BNA Bulletin

Issue No. 97
Spring 2023

THE VOICE OF BRITISH NEUROSCIENCE TODAY

Calming circuits
Gene therapy for epilepsy

Small steps
Unravelling the mysteries of small vessel disease

PLUS:
In support of neurodiversity
Neuroscience at Sussex
Culturing interneurons
Neuroscience and mental health

BNA2023 INTERNATIONAL FESTIVAL OF NEUROSCIENCE SPECIAL ISSUE

Our vision
A world in which no one is held back
by mental health problems.

Our mission
To create a step change in early intervention
in anxiety, depression and psychosis.

Understand Stratify Intervene

Have a better understanding of: Being able to better group Having better ways to
• How and why these (categorise/stratify) people with intervene as early as
conditions develop or at risk of these conditions possible for these conditions
to facilitate more targeted and
• How and why treatments
personalized interventions
work or don’t work

Lived experience is central to all our work

Field Use of common Improved Policy

building measures data work

What to look out for:

Open now: A funding call to support validation of In planning: A funding call focused on causal
biological, psychological, social or digital markers to pathways to and through anxiety (to be launched
enable stratification in anxiety and/or depression as in Summer 2023, with preliminary applications
early as possible. Access through wellcome.com, closing in Autumn 2023).
preliminary applications closing on 7 June, 2023.

Find out more at www.wellcome.org

Wellcome Trust, 215 Euston Road, London NW1 2BE, United Kingdom
T +44 (0)20 7611 8888, E contact@wellcome.org, wellcome.org
The Wellcome Trust is a charity registered in England and Wales, no. 210183. Its sole trustee is The Wellcome Trust Limited, a company
registered in England and Wales, no. 2711000 (whose registered office is at 215 Euston Road, London NW1 2BE, UK). SP-7461.3/02-2023/RK
Contents

BNA Bulletin
BNA Bulletin
Issue No. 97
Spring 2023

THE VOICE OF BRITISH NEUROSCIENCE TODAY Editor:

Calming circuits Ian Jones, Jinja Publishing Ltd
Gene therapy for epilepsy
Design and production:
Research
Small steps
News Unravelling the mysteries of small vessel disease Jag Matharu,
Thin Air Productions Ltd

05 22
Advertising in the BNA Bulletin:
Contact the BNA office
(office@bna.org.uk) for advertising
Message from Dimitri Kullmann: rates and submission criteria.

the President and Gene therapy PLUS:

Copyright: © The British
Chief Executive for epilepsy In support of neurodiversity
Neuroscience at Sussex
Culturing interneurons
Neuroscience and mental health
Neuroscience Association.
Extracts may be reproduced only
BNA2023 INTERNATIONAL FESTIVAL OF NEUROSCIENCE SPECIAL ISSUE with permission of the BNA.

06–08 24
Saint Valentine blessing a man
with epilepsy, known as ‘falling ISSN: 1475-8679
sickness’. Saint Valentine was
Neuroscience news Meng Li: Making bishop of Terni, Italy, in the BNA Office
third century, and patron saint Anne Cooke
interneurons of epilepsy (and beekeepers). University of Bristol
from stem cells On page 22, Dimitri Kullmann Dorothy Hodgkin Building
describes how gene therapy Whitson Street
may soon be an option for people Bristol BS1 3NY

26
whose epilepsy cannot Web: www.bna.org.uk
Analysis be controlled by drugs.
Image: Wellcome Library. London The British Neuroscience
Joanna Wardlaw: Association is a registered

9
charity (1103852) and a
Small vessel disease registered company (04307833)
and brain health limited by guarantee.
Latest policy updates

10 28 BNA Council and National Committee

Sue Fletcher- BNA COUNCIL

Festive Symposium Watson and Mary Rik Henson (Cambridge): President
review Doherty: In support Annette Dolphin (UCL): Immediate Past President
Tara Spires-Jones (Edinburgh): President-Elect
of neurodiversity
11
Zoe Kourtzi (Cambridge): Secretary
Trevor Bushell (Strathclyde): Treasurer
Neuroscience and Sarah Guthrie (Sussex) and
Dayne Beccano-Kelly (Cardiff): Meetings Secretary
mental health – the
Catherine Abbott (Edinburgh): Research Policy
BNA theme for 2023
Et cetera Volko Straub (Leicester): Groups Co-ordinator
Michael Ashby (Bristol): Credibility in Neuroscience

12 30
Mark Walton (Oxford): Preclinical Neuroscience
Alan M Palmer, Kevin Cox, Manfred Berners: Independent Trustees
Latest dispatches
from Brain and Leon Lagnado: NATIONAL COMMITTEE
Neuroscience The allure of lab work Camille Carroll (Plymouth): Clinical Scientist Representative for Neurology

Advances Sharon Abrahams (Edinburgh): Clinical Scientist Representative

33
for Psychology
Lindsey Sinclair (Bristol): Clinical Scientist Representative for Psychiatry

13 Postgraduate and
undergraduate
Emma Soopramanien (QMUL): Students and Early Careers Representative
Emma Yhnell (Cardiff): Equity, Diversity and Inclusion Representative
Neuroscience
at Sussex prize winners BNA EXECUTIVE
Anne Cooke: Chief Executive

14 34
Sophie Jerrold: Development Director
Joseph Clift: Head of Policy and Campaigns
What’s new in Random samples Louise Tratt: Head of Meetings and Events

neuroscience – Dani Wijesinghe: Community and Inclusion Officer

key developments
35
Sophie Grange: BNA Placement Student
Lamia Sanzana: BNA Placement Student
since 2019
Fond farewells:
BNA bids adieu
16-21 to Chief Executive
Brain Insights Anne Cooke

www.bna.org.uk Spring 2023 BNA Bulletin 03

 University of Manchester
Sun 23rd – Wed 26th July
www.bap.org.uk/BAP2023

A Guest Lecture by
Featuring a range of non-clinical and clinical presentations Professor John Cryan
across a range of neuropsychiatric conditions Gut Feelings: The Microbiome as a
Regulator of Brain and Behaviour
• The clinical application of psychedelic assisted therapy (PAP) Across the Lifespan
• Psychopharmacology in the Computer Age: How new computational power can
drive precision psychiatry and translational drug discovery Clinical and Non-Clinical Sessions,
• Catatonia and the relationship between motion and emotion: from GABA to Trainees’ Workshop, Post-
guidelines Doctoral Symposia, Short Orals,
• The mechanisms underlying early and late lack of response to antipsychotics: from Satellite Symposia and Special
brain morphology to inflammatory and oxidative stress markers Sessions
• Affective Instability: Mechanisms, Measurement and Clinical Utility PLUS bursaries, prizes and poster
• Vagus nerve stimulation for difficult to treat depression: what is the evidence and sessions
possible mechanism of action?
Welcome Reception
• Developments in Translational Research into Treatments in Anxiety Disorders and
and Disco
OCD
• EEG as a translational tool to explore the role of sleep and circadian function in Conference Dinner at Whitworth
psychiatric disorders Hall including presentation of the
• Psychopharmacology for the digital age 2023 Prizes and Awards

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 News

Festival 2023
Message from the President and Chief Executive

Dear BNA Members

Life always brings ‘firsts’ and ‘lasts’. For example, it is now
50 years since the first ever taught neuroscience course
in the UK, at the University of Sussex. It is fitting, then, that
Sussex will host our 2023 Festival in April, which itself includes
many ‘firsts’: it is our first hybrid meeting, which means that
some of our great international speakers can present online The BNA2023 International Festival of Neuroscience
from around the world, reducing carbon costs, while attendees draws ever closer. The first in-person Festival since
can still benefit from socialising in person; it is the first time 2019, organised in partnership with Parkinson’s UK
we have had so many Partners, with 23 organisations coming and the Guarantors of Brain, will take in Brighton
together to share neuroscience, including Festival Partner on 23–26 April 2023 and offers a unique blend of
Parkinson’s UK and special Partner the Guarantors of Brain; attractions for neuroscientists of all persuasions.
and it is the first time that we have held a ‘Lived Experience As well as a stellar scientific programme, there
plenary’, since it is so important to promote the perspective will be extensive poster sessions, a wide range of
of those living with neurological or psychiatric disorders. career-related events and networking opportunities,
So if you have not yet registered, please visit a special focus on credibility in neuroscience,
www.bna2023.org to do so! sustainability and building bridges between academia
In terms of ‘lasts’, this will be the last editorial from both and industry, and neuroscience and mental health,
of us. Rik’s term as President finishes at the end of the plus an extensive Festival exhibition.
Festival, when he will be replaced by Tara Spires-Jones, while, Discover the full range of attractions at
after 7.5 years at the helm of the BNA, Anne is stepping down www.bna2023.org. See you in Brighton!
as Chief Executive at the end of April. On page 33, she shares

BYOB
her reflections on her time at the BNA. She will leave big
shoes to fill, but we are busy appointing someone to take
the BNA to new levels of success.
Finally, many other things continue as before. The BNA A special programme of free public events, Bring Your
continues to grow in membership and in impact, thanks to the Own Brain, has been organised alongside the scientific
volunteers on our council and committee, to our local group programme of the BNA2023 International Festival
representatives and to our dedicated office team. If you’d like of Neuroscience.
to be involved too (for example, if your institution does not The programme includes events and activities
have a local group representative), then let us know! for people of all ages, including a science fair, a café
scientifique, a mental health photography exhibition,
‘Brains on the Beach’ (a soapbox science special),
Brains at the Sussex Library and the Sussex Brain Bus.
See https://meetings.bna.org.uk/byobbrighton/
for the full programme of activities, which take place
throughout April 2023.

Credibility
The winners of the 2023 BNA Credibility in
Neuroscience Prizes have just been announced:
• Student Researcher Credibility Prize: Maria
Korochkina (Royal Holloway, University of London),
Highly Commended: Abigail Fiske (Oxford)
• Individual Researcher Credibility Prize: Roni Tibon
(Nottingham), Highly Commended: Esther Walton
(Bath)
• Team Credibility Prize: #EEGManyLabs Project Team,
Rik Henson Anne Cooke Highly Commended: Dementias Platform UK
BNA President BNA Chief Executive We’ll have more on the prizewinners in the
next BNA Bulletin.

www.bna.org.uk Spring 2023 BNA Bulletin 05

 News

Prize winners Careers fair NS day

The BNA is holding its first careers Edinburgh Neuroscience held its annual
and talent recruitment fair on 15 June Neuroscience Day on 9 March 2023. The
2023. Organised in partnership with the Annual Distinguished Lecture, re-named
Sainsbury Wellcome Centre in London, the the Sir Colin Blakemore Memorial Lecture,
fair will enable up to 100 early-career and in honour of Sir Colin, who sadly passed
BNA student members to connect with away in 2022, was given by his daughter,
up to 10 organisations from across the Sarah-Jayne Blakemore (Cambridge).
breadth of the neuroscience sector looking Her research focuses on the development
to recruit new scientifically qualified staff. of social cognition, peer influence and
Dame Pamela Shaw
See bit.ly/41wIh7s for full details. decision-making in the adolescent brain,
and adolescent mental health. The event

Impact Prizes
included the usual mix of talks from senior
researchers, fellows and postdocs, as well
as the PhD Student Data Blitz.
Neuroscientists from Nottingham and

AAAS award
Cambridge are among those shortlisted
for MRC Impact Prizes, which recognise
individuals or teams who have made
outstanding impacts in medical research. Barry Everitt (Cambridge) has been
A team from Nottingham led by Matthew elected a lifetime fellow of the American
Sophie Stanford
Brookes was shortlisted in the ‘outstanding Association for the Advancement of
team impact’ for its development of Science (AAAS). The honour recognised
The 2022 BNA Prize winners were new lightweight and wearable imaging his outstanding research in learning,
announced at the BNA Festive Symposium technology. In the ‘early career impact’ motivation and reward, as well as his
in December 2022. The Outstanding category, Amy Orben (Cambridge) was leadership of neuroscience societies
Contribution to Neuroscience award shortlisted for her innovative contributions in both Europe and the USA.
went to Dame Pamela Shaw (Sheffield), to open science, reproducibility and
in recognition of her pioneering work research cultures. Dr Orben is also a BNA
on motor neuron disease and other Credibility in Neuroscience prize winner.
neurodegenerative conditions. Professor

ARUK awards
Shaw in an NIHR Senior Investigator and
Director of the Sheffield Institute for
Translational Neuroscience (SITraN).
In January 2023, Professor Shaw In its 2022 Supporter Awards,
was the guest on BBC Radio 4’s The Life Alzheimer’s Research UK has recognised
Scientific. Her interview can be heard neuroscientists for their commitment
Barry Everitt
at bbc.in/3Isw0rZ. outside as well as inside the lab. The
The Public Engagement with Early Career Representatives for the

Pain
Neuroscience Prize went to Sophie Scotland Network were winners of the
Stanford (Cambridge). Sophie is a final- Researchers of the Year Award for their
year PhD student at the UK Dementia fundraising efforts; in 2022, these included
Research Institute (UK DRI) at Cambridge a #RunTheBrain challenge, which involved The Academy of Medical Sciences has
and has a passion for inclusivity and travelling 668 miles (the total length published a summary of a workshop jointly
diversity. She created a new virtual of capillaries in the brain). In addition, organised with the BNA. The workshop,
STEM conference, ‘Making it Brain’, Selina Wray (UCL) was a winner of the chaired by Irene Tracey (Oxford) and
showcasing a diverse range of presenters, Outstanding Commitment Award for her Iain Chessell (AstraZeneca), focused on
to raise awareness of possible careers in work as an ambassador for dementia opportunities to accelerate translational
neuroscience for students aged 16 and over. researchers, frequent public engagement research on chronic pain. The report can
The 2022 Postgraduate Prize winner efforts and fundraising, having run both be found at bit.ly/3x9Yv8t.
was Andrija Sente (Cambridge; see the London Marathon and the Great
page 33) and the Undergraduate Prize North Run.
winner was Catherine Whittle (Durham;
see page 33).

06 BNA Bulletin Spring 2023 www.bna.org.uk

 News

AD success Diversity ACNP awards

BNA President-Elect Tara Spires-Jones award Carmine Pariante is the recipient
(Edinburgh) and Sir John Hardy (UCL) were of the 2022 American College of
interviewed by FENS following the release Mahmoud Bukar Neuropsychopharmacology (ACNP) Media
of promising clinical trial data on the use Maina (Sussex) Award. Professor Pariante is the co-founder
of lecanemab, a beta-amyloid-targeting has been awarded and editor in chief of ‘Inspire the Mind’,
therapeutic, for the treatment of mild the 2022 ALBA- a digital publication with contributions
cognitive impairment due to Alzheimer’s FKNE Diversity from researchers, clinicians, other mental
disease. Tara’s take on the findings Prize, awarded by health professionals and people with
can be read at bit.ly/3YiTTZN. the ALBA Network lived experience that aims to increase
and the FENS– Mahmoud Bukar Maina understanding of mental health conditions

MRC medal
Kavli Scholars and reduce stigma.
Network to recognise outstanding efforts ACNP also recognised Oliver Howes
to promote equality and diversity in the (KCL), recipient of the 2022 Joel Elkes
brain sciences. Dr Maina has carried out Research Award. His ground-breaking work
a range of activities to promote science has focused on the neurochemical basis
and scientific literacy in Africa, particularly and treatment of psychosis, particularly
Nigeria (see BNA Bulletin Summer 2020), the role of glutamate signalling.
and is developing induced pluripotent stem
cell lines from African donors to improve
their representation in neurodegenerative
research. An interview with Dr Maina
can be found on the FENS website at
Sarah Tabrizi
bit.ly/3lr5RSg.

