Regulation of the extracellular matrix by dopamine during adult learning

• Applicants: Dr. Renato Frischknecht; Professor Dr. Max Fabian Happel
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441274012

The central aim of this project is to understand how brevican, a key protein of the extracellular matrix (ECM) of the brain, affects cortex-dependent plasticity and acquisition learning in adult rodents. We have shown that experimental degradation of the ECM within the sensory cortex enhances cognitive flexibility during reversal learning. Recently, we described that initial training leads to transient downregulation of the ECM protein brevican. Thus, our main hypothesis is that initial downregulation of the ECM promotes synaptic plasticity that is fundamental for acquisition learning. We speculate that in the adult brain, such learning-dependent regulation of the ECM needs concomitant action of reinforcing dopaminergic neuromodulation coding the behavioral relevance of events. In this proposal we therefore want to investigate the so far elusive molecular and neuromodulatory mechanisms leading to ECM downregulation during initial training and its role for learning and memory formation. In particular, we are interested in 1) the localization and timing of ECM regulation during learning in the brain 2) the molecular mechanisms that control ECM regulation and its impact on learning and memory recall, and 3) the particular role of the learning-relevant neuromodulator dopamine. We will investigate expression and proteolysis of specific ECM proteins using biochemistry and immunohistochemistry in the mouse auditory cortex and other learning relevant brain areas (hippocampus, prefrontal cortex) immediately after acquisition learning. In order to manipulate potential key mechanisms of ECM remodeling that interfere with initial learning, we derived a set of behavioral experiments with different perturbation approaches: we will use 1) inhibition of initial proteolysis by microinjections of central metalloproteinase-blockers in learning-relevant brain areas, 2) targeted silencing of ADAMTS4 and 5 via small-hairpin RNA interference and 3) blockade or enhancement of the learning-related neuromodulator dopamine by optogenetic control of the ventral tegmental area (VTA). By chronic multichannel recordings of cortical circuit activity, we want to link adult cortical map plasticity and ECM regulation induced by classical conditioning. With our complementary expertise, we aim to identify ECM regulation as a fundamental prerequisite for acquisition learning and the subsequent formation of long-term memories. Our goal is to portend an understanding of the underlying molecular and neuromodulatory control mechanisms of this regulation on a molecular, physiological and behavioral level and to thereby endorse the unification of two current research areas.

• DFG Programme: Research Grants