Cognitive flexibility is the ability to adapt our behavior to a changing environment. It crucially depends on the prefrontal cortex. In our project, we are investigating whether and how the extracellular matrix, which surrounds neurons and determines the biophysical properties of the brain, contributes to the regulation of cognitive flexibility in mice and humans.
Prof. Dr. Alexander Dityatev
Alexander Dityatev is the head of the Molecular Neuroplasticity group at the DZNE Magdeburg. He runs a research program on the role of neural extracellular matrix in neurological and neuropsychiatric diseases such as epilepsy, Alzheimer’s disease, vascular dementia, depression and schizophrenia. His major expertise is in extracellular matrix biology, synaptic plasticity and synaptogenesis, electrophysiology, behavioral analysis and two-photon imaging in awake mice. He is serving as Editor-in-Chief of the Cellular Microenvironment section in Cells.
Dr. Dr. med. Björn Hendrik Schott
Björn Schott is a consultant psychiatrist at the University of Göttingen and, together with Constanze Seidenbecher, head of the Synapse-Brain-Cognition group in the Department of Behavioral Neurology at LIN Magdeburg. His research focuses on the extent to which genetic and immunological factors affect learning and memory processes in humans, as well as their disruption in old age and in neurological and psychiatric diseases. He serves as an associate editor for Frontiers in Human Neuroscience.
Prof. Dr. Constanze Seidenbecher
Constanze Seidenbecher is a molecular neuroscientist and member of the CRC1436 Steering Committee. She is head of the Synapse-Brain-Cognition group in the Behavioral Neurology department at LIN Magdeburg, together with Björn Schott, and also heads the LIN Science Management & Public Outreach office. Her research is focused on synaptic molecules and the perisynaptic extracellular matrix of the brain as determinants of neural and homeostatic plasticity. She is council member of the International Society for Neurochemistry and chair of the ISN Career Development committee and she serves as editor for Journal of Neurochemistry.
Dr. Stepan Aleshin
I am a postdoc in the molecular neuroplasticity group at DZNE, Magdeburg. I graduated in virology (MSc) and molecular biology (PhD). Over the course of my scientific career, I have been interested in behavioural experiments and their modelling, neurodegenerative diseases and integrative/theoretical neuroscience. In addition to my scientific activities, my interests also extend to travelling and orienteering.
Margarita is a PhD Candidate at the Leibniz Institute for Neurobiology. She has a background in neurobiology and is interested in human cognition. In her research, she uses non-invasive methods, such as Electroencephalography and Magnetic Resonance Imaging, to study human behaviour. She also applies computational methods to predict which factors may play a role in one’s cognition.
Dr. Anni Richter
Anni is a postdoctoral scientist at the Leibniz Institute for Neurobiology. She has a background in psychology and is interested in human cognition. In her research, she focuses on dopaminergic modulation of implicit and explicit learning, synaptogenetics of human learning and memory, and multimodal markers of neurocognitive aging using non-invasive methods, such as Magnetic Resonance Imaging.
What is the extracellular matrix?
The extracellular matrix (ECM) in the brain consists of a three-dimensional meshwork of macromolecules such as proteoglycans, glycoproteins and hyaluronic acid. These molecules are produced by neurons and glial cells and released into the extracellular space, where they form gel-like macrostructures. Especially around inhibitory parvalbumin-positive cells, so-called perineuronal nets are found as a specialization of the ECM, surrounding and isolating the synapses.
Is there a correlation between brain activity and ECM composition?
The molecular composition of the neural ECM changes during maturation and aging of the brain as well as during diseases such as tumors, brain trauma, epilepsy, depression, schizophrenia, or neurodegenerative diseases (Ulbrich et al., 2021). ECM is also modulated depending on the activity state of healthy neuronal networks. For example, activation of dopamine receptors in neurons of the cerebral cortex leads to increased cleavage of ECM proteoglycans by extracellular proteases (Mitlöhner et al., 2020). When the neural ECM is experimentally degraded, the plastic properties of the brain change. For example, the cognitive flexibility of gerbils in an acoustic relearning task increases when the ECM in the auditory cortex is degraded prior to relearning (Happel et al., 2014).