EPS awards
Sarah Tabrizi (UCL) is one of two winners
of the MRC Millennium Medal, the MRC’s
most prestigious personal prize. Created
Carmine Pariante
by the Royal Mint, the Medal is presented Bob Logie (Edinburgh) has been awarded
each year to a researcher who has made the Bartlett Prize for lifetime achievement
an outstanding contribution to the MRC’s in experimental psychology by the
mission to improve human health through Experimental Psychology Society (EPS),
world-class medical research. Professor honouring his major achievements in
Tabrizi has used multiple approaches to the field of working memory.
generate insight into the mechanisms of Geoff Bird (Oxford) is the recipient of
Huntington’s disease and has developed the EPS Mid-Career Award. The award is
highly promising innovative new molecular in recognition of his outstanding research
treatments. in social cognition and how it
is affected in conditions such as autism

CIFAR fellow
Oliver Howes
and alexithymia.
The EPS Prize Lecturer for 2022 is

Blavatnik
Nadine Lavan (Queen Mary, University
Steve Fleming (UCL) has been appointed of London) and the Frith Prize Lecturer

Award
a Fellow of the Canadian Institute for is Tom Arthur (Exeter).
Advanced Research (CIFAR) programme

APA award
in Brain, Mind and Consciousness. CIFAR
is a global research organisation aiming Andrew Saxe (UCL) was one of two
to bring together leading researchers finalists in the Life Sciences category
from around the world. There are just Michael Sharpe (Oxford) has been awarded of the 2023 Blavatnik Awards for Young
20 researchers in its Brain, Mind and the Adolf Meyer Award for Lifetime Scientists, which recognise outstanding
Consciousness programme, which is Achievement by the American Psychiatric UK researchers under 42 years of age.
co-directed by Adrian Owen (Western Association (APA). Professor Sharpe Dr Saxe’s work focuses on deep neural
University, Canada) and Anil Seth (Sussex). is Emeritus Professor of Psychological networks and representational learning
Medicine at Oxford and an honorary across natural and AI systems.
consultant psychiatrist.

www.bna.org.uk Spring 2023 BNA Bulletin 07

 Analysis

India links ERC grants Kandel Prize

Semir Zeki (UCL) is one of three recipients Congratulations to the following who Nominations have opened for the Eric
of Royal Society Yusuf Hamied Visiting have been awarded Starting Grants by Kandel Young Neuroscientists Prize 2023.
Professorships, which provide funding to the European Research Council (ERC): The Prize, organised by FENS and the
enable researchers to visit India and further • Rafael Almeida (Edinburgh): Hertie Foundation in Germany, recognises
develop links with Indian researchers. Axonic neurotransmission in neural outstanding work by young researchers
circuit formation and function in any field of neuroscience. All European

In memoriam
• Philip Coen (UCL): Mapping audiovisual neuroscientists under the age of 40 are
integration across learning, behaviours eligible (the age limit can be extended
and circuits for those who have taken maternity
The BNA was saddened to hear of the • Rui Ponte Costa (Bristol): Dopaminergic– or paternity leave). The Prize provides
death of Mark Stokes (Oxford) in January cholinergic neuromodulation for rapid €50,000 for personal use and €50,000 for
2023. Mark was an internationally and democratic cortex-wide learning scientific collaboration. The prize winner
renowned cognitive neuroscientist and • Chunyu Duan (UCL): Neural circuit will also deliver the Eric Kandel Prize
head of the Attention Group at the Oxford mechanisms of social decision-making Lecture at the FENS Forum 2024 in Vienna,
Centre for Human Brain Activity. He wrote • Vilaiwan Fernandes (UCL): Intra- Austria. The nomination deadline is 1
a neuroscience blog, The Brain Box, and and intercellular coordination in the May 2023 (see bit.ly/3xeeUsq for further
also co-hosted Brain Metrics at Nature. developing brain details).
December 2021 saw the passing of

NC3Rs Board Stem cell

Gregory Stores (Oxford), Professor of
Development Neuropsychiatry, who

therapy
carried out landmark studies on epilepsy
and sleep disorders. BNA Council Member
Cathy Abbott

NC3Rs funding
(Edinburgh) has A consortium led by researchers and
been appointed to clinicians from Sheffield are testing
the Board of the whether autologous hematopoietic stem
Several neuroscientists are among those National Centre for cell transplantation (use of a patient’s
receiving funding from the NC3Rs and the Replacement, own bone marrow stem cells) is a
Cathy Abbott
the BBSRC to support the development Refinement and suitable treatment for ‘highly active’ and
of non-animal technologies as alternatives Reduction of Animals ‘aggressive’ forms of multiple sclerosis.
to in vivo models: in Research (NC3Rs) for the next three years. The StarMS trial, funded by the NIHR
• Fabrice Gielen (Exeter): A high- Professor Abbott is also Chair of the Animal and MRC, will compare the stem cell
throughput spheroid fusion platform Welfare and Ethical Review Body (AWERB). approach with four highly effective newly
for the templated-assembly of 3D developed drugs.

NC3Rs PhDs
neuromuscular junctions

Ketamine
• Roisin Owens (Cambridge): A novel
approach for modelling the healthy nose–

therapy
brain axis in vitro Three new PhD students based on the
• Kirill Volynski (UCL): Novel in vitro brain and nervous system have been
platform to study molecular mechanisms funded by the NC3Rs:
of neurotransmitter release and synaptic • Alessio Vagnoni (KCL): Mapping A nationwide network led from Exeter has
plasticity mitochondrial contact sites during neuronal received £2.4m NIHR and MRC funding to
• Tilo Kunath (Edinburgh): Establishment ageing and neurodegeneration in Drosophila evaluate use of ketamine-assisted therapy
of a cryo-bank of lineage-committed neural • David Dickens (Liverpool): Novel, for severe alcohol misuse disorder. The
progenitor cells produced from engineered biologically relevant, in vitro model of the phase III KARE trial, evaluating combined
human pluripotent stem cells blood–brain tumour barrier use of ketamine and psychotherapy, will
• Robert Williams (Bath): Implementing • Robert Hindges (KCL): Zebrafish build on encouraging phase II study data,
an MEA platform in human neurons for models of major depressive disorder which showed that the combination of
studying age-related neural network as a replacement for rodent models low-dose ketamine and psychotherapy
dysfunction and testing dietary markedly enhanced alcohol abstinence
interventions in people with alcohol misuse problems.

8 BNA Bulletin Spring 2023 www.bna.org.uk

 Analysis

Putting sustainability
at the heart of the BNA
Joseph Clift discusses what the BNA is doing in response to the climate
emergency – as an organisation and for neuroscience more generally.

There are few policy challenges more Encouraging change

pressing than the immediate and future at institutions
threat of climate change. The BNA is Research labs have a large environmental
responding to this with actions not only footprint, from the various consumables

Nkapil08/WikiMedia Commons
to change how we work as an organisation, of a project and animal housing for
but to help encourage change across in vivo research, to the overall energy
neuroscience. consumption. The Laboratory Efficiency
The World Health Organization makes Assessment Framework (LEAF) has
the importance of action clear, describing been developed by UCL to provide
climate change as the single biggest an independent standard for defined
health threat facing humanity. The UK sustainability. We are encouraging
Going green in brain science.
has committed to reach net zero by 2050, neuroscience research labs to recommend
to meet the Paris Agreement’s target that their institution participates in
to limit global warming to 1.5°C. WE’VE COMMITTED TO MAKING LEAF and to then implement this within
Many countries and organisations are THE BNA AS ENVIRONMENTALLY their labs.
seeking to make greater reductions sooner RESPONSIBLE AS POSSIBLE IN UK Research and Innovation is also
– within the research sector, the MRC ALL OUR ACTIVITIES working with universities, research
is planning to halve its carbon footprint organisations and other funders to
by 2030 and achieve net zero by 2040. and provide support for neuroscientists, to develop a concordat for increasing the
how we can work with other organisations environmental sustainability of research
Declaring a climate emergency involved in neuroscience research. Our and innovation, with a public consultation
The BNA is joining other organisations Green Neuroscience Working Group will expected in 2023.
and institutions across the UK and globally guide our activities, set targets for the BNA
in declaring a climate emergency to on carbon reduction, and look at how we Reducing the environmental
highlight the urgency of the need for action. can raise the profile of green neuroscience impact of neuroscience research
We’re by no means the first organisation within the wider neuroscience community. We want to support neuroscientists
to do this, but we’re taking this step We have already made changes to to make positive steps to reduce the
as part of a broader commitment to practices at the BNA to reduce our carbon environmental impact of their own research
raise awareness within the neuroscience footprint, including: activities. Part of the remit of our working
sector of the urgent need to minimise the • Enabling up to 50% of speakers in each group is to identify ways that the BNA can
negative environmental impact of research, session of our festival of neuroscience help to support individual researchers that
teaching and practice. to present online rather than deliver their strive to make a difference – be that in
A declaration alone counts for little talk in person. their own research, their academic career,
if it is not backed up with meaningful • Asking applicants for our travel bursaries or in their own institutions.
action. One of the areas that the BNA to demonstrate how they have made We are also encouraging our Local
has been recently developing is a ‘green efforts to reduce the carbon footprint of Groups to help support individuals that
neuroscience’ policy area, backed by a their travel, encouraging a ‘train over plane’ want to raise the profile of the need for
new working group, to lead our response approach. more sustainable research. This includes
to the climate crisis and encourage more • Ensuring catering at BNA events is collective action to encourage institutions
sustainable approaches to neuroscience vegetarian and considers other low carbon to go greener.
research. impact food options as much as possible. We also want to hear your views
The BNA is also facilitating about the environmental sustainability
Changing the way the BNA works engagement on sustainability by providing of the neuroscience sector – help us by
Through this declaration, we’ve committed an opportunity to promote green completing our current survey. Visit:
to making the BNA as environmentally neuroscience and engage with delegates surveymonkey.co.uk/r/GreenNeuro
responsible as possible in all our activities at BNA2023.
– from how we organise our own events • Joseph Clift is Head of Policy and Campaigns at the BNA.

www.bna.org.uk Spring 2023 BNA Bulletin 9

 Analysis

A feel-good festive season

The 2022 BNA Festive Symposium introduced the BNA’s theme for 2023, mental health, with
speakers delivering an entertaining and informative set of talks on key mental health conditions
– and, appropriately for the season, happiness.

new strategy and the psychoactive component of magic

opportunities for mushrooms, has great promise in the
neuroscientists. treatment of depression. Positive phase
Wellcome has IIb trial results were recently published.
identified mental While mechanisms of action are not
health as one of absolutely nailed down, psilocybin is known
its three priority to act on 5-HT 2A receptors and promotes
areas, focusing on the decoherence of key brain networks,
On 12 December 2022, the much-loved anxiety, depression and psychosis (broadly particularly the default mode network
BNA Festive Symposium returned to defined) and early intervention. Basic (DMN).
its in-person format, after two years of science funding for neuroscience is available Turning to neurodevelopmental
virtual events. For the first time, it was through its Discovery funding programme. disorders, Mike Ashby (Bristol) discussed
held outside London, with Edinburgh Meike Bartels (Amsterdam) then lifted the MURIDAE initiative (see BNA Bulletin
Neuroscience doing the honours. As always, the mood by examining mental wellbeing Summer 2022). Part of the MRC National
the Festive Symposium was an opportunity and happiness. Twin studies suggest that Mouse Genetics Network initiative, the
to introduce the BNA’s annual theme, genetic factors account for perhaps 40% MURIDAE consortium is using a range of
mental health – hence the Symposium’s of happiness measures. Genome-wide tools to map the developmental trajectory
title ‘Have your mental health a merry association studies have identified genetic of mice engineered to contain genetic
little Christmas’. variants associated with a predisposition variants associated with schizophrenia.
Kicking off proceedings, Beata to happiness; their expression patterns in Machine learning methods will be used
Godlewska (Oxford) summarised what is the brain suggest a possible involvement to identify developmental measures
known about the mechanisms of action of the subiculum. However, the variants associated with later onset of psychotic
of antidepressant treatments. Although identified to date account for only a small symptoms, which could reveal potential
drug treatments have been used for 70 percentage of total variance, so many other targets and time windows of intervention.
years, it is still not absolutely clear how the factors likely contribute to a polygenic score
most commonly used treatments work. for happiness. Even less is known about Treatments
The monoamine hypothesis dominates specific environmental influences, although Wrapping up the day, Stephen Lawrie
the field, although multiple aspects of an ‘environment-wide association analysis’ (Edinburgh) provided a whistle-stop tour
the hypothesis remain unclear, including identified several socioeconomic factors of autism, bipolar disorder and psychosis.
reasons for delayed treatment effects. associated with happiness, as well as He discussed how reversal of symptoms
Recently, a possible role for neurogenesis neighbourhood safety. in a mouse model of Rett syndrome,
has come under scrutiny, while a focus on Hamish McAllister-Williams which includes autism-like features, has
negative bias in information processing (Newcastle) raised the intriguing prospect raised hopes that at least some aspects
has seen greater collaboration between that vagal nerve stimulation could be an of neurodevelopmental disorders could be
psychologists and pharmacologists. effective treatment for depression. First reversed; a gene therapy trial is due to start
used to treat epilepsy, it was also found to this year. For bipolar disorder, lithium is a
Inflammation enhance mood, independently of effects highly effective treatment, and might be
Next, Jonathan Cavanagh (Glasgow) on seizures. Mechanisms of action remain acting through circadian mechanisms.
examined the evidence for inflammatory unclear – vagal nerve stimulation has In psychosis, changes in brain volume
contributions to conditions such as multiple effects on the brain. Although could be significant and may lead to new
depression. Several lines of evidence there is limited rigorous evidence, there are methods of early diagnosis.
suggest that inflammatory mediators tantalising signs that it can have positive He also reminded delegates that,
may be accessing and acting on the brain effects on depression, quality of life and contrary to many perceptions, psychiatry
to affect mood and behaviour. However, it mortality (fewer suicides, but also lower already has good treatments – but
remains unclear which specific mediators all-cause mortality, potentially because underinvestment in mental health services
are most important and how they are patients’ self-care improves). means they do not always reach those in
exerting their impact. Discussing another unconventional need.
In a break from the science, Inês Pote therapy, Gary Gilmour (COMPASS
and Bradley Roberts outlined Wellcome’s Pathways) suggested that psilocybin,

10 BNA Bulletin Spring 2023 www.bna.org.uk

 Analysis

Mental health in focus

Mental health is the BNA’s theme for 2023.

