Sex differences in neurobehavior and the adult hippocampal neurogenic niche: influence of traumatic brain injury and CLIP antagonism

Introduction: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Alterations to adult hippocampal neurogenesis have been identified following experimental TBI, and there are known sex differences in the response to TBI. However, few studies have investigated sex differences in neurogenesis following TBI. One of the common signatures of TBI is an inflammatory response. This includes activation of antigen presenting cells, including B lymphocytes. Previous studies have identified a pathogenic role for a B cell subset, CLIP+ B cells, following TBI. However, the role of CLIP antagonism on the adult hippocampal neurogenic niche has not been fully elucidated following a TBI, and sex differences have not been previously explored. This is extremely important because sex differences in adult neurogenesis have been previously identified. Thus, the current study was designed to test the hypothesis that CLIP antagonism after TBI would differentially influence adult neurogenesis and associated behavioral outcomes in male and female subjects. Methods: 10-week-old male and female C57bl/6J mice received either lateral fluid percussion injury (FPI) or sham surgery, followed 30 min later by the administration of a CLIP antagonist peptide (CAP) or vehicle. At 35 days post-FPI, all mice underwent neurobehavioral testing using the pattern recognition test (PRT). After behavioral testing, at 60 post-FPI, harvested brains were analyzed for DCX+ newborn neurons and GFAP+ astrocytes in the hippocampus to assess the effects on the neurogenic niche. Results: FPI induced deficits in the PRT that were more pronounced in females and improved by CLIP antagonism. Immunohistological assessments revealed that female mice had reduced DCX+ neurons in the dentate gyrus and increased hippocampal GFAP+ astrocytes at 60 days post-FPI, regardless of injury or treatment condition. Further analysis showed that FPI in male mice leads to increased hypertrophy of GFAP+ radial glial in the dentate gyrus and increased presentation of hilar basal dendrites. These changes were not observed in female mice. Conclusion: The results from this study demonstrate sex differences in the neurogenic niche and associated cognitive impairment following FPI and suggest a role for CLIP after FPI in mediating these sex differences.