Genetic variability in ECM-encoding genes
Throughout the genome, there are numerous polymorphic sites that make up our genetic variability, to which ECM-encoding genes are also subject. In the NCAN gene, which encodes the proteoglycan neurocan, there is a polymorphism that is considered a genome-wide risk factor for neuropsychiatric disorders such as schizophrenia and bipolar disorder. We have shown that this polymorphism correlates with memory performance and hippocampal activation patterns in a learning task and with gray matter density in the prefrontal cortex in healthy adults (Assmann et al., 2021).
The goals of our project
We aim to investigate in rodents and humans the importance of the ECM in the frontal cortex as a neural resource for cognitive flexibility and the potential transfer of this output from one task to another. We are interested in whether changes in cognitive flexibility during aging are accompanied by changes in the matrix. In particular, we focus on the proteoglycans neurocan and brevican and the complex carbohydrate polysialic acid (PSA). Using young and older healthy humans and mice, we will perform attention tasks and virtual reality maze experiments. We want to find out if improvements in a particular test translate to other behavioral tasks.
To analyze the importance of the ECM in these processes, we are working with mice that lack the genes for the key ECM components, brevican or neurocan. In addition, we are specifically knocking down these two proteoglycans in normal mice via knockdown using shRNA in the prefrontal cortex. Thus, we aim to distinguish acute from chronic effects of these genes on neuronal excitability and behavior, and to further elucidate the importance of the frontal cortex for cognitive flexibility. In the proteoglycan-deficient mice, we will express the neurocan and brevican genetic variants known from humans to be associated with changes in cognitive traits.
Matrix variability and cognitive flexibility in humans
We also test cognitive flexibility and its transfer from one task to another in our human subjects. Behavioral results will be correlated with major polymorphisms in BCAN and NCAN genes, as well as with serum concentrations of ECM components and of the carbohydrate PSA. Using functional MRI, we determine the neural networks involved in the brain and model their interaction via Dynamic Causal Modeling. We also measure brain waves using EEG and directly compare theta oscillations in humans with mouse data.
A glimpse into the future
By working in parallel with mice and humans, we aim to dissect the basic mechanisms of how the micro-environment of neurons in the frontal cortex may affect the capacity for cognitive flexibility. Detection of brain ECM components in serum from patients could provide insight into remodeling processes of the neural ECM in disease conditions associated with impaired cognitive flexibility and stimulate the development of pharmacological tools that help control matrix integrity in the brain.
Publications of the project A05
Linking epileptic phenotypes and neural extracellular matrix remodeling signatures in mouse models of epilepsy
Armand Blondiaux, Shaobo Jia, Anil Annamneedi, Gürsel Çalışkan, Jana Nebel, Carolina Montenegro-Venegas, Robert C Wykes, Anna Fejtova, Matthew C Walker, Oliver Stork, Eckart D Gundelfinger, Alexander Dityatev, Constanze I Seidenbecher Neurobiol Dis (2023)
Inhibitory temporo-parietal effective connectivity is associated with explicit memory performance in older adults
Schott BH, Soch J, Kizilirmak JM, Schütze H, Assmann A, Maass A, Ziegler G, Sauvage M, Richter A iScience (2023)
Andres-Alonso M, Borgmeyer M, Mirzapourdelavar H, Lormann J, Klein K, Schweizer M, Hoffmeister-Ullerich S, Oelschlegel AM, Dityatev A, Kreutz MR Cell Rep (2023)
Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments
Hristo Varbanov , Shaobo Jia , Gaga Kochlamazashvili , Subhrajit Bhattacharya , Manal Ali Buabeid , Mohamed El Tabbal , Hussam Hayani , Stoyan Stoyanov , Weilun Sun , Hauke Thiesler , Iris Röckle , Herbert Hildebrandt , Oleg Senkov…
Adam I Ramsaran, Ying Wang, Ali Golbabaei, Stepan Aleshin, Mitchell L de Snoo, Bi-Ru Amy Yeung, Asim J Rashid, Ankit Awasthi, Jocelyn Lau, Lina M Tran, Sangyoon Y Ko, Andrin Abegg, Lana Chunan Duan, Cory McKenzie, Julia Gallucci, Moriam Ahmed, Rahul Kaushik, Alexander Dityatev, Sheena A Josselyn, Paul W Frankland Science (2023)
Plasma concentrations of anti-inflammatory cytokine TGF-β are associated with hippocampal structure related to explicit memory performance in older adults
M Raschick, A Richter, L Fischer, L Knopf, A Schult, R Yakupov, G Behnisch, K Guttek, E Düzel, I R Dunay, C I Seidenbecher, B Schraven, D Reinhold, B H Schott J Neural Transm (2023)
The relationship between resting-state amplitude fluctuations and memory-related deactivations of the default mode network in young and older adults
Jasmin M Kizilirmak, Joram Soch, Hartmut Schütze, Emrah Düzel, Hannah Feldhoff, Larissa Fischer, Lea Knopf, Anne Maass, Matthias Raschick, Annika Schult, Renat Yakupov, Anni Richter, Björn H Schott Hum Brain Mapp (2023)
Single-value scores of memory-related brain activity reflect dissociable neuropsychological and anatomical signatures of neurocognitive aging
Richter A, Soch J, Kizilirmak JM, Fischer L, Schütze H, Assmann A, Behnisch G, Feldhoff H, Knopf L, Raschick M, Schult A, Seidenbecher CI, Yakupov R, Düzel E, Schott BH Hum Brain Mapp (2023)
Extracellular Matrix Changes in Subcellular Brain Fractions and Cerebrospinal Fluid of Alzheimer’s Disease Patients
Lukas Höhn, Wilhelm Hußler, Anni Richter, Karl-Heinz Smalla, Anna-Maria Birkl-Toeglhofer, Christoph Birkl, Stefan Vielhaber, Stefan L Leber, Eckart D Gundelfinger, Johannes Haybaeck, Stefanie Schreiber, Constanze I Seidenbecher Int J Mol Sci (2023)
Heparan Sulfates Regulate Axonal Excitability and Context Generalization through Ca2+/Calmodulin-Dependent Protein Kinase II
I. Song, T. Kuznetsova, D. Baidoe-Ansah, H. Mirzapourdelavar , O. Senkov, H. Hayani, A. Mironov, R. Kaushik, M. Druzin, S. Johansson, A. Dityatev Cells (2023)
Structural and Functional MRI Data Differentially Predict Chronological Age and Behavioral Memory Performance
Soch J, Richter A, Kizilirmak JM, Schütze H, Feldhoff H, Fischer L, Knopf L, Raschick M, Schult A, Düzel E, Schott BH eNeuro (2022)
Emrah Düzel, Gabriel Ziegler, David Berron, Anne Maass, Hartmut Schütze, Arturo Cardenas-Blanco, Wenzel Glanz, Coraline Metzger, Laura Dobisch, Martin Reuter, Annika Spottke, Frederic Brosseron, Klaus Fliessbach, Michael T Heneka, Christoph Laske, Oliver Peters, Josef Priller, Eike Jakob Spruth, Alfredo Ramirez,…
BCAN and NCAN Cleavage Products in the Cerebrospinal Fluid – Differential Occurrence in ALS, Epilepsy and Small Vessel Disease
Hußler W, Höhn L, Stolz C, Vielhaber S, Garz C, Schmitt FC, Gundelfinger ED, Schreiber S, Seidenbecher CI Front Cell Neurosci (2022)
Weilun Sun, Ilseob Choi, Stoyan Stoyanov, Oleg Senkov, Evgeni Ponimaskin, York Winter, Janelle Pakan, and Alexander Dityatev Nature Communications (2021)
Motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function
Anni Richter, Lieke de Boer, Marc Guitart-Masip, Guaslija Behnisch, Constanze I. Seidenbecher and Björn H. Schott J Neural Transm (2021)
Alexander Dityatev, Constanze Seidenbecher, and Markus Morawski Eur J Neurosci (2021)
Markus Zweckstetter, Alexander Dityatev & Evgeni Ponimaskin Signal Transduction and Targeted Therapy (2021)
A comprehensive score reflecting memory-related fMRI activations and deactivations as potential biomarker for neurocognitive aging.
Soch J, Richter A, Schütze H, Kizilirmak JM, Assmann A, Behnisch G, Feldhoff H, Fischer L, Heil J, Knopf L, Merkel C, Raschick M, Schietke CJ, Schult A, Seidenbecher CI, Yakupov R, Ziegler G, Wiltfang J, Düzel E, Schott BH….