Wonder Season: Art & Science of the Brain
Dr Diane Hanger and Dr Teresa Rodriguez Martin and their team of volunteers hosted a stand at the Wonder Street Fair at the Barbican on 7-9 April. The Street Fair was part of the Wellcome Trust Wonder Season, inspiring children and adults alike about the world of neuroscience and talking to thousands of people about the brain and dementia.
Supported by grants from the Wellcome Trust and the King's Public Engagement Small Grants Scheme, Drs Hanger and Rodriguez Martin’s stall ‘Forget-me-not: Amazing brain cell connections’ invited children and adults to pick up pipe cleaners, jigsaw pieces and plasticine to build their own neurons and brains and find out what happens when memories fail, and how researchers are trying to understand diseases such as dementia.
The stall attracted over 2,000 people over 3 days, and with the help of an enthusiastic team of 28 volunteers answered questions ranging from “is dementia hereditary?”, “how can I get into neuroscience research?” and “can dementia be cured?”.
“The idea was to get children involved in activities relevant to the brain and also to attract adults to the stall,” said Dr Hanger, “the aim was to engage the adults in conversations about dementia and neurodegenerative disease, provide information about research and help to reduce the stigma that is often associated with these increasingly common disorders. Three long and exhausting but very rewarding days…So would we do it again? Several volunteers have already asked when the next event is, so the answer has to be yes!”
‘Wonder Season’ was part of the British Neuroscience Association (BNA) 2013 Festival of Neuroscience.
Crick seminar on ‘The Brain: Understanding Complexity’
5th December 2012 saw the inaugural ‘Crick Seminar’, that focused on the experts in neuroscience who will be part of the Francis Crick Institute when it’s completed in 2015. ‘The Brain: Understanding Complexity’, was hosted at King’s College London ‘s (KCL) Guy’s campus and introduced by Professor Noel Buckley, Head of Neuroscience at KCL’s Institute of Psychiatry (IoP). The seminar aimed to highlight the technologies employed when mapping brain complexity to data complexity.
Session one, chaired by Prof Bill Wisden from Imperial College London (ICL), started with Dr Troy Margrie from the National Institute for Medical Research (NIMR), who detailed his team’s work in tracing the synaptic receptive field of a multi-innervated, layer 5 pyramidal neuron by using modified rabies virus-mediated monosynaptic retrograde tracing utilising a combination of anti-GFP and biocytin. Next, Dr Tara Keck from the MRC Centre for Developmental Neurobiology at KCL, discussed her work on how inhibitory neurons can structurally adapt over a matter of one or two days following visual deprivation. Her model utilises an innovative ‘window to the brain’ approach that allows recording of real-time, movement-related changes in affected neurons thanks to transgenic GFP-expressing mice. Following this, Prof David Edwards, Head of the Department of Perinatal Imaging and Health at KCL, discussed how using a combination of white matter tract mapping via diffusion tensor imaging (DTI) and MRI, his team were able to show that in typical in-utero brain development between weeks 25-35 there are increasing connections in the frontal lobe and a development of thallamocortical connectivity, along with a regular pattern of intense connections and then refinements. However, being born pre-term may disrupt this growth pattern leading to later problems with intellectual development. Finally in this session was Prof Jack Price, head of the Neural Stem Cells Group at IoP, who highlighted his team’s work on how mono- or bi-allelic gene expression in neural stem cells is influenced by differential DNA methylation and histone modification. Ability to control these processes may be vital for commercial delivery of neural stem cell therapy.
