Brain Biophysical Models
BBM-CREF will address the multiscale reconstruction of brain function in pathologies and in aging, leveraging the most advanced tools running on EBRAINS. The BBM-CREF partnership with University of Pavia (dep. Of Brain and Behavioral Sciences, PI Egidio D’Angelo) will start with a specific case study about the propagation of functional effects of molecular damages documented in neurons through microcircuits and large-scale circuits to the whole brain in mice. The work of BBM-CREF will be initially dedicated to the multiscale investigation of a humanized mouse model bearing a mutation of the autistic spectrum disorder (ASD) and its corresponding multiscale modelling, adopting a blend of bottom-up and top-down techniques. In further developments beyond the starting case study, the proposal aims at developing a general multiscale and multilevel approach to the modeling of brain pathology of larger applicability for the development of biomedicine and neurotechnologies by exploiting the synergic competences and resources available @UNIPV and CREF. Further objectives will include the development of computational and network approaches to extract the statistical properties of functional MRI time series and the characterization of the association between brain networks modulation, its neurometabolic counterpart, and the underlying molecular damage associated to pathology or aging.
Multiscale modelling of brain dysfunction in autistic spectrum disorders
Autistic spectrum disorders (ASD) are pervasive developmental disorders with a recognized genetic origin. Autism causes complex alterations in brain circuit development and function leading to dramatic alterations in social life and behavior. The main hypotheses address dysfunction of the prefrontal cortex and cerebellar system. However, the mechanisms of dysfunction in the cerebellar circuits and their impact on communication with the cerebral cortex remain obscure. In this project we will investigate the issue in an animal model of autism, the IB2 KO mouse model (Giza et al., 2010; Soda et al., 2017), which has a mutation equivalent to that of familial cases of the Phelan-McDermid syndrome in humans and shows an autistic like phenotype. The proposed work plan for the initial case study includes the following steps, that can be reasonably completed in 18 months: 1) Complete the experimental investigation of changes in local microcircuits of the cerebellar and prefrontal cortex. This will be done performing specific experiments of patch-clamp and voltage-sensitive dye (VSD) imaging in mouse cerebellar and prefrontal slices (UNIPV). 2) Perform MRI experiments on the same mice at 7-T. The recordings will be done from the mouse brain in order to obtain functional data through BOLD-fMRI sequences allowing to record resting-state network activity and information about the structure of brain networks through DTI scans and tractography. 3) The connection between structural and functional data along with multiscale integration will be investigated using computational modelling and assessed in MRI data along the following steps: a. The alterations of neuronal and microcircuit activity (point 1) will be modelled and simulated using the NEURON and NEST simulators. This will allow to understand the intrinsic computational changes on the microscale. The NEST models will then be translated into suitable mean-field models that will allow to run the large-scale simulations needed to investigate pathology. b. The Virtual Mouse Brain (TVMB) model will be modified by embedding the abnormal microcircuits (3a) in NEST to run TVMB/NEST cosimulations. c. The modified “autistic” TVMB model will be inverted to match the fMRI template and optimize the connections weights. As a result, model simulations will provide an unprecedented view of what might be the rearrangement of the autistic brain. This project has the unique potential to uncover the consequences of the developmental changes that have occurred in the autistic brain because of the original gene mutation. Following a successful implementation of this case study, the BBM-CREF partnership will be extended to characterize the neurometabolic counterpart of networks modulation at multiple scales, and to investigate the statistical properties of multiscale brain network activity.
This work has a disruptive potential for understanding the mechanisms of brain pathology and opens the way to potential applications to therapy. Our research has also the potential to address rehabilitative/educational approaches as well as interventional (TMS/tDCS) and pharmacological neuromodulation toward more effective therapies.
Time frame: 18/08/2022 - 31/03/2023
Funding: CREF (Italy)