justice solution andwill define its constructsaccordingly. It will not,in any automatic sense,acknowledge scientificconstructs.”SPLSpring 2013 BNA Bulletin 17

Analysisparticular individual in this circumstancehas been affected by this medicalcondition. With the best will in the world,all the evidence from neuroscience andneuroimaging is highly probabilistic, it’snot deterministic.”This distinction is further emphasisedby Professor Eastman. In 2012, he wascalled up to assess Kiaran Stapleton,charged with the brutal murder of Indianstudent Anuj Bidve in Salford. In givingevidence, according to Professor Eastman,Stapleton displayed ‘psychopathy’, andacknowledged that there is researchevidence that psychopathic traits can beassociated with abnormal brain imagesand function. However, he adds, “Theneuropsychologist I gave evidence withdescribed the differences in brain scansof people who are psychopaths but thenquite properly she acknowledged that thishas been observed across populationsof such individuals, by comparison with‘non-psychopaths’: it doesn’t tell youanything about Mr Stapleton. Even ifbrain imaging information had beenapplied to Stapleton, it would have beenimpossible to establish a causal linkbetween any such brain abnormality andhis actions. We couldn’t know in himwhether any abnormality was relevantto his behaviour.” (Stapleton admitted tomanslaughter on grounds of diminishedresponsibility but was found guiltyof murder.)The bar is thus very high, so willneuroscientific findings ever have anyimpact in court? “I see no reason why theyshouldn’t,” concludes Professor Rose,“but I don’t think they are going to havethe knockdown effect some people say– the idea that this does away with theconcept of responsibility, ‘my brain mademe do it’.”Indeed, Nicholas Mackintosh, who leda Royal Society working group examiningneuroscience and the law, highlights afurther issue with this line of reasoning:“Genetic and neuroscience evidencemay at some point come to be seen asproviding extenuating circumstances.But the other side of the law has to beconcerned with protecting the public.And if those extenuating circumstancesmake it more likely that that personwill offend again, then it doesn’t seemplausible to suppose that’s going toresult in a reduced sentence – quitethe reverse.”So genetic or neuroscientific evidencemay be more important in decisionsabout the release of prisoners servingindeterminate sentences or due forparole, where judgements have to bemade about their likely danger to thepublic. “How do you decide whethersomeone is at risk of committing furthercrimes?” asks Professor Mackintosh.“The answer is, you don’t do it veryaccurately. Risk assessment is a veryinexact science. Any information thatmight be relevant to risk assessmentseems worth thinking about.”Although less likely to grab headlines,neuroscientific research may have greaterlong-term value in helping to minimisethe risks of offending or re-offending.The plasticity of the brain raises hopesthat interventions might be able toaddress the neurobiological abnormalitiescharacteristic of, say, psychopathyand therefore influence behaviour.Similarly, children showing ‘callous andunemotional traits’, the forerunner ofpsychopathy, may benefit from intensiveparenting interventions to develop theiremotional and behavioural skills.Free to act?What of the more general contentionthat neuroscience will whittle away atthe principle that we are all responsiblefor our actions? The existence ofcharacteristic neural activity beforeconscious awareness of decisions raisesquestions about the reality of consciouschoice. Some go so far as to argue thata deterministic universe cannot allow fora choice of possible future outcomes,however much we may feel as if we arein charge of our destiny.It is a vexed issue, however, andunlikely to be resolved anytime soon.The notion of free will is a philosophicalquestion, points out ProfessorMackintosh: “It’s not obvious to me thatneuroscience has a great deal to say aboutthis (though I’m sure some neuroscientistswould disagree very strongly!).”But even if some neuroscientistsmight beg to differ, Professor Eastman’scontention that law and science are likeoil and water would still apply. “You’d getinto a debate the law probably wouldn’tHow responsible are people for their criminal actions?want to have,” says Dr Claydon from thelegal perspective. Professor Rose pointsto the stance taken by the US academicStephen Morse: “Legal systems tend towork with a ‘folk conception’ of humanpsychology, which is that by and large,except if there are very special mitigatingcircumstances, adult human beingsintend the acts they undertake and aretherefore culpable for the consequencesof those actions.”So notions of free will ultimately havelittle direct relevance to law. Indeed, notesDr Claydon drily, “You don’t often seementions of free will in court.” ProfessorEastman agrees: “The law has to adopt apragmatic approach to questions that areultimately deeply philosophical.”And Professor Savulescu suggeststhat, whatever the reality, the approachtaken by the legal system has its widerbenefits: “It’s maybe a myth but it’s amyth we want to hold on to, because wewant to have the illusion of control andthe possibility of doing things withour lives.”Claydon L. Law, neuroscience, and criminal culpability. In:Freeman M, ed. Law and Neuroscience. 2011, pp. 141–169.Oxford: Oxford University Press.Royal Society. Neuroscience and the Law (Brain WavesModule 4). 2011. London: Royal Society.Eastman N, Campbell C. Neuroscience and legaldetermination of criminal responsibility. Nature Rev Neurosci.2006;7(4):311–8.Festival of NeuroscienceWednesday 10 April 2013 p.m. Neuroscienceand society: Opportunities, challenges and policy(with Nicholas Mackintosh)George Steinmetz/SPL18 BNA Bulletin Spring 2013www.bna.org.uk

AnalysisStem cell therapy: Will it work?Stem cells are among the past decade’s most exciting area of medical science. Notwithstanding thehype, how likely are they to benefit patients with neurodegenerative conditions?There is a temptation to imbue stemcells with quasi-miraculous powers. Withtheir remarkable capacity to generatenew cells, they have obvious promisein regenerative medicine. But can theyrepair the neural damage associated withneurodegenerative conditions such asParkinson’s disease, Alzheimer’s diseaseand Huntington’s disease?Roberta CagnettaParkinson’s disease:Early promiseIn the early 1980s, a notable series ofstudies showed that fetal brain cellstransplanted into experimental animalmodels of Parkinson’s disease couldsurvive, develop and function in vivo and,crucially, they could ameliorate motorand cognitive deficits. On the basis ofthis work, researchers in Scandinavia andelsewhere moved to human trials withtissue sourced from aborted fetuses.The results, says Roger Barker atthe Cambridge Centre for Brain Repair,were encouraging: “When it worked, itworked very well, although it didn’t workin everybody, but nevertheless therewas every belief that this was a therapydefinitely worth pursuing.”Hopes were therefore high for tworandomised controlled trials, funded bythe US National Institutes of Health.However, the results, published in 2001and 2003, were disappointing, saysProfessor Barker: “Essentially both ofthe studies said it didn’t work.” Andsignificantly, a number of patientsdeveloped involuntary movements(graft-induced dyskinesias).“Based on that, a moratorium came intoplace, with something of a schism acrossthe Atlantic,” suggests Professor Barker.The US research community was generallysceptical that the approach could work. InEurope, there was a feeling that the failureof the controlled trials reflected particularaspects of trial design, including selectionof patients, the way in which the tissuewas prepared and transplanted, and theimmunosuppression used to block rejection.“On that background we put forwardwww.bna.org.ukNeurons derived from cultured stem cells.a new proposal to the European Unionsaying let’s go back to fetal transplanttaking into account all these factors.”This new initiative, TRANSEURO, spanning14 institutions across five countries, ishoping to graft its first patients earlyin 2013.Even so, Professor Barker recognisesthat, given the practical and ethicaldifficulties associated with its use, fetaltissue is unlikely to be a long-term solution:“This trial is a stepping stone to the nextgeneration of cell-based therapies”.A possible clue to the identity of thesenext generation cells may come from anew project being led by Tilo Kunath inEdinburgh, which Professor Barker is alsocontributing to. The project is aiming toidentify the best way to use embryonicstem (ES) cells for Parkinson’s diseasecell therapy.Central to the project, says Dr Kunath,has been the pioneering work of LorenzStuder in New York. His group hasdeveloped new methods for generatingdopaminergic neurons from ES cells,achieving unprecedented improvementsin experimental studies – “an order ofmagnitude better than previous methods,”says Dr Kunath. “Transplantation rescuein rodents was fantastic. No one had seenrescue of Parkinsonian phenotypes likethis before.”With funding from what is now theMRC’s Regenerative Medicine ResearchCommittee, Dr Kunath is leading anationwide initiative to apply ProfessorStuder’s new methods to a range of ES celllines: “The UK has a massive advantageover the US. The MRC has invested alot in making GMP-grade human EScell lines – there are about 15 alreadyestablished in the UK in different cities.”By systematically testing each of theselines, Dr Kunath aims to identify whichwould be most suitable to go forward toclinical trials, building on the experience ofthe TRANSEURO trial. Professor StuderSpring 2013 BNA Bulletin 19