One of the less obvious sector partnerships to address this huge

consequences of the unmet need.
COVID-19 pandemic The stigma associated with mental
was an increased focus health conditions persists but there are
on mental health. Fear encouraging signs of greater openness
of the disease, the and a willingness to acknowledge mental
loss of loved ones and health difficulties. Most people now have
the social isolation experienced, or know someone who has
associated with experienced, mental health difficulties.
lockdowns all led to an With its unique insights into the brain,
alarming rise in mental the neuroscience community has an
health conditions opportunity to deepen understanding
such as anxiety and https://pixabay.com/users/905513-905513/ of these conditions and to shape
depression. interventions that protect mental health
These impacts have been layered upon brain function – placing neuroscience at and can effectively treat mental health
an already high mental health disease the heart of mental health. Psychiatry conditions when they arise.
burden, in the UK and globally (see Box). and neuroscience have not always seen
As well as these personal impacts, a recent eye to eye, but recent years have seen a
report from the Mental Health Foundation strengthening of relationships between the The burden of mental health conditions
and the London School of Economics and two, illustrated by the BNA’s partnerships Globally in 2019:
Political Science (LSE) put the economic with the Royal College of Psychiatrists and • 1 in every 8 people, or 970 million
cost of mental health problems at £118bn the Psychiatry Consortium. people around the world, were living with
a year, or 5% of the UK’s GDP. Neuroscience offers an opportunity a mental health condition
Mental health is a broad and complex to provide a deeper mechanistic • 301 million people were living with
area. Many different mental health understanding of mental health conditions. an anxiety disorder, including 58 million
conditions are recognised – around 300 in A combination of work on humans and children and adolescents
the latest version of DSM-5, the influential animal models – plus theoretical studies • 280 million people were living with
diagnostic manual for psychiatry. Mental – is beginning to shed light on key neural depression, including 23 million children
health difficulties may also co-exist or be mechanisms underpinning a wide range and adolescents
co-morbidities associated with physical of mental health conditions. One critical • 24 million people or 1 in 300 people
health conditions. More broadly, it is clear trend has been to consider mental worldwide were living with schizophrenia,
that poor mental health can affect quality health problems in terms of underlying associated with a life expectancy
of life even without a clinical diagnosis, mechanisms rather than diagnostic criteria 10–20 years below that of the general
supporting efforts to promote greater based on symptoms. This transdiagnostic population
mental wellbeing. approach addresses the challenge that • 14 million people experienced eating
This complexity is reflected in the there is considerable overlap in symptoms disorders, including almost 3 million
causes of mental health conditions. across diagnoses, and the fact that children and adolescents
Rarely, they are the result of single-gene particular conditions may have distinct • Over 700 000 people die due to suicide
disorders. More commonly, genetic underlying causes. every year
factors increase the risk of a condition There is an urgent need for new
but are not fully predictive. Clearly, and improved treatments for mental In England:
psychological make-up, life events and health conditions, and for better • 2.0 million adults and 0.8 million
social circumstances can also have a matching of treatment to patient. children accessed NHS mental health,
profound impact on mental health. The Pharmaceutical development in this area learning disability and autism services in
biopsychosocial framework recognises is highly challenging, with high failure 2020/21
that it is the interplay between all these rates, at least in part because of poor • NHS England spent £14.3bn on mental
factors that drives mental health status. understanding of disease mechanisms. health services in 2020/21
Common to all mental health With external partners, the BNA’s Building • Around 1 in 6 children aged 6 to 16
conditions, however, is the involvement of Bridges Between initiative has been had at least one probable mental health
the brain. Ultimately, all factors influencing strengthening links between industry and problem in 2021, up from 1 in 9 in 2017.
mental health do so by impacting on academia to try to encourage more cross-

www.bna.org.uk Spring 2023 BNA Bulletin 11

 Analysis

Join the journal club

Brain and Neuroscience Advances’ new ‘Journal Club’ articles provide
opportunities for early-career researchers to reflect on newly published
papers – and gain a new publication themselves.

Brain and Neuroscience Advances offers sections (stage 2). Publication of stage 2
several different article formats. A newly submissions is guaranteed as long as the
introduced category is the ‘Journal Club’ approved stage 1 protocol is followed and
article, short scholarly reviews of recently conclusions are appropriate. Full details
published neuroscience articles. can be found at bit.ly/3kVkcWT. Neuroscience Advances will also be
In addition, on Tuesday Journal Club publishing poster abstracts as a special
articles offer opportunities for contributors BNA Festival supplement.
to comment on new papers and place Brain and Neuroscience Advances will
new findings in a wider context, by have a strong presence at the BNA2023 Publishing in Brain and
providing a short overview of the topic International Festival of Neuroscience. Neuroscience Advances
and questions addressed in the reviewed On Sunday 23 April, 18:20–19:20, There are many great reasons to publish
paper, a description of the key findings, SAGE (publishers of Brain and Neuroscience in Brain and Neuroscience Advances
and a brief discussion of the significance Advances) is sponsoring the Brain and (see www.bna.org.uk/publications/bna-
of the paper. The article should go beyond Neuroscience Advances opening plenary, journal/), and you’ll be helping to support
what was included in the original article, focused on credibility in neuroscience, the BNA. Don’t forget that BNA members
for example by presenting a broader which will feature presentations by Russ are entitled to a 50% discount on article-
interpretation of the results in the context Poldrack (Stanford), Saloni Krishnan processing charges (APCs). Plus, if you are
of wider related work. (Royal Holloway, University of London), affiliated with one of the many institutions
Journal Club articles are intended Madeline Lancaster (Cambridge) and with Open Access Prepaid Accounts
to provide an ideal opportunity for Mike Ashby (Bristol), plus an introduction with SAGE, the publisher of Brain and
graduate students, postdoctoral fellows, from Jeff Dalley on how the journal is Neuroscience Advances, you can recover the
or other early-career researcher to hone promoting credibility. full cost of the APC and not pay anything at
their analytical and writing skills and On Tuesday 25 April 2023 (15:30–17:10), all. Why not try it out for your next paper?
to enhance their publication record. Editor-in-Chief Jeff Dalley (Cambridge)
Prospective authors can select any paper will be taking part in a workshop on the Kate Baker has
in any journal that they consider merits future of publishing in translational joined Brain and
further discussion and submit a Journal neuroscience, alongside Phil Bishop (Oxford Neuroscience
Club article, within 2 months of publication University Press), who will be talking on Advances as joint
of the original article. Submission should open access, Masud Husain (Oxford), who Editor-in-Chief.
not focus on the author’s own work will be discussing publishing in Brain, and Kate is a
or include new or additional results. Manuela Marescotti (Edinburgh), who will programme
All submissions will be peer-reviewed. be discussing gender bias. leader at the MRC
Full details can be found at There will also be other opportunities Brain Sciences
https://journals.sagepub.com/author- at the Festival to catch hold of Jeff and Cognition Kate Baker
instructions/BNA#ArticleTypes or fellow Editor-in-Chief Kate Baker Unit, Cambridge,
Another notable feature of Brain and (Cambridge) to discuss submission where she leads
Neuroscience Advances is its publication to Brain and Neuroscience Advances. the Genomic Disorders and Cognitive
of Registered Reports. These submissions On Wednesday 26 April 2023, Development Programme. She is also an
are reviewed in two stages. In stage 1, 9:30–11:10, Jeff and Kate will also be honorary consultant in clinical genetics.
a study proposal is considered for hosting a career development workshop
publication prior to data collection. Stage 1 on ‘how to review (and do it well)’,
submissions should include the complete offering advice to budding peer reviewers.
introduction, methods and proposed They will also be making an appearance
analyses, as well as the results of pilot at the Brain and Neuroscience Advances
studies, if available. High-quality proposals stand in the exhibition area, where you
will be accepted in principle before data can find out all you need to know about
collection commences. Once the study publishing in the journal and suggest
is completed, the author will finish the ideas for its future development.
article, including results and discussion Following the Festival, Brain and

12 BNA Bulletin Spring 2023 www.bna.org.uk

 Analysis

Neuroscience in Sussex
2023 marks 50 years since the first cohort of Neurobiology
BSc students graduated from the University of Sussex.
Miguel Maravall and Ruth Staras look back.

We think that Sussex was the first Simon Carey/WikiMedia Commons scanning facilities and clinical patients
university in the UK to offer a degree in through BSMS and the local NHS Trust,
neurobiology, and among the first in the has underpinned more recent research
world. Since then, neuroscience research successes in these areas and results in
and teaching has continued to grow, with exceptional opportunities for collaboration
around 400 research staff and students between basic and clinical neuroscientists.
working across 60 labs, and about 150 World-leading experimental research into
students per year joining our taught fundamental principles of consciousness
courses. and perception has also had significant
The description of our environment wider impact through public engagement.
The distinctive University of Sussex Meeting House.
should start with the Sussex campus At the molecular and cellular
itself. A few miles inland from Brighton levels, the mechanisms of synaptic
and the seaside, the beautiful campus activities, shared funding bids, a 4-year transmission, ion channels and receptors,
adjoins the South Downs National PhD Programme, dedicated senior research and neurodegenerative diseases are
Park, with sweeping views and many technicians, and management to cut across also central themes in our research and
opportunities for wellbeing on the daily the boundaries between traditional schools teaching, and benefit from strong local
commute or at the weekends. While the of study has fostered a vibrant community. links with Sussex centres for genetics and
campus has seen much new development Many of the major interdisciplinary drug discovery.
for student housing, it retains its research themes conceived in the early
own green spaces and remains clearly days of Sussex have benefited from this Broader benefits
recognisable by its distinctive Sir Basil environment and have continued to thrive The rapid development of advanced
Spence architecture, which still houses as they incorporate the phenomenal technologies and expansion of datasets
many research groups. technological advances of the last few has been a feature of progress in
The campus location and its decades. neuroscience research here, as elsewhere.
infrastructure have had a major Sensory neuroscience and computation One critical focus for Sussex Neuroscience
impact on the development of the is one such example. The pioneering work is the development of collaborative Open
neuroscience community at Sussex. of the late Mike Land, whose legacy we Science approaches. For example, MRI
Since the beginning, there have been will celebrate in a symposium on 27 April datasets acquired at Sussex on special
interdisciplinary collaborations between 2023 (see bit.ly/3EzjMwl for registration and normative samples are interoperable
biologists, neuroethologists and details), examined basic mechanisms and with national and international ‘big data’
experimental psychologists, joined more evolution of sensory systems and neural initiatives.
recently by computational neuroscientists circuits, and this is an enduring theme. Our work in producing affordable lab
and medics in the Brighton and Sussex Over the last ten years, the establishment hardware and efficient software that is
Medical School (BSMS), a partnership with of several large research groups freely available aims to improve access to
the University of Brighton created in 2003 specialising in advanced optical imaging neuroscience research in parts of the world
and which shares the same campus. of neural activity in behaving animals has currently excluded by the prohibitive costs
made a major contribution and brought of new technology. Examples such as
Encouraging collaboration cutting-edge technique development. these highlight ways in which we hope to
Research groups and their equipment are Similarly, seminal work on the contribute to reproducibility, collaboration
distributed across an array of buildings, computations underpinning behaviours and interdisciplinary skills sharing with
but remain within a few hundred metres such as foraging and navigation in ants neuroscientists everywhere.
of each other. In the past, this close yet has continued alongside innovations in
fragmented layout meant that some of GPU design, biomimetic AI and robotics. Miguel Maravall is Co-Director of Sussex Neuroscience;
the potential for wider collaboration and Another long-standing strength at Ruth Staras is Sussex Neuroscience Programme Manager
and BNA Local Group Rep (jointly with Sarah King).
sense of cohesion remained untapped. This Sussex is in experimental psychology and
changed in 2013 with a major investment human cognitive neuroscience, including
from the university to establish a new memory, ageing and neurodegeneration,
strategic research programme, Sussex addiction and consciousness. Local
Neuroscience. The resulting focus on expertise in human neuroimaging
creating shared lab space, building core technologies, together with access to MRI

www.bna.org.uk Spring 2023 BNA Bulletin 13

 Analysis

What's new in
neuroscience?
We asked some leading figures
in neuroscience what’s changed Leon Lagnado Anne Cooke
since the last BNA Festival in 2019.

Luis de la Torre-Ubieta. UCLA/Wellcome Images

An AI world Giant strides
“The growth of AI-based methods is “It’s been a transformative few years
having a profound impact on neuroscience. for the BNA.
Good examples are AI-based methods for Launching our Credibility in Neuroscience
image analysis and behavioural analysis. campaign at the House of Commons,
These tools have actually been around for pioneering the BNA Scholars Programme,
a long time, but they’ve been developed establishing a Green Neuroscience Working
in an open way and shared much more Group, and seeing the Building Bridges
effectively over the last few years. Better Between: Industry & Academia initiative go
software that’s better shared has caused from strength to strength are just some
very profound reverberations through of highlights: we have also been busy
neuroscience. strengthening the BNA’s foundations with,
Then there’s AI-based help for coding. amongst other things, an expanded staff
Nowadays, whatever kind of neuroscience team and securing a further £480,000
you do, coding is a basic skill. And how award from the Gatsby Foundation.
you code might be about to undergo a Events have continued online and in-
fundamental change. A time-consuming person (and both). We were ‘virtual host’
aspect of coding is adapting code written for the FENS Forum 2020, held the online
in one program for the program you are 2021 Festival of Neuroscience, ran our
using. Tools like ChatGPT and GitHub will first ever BNA Members’ Meeting, and our
very quickly help you translate it or give you first ever hybrid Festive symposium too.
alternative solutions to the same problem. Perhaps most importantly, though,
This is going to be incredibly useful for since 2019, we’ve increased our membership
people learning to code and people learning by 30% – so a big thank you to all existing
to code better. and new members, who enable us to truly
But this is all very new. I’m not quite ‘advance neuroscience together’.”
sure how it’s going to develop. To be
honest, we’re going to need to learn how Anne Cooke is BNA Chief Executive.
to use these things effectively. I still don’t
know how I’m going to be using it in a year
or two.”

Leon Lagnado is Professor of Neuroscience at the

University of Sussex.

