CRCNS: Assessing long-term impacts of disruption to large-scale brain networks

Large-scale complex networks support brain function across the lifespan, and features of brain networks are hypothesized to confer both vulnerability and resilience to the brain changes that accompany healthy and pathological aging. Brain network organization can be characterized during resting wakefulness using functional magnetic resonance imaging and system segregation is a measure of this organization which quantifies the degree to which an individual’s brain network contains functionally distinct brain systems. In healthy adult humans, increasing age is associated with decreasing system segregation; declining system segregation is associated with worsening memory ability, alterations in brain activity, and is prognostic of Alzheimer’s Disease dementia beyond brain atrophy and pathology. The precise mechanism of aging-accompanied brain network changes is presently unclear and gaining a deeper understanding of them would be greatly advanced by the development of non-human models of brain network aging. A precision imaging-based approach will be used to develop and characterize a comprehensive longitudinal description of functional brain network changes across the mouse lifespan. Awake resting-state fMRI will be measured in individual mice as they grow older (from 3 to 21 months) and will be used to quantify changes in brain network organization (particularly segregation). Brain network changes will be related to behavior and cognition (including measures of memory, learning, and sensory-motor function), both as a function of age and sex. Targeted lesions to vulnerable brain network locations (network hubs) will be administered at younger and older ages, to test the causal contributions of hub nodes towards maintaining brain network integrity, and evaluate the susceptibility of older-age brain networks to focal damage. This work will broaden understanding of complex network function, large-scale network mechanisms underlying aging-related behavioral alterations, and the impacts of brain network disruption occurring at different life stages. The characterization of large-scale brain network organization with respect to aging-related decline in the intact brain, together with the use of targeted lesions, will set the stage to study the impact of neurodevelopmental and neurodegenerative pathologies on brain network organization and function in a valuable cross-species model.