Analysisis also part of the collaboration, so theUK cells might also ultimately be used inUS trials.ES cells come with some ethicalbaggage, so there is also interest in usingadult stem cells, such as mesenchymalstem cells. Although easier to obtainand available as a treatment in somecountries, they have shown few effectsin animal studies and Professor Barkeris sceptical of their value: “While they’reoffered around the globe for treatmentof Parkinson’s disease, the evidence thatthey will do anything substantial to yourdisease is pretty minimal.”iPS cells: a new routeto therapy?Another option might be ‘inducedpluripotent stem (iPS) cells’ – adultcells reprogrammed into a pluripotentprecursor state, which can then be used togenerate replacement neural cells. “Thatmay become a possibility,” acknowledgesProfessor Barker, but he highlights anobvious drawback. “The idea that you usethe patient’s own cells, while intuitivelyattractive, has problems, as the patienthas the disease. So if you make dopaminecells from the patient’s skin, what’s tostop them going the same way as thepatient’s own nigral dopamine cells?”Perhaps more significantly, iPS cellsare offering exciting new opportunitiesto study mechanisms of disease. Backin Edinburgh, Dr Kunath’s group hasmade an important step forward bygenerating iPS cells from a family in Iowawith a rare inherited form of Parkinson’sdisease, caused by triplication of theα-synuclein gene. As a result, affectedfamily members develop a severe earlyonsetform of Parkinson’s disease: “Allthe pathology is very similar to sporadicParkinson’s,” says Dr Kunath, “it’s justsped up.”The severity of the condition increasedthe likelihood that a phenotype wouldbe apparent in cultured cells, while theinvolvement of α-synuclein maintained thelink to the common form of the disease:“Everyone with sporadic Parkinson’s has aproblem with this protein.”Work on these cells has shown thatthey do indeed contain much moreα-synuclein in striatal cells. Since thefamily’s mutation actually spans multiplegenes, Dr Kunath has also developedES cells with an engineered α-synucleintriplication for use as an additionalexperimental system.Labelling in fibroblasts for DNA (left panel) and two fibroblast proteins (centre panels), merged in final panel.As well as providing a valuable toolfor investigating pathological changesin manageable timescales, the systemcan also be used to screen for drugs thatmight interfere with disease processes.Reactive oxygen species have beenimplicated in Parkinson’s pathology, andalthough trials with antioxidants suchas coenzyme Q have been disappointing,Dr Kunath believes that new agentsmay show more success: “We havea very interesting, potent compoundthat targets the mitochondria. Whenwe compare it with every commercialantioxidant that we can find, this novelone is much much better.” He is nowcollaborating with Manfred Auer inEdinburgh’s Chemistry Department todevelop a high-throughput screeningplatform to test a library of compoundscustom-designed by Professor Auer.Beyond Parkinson’sParkinson’s disease has been in thevanguard of cell-based therapies, butwhat about other neurodegenerativeconditions? Huntington’s disease hasfollowed a similar path to Parkinson’s butis, suggests Professor Barker, “severalsteps behind”. Similarly positive animalstudies led to open label clinical trials inFrance, the USA and the UK (carried outby Professor Anne Rosser and ProfessorSteve Dunnett, both of whom movedto Cardiff in 2000, Professor Barker anda team in London). Although one of hispatients has done “fabulously well”,overall the clinical results have beendecidedly mixed.French researchers were sufficientlyencouraged to begin a 60-patient trial, butgenerally prospects may be less bright:“The emerging picture is that the striatalpathology of Huntington’s disease is partof a much greater distributed network ofpathology. Simply trying to repair one partof it isn’t really going to work.”A similar picture may hold true ofthe most common neurodegenerativecondition, Alzheimer’s disease. “Thetrouble with AD is it’s hard to know whatyou want to target,” points outProfessor Barker.One option might be cholinergicneurons, the target of existing drugtherapies, but such cells are innervatingcortical areas that are themselvesatrophying. “That’s finger in the dyke stuff,”says Rick Livesey at the Gurdon Institutein Cambridge. “You’re losing so much realestate over so much of your brain.”Again, however, iPS cells aregenerating valuable information aboutdisease processes. Dr Livesey hasdeveloped highly efficient methodsto generate cortical neurons from iPScells. Notably, the recipe generates celltypes from all cortical layers, as well asastrocytes, and they organise themselvesinto rudimentary networks. “We replaycortical development in a dish,” says DrLivesey. “That gives us another level ofinsight into how networks form, how theyfunction, and how they go wrong.”His lab generates iPS cells frompatients with various forms of dementia,including Alzheimer’s disease butalso less common conditions such asfrontotemporal dementia. Inheritedforms of disease are again important.Notably, Professor Livesey’s group hasgenerated iPS cells from Down syndromepatients. Their cells carry an additionalcopy of chromosome 21, which carriesthe gene for amyloid precursor protein,the source of β-amyloid. Cortical neuronsgenerated from these cells show markedAlzheimer’s-like features, includingsubstantial β-amyloid accumulation: “It’snot subtle, it’s not like 10 per cent – it’sfivefold more, tenfold more.”Selina Wray20 BNA Bulletin Spring 2013www.bna.org.uk

AnalysisThis contrasts markedly with animalmodels of Alzheimer’s disease. Mice areoddly refractory to Alzheimer’s – theclosest models rely on expression ofmutant forms of three proteins implicatedin the condition. “You have to push themreally hard,” says Dr Livesey. “Someonedescribed the mouse model as having anamyloid hand grenade going off in thebrain.” Even then the animals do not showthe full range of pathological featurestypical of the human disease.As well as looking at diseasemechanisms, Dr Livesey’s lab is alsogathering information about drugaction. As part of the EU InnovativeMedicines Initiative, a large public–privatepartnership, his lab is testing models ofAlzheimer’s disease with industry partners.With MRC funding, his lab is alsoexamining the impact of drugs withknown mechanisms of action. “Theidea being, can we identify new ways tochange the biology of disease using drugsthat hit known targets.” And as well assmall-chemical agents, he also hopes tolook at biological interventions, such asmonoclonal antibodies. An emerging ideais that one of the proteins implicatedin Alzheimer’s, tau, may play a rolein transferring disease between cells.Potentially, antibodies against tau mightprevent this intercellular transmissionof disease.Coping with Alzheimer’s disease.Selina Wray, who works on iPS cellsin John Hardy’s lab at UCL, agrees thatstem cell therapy for Alzheimer’s diseaseis a long shot. Some speculative animalmodel studies have obtained positiveresults, but probably because transplantedcells developed into astrocytes, whichprovided support for the degeneratingcortical neurons. “Those studies are stillpromising as it suggests that you couldlook for whatever factors the astrocyteswww.bna.org.ukUrsula Markus/SPLwere producing that are beneficial anduse those as therapy, but a neuronalreplacement therapy would be really toughfor Alzheimer’s.”Dr Wray has begun to work with DrKunath and Professor Livesey to studyan enigmatic gene, C9ORF72, mutationsin which have been implicated in bothfrontotemporal dementia and amyotrophiclateral sclerosis (a form of motor neurondisease). By generating iPS cells and thenturning them into either cortical cells ormotor neurons, she hopes to gain betterunderstanding of disease processes in thetwo situations.With Professor Hardy, she is also leadingan international initiative to accelerateresearch on iPS cells from patients withinherited forms of disease. Access tosuitable material is often an issue, soProfessor Hardy and other labs havedeveloped fibroblast patient cell lines whichare made available through the NationalInstitute for Neurological Disorders andStroke cell line repository held by the CoriellInstitute for Medical Research.ProspectsMuch as everyone might hope for amiracle cure, cell-based therapies forneurodegenerative conditions may yet besome way off. And even in the promisingcase, Parkinson’s disease, demonstrationsof efficacy may not be the final word,says Professor Barker: “If I’m honest thebig challenge for the field is not whetherit works, because I think it probably willwork, based on the fetal tissue. Thequestion is whether it works better andis competitive against conventionaldopamine therapies.”Potentially, cell therapy could formpart of a suite of treatment options, forselected patients early in disease. In thelonger term, though, it may be as tools tounderstand disease processes and screendrugs that stem cells have their biggestimpact on neurodegenerative disease.Devine MJ et al. Parkinson’s disease induced pluripotentstem cells with triplication of the α-synuclein locus. NatureCommun. 2011;2:440.Shi Y et al. A human stem cell model of early Alzheimer’sdisease pathology in Down syndrome. Sci Transl Med.2012;4(124):124ra29.Wray S et al. Creation of an open-access, mutation-definedfibroblast resource for neurological disease research. PLoSOne. 2012;7(8):e43099.Festival of NeurosciencePlenary lecture: Stem cell therapy forParkinson’s disease: Problems and prospects(Anders Björklund)Monday 8 April 2013 p.m. Human inducedpluripotent stem cells for nervous system diseasemodelling and development of new therapeutics(with Rick Livesey and Tilo Kunath)Tuesday 9 April 2013 p.m. Stem cells astherapies for the neurosciences and tools forpharmacology and toxicologyHuman ES cells differentiated into neural precursors(green) and neurons (red).Tilo KunathSpring 2013 BNA Bulletin 21

AnalysisMemories are made of thisWill it be possible to selectively erase unwanted memories?It is an unwritten rule that any article onmemory erasure must mention EternalSunshine of the Spotless Mind, in which aheartbroken Jim Carrey and Kate Winsleterase memories of each other after abreak-up. Recent work suggests thatmemory disruption may become a reality– perhaps not to soothe a broken heartbut to treat post-traumatic stress disorder(PTSD) or prevent recovering drug addictsfrom relapsing.A key factor in this surge of interesthas been the realisation that the act ofremembering can reactivate memorytraces, after which they are re-embeddedin long-term memory, or ‘reconsolidated’.In this labile state, memories may bevulnerable to disruption.The classic experimental paradigm isto use Pavlovian conditioning to createa fear-inducing memory for a stimulus,such as the ring of a bell. If interventionseliminate the fearful response to the bell,they have been able to disrupt the fearinducingmemory.Early amnesiaSurprisingly, this idea has been around foralmost 50 years. In the late 1960s, DonaldLewis and colleagues carried out a rangeof landmark studies artificially blockingreconsolidation – a process they called‘cue-dependent amnesia’. Attempts wereeven made to exploit this phenomenonclinically, with electroconvulsive shocksbeing used to treat patients withobsessive compulsive disorder anddepression, with mixed results.However, there was considerableresistance to Lewis’s findings. “It wasa complete shock at the time,” saysAmy Milton who works on memoryin Barry Everitt’s lab in Cambridge.“The dogma was that when you hadacquired information and consolidated amemory, it’s immutable. You change thestructure of the brain essentially and it’sfixed. You might forget but it’s alwaysthere, you just need to retrieve it or accessit. Lewis’s observation was shocking.”“It was so heretical it was ignored,”adds Professor Everitt. About a decadeago, however, interest was reignitedwhen Karim Nader and colleagues showedthat inhibition of protein synthesis inthe amygdala, during the timeframeof reconsolidation, was sufficient toabolish fear conditioning in mice. Withreconsolidation better established andunderstood neurobiologically, the field wasmore receptive to the new findings.Again, some groups were swift totranslate the findings. Experimental proteinsynthesis inhibitors are too toxic for humanuse, but the beta-blocker propranololappears to have similar effects when givenin association with memory reactivation.Canadian researchers have describedpositive, preliminary results with PTSDpatients, gathering much media attention,but full details and long-term follow up ofthese studies have yet to be published.Extinction versus disruptionMeanwhile, the psychology field has beentaking a different tack, pursuing the ideaof exposure therapy or extinction. Theidea is that on repeated exposure to afear-inducing cue – a spider, say – a phobicsubject comes to learn that they areharmless. This is rather different, pointsout Professor Everitt: “You learn a newassociation, that spiders aren’t nasty ordangerous. You don’t unlearn theoriginal one.”He also points out problems withexposure therapy as a treatment: “It haslimitations.” Relapse is a big problem,especially because the effect is so contextspecific.“So if you bring someone into theclinic and extinguish a memory, when they’reback out in the outside world and comeacross the old feared object in the normalcontext, the memory is intact and the fearspontaneously reappears, or renews.”There is also the issue of underlyingmechanisms. Extinction and inhibition ofreconsolidation are clearly related to oneanother, but they are not the same –one creates a new memory, the otherseemingly erases the original one. Inpreliminary work, Professor Everitt’s teamis beginning to tease apart differencesbetween the two processes.Perhaps the best strategy, though, isto combine the two approaches. Recently,Joseph LeDoux, Elizabeth Phelps in NewYork and others have attempted toreactivate memories, to bring them into alabile state, and then ‘rewrite’ them usingextinction, eliminating the fear-inducingelements. Encouraging findings wereobtained in both rats and humans.And while anxiety disorders, PTSD andphobias are one obvious area of interest,interventions may also be able to addressdrug addiction. This area is even morechallenging – “It’s very hard to extinguisha drug memory,” says Professor Everitt.Extinction-based methods havehad limited success in treatments foralcoholism, smoking or drug addiction.Relapse is the typical problem, whenaddicts encounter drug-associatedcues when back in normal life. Similarly,associations can be extremely hard tobreak in experimental animals.Nevertheless, in 2012 a Chinesegroup reported remarkable success atapparently erasing drug memories. Usingdrug-associated cues to reactivate amemory, followed by extinction in thereconsolidation ‘window of opportunity’,they were able to achieve long-termreductions in cue-induced heroin seekingin rats. Even more startling, theyobtained similarly positive results witha group of human heroin addicts whoshowed reduced craving to the ‘superextinguished’drug cues.However, despite these encouragingfindings, Professor Everitt sounds a note ofcaution. There is a chance, he suggests, thatunder certain circumstances the ‘editing’ ofmemory may be counter-productive. “If theparameters used to enhance extinction arenot optimised or extensive enough, thereactivated memory may be strengthenedand not diminished – precisely theopposite of the intended outcome.”Such fears reinforce the need tounderstand the different mechanismsof memory modification. In his owntranslational studies, Professor Everitt andDr Milton plan to explore pharmacologicalmanipulation or reconsolidation with22 BNA Bulletin Spring 2013www.bna.org.uk

