The World Health Organization predicts that depressive disorders will be the greatest contributor to the global burden of disease by 2030. Major depression is thought to comprise a heterogeneous group of diseases caused by genetic, epigenetic and environmental factors. In humans, detrimental early life events, such as maternal neglect or abuse during childhood, are associated with increased risk of emotional disorders including major depression that may persist into adulthood. In fact, experimental and clinical studies have shown that the immaturity and plasticity of the central nervous system during childhood make it particular sensitive to stress at a young age, which may cause significant and permanent changes in brain structure and function.
On the other hand, recent clinical and experimental data suggest that the pathophysiology of several neuropsychiatric disorders, including depressive syndromes, involves activation of the immune system in response to inflammatory agents. In fact, pro-inflammatory cytokines alter tryptophan metabolism, affecting the activity of serotonin, a neurotransmitter with a key role in the modulation of mood. Therefore, the tryptophan metabolic route becomes imbalanced during depression, enhancing an alternative metabolic pathway, the kynurenine synthesis pathway, and decreasing the availability of tryptophan to be metabolized into serotonin. This metabolic change has been directly associated to the development of depressive symptoms in humans and in experimental animal models.
In a recent study published in Progress in Neuro-Psychopharmacology & Biological Psychiatry, we have shown that maternal separation indeed induces both neuroinflammation and long-lasting emotional alterations in mice. The study was developed during Irene Gracia-Rubio’s PhD training at the GReNeC and done in collaboration with other research teams: the group led by Roser Nadal in UAB for maternal behaviour evaluation, and also with Oscar Pozo and Josep Marcos, researchers of the Neuroscience Program at IMIM (Hospital del Mar Research Institute) for the analysis of the kynurenine pathways. To have the opportunity to work with all these researchers in a collaborative project has been a very positive experience.
Our aim was to explore the interplay between depressive symptoms in behavioural models, neuroinflammation, and alterations in the tryptophan-kynurenine pathway since these mechanisms could lead to the discovery of new therapy approaches.
For that, we set up different behavioural models to induce conditions of early life adversity in male and female mice. Although most studies are done only in males, we decided to study female mice since the risk of suffering depression is double in women than in men.
We used two conditions: the maternal separation paradigm in mice as a model of early life neglect, and the standard rearing condition (the ‘control’), in which offspring remained with their mothers for 21 days. We then looked at the effect of both conditions on emotional behaviour during adolescence and into adulthood.
To test these effects, we performed a range of tests of anxiety, depressive symptoms and other emotional-related behaviours. To test anxiety, we used the elevated plus maze, a test that evaluates the capability of a rodent to explore new and stressful environments. Anxiety-like behaviour is reflected by an attenuated exploratory behaviour in mice. For testing depressive-like symptoms, we used the tail-suspension test, a model to evaluate despair behaviour, in this case, the time spent immobile when a mouse is confronted to an inescapable stressful situation.
At the physiological level, we looked for signs of neuroinflammation in different brain areas, and analysed metabolites of the tryptophan-kynurenine pathway to explore the link between depressive symptoms and inflammatory reactions.
Our results showed that adverse events during early life in mice increase risk of long-lasting emotional alterations during adolescence and into adulthood. These emotional disturbances were particularly severe in females. Behavioural impairments, including depressive symptoms, were associated with neuroinflammatory reactions in the two brain regions evaluated (prefrontal cortex and hippocampus).
In conclusion, these findings support the preeminent role of neuroinflammation in emotional disorders. Our results lead us to propose that detrimental early life events such as maternal neglect reproduce most of the behavioural alterations associated with depressive symptoms in mice. These alterations seem to be long lasting since adult mice also showed these emotional alterations. We also found that females were more sensitive to adverse conditions than males since the detrimental effects observed were more intense and persisted longer in time in female mice. Our study also supports the notion that the imbalance of the tryptophan-kynurenine metabolism and the association of neuroinflammatory reactions underlie these emotional impairments under our experimental conditions.
Future investigations will explore the influence of maternal separation and neuroinflammation in other psychiatric disorders, in particular psychotic and drug use disorders.
