Search

Gray matter (GM) atrophy is considered one of the best predictors of disability accumulation in multiple sclerosis (MS) yet the mechanisms underlying its progression are poorly understood. Currently, there are no directly neuroprotective therapies in MS that can halt the progression of GM atrophy. While GM atrophy has been established in the most commonly used mouse model for MS, experimental autoimmune encephalomyelitis (EAE), there is a lack of studies directly investigating associated pathologies of GM atrophy and methods of sparing GM volume. The projects in this dissertation were designed with the goal of characterizing changes in GM volume and associated pathology. In the second chapter, I investigated baseline sex differences in the C57BL/6 mouse brain. This was an important step in establishing the use of magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to identify differences in GM volume. Moreover, it highlighted the importance of performing experimental analyses within sex as we determined that differences exist in the brain in healthy mice. In the third chapter, I sought to utilize VBM to localize atrophy in vivo in a chronic mouse model of EAE and to identify the spatial relationship between downstream axonal damage in the spinal cord and gray matter loss. I found substantial GM volume loss throughout the brain particularly within the cortex, caudoputamen, and thalamus during EAE. Further, I found axonal damage in the spinal cord was negatively correlated to GM volume in motor and sensorimotor regions of the cerebral cortex. In the fourth chapter, I describe a network of pathology associated with GM atrophy that is disrupted by estriol treatment. I further identified ligation of ERbeta as method of inducing remyelination in GM. Lastly, in chapter five, I used VBM to identify sex differences in GM atrophy during EAE. Using voxel-wise regression analysis I found a sex-specific relationship between disability and GM atrophy in the somatosensory cortex in males. I further found evidence of increased neuronal loss and increased axonal transection in males with EAE compared to their healthy controls than females with EAE compared to their healthy controls.Localizing atrophy and related pathology will allow for us to investigate the molecular underpinnings of GM volume loss and potentially lead to the development of better neuroprotective therapies for patients with MS

Gray matter (GM) atrophy is considered one of the best predictors of disability accumulation in multiple sclerosis (MS) yet the mechanisms underlying its progression are poorly understood. Currently, there are no directly neuroprotective therapies in MS that can halt the progression of GM atrophy. While GM atrophy has been established in the most commonly used mouse model for MS, experimental autoimmune encephalomyelitis (EAE), there is a lack of studies directly investigating associated pathologies of GM atrophy and methods of sparing GM volume. The projects in this dissertation were designed with the goal of characterizing changes in GM volume and associated pathology. In the second chapter, I investigated baseline sex differences in the C57BL/6 mouse brain. This was an important step in establishing the use of magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to identify differences in GM volume. Moreover, it highlighted the importance of performing experimental analyses within sex as we determined that differences exist in the brain in healthy mice. In the third chapter, I sought to utilize VBM to localize atrophy in vivo in a chronic mouse model of EAE and to identify the spatial relationship between downstream axonal damage in the spinal cord and gray matter loss. I found substantial GM volume loss throughout the brain particularly within the cortex, caudoputamen, and thalamus during EAE. Further, I found axonal damage in the spinal cord was negatively correlated to GM volume in motor and sensorimotor regions of the cerebral cortex. In the fourth chapter, I describe a network of pathology associated with GM atrophy that is disrupted by estriol treatment. I further identified ligation of ERbeta as method of inducing remyelination in GM. Lastly, in chapter five, I used VBM to identify sex differences in GM atrophy during EAE. Using voxel-wise regression analysis I found a sex-specific relationship between disability and GM atrophy in the somatosensory cortex in males. I further found evidence of increased neuronal loss and increased axonal transection in males with EAE compared to their healthy controls than females with EAE compared to their healthy controls.Localizing atrophy and related pathology will allow for us to investigate the molecular underpinnings of GM volume loss and potentially lead to the development of better neuroprotective therapies for patients with MS