AnalysisMemory erasure has attracted considerable media attention.propranolol as a treatment for alcoholicstrying to maintain abstinence.Not so spotless mind‘Eternal Sunshine’ may therefore be ared herring. Current procedures are nottargeting the ‘episodic’ memory of particularpeople, places and events, which usesentirely different brain systems. Rather, theaim is to maintain such memories but tosever the links to distressing feelings which,in the most severe cases, can make lifealmost unbearable.The idea of memory erasure hascaptured much public interest, andprompted much discussion about its ethicalimplications. Some argue that the negativeexperiences have value to us, and we wouldbe diminished without them – a casemade most notably by the US President’sCouncil on Bioethics in 2003. While theremay be necessary debate about thepotentially trivial use of ‘anti-memory pills’www.bna.org.ukfor uncomfortable experiences, the moreimmediate goal is to help those whosedaily lives are significantly disrupted by thetraumas they have experienced in the pastand are embedded in the neurochemistryof their brains.Misanin JR, Miller RR, Lewis DJ. Retrograde amnesiaproduced by electroconvulsive shock after reactivation of aconsolidated memory trace. Science. 1968;160(3827):554–5.Nader K, Schafe GE, Le Doux JE. Fear memories requireprotein synthesis in the amygdala for reconsolidation afterretrieval. Nature. 2000;406(6797):722–6.Monfils MH, Cowansage KK, Klann E, LeDoux JE. Extinctionreconsolidationboundaries: key to persistent attenuation offear memories. Science. 2009;324(5929):951–5.Schiller D et al. Preventing the return of fear in humansusing reconsolidation update mechanisms. Nature.2010;463(7277):49–53.Xue YX et al. A memory retrieval-extinction procedureto prevent drug craving and relapse. Science.2012;336(6078):241-5.Milton AL, Everitt BJ. The psychological and neurochemicalmechanisms of drug memory reconsolidation:implications for the treatment of addiction. Eur J Neurosci.2010;31(12):2308–19.Festival of NeuroscienceWednesday 10 April a.m. Drugs and Society:The neuroethics of enhancing or erasingmemories (with Barry Everitt)Spring 2013 BNA Bulletin 23

ResearchBrain stimulation could be used to boost numerical abilities.Bright sparksCombined with the right cognitive training, mild electricalstimulation of the brain may be able to significantly enhancemathematical abilities.The idea of electrical stimulation of the brain raises deep-seated anxieties, alegacy perhaps of films such as One Flew Over the Cuckoo’s Nest. Yet, suggestsRoi Cohen Kadosh, mild electrical stimulation could be an important tool forboosting mathematical or other cognitive abilities.Dr Cohen Kadosh, a Wellcome Trust Research Career Development Fellowat the University of Oxford, has pursued an interest in how the brain handlesnumbers. Generally, numbers are indicative of quantities (though not always,as with bus routes). One key question is whether the same brain system isresponsible for both symbolic representations of numbers (such as the Arabicnumeral ‘5’ or the word ‘five’) as well as graphical representations of quantities(such as five dots, •••••, or five sheep).A discrete part of the parietal cortex has been implicated in numericalabilities, and until recently it has been generally assumed that a single systemoperates for all forms of number processing. Recently, though, Dr CohenKadosh has generated evidence suggesting that separate systems may existfor symbolic and graphical representations of quantities, mapping to a centralintegrating area. This could have important implications for education andtreatments, some of which target graphical recognition in the belief that it willalso benefit numerical skills more generally.His interest in number processing reflects a long-term aim to improvenumerical processing abilities. This could have medical benefits, for thosewith developmental conditions affecting mathematical abilities, for example,or during rehabilitation of patients after stroke or injury. In addition, hesuggests, successful techniques could be used to enhance the abilities ofnormal individuals.His chosen route to mathematical skillsenhancement is the under-exploited technologyof transcranial direct current stimulation (TDCS),whereby small electrical currents – from two AAbatteries – are applied through the scalp. Not to beconfused with transcranial magnetic stimulation(TMS), mainly used to interfere temporarily withbrain function, TDCS is designed to enhance brainactivity. It is thought to act, firstly, by lowering thepolarisation threshold of neurons, rendering themmore excitable, and secondly through a longer-termeffect on NMDA receptors and synaptic plasticity,creating a window when learning can be enhanced.It appears to be safe, generating just a mild tingleon the scalp.In a remarkable display of its powers, in 2010 DrCohen Kadosh used TDCS on normal volunteers asthey figured out the relative values assigned to aset of abstract symbols. Not only did TDCS enhancesubjects’ learning, relative to controls, but thepositive effects were still apparent six months later.In follow-up studies due to be published shortly,Dr Cohen Kadosh has demonstrated similar effectswith arithmetical calculations, again achieving longtermimprovements in cognitive function.Media attentionNot surprisingly, the initial studies garnered muchmedia interest. Equally unsurprisingly, TDCS hasalso been seen as a way to enhance bank balances,with TDCS being offered to consumers (in atleast one case, even to the parents of a child withautism). It is even possible to buy DIY kits for useat home. Dr Cohen Kadosh is at pains to stress thelimited validated data on what TDCS can actuallyachieve, in whom, and under what circumstances,as well as the need for another key ingredient –a well-designed cognitive training programme.Nevertheless, studies at Dr Cohen Kadosh’sand other labs are generating promising results.Dr Cohen Kadosh next hopes to use the techniqueon young people with numerical learningdifficulties, using a computer game set up toprovide a more engaging cognitive trainingexperience. He has also begun to raise awareness ofthe potential ethical implications of the technique,which could have substantial medical benefits butalso widespread social impact.Cohen Kadosh R et al. Notation-dependent and -independentrepresentations of numbers in the parietal lobes. Neuron. 2007;53(2):307–14.Cohen Kadosh R et al. Modulating neuronal activity producesspecific and long-lasting changes in numerical competence. Curr Biol.2010;20(22):2016–20Cohen Kadosh R et al. The neuroethics of non-invasive brain stimulation.Curr Biol. 2012;22(4):R108–11.Fox D. Neuroscience: Brain buzz. Nature. 2011;472(7342):156–8. [a featureon use of TCDS]24 BNA Bulletin Spring 2013www.bna.org.uk

Researchhas come to light. When the first wordof English word pairs was emotionallycharged and negative – such as ‘violence’or ‘injury’ – the ERP measurementsshowed no signs of subconscioustranslation into Chinese. Thus the brainsomehow seems to block the usuallyautomatic translation of potentiallydisturbing stimuli – a highly unusualexample of emotional interference withcognitive processing.EEGs have revealed subconscious translation of words in Chinese–English bilinguals, but not if the English words are threatening.Bilingual lessonsEEG-based research is uncovering some curious features of bilingualism.Sophisticated language is a uniquelyhuman skill. At Bangor University,Guillaume Thierry has been looking atpeople who have mastered two languages,revealing novel insights not just intolanguage processing but potentially othercognitive skills as well.A central question in bilingualismresearch has been the relationshipbetween processing of two differentlanguages in the brain. More specifically, ifa native English speaker is reading French,say, does the brain work entirely in Frenchor is some form of English languageprocessing happening at the same time?Several studies have suggestedthat interactions between languagesystems do occur, but it can be difficult todiscriminate between internal translationand inadvertent but direct activationof the second language. To tackle thisissue, Yan Jing Wu and Professor Thierrydeveloped a neat protocol for Chinese–English bilinguals.The basic task was to determinewhether pairs of English words wererelated to one another (e.g. post andmail, train and ham). Unbeknownstto participants, half the pairs, whenwww.bna.org.uktranslated into Chinese, shared the samesound and Chinese character (train andham translate to ‘huo che’ and ‘huo tui’).EEG was used to monitor brain activityduring the task.In terms of task performance, thehidden patterns had no impact. Yetthe event-related potentials (ERPs)recorded showed a marked shift whenthe word pairs were connected in Chinesetranslation. Notably, the shifts wereexactly as predicted if Chinese languageprocessing was taking place, and brainactivity matched that seen in monolingualChinese speakers shown the word pairsin Chinese. Similar results were obtainedusing spoken rather than written tests.Asked afterwards, none of the subjectshad noticed the hidden patterns. Yet theirunconscious brain activity revealed thatthey had been mentally translating thewords into their native language.Follow-up studies, again using pairsof English words with hidden patternsin translation, revealed that it wasconnections in sound rather than spellingthat were being subconsciously accessed.More recently, another remarkablefeature of this unconscious translationA word in WelshProfessor Thierry has also worked withWelsh–English bilingual individuals,uncovering other curious features oflanguage processing. These studies havetaken advantage of peculiarities in theWelsh language. Word order in Welsh,for example, can differ from English(adjectives follow nouns so ‘a blue car’,for example, would be written in theorder ‘a car blue’). Although the brain’sgrammatical procedures have beenconsidered independent, there does in factappear to be interference, with bilingualsmore accepting of ‘incorrect’ Englishformations when they map them onto anacceptable Welsh equivalent.A similar effect is seen with wordsounds. Unusually, the sounds of Welshwords can vary depending on their contextin a sentence. Bilinguals tolerate similarchanges to English words, even if theycreate nonsense words, as long as thechanges follow the Welsh rules.There have been concerns that learningtwo languages at the same time coulddisadvantage infants. In fact, suggestsProfessor Thierry, the reverse may be true.Bilinguals are particularly good at spottinga shift in language, and recently he hasfound that these skills spill over into othercognitive domains. Bilinguals also showenhanced abilities on non-verbal testsof congruency, possibly because they areparticularly adept at directing attentionin any condition where there is mentalinterference.Thierry G, Wu YJ. Brain potentials reveal unconscioustranslation during foreign-language comprehension. ProcNatl Acad Sci USA. 2007;104(30):12530–5.Wu YJ, Thierry G. Chinese-English bilinguals reading Englishhear Chinese. J Neurosci. 2010;30(22):7646–51.Wu YJ, Thierry G. How reading in a second language protectsyour heart. J Neurosci. 2012;32(19):6485–9.Spring 2013 BNA Bulletin 25

