The Fitzsimons Lab

The focus of my lab is to identify common mechanisms by which brain insults affect the hippocampus. For this, we focus on a group of insults that modify the proliferation of neural stem cells, resulting in the presence of abnormal neurons and circuit alterations associated with neurodegeneration and cognitive impairment. Please visit for more information

 https://www.fitzsimonslab.eu/

Our hypotheses are presented in our recent position paper article in Behavioral Brain research:

https://www.sciencedirect.com/science/article/pii/S0166432819305789?via%3Dihub

My lab is financed by the Innovational Research Incentive Scheme VIDI from The Netherlands Organisation for Scientific Research (NWO), the International Foundation for Alzheimer's Research (ISAO) and Alzheimer Nederland and by ERA-NET NEURON. The Network of European Funding for Neuroscience Research (NEURON) is a European Research Area Network (ERA-NET) co-funded by the European Commission that supports basic, clinical and translational research in the field of disease-related neuroscience. As a co-fund, this ERA-NET NEURON project receives local financial support from NWO/ZonMw, Hersenstichting Nederland, the National Initiative Brain and Cognition and is part of the Topsector Life Sciences & Health program. More information on our project can be found at https://reactnsc.org/

News

In a recent paper published in the prestigious journal Molecular Psychiatry, we demonstrate how hormone cycles preserve a population of neural stem cells in the aging brain. The Open Access article can be accessed here:

https://www.nature.com/articles/s41380-019-0440-2

Our recent article in Frontiers in Molecular Neuroscience is highlighted at the Scientific News page of the Faculty of Sciences, University of Amsterdam " A team of neuroscientists led by Carlos Fitzsimons (SILS-UvA) has discovered how to revert effects of small RNA molecules present after a seizure, thereby protecting affected stem cells in the brain...The study by Fitzsimons and team supports the promise for a future application for RNA interference-based therapies for epilepsy syndromes"

http://www.uva.nl/en/shared-content/faculteiten/en/faculteit-der-natuurwetenschappen-wiskunde-en-informatica/news/2019/03/therapeutic-insights-into-the-molecular-effects-of-epileptic-seizures.html?origin=TcWv2FH7QiyRJQ3nsarwIQ

The effect of convulsive seizures on adult hippocampal neural stem cells has been extensively studied.  However, in many epilepsy patients, only non-convulsive seizures are observed. In our recent paper, we characterize for the first time the effect of non-convulsive seizures on adult hippocampal neural stem cells and demonstrate that simultaneous antagonism of two microRNAs rescues alterations in NSPC. Our observations support the possible use of anti-microRNA oligonucleotides (AMOs) for future seizure therapies.

The full-text article, Published in Frontiers in Molecular Neuroscience is available here (Open Acess):

https://www.frontiersin.org/articles/10.3389/fnmol.2019.00031/full

Microglia are the immune cells of the brain and have recently been implicated in neurodegenerative diseases, such as Alzheimer's. Microglia dynamically adapt their morphology and function with increasing age. In a recent paper done in collaboration with my ex Ph.D. student Marijn Schouten, now at the AMC Amsterdam,  we demonstrate that age-associated elevations in glucocorticoid levels regulate microglia function and morphology. Our data show that glucocorticoids increase ramification of hippocampal microglia and may modulate age-associated changes in microglial morphology, demonstrating a new pathway by which glucocorticoids may promote age-associated brain disorders.

The full-text article, Published in Aging Cell is available here (Open Acess):

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12790

Scientific reproducibility is a growing concern and weak experimental practices may contribute to irreproducibility. To help tackling this problem, we have described an optimized and versatile protocol for stereotaxic intrahippocampal administration of Kainic Acid (KA) in mice with a C57Bl6 background. In this protocol, KA administration is combined with in-vivo recording of neuronal activity with wired and wireless setups. The procedure was cross-validated in three independent research centers and consists of three main steps: Craniotomy, stereotaxic administration of KA, and placement of recording electrodes in intrahippocampal, and subdural locations. As such, the procedure can be easily adapted to the titrated intrahippocampal administration of other drugs. The Open Acess article describing the protocol can be found here:

http://journal.frontiersin.org/article/10.3389/fnins.2017.00160/full

Since recently, we keep an up-to-date version of our scientific and social news using social media here:

https://www.facebook.com/fitzsimons.lab

please feel free to follow us.

