CognitionNet

Fourteen Marie Curie fellows joined the EU IDP Project CognitionNet

(funded by the EC under FP7-PEOPLE-2013 (607508))

CognitionNet Marie Curie fellows investigated brain mechanisms of cognition at the molecular, cellular, neural network and on behavioural level, from both a basic and a clinical perspective and integrated the results to develop novel treatment options for various forms of cognitive impairment. CognitionNet Marie Curie fellows built on the availability of completed genomic databases to facilitate forward (phenotype to genotype) and reverse (genotype to phenotype) genetic approaches and combined mouse models and human cohorts for cross-species analysis.

Marie Curie fellows, supervisors, key objectives and results per research team:

Aim team 1: To investigate mechanisms of synaptic plasticity in cognition, in particular related to molecules with importance for modulating synaptic efficacy.

Results: Four Early Stage Researchers (ESRs) in Work package 1 (WP1) studied plasticity of cognition during adulthood from the molecular to the behavioural level. One of the two papers that have been published focussed on the architecture of pyramidal neurons in the human cortex. From the papers in preparation, one discovered many synaptic proteins related to associative learning, and this will be followed up in the coming year(s) with intervention studies to show their causal role.

Team members:

ESR1 Sonia Vázquez Sánchez – Synaptic morphology and function in cognitive disorder models – PI: Dr. Jan van Weering

ESR2 Keerthi Kumar Doreswamy – The link between single cell activity and cognitive performance – PI: Dr. Christiaan de Kock

ESR3 Aina Badia Soteras – Glial modulation of cognitive function – PI: Dr. Mark Verheijen

ESR4 Demirhan Cetereisi – Molecular pathway of cognition and cognitive deficits – PIs: Prof. dr. Sabine Spijker & Dr. Ka Wan Li

Publications:

  • VPS35 depletion does not impair presynaptic structure and function. Vazquez-Sanchez, Sonia, Sander Bobeldijk, Marien P. Dekker, Linda van Keimpema, and Jan RT van Weering. Scientific reports 8, no. 1 (2018): 2996. DOI:10.1038/s41598-018-20448-4 >Read PDF
  • Extension of Helix 12 in Munc18-1 Induces Vesicle Priming; Munch, Anders S., Girish H. Kedar, Jan RT van Weering, Sonia Vazquez-Sanchez, Enqi He, Timon André, Thimo Braun, Thomas H. Söllner, Matthijs Verhage, and Jakob B. Sørensen; 2016; The Journal of Neuroscience 36, no. 26: 6881-6891. >Read PDF
  • Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex. Mohan H, Verhoog MB, Doreswamy KK, Eyal G, Aardse R, Lodder BN, Goriounova NA, Asamoah B, B Brakspear AB, Groot C, van der Sluis S, Testa-Silva G, Obermayer J, Boudewijns ZS, Narayanan RT, et al.. 2015, Cerebral Cortex. PMID26318661 DOI: 10.1093/cercor/bhv188 >Read PDF

In preparation (authors list needs to be finalized):

  • Cell-type specific coding and decoding of naïve, exploratory whisker touch in rat primary somatosensory cortex. Keerthi K. Doreswamy.
  • Cell-type and Layer specific spike patterns representing standard and non-standard stimulus in rat primary somatosensory cortex. Keerthi K. Doreswamy,
  • Orphan GPCR158 is essential for neuronal outgrowth. Demirhan Çetereisi,
  • The role of GPR158 during learning and memory Demirhan Çetereisi,
  • Molecular function of GPR158 and possible ligands in the brain. Demirhan Çetereisi,
  • Hippocampal synaptic proteomic profiling of GPR158-null mice. Demirhan Çetereisi,
  • Retromer imparement does not alter presynaptic structure nor function; Sonia Vazquez-Sanchez.

 

 


 

Aim team 2: To identify mechanisms that contribute to homeostatic synaptic function and plasticity and to cognitive dysfunction during early development, with emphasis on impulsivity and working memory problems, as observed in autism spectrum disorders, and in fragile X syndrome patients.