ResearchHow an ant gets from A to BTo understand ant navigation, it is important to take an ant’s-eye viewof the world.University of SussexFor most animals, navigation is a criticalskill, be it to find food, a mate or safety.One option is to generate internalrepresentations of the outside world, ashumans and other mammals appear to do,but what about creatures with more simplenervous systems such as insects? Workingwith ants, Paul Graham and colleagueshave identified possible alternativestrategies. The key, he suggests, is to putoneself in an ant’s shoes.Dr Graham combines laboratory workon British wood ants with field studies of adesert ant, which lives in scrubland in centralAustralia. Such animals are capable of greatfeats of navigation, travelling hundreds ofmetres during foraging while still being ableto return to the safety of a nest.In part, ants can navigate throughthe world through an innate mechanismknown as path integration. Broadlyspeaking they can track how far they havetravelled (the number of steps they havetaken) and in which direction they havetravelled (using the sun as a referencepoint). By integrating information fromeach step of their journey, ants cancalculate how to return to their startingpoint, typically their nest.Such a system is not perfect, however,and is augmented by a learnt systembased on memory of environmental cues.Put simplistically, the ant nervous systemis believed to capture visual ‘snapshots’of the environment. By comparing currentand target snapshots, an ant can workout how to adjust its direction of travel toimprove the match, orienting it towardsits destination.The key to understanding these feats,suggests Dr Graham, is to consider whatthe world looks like to an ant. Its visualsystem has low visual acuity, so cannotextract much detail, but its field of view isfar wider, approaching 360°. Its viewpointis obviously from very close to the ground.The world therefore looks verydifferent to an ant. Using sophisticatedcamera equipment and image processingsoftware, Dr Graham has generatedant’s-eye views of the environment andcan begin to determine what informationis being extracted to guide navigationaldecision-making. Landmarks, for example,though important for mammals, appearto be of little use to ants as they lackthe visual acuity to discriminate them.Factors such as the skyline and variation incontrast appear more important.Dr Graham and colleagues have usedthis information to develop models ofnavigation that have been tested inbehavioural simulations. After training, anartificial neural network based on simplerules was highly successful at navigatingthrough its environment, in ways thatshowed striking similarities to the actualbehaviours of desert ants.University of SussexBritish wood ants, with identifying marks.Differing world views of a human (top) and an ant.Exactly how visual information is storedand referenced in the ant brain remainsunclear – little is currently known about thecircuitry and physiology of the ant nervoussystem. Comparisons can be made withmodel insect systems, such as Drosophila,though fly vision is usually explored withfast-moving stimuli rather than thelargely static landscapes important to antnavigation. Nevertheless, these findings,plus those obtained with other foraginginsects such as honeybees, may reveal someof the computational processes that enableorganisms with simple nervous systems toperform such impressive feats of navigation.Harris RA, Graham P, Collett TS. Visual cues for the retrievalof landmark memories by navigating wood ants. Curr Biol.2007;17(2):93–102.Philippides A, Baddeley B, Cheng K, Graham P. How mightants use panoramic views for route navigation? J Exp Biol.2011;214(Pt 3):445–51Baddeley B, Graham P, Husbands P, Philippides A. A modelof ant route navigation driven by scene familiarity. PLoSComput Biol. 2012;8(1):e1002336.Festival of NeuroscienceSunday 7 April p.m. Visual ecology(with Paul Graham)British wood ants, Formica rufa.26 BNA Bulletin Spring 2013www.bna.org.uk

ResearchPhotosensitive retinal ganglion cells (pRGCs) labelled with antibodies against the photopigment melanopsin. The pRGCs form a ‘photosensitive net’ for light detection.Seeing the lightAn early fascination with the ‘third eye’ of lampreys has led to new insights into thelinks between sleep and mental health.Russell Fosterwww.bna.org.ukHow light affects the body’s circadian rhythms hasbeen of long-standing interest to Russell Foster.From early work on light detection in amphibiansand birds, he has been on an extraordinaryintellectual and career journey making startlingdiscoveries, overturning dogma and findingunexpected medical applications.The journey began in an undergraduate courseat Bristol. “I was reading JZ Young’s Life of theVertebrates, a classic zoology tome,” ProfessorFoster recalls. “I was reading the stuff all aboutlampreys and the fact that they have these pinealphotoreceptors, a ‘third eye’. I just thought this wasso extraordinary.” Keen to explore further, in hisundergraduate project with Alan Roberts he studiedthe pineal photoreceptors of Xenopus embryos,which led to his first published paper.The flame of curiosity had been lit. For his PhD,Professor Foster turned his attention to birds. “Weknew right back from the 1930s that a duck with noeyes could still detect long day lengths and use daylengthinformation to regulate its seasonal biology.”The duck, like all birds, has a light-detectingsystem in its hypothalamus, which becameProfessor Foster’s main focus. “When you firsttalk about the brain photoreceptors of birdspeople think you are crazy, not least because theassumption is that no light gets into the brain. Buthuge amounts of light pass through nervous tissue.It’s scattered and filtered and so useless for imagedetection but ideal for assessing how much overalllight there is in the environment – and hence timeof day”.In the mid-1980s, he ventured to Germany tolearn new immunocytochemical techniques. Avisitor from Virginia in 1987 led to the offer of athree-month stay at the University of Virginia, andthen a longer-term position.At this point, his switched attention tomammals, and how they were able to detectlight–dark cycles to regulate their 24-hourbody clock. “Mammals are very different fromall other vertebrates. Because of their uniqueevolutionary history – all mammals are descendedfrom nocturnal ancestors – they have lost deepbrain and pineal photoreceptors and only havephotoreceptors within the eye. And when westarted, the only known photoreceptors of theeye were the rods and cones, so we used a wholerange of retinal mutant mice, which had appallingSpring 2013 BNA Bulletin 27

Researchspectrum at a wavelength of 480 nm. Moreover,Professor Foster was able to show that thesephotosensitive retinal ganglion cells are not just‘circadian photoreceptors’ but regulate a wholerange of brightness-detection tasks ranging fromsleep to pupil constriction.“The logicwas ‘oh forgoodness sakeFoster, we’rebeen studyingthe eye for 150years – areyou seriouslytelling uswe’ve missed anentire class ofphotoreceptor?”Paired suprachiasmatic nuclei, which contain the master circadianpacemaker in mammals.loss of their rods and cones. Yet the response ofthe circadian system was perfectly intact.”These surprising findings led him to suggestthat there must be another kind of photoreceptor inthe eye, distinct from the familiar rods and cones.“Of course, when you propose that to the visioncommunity it goes down very very badly. I hadsomeone stand up in a seminar and say ‘bullshit’and walk out.”Ophthalmologists were less than impressed:“The logic was ‘oh for goodness sake Foster, we’rebeen studying the eye for 150 years – are youseriously telling us we’ve missed an entire class ofphotoreceptor?’”For Professor Foster, with his background inalternative light-detecting systems in amphibiaand birds, the idea was much less far-fetched.Nevertheless, perhaps the tiny number of residualrods and cones in his mice could be enough toinfluence circadian rhythms. Returning to the lab,he crossed transgenic and mutant strains of mice,generating animals with absolutely no rods andcones. The results were unequivocal: the animalsshowed entirely normal circadian rhythms. “Therehad to be another photoreceptor system.”At this point, fish made a major contribution.“What was exciting was the parallel work on fishwhere we’d discovered a photoreceptor gene calledVA opsin, vertebrate ancient opsin, and this genewasn’t located in rods and cones but was actuallylocated in horizontal retinal ganglion cells.” Thedemonstration that fish had a third photoreceptor inthe eye made the concept in mammals less radical.“That was important as we were still getting a hellof a lot of stick from the vision community and,rather importantly, the funding bodies too!”With colleagues at Imperial College, ProfessorFoster turned his attention to retinal ganglioncells. In a burst of discovery, he and a range ofcollaborators showed that retinal ganglion cellsresponded to light directly, thanks to the presenceof a newly discovered pigment, melanopsin,maximally responsive to light in the blue part of theHuman responsesSo much for fish, birds and mice: what abouthumans? An unusual female patient soonanswered the question. Despite having no rodsand cones, and no conscious light detection, shecould still regulate her body clock and showed pupilconstriction. “Critically these responses were notpeaking where the visual responses would peak butwhere the melanopsin system peaks, at 480 nm.So that all slotted in beautifully.”The discovery has had important practicalimplications. Visually impaired patients mayretain the ability to reset their body clocks, soneed to be advised to maintain contact withlight. And although eyes are easily damaged orinfected, replacing them with prosthetics could robpeople of the ability to regulate their body clocks.“Unwittingly you may be plunging somebody intounremitting jet lag for the rest of their life.”In Oxford, Professor Foster now heads theDepartment of Ophthalmology, and works withclinicians on the impact of blindness and eyedamage on circadian rhythms, particularly sleep.The practical importance of his work led theBiotechnology and Biological Sciences ResearchCouncil to recognise Professor Foster as its SocialInnovator of the Year in 2012.His work has led him into other areas of clinicalimportance, particularly mental health. Thanks toa chance encounter with a psychiatrist in a lift, hediscovered that the sleep problems of patients withmental illness were generally supposed to be downto their chaotic lives. “That just didn’t make senseto me. That’s not how circadian systems work.”Teaming up with Katharina Wulff, he setabout monitoring the daily rhythms of patients.“The data that emerged showed that patientswith schizophrenia had appalling, just awfulsleep–wake rhythms.”The general consensus was that disruptedsleep was down to antipsychotic medication, or aconsequence of stress. Professor Foster suggestedan alternative idea – that sleep and circadiansystems draw on such fundamental neural systemsthat any abnormalities predisposing to schizophreniawould almost certainly also affect sleep. Rather thanone causing the other, both mental health and sleepabnormalities might have a common origin.One prediction of this model was that sleepdisruption would be seen before any overt signs of28 BNA Bulletin Spring 2013www.bna.org.uk