I have been recently honored with an invitation to join Nature's Scientific Reports Editorial Board, section Neuroscience.

http://www.nature.com/srep/about/editorial-board#eb

Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit characteristics and can be modeled in mice by administration of kainic acid (KA). We developed a multi-omics experimental setup and analyzed hippocampal (specifically dentate gyrus) tissue samples using proteomics, transcriptomics, and microRNA profiling techniques, detecting the expression of 2327 proteins, 13401 mRNAs and 311 microRNAs. Our data may help to further identify and characterize molecular mechanisms involved in the alterations induced shortly after KA-SE in the mouse hippocampus. We  present a full description of how these data were obtained and make them available for further analysis and validation in a recent Open Access Publication in Nature's Scientific Data, which can be found here:

http://www.nature.com/articles/sdata201668

Inflammation is a complex protective biological reaction aimed at eliminating the initial cause of tissue injury, clear out damaged and necrotic cells and initiate tissue repair. The inflammatory reaction takes place in all tissues, including the brain, and involves a multitude of different local and systemic mediators at different stages, such as histamine and glucocorticoid hormones. However, how these mediators may work together is still under debate. Our recent work provides an extensive characterization of molecular mechanisms underlying the interaction between (anti)histamine(s) and glucocorticoids and contributes to understanding dosage optimization and well-described side effects associated with glucocorticoid administration for the treatment of inflammatory diseases. The open-access article can be found here:

http://www.nature.com/articles/srep17476

Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution. We have recently described for the first time that the combinatorial action of two microRNAs, miR-124 and miR-137 fine-tunes the expression of the proapoptotic protein BCL2L13, which controls casp3 activity and thereby favors non-apoptotic caspase-3 functions in NSPC exposed to seizures.

This new mechanism may contribute to the early neurogenic response to epileptic seizures in the dentate gyrus. The open access article can be found here:

http://www.nature.com/articles/srep12448

I have been recently honored with an Associate Editor position at the journal Frontiers in Neuroscience, section Neurogenesis.

http://loop.frontiersin.org/people/24204/bio

My presentation to the Adult Neurogenesis Meeting in Dresden, in which I reported our findings on the epigenetic regulation of neural stem cells in the adult hippocampus has been highlighted in the scientific news website "The Node" maintained by The Company of Biologists:

The highlights can be seen at:

http://thenode.biologists.com/adult-neurogenesis-at-50-the-dresden-chronicles/events/

Lynnet Frijling, Master student at the Fitzsimon's Lab, won one of the Best Poster prizes at the last Dutch Neuroscience meeting 2015 for her work entitled "Modulation of adult hippocampal neurogenesis after intrahippocampal Kainic Acid- induced seizures using microRNAs". Congratulations Lynnet!!

The International Foundation for Alzheimer's Research (Internationale Stichting Alzheimer Onderzoek (ISAO)) has recently funded 10 new research lines to a total of 1.100.000 euro. I feel very proud that my lab is one of the awardees. The project is aimed to investigate the epigenetic programming of hippocampal neurogenesis by stress in sporadic Alzheimer’s disease models.

Most current animal models of Alzheimer’s disease (AD) are based on the expression of mutated genes associated with the familiar form of AD. These models have played a major role in identifying pathological mechanisms linked to and in evaluating novel therapies. However, familial AD affects only a minority of AD patients. Moreover, in these models pathology starts early in life and is driven fundamentally by the expression of the mutated gene, making them especially unsuitable for the study of the effect of environmental factors, such as stress, on AD progression.

More information can be found at:

https://www.alzheimer.nl/onderzoek/onderzoeksprojecten/2014

This project covers experimentally a part of the concepts on epigenetic regulation of neural stem cells we have put forward in a recent article published in a highly accessed article in Molecular Neurodegeneration, a Journal dedicated to all aspects of neurodegeneration research at the molecular and cellular levels. This article is open access and can be found at:

http://www.molecularneurodegeneration.com/content/9/1/25 

In 2014, Erik Betzig, Stefan W. Hell, and W. E. Moerner received the Nobel Prize in Chemistry 2014 for the development of super-resolution fluorescence microscopy. This is a group of techniques developed to overcome the long-standing limitation imposed by light's diffraction limit. Before this development diffraction limit prevented light microscopy from being used to unveil details of cellular structure and function. In Neuroscience, the imaging of the synapse physical location represented by dendritic spines is affected by this limitation. We have recently described a method to apply Structured Illumination Microscopy (SIM), a super-resolution technique, to the detailed imaging of dendritic spines. The article, published in the video journal The Journal of Visualized Experiment (JoVE) is available here:

http://www.jove.com/video/51276/imaging-dendritic-spines-rat-primary-hippocampal-neurons-using

On May 22, 2014, I received the Top Paper Prize 2014, awarded by the Dutch Neurofederation. The award ceremony took place during the 2014 EndoNeuroPsycho Meeting in Lunteren. After accepting the prize in the name of all the paper's authors, I gave a plenary lecture discussing the main findings of the paper. 