14 BNA Bulletin Spring 2023 www.bna.org.uk

 Analysis

Tara
Dimitri Kullmann Spires-Jones Jeff Dalley Kate Baker

No more Hope at last Back

breakthroughs “Since 2019, the Alzheimer’s field has had and forth
anymore?
a huge advance with the first disease-
modifying drug, lecanemab, approved “The past few years have seen astonishing
in the US. This treatment is an antibody growth in AI capabilities. Drawing on
“More of the science that we see is either that lowers levels of the pathological principles discovered in neuroscience
‘omics’, where people generate oceans of peptide amyloid beta, and in a large clinical research, particularly reinforcement
data, or based on the latest fancy tool that trial, it slightly but significantly slowed learning, as well as greatly increased
has been invented. I think we need to slow cognitive decline. computing power, AI engineers have
down a bit and just try to use those tools While the drug is expensive and has developed tools of unprecedented
a bit better, rather than moving on to the side effects that may outweigh the modest sophistication.
next tool every time. benefits, it’s a real win for neuroscience as These tools are finding application
Also, so much research that we see many of us have been working for decades in all walks of life, including the lab.
now is based on the integration of different to understand how amyloid beta damages Neuroscientists are not alone in applying
methods. This can make it difficult for the brain. This proves finally that we can AI tools to data analysis and interpretation.
young people to break through. To get a develop treatments that alter the course Work on AI systems is also generating
big paper, you need to assemble a team of dementia. insights that may shed light on the
with expertise in so many different areas. Closer to home, we had good news in mechanisms of neural processing in
Obviously, you have to collaborate, but then the Alzheimer’s research field with the the brain and how they may go wrong
collaborations are very time-consuming and renewal of the UK Dementia Research in psychopathologies. The benefits are
they can be restricting if you find yourself Institute for another 5 years to continue reciprocal.
wanting to go off in a different direction. pioneering work understanding the brain It’s safe to say that we are only at the
I think the ‘lone wolf’ scientist has a very changes that cause dementias and working beginning of understanding where ever-
difficult time nowadays. towards more effective treatments.” more sophisticated AI systems may take
Based on textual analysis, a recent us, socially or in science. Perhaps they will
paper in Nature argued that paradigm- Tara Spires-Jones is Professor of Neurodegeneration at the transform manuscript writing, peer review
busting papers are less common these days. University of Edinburgh and President-Elect of the BNA. or scholarly publishing. More immediately,
I’m not as pessimistic about the future as if your work is on the AI–neuroscience
that paper implied. I think that perhaps that crossover, there’s always space for
trend’s more to do with the fact there are so your findings in Brain and Neuroscience
many people working in science that most Advances.”
outputs are inevitably incremental. It’s
definitely an exciting time to be working in Jeff Dalley and Kate Baker are Editors-in-Chief
neuroscience.” of Brain and Neuroscience Advances.

Dimitri Kullmann is Professor of Neurology at UCL.

Park M, Leahey E, Funk RJ. Papers and patents are becoming

less disruptive over time. Nature. 2023;613(7942):138-144.

www.bna.org.uk Spring 2023 BNA Bulletin 15

 Issue No. 8
Spring 2023

Welcome to Brain Insights!

Being a student is one of those moments in If you have ideas or suggestions for
life when the future seems like a list of endless Brain Insights, or would like to get in touch,
possibilities. Will I be a researcher? Will I be a contact us:
clinician? Will I work on something that I don’t • Autumn/Winter Lead Editor:
even know exists right now? Ryan Stanyard
Your job is to learn and find what you like, and ryan.a.stanyard@kcl.ac.uk
when you are a student in neuroscience there is • Spring Lead Editor:
Ariane Delgado Sanchez Ryan Stanyard
so much to learn and so much to like. There is a
ariane.delgadosanchez@manchester.ac.uk Autumn/Winter
great deal of knowledge in our field waiting for
• Summer Lead Editor: Lead Editor
new students to come and learn about it.
Our incredibly talented student writers have Harriet Hobday
done an amazing job at presenting the area of harriet.hobday@kcl.ac.uk
neuroscience that they find the most fascinating.
We invite you to come and read their great work.
Who knows? You might find your future
passion in these pages, maybe in a topic you did
not even know existed until now.

Ariane Delgado Sanchez

Spring Lead Editor, PhD Candidate Ariane Delgado
Sanchez
• Versions of articles with references can be Spring Lead Editor
found on the BNA website.

Harriet Hobday
Summer Lead Editor

16 BNA Bulletin Spring 2023 www.bna.org.uk

BRAIN INSIGHTS

Photobiomodulation for the and neurogenesis via brain-derived

treatment of major depressive disorder neurotrophic factor (BDNF). These are all
Lydia Kitchen, third-year PhD student factors that should benefit MDD patients,
in Biological Sciences, Durham University particularly the BDNF increase. BDNF is
involved in synaptic plasticity, and its
expression is typically lower in depressed
Major depressive disorder (MDD) is a clinical study of PBMT with MDD patients patients. PBMT increases BDNF by the
psychiatric disorder that affects 5% of found that a single forehead exposure to stimulation of transcription factors and
adults worldwide, making it a leading 810 nm light decreased the mean Hamilton antioxidant effects. In addition, the NO
cause of disability and a main contributor Depression Rating Scale score by more release and oxygen availability caused by
to the global burden of disease. To than 50%. Another proof-of-concept PBMT allow for improved cerebral blood
this day, one in three patients show no study found that six sessions of 808 nm flow, which has also been associated with
improvement after multiple treatment treatment resulted in 50% temporary MDD remission.
approaches (typically drugs from different remission 6–7 weeks post-irradiation. Although larger clinical studies are
pharmacological classes combined with The exact mechanisms by which required to further understand the
psychotherapy). There is, therefore, a PBMT targets depression are not yet fully effectiveness of this novel therapeutic
pressing need for the scientific community understood but several biological effects option, the current evidence suggests that
to better understand the pathophysiology have been proposed. PBMT begins with PBMT is a promising, low-cost, safe and
of MDD, as well as approaching treatment the application of red or NIR light, causing easily administered treatment option for
from a different biological perspective. photodissociation of nitric oxide (NO) MDD.
One proposed alternative treatment from cytochrome c oxidase, which is the
is photobiomodulation therapy (PBMT): terminal enzyme of the mitochondrial
a light-based therapy that stimulates, electron transport chain. The stimulation
enhances and heals cellular function. In this of the respiratory chain and resultant ATP
therapy, red (600–700 nm) or near infrared production cause downstream effects,
(NIR, 750–1500 nm) light can be applied including the induction of transcription
to the head, often with light-emitting factors such as NF-κB and a brief release
helmets. PBMT has been shown to help a of reactive oxygen species, leading to
number of psychiatric conditions. The first inflammatory changes, cytoprotection,

Can physical exercise improve norepinephrine signalling, both of which

ADHD symptoms in children? are associated with ADHD symptoms.
Maite Lopez, MPhil in Medical Sciences Although exercise seems to be a good
(Clinical Neurosciences), University of Cambridge intervention for children with ADHD, some
limitations still exist. Firstly, exercise has
not shown an effect as large as the one
ADHD is a neurodevelopmental disorder Recent studies demonstrate that observed with pharmacological treatment.
that is characterised by inattention, physical activity might be an alternative Furthermore, evidence also shows that
hyperactivity and impulsivity, with intervention to reduce symptoms and the extent to which exercise may reduce
symptoms first appearing in childhood. improve mental health in children with ADHD symptoms decreases with age.
Although the physiological processes ADHD. In particular, one meta-analysis Nevertheless, exercise may help children
underlying ADHD are not yet fully discusses the positive effects of exercise with ADHD manage their symptoms,
understood, dysregulated brain activity on attention, motor skills and executive potentially providing developmental
– such as reduced neurotransmitter function, all of which are often impaired benefits later in life. Therefore, exercise
signalling and reduced cerebral blood flow in ADHD. A potential mechanism through could be a good alternative for young
– appears to be involved. Pharmacological which this might be taking place is children with ADHD for whom medication is
treatment is standard for ADHD, with through the effect of exercise on brain not the best option or for those who would
stimulant medication being the most development. Exercise has been associated like to pair pharmacological treatment with
widely used. Stimulants act by increasing with the development of higher cognitive non-pharmacological alternatives.
activity in certain areas of the brain, function, which may be involved in reducing
specifically where the neurotransmitters cognitive impairments typically found in
dopamine and norepinephrine are involved. ADHD. Furthermore, another mechanism
However, pharmacological treatment may through which exercise may improve
not always be the best option due to side ADHD symptoms is by increasing cerebral
effects or other reasons. blood flow, as well as dopamine and

www.bna.org.uk Spring 2023 BNA Bulletin 17

BRAIN INSIGHTS

MDMA: Can the party drug promising, there are certain factors that
be used to treat PTSD? could limit the advancement of research in
Taneisha Patel, MSci Cognitive Neuroscience this area. Firstly, MDMA has been classed
and Psychology Student, University of Manchester as a schedule 1 drug since the 1970s war on
drugs, implying that it has no therapeutic
value. Consequently, until the rescheduling
Post-traumatic stress disorder (PTSD) is promising treatment for PTSD. of MDMA, it will not be possible to use
a highly prevalent anxiety disorder, with MDMA is a synthetic drug, often used MDMA-assisted therapy clinically, a major
trauma-focused therapy as its first-line recreationally for its creation of euphoria, drawback of the treatment for patients,
treatment. During this type of therapy, energy and prosocial effects. This drug societies and finances. Promisingly,
individuals are asked to reimagine and works by increasing the effects of the rescheduling of MDMA and approval from
reprocess their trauma. However, drop- monoamine neurotransmitters, serotonin, regulatory agencies seems more probable
out rates for this therapy are high in norepinephrine and dopamine. This causes since the recent phase III clinical trial.
comparison with other therapies for PTSD, an increase in good mood, attention and Nevertheless, this is not the only factor
presumably because of the challenging pleasure. In addition, MDMA increases slowing down this research. Past research
nature of the process. Pharmacological oxytocin levels, increasing feelings of into the attitudes towards psychedelic
interventions are also used; however, their bonding. MDMA also decreases amygdala therapies indicates that there will also be
efficacy profiles are not encouraging, with activity, which is found to be hyperactive barriers stopping clinicians wanting to use
the most used selective serotonin reuptake in PTSD, which causes the patient’s this therapy.
inhibitors (SSRIs) showing only a 30% upregulated fight or flight responses. Future research should investigate
recovery rate. These effects of MDMA help in therapy doctors’ and medical students’ attitudes
Recently, a wave of research into using sessions for PTSD by aiding the patient– towards MDMA-assisted therapy, perhaps
3,4-methylenedioxymethamphetamine therapist relationship and allowing through frameworks such as a behaviour
(MDMA; ‘ecstasy’) to aid therapy sessions patients to talk openly about themselves change model to find out what these
is unfolding, with a first phase III clinical and their past, without defensive barriers are and what may help clinicians
trial finding that MDMA-assisted conditioning intervening. to implement the new therapy once
psychotherapy is an efficacious, safe and Although preliminary results are permitted.

States of mind: Balancing perception have gained increasing interest over the
and memory in the hippocampus past decade. fMRI studies have provided
Jude Ray, MSci Neuroscience Student, evidence for the hypothesis that mnemonic
University of Manchester prediction errors bias the hippocampus
to an encoding state, driving memory
updating. On the other hand, when
Hierarchical predictive coding models have information is not being encoded, or a state predictions are correct, an internal state is
advanced our understanding of perception where our model of the world is switched prioritised where memories are reactivated
and memory in the last two decades. In off, could lead to adverse recognition and and even consolidated. Recent research
these models, perception is driven by the memory. Why is this switching between investigated how prediction error affects
brain’s attempts to match its internal states then so important? The reason perception and learning mechanisms
representations with incoming perceptual seems to lie in the fact that if current when the hippocampus is biased towards
input, by making predictions based on information is encoded at the same time retrieval. Results showed that prediction
past experience. Prediction errors, formed as retrieval of memories, these related error increased perceptual processing and
from the disparity between predictions and memories can become difficult to separate. engaged an implicit external encoding
representations at a level below, trigger In other words, the brain cannot distinguish mechanism, even when the context was
encoding mechanisms and facilitate future what is its internal model and what is biased to retrieval.
predictions. The hippocampus supports information coming from the environment In closing, we go back to the issue
the representation of predictions and if both states are equally weighted. of how the brain balances encoding and
predictive errors by fluctuating between Furthermore, computational models have retrieval of information. How does the
internal and external states. The internal provided evidence that state switching context of our environment, internal model
state refers to the retrieval of associated may provide the conditions to generate and brain state affect what we perceive
representations to generate predictions, prediction errors. and remember? Empirical research,
via pattern completion. The external state Characterising the psychological and driven by theoretical hypothesis and
is characterised by encoding perceptual neurological mechanisms that govern computational modelling, may hold the
inputs into memory, via pattern separation. hippocampal state shifting, and its answer to these questions. Only the future
Intuitively, switching to a state where consequences for perception and memory, can tell.

18 BNA Bulletin Spring 2023 www.bna.org.uk

BRAIN INSIGHTS

The brain–gut microbiome axis short-chain fatty acids and secondary bile
and neurological pathologies acids, regulate the synthesis and release
Amaarah Udat, Medicine Student, of serotonin (5-HT) from enterochromaffin
Queen’s University Belfast cells (the cells that produce and store
most of our body’s 5-HT). The increased
stimulatory actions of enterochromaffin
The brain–gut microbiome axis refers spectrum disorder, Parkinson’s disease cells leads to their communication with
to the bidirectional interaction between (PD) and multiple sclerosis. In particular, vagal afferent nerve terminals that send
microbial communities in the gut and the studies have shown that dysfunction in signals to the CNS – a clear example of
CNS. This axis, which has gained research the brain–gut microbiome axis provides brain–gut microbiome interplay.
interest in the last decades, seems to vital insight into the pathogenesis of the When it comes to the top-down
play an important role in neurological gastrointestinal symptoms of PD. This has modulation, it is well-established that
functioning. been considered an indication for the need human gut bacteria are sensitive to the
To begin with, research in mice has to study whether gut microbiota could be neurohormone melatonin, produced
shown that the absence of a conventional used as a biomarker or therapeutic target in the pineal gland of the brain, which
intestinal microbiota results in an altered for those in the premotor stage of PD. is secreted into the gastrointestinal
neurochemical make-up within the brain. In With these promising results regarding system. Melatonin plays a key role in the
particular, a study found that the absence the link between the brain and the gut, the regulation of circadian rhythm. A circadian
of normal gut microbiota early in life question arises of how these two systems rhythm exists within the gastrointestinal
resulted in an exaggerated hypothalamic– communicate with each other. There are system, where disruption to the rhythm
pituitary–adrenal (HPA) stress response in multiple signalling mechanisms implicated affects the distribution of gut microbiome
adult life. Interestingly, reversal of these in the brain–gut microbiome axis, with constituents. In this way, the top-down
changes by early colonisation of the gut evidence suggesting both a bottom-up and modulation of brain secretions affects the
with at least a single species of microbiota top-down modulation between the CNS composition of the gut microbiome.
corrected, in part, the enhanced HPA stress and the gut microbiome. In conclusion, the brain–gut microbiome
response. Bottom-up modulation of the CNS axis shows both bottom-up and top-down
Furthermore, alterations in this is via microbially derived molecules and communication. Understanding these
brain–gut microbiome axis have been cells of the gastrointestinal tract. In mechanisms could inform the development
implicated in both psychiatric and particular, it has been observed that certain of new interventions for neurological
neurological pathologies, including autism microbial-derived substances, known as pathologies such as PD.