Research“By God do thosemice have anappallingsleep–wakepattern – justlike people.”mental illness. Sure enough, in unpublished workwith psychiatrist Guy Goodwin, Professor Foster hasfound that young adults at risk of bipolar disordershow markedly abnormal sleep patterns before anysigns of psychological illness. Conversely, stabilisationof sleep might be beneficial to mental health – andindeed preliminary evidence suggests it is.Work on a mutant mouse had provided furthersupportive evidence. The blind-drunk (Bdr) mousestrain has a mutated form of a synaptosomalprotein, Snap-25, the human form of which hasbeen implicated in susceptibility to schizophrenia.Bdr mice also show schizophrenia-like traits whichcan be reversed by treatment with antipsychoticdrugs. Critically, they also show severely disruptedcircadian behaviours: “By God do those mice havean appalling sleep–wake pattern – just like people.”A further feature of these mice excitesProfessor Foster: “What I find extraordinary isthat here is a group of mice, some of whom arelittermates living in a very similar environment,yet you get a real range of phenotypes. So therecould well be plasticity in this system, and subtleenvironmental influences could have a big effect onthe expression of the abnormal phenotype.”Therapeutic application is an important strandof Professor Foster’s new Sleep and CircadianNeuroscience Institute, funded through a StrategicAward from the Wellcome Trust. It aims to developa better understanding of the mechanisms ofsleep and circadian rhythms, how they go awry inconditions such as ageing and neurodegenerativedisease, and the impact of today’s ‘24/7’ society.Outreach and engagement will be a further importantaim, as awareness of sleep and mental health is lowamong both professionals and the public.In such uncharted territory, exactly how light, theeye and the brain interact to influence mental healthremains to be identified. But, concludes ProfessorFoster, “At least we’ve got a framework to think aboutthose sorts of things which we’ve never had before.”Soni BG et al. Novel retinal photoreceptors. Nature. 1998;394(6688):27–8.Freedman MS et al. Regulation of mammalian circadian behavior by nonrod,non-cone, ocular photoreceptors. Science. 1999;284(5413):502–4.Lucas RJ et al. Regulation of the mammalian pineal by non-rod, non-cone,ocular photoreceptors. Science. 1999;284(5413):505–7.Hattar S et al. Melanopsin and rod-cone photoreceptive systemsaccount for all major accessory visual functions in mice. Nature.2003;424(6944):76–81.Lupi D et al. The acute light-induction of sleep is mediated by OPN4-based photoreception. Nature Neurosci. 2008;11(9):1068–73.Wulff K et al. Sleep and circadian rhythm disruption in psychiatric andneurodegenerative disease. Nature Rev Neurosci. 2010;11(8):589–99.Wulff K et al. Sleep and circadian rhythm disruption in schizophrenia. Br JPsychiatry. 2012;200(4):308–16.Oliver PL et al. Disrupted circadian rhythms in a mouse model ofschizophrenia. Curr Biol. 2012;22(4):314–9.Lockley SW, Foster RG Sleep: A very short introduction. 2012. Oxford:Oxford University Press, UK.The blind mole rat, Spalax ehrenbergi.GoingundergroundAn evolutionary curiosity, the blind molerat, provided important insight intomammalian light detection.Professor Foster’s research has been stronglyinfluenced by a comparative approach. He and hisgroup have studied light responses in a whole hostof different animals, each of which has provided apiece of the overall jigsaw. Perhaps none of theseanimals, though, is as strange as the blind molerat (Spalax ehrenbergi).A native of the Middle East, blind mole rats areentirely subterranean, and have lived undergroundfor some 30 million years. During this time, theyhave gradually lost their ability to see and are nowentirely blind.However, S. ehrenbergi does retain tiny eyes,just half a millimeter in diameter, covered by alayer of skin. And, remarkably, these structuresenable it to maintain its circadian rhythms. “It stilluses these tiny vestigial eyes for regulation ofthe body clock,” says Professor Foster. “That wasincredibly helpful for informing our understandingof visual versus nonvisual systems. It’s twoparallel systems.”What remains a mystery, however, is why ananimal that spends most of its life in undergroundtunnels has retained the ability to use light to setits body clock.David-Gray ZK et al. Light detection in a ‘blind’ mammal. NatureNeurosci. 1998;1(8):655–6.Bassem18www.bna.org.ukSpring 2013 BNA Bulletin 29

ResearchStress the positiveStress can be beneficial, in moderation. A better understanding of thereasons why – and of the critical role played by the epigenetic controlof gene expression – could ultimately help those with stress-linkedconditions such as major depression.Hans Reul“…for 40–50years we’veknown thatsecretion ofthese hormonesis importantfor adaptationbut we’ve neverreally knownhow they areacting.”A little bit of stress is good for us. Psychologically, itmay focus our minds on the task in hand. From anevolutionary perspective, it can prepare us to dealbetter with similarly challenging situations in thefuture. But not everyone can deal with stress, andpersistent stress is highly damaging. By examininghow stressful experiences impact on the brain,Hans Reul at the University of Bristol hopes togenerate insight to underpin better therapies forpsychopathologies, such as anxiety and depression,arising from abnormal stress responses.His main focus is the hippocampus, whichplays a critical role in the formation of memories ofstressful and other significant events in people’slives. “Everyone has childhood memories that arevery strong, certainly of adverse events. As a childI used to be extremely afraid of the dentist. WhenI think back I still know exactly what the waitingroom looks like, I still know exactly the sound ofthe buzzer, I still know the smell of the disinfection.These kinds of memories are burnt into my brain.This is a typical hippocampal function, to createsuch contextual memories.”The formation of such emotionally chargedmemories is dependent on the action of stresshormones, glucocorticoids such as cortisol. Workingwith classic triggers of stress in rats and mice, suchas exposure to the Morris water maze or forcedswimming, Professor Reul has been exploring themolecular mechanisms by which such factors caninfluence learning and memory – and in particularthe pivotal role played by the epigenetic control ofgene expression.Activating genesEpigenetics is the chemical modification of DNAor the histone proteins associated with it. Manydifferent modifications are known, but ProfessorReul has been particularly interested in thoseaffecting the N-terminal tail region of histone H3.These control whether chromatin is in an ‘open’ or‘closed’ conformation, and hence whether DNA isaccessible to the cell’s transcriptional machinery.“It’s almost like a go or no-go mechanism,” he says.In early studies, he discovered thatforced swimming led to increased histone H3phosphorylation and acetylation in a specific set ofneurons in the hippocampus. This epigenetic effectwas dependent on glucocorticoid hormones andwas required for the consolidation of a behaviouralimmobility response after forced swimming. Hesubsequently discovered that the stress-inducedbehavioural responses also depended on a wellknownintracellular signalling pathway, the ERK/MAP kinase pathway, activated through theNMDA receptor.And in recent studies he has been able to tiethese threads together. Glucocorticoids were foundto promote phosphorylation of two downstreamtargets of the ERK/MAP kinase pathway, MSK1 andElk-1, thereby enhancing signalling and epigeneticchanges driven by activation of the NMDA receptor.Although the epigenetic changes are transient,altered patterns of gene expression drive structuralchanges in the neuron that modify its subsequentactivity. “This gives us completely new insight intowhich kinds of gene products are definitely andspecifically involved in the adaptation of neurons inour brains.”Furthermore, it helps explain the wellestablishedbehavioural effects of glucocorticoids,says Professor Reul. “The nice thing is, that for40–50 years we’ve known that secretion of thesehormones is important for adaptation but we’venever really known how they are acting.”Exercising mindsIn parallel, Professor Reul has maintained an interestin understanding how exercise interacts with stressresponses. Rodents, it turns out, are exercisefanatics. “A rat runs 5, 6 km every night in a runningwheel, a mouse around 3 or 4 km at least. We don’tforce them, it’s voluntary – they love to do it.”Moreover, it seems to be good for them: “Theanimal sleeps better, it’s nice and lean, it doesn’tget obese like normal rats and mice do, and they’resmarter and less anxious.” Professor Reul has beenkeen to test their response to stress, and howexercise affects the mechanisms of gene control:“How does that tap into the whole epigeneticsbusiness?”After being stressed, exercised and couchpotatorats showed markedly different behaviour toa second stressful experience. When exposed to anovel environment, for example, the active animalsexplored it for around 15 minutes before returningto their normal behaviour (resting or sleeping),while unexercised rats continued to explore their30 BNA Bulletin Spring 2013www.bna.org.uk

