The flexible control of behavior and behavioral change due to learning requires the neuronal interaction of several brain areas, including cortical areas (as the sensory cortices and the prefrontal cortex) and the hippocampus. In our project we investigate how malfunction due to age or disease in one of the interacting systems can be compensated by neuroplastic processes in the respective other areas. To this aim, we investigate the effects of optogenetically controlled release of the neurotrophic factor BDNF in cortical areas or in the hippocampus on the cortico-hippocampal interaction, and whether this altered interaction can compensate learning deficits observed in mouse models of ageing and Alzheimer’s disease.
Prof. Dr. Dr. med. Volkmar Leßmann
Volkmar Leßmann is the Director of the Institute of Physiology at the Medical Faculty of the Otto-von-Guericke-University Magdeburg. His research is focussed on molecular and cellular mechanisms of synaptic plasticity in health and disease. Using combined electrophysiological and advanced fluorescence microscopy techniques, his group investigates how neuromodulatory transmitters like dopamine and neurotrophins like BDNF shape synaptic transmission in neuronal circuits of the mouse hippocampus, amygdala, and prefrontal cortex, and how this affects learning in vivo. In collaboration with Psychiatrists, Neurologists, and Sports scientists from Magdeburg and Jena, his team further investigates the role of BDNF as a biomarker in patients of major depressive disorder (MDD), schizophrenia and dementia. Together with the group of Frank Ohl from the LIN, his research addresses optogenetically driven BDNF regulation of neuronal circuits in maladapted cortico-hippocampal interactions that are involved in Alzheimer’s disease and fear learning.
Prof. Dr. Frank Ohl
Frank Ohl is Director of the Department “Systems Physiology of Learning” at the Leibniz Institute for Neurobiology Magdeburg and is Professor of “Neurobiology” at the Institute of Biology of the Faculty of Natural sciences of the Otto-von-Guericke University Magdeburg. His background is neurophysiology and physics. He has developed rodent modes for cognitive processes (including concept learning and category formation) und investigates neuronal dynamics during learning using electrophysiological, optical and optogenetic methods. In collaboration with mathematicians and computer scientists he also develops neurocomputational models of experimentally investigated neuronal processes and helps with the advancement of machine learning strategies using novel neuro-inspired algorithms.
Dr. Thomas Endres
Dr. Michael Lippert
Dr. Susanne Meis
Dr. Thomas Munsch
Amber Ruth Schembri
My name is Amber Schembri and I am a PhD student and work within the Institute of Physiology at the University Hospital, Magdeburg. I joined the CRC in the September of 2021 yet have a background in biochemistry and neuroscience. I specialize in whole-cell patchclamp and my current interests include how neural resources are able to change the neuroplasticity in the brain during memory and learning tasks – and how age and disease can affect this.
What is the role of neuronal interactions in behavior, learning, and compensatory plasticity
Brains of higher vertrebrates including humans have a complex architecture, where local neuronal networks (e.g., in the hippocampus or cortical areas) are connected via long-range neuronal projections with other local networks. Current concepts of the functional principles of such interacting networks are based on the idea of a “division of labor” between local networks in the sense that individual functions of the global network are assigned to distinct brain areas. In this project we pursue the idea of mutual compensation, i.e., the idea of “stepping in” of one functional network partner in case of failure or malfunction of the other local network. The mechanistic neuronal implementation of such compensatory processes thereby reorganizes the interaction dynamics in the long-range global network and can (presumably) be controlled by (locally induced) changes in synaptic plasticity of local networks.
What is the neurotrophic
The neurotrophic protein BDNF is released in an activity-dependent manner at synapses of glutamatergic neurons. It is one of the key molecules for use-dependent leveling of the strength of synaptic transmission at GABAergic and glutamatergic synapses by controlling both synaptic potentiation (LTP) and synaptic depression (LTD) via opposing signaling cascades. While the local regulation of strengthening or weakening of synapses by BDNF signaling is increasingly better understood, possible mechanisms of a resulting BDNF control of long-range network interactions between communicating brain areas are still completely unclear.
Aims of our project
In this project we investigate, whether the neuronal interaction dynamics between cortical areas and the hippocampus represent a mechanism of (mutual) compensation of malfunction or failure in one brain region by the other and whether this compensatory mechanism can be boosted by optogenetic control of local BDNF release. In all project parts, we characterize local changes in synaptic plasticity using electrophysiological patch-clamp recordings in vitro, and transregional neuronal interaction dynamics using multi-channel recording in vivo. In the first work package, we characterize how changes in synaptic plasticity and neuronal interactions between cortical areas and hippocampus change in different learning scenarios, viz. sensory cued spatial learning and so-called fear extinction learning. In a second work package, we investigate, how synaptic plasticity (mechanisms) and neuronal interaction patterns between cortex and hippocampus change during ageing and in the context of Alzheimer’s disease, thereby accounting for reduced learning and memory performance, and whether an optogenetically controlled elevation of BDNF release in the hippocampus can restore neuronal interaction with the cortical areas and cognitive performance. In a third work package we investigate the analogous question, but this time using optogenetic control of BDNF release in cortical areas and with respect to the neuronal interaction of these brain areas with the hippocampus.
A vision for the future
This project aims at establishing the optogenetically controlled local release of BDNF as a strategy for recruiting compensatory plasticity of the cortico-hippocampal interaction, which is disturbed in old age and in Alzheimer’s disease. If successful, this interventional strategy lends itself to application in other diseases for which dysfunction of the cortico-hippocampal interaction is also typical, like in major depressive disorder. Finally, this approach could also be tested in cases where the neuronal interaction between other brain areas is disturbed, like in cortex and basal ganglia in Parkinson’s disease.
Publications of the project A06
Repurposing drugs against Alzheimer’s disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?
Volkmar Leßmann, Georgia-Ioanna Kartalou, Thomas Endres, Marc Pawlitzki, Kurt Gottmann J Neural Transm (2023)
Laser-Induced Apoptosis of Corticothalamic Neurons in Layer VI of Auditory Cortex Impact on Cortical Frequency Processing
Katja Saldeitis, Marcus Jeschke, Eike Budinger, Frank W Ohl, Max F K Happel Front Neural Circuits (2021)
State Transitions During Discrimination Learning in the Gerbil Auditory Cortex Analyzed by Network Causality Metrics
Sebastian Samer, Rajeev Raman, Gregor Laube, Michael R. Kreutz & ARobert Kozma, Sanqing Hu, Yury Sokolov, Tim Wanger, Andreas L Schulz4, Marie L Woldeit, Ana I Gonçalves, Miklós Ruszinkó, Frank W Ohl Front Syst Neurosci (2021)
BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment
Mahmoud Harb, Justina Jagusch, Archana Durairaja, Thomas Endres, Volkmar Leßmann & Markus Fendt Translantional Psychiatry (2021)