Session two, chaired by Prof Steve Hunt, Professor of Molecular Neuroscience at University College London (UCL), started with Prof Stephen Davies, Head of the Neurodegenerative Research Group at University College London. His team is investigating the prion-like behaviour of disease-related components; for instance alpha-synuclein, which can initiate Parkinson’s disease-like Lewy bodies that spread to anatomically connected areas. They have found similar behaviour by Tdp-43, a disease-related protein found in motor neuron disease and frontotemporal dementia among others. Following this was Dr David Sharp from ICL who runs a multidisciplinary traumatic brain injury (TBI) clinic at Charing Cross hospital. His group’s work focusing on network dysfunction after TBI utilised DFI to complement functional MRI and show that white matter disruption and therefore brain connectivity may contribute to impairments of learning that limit functional recovery. Next, Dr Richard Dobson, a lecturer in Bioinformatics at KCL, discussed how he was using gene co-expression network analysis to elucidate changes over the course of a disease, for instance in cases that spanned the range from controls through mild cognitive impairment to frank Alzheimer’s disease.
The last section, chaired by Prof Noel Buckley, introduced more up-and-coming researchers and started with Dr Liz Bradbury who heads a team based at KCL’s Wolfson Centre for Age-Related Diseases. Their work has helped restore function in rats following spinal cord injury by enhancing degradation of chondroitin sulphate proteoglycans that are associated with inhibition of re-growth of injured neuronal projections. Clare Loane, a PhD Student within the Department of Experimental Medicine at ICL, discussed her work using fMRI to investigate the hypersexuality found in around 3.5-7% of people with Parkinson’s disease taking dopamine agonists or L-Dopa. She has helped show that higher sexual desire scores following sexual stimuli are related to increased activation in cortical and limbic areas (which are, respectively, less or not activated in controls), and decreased activation of inhibitory signals in the claustrum and insula. Dr Ben Martynoga from the NIMR then highlighted his work elucidating gene expression enhancers in embryonic stem cells. He found that epigenomic annotation of enhancers identify specific nuclear factor 1 transcription factors as key regulators of quiescence. To round things off, Dr Sandrine Geranton from UCL discussed her findings on how epigenetic mechanisms correlate with changes in gene expression in the superficial dorsal horn during development of inflammatory pain states.
This was a great venue for highlighting the varied areas of expertise within KCL, UCL, IC and NIMR and provided an insight into where future partnerships might be fostered. We will work on further meetings.
Frank Hirth's Lab
Frank Hirth's lab has had a paper published in Cell Reports.
Vanden Broeck et al identified for the first time a process how ALS may form. They used the fruitfly Drosophila as an animal model to study the causes underlying ALS formation. Similar to the disease condition, Vanden Broeck and colleagues generated flies which either produce too much or not enough of TDP-43, the major disease protein in ALS. They found that in both cases, the flies did not develop properly and showed signs of neurodegeneration caused by defective steroid receptor signalling, a process whereby hormones regulate the maturation and survival of nerve cells. Since defective hormone signalling has been implicated in motor neuron diseases, the study by Vanden Broeck et al identifies a disease pathway leading to ALS which can be targeted for therapeutic treatment of this devastating disease for which no cure exists at the moment.
TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophila.
Vanden Broeck L, Naval-Sánchez M, Adachi Y, Diaper D, Dourlen P, Chapuis J, Kleinberger G, Gistelinck M, Van Broeckhoven C, Lambert JC, Hirth F, Aerts S, Callaerts P, Dermaut B.
Cell Rep. 2013 Jan 15. doi:pii: S2211-1247(12)00459-7. 10.1016/j.celrep.2012.12.014. [Epub ahead of print]
Research reveals new properties for tau, a key protein in dementia
Researchers from King’s College London’s Institute of Psychiatry (IoP) have discovered that tau, a key constituent of the tangles present in the brain in Alzheimer’s disease, can be released from healthy neurons in the absence of cell death.
Frank Hirth has had a paper published in Human Molecular Genetics.
Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes
In their study, Diaper et al used the fruitfly Drosophila to study the role of TDP-43 in an animal model of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 has been identified as a major disease protein in ALS and FTD, but the underlying pathogenic mechanisms have remained elusive. The new findings demonstrate that both loss and gain of TDP-43 function can trigger disease formation. Moreover, for the first time, the findings by Diaper, Adachi and colleagues identify pre-synaptic deficits as an initiating event underlying TDP-43 pathogenesis which in turn leads to motor abnormalities and the progressive deconstruction of neuronal connections, ultimately causing the age-related loss of nerve cells which characterizes ALS and FTD.