Results: Four ESRs in WP2 studied the role of genes with human mutations related to these diseases in the context of synaptic plasticity and cognitive control in adulthood. There was a focus on Rett syndrome, for which mouse models and human induced pluripotent stem cells were used. Data from human post-mortem brain tissue showed specific protein changes that are now being studied in Rett-derived iPSC neurons as well. These neurons seem to have a slower development, likely contributing to the observed disease symptoms of cognitive decline. In addition, critical for healthy development of neurons in the prefrontal cortex is that the main inhibitory receptor evolves from being excitatory to inhibitory.

Team members:

ESR5 Lisa Hinz – Genetic interactions and phenotypic processes in cognitive (dis)ability – PI: Dr. Vivi Heine

ESR6 Ana Rita Agra de Almeida Quadros – Retrograde signalling in homeostatic synaptic plasticity – PI: Dr. Ruud Toonen

ESR7 Johny H. Pires – Inhibitory control of immature networks in Neurodevelopmental disorders (NDD) – PI: Dr. Rhiannon Meredith

ESR8  Roberta Mancini – The role of CNV hotspots in autism and intellectual disability – PI: Dr. Sander Groffen

Publications:

  • Detection of silent cells, synchronization and modulatory activity in developing cellular networks. Johannes J.J. Hjorth, Julia Dawitz, Tim Kroon, Johny Pires, Valerie J. Dassen, Janna A. Berkhout, Javier Emperador Melero, Aish G. Nadadhur, Mihai Alevra, Ruud F. Toonen, Vivi M. Heine, Huibert D. Mansvelder, Rhiannon M. Meredith; 2015; Developmental Neurobiology; DOI: 10.1002/dneu.22319 >Read PDF
  • Tomosyn associates with secretory vesicles in neurons through its N- and C-terminal domains, Cornelia J. Geerts, Roberta Mancini, Ning Chen, Frank T. W. Koopmans, Ka Wan Li, August B. Smit, Jan R. T. van Weering, Matthijs Verhage, Alexander J. A. Groffen*PLoS ONE 12(7): e0180912. doi.org/10.1371/journal. pone.0180912 >Read PDF

In preparation (authors list needs to be finalized):

  • Pluripotency State and X-Chromosomal Re-activation in iPSCs Generated With Different Reprogramming Techniques. Lisa. Hinz
  • Delay in Neuronal Network Maturation of iPSC-derived Neurons from Rett Syndrome Patients. Lisa.Hinz, Johny H. da Silva Dias Pires
  • Fbxo41 promotes disassembly of neuronal primary cilia; Cillian R. King, Ana R. Quadros
  • Exploring Ca2+ transients and their spatio-temporal correlation with quantal neurotransmission in mouse hippocampal neurons. Roberta Mancini
  • Automated detection and supervised quantification of spontaneous neuronal Ca2+ transients. Roberta Mancini

 


 

Aim team 3: To identify the gene and protein networks that contributes to age-related cognitive decline under healthy conditions and in neurodegenerative disease.

Results: Three ESRs in WP3 worked on novel therapeutic entry points for treatment of age-related cognitive decline. A paper authored by one ESR showed that resting state EEG measurements could be used as possible biomarkers, in this case for insomnia. This could bring diagnostic and prognostic use of these tools one step closer to the clinic in which personalized treatment strategies can be designed. Furthermore, in a paper on a mouse model of Alzheimer’s disease, the authors showed the specific role of the disease-related increase in extracellular matrix in the hippocampus contributing to memory loss. After using enzymes to degrade this matrix, memory impairments were alleviated in these mice.

Team members:

ESR9 Sara Hijazi – The aging synapse – PI: Dr. Ronald van Kesteren

ESR10 Aishwarya Nadadhur – iPS cells and neurological disorders – PI: Dr. Vivi Heine

ESR11 Sonja Šimpraga – Neurophysiological Biomarker Toolbox for M/EEG diagnostics – PI: Dr. Klaus Linkenkaer-Hansen

Publications:

