Alteration of mechanical stresses in the murine brain by age and hemorrhagic stroke

Residual mechanical stresses in tissues arise during rapid differential growth or remodeling such as in morphogenesis and cancer. These residual stresses, also known as solid stresses, are distinct from fluid pressures and dissipate in most healthy adult organs as the rate of growth decreases. However, studies have shown that residual stresses remain substantially high even in mature, healthy brains. The genesis and consequences of these mechanical stresses in a healthy brain, and in aging and disease remain to be explored. Here, we utilized and validated our previously developed method to map residual mechanical stresses in the brains of mice in three different age groups: 5-7 days, 8-12 weeks, and 22 months old. We found that residual solid stress increases rapidly from 5-7 days to 8-12 weeks in mice, and remains high even in mature 22-month-old mice brains. Three-dimensional mapping of the residual stresses revealed an increasing trend from anterior to posterior in coronal sections of the brain. Since the brain is rich in negatively charged hyaluronic acid, we evaluated the contribution of charged extracellular matrix (ECM) constituents in maintaining solid stress levels. We found that lower ionic strength leads to elevated solid stresses, a finding consistent with the unshielding effect of low ionic strength and the subsequent expansion of charged ECM components. Lastly, we demonstrated that hemorrhagic stroke, accompanied by loss of cellular density, resulted in decreased levels of residual stress in the murine brain. Our findings contribute to a better understanding of the spatiotemporal alteration of residual solid stresses in healthy and diseased brains, a crucial step toward uncovering the biological and immunological consequences of this understudied mechanical phenotype in the brain. Significance StatementWhile emerging evidence highlights the importance of solid stresses in embryogenesis and tumor growth, the genesis and consequences of residual solid stresses in the adult normal brain remain poorly understood. Understanding the spatiotemporal distribution and alteration of the residual solid stresses as the brain ages and is impacted by neuropathologies, such as a stroke, will elucidate the biological and immunological consequences of maintaining these stresses. This study suggests solid stress could serve as a potential biomarker in aging and diseases associated to the brain.