Nick Bray has had a paper published in the American Journal of Psychiatry.
Evidence that a genetic risk variant for schizophrenia operates during foetal brain development
The single nucleotide polymorphism (SNP) rs1344706 was the first genetic variant to exhibit genome-wide significant association with psychosis and has since shown robust association with schizophrenia. In a study published in the December 2012 edition of The American Journal of Psychiatry, Drs Matthew Hill and Nick Bray provide evidence that genotype at this SNP alters the RNA expression of the gene in which it resides at a particular time in human brain development. Hill and Bray found no effect of this SNP on ZNF804A expression in any of the adult human brain regions they looked at, nor in human brain tissue from the first trimester of foetal development. In contrast, they found a significant effect of genotype at this SNP in human brain tissue from the second trimester of gestation, with the risk allele associated with relatively reduced expression. This is the first study to show an effect of a genetic risk variant for psychiatric illness in foetal brain and supports the idea that schizophrenia is, at least in part, a neurodevelopmental disorder.
Hill MJ, Bray NJ (2012) Evidence That Schizophrenia Risk Variation in the ZNF804A Gene Exerts Its Effects During Fetal Brain Development. Am J Psychiatry 169: 1301-8. PMID: 23212061
8th International Conference on Frontotemporal Dementia, Best Science Poster
MRC, MNDA and Fondation Thierry Latran-funded work by Danielle Diaper and Yoshitsugu Adachi, postdocs in Frank Hirth's lab, won the "best science poster" prize at the 8th International Conference on Frontotemporal Dementia. Their work is entitled: "Both loss and gain of TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration in Drosophila".
The prize came with a certificate and a 1 year free subscription to Acta Neuropathologica.
From July 16th - July 20th the CCBB held it’s annual work experience week. The aim was to provide AS level students who have an interest in pursuing a career in Biomedical Science with the opportunity to discover what life in a research laboratory is actually like. This year, eight students from schools across London joined us for hands-on experience in conducting experiments using current techniques in molecular and cellular biology. We also had the pleasure of being joined by Rhys Bearder from King’s Widening Participation partnership who discussed the practicalities and benefits of being a student at King’s.
The week was a resounding success with student comments like:
‘Absolutely everything I wanted from a work experience week’
‘This was not like any other work experience - no shadowing - we had a taste of the ‘real thing’’
More information about work experience week at the CCBB can be obtained from Dr Brenda Williams
For details of King’s new Widening Participation Programme see New widening participation programme - Simon Hughes MP launches K+
A recent paper by Deepak Srivastava and colleagues, entitled: "An Autism-Associated Variant of Epac2 Reveals a Role for Ras/Epac2 Signaling in Controlling Basal Dendrite Maintenance in Mice", was a featured article in PLoS Biology.
This article uses a naturally occurring mutation of the protein Epac2, that is found in autistic patients, to understand the underlying biological mechanisms that allows a neuron (brain cell) to maintain its overall structure.
The overall structure of a neuron, which is determined by its dendrites is a fundamental feature of neurons, and is thought to be essential to how a cell integrates signals in a neuronal circuit. Abnormal maintenance of dendrites could therefore, result in an impairment in how neurons integrate signals from other neurons.
A synopsis of this paper can be found here,
while the full length article (open access) can be found here.
On Tuesday 12th of June we held the annual Pediatric Storage Disorders Lab Open Day in the James Black Centre. This is the day each year when we welcome Batten disease family members, health care professionals and support workers to meet everyone from the PSDL and learn more about what we are doing here, and the advances being made in the world of Batten disease research.
Following on the success of the recent NCL2012 international Congress, this was the largest ever PSDL Open Day with nearly 40 attendees. As always the hot topic of debate was the progress being made towards therapies for these devastating diseases. Recent promising pre-clinical data from animal models of Batten disease has lead to several clinical trials starting, but the challenge will be in translating these advances to the much larger and more complicated human brain.