ResearchExposure to stress can enhance a signalling cascade leading to histone modification, opening up chromatin for transcription.Festival ofNeuroscienceSunday 7 April a.m.Epigenetics in neuroscience:Neuroepigenetics - fromdevelopment to disease(with Hans Reul)www.bna.org.uknew surroundings for much longer. The fitteranimals thus seem to need less time to assess theirsurroundings, suggests Professor Reul.Furthermore, epigenetic mechanisms againseemed to be at work. Exercised animals showedgreater histone H3 phosphorylation and largerchanges in gene activity.Professor Reul has recently been awardeda grant from the Biotechnology and BiologicalSciences Research Council to examine further theinteractions between transcription factors andepigenetic regulation in hippocampal neurons, andhow they are affected by exercise. There is alsoevidence for an effect on GABA, which has a stronginhibitory impact on hippocampal neurons.The results are particularly significantas, although exercise has been repeatedlydemonstrated to have value in conditions suchas depression (or at least mild or moderate formsof it), there have been few clues as to how itwas exerting its effects. Professor Reul’s studiesimply that at least part of the impact is related toepigenetic changes in hippocampal neurons.Stress: good and badStress is generally perceived as a bad thing, yetin the short term it can be beneficial and enhanceadaptation, helping us to cope better if a similarsituation arises again.On the other hand, stress may have lesspositive effects on people who are intrinsically morevulnerable to stress, or affected by debilitating healthconditions. Chronic stress is also generally harmful.Stress has multiple physiological effects, and chronicstress impacts on the function of the brain, includingthe hippocampus. A better understanding of themolecular basis of stress responses in the brain may,in time, shed light on these impaired responses andhow they lead to anxiety and depression.In particular, Professor Reul hopes thatunderstanding how exercise exerts its beneficialeffects advances could provide greater scope tointervene therapeutically. “Maybe at some stagewe could find an antidepressant to tap into thosemechanisms to optimise our antidepressant therapy.”Bilang-Bleuel A et al. Psychological stress increases histone H3phosphorylation in adult dentate gyrus granule neurons: involvement ina glucocorticoid receptor-dependent behavioural response. Eur J Neurosci.2005;22(7):1691–700.Chandramohan Y, Droste SK, Arthur JS, Reul JM. The forced swimminginducedbehavioural immobility response involves histone H3 phosphoacetylationand c-Fos induction in dentate gyrus granule neurons viaactivation of the N-methyl-D-aspartate/extracellular signal-regulatedkinase/mitogen- and stress-activated kinase signalling pathway. Eur JNeurosci. 2008;27(10):2701–13.Gutièrrez-Mecinas M et al. Long-lasting behavioral responsesto stress involve a direct interaction of glucocorticoid receptorswith ERK1/2-MSK1-Elk-1 signaling. Proc Natl Acad Sci USA.2011;108(33):13806-11.Collins A et al. Exercise improves cognitive responses to psychologicalstress through enhancement of epigenetic mechanisms and geneexpression in the dentate gyrus. PLoS One. 2009;4(1):e4330.Binder E, Droste SK, Ohl F, Reul JM. Regular voluntary exercise reducesanxiety-related behaviour and impulsiveness in mice. Behav Brain Res.2004;155(2):197–206.Trollope AF et al. Stress, epigenetic control of gene expression andmemory formation. Exp Neurol. 2012; 233(1):3–11Spring 2013 BNA Bulletin 31

ResearchThe ups and downs of systems biologyMichael WhiteDynamic systems of gene expressioncontrol a cell’s behaviour – withsurprising consequences for the tissueit is part of.Cells, and the tissues they are part of, are complexdynamic systems. Through a systems-basedapproach to cell and tissue function, MichaelWhite at the University of Manchester aims toexplain their behaviour in terms of the integratedactivities of their constituent parts. By combiningexperimental studies with mathematical models,he is providing unexpected insight not just into howcells respond to external signals, but also into theimportance of natural variation in these responses.Professor White spent his first ten years inindustry, pioneering imaging techniques based onluciferase to visualise gene expression in singlecells. While stimulus–response relationships lookvery stereotyped at a population level, individualcells showed much more variability. “That toldme that transcription was far more dynamic thananyone had suspected.”This phenomenon has now been widelyobserved. “Wherever you look at signallingand transcription, you see very heterogeneousresponses at the cellular level. To some extent that’sfundamental physics. If you have small numbers ofmolecules then you’re going to have variation – it’svery hard to make every cell the same.”Biological systems are therefore inherently‘noisy’. It has been widely assumed that noise is anuisance, and cells have had to evolve mechanismsto cope with it. But, asks Professor White, whatif this variability actually has value? “It raises aninteresting idea that heterogeneity within cells maybe an engineered part of the system.”Oscillators in actionHis thinking is based in large part on extensive workon the NF-κB regulatory system. Initially thoughtto be active solely in immune cells, NF-κB hasnow been implicated in multiple processes. “It’san absolutely fundamental signalling process incells, a core signalling hub that seems to integrateinformation that’s involved in life and deathdecisions in many different cell types.”NF-κB regulates several hundred genes, andis itself subject to a complex regulatory regime.In resting cells, it is held in an inactive state inthe cytoplasm, bound by an inhibitor (a memberof the IκB family of proteins). On stimulation(generally by TNFα), phosphorylation of IκB freesNF-κB which migrates to the nucleus and activatesits target genes. However, one gene turned oncodes for its inhibitor, IκB, which binds NF-κB andreturns it to the cytoplasm – creating a classicnegative feedback loop. (The situation is slightlymore complex owing to the existence of additionalinhibitory loops.)Professor White noticed that this mechanismwas reminiscent of the intracellular circadian clock,which relies on a negative feedback loop to generateits periodicity. “Wherever you get a delayed negativefeedback loop, you tend to create an oscillator, interms of basic engineering systems.”Using fluorescently labelled proteins in singlecells, he was able to show that NF-κB was anoscillating system – but with an interesting twist:“No one had seen it clearly before because all thetechniques were averaging across cells, and cellsoscillate out of phase which each other. So you canonly really see it at the single cell level.”Within each cell, NF-κB oscillates between thecytoplasm and the nucleus, with a period of about100 minutes. To understand the implications ofthis behaviour, Professor White realised he neededto develop mathematical models: “The complexityis so great that you can’t really understand it inyour own head, so you have to build a model of it.”Modelling goes hand in hand with experimentalstudies: the former generate predictions that canbe tested experimentally, while the latter providedata to validate and refine the model.This powerful combination has led ProfessorWhite to propose a radical view of how cellscollectively respond to a NF-κB -activatingsignal. The general idea is that heterogeneity inresponses across a population of cells is actuallyadvantageous, providing a kind of ‘buffer’ that canabsorb the inevitable variation in incoming signals.Population-level responses can be modulated in away that would not be possible with a collection ofuniformly sensitive cells.Moreover, this may be a more generalphenomenon. Oscillations have been reportedin several other signalling systems, includingp53, ERKs, STATs and Notch: “These are criticalsignalling molecules,” points out Professor White.And if they are widespread, he adds, they areunlikely to be independent: “It raises the interestingquestion of how these oscillators might interactwith one another.” The modelling strand of workcan provide an indication of what might happen.“You can get some very interesting emergentproperties from coupled oscillators. Potentially you32 BNA Bulletin Spring 2013www.bna.org.uk

Research“…heterogeneitywithin cellsmay be anengineered partof the system.”Feedback loops lead to fluctuations in nuclear NF-κB levels (red) and IκB (green) in single cells.Festival ofNeurosciencePlenary speakerwww.bna.org.ukcan have very subtle changes in coupled oscillatorsthat can robustly switch cellular behaviour in quitedramatic ways.”To test the relevance of these theoreticalfindings, Professor White needs to go back tothe lab. His aim is to enhance the methods fortracking gene expression and protein behaviour inliving systems, animal models as well as individualcells and cell lines. A major technical challengeis to label biomolecules without interfering withtheir behaviour. As well as a range of fluorescentlylabelled proteins, he is also using his old workhorse,luciferase, and developing methods for combinedluminescent and fluorescent imaging and 3Dimaging in living tissue.Systems approachesProfessor White’s approach reflects a trend towardsmore holistic, integrated accounts of biologicalsystems often referred to as ‘systems biology’ –a description not without its problems. “The term‘systems biology’ means a lot of different thingsto different people,” says Professor White. “Mydefinition is it’s measuring as many differentcomponents of the system as you need to measureto better understand the whole system. Thatmeans also not just measuring them quantitativelyexperimentally but also building a quantitativemodel of it and using the two iteratively.” Theapproach is being used in multiple disciplines, notleast computational neuroscience.Although progress has been made in a varietyof areas, suggests Professor White, a big problemwill be knitting different areas together acrossdifferent scales: “The challenge is to go from thegene to the neuron, or from the neuron to thetissue. That’s where we’re really struggling. There’snew theory needed because of the different levelsof information at those different scales. That’s amassive challenge.”Part of the challenge is getting the right peopletogether. “We need to get used to talking andworking in multidisciplinary teams and it’s noteasy.” One of Professor White’s solutions is simplyto sit mathematicians next to the experimentalbiologists. “After about a year they start talking thesame language.”Training is a major issue. But technical issuesaside, the importance of social skills, of buildingand leading teams, should not be underestimated.“It’s not easy, it takes time and it’s expensive.But I think it’s worth it. I think there’s almostno alternative in terms of where we have to goin terms of developing an understanding ofthe science.”It’s also important that the mathematicians,physical scientists and computer specialists are notsimply seen as slaves to the biologists. “The realsuccess comes when the two elements, the theoryand the experiments, are equal and you can getgenuine parity. That’s what I spend most of my lifetrying to do!”Nelson DE et al. Oscillations in NF-kappaB signaling control the dynamicsof gene expression. Science. 2004;306(5696):704–8.Ashall L et al. Pulsatile stimulation determines timing and specificity ofNF-kappaB-dependent transcription. Science. 2009;324(5924):242–6.Turner DA et al. Physiological levels of TNFalpha stimulation inducestochastic dynamics of NF-kappaB responses in single living cells. J CellSci. 2010;123(Pt 16):2834–43.Paszek P et al. Population robustness arising from cellular heterogeneity.Proc Natl Acad Sci USA. 2010;107(25):11644–9.Harper CV et al. Dynamic analysis of stochastic transcription cycles. PLoSBiol. 2011;10:1371.Spring 2013 BNA Bulletin 33