  • Multi-level characterization of balanced inhibitory-excitatory cortical neuron network derived from human pluripotent stem cells. Aishwarya G. Nadadhur, Javier Emperador Melero, Marieke Meijer, Desiree Schut, Gerbren Jacobs, Ka Wan Li, Stephanie Dooves, Johannes J.J. Hjorth, Rhiannon Meredith, Ruud F. Toonen, Ronald E. Van Kesteren, August B. Smit, Matthijs Verhage, Vivi M. Heine. Plos One, 2017 >Read PDF
  • Differential maturation of two regulated secretory pathways in human iPSC-derived neurons. Javier Emperador Melero, Aishwarya G. Nadadhur, Desiree Schut, Jan v Weering, Vivi M. Heine, Ruud F. Toonen, & Matthijs Verhage.  Stem cell reports, 2017. >Read PDF
  • Multiple phenotypes of resting-state cognition are altered in insomnia disorder. Laura Palagini, Nicola Cellini, Mauro Mauri, Irene Mazzei, Sonja Simpraga, Liliana dell’Osso, Klaus Linkenkaer-Hansen, Dieter Riemann: 2016, Sleep Health (volume 2) >Read PDF
  • Detection of silent cells, synchronization and modulatory activity in developing cellular networks. Hjorth, J. J.J., Dawitz, J., Kroon, T., Pires, J., Dassen, V. J., Berkhout, J. A., Emperador Melero, J., Nadadhur, A. G., Alevra, M., Toonen, R. F., Heine, V. M., Mansvelder, H. D. and Meredith, R. M., Developmental Neurobiology, 2016. >Read PDF
  • Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease. Végh MJ, Heldring CM, Kamphuis W, Hijazi S, Timmerman AJ, Li KW, van Nierop P, Mansvelder HD, Hol EM, Smit AB, van Kesteren RE. Acta Neuropathol Commun. 2014 29;2:76. doi: 10.1186/s40478-014-0076-z.>Read PDF
  • EEG machine learning for accurate detection of cholinergic intervention and Alzheimer’s disease. Sonja Šimpraga, Ricardo Alvarez-Jimenez, Huibert D. Mansvelder, Joop M.A. van Gerven, Geert Jan Groeneveld, Simon-Shlomo Poil, Klaus Linkenkaer-Hansen. Scientific reports| 7: 5775 | DOI:10.1038/s41598-017-06165-4 1 >Read PDF

In preparation (authors list needs to be finalized):

  • Early amyloid-induced dysfunction of hippocampal parvalbumin interneurons causes memory deficits and network imbalance in APP/PS1 mice. Sara Hijazi
  • EEG-based machine learning identifies a nicotinic acetylcholine index to assess the efficacy of procognitive compounds. Sonja Šimpraga
  • An EEG-based decision-support system for diagnosis and prognosis of autism spectrum disorder. Jan Sprengers, Erika Juarez Martinez, Sonja Šimpraga
  • Increased neuronal network activity with defective neuronal and oligodendrocyte properties in Tuberous sclerosis complex patient iPSC-based models. Aishwarya G. Nadadhur
  • Patterning factors during neural progenitor induction determine regional identity and differentiation potential. Aishwarya G. Nadadhur

 


 

Aim team 4: To dissect the mechanisms of molecular plasticity and brain circuitry that are related to cognitive decline in neuropsychiatric disease, including impulsivity, depression and addiction.

Results: Three ESRs in WP4 reported affected states of the network that lead to maladaptive behavioural output. These ESRs studied emotional memory, drug addiction, attention and depression, for which they formed the molecular and cellular basis of subsequent functional network analysis. Using optogenetic intervention of subregions of the prefrontal cortex, the authors showed involvement of these regions in attention. Furthermore, specifically the ventral part of the medial prefrontal cortex is important for the exact timing of attention in the second-range.

Team members:

ESR12 Joshua Obermayer – Cholinergic control of attention – PI: Prof. dr. Huibert Mansvelder

ESR13 Mariana Raimundo Matos  – Neuronal circuitry of addiction memory – PI: Dr. Michel van den Oever

ESR14 Maija Koskinen – Neuronal circuitry of cognition – PI: Prof. dr. Sabine Spijker

Publications:

  • Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like….  Danai Riga, Ioannis Kramvis, Maija K. Koskinen, Pieter Van Bokhoven, Johanneke E. Van der Harst, Tim S. Heistek, A. Jaap Timmerman, Pim Van Nierop, Roel C. Van der Schors1, Anton W. Pieneman, Anouk de Weger, Yvar Van Mourik, Anton N.M. Schoffelmeer, Huib D. Mansvelder, Rhiannon M. Meredith, Witte J.G. Hoogendijk, August B. Smit, Sabine Spijker. Science Translational Medicine 9 (421). DOI: 10.1126/scitranslmed.aai8753 >Read PDF
  • Layer-specific cholinergic control of human and mouse cortical synaptic plasticity. Verhoog MB, Obermayer J, Kortleven CA, Wilbers R, Wester J, Baayen JC, De Kock CP, Meredith RM, Mansvelder HD. Nat Commun. 2016 Sep 8;7:12826 >Read PDF
  • Sustained Attentional States Require Distinct Temporal Involvement of the Dorsal and Ventral Medial Prefrontal Cortex. Front Neural Circuits Luchicchi A, Mnie-Filali O, Terra H, Bruinsma B, de Kloet SF, Obermayer J, Heistek TS, de Haan R, de Kock CP, Deisseroth K, Pattij T, Mansvelder HD. 2016 Aug 31;10:70. >Read PDF
  • The Extracellular Matrix Protein Brevican Limits Time-Dependent Enhancement of Cocaine Conditioned Place Preference. Lubbers BR, Matos MR, Horn A, Visser E, Van der Loo RC, Gouwenberg Y, Meerhoff GF, Frischknecht R, Seidenbecher CI, Smit AB, Spijker S, van den Oever MC.; Neuropsychopharmacology. 2016 Jun;41(7):1907-16. >Read PDF
  • Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex. Mohan H, Verhoog MB, Doreswamy KK, Eyal G, Aardse R, Lodder BN, Goriounova NA, Asamoah B, B Brakspear AB, Groot C, van der Sluis S, Testa-Silva G, Obermayer J, Boudewijns ZS, Narayanan RT, Baayen JC, Segev I, Mansvelder HD, de Kock CP. Cereb Cortex. 2015 Dec;25(12) >Read PDF
  • Optogenetic dissection of medial prefrontal cortex circuitry. Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC (2014)., Front Syst Neuroscience, 230 (8). >Read PDF

In preparation (authors list needs to be finalized):

  • Cortical lateral inhibition by Somatostatin-positive interneurons is facilitated by basal forebrain cholinergic inputs. Joshua Obermayer
  • Early memory allocation to cortical ensembles is critical for remote memory expression. Mariana Raimundo Matos.
  • Prefrontal cortex parvalbumin interneurons are required for extinction of a cocaine memory trace. Mariana Raimundo Matos.
  • A mouse model of sustained depression recapitulates the rat model. Maija K. Koskinen
  • Neocortical ChAT‐VIP interneurons release acetylcholine and control attention. Joshua Obermayer
  • From stress to depression: Development of extracellular matrix-dependent cognitive impairment following social defeat. Maija K. Koskinen

 


Management, Outreach and Dissemination

ESRs also had at least two secondments, one with an industrial partner, and one within academia. In this way, trainees have gained experience in both ‘worlds’, preparing them for a future career in either of them. In addition, specific focus has been on broadening the career prospects of the trainees by providing inter-MSCA ITN training and dissemination together with the FP7 MSCA ITN INSENS network.

Trainees have presented their results (in poster-format and by oral presentation) in both host organized CNCR-based meetings, as well as scientific national (Dutch Neuroscience meeting, mid-term meeting with FP7 MSCA ITN INSENS ESRs, Graduate school Neuroscience meeting), and international meetings (Society for Neuroscience meeting (USA), FENS meeting (Europe), and smaller topically more focused meetings abroad). In addition, trainees have participated in several outreach and dissemination events, e.g. Sonia Vazquez gave an interactive lecture for prospective academic students in high school (last grade students) at Johannes Fontanus College, Barneveld (NL) and was a speaker in Shanti India school in Bodhgaya. All explained their research to the general public in a Dutch museum (Dolhuys, Haarlem), where they also generated a video clip about their scientific motivation and goals (https://www.youtube.com/watch?v=ZAQbjPVg7qk). Some ESRs participated in the national science weekend ‘Weekend van de Wetenschap’. Liza Hinz organized a “Meeting for parents and relatives of children with Rett Syndrome”, and gave an overview and update on current research and laboratory tour (2017). Joshua Obermayer organized a PhD meeting (European Neuroscience Conference by Doctoral Students / ENCODS) in Helsingør, Denmark, a satellite event of the FENS (2016).

ESRs supervised in total 13 bachelor students, 18 master students and one Higher Education Student.