Dottorato in MODELLI MATEMATICI PER L'INGEGNERIA, ELETTROMAGNETISMO E
NANOSCIENZE

Titolo della tesi: rs-fMRI and DTI reveal alterations in brain functional networks and structure in neuroscience research on preclinical model

Neurodegenerative diseases represent one of the main causes of death and disability in the world. They are caused by the progressive loss of structure and function of neurons and are increasingly present in the elderly. As life, on average, has become longer, it is important to expand knowledge through a deeper understanding of the molecular mechanisms both for healthy aging and for oxidative damage. Therefore, it is essential to develop strategies capable of diagnosing and preventing the development of any diseases. This represents a major challenge for neuroscience and a public health priority. In the field of neuroscience, several studies have been conducted on neurodegenerative diseases in animal models and humans, and specific highly connected functional networks have been identified in both. These functional networks have been found in various subjects, demonstrating the consistency of the networks between different subjects, the main ones are: the Default Mode Network (DMN), the Executive Control Network (ECN) and the Salience Network (SN). Differences in the functional connectivity circuits present in the brains of healthy individuals have been highlighted compared to models of neurodegenerative diseases and brain disorders. To carry out this preclinical study, innovative magnetic resonance imaging sequences were used such as resting state functional magnetic resonance imaging (rs-fMRI) to identify alterations in functional connectivity and diffusion tensor imaging (DTI) to identify alterations in the microstructure of the brain anatomy on mouse models. In particular, the following mouse models were used: C57BL/6MTH1 transgenic mice (model protected from oxidative damage) to analyze the effects of exposure to an oxidizing agent, that can contribute to the development of neurodegenerative diseases and CD-1 mice (model of healthy aging) to evaluate the involvement of RhoGTPases proteins modulation during healthy aging processes. The functional analyzes were carried out on software developed in Matlab, while those of the diffusion parameters were carried out on Paravision. Although this is a preliminary analysis, some very interesting results have been obtained. In particular, it has been observed that CD1 mice treated with fasudil (ROCK inhibition) show a strengthening of the Default Mode Network, while mice treated with CNF1 (RhoGTPase modulation) also show a strengthening of the Salience Network together with a weakening of the Executive Control Network. In light of this result, a beneficial effect on functional connectivity and an increase in cognitive performance obtained through treatment with CNF1 compared to the control has been hypothesized. As regards the MTH1 mouse, it has been observed that before treatment with Paraquat, the transgenic mice showed a strengthening of the Executive Control Network and a weakening of the Salience Network compared to the controls, while in the acute phase (after treatment) they show a weakening of the Executive Control Network. Thanks to these innovative magnetic resonance techniques, a neuronal rearrangement and a different vulnerability of the brain regions depending on the treatment have been observed. Regarding DTI analyses, structural differences due to the different treatments were observed: in particular a decrease in Mean Diffusivity in mice treated with fasudil and an increase in Fractional Anisotropy in mice treated with CNF1; while MTH1 mice show an increase in Fractional Anisotropy (FA) and a decrease in Mean Diffusivity (MD) in the hippocampus of transgenic mice compared to controls, resulting in a decrease of the extracellular space (MD variation) and an increase of the fiber density in the brain (FA variation). MTH1 transgenic mice instead show a higher fractional anisotropy value than controls both before and after treatment with paraquat. The evaluation of these anatomical and functional imaging parameters has given us a complete picture of the circuits and connections that may be altered during brain aging and during the development of neurodegenerative diseases. The preclinical study on animal models takes on particular relevance since functional imaging is configured as a versatile and applicable analysis technique, from a translational perspective. The application of this new knowledge in human diagnosis, given the translational nature of preclinical research, can contribute to the prevention and treatment of neurodegenerative and psychiatric diseases with important repercussions on the healthcare system, allowing for the early identification of alterations.