Perhaps the highlight of the day was the chance to show our visitors around the lab and for them to see several different aspects of the work we are doing. We set up four different stations around the lab and PSDL lab members acted as tour guides, demonstrating how we actually work in the lab, whether it is cutting and staining brain sections, how we use microscopes collect data from these tissues, or the increasing use of tissue culture to model Batten disease in a dish.
Not only did this allow us to continue demystifying how our science is done, but gave the opportunity for plenty of discussion between lab members and our visitors. This informal discussion continued over lunch before we had a short presentation from each member of the PSDL, describing what their project is about and why it is important. We then reviewed the major points to come out of the NCL2012 conference, which in addition to being the main international scientific conference focussing on Batten disease, also included a parallel conference for the Patient Organisations from all over the world.
There were several shared sessions and a major focus on public engagement, making science understandable to the widest possible audience, much as we have always done at our PSDL open days. A big thank you to everyone in the PSDL for their input into making the day a success, and to the Batten Disease Family Association who helped support the event. We'll look forward to next year's PSDL Open Day, which will take place on Tuesday 11th June 2013.
A recent paper from the Pediatric Storage Disorders lab in the Department of Neuroscience was recently featured as the main story on the IOP website. This paper in Annals of Neurology, was co-authored by Prof. Jon Cooper, together with senior author Prof. Mark Sands at Washington University Medical School, St Louis, USA. Previously, all attempts to treat infantile Batten Disease have been relatively unsuccessful, providing only small benefit to mice that have this fatal inherited disorder. However, combining two different approaches, one that treats the brain via gene therapy, and another to treat the body via a bone marrow transplant, has dramatic synergistic effects. These mice that received both treatments not only live for twice as long as untreated mice, but also displayed a slowing of their disease and a better quality of life in terms of their behaviour and neurological measures of disease severity. Work continues to improve the efficacy of this combined treatment approach and to find a way to translate these advances into the clinic.
You can read the press release about the paper http://www.kcl.ac.uk/iop/news/records/2012/March/Batten-disease.aspx and/or access it via PubMed http://www.ncbi.nlm.nih.gov/pubmed/22368049
Prof. Jon Cooper co-organised the NCL2012 conference that took place recently at the Royal Holloway College, from March 28-31 2012. This was not only the 13th International Conference on Neuronal Ceroid Lipofuscinosis (Batten Disease), but was also the first ever International Meeting of the Patient Organisations from all over the world, including those from as far away as Argentina and New Zealand. Feedback from attendees was uniformly positive, with the selection of presentations after peer-review of submitted abstracts responsible for significantly raising the scientific standard of the meeting. There was also a big effort to make the science accessible to family members with a variety of initiatives to decode the science sessions and including lay summaries in all talks and poster presentations. You can find out more about the conference at www.ncl2012.org.
Eating your way to happiness!
Dr Sandrine Thuret commented on the impact of certain foods on neurogenesis and the relationship between food and mood.
The present study, published this month in PLoS One by Thuret et al. investigates the spinal cord regenerative abilities of a natural occurring mutant, the MRL/MpJ mouse strain. Adult MRL/MpJ mice have been shown to possess unique skin and heart regeneration capabilities. Here we present functional and histological evidence for enhanced recovery following spinal cord injury.
Our data shows that MRL/MpJ mice recovered the ability the walk significantly faster and more completely than other mouse strains. We observed enhanced regeneration of nerve fibers in the spinal cord at the site of injury. Furthermore, we observed less scar tissue and fewer cavities at the injury site, which appear to create a more growth-permissive environment for the regenerating nerves.
Our data suggest that the reduced scar tissue formation is in part due to a lower production of specific cells responsible for scar tissue formation after spinal cord injury.
Interestingly, we also found an increased number of cells involved in immune defense, which could be involved in the MRL/MpJ spinal cord repair mechanisms. Finally, we identified some of the molecules associated to these mechanisms, which may be responsible for the more efficient spinal cord repair in MRL/MpJ mice.