Exploring facial expression negative emotions versus a unique easily

recognition in Parkinson’s recognisable positive emotion (happiness).
Maille Frances Gracey, PhD in Psychology, The difficulties in reaching conclusions
University of Birmingham might be partly attributed to the
methodological issues in this field of
research. In particular, one major limitation
Parkinson’s is a neurodegenerative quantified differences with the recognition is that studies in this topic have typically
disease of the basal ganglia, primarily of emotional expression in PwP for over-relied on ‘static stimuli’ such as
involving the degeneration of dopamine almost 40 years. In fact, a recent review photographs, which lack realism (since
neurons. For many years, Parkinson’s of the literature noted that 64% of real-life facial expressions are dynamic/
was considered to be purely a ‘motor studies confirmed differences with facial moving).
condition’, with symptoms such as emotion recognition in PwP. Interestingly, In the future, studies could aim to
tremor (shaking) as the main focus. although studies found differences in overcome methodological limitations
However, a body of evidence has also the recognition of the six basic emotions (perhaps by using dynamic displays as
linked dopamine neurodegeneration to – anger, happy, sad, disgust, fear and stimuli) and reach conclusions on the
‘non-motor symptoms’ such as cognitive surprise – in PwP, the level of differences mechanisms behind the disparities in
impairment. A recent report suggests that did not seem to be equal in all of them. the recognition of emotions of different
people with Parkinson’s (PwP) experience One argument put forward is that PwP valences. This is an important research
socio-cognitive (social and information struggle more with recognising negative endeavour since differences in recognising
processing) challenges. These differences emotions, such as anger and sadness, others’ emotions can have a significant
can manifest in various ways, with one than positive emotions, such as happiness. and negative impact on PwP’s social
of these ways being facial expression Although, it is not clear why this might relationships, and ultimately have a major
perception. be, researchers have hypothesised that and detrimental impact on their lives.
Researchers have observed and it could be due to the greater diversity of

www.bna.org.uk Spring 2023 BNA Bulletin 19

BRAIN INSIGHTS

Why study death in worms? multiple circuit layers.

Robert Golightly, MSc Biomedicine Student, Through this methodology, a study
Lancaster University performed by Coburn et al. identified a blue
death fluorescence (DF) assay generated
within intestinal cells that allowed the
tracking of necrotic cell death in C. elegans.
Death in neurology is defined as the It has been proposed that a good Further studies then determined that,
irreversible sequence of events culminating candidate for such an experimental in C. elegans, this DF and necrosis are
in permanent cessation of cerebral system could be C. elegans. C. elegans coupled. Moreover, researchers determined
functions. Due to human nature, neuronal is a nematode worm that is utilised that organismal death is triggered by a
and brain death has been thoroughly throughout biological research. It is systemic decrease in ATP levels and the
researched in neurology using multiple a model organism that shares many generation of a Ca2+ wave, which were
organisms, yet the relationship between essential characteristics which make it responsible for triggering a terminal muscle
neuronal death and organismal death still perfect for studying problems of human contraction which then led to a coupled
remains a mystery. To study and define biology. In particular, it is an organism wave of intestinal necrosis.
death in an organism, an experimental that has experimental amenability This process in C. elegans appears to be
system is needed that has an accessible and a well-defined nervous system. a major factor contributing to organismal
and well-defined nervous system that Recent advances in the study of death. Therefore, this study, along with
can be used to easily observe neuronal C. elegans have allowed assays to be the generation of the DF assay, is an
and brain death. This experimental system generated that can be used for the important showcase of how C. elegans
should provide the foundations to allow quantification of worm motor output in (and worms in general) can be used
the study of neuronal cell death as a whole defined stimulus environments. Thanks to as models to understand conserved
and allow the observation of culminative these assays, a comprehensive description mechanisms of organismal death. And this
neuronal death in the brain so that this of pathways can be extracted to define is why we should study death in worms.
phenomenon in tissue can be visualised in motor response; specifically, this method
a process to show the exact point where allows for the identification of where
this culmination becomes irreversible. sensory stimuli are relayed, through

The oppressed brain: Unfortunately, research seems to show

Long-term effects that these effects could be long-lasting,
Juan Felipe Espitia Jaramillo, as trauma leaves a generational scar. For
first-year medical student, Lancaster University instance, a study found that telomeres
present in babies correlate strongly with
the telomere length of their mothers at
Chronic social defeat, a stress associated performance and working memory. conception, and to a lesser degree with
with repeatedly losing, has been analysed Stress shakes us to our core, their fathers’ telomere length.
in studies where mice have had their from dendritic density to genes and At an early stage, these results are
space continually invaded. The results chromosomes. Data continue to show alarming, particularly if we think about
show a conserved transcriptional response that telomeres, the non-coding protective the potential implications for those
to adversity. In particular, it has been caps at the ends of chromosomes, are communities who have suffered the most
found that when faced with adversity, shortened after continuous stress until oppression. Historically, black, indigenous
the ‘defeated’ individuals show an cells may stop replicating and become and people of colour communities have
increased activation in proinflammatory senescent. This can be stopped by an struggled from the moment that colonists
mechanisms, such as myelopoiesis of enzyme that can replenish telomere length arrived in their lands, up to recent crises
monocytes and granulocytes. called telomerase, but cortisol stemming such as COVID-19. They also continue to
Alarmingly, this ‘defeat’ seems to also from stress reduces its activity. Once a cell have cultural stressors that increase the
elicit issues such as neuroinflammation, by adopts a senescence-associated secretory burden of mental health issues such as
unleashing inflammatory mediators such phenotype (SASP), it starts releasing depression. How this constant long-term
as corticotropin-releasing hormone (CRH). immune modulators, growth factors, oppression might have affected aspects
CRH activates cofilin which, alongside proteases and cytokines. The effects of such as neuroinflammation or telomere
protein kinase C, has been hypothesised senescence on the brain are multiple. length is still an open question that future
to degrade actin monomers of filaments When astrocytes and neurons take up research must address.
(the main component of dendritic spines SASP, this correlates with Alzheimer’s
at the prefrontal cortex and hippocampus). disease and other neurodegenerative
This has been shown to impair cognitive disorders.

20 BNA Bulletin Spring 2023 www.bna.org.uk

Hosted by In partnership with And Special Partner

THE INTERNATIONAL

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 Research

In the loop
Could gene therapy to modulate excitatory/inhibitory balance
provide new options for treatment of drug-resistant epilepsy?

After oscillating between medicine and of these disorders are actually very, very looked reasonably surmountable but
science, Dmitri Kullmann now combines rare. But it made me think about ways regulators would require very persuasive
both as a consultant neurologist and of manipulating the synapses to treat evidence before approving clinical studies.
researcher at the UCL Queen Square diseases. So rather than understanding To make the scientific case, he and
Institute of Neurology. Having developed what goes wrong, causing a disease, do it his colleagues used technologies such
a particular interest in genetic causes of the other way around and see if one can as EEG and electrocorticography (ECoG)
rare neurological conditions, he is now alter synaptic function in order to fix a to continuously monitor seizure activity
exploring whether gene-based approaches disease. And the obvious one was epilepsy.” using wireless transmitters. There were
might be a way to adjust the activity of Epilepsy is a well-characterised also opportunities to learn from the gene
neural circuits and treat conditions such condition, with seizures arising from therapy techniques already being trialled in
as epilepsy. unstable networks where the normal conditions such as Parkinson’s disease.
“I studied medicine at Oxford,” Dmitri balance of excitation and inhibition breaks He and his team also began to
says, “but I sort of stumbled into medicine. down. Working with Stephanie Schorge, investigate alternative gene therapy
I wasn’t quite sure what I wanted to do, Dimitri’s group had developed genetic strategies for epilepsy. As well as
but I was interested in mind and spirit.” The approaches to modulate synaptic function, potassium channel overexpression, he and
Oxford course was split into three years of and he wondered whether these could his group also showed that optogenetic
pre-clinical study followed by three years be used to restore balance in unstable approaches could stop seizures. They
in the hospital. “After the first three years, networks. One candidate was the were also able to apply DREADD (designer
I thought why not spend some more time KCNA gene, which encodes the Kv1.1 receptor exclusively activated by designer
thinking about the brain and the mind?” potassium channel. drugs) technology, through which an
This thinking took the form of a “We discovered that if we inhibitory receptor is introduced into the
DPhil, after which he returned to finish overexpressed this wild-type potassium relevant brain region and activated by
his medical degree. He then returned channel, we could reduce neuronal drug administration.
to science for 18 months, reverted to excitability, reduce neurotransmitter Some of the most elegant strategies
medicine, before heading off to the release, and stabilise neurons and neuronal have been based on ‘closed loop’ models
University of California San Francisco circuits.” Working with colleagues including that incorporate feedback mechanisms
for a postdoc in basic neuroscience. Matthew Walker who had well-described to terminate interventions. These include
Realising that he missed medicine rodent models of epilepsy, they found introduction of a glutamate-gated chloride
while doing science, and missed science that they could suppress seizures in living channel: when seizures happen, glutamate
while doing medicine, through an MRC animals. “And once we discovered that, is released, which is normally an excitatory
Clinician Scientist Fellowship he was we thought, well, why don’t we take this neurotransmitter. With the glutamate-
able to combine both. Now a consultant into the clinic?” gated chloride channel present, however,
neurologist, he sees patients for a day and Of course, moving from animal to neural activity is inhibited.
a half a week and devotes the rest of his human studies is far from trivial. Dimitri The most recent approach, developed
time to a mix of clinical and basic research. reasoned that the scientific challenges with Gabriele Lignani, has been to use an
activity-dependent promoter to drive the
A genetic approach expression of a potassium channel. “The
At the heart of his clinically oriented studies idea there is that when seizures happen,
is an innovative approach to gene therapy neurons fire excessively, and certain
for epilepsy. “About 1% of the population immediate-early genes switch on in these
has epilepsy,” Dimitri points out, “and about neurons. So we took the promoter for
a third of people with epilepsy continue to one of these immediate-early genes, and
have seizures, despite optimal medication. use that to drive the expression of the
So there’s an enormous unmet need.” potassium channel.”
His research had focused on basic The science is highly promising, so
synaptic physiology but also on how when might clinical studies begin? “I’ve
synapses go wrong in neurological been saying it’s a year away for about five
conditions, including rare inherited and years,” Dimitri acknowledges. “Now, I’m
autoimmune conditions affecting the saying it’s six months away.” There are still
CNS or neuromuscular junction. “A lot Dimitri Kullmann. several regulatory obstacles to overcome,

22 BNA Bulletin Spring 2023 www.bna.org.uk

 Research

“The challenge is, in a very highly

connected brain, how do you route
information from one part of the brain
through to another part of the brain, and
then rapidly switch the routing to another
connection?” A modelling study suggested
that the properties of interneurons
could enable oscillations to be a way of
transmitting information: “We showed
that you could actually use oscillations to
multiplex the transmission of information
through profusely connected pathways in
A pyramidal neuron and some neurogliaform neurons in the cortex.
the brain, that you can encode information
in the oscillation.”
“THE CHALLENGE IS, IN A VERY HIGHLY CONNECTED BRAIN, HOW DO The theory looked sound but what
YOU ROUTE INFORMATION FROM ONE PART OF THE BRAIN THROUGH about real life? “Then we asked the
TO ANOTHER PART OF THE BRAIN, AND THEN RAPIDLY SWITCH THE question, is this biologically plausible –
ROUTING TO ANOTHER CONNECTION?” do brain circuits actually have some of
the properties of oscillations that will be
for example to demonstrate biodistribution which are common in people with required to do this?” Laboratory studies
in a larger brain and alignment with Good epilepsy (although in one study in mice suggested that they did indeed have the
Manufacturing Practice. “We’re slowly an improvement in spatial memory right dynamical properties. “We did actually
inching towards a clinical trial,” says Dimitri. was seen after treatment). Even so, find a very nice correspondence between
First-in-human studies are likely to be the treatment is less invasive than the ways that the oscillations behave in
carried out on patients with drug-resistant conventional neurosurgery and focuses the real neural circuitry and the sorts of
epilepsy who are being evaluated for specifically on the abnormal circuits, properties you’d expect for oscillations.”
surgery. Gene therapy will be offered as an unlike drug treatments which can have In the future, Dimitri hopes to take
alternative but if it is unsuccessful patients ‘off-target effects’. this a step further and see if optogenetic
will still be able to proceed to surgical Furthermore, the general approach approaches can be used to modulate
treatment. This will enable the team to could be applicable to other conditions oscillations: “Then we’d like to see if that
take advantage of all the preparatory work characterised by overactive neural circuitry, has the ability to alter behaviour in some
done on patients, such as MRI scans and such as some forms of pain, although way that reflects, for instance, a change
other tests, and also means that, if the a lack of good animal models of pain in in the gain of transmission of signals
treatment is not successful, they will be is a significant drawback. Moreover, between brain regions. That’s an ambitious
able to analyse patient tissue to find out he adds, “There is evidence that OCD, task, but we’re working on it.”
why. “We see this as a win–win situation – migraine, Parkinson’s, even Alzheimer’s
either we get some evidence of efficacy, or and psychosis may be associated with Kätzel D et al. Chemical-genetic attenuation of focal
we get the tissue and then we could see if overactivity of certain circuits in the brain. neocortical seizures. Nat Commun. 2014;5:3847.
Wykes RC et al. Optogenetic and potassium channel gene
there was an obvious reason why the gene Perhaps we could try to interfere with that therapy in a rodent model of focal neocortical epilepsy.
therapy didn’t work.” using this approach at some critical stage Sci Transl Med. 2012;4(161):161ra152.
Initially, the focus is likely to be on in the disease process, though this is still Lieb A et al. Biochemical autoregulatory gene therapy for focal
epilepsy. Nat Med. 2018;24(9):1324-1329.
anterior temporal lobe epilepsy. However, quite speculative.” Qiu Y et al. On-demand cell-autonomous gene therapy for
although epilepsy is a disease will multiple brain circuit disorders. Science. 2022;378(6619):523-532.
causes, the gene therapy approach is Oscillations Akam T, Kullmann DM. Oscillations and filtering
networks support flexible routing of information. Neuron.
‘cause-agnostic’. “We’re not trying to undo Alongside this clinically focused work, 2010;67(2):308-20.
the underlying lesion,” Dimitri stresses. Dimitri has also been looking at the role Nicholson E et al. Analogue closed-loop optogenetic
“What we’re trying to do is to stop the that oscillations, particularly gamma- modulation of hippocampal pyramidal cells dissociates gamma
frequency and amplitude. Elife. 2018;7:e38346.
seizures, not necessarily to undo the frequency oscillations, might play in
underlying problem.” As a result, treatment transmitting and routing information
will not necessarily reverse co-morbidities, across the brain.

www.bna.org.uk Spring 2023 BNA Bulletin 23

 Research

Neurons on demand
Disentangling the pathways by which neural progenitors differentiate could help
to shed light on neurodevelopmental disorders such as schizophrenia and autism.

