Time frame: 2020 - 2023
Origin: FLAG-ERA JTC2019
The MILEDI (Multiscale Modelling of Impaired LEarning in Alzheimer’s Disease and Innovative Treatments) project involves teams of computational and experimental neuroscientists from the Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania, Institut de Pharmacologie Moléculaire et Cellulaire/ Centre national de la Recherche Scientifique, Valbonne, France and Institute of Biophysics, National Research Council, Palermo, Italy in collaboration with the Human Brain Project.
The project aims at developing a new multi-scale (integrated molecular, cellular and network levels) data-driven in silico model of the hippocampal CA1 region under Alzheimer's disease conditions.
Project Description and Objectives
Alzheimer’s disease (AD) affects over 46 million people worldwide, estimated to triple by the year 2050. It has a long preclinical stage and, before any clinical symptoms appear, pathological processes are observed in the hippocampus and entorhinal cortex, key brain structures responsible for memory encoding and retrieval. AD cannot be prevented, halted or cured today, and new interdisciplinary ways are urgently needed for the understanding and treatment of this devastating disease.
Recent experimental evidence supports the fundamental role of AD-related peptides early in the pathology: in particular the most widely studied Amyloid beta (Aβ), and the less investigated Amyloid eta (Aη) and Amyloid precursor protein (APP) C-terminal peptide (AICD). Their differential effects on synaptic function and intrinsic excitability of hippocampal CA1 pyramidal neuron at a single cell level are currently being investigated. However, the dose-dependent impact and complex interaction effects of Aβ, Aη, AICD on hippocampal synaptic plasticity, CA1 network activity, memory encoding and retrieval capacity and dynamics remain largely unknown.
The interdisciplinary consortium will perform ex-vivo whole-cell patch clamp electrophysiology recordings in hippocampus CA1 (Dr. Hélène Marie, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France), computational modeling of hippocampal synaptic plasticity (Prof Ausra Saudargiene, Lithuanian University of Health Sciences, Kaunas, Lithuania), of neuronal excitability and large scale network (Prof. Michele Migliore, Institute of Biophysics, Palermo, Italy) under control and Alzheimer's disease conditions.
The consortium has a proven track-record of experimental, theoretical and computational expertise to successfully achieve these goals. The project extends beyond the state-of-the-art by integrating ex-vivo experimental data into multi-scale in silico approaches to suggest potential targets for more effective treatments in the initial phase of Alzheimer's disease.
The main project objectives are:
1. Extend the experimental evidence of Amyloid beta (Aβ), Amyloid eta (Aη), AICD-related changes in the properties of hippocampal CA1 pyramidal neuron synaptic plasticity, synaptic signal integration and neuronal excitability.
2. Incorporate the dose-dependent effects of AD-related peptides into computational models of hippocampal synaptic plasticity, CA1 pyramidal neurons and CA1 network; identify and suggest experimentally testable predictions on the molecular, synaptic, cellular, network-level mechanisms of altered hippocampal function that leads to impaired learning and progressive irreversible memory loss in Alzheimer's disease.
3. Identify and assess experimentally and by computational modeling potential targets for innovative treatment of Alzheimer's disease.
The consortium will include the developed models into the EBRAINS Platform of the Human Brain Project and provide the community an essential multi-scale modelling tool for Alzheimer's disease. New use cases will be created and will become part of the EBRAINS Service Component 3.
All experimental data used for the models will be made publicly available through the HBP Knowledge Graph database. They will be formatted using HBP standards for data and model representation and will adhere to all ethical considerations and legal regulations.
Ausra Saudargiene, PhD (Project Coordinator)
Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
Prof. Ausra Saudargiene obtained her PhD degree in Informatics at the Institute of Mathematics and Informatics, Vilnius University, Lithuania in 2001 and continued her research as a postdoc in computational neuroscience at the University of Stirling, UK in 2002-2004. Currently she holds a position of a researcher at the Neuroscience Institute of Lithuanian University of Health Sciences, Kaunas, Lithuania, and she is a professor at the Department of Informatics, Vytautas Magnus University, Kaunas, Lithuania. Her main research interest is computational modeling of synaptic plasticity in hippocampus, and she has developed biophysical and molecular models of synaptic plasticity and models of memory encoding and retrieval in hippocampal CA1 microcircuit and cortex. Prof. Ausra Saudargiene is a leader of the HBP Infrastructure Voucher Call 2019 project Multiscale Hippocampal Models for Neuronal Plasticity: Integration to the Brain Simulation Platform(HippoPlasticity).
Hélène Marie, PhD
Institut de Pharmacologie Moléculaire et Cellulaire/Centre national de la Recherche Scientifique, Valbonne, France
Dr. Hélène Marie has more than 15 years of expertise on the first topic with training in Dr. Malenka’s lab at Stanford University (e.g. Marie et al., 2005), and more than 10 years of expertise in the second topic with key publications on the effects of AD peptides on neuron function. Dr. Hélène Marie has a long-standing expertise in collaborating with computational neuroscientists, notably with Prof. Michele Migliore. She is currently co-coordinator of a large local trans-disciplinary project ‘ComputaBrain’ financed by the French initiation of excellence IDEX UCA-Jedi, which gathers neurobiologists and neuromathematicians. In direct link with this project, Dr. Hélène Marie is a leader of the HBP Infrastructure Voucher Call 2018 project Building Alzheimer Disease Neuron Model (ADNeuronModel).
