Multiple sclerosis (MS) is a neurodegenerative, demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS, has been used extensively to understand disease mechanisms in MS. Neuropathological studies in EAE have found inflammation, demyelination, neuronal and synaptic loss by histopathology, a recapitulation of findings in MS. However, these observations are based on sparse sampling of the brain and spinal cord, not a complete evaluation of these processes throughout the entire CNS. The ability to evaluate these processes in 3D across an intact CNS would be enormously helpful for evaluating their true extent in disease. Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) is a recently developed optical clearing technology that permits the intact imaging of the entire CNS. This approach embeds the CNS in a porous matrix that provides structural integrity to proteins, nucleic acids, and small molecules, while leaving lipids unbound. The lipids are then removed, culminating in an optically cleared CNS that can be easily visualized and easily probed using commonly available techniques. We propose to use CLARITY to examine white and gray matter pathology in the context of the entire CNS. We will correlate this analysis with magnetic resonance imaging (MRI) to determine the relationship between GM atrophy and its underlying neuropathologies.
Progressive brain atrophy is a common feature of multiple sclerosis (MS). Brain atrophy has been strongly liked to clinical disability and cognitive impairment; however, we do not understand the underlying cellular changes that lead to it. This proposal will determine what the cellular changes that lead to brain atrophy are in an animal model of MS with the aim of better understanding the human disease.
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