There is growing evidence that the origins I thought, ‘oh, I can do that, I can try that.’
of conditions such as schizophrenia and So that’s how I started really.”
autism are sown early in life and reflect
abnormalities in development of the brain. Making neurons
As the work of Meng Li (Cardiff) illustrates, With the derivation of human ESCs in 1998,
the ability to grow and differentiate the stem cell field has since blossomed.
neural progenitor cells is shedding light on Alongside ESCs, induced pluripotent
normal neuronal development and how stem cells (iPS cells) have become an
it goes awry in such neurodevelopmental essential research tool. Reprogrammed to
conditions. a pluripotent state, iPS cells can be derived
During her PhD, Meng worked with from adult tissues and induced to develop
Austin Smith, one of the key figures in into a range of cell types, including various
stem cell biology. Her project focused on categories of neuron. Importantly, they can
the LIF receptor, whose ligand is known also be derived from individuals carrying
Meng Li
to be critical for maintaining stem cells in risk genes for neurodevelopmental or other
an undifferentiated state. She generated disorders affecting neurons, providing an
a mouse knockout: “And the phenotype opportunity to understand what these TO MAKE SOME SPECIFIC
turned out in motor neurons not the risk genes might be doing. TYPES OF NERVE CELLS,
peri-implantation deficits we predicted.” “I was using stem cells to make IT’S STILL CHALLENGING.
This finding, made via a productive nerve cells and as a way to study neuron
collaboration with Michael Sendtner in development,” Meng explains. Generating the progenitor of various kinds of neurons,
Würzburg, Germany, triggered a shift in particular types of neuron can be clinically is actually fairly easy,” Meng suggests.
Meng’s research. “He invited me to spend important, for example for transplantation “But to make some specific types of nerve
a week his lab, where I learned how they studies. But there is also the fundamental cells, it’s still challenging.” Good progress
grow primary neurons. And that got me question of the cellular and molecular has been made in production of dopamine
interested in the brain and neurons.” mechanisms that cause a pluripotent neurons, as well as cortical projection
The other key development was the stem cell to turn into a specialised neuron, neurons: “That is generally considered the
publication of a paper by Gerard Bain et al. and how these processes are affected in default path – if you don’t do anything,
on the generation of neuronal-like cells neurodevelopmental or neurodegenerative they tend to make cortical projection
from mouse embryonic stem cells (ESCs). conditions. neurons.”
“With my new interest in nerve cells, “Generally, making a neural stem cell, A bigger challenge is generation of
inhibitory cortical interneurons. Although
GABA-ergic neurons are easy to produce,
says Meng, “they’re not exactly the
inhibitory cortical neuron that we want”.

Understanding development
The classic approach to generate neurons
of interest is to try to mimic the early
developmental environment that
drives differentiation down a particular
developmental pathway. If the genes
controlling particular neuronal cell fates
are known, another approach is to engineer
the desired fate by direct programming.
Much of Meng’s earlier work focused on
midbrain dopamine neurons, the type of
nerve cells that preferentially degenerate
Cortical interneurons.
in the brains of people with Parkinson’s

24 BNA Bulletin Spring 2023 www.bna.org.uk

 Research

disease. Her previous studies highlighted

the importance of a range of transcription
factors, including Pitx3, FoxP1 and Dmrta2,
as well as Erk signalling in dopamine
fate specification and/or terminal
differentiation. Her lab also identified
activin A as a robust inducer of stem cell
differentiation into striatal medium spiny
neurons, the loss of which is the primary
pathology of Huntington’s disease.

Neurodevelopmental conditions
Following her move to Cardiff, Meng has
been increasingly drawing on the extensive
local expertise in psychiatric genetics.
Cardiff researchers have been central
to global efforts to identify genetic risk
factors for a range of neuropsychiatric
Striatal projection neurons.
conditions, several thousand of which
now exist. In addition, local clinics provide
opportunities to collect samples from Meng off in another new direction. is a more general deficit of
patients and carriers that can be used The mechanisms of neurodevelopmental neurodevelopmental disorders and to
to generate iPS cells. conditions are very poorly understood, and explore the roles of oxysterol in the
One option is to study the impact of the risk factors identified in genetic studies pathogenesis of associated conditions.
genetic risk factors on the development might reveal biological pathways that
and properties of neurons derived from could be targeted through interventions. Arber C et al. Activin A directs striatal projection neuron
patients. One disadvantage of this Although thousands of risk factors have differentiation of human pluripotent stem cells.
Development. 2015;142(7):1375-86.
approach is that patients’ background now been identified, understanding Fjodorova M, Noakes Z, Li M. A role for TGFβ signalling in
genetics generates noise that may their role is a major bottleneck. However, medium spiny neuron differentiation of human pluripotent
mask the impact of genetic risk factors. Meng’s studies on one particular copy stem cells. Neuronal Signal. 2020;4(2):NS20200004.
Fjodorova M et al. CTIP2-regulated reduction in PKA-
A complementary approach is therefore number variant suggests a possible role dependent DARPP32 phosphorylation in human medium
to engineer specific mutations into control for disrupted cholesterol biosynthesis spiny neurons: Implications for Huntington disease.
cells or correct the risk mutation in patient underlying altered neural stem cell Stem Cell Reports. 2019;13(3):448-457.
Young FI et al. The doublesex-related Dmrta2 safeguards
iPS cells, using gene editing techniques behaviour in patient cells. neural progenitor maintenance involving transcriptional
such as CRISPR/Cas9. By sequencing RNA transcripts in regulation of Hes1. Proc Natl Acad Sci USA.
Using genome-edited human ESCs, affected and unaffected cells, Meng 2017;114(28):E5599-E5607.

Meng recently showed that the BCL11B discovered significant changes in

protein is important in medium spiny expression of genes associated with
neuron development and function – of cholesterol biosynthesis, and mass
particular significance because BCL11B spectroscopy studies indicated that the
interacts with huntingtin, the abnormal oxysterol profile of neurons had changed.
protein central to Huntington’s disease, Oxysterols are oxidised forms of cholesterol
which preferentially affects medium-sized or of its precursors and, unlike cholesterol,
spiny neurons. Moreover, polymorphisms can cross the blood–brain barrier from the
in the BCL11B gene are associated with brain to periphery and vice versa. Hence
increased risk of schizophrenia, in which they may have therapeutic potential or
striatal medium spiny neurons have could be used as a biomarker of a disease.
been implicated. Meng now hopes to secure funding
An intriguing recent finding is sending to see if altered cholesterol biosynthesis

www.bna.org.uk Spring 2023 BNA Bulletin 25

 Research

Big thinking
around small vessels
Small vessel disease appears to be a distinct form of stroke – and may also be making a major contribution to dementia.

With a background in stroke medicine “THERE’S A HUGE FOCUS ON

and brain imaging, Joanna Wardlaw ABNORMAL PROTEINS AND
(Edinburgh) is often compelled to remind NEURONS AND SYNAPSES. OF
people that blood vessels are just as COURSE, ALL OF THESE ARE
important to brain function as the neurons, IMPORTANT, BUT I THINK THE
astrocytes and other cells that typically BRAIN IS SOMETHING YOU NEED
hog the limelight. Her special interest lies TO CONSIDER HOLISTICALLY.
in small vessel disease, dysfunction of
the arterioles, capillaries and venules that the white matter of stroke patients, known
disseminate through the brain, delivering as white matter hyperintensities, are also
oxygen and metabolites and carrying away areas of damaged ischaemic tissue. But,
waste material. This dysfunction can lead Joanna points out, ischaemic tissue is not
to a type of stroke, cognitive impairment, the only possible cause of white matter
Joanna Wardlaw
and vascular and mixed dementias. hyperintensities: “Lots of different things
“I originally got interested in brain can make an area of tissue look white on
disease when I was a junior doctor Joanna, however, began to focus more on an MRI scan.” Furthermore, by repeatedly
training,” Joanna recalls. She began to the smaller vessels that ramify through scanning the brains of patients with white
specialise in radiology and happened to the brain: “I got quite intrigued because I matter hyperintensities with or without
read a case report about a patient who went back and read some of the original stroke, she discovered that white matter
had had a clot in the basilar artery and literature of pathology descriptions, and hyperintensities can become smaller
was given drug treatment to dissolve the the way people were thinking about small (as well as larger) over time and their
clot to improve blood flow. “I got quite vessel disease seemed to be quite different shrinkage (or increase) correlates with
intrigued, because at that time giving a to what was actually written in these improvements (or worsening) in motor
clot-busting drug to somebody who had original papers.” and cognitive function.
just had a stroke was the number one With her background in imaging, “It’s proved to be a really complex
contraindication.” Joanna was able to begin a more detailed problem,” Joanna suggests. “But I think
Joanna got involved in trials and now characterisation of small vessels, their we’ve got to the point where quite a lot
clot-busting drugs are routine treatment function and their effect on brain structure. of very confusing aspects of small vessel
for acute ischaemic stroke. This was the Her studies began to suggest that the versus large artery disease are now more
start of a fascination with brain vascular conventional view of small vessel disease clear. Small vessel disease is obviously
disease, aided by technological advances: might need updating. a very different condition to large artery
“One of the things about the last few The traditional view was that small stroke. It appears that the primary
decades is that modern medical imaging, vessel disease was essentially a miniature abnormality is largely in the lining of the
particularly magnetic resonance imaging, version of a large artery ischaemic stroke: blood vessels.”
has meant that you can see and measure a vessel becomes blocked and surrounding Further evidence for this distinction
what’s going on in a way that was never cells die because of lack of oxygen. What comes from the study of risk factors.
possible before.” Joanna discovered, however, was that “Everybody tends to think that
small vessel disease was associated hypertension is the main cause, and
Small details with abnormalities in the properties and therefore, if we treat hypertension, it will
Many ischaemic strokes reflect blockage function of small vessels, which appeared all go away. In fact, it’s very obvious that
of large blood vessels, through build-up to be abnormally leaky and stiff. you can have two people with very similar
of fatty material in the blood vessel wall This new view was based in part blood pressure, very similar adequacy of
(atheroma) or clots becoming trapped on a reinterpretation of the results of control of blood pressure, but one of them
and preventing blood flow. Deprived of brain imaging. For example, typically, an will have potentially quite bad small vessel
oxygen (ischaemia), surrounding brain ischaemic stroke appears white on MRI disease, and the other one will not have
tissue dies, triggering the physical and scans; therefore, it is easy to think that a whiff of small vessel disease.”
mental symptoms seen post-stroke. other ‘white’ spots that are common in These findings suggest that other

26 BNA Bulletin Spring 2023 www.bna.org.uk

 Research

Small vessel disease may be contributing to both stroke and dementia.

factors increase susceptibility to small which were hypothesised to improve at least for those with mixed dementia.
vessel disease, including genetic and endothelial function. In the LACI trial, Associated with UK Dementia Research
epigenetic risk factors, and that life history these were given to patients who had Institute (UK DRI) at Edinburgh, Joanna
has a significant effect on disease. Which experienced a small vessel-related stroke is keen to ensure that the blood system
is not to say that hypertension is irrelevant: and were at risk of recurrence. The study is not neglected. “There’s a huge focus
“You don’t have to have hypertension to explored the number of recurrent events, on abnormal proteins and neurons
get small vessel disease. But if you get as well as multiple measures of cognitive and synapses. Of course, all of these
hypertension, it makes it worse – if you’re and physical function, quality of life, and are important, but I think the brain is
vulnerable to small vessel disease, and you endothelial function biomarkers. something you need to consider holistically.
get hypertension, then that’s bad news.” “They’re both drugs which are widely And while you might need to break it down,
Additional evidence has come from available and have been used either in to do very specific experiments, there’s
studies of animal models, conducted heart disease or in other parts of the world always a danger that you lose sight of the
in collaboration with Anna Williams in for stroke prevention. We tested them big picture. I hope that there will be more
Edinburgh, particularly the spontaneously individually and together, and the results recognition of the importance of all the
hypertensive stroke-prone rat. This strain have been quite encouraging.” This was cells in the brain, and endothelial cells
was selectively bred to be hypertensive despite the fact that the treatments were are not outside the brain – they’re inside
and one of its characteristics turned out given on top of the existing standard of the brain.”
to be loss of a ‘fippase’, an enzyme that care for stroke patients.
flips phospholipids from one side of a Clancy U et al. Impact of small vessel disease progression
lipid bilayer to the other. An engineered A role in dementia? on long-term cognitive and functional changes after stroke.
Neurology. 2022;98(14):e1459-e1469.
rat specifically lacking this flippase turned Stroke may not be the only consequence Blair GW et al. Effects of cilostazol and isosorbide mononitrate
out to have endothelial abnormalities of small vessel disease, Joanna points out: on cerebral hemodynamics in the LACI-1 randomized controlled
but was not spontaneously hypertensive, “There’s a lot of overlap between small trial. Stroke. 2022;53(1):29-33.
Backhouse EV et al. Early life predictors of late life cerebral
emphasising again that small vessel vessel disease and Alzheimer’s disease. small vessel disease in four prospective cohort studies.
disease is not dependent on hypertension. Small vessel disease is the commonest Brain. 2021;144(12):3769-3778.
In terms of underlying mechanisms, cause of vascular dementia and a lot of Valdés Hernández MDC et al. post-stroke cognition at
1 and 3 years is influenced by the location of white matter
Joanna suspects that small vessel disease people have a mixed dementia where hyperintensities in patients with lacunar stroke.
is linked to changes in endothelial cell there’s an Alzheimer’s component Front Neurol. 2021;12:634460.
function, causing vessels to become pathologically and also a microvascular Blair GW et al. Intracranial hemodynamic relationships
in patients with cerebral small vessel disease. Neurology.
stiffer, less able to dilate and leaky. component.” 2020;94(21):e2258-e2269.
While hypertension may exacerbate this Even in inherited forms of Alzheimer’s Sweeney MD et al. Vascular dysfunction – The disregarded
situation, there is also some evidence disease, which could be considered the partner of Alzheimer’s disease. Alzheimers Dement.
2019;15(1):158-167.
that it could actually be secondary to ‘purest’ form of the disease, there is
Wardlaw JM et al. White matter hyperintensity reduction
these endothelial changes. “This is all evidence of blood flow abnormalities and outcomes after minor stroke. Neurology.
quite subtle,” Joanna notes. “It’s not really some years before cognitive symptoms or 2017;89(10):1003-1010.
obvious stuff. Otherwise, somebody would shrinkage of medial temporal lobes.
have noticed it a long time ago.” It is unclear whether small vessel disease
These insights led Joanna to propose is contributing to Alzheimer’s dementia
a clinical trial of two existing medications, or is a separate co-morbidity. Either way,
cilostazol and isosorbide mononitrate, targeting blood vessels could hold promise,

www.bna.org.uk Spring 2023 BNA Bulletin 27

 Research

Speaking up for
the neurodivergent
Perhaps we should be spending more time considering how the world can accommodate
neurodivergent people, rather than trying to make them more neurotypical.