ResearchThe original 1932 mental survey test.“If you puttogether thesemeasures andget an overallmeasure ofwhite matterintegrity,it explainsabout 10 percent variationin cognitivefunctionin old age.Most of thatis mediatedvia simplemeasures ofprocessingspeed.”Festival ofNeuroscienceWednesday 10 April p.m.Improving cognitivefunctions in normal ageing(with Ian Deary)Genes in actionThe cohort studies have also had a focus on geneticcontributions to cognitive ageing, looking initiallyfor possible effects of a range of candidate genes.This revealed that a key susceptibility variant forAlzheimer’s disease, the ε4 allele of the APOEgene, had a small but detectable detrimentaleffect on cognition – but only in old age. “Thereare no differences in cognitive function aged 11,but, if you give the same tests to the same peopleaged 80, there are significant differences betweenthem.” Further work on neuroscientists’ favouritegenes found only minor, rarely replicable effects.More recently, work has focused on genomewidestudies, either just on the two Lothiancohorts or as part of wider consortia. These toohave identified APOE as a risk factor for nonpathological,age-related cognitive decline. Furtheranalyses are due to be published through 2013.Novel statistical techniques also enabledProfessor Deary to calculate, directly from DNAdata, that around 40–50 per cent of the variationin general cognitive ability in old age is due togenetic factors. In addition, data from the Lothiancohorts suggest that genetic factors account foraround 25 per cent of the change from childhoodto old age.Plans are now afoot to combine data fromother US and European cohorts, and to begincollection of genome-wide methylation data toexamine potential epigenetic influences.The brain scans are providing further excitingavenues to explore. As well as confirming theimportance of white matter lesions, data fromthree methods of white matter integrity analysisrevealed another significant factor: “If you puttogether these measures and get an overallmeasure of white matter integrity, it explainsabout 10 per cent variation in cognitive functionin old age. Most of that is mediated via simplemeasures of processing speed.”Such work reveals a possible neural foundationfor some of differences in cognitive function in oldHM The Queen meets members of the 1921 Lothian birth cohort.age. “That’s been the holy grail,” says ProfessorDeary. “You can then ask the question, what is themechanism that keeps some people’s white matterhealthier than others?”Ultimately the research may suggest waysto preserve cognitive skills in old age. “We’relooking for a recipe for healthy cognitive ageing.And by ‘recipe’, I mean it’s going to have a lot ofingredients, most of which have small effects.I can’t envisage a magic bullet that keeps ourcognition healthy. Cognitive health will, I think, belike other aspects of health: we’ll need to play thenumbers by making sure we are minimising the riskfactors and maximising the protective factors, atleast for those that we can influence.”Moreover, he adds, working with cohortsembeds a life course perspective. What happensin old age depends critically on earlier life. Hence,building up a ‘cognitive reserve’ in formative yearswill reap benefits years later: “I am sceptical aboutthe uncritical use of the term ‘reserve’, but it doesmake sense to try to have more in the bank when itcomes to weathering the effects of old age. Lookingafter your brain is a part of a healthy lifestyle.”Gow AJ et al. Neuroprotective lifestyles and the aging brain: activity,atrophy, and white matter integrity. Neurology. 2012;79(17):1802–8.Corley J et al. Alcohol intake and cognitive abilities in old age: the LothianBirth Cohort 1936 study. Neuropsychology. 2011;25(2):166–75.Deary IJ et al. Cognitive change and the APOE epsilon 4 allele. Nature.2002;418(6901):932Davies G et al. Genome-wide association studies establish thathuman intelligence is highly heritable and polygenic. Mol Psychiatry.2011;16(10):996–1005.Deary IJ et al. Genetic contributions to stability and change in intelligencefrom childhood to old age. Nature. 2012;482(7384):212–5.Davies G et al. A genome-wide association study implicates the APOElocus in nonpathological cognitive ageing. Mol Psychiatry. 2012. doi:10.1038/mp.2012.159.Penke L et al. Brain-wide white matter tract integrity is associated withinformation processing speed and general intelligence. Mol Psychiatry.2012;17(10):955.Deary IJ et al. Cohort profile: the Lothian birth cohorts of 1921 and 1936. IntJ Epidemiol. 2012;41(6):1576–84.www.bna.org.ukMembers of the 1936 Lothian birth cohort.Spring 2013 BNA Bulletin 35

ResearchA happy accidentAn unexpected turn of events for a young PhD student has led to a ground-breakingcareer in the genetics of deafness.Karen SteelDeveloping mouse inner ear structures.In 2012, Karen Steel was one of two winners ofthe €1m Brain Prize 2012, awarded by the GreteLundbeck European Brain Research Foundation inrecognition of her work on hearing and deafness. Yetit was chance that led her down this route. “It was acomplete accident, actually,” she says. “I’d lined up aPhD position at University College London and hada particular project that my supervisor had agreed.Then when I turned up he had changed his mind!”Instead, he suggested she study the hearingdeficits of mutant mice. “I read a bit about it andhad access to several different mouse lines thathad genetic deafness, and I got really interested init. I realised that, at that stage, just about no oneelse in the world was working in the area using agenetic approach.”Professor Steel’s main interest lay indevelopmental genetics, and the mouse mutantsprovided an opportunity to map the developmentof the intricate structures that make up the mouseauditory system. It was a steep learning curve – herpast experience amounted to an A-level diagramof the organ of Corti. Much of her PhD was spentgetting far more familiar with the auditory system,documenting its histology in various mouse mutants.One thing that struck her early on – and remainsa source of mystery today – was why some animalsshowed impaired hearing in behavioural testseven though their sensory hair cells were stillpresent and looked normal. The view of the daywas that hearing loss was caused by degenerationof hair cells, so what was going on in theseanimals? “I really needed to understand moreabout the function of them. And that’s why doingelectrophysiology to measure what these hair cellswere really doing was very important.”This desire to learn electrophysiologicaltechniques took her to Nottingham. There shebegan a series of influential studies characterisingthe hearing impairments of exotically namedmice strains – such as whirler, flouncer, waltzer,deafwaddler, tasmanian devil and tailchaser. Along-term hope was that it might also be possibleto track down the specific genes involved. “This waslong before the days of positional cloning, so it wasonly a dream. I thought in maybe 100 years’ timewe might know what these genes were. It camearound much faster than I imagined!”The first deafness genesWith technologies advancing in leaps and bounds,the mutations affecting hearing began to beisolated – with surprising results. “When I started Ithought they were all going to be ion channels – itjust seemed such an obvious class of protein tobe involved in deafness.” Yet the first mutationshe pinned down was in a gene encoding anunconventional myosin (Myo7a). And so was thesecond. “Since then just about every sort of geneproduct you can imagine has turned out to beassociated with deafness.”Soon, mapping abnormal genes became routine,and a problem arose. “We were running out of deafmouse mutants, our basic tool for identifying newgenes involved in deafness. That’s when I startedthinking about how we could generate more mousemutants, so we had more tools to get access to themolecules that are needed for normal hearing.”To this end, Professor Steel became involvedin two large programmes using the chemicalmutagen n-ethyl-n-nitrosourea (ENU) to introducerandom changes into the mouse genome. She ledan EC-funded project to add a screen for deafnessto these ENU programmes, revealing many withhearing abnormalities and replenishing the supplyof mutants.Then in 2003, Professor Steel moved south,to the Sanger Institute to establish a large-scaleMouse Genetics Project. While ENU scatteredmutations at random across the genome, Sangerresearchers were adopting a more targetedapproach, systematically mutating genes acrossthe mouse genome. This programme generatedmutant embryonic stem cells, which ProfessorSteel’s team used to generate mutant mice to36 BNA Bulletin Spring 2013www.bna.org.uk

ResearchLabelling of hair bundles.Hair cell stereocilia.Swollen nerve terminals (green)in the organ of Corti in a mousemutant (lower panel).Festival ofNeurosciencePlenary speakerwww.bna.org.ukscreen for various abnormalities, includinghearing problems.Such approaches have vastly increased thenumber of genes known to be involved in hearing,but there are still many waiting to be discovered.“I think there will probably be between 500 and1000 genes, any one of which could be involved indeafness,” she suggests.Genetics, she argues, has opened up functionalstudies of hearing that would have been verydifficult through other techniques. “It’s a reallypowerful tool. Some people find it baffling why Iwould be interested in genetics because deafness isso heterogeneous – there are hundreds of differentgenes involved so what’s the value in studying oneat a time? But the thing is, it’s not just relevant topeople who have a mutation in that particular gene,it’s actually a tool to get access to a molecule that’scritical in normal hearing processes.”From mice to humans (and back again)The interplay between mouse studies and humandeafness has always been an aspect of her research,with many mouse deafness genes turning out tobe responsible for hearing impairment in people. Asnew genes are discovered, they are candidates forinvolvement in unexplained hearing loss.One of the most startling examples was thediscovery of a mutation affecting a microRNA – ashort non-coding RNA involved in gene regulation– in the diminuendo mouse mutant. At the sametime, collaborators in Madrid, led by Miguel Moreno-Pelayo, were honing in on a gene causing progressivedeafness in two families. “We knew the mutationslocalised to the equivalent part of the human andmouse chromosome so we thought they mightbe involved in the same gene. So we both foundmutations in this microRNA, Mir96, more or less atthe same time – more or less the same day, actually.”With colleagues in her own team and inSheffield, Professor Steel has gone on to show thatmutation of miR-96 blocks differentiation of innerand outer hair cells at or around the time of birth.Indeed, miR-96 appears to act as a ‘master switch’Altered distribution of synapses at the basolateral membrane of innerhair cells in a mouse mutant.driving the intricate structural and functionaldevelopment of hair cells.Recently, Professor Steel has returned to London,to the Wolfson Centre for Age-Related Diseasesat King’s College London. A big advantage, shesuggests, is that she is surrounded by neuroscientistslooking at the impact of ageing, a benefit as her focusshifts to progressive hearing loss – a condition usuallybut not always associated with older people.Opportunities are also arising to translate basicdiscoveries into new treatments for deafness, whichsignificantly affects the quality of life of manypeople in old age. The best approach, she suggests,may be to intervene in the processes that lead todegeneration of sensory hair cells, the endpoint ofmultiple genetic or environmental insults. “Whateverthe trigger is I’m sure there are going to be commonmechanisms that lead to progressive hearing loss.”Early intervention could be key, she adds: “We shouldbe thinking more about stopping the progression ofhearing impairment or even reversing it.”She is currently planning studies of potentialtherapeutic agents for two different mechanismsunderlying progressive hearing loss. “It’s going to bea long time coming, but I’m very optimistic that wewill eventually find some kind of medical treatmentfor hearing impairment.”Kuhn S et al. miR-96 regulates the progression of differentiation inmammalian cochlear inner and outer hair cells. Proc Natl Acad Sci USA.2011;108(6):2355–60.Mencía A et al. Mutations in the seed region of human miR-96 areresponsible for nonsyndromic progressive hearing loss. Nat Genet.2009;41(5):609–13.Lewis MA et al. An ENU-induced mutation of miR-96 associated withprogressive hearing loss in mice. Nature Genet. 2009;41(5):614–8.Gibson F et al. A type VII myosin encoded by the mouse deafness geneshaker-1. Nature. 1995;374(6517):62–4.Spring 2013 BNA Bulletin 37

