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Biomechanical investigation of neurogenesis and neuroinflammation in the mouse brain by elastography

Morr, A;

Investigation of the brain´s biomechanical properties provides information on its function in physiological conditions and during disease. Adult neurogenesis in the rodent hippocampus ensures homeostasis and repair. This unique function is tightly controlled by chemical cues and has been related to mechanical properties ex vivo, while little is known about in vivo tissue mechanics of the subgranular zone (SGZ), the hippocampal neurogenic niche. Next to the importance of biomechanics in physiological processes, tissue mechanics are altered in neuroinflammatory diseases, such as multiple sclerosis (MS). Inflammatory changes in brain mechanics are influenced by different factors including immune cell infiltration, the extracellular matrix (ECM) and sex. However, the specific neuroinflammation-mediated tissue alterations underlying changes in mechanical integrity remain elusive. Tissue mechanics, measured as stiffness and fluidity, can be assessed in vivo by magnetic resonance elastography (MRE) and ex vivo using microin-dentation methods such as atomic force microscopy (AFM). This thesis comprises three studies investigating (i) the in vivo biomechanical properties of the SGZ, a zone of neurogenesis in the rodent brain and exploring (ii) bio-mechanical changes during different neuroinflammatory processes, (iii) taking sex into account. More specifically, it was investigated if in vivo MRE, despite its much lower spa-tial resolution, shows similar spatial mechanical properties in the SGZ as ex vivo AFM measurements. Further, the experimental autoimmune encephalomyelitis model, a MS animal model, was used to investigate changes in biomechanics in areas of widespread inflammation and a leaky blood-brain barrier identified with a gadolinium-based contrast agent as well as in areas of focal inflammation visualized by accumulation of europium-doped particles. Finally, biomechanical sex differences in neuroinflammation were inves-tigated by MRE and correlated with sex-specific properties of the ECM. Collectively, these studies yielded the following results (i) the SGZ has softer mechanical properties in vivo compared to surrounding tissue, which is confirmed by ex vivo findings, (ii) during neuroinflammation, alterations in brain tissue mechanics are most pronounced in areas with severe focal inflammation, and (iii) in health and neuroinflammation, sex differences in cortical stiffness are associated with sex dimorphism in ECM protein expression. These findings suggest that brain tissue mechanics are important for physiological processes such as neurogenesis, influenced by sex and are markedly affected in focal inflammation. Macroscopic mechanical properties, resolved by MRE, are sensitive to these micromechanical structures and their pathological alterations. Hence, MRE is a promising imaging tool for investigation of physiological processes such as neurogenesis and for non-invasive clinical assessment of different pathological aspects of neuroinflammation.