A05
We will deepen our understanding how the brain’s extracellular matrix (ECM) contributes to cognitive flexibility (CFL) and memory in mice and men. Using molecular tools, we will restore the ECM in aged and 5xFAD mice and study CFL, information encoding and engram updating. We shall test free-water diffusion tensor imaging and quantitative susceptibility imaging as promising MRI-based proxies for whole-brain ECM distribution in mice and humans to investigate the link between neural ECM and its peripheral markers, neuronal information processing in candidate brain regions and CFL.
Principal Investigators
Prof. Dr. Alexander Dityatev
Dr. Dr. med. Björn Hendrik Schott
Prof. Dr. Constanze Seidenbecher
Co-Workers
Dr. Stepan Aleshin
Dr. Carla Cangalaya Lira
Margarita Darna
Dr. Anni Richter
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), and diminishing the amount of neurocan elevates spontaneous neuronal activity (Baidoe-Ansah et al., 2025).
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 integrity in the frontal cortex as a potential source for cognitive reserve to maintain cognitive flexibility upon aging or under neurodegenerative conditions. We will study how neural ECM composition affects cognitive flexibility and memory precision via inhibitory circuit modulation and measure engram properties and neuronal activity in rodents after modulating their ECM integrity and PNN composition. Together with Z03, B06 and C01 we will correlate ECM serum levels and brain expression patterns as well as SNPs in ECM-encoding genes with cognitive flexibility and memory and with potential MRI-based proxies of ECM integrity.
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. Now will use our newly developed tools to weaken or strengthen ECM structures in mouse brains to distinguish acute from chronic effects of these genes on neuronal excitability and behavior, and to further elucidate the importance of the prefrontal cortex for cognitive flexibility.
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). Furthermore, we identified polymorphisms in the BCAN gene encoding brevican, which correlate with cognitive flexibility measures in humans.
A glimpse into the future
By studying in parallel mice and humans, we aim to dissect the basic mechanisms of how the micro-environment of neurons in the prefrontal 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 or viral tools to control matrix integrity in the brain. Successful establishment of proxies of neural ECM integrity in MRI data could pave the way for non-invasive in vivo monitoring of ECM remodeling.