Et ceteraObituaryAlan Cowey(1935–2012)Alan Cowey was a leading figure in visualneuroscience for four decades. His first majordiscovery came in 1964 when he described V2in the monkey – the first extrastriate visualarea to be mapped. Now we know of over 30extrastriate visual areas it is difficult to imaginethe excitement at discovering a retinotopic mirrorimage surrounding V1. Subsequent papers on theeffects of extrastriate lesions on many aspectsof perception and behaviour were landmarksfrom which followed others’ work on functionalspecialisation and visual cortical organisation.In particular, the work with Charles Grosssegregating the functions of extrastriate andinferotemporal regions, and the description ofhuman cortical magnification, have stood the testof time. Along with Hubel, Wiesel, Weiskrantz,Mishkin, Ungerleider, Gross and others, Alan wasone of a small group who in the 1960s and 1970s laidthe foundations for modern visual neuroscience.His work was interdisciplinary because he sawno way of understanding anatomy, physiology orbehaviour without understanding them all. Hiswork on blindsight, inspired both by basic scientificquestions and clinical possibilities, is a goodexample. As Trevor Robbins put it: “His insightsinto the phenomenon of ‘blindsight’, throughexperiments with impeccable logic and elegantdesign, have led us to a new understanding ofthe functional organisation of the primatevisual system.”Throughout the 1980s Alan led a scholarlyresistance to oversimplifications of functionalspecialisation in visual cortex in a series ofpapers on the effects of extrastriate lesions. Hecomplemented this by extending his work onpatients suffering from achromatopsia, visualagnosia and blindsight, while continuing to publishtechnically demanding papers on retinal andcortical anatomy.Alan helped and inspired an A to Z of firstclassscientists including Michael Morgan, ColinBlakemore, Edmund Rolls, Hugh Perry, DickPassingham, Peter Somogyi and Petra Stoerig. ButAlan’s help and loyalty were not reserved for thestars and he was supportive to the many others ofus who passed within the orbit of his influence.Alan never became an ‘executive’ scientist,merely supervising the experiments of others.Even as a senior scientist with many externalduties he began every weekday by running hisown experiments. He bemoaned the “rising tideof rewarded mediocrity, spoon feeding, stiflingbureaucracy, mission statements...it is not therecipe for independent thinking”.Alan’s achievements were widely recognised.His first award was the British Psychological SocietySpearman Medal (1967). Subsequent highlightsincluded the Royal Society Henry Head ResearchFellowship (1968–73), MRC Council Membership(1981–4), Presidency of the European Brain andBehaviour Society (1966–8), Fellow of the RoyalSociety (1988) and Founding Fellow of the Academyof Medical Sciences (1998). Alan’s last award, theBPS Lifetime Achievement award, showed theprescience of his first.Vincent Walsh (University College London)(this obituary was first published in Current Biology)ObituaryRita Levi-Montalcini(1909–2012)One of the most notable figures in 20th-centuryneuroscience, Rita Levi-Montalcini, died on 30December 2012 aged 103. She received the NobelPrize for Physiology or Medicine in 1986, alongwith her former student Stanley Cohen, for heridentification and isolation of nerve growthfactor (NGF).Levi-Montalcini was born in April 1909 in Turin,Italy, where, initially against her father’s wishes,she also attended medical school. Despite sufferinganti-Semitic discrimination during Mussolini’s rule,she managed to continue research – even turningher own bedroom into a makeshift lab. She waseventually forced into hiding in Florence until itsliberation in 1944.The bulk of her research career was spent atWashington University, St Louis, where she helda position as Professor of Neurobiology until herretirement in 1977.She also established a research group in Romein 1962, splitting her time between Italy and theUSA. She remained active in research well into her80s, continuing her work on NGF. In 1992 she andher twin sister Paola, a notable artist, created theLevi-Montalcini Foundation, to promote youngpeople’s education. Her autobiography, In Praise ofImperfection, was published in 1988.BNA BulletinonlinePDFs of back issues ofthe BNA Bulletin – andother publications can befound at www.bna.org.uk/publications.html38 BNA Bulletin Spring 2013www.bna.org.uk

Et ceteraMeet the memberQ/ Who are you?A/Michael HastingsQ/ Where are you?A/ MRC Laboratory of Molecular BiologyDivision of Neurobiology, CambridgeQ/ What are you studying?A/ Molecular neurobiology of circadianclocks in mammals.Q/ What got you into neuroscience?A/ A (mad) gamble taken by Joe Herbertin Cambridge to give a hairy, invertebratemarine ecologist a job studyingseasonality in mammals. It was difficultfor me to avoid confusing the pineal andthe pituitary during the first few months,even though I did know all about Lewiszonation on rocky shores.Q/ If you weren’t doing research, whatwould you like to do?A/ Be a nature warden, RSPB or similar(I’m too old for Africa). I told my careersteacher at school that I wanted to be agame-keeper – just to get close to realanimals, out there. It’s not changedmuch. What little money I’ve had tosplash around has been spent on being inthe bush, in Africa.Q/ Who inspires you and why?A/ Professionally, Joe Herbert for his madgambles that reflect this love for scienceand ideas (regardless of the currentlyavailable data), and people such as BarryEveritt, Trevor Robbins and Tom Jessellfor having boundless energy and themost astonishing helicopter views ofneuroscience. How do they do it? Toomany synapses Mr Mozart………Q/ What do you like to do out of the lab?A/ Chop firewood (seriously therapeuticand atavistically rewarding), referee mychildren’s football matches, get into openair and open skies (preferably African,with serious predators outside thetent), look after my village’s 11th centurythatched church (All Saints’, Rampton – ifGod is anywhere, She’s in there), keepthe children amused, watered and fed:domestic bliss should not be under-rated,it’s another atavistic reward.Q/ What one invention would makeyour life easier?A/ A red tape cutter. There is so muchpointless and unhelpful regulation in(biological) science: the box-ticking withingrant applications, the endless appraisalsthat lead to nothing, the governmentinspection with no court of appeal (thedefinition of tyranny). It is the productionof new knowledge that matters to peoplein the street who pay my wages, notleaving the audit trail.Q/ Where is the best place research hastaken you?A/ The terrace overlooking the Malloutside the Royal Society. I was therewith my Mom and Dad, my wife Angela,my sister Deborah and my long-termcolleague Liz Maywood on the day theyshowed me the secret handshake. Itwould be a stupid falsehood to pretendthis was not my professional zenith. It isnot a boast because it could very easilynever have happened (see below).Q/ What was the best day in yourresearch career?A/ When Liz told me that Current Biologyhad accepted our circadian imaging paper.We had taken a big gamble in movingfrom our comfort zone in the universityto the LMB. The aim was to re-cast ourscience as circadian biology became acell and molecular biological problem (ofwhich I knew diddly-squat). We dived in,went under and our heads did not popabove the water for at least 3 years – thispaper was our first LMB ‘product’. Themove might never have worked – perhapsI learned from Joe Herbert that gamblesare necessary to advance, and wegambled luckily.Q/ …and the worst?A/ Every one of the three years beforethe day above. Can I do it? Everyonehere at the LMB is so bloody clever andin comparison I am a duffer – will I berumbled? Calm down, Michael – do yourbest. At least you’re not out in the rain,lifting heavy things in order to put breadon the table.Slowly does it: Rafa Nadal in action.Making timeTime appears to slow down as weprepare for movement.Sporting professionals often suggest thatthey strike balls in slow motion, or see aball more clearly when they come to hit it.Nobuhiro Hagura and colleagues at UCLhave documented a similar effect in meremortals, and identified how it mightcome about.The anecdotal reports that ball-playersperceive time to slow down as theyprepare for shots suggested to Dr Hagurathat preparation for movement mightinfluence the perceived passage of time.Indeed, in laboratory tests, participants’estimates of the duration of visual stimuliwere longer when they were preparing tomake a reaching movement.In addition, flicker rates of fluctuatingstimuli were judged to be slower. Subjectsalso showed an enhanced ability to detectrapidly presented letters when preparingto move.The explanation, suggest Hagura etal., is that channels of sensory input areopened up as we prepare for action.The additional sensory information givesus more opportunity to make fine and rapidadjustments to movements. The enhancedclarity of perception creates a sense of timeslowing – vital for that perfect golf swing orbackhand passing winner.Hagura N, Kanai R, Orgs G, Haggard P. Ready steady slow:action preparation slows the subjective passage of time. ProcBiol Sci. 2012;279(1746):4399–406.MachoCariocawww.bna.org.ukSpring 2013 BNA Bulletin 39

Meet the memberQ/ Who are you?A/ Trevor BushellQ/ Where are you?A/ University of StrathclydeQ/ What are you studying?A/ Modulation of neuronal excitabilityand synaptic transmission, including therole of proteinase-activated receptorsin central neurones, the G-proteincoupled receptor modulation of twoporeK + channels (K2Ps) and immune cellinvolvement in neurological disorders.Q/ What got you into neuroscience?A/ My original goal was to be an RAFpilot but I found this was not an optiongoing into the final year of my A levelsdue to blood pressure issues. Up to thatpoint I had not even thought of goingto university. However, I was acceptedat the University of Glasgow to studypharmacology. The most interesting partof the course was the actions of drugs inthe CNS and it became clear how little weunderstood about the CNS and even howcommonly prescribed drugs really worked.By this point I was hooked, as I still am.Q/ Who inspires you and why?A/ My late father is still the biggestinspiration in my life. He was such anintelligent man who didn’t have theopportunities that I’ve had. He workedlong hard hours all his life as a greengrocerso that my sister and I would have thoseopportunities that he missed out on andfor that I will be eternally grateful.Q/ What do you like to do out of the lab?A/ Spending as much time as possible inthe great outdoors with my wife and twoyoung daughters.Q/ What one invention would makeyour life easier?A/ Teleportation.Q/ Where is the best place research hastaken you?A/ During my PhD, I was lucky enoughto spend a couple of weeks at the SalkInstitute in La Jolla, California. Theexperience convinced me not only thatneuroscience was what I wanted topursue as a career but also that you coulddo it in some great places!Q/ What was the best day in yourresearch career?A/ Getting my first project grant: arealisation that the ideas that you hadwere good and some of your peersthought so.Q/ …and the worst?A/ Not getting the first project grant Iapplied for. I thought it was the end ofthe world, but with experience you realiseit’s a marathon, not a sprint!www.bna.org.ukSpring 2013 BNA Bulletin 41

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