Over the past decade, two new words

have entered the lexicon: neurotypical and
neurodivergent. The former is intended
to describe a so-called ‘normal’ individual,
without traits that might gain them a
diagnosis of a condition such as autism
and ADHD, when they would be considered
neurodivergent. In the fields of medicine
and science, Mary Doherty and Sue
Fletcher-Watson, plenary lecturers at the
BNA2023 Festival of Neuroscience, have
been working to promote more positive
attitudes to neurodiversity, challenging
Mary Doherty Sue Fletcher-Watson
conventional models that assume
divergence from the norm is a deficit that
needs to be corrected. The diagnosis also brought Mary into stakeholders.”
A consultant anaesthetist based in the contact with other people who experienced Sue has a particular interest in
Republic of Ireland, Mary is the mother the world in similar ways. “But I just found involving autistic people in research:
of two neurodivergent children. She was myself craving medical peers, autistic “Over the last decade, I have been
herself diagnosed as autistic in 2013, just medical peers, and found it really hard to slowly, incrementally cultivating a more
after her son was. “Looking back, how find anybody. So I started a peer support participatory research practice. That is
on earth did I get to my mid-40s without network, Autistic Doctors International.” about ensuring, as far as I possibly can,
anyone realising?” she asks. “I mean, The network has grown to 650 members that I don’t do anything that the autistic
really, it was so blindingly obvious.” and a linked group for autistic medical people around me can’t see the benefit
She recalls always feeling different: students has been established. of. If I can’t articulate a genuine benefit to
“Right back from a small child, I stood Through the autistic community, autistic people, then I just don’t think it’s a
out from my peers.” She struggled to Mary met developmental psychologist good use of my time.”
fit in at primary school and secondary Sue Fletcher-Watson, based in Edinburgh, Of course, views may differ widely:
school, finding social relationships and whose research focused on autism: “It’s not about consensus, necessarily,
understanding other people very difficult. “I had my first experience of working or complete consensus, but it is about
Her challenges were put down to family with autistic kids when I was a teenager, caring about what autistic people think,
upheavals and other issues, never getting volunteering in a specialist school setting, and making every effort to bring that into
near the root cause: “When I got that and then I went into residential holiday my research in a way that’s genuinely
diagnosis, then everything fitted into schemes supporting all sorts of kids, influential and not a tokenistic exercise.”
place. And I realised, yeah, this makes neurodivergent kids, kids with learning
total sense.” disabilities. I thought, I want to do this in The beauty of neurodiversity
The diagnosis provided an explanation, my career, I want to do something that Both Mary and Sue are committed to the
and relief: “It was like getting a manual helps autistic kids.” cause of neurodiversity. “It’s a really simple
to my brain,” she suggests. “Finally, I was During her psychology degree she fact that we’re all different in the way that
able to look for the information and find realised she was more cut out for research our brains work,” Sue points out. “And those
the information that explained how I was than practice and began to specialise in differences result in differences in how we
experiencing the world.” Relief came from autism-related research. The issue became experience the world and how we respond
not feeling in some way defective: “I’m even closer to home when her daughter to the world around us.”
not this failed neurotypical, I’m a perfectly was diagnosed with autism: “That was an This is uncontroversial but Sue takes
good autistic person. It totally changed my interesting transition for me from being the argument a step further: “I think one
self-perception, my self-identity.” an autism researcher to now one of the of the big core principles of neurodiversity

28 BNA Bulletin Spring 2023 www.bna.org.uk

 Research

“I THINK ONE OF THE BIG CORE PRINCIPLES OF NEURODIVERSITY

IS THAT THERE ISN’T A BETTER WAY TO BE IN THE WORLD THAN
ANY OTHER. JUST LIKE MARY IDENTIFYING HERSELF AS AUTISTIC
WAS ABOUT RECOGNISING THAT SHE WASN’T A RUBBISH VERSION
OF A NON-AUTISTIC PERSON.”

is that there isn’t a better way to be in rather than expecting neurodivergent behaviour; for her, sensory inputs can be
the world than any other. Just like Mary people to adapt to a world populated overwhelming and interfere with daily life.
was saying, identifying herself as autistic mainly by and designed for neurotypicals, An intervention that addressed this aspect
was about recognising that she wasn’t a steps should be taken to ensure of autism would be much more welcome
rubbish version of a non-autistic person.” that neurodivergent people are not than one attempting to make her more
Mary agrees, stressing the basic unnecessarily disadvantaged. As such, neurotypical.
human right that neurodivergent people it is part of a wider equity, diversity and Talking with autistic people can
have to access the world. But she also inclusion agenda. therefore help challenge assumptions
emphasises the harmful mental health Some negotiation may be necessary, and reveal priorities that could shift the
impact that seeing conditions such as as it may be difficult to fully adapt. direction of research. Sue suggests that
autism and ADHD as a defect can have: But much more can be done to ensure even people working in laboratory science,
“Framing them in a very deficit-focused that neurodivergent people can enjoy far away from practical application,
manner does horrible things to people’s worthwhile and fulfilling lives on their would benefit from more contact with
self-esteem and self-identity and mental own terms. the people whose interests they are
health. But the mental health effects of There are also important implications supposedly pursuing. As an example,
growing up with the constant message for science and medicine. It is likely that Sue highlights research related to a rare
that you are at your core defective, that’s some people working in science are syndrome associated with seizures and
just wrong. It’s not true for a start. But it neurodivergent, and increasing numbers intellectual disability. Animal models were
is the message that so many are ‘coming out’, though mostly younger being developed with a main focus on the
neurodivergent kids get.” researchers. Institutions can do much development of drugs to prevent seizures.
The alternative, she suggests, is a to support such people and ensure they “But we did some work with parents
neurodiversity affirmative approach. are not disadvantaged and have equal and carers of young people with this
This means recognising differences but opportunities to thrive. syndrome. And they were saying, actually,
seeing them as an entirely valid aspect For those working in the field of what we really need is something to help
of the human behavioural repertoire, autism or other conditions affecting with sleep.” Sleep is something that can
not something to be ‘corrected’. Her own human behaviour, both Sue and Mary be monitored relatively easily in rodents,
experience supports this approach – her stress the importance of talking with and the researchers were able to adjust
elder daughter has struggled with mental and listening to neurodivergent people. their behavioural paradigms.
health problems having experienced the The starting point for research has often Sue and Mary believe we are moving in
deficit model while her son is, in Mary’s been a desire to ‘correct a deficiency’. Yet, the right direction: “I think it’s incredibly
words, “a happy healthy bouncy autistic in many cases, the problem may not lie positive. And I think it’s particularly
teenager, with a solid and positive self- with the individual but with the way that positive in terms of mental health
identity”, having been brought up in a society is organised, and perhaps it is outcomes for kids who are growing up in
neurodiversity affirmative environment. society that needs the ‘treatment’ not the the neurodiversity affirmative paradigm.”
Both Sue and Mary recognise that this individual. While mental health problems Exactly how change plays out over
could be seen as glossing over the more may have some biological connection with the longer term is difficult to predict,
impactful traits of some autistic people. autism, for example, it is certain they are but by engaging in conversations with
“It’s not rainbows and unicorns,” argues also driven by the challenges that autistic neurodivergent people, and recognising
Mary. “It’s not pretending that everything people face in a world that is not designed that adaptation may be necessary on both
is fine or that everything is rosy. Lots of for them. sides, the world may eventually be more
us are disabled, and disabled in ways that Which is not to say that people with accommodating for the rich diversity of
make it really, really difficult to live in this conditions such as autism do not need human life.
world that isn’t set up for us.” support or interventions – they just may
What are the implications for not be the ones that outsiders may think
neurotypicals? The neurodiversity are needed. For example, Mary stresses
affirmative approach makes the case that, that autism is not just about social

www.bna.org.uk Spring 2023 BNA Bulletin 29

 Et cetera

Messing about in the lab

Leon Lagnado has gone from being a note-taker for Alan Hodgkin to overseeing Sussex
Neuroscience. But he still finds time to tinker in the lab.

Growing up, Leon Lagnado had a practical Leon opted for the former: “I did
streak: “When I was a kid, I did things like a wonderful course called synaptic
build pinhole cameras and crystal radios. I physiology and pharmacology, which
liked mucking about with things, building was organised by Stuart Cull-Candy.”
things.” Like many of his generation, he This was highly practical – Leon recalls
was inspired by the Moon landings and, repeating one of the experiments carried
closer to home, the Ladybird Book of Great out by Nobel laureate Bernard Katz,
Inventors, a copy of which he still has. which involved taking photographs of
Not surprisingly, therefore, he took an oscilloscope screen recording signals
A-levels in physics, maths and chemistry. emerging from a muscle fibre preparation.
Oddly, though, he went on to study “I remember sitting on my bed with a ruler,
medicine at UCL – influenced, he suggests, measuring off the film the amplitude of
by his parents who wanted him to have all these little blips and trying to construct
Leon Lagnado
a stable profession. Attending his local from that an amplitude histogram.”
comprehensive, at this stage he had
little idea about what a career in science Early stages chart recorder for these experiments,
might involve. With a sigh of relief, Leon dropped medicine with Alan Hodgkin sitting behind me
Leon soon realised that medicine was and opted for a PhD, which took him to the directing what Brian had to do. That was
not his thing, but the UCL course enabled lab of Peter McNaughton in Cambridge, a wonderful and interesting experience.
him to undertake a one-year intercalated where he began a lifelong relationship These were the last few experiments
degree – which proved life-changing. “I’d with signal detection and processing in the that Hodgkin was involved in.”
already started becoming interested in retina. His focus was on the earliest stages Hodgkin had a lasting impression on
neuroscience,” he recalls. “In the preclinical of sensory processing, light detection in Leon: “He was very, very, very kind man,
stages, it was the area of biology which photoreceptor cells. very encouraging.” In an understated way,
had most of the physics I was interested While he was there, he was enlisted he also had a significant impact on Leon’s
in, it had some mathematics in it. And it to help another Nobel Laureate, Alan career. Hodgkin was always keen to see
was very experimental. You couldn’t do a Hodgkin. Hodgkin sat at the back in charge how Leon was progressing: “Being a good
neuroscience degree in those days – if you while his postdoc, Brian Nunn, operated boy, I dated my plot on my bits of graph
wanted to study neuroscience, you usually some highly complicated equipment. paper. He said, ‘If you ever do a postdoc
did a degree in physiology or in anatomy.” “I was drafted in to write notes on the in the US, remember that when you date
things, you put the month before the day’.
I think this is was his way of encouraging
me to think about a career in science.”
Leon took the hint and went to
Stanford for a postdoc with Dennis Baylor.
Here, he suggests, he really began his
science education. “I think I was growing
up,” he suggests. “In the UK, you get
rushed through your PhD too quickly.”
At Stanford, he began to work
with a wider range of people, many of
whom became life-long colleagues and
friends, and he was exposed to scientific
controversies outside his immediate field,
such as whether long-term potentiation
was a pre- or post-synaptic phenomenon.
The experience broadened his horizons
WikiMedia Commons
and primed him for a career in science.
Cells of the mammalian retina, as drawn by Santiago Ramon y Cajal in 1901.
Come the early 1990s, Leon was

30 BNA Bulletin Spring 2023 www.bna.org.uk

 Et cetera

“I WAS DRAFTED IN TO WRITE NOTES ON THE

CHART RECORDER FOR THESE EXPERIMENTS,
WITH ALAN HODGKIN SITTING BEHIND ME DIRECTING.”

My three favourite papers represented within a neuron is the spike. There were two competing
Leon Lagnado chooses the three papers And this paper analysed how the spike hypotheses, the calcium hypothesis and
that had the greatest impact on his was generated and provided an incredibly the cyclic GMP hypothesis. People had
scientific work. complete mathematical description of been debating these two very vigorously
the underlying processes that generates for 10 to 15 years. The balance of the
Fatt and Katz, 1952 a spike. evidence would ebb and flow between the
This is one of Here are the two fundamentals of two. Physiologists tended to weigh the
the papers that information processing in the brain, the evidence more in favour of the calcium
helped Bernard vesicle and the spike. I chose the Hodgkin hypothesis, I think, because they were
Katz win a Nobel paper as he encouraged me when I was people with electrodes; biochemists
Prize, for basically a PhD student as well. He gave me a tended to put more emphasis on the
working out the copy – I’ve got one of his pre-prints of evidence for the cyclic GMP hypothesis,
fundamentals of that paper. These papers turned me on to because that’s what they measured.
how synapses work. science and I’m still living off them now Out of nowhere, three Russian
They measured Bernard Katz as a nearly 60-year-old scientist. scientists did the crucial experiment.
what Katz himself I’ve got to say, any neuroscientist They did an extremely direct and
called the ‘blips’, the signals that are of any ilk, anywhere in the world, who straightforward experiment. They said,
generated in a muscle fibre when vesicles isn’t familiar with Hodgkin and Huxley right, we’re going to take bits of the
fuse to release acetylcholine. is not a neuroscientist at all. Its impact plasma membrane, and we’re going
These blips were the basis of the is so profound; that you could approach to chuck calcium on and we’re going
quantal theory of neurotransmission – neuroscience from such a quantitative, to chuck cyclic GMP on to the inside
the idea that the fundamental symbol for physics-based standpoint was revelatory. of that membrane. Even though they
transmitting information at a synapse were physiologists, they knocked the
is the vesicle. That’s the quantum, Hodgkin AL, Huxley AF. A quantitative description of debate dead in favour of the cyclic GMP
the quantum of neurotransmitter, and membrane current and its application to conduction hypothesis. I learned so much from that
and excitation in nerve. J Physiol. 1952;117(4):500-44.
just about everything that we now doi: 10.1113/jphysiol.1952.sp004764. about how to balance evidence. I learned
understand and think about in terms of that the crucial thing is to do the right
how information is transmitted in the Fesenko, Kolesnikov, experiment, the experiment that leads
brain harks back to that and Katz’s work. Lyubarsky, 1985 to the clearest possible interpretations.
I chose this paper because it was a
Fatt P, Katz B. Spontaneous subthreshold activity formative experience just when I started Fesenko EE, Kolesnikov SS, Lyubarsky AL. Induction by
at motor nerve endings. J Physiol. 1952;117(1):109-28. my PhD. It was going to be about the cyclic GMP of cationic conductance in plasma membrane
of retinal rod outer segment. Nature. 1985;313(6000):310-3.
first steps in vision, how the absorption doi: 10.1038/313310a0.
Hodgkin and Huxley, 1952 of photons is converted into an electrical
Hodgkin and Huxley published three signal. I was doing a lot of reading around
back-to-back papers where they provide the topic, and there were two competing
a mathematical description of the action hypotheses about what was called the
potential. The fundamental electrical second messenger. It was known that the
symbol by which information in the brain is photon was absorbed by rhodopsin, stuck
in the middle of a rod photoreceptor, and
that somehow that event got signalled
to the plasma membrane. So the search
was on for a second messenger molecule
that would diffuse through the cytoplasm
to communicate the absorption of the
photon to the plasma membrane, and
thereby change the current flowing across
Alan Lloyd Hodgkin Andrew Fielding Huxley the membrane.