The awarded paper was:

Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior.

Fitzsimons CP, van Hooijdonk LW, Schouten M, Zalachoras I, Brinks V, Zheng T, Schouten TG, Saaltink DJ, Dijkmans T, Steindler DA, Verhaagen J, Verbeek FJ, Lucassen PJ, de Kloet ER, Meijer OC, Karst H, Joels M, Oitzl MS, Vreugdenhil E.

Mol Psychiatry. 2013 Sep;18(9):993-1005. 

 For more details please see the Faculty of Sciences's News website at:

http://www.science.uva.nl/cms/nb/EN-2014-05-27 

Several factors, including epileptic seizures, can strongly stimulate ongoing neurogenesis in the adult hippocampus.

However, the exact role of the neurogenic response during epilepsy and its possible involvement in epileptogenesis have remained elusive.

In a recent article in The European Journal of Neuroscience, we discuss recent studies shedding new light on the interplay between epilepsy and neurogenesis.

The article is available here: 

Recently, I gave some invited oral presentations in international scientific meetings:

The 2012 Meeting of the SFN:

 http://www.abstractsonline.com/Plan/SSResults.aspx

The 2013 Eurogenesis Meeting in Bordeaux

http://www.eurogenesis.com/

And the 2013 SENS meeting in Oviedo

http://www.senc2013.com/ponentes.html 

My  presentation at the last Abcam’s Meeting "Regulation of Adult Neurogenesis: From Epigenetics to Behavior", held on July 12-13th 2012 in Barcelona as satellite event to the 2012's FENS meeting, has been highlighted together with those From G. Kempermann, F. Gage and A. Fischer, in Epigenie, a blog dedicated to epigenetics news:

 http://epigenie.com/conferences/regulation-of-adult-neurogenesis-from-epigenetics-to-behavior/

We have recently published a new article in Molecular Psychiatry where we describe the role of the Glucocorticoid Receptor in the regulation of adult hippocampal neurogenesis and fear-motivated behavior:

Master internships available

Previously on...

We were amongst the six finalists of the 2012's version of the Amsterdam Science Innovation Award (AMSIA). The AMSIA is a competition between researchers and students from the University of Amsterdam (UvA), the Academic Medical Centre (AMC), the Amsterdam Technical Highschool (HvA) and other research Institutes with innovative, original and applicable ideas. We were honored to receive the Public's Award for the project "Modular Proteins as innovative non-viral vectors for gene therapy".   This project is a collaboration between the Fitzsimons' Lab and The Institute of Biotechnology and Biomedicine, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, University of Barcelona, Spain. 

Research Interests

Neural stem cells, hormones and microRNAs
Experiments at the laboratory are aimed at understanding the role of microRNAs and hormones in the generation of new neurons in the hippocampus. In doing so,we focus our work inutilizing RNA interference (RNAi) as a tool to study and treating neurologic diseases, such as epilepsy, depression and others, that may be related to chronic alterations in hippocampal neurogenesis.
We use a wide range of RNAi effectors from synthetic siRNAs to short hairpin RNAs and artificial microRNAs. In combination with viruses engineered and optimized to deliver RNAi effectors to stem cells and newborn neurons in the hippocampus in vivo, our experimental approach provides and excellent opportunity to contribute substantially to a currently booming scientific field.

Within this line of research, we are particularly interested in studying the interplay between microRNAs and hormone receptors in the regulation of neural stem cells in vitro and in vivo.

A central interest of the lab is the role of hormone receptors and microRNAs in the regulation of synaptic connectivity at the level of dendritic spines. With this aim we use state-of-the-art microscopy techniques.
 