These results contribute to a better understanding of mammalian spinal cord repair, they do demonstrate that the repair process after spinal cord injury is multifaceted. Many pathways are involved, all of which need to be considered and each of which needs to work at an optimal “level” to result in behavioral recovery. These results also point at some potential mechanisms that could be targeted to enhance spinal cord regeneration.
NB: This study was part of the work Dr. Thuret undertook while a postdoctoral fellow at the Salk institute in the laboratory of Genetics, led by Prof. Gage. Dr. Thuret is now a lecturer and principal investigator at the Institute of Psychiatry. For information on her current work visit her lab web page.
Prof Jack Price is part of a working party convened by the Nuffield Council on Bioethics to explore ethical issues around novel neurotechnologies.
Technologies and devices that alter brain function are in development for the treatment of diseases such as stroke, dementia, and depression. Some of these also have potential for non-medical purposes, including military applications. The technologies include deep brain stimulation, transcranial stimulation, brain-computer interfaces, and neural stem cell therapies.
This Working Party will explore the ethical, social and legal issues arising from the development and impact of these 'novel neurotechnologies'.
At the last Society for Neuroscience meeting in Washington, in November 2011, Deepark Srivastava organised and chaired a mini-symposium on rapid estrogen signaling in the brain - this lead to a publication as well as a news story in the alzheimer's research forum:
First data on the functions of the psychosis susceptibility gene ZNF804A
Genome-wide association studies (GWAS) have identified several novel gene loci involved in susceptibility to major psychiatric illnesses. The first genetic variant to show ‘genome-wide significant’ association with psychosis (encompassing both schizophrenia and bipolar disorder) was in the ZNF804A gene. This gene appears to encode a zinc finger protein, which regulate the expression of other genes.
However, the role of ZNF804A and the genes that it potentially regulates have until now been unknown. In a paper recently published in Human Molecular Genetics, Drs Matthew Hill, Nick Bray and colleagues in the Department of Neuroscience show that experimentally reducing the amount of ZNF804A in human neural cells leads to changes in the expression of genes involved in cell adhesion, suggesting a role for ZNF804A in processes such as neural migration, neurite outgrowth and synapse formation. These data shed light on the molecular and cellular mechanisms by which genetic variation in ZNF804A confers risk to schizophrenia and bipolar disorder, and provide a basis for more targeted investigations of ZNF804A function.
Hill MJ, Jeffries AR, Dobson RJ, Price J, Bray NJ. Knockdown of the psychosis susceptibility gene ZNF804A alters expression of genes involved in cell adhesion. Hum Mol Genet, 2011, Nov 22. [Epub ahead of print]. PMID: 22080834
Novel neuronal communication for memory
Memory deficits are associated with many mental disorders but these cannot be cured due to the lack of mechanistic insights. Peter Giese's lab has discovered a novel neuronal communication for memory, which provides a new direction for studying memory deficits in mental disorders, including autism, Alzheimer's disease, schizophrenia, and post-traumatic stress disorder. Using a mouse model, the Giese lab found that after repeated training memory can be formed due to generation of multi-innervated spines, specific connections where two neurons contact another neuron. This type of memory requires not only more training, it is also invariant in comparison with healthy memory. Based on the underlying molecular processes, it is likely that various memory deficits in disease are caused by abnormal production of multi-innervated spines.
For further infromation see here
For full paper: Radwanska et al., (2011), “Mechanism for long-term memory formation when synaptic strengthening is impaired”, Proceedings of the National Academy of Sciences doi:10.1073/pnas.1109680108
Observer article on the Science of Food and Mood
On Sunday, 18th September, an article in the Observer featured an article on the Science of Food and Mood. This is part of a collaboration with the Observer and the Wellcome trust to produce a special series of events exploring the connections between food, health and life.