Gracia-Rubio I, Moscoso-Castro M, Pozo OJ, Marcos J, Nadal R, Valverde O. Maternal separation induces neuroinflammation and long-lasting emotional alterations in mice. Prog Neuropsychopharmacol Biol Psychiatry. 65: 104-17, 2016. DOI: 10.1016/j.pnpbp.2015.09.003.
Núria López-Bigas started her lab on Computational Oncogenomics at the GRIB, within the PRBB, ten years ago. After a very successful decade, we are sad to see her leaving. We wish her all the best in her lab’s new adventure, and we hope the very fruitful interactions she has started with the different groups at the park will continue to prosper.
In her last post on her blog, Núria says thanks to the GRIB, the UPF, the PRBB community and the PRBB Intervals programme… We want to say, thanks to you Núria, for the great research you have done and for being such an open, collaborative and supportive person, both within the scientific community at the park and with outreach events for the general public! You will be missed. Good luck and see you soon!
Congratulations to Núria López-Bigas at the GRIB (UPF-IMIM) for her lab’s latest paper in Nature describing why there’s an increased mutation rate in Transcription Factor Binding Sites (TFBS) in melanomas and lung tumors!!!!
You can read more about the experience publishing this paper in this post from her lab’s blog, where she explains how, after a long process of reviewing, they felt they “had the responsibility to describe our finding as soon as possible to the community”, and decided to publish the manuscript in bioRxiv. Later on, the paper was accepted and published by Nature.
Here’s for this success story!
You can read the paper here:
Radhakrishnan Sabarinathan, Loris Mularoni, Jordi Deu-Pons, Abel Gonzalez-Perez & Núria López-Bigas. Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature 532, 264–267 (14 April 2016) doi:10.1038/nature17661
On January 21, Judit Vall Castelló from the Centre for Research in Health and Economics (Pompeu Fabra University) gave a conference at the PRBB invited by the CREAL. She talked about her last study on the effect of business cycle conditions on children’s weight.
She explained that the majority of the research connecting recessions with body-weight has so far focused on adults or babies. In adults, most of the literature finds a link between better economy and weight increase, which would suggest that recessions are “good” for adult’s health. But, is it the same for children?
Spain is one of the ten countries of the OECD with a higher prevalence of infant overweight – about 25% of children aged 5 to 17. Children’s obesity rates represent an important public policy issue as a number of short-term adverse effects and risks have been associated with obesity in the early stages of life. For example, obese children have a greater risk of being bullied and they are more likely to stay obese into adulthood, therefore having a higher probability of suffering certain chronic diseases later in life.
The relationship between the business cycle conditions and children’s weight is not in the political agenda of Spanish politicians, it’s an unexplored topic on the scientific literature about children, and it has relevant consequences in the short and long-term. These were the main motivations for Vall Castello’s research.
Her team used data from 8 waves (1987-2012) of the Spanish National Health Survey. The pooled sample contained 37,562 observations of children between the ages of 2 and 15 years old.
She explained to an attentive audience how their strategy takes advantage of the variation in the unemployment rate across regions and survey years to look for potential effects. They used the regional unemployment rate as a proxy for the business cycle phase at the local level.
The researchers found that an increase in the unemployment rate is associated with lower obesity incidence, especially for children under 6 years old and over 12 years old – similarly to what was known in adults. A decrease in obesity is actually good news, but what happens to the other extreme of the population, the ones that were already underweight when the economy was good?
They found that negative economic conditions increased the prevalence of infant underweight, particularly for those under 6. So, an increase in the unemployment rate shifts the entire weight distribution to the left, decreasing the probability of suffering obesity and overweight but at the same time increasing the probability of being underweight for children under 6 and children over 12.
Vall Castello was also interested in the possible channels through which the economy could be impacting infant underweight and obesity, such as changes in the nutritional composition of the children’s diet or in the frequency of exercise.
Their results suggest that an increase in the local unemployment rate may be linked to a decrease in the probability of following a Mediterranean Diet, which is considered as one of the healthiest dietary options. More worryingly, this negative correlation was most significant for children under 6 years old.