Michele Migliore, PhD
Institute of Biophysics, National Research Council, Palermo, Italy
Prof. Michele Migliore has extensive experience in modeling realistic neurons and networks, synaptic integration processes, plasticity mechanisms, and ionic channels, to study their role in modulating neuronal excitability, firing behaviors, and the emergence of pathologies and dysfunctions, using state of the art simulation environments on different supercomputer systems.
Breton-Provencher V, K Bakhshetyan, D Hardy, R Bammann, F Cavarretta, M Snapyan, D Coté, M Migliore, and A Saghatelyan (2016) Principal cell activity induces spine relocation of adult-born interneurons in the olfactory bulb, Nature Comm, 7:12659. doi: 10.1038/ncomms12659.
Einevoll GT, Destexhe A, Diesmann M, Grün S, Jirsa V, de Kamps M, Migliore M, Ness TV, Plesser HE, Schürmann F. The Scientific Case for Brain Simulations. Neuron 2019;102:735-744.
Kootar S, Frandemiche ML, Dhib G, Mouska X, Lorivel T, Poupon-Silvestre G, Hunt H, Tronche F, Bethus I, Barik J, Marie H. Identification of an acute functional cross-talk between amyloid-β and glucocorticoid receptors at hippocampal excitatory synapses. Neurobiol Dis. 2018;118:117-128.
Havela R, Manninen T, Saudargiene A, Linne M-L. Modeling neuron-astrocyte interactions: towards understanding synaptic plasticity and learning in the brain. 13th International Conference on Intelligent Computing (ICIC 2017) published in Intelligent Computing Theories and Application, Part II, Lecture Notes in Computer Science. 2017; 10362,157-168, Liverpool, UK.
Martinello K, Giacalone E, Migliore M, Brown DA, Shah MM. The subthreshold-active KV7 current regulates neurotransmission by limiting spike-induced Ca2+ influx in hippocampal mossy fiber synaptic terminals. Nature Commun Biol. 2019;26;2:145.
Migliore M, Cavarretta F, Marasco A, Tulumello E, Hines ML, Shepherd GM. (2015) Synaptic clusters function as odor operators in the olfactory bulb, Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8499-504.
Migliore R, Lupascu CA, Bologna LL, Romani A, Courcol JD, Antonel S, Van Geit WAH, Thomson AM, Mercer A, Lange S, Falck J, Rössert CA, Shi Y, Hagens O, Pezzoli M, Freund TF, Kali S, Muller EB, Schürmann F, Markram H, Migliore M. The physiological variability of channel density in hippocampal CA1 pyramidal cells and interneurons explored using a unified data-driven modeling workflow. PLoS Comput Biol. 2018;14(9):1-5.
Pousinha PA, Mouska X, Bianchi D, Temido-Ferreira M, Rajão-Saraiva J, Gomes R, Fernandez SP, Salgueiro-Pereira AR, Gandin C, Raymond EF, Barik J, Goutagny R, Bethus I, Lopes LV, Migliore M, Marie H. The Amyloid Precursor Protein C-Terminal Domain Alters CA1 Neuron Firing, Modifying Hippocampus Oscillations and Impairing Spatial Memory Encoding. Cell Rep. 2019 Oct 8;29(2):317-331.
Pousinha PA, Mouska X, Raymond EF, Gwizdek C, Dhib G, Poupon G, Zaragosi L-E, Giudici C, Bethus I, Pacary A, Willem M, Marie H. Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein. Elife. 2017;6:1–29.
Saudargiene A, Graham BP. Factors affecting STDP learning rules in the dendrites of CA1 pyramidal cells. Hippocampal Microcircuits: A Computational Modeler’s Resource Book. Springer Series in Computational Neuroscience. 2nd Edition, 2018.
Saudargiene A, Cobb S, Graham BP. A computational study on plasticity during theta cycles at Schaffer collateral synapses on CA1 pyramidal cells in the hippocampus. Hippocampus. 2015; 25(2):208-18.
Saudargiene A, Jackevicius R, Graham B. Interplay of STDP and Dendritic Plasticity in a Hippocampal CA1 Pyramidal Neuron Model. Proc. of the 26th International Conference on Artificial Neural Networks, 11-15 September 2017, Alghero, Italy. Springer-Verlag Lecture Notes in Computer Science. 217;381-388.
Solinas SMG, Edelmann E, Leßmann V, Migliore M. A kinetic model for Brain-Derived Neurotrophic Factor mediated spike timing-dependent LTP. PLoS Comput Biol. 2019;15(4): e1006975.
Temido-Ferreira M, Ferreira DG, Batalha VL, Marques-Morgado I, Coelho JE, Pereira P, Gomes R, Pinto A, Carvalho S, Canas PM, Cuvelier L, Buée-Scherrer V, Faivre E, Baqi Y, Müller CE, Pimentel J, Schiffmann SN, Buée L, Bader M, Outeiro TF, Blum D, Cunha RA, Marie H, Pousinha PA, Lopes LV. Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors. Molecular Psychiatry. 2018;doi: 10.1038/s41380-018-0110-9.