In this article, the public can appreciate the role diet can play on mental health, as scientists around the world were interviewed to explain their findings. Doris Stangl, a last year PhD student from the Nutrition, Neurogenesis and Mental Health Research laboratory, lead by Dr. Sandrine Thuret from the Institute of Psychiatry at King's College, explained how her research has lead to a direct link between diet and the generation of new brain cells and their impact on mood. The full Observer article is available at :
For more information on the Nutrition, Neurogenesis and Mental Health Research laboratory, please visit:
Proliferation and differentiation in the embryonic brain
Most of the neurons in the adult brain are generated in the embryonic brain from neural stem cells and progenitors cells that proliferate before leaving the cell cycle and differentiating. In the embryonic forebrain, neural stem cells (known as radial glial cells), found in the ventricular zone, can divide to give rise to further neural stem cells as well as to neurons (and glia) and to intermediate progenitors in the adjacent subventricular zone that also generate neurons. This balance of proliferation and differentiation is critical in both development and disease. Important proteins, known as proneural transcription factors, are largely responsible for regulation of neurogenesis in the embryo. Whilst proneural proteins are known to promote differentiation and suppress proliferation, the mechanism(s) by which they do so are not well understood. However, work done by Noel Buckley and Angela Bithell in collaboration with Francois Guillemot, Diogo Castro and colleagues at the National Institute for Medical Research, sheds light on how proneural factors drive multiple stages of neuronal differentiation and also reveals a surprise role for one such factor in the promotion of neural progenitor cell proliferation.
The Ascl1 gene encodes a developmental transcription factor Mash1 that is known to be required for cell cycle exit and neuronal commitment of neural progenitors. In this study Castro et al. (Genes & Development, 2011 May 1;25(9):930-45) mapped Mash1 binding sites to over 1200 genes throughout the genome in the embryonic mouse forebrain and in mouse neural stem cells. The vast majority of these genes had hitherto not been identified as regulatory targets of Mash1 and, unexpectedly, many of these novel targets included positive as well as negative regulators of cell cycle, implying that Mash1 might promote both cell cycle progression and cell cycle arrest. By genetically deleting Mash1 in embryonic mouse brain and in neural stem cells, they confirmed that Mash1 was required to maintain normal neural stem cell and progenitor cell proliferation. Their findings also revealed that Mash1 orchestrates neurogenesis via targeting not only other transcriptional regulators but also direct effectors at multiple stages of the differentiation program. These experiments show how a single transcription factor can control the proliferation of progenitors and their subsequent cell cycle arrest and differentiation. Since the target genes discovered also include known oncogenes such as E2f1, involved in aberrant control of cell cycle in malignant brain tumours, it is clear that examining normal neurodevelopment provides novel insight into mechanism of brain disease.
Cancer drugs may help treatment of schizophrenia
Cyclin-dependent kinase 5 (Cdk5) is a a signalling molecule that is expressed in neurons during development after cell division. Cdk5 is required for neuronal migration and axonal outgrowth, and it also required for synaptic plasticity in the adult nervous system. The primary route for Cdk5 activation is by binding to the protein p35. A recent paper in Brain from a group led by Peter Giese, has shown that the expression of p35 protein is reduced by approximately 50% in brain regions of patients with schizophrenia. This molecular change can be modelled in heterozygous p35 knockout mice. They found found that p35 mutants have impaired cognition that includes deficits in prepulse inhibition (PPI) that is considered to be an endophenotype of schizophrenia. Further, the p35 mutants have impaired histone acetylation and expression of two synaptic proteins, septin 7 and OPA1, that have been implicated in spine formation. These impairments in protein expression were rescued with an inhibitor of histone deacetlyase 1 (MS-275). MS-275 treatment also rescued the PPI deficits in the p35 mutants. In summary, we provide evidence, for the first time, that Cdk5 signalling is impaired in patients with schizophrenia and that these impairments contribute to cognitive deficits associated with schizophrenia. Giese and colleagues have proposed that MS-275, a drug currently used in clinical trials with cancer patients, could be suitable for treating impaired cognition in schizophrenia.