www.bna.org.uk Spring 2023 BNA Bulletin 31

 Et cetera

thinking about returning the UK. By IchaJaroslav/WikiMedia Commons

chance, his wife’s former supervisor

mentioned that the MRC Laboratory of
Molecular Biology (LMB) was establishing
a Division of Neurobiology and was looking
for new recruits. He got in touch with
the head of the division, Nigel Unwin,
who suggested they chat by phone.
“I remember Nigel asking me whether
I did developmental neurobiology.
And I had to say, ‘No, I don’t’.”
Leon wasn’t sure that was what his
future boss wanted to hear; nevertheless,
he was offered a position. There followed
an exciting time as the new blood bedded
in. “Over a period of about two or three
years, there were four or five youngsters
rushing around setting up labs. But it was
wonderful – it was just great fun, and an
incredibly supportive environment.”
The retina of a 3-day-old zebrafish embryo.
By now, Leon was particularly focusing
on ribbon synapses, the highly specialised
structures found in sensory systems. Still “WE TRIED TO CREATE AN ENVIRONMENT WHERE YOUNG SCIENTISTS
profoundly influenced by Stuart Cull- ARE SUPPORTED WELL, THAT’S REALLY, REALLY IMPORTANT, AND
Candy’s UCL course, he was becoming less WHERE THEY’RE GIVEN THE OPPORTUNITY TO SHOW WHAT THEY’RE
interested in the cellular mechanisms of CAPABLE OF.”
synaptic transmission and more in the
general principle of information processing strategic development of neuroscience at strong behavioural science presence in
through circuits. Sussex: “They knew they had a strength Sussex, as well as its strengths in areas
“There did come a point where my in neuroscience, but didn’t feel that they such as computational neuroscience.
interests diverged from what the core were coordinating it as well as they could Today’s neuroscience, he argues, is
strengths of the LMB were,” he suggests. and perhaps not making it known to the inherently multidisciplinary and requires
“I became more interested in looking at outside world as well as they could.” teamwork, especially among early-career
things at the whole circuit level. I made With university support, Leon and researchers: “It’s too much to expect any
this transition, trying to get away from his team were able to launch a four-year single individual to be master of all these
just using isolated cell preparations to PhD programme, strengthen research different approaches.”
looking actually in the live animal. So we infrastructure, including multiphoton Moving from an MRC research institute
switched the lab over to using zebrafish.” microscopy facilities and a new aquarium, to a university was a shock to the system:
and recruit new staff, with a particular “It’s been a rollercoaster ride with British
Heading south focus on sensory neuroscience. With universities in the last 10 years,” he
This shift enabled him to start studying neuroscientists spread over multiple suggests. Scientifically, he grew up with
intact circuits, particularly using departments, he has sought to create senior researchers who were a regular
multiphoton microscopy to visualise activity more opportunities for collaboration and presence in the lab and it is an approach
at the synapse. As these scientific interests ‘team science’. In particular, he has sought he tries to emulate: “I still try and do that
developed, Leon also found himself to ensure that young scientists can thrive. – I still try and fix things in the lab and
considering his longer-term future: “I got “We tried to create an environment where help people, go and sit in on experiments
to a stage in my career where I thought, young scientists are supported well, with people in the lab.” The spirit of the
should I make contributions beyond just that’s really, really important, and where crystal set lives on.
my own lab?” they’re given the opportunity to show
Fortunately, an enticing opportunity what they’re capable of.”
soon arose: “I became aware that Sussex Leon’s own work illustrates the
were looking for somebody to direct a benefits of this environment. His work
neuroscience research centre of some sort. has evolved to encompass the circuitry
I just called up to find out more. And it downstream of photoreceptor cells, and
kind of snowballed from there.” increasingly its links to visually driven
The role, says Leon, was to focus on behaviours. This has benefited from the

32 BNA Bulletin Spring 2023 www.bna.org.uk

 Et cetera

Q&A: Catherine Whittle

Catherine Whittle (Durham) was the winner of the BNA’s Undergraduate Award 2022.

What did you discover What are you doing now?

in your research? I am currently doing an MRes in
My summer research project at Lausanne Experimental Neuroscience at Imperial
University investigated mitochondrial College London. The course is entirely
function in a mouse model of autism research-based and involves three discrete
spectrum disorder and found promising projects, enabling me to gain a broad range
effects following dietary treatment. of experimental skills. I have just finished
While the project was undoubtedly my first rotation in the lab of Giorgio
interesting, I don’t think it was a Gilestro investigating Drosophila sleep,
main reason why I was awarded the and started my second rotation last week.
Catherine Whittle
undergraduate prize. The achievements
I am proudest of include writing a review What are your long-term plans?
paper on mosquito olfaction and founding What did you think when you I have recently accepted a 4-year PhD
the Durham University Neuroscience heard you’d won the BNA award? studentship at the MRC Laboratory of
Society. Through these experiences, I thought what an enormous privilege it Molecular Biology (Cambridge University)
alongside my involvement with Durham’s was to receive the award and reflected to work in Greg Jefferis’ lab. The group
Insect Neuro Lab, I made a more personal on my achievements over the last three has broad interests surrounding how
discovery: a keen interest in researching years. The experience gave me some neural circuits generate behaviour in
the neurobiology of insects. This was not much-appreciated confidence going into Drosophila, and I will be thinking more
an area I had originally envisioned pursuing my PhD interviews, which I believe made about the specific details of my project in
– in fact, I had intended to steer well clear a real difference. I was also very excited the coming months. After that, I aim to
of everything entomological due to my to share the news of my award with my continue in science through a position in
longstanding arachnophobia – but I have undergraduate supervisor, Lena Riabinina, either academia or industry, where I hope
since discovered the appeal of investigating and all of the friends who helped make to further investigate how the brain works
organisms with small brains and will be my time at Durham such a success – I am using relatively simple model organisms.
working with Drosophila for my PhD. beyond grateful for their help and support.

Q&A: Andrija Sente

Andrija Sente (Cambridge) was the winner of the BNA’s Postgraduate Award 2022.

What did you discover we characterised by electron microscopy,

in your research? electrophysiology and single-cell RNA
The main discovery pertains to the sequencing. Permutational assembly
assembly of type A GABA receptors. These increases the number of possible receptor
receptors are abundantly expressed in subtypes by several orders of magnitude,
the brain and peripheral tissues, where thereby also increasing the number of
they form pentameric ion channels possible drug targets. Mechanistically, we
modulated by the neurotransmitter GABA are just scratching the surface of how the
as well as numerous widely prescribed assembly of GABA-A receptors is regulated
medicines, including anxiolytics, general and making more progress on this front is
anaesthetics and anticonvulsants. The required before the translational potential
subunits that form the ion channel can be realised.
are encoded by 19 genes in the human
genome and we discovered that a set of What did you think when you
subunits can permutationally assemble heard you’d won the BNA award?
into receptors with distinct relative subunit On a personal level it feels inspiring and
Andrija Sente stoichiometries or arrangements, which humbling but the prevailing thought is

www.bna.org.uk Spring 2023 BNA Bulletin 33

 Et cetera

that of gratitude that our work has been What are your long-term plans? What do you enjoy doing outside
recognised by the community. I’m currently exploring options for the next science and medicine?
step; mostly I’m searching for a postdoc Many things! I enjoying reading, playing
What are you doing now? position in systems neuroscience, for a music, I actively follow several sports
Currently I am a postdoctoral researcher in change. But in the long term, I am not (occasionally I get involved as well, mostly
Radu Aricescu’s lab at the MRC Laboratory completely committed to any specific tennis these days). Last year I started a
of Molecular Biology in Cambridge, career route and am keeping an eye open chess club at the LMB, which now has a life
wrapping up experiments from my PhD. for any exciting opportunities that may of its own, and we play tournaments on a
During the past four months I’ve also arise. Currently I enjoy and cherish my time weekly basis.
had the privilege to supervise a fantastic in academic research, but you never know
visiting master’s student, which I had been what tomorrow brings.
looking forward to for a long time. This was
tremendous fun – I hope she enjoyed it
nearly as much as I did!

Random
samples
A quick guide to some
of the more unusual brain-
and neuroscience-related
studies published recently.
Fine tuning Music on the brain
Arousal state is regulated by Neural decoding models can recognise
neurotransmitters released by neurons neural representations of acoustic
originating in the hypothalamus. Lucaci or other stimuli, using a range of
et al. show that histamine and GABA signal types including EEG and
released by neurons originating in electrocorticography (ECoG). Daly has
the tuberomammillary nucleus have combined two non-invasive methods,
differential effects on neuron types EEG and fMRI, to create an acoustic
within the prefrontal cortex: histamine decoder. The combination of the two
stimulates fast spiking interneurons and was used to extract EEG information
Born free GABA enhances extra-synaptic inhibition related to musical stimuli, different
Neuro-economics studies have shown on pyramidal cells. These effects fine- piano pieces. The decoder identified
that, when something is available for tune circuit activity, with histamine which music a participant was listening
free, it is seen as particularly desirable promoting synchronisation of cortical to with 72% accuracy, with the
to have – a phenomenon known as the circuitry typical of the awake state and fMRI-informed approach improving
zero-price effect. It is thought that GABA broadening the dynamic range of performance over analysis of EEG-only
this represents an affective response, pyramidal cells, contributing to enhanced data. The study illustrates how fMRI
biasing choice towards free items. cognitive flexibility. In addition, the can enhance EEG-based decoding and
Supporting this idea, Lenglin et al. have GABA effects were potentiated in older reconstruction of acoustic information
shown that this bias is markedly reduced mice, which the authors suggest could from brain activity, an approach that
in individuals with damage to the represent compensation for the drop in could be applied to other uses of
ventromedial prefrontal cortex, a brain global GABA levels seen in the prefrontal decoding.
area previously implicated in affective cortex in ageing. Daly I. Neural decoding of music from the EEG.
decision-making. Lucaci D et al. Histamine release in the prefrontal cortex
Sci Rep. 2023;13(1):624.

Lenglin V et al. Zero the hero: Evidence for involvement excites fast-spiking interneurons while GABA released
of the ventromedial prefrontal cortex in affective bias from the same axons inhibits pyramidal cells. J Neurosci.
for free items. Cortex. 2022;160:24-42. 2023;43(2):187-198.

Picture credits, left to right: Elliott Bledsoe/WikiMedia

Commons; Engradio/WikiMedia Commons; Lukasz
Kobus/WikiMedia Commons

34 BNA Bulletin Spring 2023 www.bna.org.uk

 Et cetera

The people, the people,

the people
When Ian (Bulletin Editor) asked me to COVID-19. Both these events continue
reflect on my time at the BNA, including to challenge the BNA and neuroscience.
what I’d miss most, the people is the • (and more!)
first and most important thing that
came to mind. What else could it be, Highlights
for a membership organisation with Working with incredible, inspiring individuals
community at its heart? But beyond that, (special mention to John Aggleton, ‘my’ first
the individuals I have had the privilege President).
to meet through the BNA are truly the • Having staff and students who have put
thing I both treasure and will miss most. up with my micro-management of fonts,
I love interacting with those just starting formatting and styling (Louise Tratt,
in neuroscience and discovering the field Sophie Jerrold, Alex Collcutt, Georgina
afresh. I love talking with those who have Hazell, Alex Campbell, Dani Wijesinghe;
Anne Cooke
been in it a lifetime, and remain as curious and the 19 students who I’ve had the
as ever. I love meeting people from all pleasure of supervising but whose names
walks of life, who may not have heard of – I had the luck of seeing the job ad for will surpass my word allowance).
acetylcholine or Cajal, but are fascinated in CE and the double luck of being appointed • The Scholars programme and all the
this thing that enables us to interact with to the role. people involved with it. What an indictment
the world and makes us all unique. I’m What’s changed since I started as of positivity coming from injustices.
humbled by those who make inroads into CE? Some changes are quantifiable and • Seeing Credibility in Neuroscience take
understanding it, revel in the fact there’s obvious: our staff has grown from half a hold and make a difference. I am excited
still so much to learn, and intrigued to see Louise (!) to a team of six, we’ve increased that the way biomedical research is done
what you will all go on to discover next. membership by >30%, our meetings is being challenged, and changing for the
My introduction to the BNA* was have increased and diversified, and we’ve better for both science and scientists.
presenting my first ever conference poster, started major initiatives including our I’m incredibly proud of the BNA’s role
at the FENS Forum hosted by the BNA in journal Brain and Neuroscience Advances, in this space.
Brighton in 2000. It’s strangely apt that the Credibility in Neuroscience campaign, • The Festivals! Nothing can compare
my final BNA meeting will be back where our BNA Scholars Programme, Building with meeting with the crowd and crew of
it all started, in Brighton, for the BNA2023 Bridges Between: Industry and Academia, the BNA community in person. I can’t wait
Festival of Neuroscience. (It’s also and Green Neuroscience. What’s perhaps for the next one, in Brighton, but also very
strange to think that the BNA has been less easy to pin down is a shift in sad it will be my last.
in my life longer than almost anything confidence and purpose of the BNA.
else, including the city I live in and my Not that it ever lacked those things; *I think! Memory is nothing if not fallible …. maybe I came
husband!) I well remember that first but it feels, I think, that it has identified across the BNA before then? But I was definitely in Brighton!

meeting in Brighton. I especially remember how it can be of most value to the

explaining my poster to a very patient neuroscience community and is now
visitor, ignorant as to their identity, only embracing that with new vigour.
to be told later that it was the person who Ian has asked me to include ‘personal
discovered the type of neuron on which my highlights and challenges’ with ‘amusing
poster was based, who undoubtedly knew stories a must’. Recalling amusing
a whole lot more about them than my anecdotes comes with a high risk of being
student project would ever uncover. unamusing. I’m therefore going to stick
After that initial encounter with the with just the first two.
BNA, my next was becoming LGR for
Bristol, where I had moved after being Challenges
appointed to set up ‘Bristol Neuroscience’. • Learning about VAT, Profit & Loss,
In around 2008 I undertook editorship of and Balance Sheets. I swear they’re more
the Bulletin. And then, in late 2015 – after complicated than any neuroscience.
a number of years outside of neuroscience • Forces from outside, namely Brexit and

www.bna.org.uk Spring 2023 BNA Bulletin 35