Since compulsory education starts at age 6 in Spain – and, for most children, it includes lunch at school – this research seems to point out just how important it is to ensure that all children, regardless of their parents’ economic situation, have at least one balanced meal a day, and the key role schools play in this.
A report by Mari Carmen Cebrián
The research group of Biomedical Genomics from the Research Programme on Biomedical Informatics (GRIB), led by Núria López-Bigas, has been awarded an European Research Council (ERC) Consolidator Grant. These grants are aimed at the development of innovative and excellent projects conducted by young postdoctoral researchers of a consolidated career between 7 and 12 years. The project that received the ERC, named “NONCODRIVERS” aims at identifying mutations involved in tumour development in non-coding regions. It is set to start in 2016 and to last for five years. You can read more about this here.
The ERC has also recognized the work of another female researcher from the PRBB, Josefa González, a PI at the IBE. She has been nominated to join AcademiaNet, an expert database for outstanding female academics. It was created in 2010 with the aim of raising the visibility of exceptional women in science and increasing their number in leadership positions.
Congratulations to both of them!
Different targeted strategies have recently emerged in the field of proteomics that enable the detection and quantification of a predetermined subset of proteins with a high degree of sensitivity and reproducibility across many samples. Major advances have been achieved in the targeted proteomics workflow, including advances in instrumentation, the generation of thousands of publicly available targeted assays, and the development of multiple computational tools for convenient data analysis.
This field is known as targeted proteomics and although it has successfully been applied in several research projects of molecular biology, systems biology and translational medicine, there is still a strong gap between theory and real application.
To address this mismatch and boost the applications of targeted proteomics, the PRBB held a new edition of the 6-day long EMBO Practical Course “Targeted proteomics: Experimental design and data analysis” co-organised by Eduard Sabidó, head of the CRG/UPF Proteomics Unit and Ruedi Aebersold from the ETH in Zurich.
Twenty-five participants coming from 20 countries from all continents attended the course, which offered a combination of keynotes, practical demonstrations and tutorials to provide the participants with the required knowledge and skills to design and analyse their own targeted proteomic experiments using the most advanced and state-of-the-art methods.
Each day started with a keynote open to all PRBB residents by different renowned proteomics researchers that reviewed the latest achievements in the field of targeted proteomics and introduced the “topic of the day”. The students also attended to several practical session to master the complete workflow associated to targeted proteomics, thus filling the gap between theory and the actual implementation of targeted proteomics experiments. During the practical sessions the students generated, refined and optimized targeted proteomics methods for a set of selected proteins of interest, and automated manual data analysis by reviewing concepts such as peak picking, quality assessment, and statistics for accurate protein quantitation. The program was complemented with poster sessions and several social events to foster informal scientific discussions and to adapt the technology to each participant’s particular interests.
The participants, ranging from PhD students to postdocs and senior researchers, gave a very positive feedback on the course, with an overall score of 4’75 on a scale from 0 to 5 and very encouraging comments:
“Very motivating meeting with very interesting researchers from very different fields but same interest in proteomics, and high quality seminars and tutorials that made me want to continue research in proteomics”
“I feel confident to start my own experiments now”
“Informative and engaging with strong relevance to my research”
“The most useful course so far and also great to share knowledge and tips between us!”
“Excellent speakers, plenty usufull, practical informations, nice atmosphere it is shortest description of the course”
“A wonderful course instructed by cutting edge and innovative field leading scientists whom together have passed on the necessary tools to enable me to design and implement successful targeted proteomic workflows”
This course disseminated the know-how present at the CRG/UPF Proteomics Unit to a broader scientific community and strengthened the interdisciplinary exchange of knowledge and ideas. Thus, by transferring the expertise on experimental design and data analysis for targeted proteomics, the CRG/UPF Proteomics Unit aims to facilitate a wider and more routine application of targeted proteomics among non-proteomic laboratories worldwide.
For those who could not attend this year, the EMBO Practical Course “Targeted proteomics: Experimental design and data analysis” will take place again at the PRBB in November 2016. You will soon be able to access this website to register for the 2016 edition – do not miss this opportunity!
