A05
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.
Principal Investigators
Prof. Dr. Alexander Dityatev
Dr. Dr. med. Björn Hendrik Schott
Prof. Dr. Constanze Seidenbecher
Co-Workers
Dr. Stepan Aleshin
Margarita Darna
Shaobo Jia
Hadi Mirzapourdelavar
Dr. Anni Richter
Annabell Ernst
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.
Matrix-deficient mice
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.