Characterization of the behavioral and histopathological responses in nuclear factor kappa B-I kappa B alpha-dominant negative mice before and after traumatic brain injury
Date of Award
Doctor of Philosophy (Ph.D.)
First Committee Member
Edward Green, Committee Chair
The nuclear factor kappa B (NF-kappaB) pathway is activated in diverse tissue in response to physical, chemical, psychological, and immunological stress. In the central nervous system NF-kappaB is expressed in neurons, oligodendrocytes, and astrocytes and is elevated following spinal cord, ischemic, and traumatic brain injury. In this study, we over expressed a dominant negative (dn) form of the inhibitory IkappaBalpha gene (IkappaBalpha-dn) under the control of the glial fibrillary acidic protein (GFAP) promoter site. This promoter drives the mutant IkappaBalpha protein in astrocytes preventing nuclear translocation of NF-kappaB and thus blocks activation of NF-kappaB target genes. The GFAP-IkappaBalpha-dn mice along with their wild type (WT) littermates were evaluated using a battery of behavioral tests to determine if there were any behavioral manifestations of the transgene. These transgenic animals also allowed us to investigate the role of NF-kappaB in astrocytes after traumatic brain injury.Compared to their wild type littermates, the transgenic animals showed no overt abnormalities in physical appearance, brain structure or sensorimotor responses. During cognitive testing using the Barnes circular maze, female GFAP-IkappaBalpha-dn mice showed significant spatial learning deficiencies on the cued goal paradigm (p < 0.01). Male GFAP-IkappaBalpha-dn mice were not different from wild type. Transgenic female mice also performed significantly worse than the wild type group on the hidden platform (p < 0.04) and probe trial (p < 0.01) phase of the Morris water maze test.To evaluate behavioral and histopathological responses to brain injury, groups of wild type and GFAP-IkappaBalpha-dn males were subjected to controlled cortical impact injury. Our sensorimotor tests showed that all animals had significant contralateral forelimb deficits seven days after injury. However, the GFAP-IkappaBalpha-dn group had a significantly greater percent change from baseline compared to the wild type group (p < 0.04). Stereological measurements of the lesion volumes indicated subtle exacerbation of the injury in mice with inhibition of NF-kappaB compared to the wild type animals (p < 0.05).Our results suggest that inhibition of NF-kappaB in astrocytes is associated with learning and memory deficits. After cortical impact injury, GFAP-IkappaBalpha-dn animals showed exacerbated sensorimotor defects and greater cortical injury volume. Taken together, these findings suggest that inhibition of NF-kappaB in astrocytes may not be beneficial following TBI.
Nicholson-Bramwell, Annmarie Jacqueline, "Characterization of the behavioral and histopathological responses in nuclear factor kappa B-I kappa B alpha-dominant negative mice before and after traumatic brain injury" (2005). Dissertations from ProQuest. 2273.