You can see the videos of the 2015 edition here.
Course instructors that participated in the 2015 edition
Abersold, Ruedi; ETH Zürich, Switzerland
Altelaar, Maarten; Utrecht University, The Netherlands
Borràs, Eva; CRG-UPF Proteomics Unit, Spain
Bensimon, Ariel; ETH Zürich, Switzerland
Chiva, Cristina; CRG-UPF Proteomics Unit, Spain
Guillet, Ludovic; ETH Zürich, Switzerland
Ludwig, Christina; ETH Zürich, Switzerland
MacCoss, Michael; University of Washington, USA
MacLean, Brendan; University of Washington, USA
Reiter, Lukas; Biognosys GmbH, Switzerland
Sabidó, Eduard; CRG-UPF Proteomics Unit, Spain
Vitek, Olga; Northeastern University, USA
A couple of months ago, the CRG-UPF Proteomics Unit at the PRBB – run by the Centre for Genomic Regulation (CRG) and the Pompeu Fabra University (UPF) – announced the installation of one of the most precise mass spectrometers in the world, marketed as Orbitrap Fusion Lumos, becoming the first place in Europe and the third in the world to have this tribrid instrument.
You can read more about this innovative mass spectrometer – which can achieve simultaneous analysis and quantification of more than 10,000 proteins from ten different samples in a single day! – in a post entitled “The CRG Becomes the First European Centre to Have One of the Most Precise Mass Spectrometers in the World” and published on September 29th in Biocores – a directory of the core facilities, technological platforms, and scientific services in Barcelona.
You can also read an article published in Ellipse – the monthly newspaper of the PRBB – in which Eduard Sabidó, head of the Proteomics Unit, tells us about how mass spectrometry-based proteomics is helping to solve complex problems of molecular biology and translational research (see page 6 of this months’ edition of the Ellipse).
On “Back to the future” day, October 21st, 2015, Luís Seoane, member of the Complex Systems Lab at the IBE (UPF-CSIC) led by Ricard Solé, wrote a blog post called “Images of the mind”. In it, he discusses how much technology has advanced in the last 30 years. Our present is not quite the ‘future’ of the characters of the film directed by Robert Zemeckis, produced by Steven Spielberg and starring Michael J. Fox. But we have gone a long way.
In this post, Seoane focuses on Brain Computer Interfaces, which are bringing back motility and communication to injured patients, and on which he himself has worked prior to joining the Complex Systems Lab at the PRBB. In particular, he talks about one he came up with in 2011, which he then developed together with Stephan Gabler and Benjamin Blankertz.
“Early this morning Marty McFly has arrived to the future. It is true that cars don’t fly quite yet. Hoverboards are not available either. Households are not powered by their own nuclear reactors and clothes don’t dry and adjust automatically. Good old Marty has got reasons to be disappointed. But advances in some other directions have been astonishing during the last 30 years. Who could foresee the transformative power of the internet? Everyone is plugged to a tablet or smartphone, immediately accessing far away friends and personalized web content. Synthetic biology is taking its first, promising steps (to which we are glad to contribute) and advances in prosthetics and Brain Computer Interfaces are bringing back motility and communication to injured patients….”
You can read here the whole post, published on the lab’s blog.
A new study in which Sergi Valverde, from the Complex Systems Lab at DCEXS-UPF has collaborated, provides an open source MATLAB package to study the structure of bipartite ecological networks inspired by real problems in microbiology and with broader applications.
Bipartite networks are a special type of ecological network where individuals of a certain species interact with individuals of different species. They are ubiquitous in community ecology, such as the relation between phages (viruses that infect bacteria) and their bacterial hosts.
You can read more about this tool, called BiMat, at the group’s blog.
In this sort video the physicist Jordi Garcia-Ojalvo, at the Department of Health and Experimental Sciences of the University Pompeu Fabra – located at the PRBB in Barcelona – talks about his group’s studies on circadian rhythms and other biochemical oscillations at a systems biology level.
Video produced by the Barcelona Biomedical Research Park www.prbb.org