Nuclear receptor and G-protein coupled receptor signaling

A second part of the group's research focuses on understanding the molecular mechanisms involved in crosstalk between GPCRs and between GPCRs and nuclear receptors for hormones

Lab members

Carlos P. Fitzsimons, Ph.D., Group Leader

Carlos Daniel Zappia, Postdoctoral fellow (2018)

Pascal Bielefeld, Postdoctoral fellow (2017)

Marijn Schouten, Postdoctoral fellow (2015)

Rui Rodrigues Da Silva, Ph.D. Student, Fundação para a Ciência e Tecnologia, Portugal (FCT)

Marijn Schouten, Ph.D. Student

Pascal Bielefeld, Ph.D. Student

Carla Verissimo, Ph.D. Student

Anna Davidson, MS Student, Erasmus Program

Bruno Miguel Macedo Seguro, Erasmus Program

Marit Breuk, MS Student

Emma Paschier, MS Student

Junlin Wong, MS Student

Karlijne Geijtenbeek, MS Student

Sedef Karayel, MS Student

Alisa TIaglik, MS student

Ruth Willems, MS student

Anneke Vuuregge, MS student

Lynnet Frijling, MS student

Diede Witkamp, MS student

Pablo Marco Moreno, MS student

Ilse de Bruin, MS student

Luuk Picavet, MS student

Diana Karina Alatriste, MS student 

Peter Roemers, MS student 

Joan Domingo-Espin, Guest Ph.D. Student     
Renee Schreurs, BS, MS Student 
Erik van Heesbeen, BS, MS Student

Gideon Meerhoff, BS, MS, Lab. Assistant

Selected literature (outdated)

>Fitzsimons CP, van Hooijdonk LW, Schouten M, Zalachoras I, Brinks V, Zheng T, Schouten TG, Saaltink DJ, Dijkmans T, Steindler DA, Verhaagen J, Verbeek FJ, Lucassen PJ, de Kloet ER, Meijer OC, Karst H, Joels M, Oitzl MS, Vreugdenhil E. Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. Mol Psychiatry. 2012 Aug 28. doi: 10.1038/mp.2012.123.  >Lucassen PJ, Fitzsimons CP, Korosi A, Joels M, Belzung C, Abrous DN. Stressing new neurons into depression? Mol Psychiatry. 2012 May 1. doi: 10.1038/mp.2012.39. >Lentivirus-mediated transgene delivery to the hippocampus reveals sub-field specific differences in expression.van Hooijdonk LW, Ichwan M, Dijkmans TF, Schouten TG, de Backer MW, Adan RA, Verbeek FJ, Vreugdenhil E, Fitzsimons CP. BMC Neurosci. 2009 Jan13;10:2.
>MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Vreugdenhil E, Verissimo CS, Mariman R, Kamphorst JT, Barbosa JS, Zweers T, Champagne DL, Schouten T, Meijer OC, de Kloet ER, Fitzsimons CP. Endocrinology . 2009 May;150(5):2220-8.
>The microtubule-associated protein doublecortin-like regulates the transport of the glucocorticoid receptor in neuronal progenitor cells. Fitzsimons CP, Ahmed S, Wittevrongel CF, Schouten TG, Dijkmans TF, Scheenen WJ, Schaaf MJ, de Kloet ER, Vreugdenhil E. Mol Endocrinol . 2008 Feb;22(2):248-62.
>Expression of a G protein-coupled receptor (GPCR) leads to attenuation of signaling by other GPCRs: experimental evidence for a spontaneous GPCR constitutive inactive form. Tubio MR, Fernandez N, Fitzsimons CP,Copsel S, Santiago S, Shayo C, Davio C, Monczor F. J Biol Chem . 2010 May 14;285(20):14990-8.
>Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein. Fitzsimons CP, Monczor F,Fernández N, Shayo C, Davio C. J Biol Chem . 2004 Aug 13;279(33):34431-9.

Past and ongoing collaborations

• Neus Ferrer and Joan Domingo-Espin. The Institute of Biotechnology and Biomedicine, Networking Centre on Bioengineering, Biomaterials and Nanomedicine,University of Barcelona, Spain.
• Paul Lucassen, Harm Krugers, SILS Center for Neurosciences, University of Amsterdam
• Marian Joels, Rudolf Magnus lab Utrecht and SILS, University of Amsterdam
• Ron de Kloet, Erno Vreugdenhil and Onno Meijer. Medical Pharmacology Department, LACDR, Leiden
• Davide de Petri-Tonelli, Department of Neuroscience and Brain Technologies,
  Italian Institute of Technology, Genoa, Italy.
• Federico Monczor, Laboratory of Receptor Pharmacology, Department of Medicinal Chemistry, Faculty of Biochemistry and Pharmacy, University of Buenos Aires, Argentina.
• Dennis Steindler, Department of Neuroscience, The McKnight Brain Institute,
  University of Florida College of Medicine.
• Connie Jimenez, OncoProteomics Laboratory, Dept. Medical Oncology, VUMC-Cancer Center Amsterdam
• Fons Verbeek, Section Imaging & BioInformatics, Leiden Institute of Advanced Computer Science
• Joost Verhaagen, Netherlands Institute of Neurosciences